Title of Invention

"A PIPERIDINE COMPOUND AND A PROCESS FOR PREPARING THE SAME THEREOF"

Abstract

The present invention relates to a compound of Formula (I) wherein: R1 is phenyl optionally substituted by halogen, cyano, C1-4 alkyl or C1-4 haloalkyl;R2 is hydrogen, C1-6 alkyl or C3-6 cycloalkyl; and, R3 is a group having an acidic NH or OH are as defined that has a calculated or measured pKa of 1.0 to 8.0; or a pharmaceutically acceptable salt thereof, are modulators of chemokine (for example CCR3) activity (for use in, for example, treating asthma) and a process for preparing the same.

Full Text

FIELD OF THE INVENTION The present invention concerns piperidine compounds having pharmaceutical activity, to processes for preparing such compounds, to pharmaceutical compositions comprising such compounds and to the use of such derivatives as active therapeutic agents BACKGROUND & PRIOR ART Pharmaceutically active N-(2-hydroxyprop-l-yl) piperidine derivatives are disclosed in WO 03/068743. Histamine is a basic amine, 2-(4-imidazoIyl)-ethylamine, and is formed from histidine by histidine decarboxylase. It is found in most tissues of the body, but is present in high concentrations in the lung, skin and in the gastrointestinal tract. At the cellular level inflammatory cells such as mast cells and basophils store large amounts of histamine, It is recognised that the degranulation of mast cells and basophils and the subsequent release of histamine is a fundamental mechanism responsible for the clinical manifestation of an allergic process. Histamine produces its actions by an effect on specific histamine G- protein coupled receptors, which are of three main types, H1, H2 and H3. Histamine H1 antagonists comprise the largest class of medications used in the treatment of patients with allergic disorders, for example rhinitis and urticaria. Antagonists of H1 are useful in controlling the allergic response by for example blocking the action of histamine on post- capillary venule smooth muscle, resulting in decreased vascular permeability, exudation and oedema. The antagonists also produce blockade of the actions of histamine on the H1 receptors on c-type nociceptive nerve fibres, resulting in decreased itching and sneezing. Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract macrophages, T cells, eosinophils, basophils and neutrophils to sites of inflammation and also play a role in the maturation of cells of the immune system. Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma and allergic diseases, as we!1 :ns autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. These small secreted molecules are a growing superfamily of 8-14 kDa proteins characterised by a conserved four cysteine motif. The chemokine superfamily can be divided into two main groups exhibiting characteristic structural motifs, the Cys-X-Cys (C-X-C, or a) and Cys-Cys (C- C, or P) families. These are distinguished on the basis of a single amino acid insertion between the NH-proximal pair of cysteine residues and sequence similarity. The C-X-C chemokines include several potent chemoattractants and activators of neutrophils such as interleukin-8 (IL-8) and neutrophil-activating peptide 2 (NAP-2), The C-C chemokines include potent chemoattractants of monocytes and lymphocytes, but not neutrophils, such as human monocyte chemotactic proteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated on Activation, Normal T Expressed and Secreted), eotaxjns and the macrophage inflammatory proteins 1 a and 1 P (MIP-1 a and MIP-1 P). Studies have demonstrated that the actions of the chemokines are mediated by subfamilies of G protein-coupled receptors, among which are the receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3 and CXCR4. These receptors represent good targets for drug development since agents which modulate these receptors would be useful in the treatment of disorders and diseases such as those mentioned above. Viral infections are known to cause lung inflammation. It has been shown experimentally that the common cold increases mucosal output of eotaxin in the airways. Instillation of eotaxin into the nose can mimic some of the signs and symptoms of a common cold. (See, Greiff L et al Allergy (1999) 54 (11) 1204-8 [Experimental common cold increase mucosal output of eotaxin in atopic individuals] and Kawagnchi M et al Int. Arch. Allergy Immunol. (2000) 122 S 44 [Expressionof eotaxin by normal airway epithelial cells after virus A infection].) STATEMENT OF INVENTION: Accordingly, the present invention relates to a N-(2-hydroxyprop-l-yI)piperdine derivative of formula (I): (Formula Removed) wherein: R1 is phenyl optionally substituted by halogen, cyano, C1-4 alkyl or C1-4 haloalkyl; R2 is hydrogen, C1-6 alkyl or C3-6 cycloalkyl; and R3 is a group having an NH or OH that has a calculated or measured pKa of 1.0 to 8.0 or a pharmaceutically acceptable salt thereof. Also, the present invention relates to a process for preparing a compound as claimed in any one of the claims 1 to 16, the process comprising reacting a compound of formula (II)} (Formula Removed) wherein R1 and R2 are as defined in claim 1, with a compound of formula (III): (Formula Removed) wherein L1 is a leaving group and R3 is as defined in claim 1; in the presence of a base, optionally in the presence of a coupling agent. SUMMARY OF THE INVENTION The compounds of the present invention are useful in the treatment of CCR3 mediated disease states (such as asthma and/or rhinitis) and show good specificity (for example 100-fold difference in activity) for the CCR3 receptor over other receptors present in a mammal such as G-Protein Coupled Receptors (for example: alpha 1 adrenoceptor and 5HT2B receptors) and ion channels (for example: the human ether-a-go-go-related gene (hERG) potassium channel). The present invention provides a compound of formula (I): (Formula Removed) wherein: R1 is phenyl optionally substituted by halogen, cyano, C1-4 alkyl or C1-4 haloalky; Ra is hydrogen, C1-6 alkyl or C3-6 cycloalkyl; and, R3 is a group having an NH or OH that has a calculated or measured pKa of 1.0 to 8.0; or 4 pharmaceutically acceptable salt. Certain compounds of the present invention can exist in different isomeric forms (such as enantiomers, diastereomers, geometric isomers or tautomers). The present invention covers all such isomers and mixtures thereof in all proportions. Suitable salts include acid addition salts such as a hydrochloride, dihydrochloride, hydrobromide, phosphate, sulfate, acetate, diacetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulfonate or p-toluenesulfonate. Salts also include metal salts, such as an alkali metal salt (for example a sodium or potassium salt) or an alkaline earth metal salt (for example magnesium or calcium). The compounds of the invention may exist as solvates (such as hydrates) and the present invention covers all such solvates. The pKa of a compound of formula (I) is calculated using ACD/Labs 6.00 software available from Advanced Chemistry Development Inc, 90 Adelaide Street, West Toronto, Ontario, Canada. The pKa of a compound of formula (I) is measured using one of the methodologies recited below. Halogen is, for example fluorine or chlorine. Alkyl groups and moieties are straight or branched chain and are, for example, methyl, ethyl, n-propyl, iso-propyl or tert-butyl. Cycloalkyl is monocyclic and is, for example, cyclopropyl, cyclopentyl or cyclohexy). Haloalkyl is an alkyl group carrying one or more (such as 1 to 6) halogen (such as chloro or fluoro atoms) and is, for example, CF3, CH2CF3 or C2F5. FluoroalkyI is an alkyl group carrying one or more (such as 1 to 6) fluoro atoms and is, for example, CH2F, CF3, CH2CF3 or C2F5. DETAILED DESCRIPTION In one aspect the present invention provides a compound of formula (1) wherein R1 is phenyl optionally substituted by halogen, cyano or C1-4 alkyl. In another aspect the present invention provides a, compound of formula (I) wherein R1 is phenyl substituted with one, two or three of : halogon (such as fluoro or chloro), cyano or C1-4 alkyl (such as methyl); for example R1 is phenyl substituted by one, two or three of ; fluoro, chloro, methyl or cyano. In another aspect R1 is phenyl substituted by one, two or three (such as two or three) of: fluoro, chloro, cyano or methyl (such as chloro, cyano or methyl). R1 is, for example, 3, 4-dichlorophenyl, 2-methyl-3-chloro-4-cyanophenyl, 2- methyl-4-chlorophenyL, 3-nethyl-2,4-dichlorophenyl, 2-metnyl-3,4-dichIorophenyl, 3- cbloro-4-cyanophenyl, 3,4-diftuorophenyl, 3-fluoro-4-chlorophenyl or 4-chlorophenyl (such as 2-methyl-4-chtarophenyl, 3-methyl-2,4-dichlorophenyl, 2-methyl-3,4- dichlorophenyl, 3-chloro-4-cyanophenyl, 3,4-difluorophenyl, 3-fluoro-4-chlorophenyl or 4-chlorophenyl). In a still further aspect Rl is 3,4-dichlorophenyl or 3-chloro-4- cyanophenyl. In a further aspect of the invention R1 is phenyl substituted by one or more of chloro or methyl and optionally further substituted by flnoro. For example R1 is 2-methyl- 4-chlorophenyl, 3-methyl-2,4-dichlorophenyl, 2-methyl-3,4-dichlorophenyl, 3-fhioro-4- chlorophenyl, 4-chlorophenyl or 3,4-dichlorophenyl. In another aspect of the invention R1 is 3,4-dichlorophenyl, 2-methyl-4- chlorophenyl, 3-methyl-2,4-dichlorophenyl, 2-methyl-3,4-dichlorophenyl or 2-methyl-3- chloro-4-cyanophenylIn a still further aspect the present invention provides a compound of formula (I) wherein R2 is hydrogen or CM alkyl (such as methyl). In yet another aspect of the invention R2 is hydrogen. The acidic NH (mat is the NH having a calculated or measured pKa of 1.0 to 8.0) of R3 can be part of a ring or it can be part of a substituent on an aryl or heterocyclylring. The acidic OH (that is the OH having a calculated or measured pKa of 1.0 to 8.0) of R3 can be a substituent or part of a substituent (such an OH in a carboxylic acid group) on an aryl or heterocyclyl ring. Thus, for example, the acidic OH of R3 can be part of an acidic phenol, in a carboxylic acid, or in a hydroxy aromatic heterocyclyl (such as a hydroxypyridine which may tautomerise to a pyridone). Aryl includes optionally substituted phenyl and naphthyl. Heterocyclyl is an optionally substituted aromatic or non-aromatic 5- or 6- membered ring, comprising, as required, at least one heteroatom selected from the group comprising nitrogen, oxygen and sulphur; or anN-oxide thereof, or an S-oxide or Sdioxide thereof. Heterocyclyl is, for example, furyl, thienyl (also known as thiophenyl), pyrrolyl, 2,5-dihydropyrrolyl, tbiazolyl (for example in 2-oxo-2,3-dihydro-l53-thiazolyl), isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl (for example in IH- 1,2,3-triazolyl), pyridinyl (for example in 6-oxo-l,6-dihydro-pyridinyl) or pyrimidinyl. In an aspect of the present invention the acidic NH of R3 is part of a suitably substituted ring (for example part of a pyrrolyl, 2,5-dihydropyrrolyl, thiazolyl, isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, pyridinyl or pyrimidinyl ring) or part of a substituent on a suitably substituted aryl (for example phenyl or naphthyl) or suitably substituted heterocyclyl (for example furyl, thienyl, pyrrolyl, 2,5-dihydropyrrolyl, thiazoh/1, isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, pyridmyl or pyrimidinyl) ring. In another aspect of the present invention the acidic OH of R3 is a substituent or part of a substituent (such an OH in a carboxylic acid group) on a suitably substituted aryl (for example phenyl or naphthyl) or suitably substituted heterocyclyl (for example furyl,, thienyl, pyrrolyl, 2,5-dihydropyrrolyl, thiazolyl, isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, pyridinyl or pyrimidinyl) ring. Thus, for example, the acidic OH of R3 can be part of an acidic phenol (substituted or unsubstituited), in a carboxylic acid, or in a suitably substituted hydroxy aromatic heterocyclyl (such as a hydroxypyridme which may tautomerise to a pyridone). Further examples of suitably substituted hydroxy aromatic heterocyclyl are hydroxyquinolines, hydroxyisoqirinolines andhydroxybenzhnidazoles. In one aspect of the present invention when Hie acidic NH of R3 is part of a suitably substituted ring it is, for example, part of a 2-oxo-thiazol-5-yl, 2-oxo-oxazol-5-yl, 2-oxoraridazol- 5-yl, !H-lA3-triazol-4-yl,4Hxo-lH-l,4-6%vdropyridm-3-yl, 2,6-dioxo-lHl, 3,6te1rahydropyrimidm-4-yl, 6xo-lH-l,6Khydropyridm-3-yl or 2H-tetrazol-5-yl ring. In another aspect of the present invention when the acidic NH of R3 is part of a suitably substituted ring it is, for example, part of a 2-oxo-thiazol-5-yl, lH-l,2,3-triazol-4- yl or 6-oxo-lH-l,6-dihydropyridin-3-yl ring. In a further aspect of the present invention when the acidic NH of R3 is part of a substituent it is, for example, part of NHS(O)2(Ci_4 alkyl). In another aspect the present invention provides a compound of formula (I) wherein R3 is a group having an NH or OH that has a calculated or measured pKa of 3 to 6.5. In yet another aspect the present invention provides a compound of formula (I) wherein R3 is a group having an NH or OH that has a calculated or measured pKa of 8.0 (for example 3 to 6.5), the group R3 being, for example, • 2-oxo-thiazol-5-yl having a suitable electron withdrawing substituent {such as fiuoroalkyl (for example CFs, CH2CF3 or CzPs), an aryl group (for example 4- fluorophenyl), a heterocyclyl poop (for example pyridyl) or a group CH2S(Oz(CM alkyl)} in the 4-position; • 2-oxo-oxazol-5-yl having a suitable electron withdrawing substituent {such as CM fluoroalkyl (for example CF3, CH2CF3 or CaFs) or CH2S(O)2(CM alkyl)} in the 4- position; • lH-l,2,3-triazol-4-yl having a suitable substituent {such as CM alkyl (for example CH3 or CH(CH3)z), Q- cycloalkyl (for example cyclopropyl), CM fhioroalkyl (for example CF3, CH2CF3 or QzFs), S-R4 (wherein R4 is CM alkyl [for example CH3], CM fluoroalkyl [for example CFs, CHaCF3 or CzFs] or C cycloalkyl [for example cyclopropyl]), NHS(O)2(CM alkyl), N(CM alkyl)S(O)a(CM alkyl), an aryl group (for example 4-fluorophenyl), a heterocyclyl group (for example pyridyl) or a group CH2S(O)2(CM alkyl)} in the 5-position; • 4-oxo-lH-1,4-dJhydropyridin-3-yl having a suitable electron withdrawing • substituent {such as CM fluoroalkyl (for example CF3 of CjFs)} in the 2-position; • 2,6oxo-lH-13»6etrabydropyrimidin-4-yl having a suitable substituent {such as CM alkyl (for example CH3X C3 cycloalkyl (for example cyclopropyl) or CH2(Ci-3 fluoroalkyl) (for example CH2CF3)} in the 3-position and optionally substituted in one or more other ring positions; • 6-oxo-lH-l,6-dihydropyridin-3-yl having a suitable electron withdrawing substituent {such as CM fluoroalkyl (for example CF3, CH2CF3 or CaFs), cyano or phenyl} in the 2-position and/or the 5-position and optionally substituted in one or more other ring positions; • 6-oxo-lH-l,6-dihydropyridin-3-yl having CEfeCCH on the ring nitrogen and optionally substituted in one or more other ring positions; • 2H-tetrazol-5-yl; • a CCH, CH2CO2H or OCKfcCCbH group on an optionally substituted phenyl, optionally substituted CHjOphenyl, optionally substituted naphthyl ring or optionally substituted acylated (such as with C(O)(CM alkyl)) dihydroisoquinolinyl ring; or, • an NHS(O)z(CM a&yO (for example NHS(O)2CH3) group on an optionally substituted aromatic heterocyclyl ring (for example pyridinyl, pyrimidinyl or thiazolyl); or, where possible, a tautomer thereof. In one aspect of fee invention acylated (such as with C(O)(d» alkyl)) dihydroisoqirinolinyl carries the COzH, OHbCOjH or OCHzCOaH group on position 7. In yet another aspect the present invention provides a compound of formula (T) wherein R3 is a group havmg an NH or OH that has a calculated or measured pKa of 1.0 to 8.0 (for example 3 to 6.5), the group R3 being, for example, • 2-oxo-thiazol-5-yl having a suitable electron withdrawing substituent {such as CM fluoroalkyl (for example CF3, CH2CFa or CaFs), an aryl group (for example 4- fluorophenyl), a heterocyclyl group (for example pyridyl) or a group CH2S(O)2(CM alkyl)} in the 4-position; • 2-oxo-oxazol-5-yl having a suitable electron withdrawing substituent {such as CM fluoroalkyl (for example CF3, CH2CF3 or C2F5) or CH2S(O)2(CM alkyl)} in the 4- position; • lH-l,23-triazol-4-yl having a suitable substituent {such as CM alkyl (for example CHbX CM cycloalkyl (for example cyclopropyl), CM fluoroalkyl (for example CFj, CHjCFs or CiFs), S-R4 (wherein R4 is CM alkyl [for example CH3], CM fluoroalkyl [for example CF3, CH2CF3 or C2F5] or CM cycloalkyl [for example cyclopropyl]), NHS(O2(CM alkyl), an aryl group (for example 4-fluorophenyl), a heterocyclyl group (for example pyridyl) or a group CH2S(O)2(CM alkyl)} in the position; • 4-oxo-lH-l,4-dihydropyridin-3-yl havmg a suitable electron withdrawing substituent {such as CM fluoroalkyl (for example CF3 of CaFs)} in the 2-position; • 2,6-dioxo-lH-l,2,3,6-tetrahydropyrimidin-4-yl having a suitable substituent {such as CM alkyl (for example CH3), C3.6 cycloalkyl (for example cyclopropyl) or CH2(Ci_3 fluoroalkyl) (for example CH2CF3)} in the 3-position; • 6-oxo-lH-1,6-dihydropyridin-3-yl having a suitable electron withdrawing substituent {such as CM fluoroalkyl (for example CF3, CH2CF3 or CjFs) or cyano} in the 2-position or tiie 5-position and optionally substituted in other positions; • 2H-tetrazol-5-yl; • a COjH group on an optionally substituted phenyl or naphthyl ring; or, • an NHS(O)2(Ci.4 alkyl) (for example NHS(O)2CH3) group on an optionally substituted aromatic heterocyclyl ring (for example pyridinyl, pyrimidinyl or thiazolyl); or, where possible, a tautomer thereof. Where radicated above that a heterocych/1 ring in R3 may be optionally substituted it can be optionally substituted by, for example: fluoro, chloro, bromo, CM alkyl (for example methyl), C$.6 cycloalkyl (for example cyclopropyl), CM fluoroalkyl (for example CF3, CH2CF3 or C2Fs), S-R4 (herein R4 is CM alkyl [for example CH3], CM fluoroalkyl [for example CF3, CH2CF3 or Cs] or C3 cycloalkyl [for example cyclopropyl]), cyano, SCOMCM alkyl) (for example S(O)2CH3) or S(O)zNH(CM alkyl) (for example S(O)2NHCH3). Where indicated above that a phenyl or naphthyl ring in R3 may be optionally substituted it can be optionally substituted by, for example, halogen, cyano, CM alkyl, C alkoxy, CM fluoroalkyl (for example CFj, CH2CF3 or C2FS)}, OCF3, SCF3 nitro, S(CM alkyl), S(OXCM alkyl), S(OMCM alkyl), S(O)2NH(C1 alkyl), S(O)2N(CM alkyl)2, NHC(OXCM alkyl), NHSMCM alkyl). In one aspect of the invention R3 is . . • 2-oxo-thiazol-5-yl having CM fluoroalkyi (for example CF3 CH2CF3 or CzF3) in me 4-position; • 1H-1 ,23-triazol-4-yl having a suitable substituent {such as CM alkyl (for example CH3) or S-R4 (wherein R4 is CM fluoroalkyl [for example CF3, CH2CF3 or CjF5])} intheS-position; • 2,6-dioxo-lH-l 3,6-tetrahydropyrhnidin-4-yl having a suitable substituent {such as CM alkyl (for example CH3) or CM fluoroalkyl (for example CF3, CHzCF3 or C2Fs)} in me 3-position; • 6-oxo-lH-l ,6-dihydropyridin-3-yl having a suitable electron withdrawing substituent {such as CM fluoroalkyl (for example CF3, CEfcCFs or C2Fs) or cyano} in the 2-position or the 5-position and optionally substituted in other positions; • a CO2H group on an optionally substituted naphthyl ring; or, • an NHS(O)a(CM alkyl) (for example NHSCHs) group on an optionally substituted aromatic heterocyclyl ring (for example pyridinyl, pyrimidinyl or thiazolyl); or, where possible, a tautomer thereof; the optional substituents being as defined above. In yet another aspect the present invention provides a compound of formula (T) wherein R3 is: • 2-oxo-thiazol-5-yl having a suitable electron withdrawing substituent {such as i fluoroalkyi (for example CF3, CH2CF3 or C2Fs), a phenyl group (for example 4- fluorophenyl) or a heterocyclyl group (for example pyridyl)} in me 4-posrtion; • lH-l,2,3-triazol-4-yl having a suitable substituent {such as CM alkyl (for example CH3 or CICH), CM fluoroalkyl (for example CF3, CH2CF3 or C2F5), S-R4 (wherein R4 is CM alkyl [for example CH3] or CM fluoroalkyl [for example CF3, CH2CF3 or Cyy), N(CM alkylOMCM alkyl) or a phenyl group (for example 4- fluorophenyl)} in the 5-position; or, • 6-oxo-lH-l,6-dihydropyridin-3-yl havhig CM fluoroalkyl (for example CF3, CH2CF3 or CJFs) or cyano in the 2-position or the 5-position. In another aspect the present invention provides a compound of formula (I) wherein R3 is: • 2-oxo-thiazol-5-yl having CF3 or CFs in the position; • lH-l,2,3-triazol-4-yl having CFs, CaFs, SCF3, SCH2CF3 or SCiFs (for example CF3 or SCH2CF3) in the 5-position; or, • 6xcKlH-l,6ihydropyridin-3-yl having CF3 or CFsm me 2-posW la. yet another aspect the present invention provides a compound of formula (I) wherein the 2-hydroxy group has the stereochemistry shown below: 0) Compounds of the invention are illustrated in the Examples below. Compounds of the present invention can be prepared by methods described, or analogous to those described, in the art (for example WO 03/068743). Intermediates for such processes can be prepared by methods described, or analogous to those described, in the art (for example WO 03/068743). A compound of formula (I) can be prepared by reacting a compound of formula wherein L1 is a leaving group (for example a hydroxy or chloro leaving group), and R3 is as defined above; in the presence of a base (for example a tri(Ci-« alkyl)amine base (such as triethylamine or diisopropylethylamine) or N-dimethylformamide), in the presence of a suitable solvent (for example NJ-dimethylformamide, tetrahydrofuran, dichlorometfaane or dioxane, or a mixture of one or more of these solvents) optionally in the presence of a coupling agent (for example bromo-tris-pyrrolidinophosphonium hexafluorophosphate, PyBrOP or O-(7-azabenzotriazol-l-ylN-tetramemyluronium hexafluorophosphate). A compound of formula (IT) can be prepared as described hi WO 00/58305 or WO 01/77101, or by reacting a compound of formula (IV): wherein R1 is defined above, with: (i) a compound of formula (V): in which L2 is a leaving group (for example chloro or nosyloxy {3-NO2-CeH4-S(O)2O-}) followed by reaction with ammonia, an atnine R2-NH3 or with sodium azide and subsequent reduction with, for example, triphenylphosphine; or, (ii) with a compound of formula (VI): CH2 — NP'P2 (VI) H in which P1 and P2 are, alone or together, suitable protective groups (for example together they form phthalimide), or either P1 or P2 is R2, followed by deprotection using, for example when P1 and P2 form phthalimide, hydrazine. A compound of formula (V) can be obtained commercially or can be prepared using methods described in the literature. compound of formula (VI) can be prepared by reacting (K) or (5) glycidol under Mitsunobu reaction conditions with, for example, phthalimide, l,l-(azodicarbonyl) drpiperidine and tributylphosphine (Tetrahedron Lett. 1993,34,1639). Further, a compound of formula (I) can be prepared by routine adaptation of: the routes described above, methods described in the art, or the Examples recited below. The intermediates identified aTxve are commercially available or can be prepared by using or adapting methods described in the art In another aspect the present invention provides processes for the preparation of compounds of formula (I). The compounds of the invention have activity as Pharmaceuticals, in particular as modulators of chemokine receptor (for example CCR3) activity, and may be used in the treatment of autoimmune, inflammatory, proliferative or hyperproliferative diseases, or immunologically-mediated diseases (including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (ADDS)). ID one aspect examples of these conditions are: (1) (the respiratory tract) obstructive diseases of airways including: chrome obstructive pulmonary disease (COPD) (such as irreversible COPD); asthma {such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness)}; bronchitis {such as eosinophilic bronchitis}; acute, allergic, atrophic rhinitis or chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis; sarcoidosis; farmer's lung and related diseases; nasal polyposis; fibroid lung, idiopathic interstitial pneumonia, antitussive activity, treatment of chronic cough associated with inflammatory conditions of the airways or iatrogenic induced cough; (2) (bone and joints) arthrides including rheumatic, infectious, autoimmune, seronegative spondyloarthropathies (such as ankylosing spondylitis, psoriatic arthritis or Reiter's disease), Bebet's disease, Sjogren's syndrome or systemic sclerosis; (3) (skin and eyes) psoriasis, atopic dermatitis, contact dermatitis or other eczmatous dermitides, seborrhoetic dermatitis, Lichen planus, Phemphigus, bullous Phemphigus, bullosa, urticaria, angiodennas, vascuUtides erythemas, cutaneous eosinophilias, uveitis, Alopecia areata or vernal conjunctivitis; (4) (gastrointestinal tract) Coeh'ac disease, proctitis, eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis, irritable bowel disease or foodrelated allergies which have effects remote from the gut (for example migraine, rhinitis or eczema); (5) (AUograft rejection) acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea; or chronic graft versus host disease; and/or (6) (other tissues or diseases) Alzheimer's disease, multiple sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome (ADDS), Lupus disorders (such as lupus erythematosus or systemic lupus), erymematosus, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, leprosy (such as lepromatous leprosy), Peridontal disease, Sezary syndrome, idiopamic mrombocytopenia pupura or disorders of the menstrual cycle. The compounds of the invention are also HI antagonists and may be used in the treatment of allergic disorders. The compounds of the invention may also be used to control a sign and/or symptom of what is commonly referred to as a cold (for example a sign and/or symptom of a common cold or infhipnra or other associated respiratory virus infection). According to a further feature of the invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treatment of a warm blooded animal (such as man) by therapy (including prophylaxis). According to a further feature of the present invention there is provided a method for modulating chemokine receptor activity (for example CCR3 receptor activity), or antagonising HI, in a warm blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the formula (1), or a pharmaceutically acceptable salt thereof. The invention also provides a compound of the formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament In another aspect the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in therapy (for example modulating chemokine receptor activity (for example CCR3 receptor activity), or antagonising HI, in a warm blooded animal, such as man) is a synergistic composition and exhibits surprising results. The invention further provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of: (1) (the respiratory tract) obstructive diseases of airways including: chronic obstructive pulmonary disease (COPD) (such as irreversible COPD); asthma {such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness)}; bronchitis {such as eosinophilic bronchitis}; acute, allergic, atrophic rhinitis or chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis; sarcoidosis; farmer's lung and related diseases; nasal polyposis; fibroid lung, idiopathic interstitial pneumonia, antitussive activity, treatment of chronic cough associated with inflammatory conditions of the airways or iatrogenic induced cough; (2) (bone and joints) arthrides including rheumatic, infectious, autoimmune, seronegative spondyloarthropathies (such as spondylitis, psoriatic arthritis or Reiter's disease), Beget's disease, Sjogren's syndrome or systemic sclerosis; (3) (skin and eyes) psoriasis, atopic dermatitis, contact dermatitis or other eczmatous dermitides, seborrhoetic dermatitis, Lichen planus, Phemphigus, bullous Phemphigus, Epidermolysis bullosa, urticaria, angiodermas, vasculitides erythems, cutaneous eosinophilias, uveitis, Alopecia areata or vernal conjunctivitis; (4) (gastrointestinal tract) Coeliac disease, proctitis, eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis, irritable bowel disease or food-related allergies which have effects remote from the gut (for example migraine, rhinitis or eczema); (5) (Allograft rejection) acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea; or chronic graft versus host disease; and/or (6) (other tissues or diseases) Alzheimer's disease, multiple sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS), Lupus disorders (such as lupus erythematosus or systemic lupus), erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, leprosy (such as lepromatous leprosy), Peridontal disease, sezary syndrome, idiopathic throrabocytopenia pupura or disorders of the menstrual cycle; in a warm blooded animal, such as man. In a further aspect a compound of formula (I), or a pharmaceuticalty acceptable salt thereof, is useful in the treatment of asthma {such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness)}; or rhinitis {including acute, allergic, atrophic or chronic rhinitis, such as rhinitis caseosa, hypertrophic rhinitis, rhinitis purulcnta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofulous rhinitis; seasonal rhinitis including rhinitis nervosa. (hay fever) or vasomotor rhinitis}. -.--..- •.; hi a still further aspect a compound of formula (I), or a pharmaceutically acceptable' salt thereof, is useful in the treatment of asthma. The present invention also provides the use of a compound of formula CD, or a pharmaceutically acceptable salt thereof, in the rnanufacture of a medicament for use in the treatment of asthma or rhinitis. The present invention further provides a method of treating a chemokine mediated disease state (for example a CCR3 mediated disease state, such as asthma) in a warm blooded animal, such as man, which comprises administering to a mammal in need of such treatment an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. In order to use a compound of the invention, or a pharmaceutically acceptable salt thereof, for the therapeutic treatment of a warm blooded animal, such as man, in particular modulating chemokine receptor (for example CCR3 receptor) activity or antagonising HI, said ingredient is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. Therefore in another aspect the present invention provides a pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof (active ingredient), and a pharmaceutically acceptable adjuvant, diluent or carrier. In a further aspect the present invention provides a process for the preparation of said composition which comprises mixing active ingredient with a pharmaceutically acceptable adjuvant, diluent or earner. Depending on the mode of administration, the pharmaceutical composition will, for example, comprise from 0.05 99%w (per cent by weight), such as firom 0.05 to 80%w, for example from 0.10 to 70%w, such as from 0.10 to 50%w, of active ingredient, all percentages by weight being based on total composition. The pharmaceutical compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by topical (such as to the lung and/or airways or to the skin), oral, rectal or parenteral administration. For these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, aerosols, dry powder formulations, tablets, capsules, syrups, powders, granules, aqueous or oily solutions or suspensions, (Hpid) emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions. . A suitable pharmaceutical composition of mis invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule which contains between O.lmg and Ig of active ingredient In another aspect a pharmaceutical composition of the invention is one suitable for intravenous, subcutaneous or intramuscular injection. Each patient may receive, for example, an intravenous, subcutaneous or intramuscular dose of 0.01 mgkgf1 to 100 mgkg"1 of the compound, for example in the range of 0.1 mgkg"1 to 20 mgkg"1 of this invention, the composition being administered 1 to 4 times per day. The intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection. Alternatively the intravenous dose may be given by continuous infusion over a period of time. Alternatively each patient will receive a daily oral dose which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day. The invention further relates to combination therapies or compositions wherein a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered concurrently (possibly in the same composition) or sequentially with an agent for the treatment of any one of the above disease states. In particular, for the treatment of the inflammatory diseases rheumatoid arthritis, psoriasis, inflammatory bowel disease, COPD, asthma and allergic rhinitis a compound of invention can be combined with a TNF-a inhibitor (such as an anti-TNF monoclonal antibody (such as Renricade, CDP-870 and D.sub2.E.sub7.), or a TNF receptor immunoglobulin molecule (such as Bnbreljeg.))» a non-selective COX-1 / COX-2 inhibitor (such as piroxicam or diclofenac; a propionic acid such as naproxen, flubiprofen, fenoprofen, ketoprofen or ibuprofen; a fenamate such as mefenamic acid, indomethacin, sulindac or apazone; apyrazolone such as phenylbutazone; or a salicylate such as aspirin), a COX-2 inhibitor (such as meloxicam, celecoxib, rofecoxib, valdecoxib or etoricoxib) low dose methotrexate, lefunomide; ciclesonide; hydroxychloroquine, d-peniciUamine or auranofin, or parenteral or oral gold. The present invention still further relates to the combination of a compound of the invention together with: • a leukotriene biosynthesis inhibitor, a 5-lipoxygenase (5-LO) inhibitor or a 5- lipoxygenase activating protein (FLAP) antagonist, such as zileuton, ABT-761, fenleuton, tepoxalin, Abbott-79175, Abbott-85761, anN-(5-substituted)-thiophene- 2-alkylsulfonamide, a 2,6-di-tert-burylphenol hydrazones, a methoxytetrahydropyran such as Zeneca ZD-2138, SB-210661, a pyridinylsnbstituted 2-cyanonaphthalene compound such as L-739,010; a 2-cyanoquinoline compound such as L-746,530; an indole or qirinohne compound such as MK-591, MK-886orBAYxl005; • a receptor antagonist for a leukotriene LTB.sub4., LTC.sub4., LTDjsuM. or LTE.suM. selected from the group consisting of a phenothiazin-3-one such as L- 65192; an amidino compound such as CGS-25019c; a benzoxalamine such as ontazolast; a benzenecarboximidamide such as BIIL 284/260; or a compound such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 457 ISA) or BAY x 7195; • a PDE4 inhibitor including an inhibitor of the isoform PDE4D; • an antihistaminic H.subl. receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, astemizole, azelastine or chlorpheniramine; • a gastroprotective H.sub2. receptor antagonist; • an cusub 1.- and a.sub2.-adrenoceptor agonist vasoconstrictor sympalhomimetic agent, such as propylhexedrine, phenylephrine, phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, -IItetrahydrozoline hydrochloride, xylometazoline hydrochloride or ethylnorepinephrinehydrochloride; ' an anticholmergic agent such as ipratropium bromide, tiotropmm bromide, oxitropium bromide, pirenzepine or telenzepine; a p.subl.- to p.sub4.-adrenoceptor agonist such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate or pirbuterol, or a methylxanthanine including theophylline and aminophylline; sodium cromoglycate; or a muscarinic receptor (Ml, M2, and M3) antagonist; an insulin-like growth factor type I (IGF-1) mimetic; an inhaled glucocorticoid with reduced systemic side effects, such as prednisone, prednisolone, fhinisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate or mometasone furoate; an inhibitor of a matrix metalloprotease (MMP), such as a stromerysin, a collagenase, or a gelatmase or aggrecanase; such as collagenase-1 (MMP-1), coHagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stroraelysin-2 (MMP-10), and stromelysin-3 (MMP-11) or MMP-12; a modulator of chemokine receptor function such as CCR1, CCR2, CCR2A, CCR2B, COG, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C-C family); CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for the CX- C family) and CX3CR1 for the C-X3-C family; an osteoporosis agent such as roloxifene, droloxifene, lasofoxifene or fosomax; an immunosuppressant agent such as FK-506, rapamycin, cyclosporine, azathioprine or methotrexate; a compound useful in the treatment of AIDS and/or HTV infection for example: an agent which prevents or inhibits the viral protein gp!20 from engaging host cell CD4 {such as soluble CD4 (recombinant); an anti-CD4 antibody (or modified/ recombinant antibody) for example PRO542; an anti-group 120 antibody (or modified / recombinant antibody); or another agent which interferes with the binding of group!20 to CD4 for example BMS806}; an agent which prevents binding to a chemokine receptor, other than CCR5, used by the HIV virus (such as a CXCR4 agonist or antagonist or an anti-CXCR4 antibody); a compound which interferes in the fusion between the HIV viral envelope and a cell membrane {such as an anti-group 41 antibody; enfuvirtide (T-20) or T-1249}; an inhibitor of DCSIGN (also known as CD209) {such as an anti-DC-SIGN antibody or an inhibitor of DC-SIGN binding}; a nucleoside/nucleotide analogue reverse transciptase inhibitor (for example zidovudine (AZT), nevirapine, didanosine (ddl), zalcitabine (ddQ, stavudine (d4T), kmivudine (3TC), abacavir, adefovir or tenofovir (for example as tree base or as disoproxil fumarate)}; a non-nucleoside reverse transciptase inhibitor {for example nevirapine, delavirdme or efavirenz}; a protease inhibitor {for example ritonavir, indmavir, saquinavir (for example as free base or as mesylate salt), nelfinavir (for example as free base or as mesylate salt), amprenavir, lopinavir or atazanavir (for example as free base or as sulphate salt)}; a ribonucleotide reductase inhinbitor {for example hydroxyurea); or an antiretroviral {for example emtricitabine); or, • an existing therapeutic agent for the treatment of osteoarthritis, for example a nonsteroidal anti-inflammatory agent (hereinafter NSAID'S) such as piroxicam or diclofenac, a propionic acid such as naproxen, flubiprofen, fenoprofen, ketoprofen or ibuprofen, afenamate such asmeienamic acid, indomethacin, sulindac or apazone, a pyrazolone such as phenylbutazone, a salicylate such as aspirin, a COX- 2 inhibitor such as cdecoxib, valdecoxib, rofecoxib or etoricoxib, an analgesic or intxa-articular&erapysuchasacorticosteroidor a hyahironic acid such as hyalgan or synvisc, or a P2X7 receptor antagonist The present invention still further relates to the combination of a compound of the invention together with: (i) a tryptase inhibitor; (ii) a platelet activating factor (PAF) antagonist; (iii) an interleukin converting enzyme (ICE) inhibitor, (iv) an IMPDH inhibitor; (v) an adhesion molecule inhibitor including a VLA-4 antagonist; (vi) a cathepsin; (vii) a MAP kinase inhibitor; (viii) a glucose-6 phosphate dehydrogenase inhibitor; (ix) a kmin-B.subl. - and B.sub2. -receptor antagonist; (x) an anti-gout agent, e.g., colchicine; (xi) a xanthine oxidase inhibitor, e.g., allopurinol; (xii) an uricosuric agent, e.g., probenecid, sulfinpyrazone or benzbromarone; (xiii) a growth hormone secretagogue; (xiv) a transforming growth factor (TGFp); (xv) a pktelet-derived growth factor (PDGF); (xvi) a fibroblast growth factor, e.g., basic fibroblast growth factor (bFGF); (xvii) a granulocyte macrophage colony stimulating factor (GM-CSF); (xviii) a capsaicin cream; (xix) a Tachykinin NK.subl. and NKLsubS. receptor antagonist selected from the group consisting of NKP-608C; SB-233412 (talnetant); and D-4418; (xx) an elastase inhibitors selected from the group consisting of UT-77 and ZD-0892; (xxi) a TNFa converting enzyme inhibitor (TACE); (xxii) an induced nitric oxide synthase inhibitor (iNOS); or (xxiii) a chemoatiractant receptor-homologous molecule expressed on TH2 cells (a CRTH2 antagonist). The pKa of a compound of formula (I) is measured using one of the following methodologies. MethodA The apparatus used consists of a Sinus GLpK. instrument with DPAS (Dip Probe Absorption Spectroscopy) attachment Key elements of the apparatus are a Sinus pH electrode, stirrer, titrant dispensing tubes, a multi-tipped dispenser, motor driven dispensing syringes, fibre optic UV probe and diode array detector. In addition, solutions in PTFE containers of ionic strength adjusted (0.1 OM KC1) distilled water, nominally 0.50 M HO, nominally 0.50 M KOH and 80% v/v methanolrwater are also housed within the instrument Thetitration solutions are constantly purged with oxygen free nitrogen. The reservoir for the potassium hydroxide solution is further protected from atmospheric contamination by a soda-lime guard-tube. Samples are placed in titration vessels which in turn are placed in a movable autosampler tray (maximum capacity 48 samples). The electrode, stirrer, dispensing tubing/tips and DPAS probe are housed on a movable, automated z-tower unit, which, controlled by software, positions itself in the appropriate titration vessel when titrating. The Sinus GLpKa instrument is directly connected to a dedicated PC supporting software for assay setup and subsequent data analysis. Assays are set up using the GlpKaControl software and results are analysed using the pKaLOGP and pKaUV software on the PC. The software also allows determination of multiple pK«s using complex curve fitting analyses. Method B: Potentiometric Method Two types of potentiometric titrations may be performed in order to determine a compound's pKa/pKgS; a purely aqueous titration (recommended for fairly water soluble compounds) and a cosolvent titration, where variable amounts of methanol are added to the sample in addition to ionic strength adjusted water (recommended for compounds which are not soluble in water). For the latter, a value for the compound's pK« in pure ionic strength adjusted water can be estimated by the Yasuda-Shedlovsky procedure. This involves measuring the apparent pK. of me compound at three known weight percentages of methanolrwater (transposed into reciprocals of the dielectric constants of the medium, I/ET) and men extrapolating to 0 wt% methanol (l/sl.282 x 10'3). The GLpK, instrument unit also houses two aqueous wash containers (containing distilled water), a waste beaker (to dispense extraneous solutions into) and a container holding pH 7.00 buffer solution for the electrode to be immersed in during periods between titrations. Each time a set of titrations is carried out, these solutions are replaced. Position 1 in the autosampler contains a titration vessel containing pH 7.00 buffer solution (changed for each titration set). For each titration set to be run, position 2 houses a titration vessel into which ionic strength adjusted water is dispensed (typically 15.00 ml/). This in turn is adjusted to pH 1.80 with aqueous HC1 and then titrated to pH 12.20 by gradual addition of aqueous KOH. This is referred to as a blank titration and is employed by the pKaLogP software in order to calibrate the pH electrode and to standardise the HC1 solution, using the so-called four-plus parameter procedure. Periodically, (typically every 3 months, or when the titration solutions run low) the titration solutions are replaced and the KOH solution standardised against potassium hydrogen phthalate using a standardisation procedure within the GLpKaControl software. Between 1-2 nog of each sample must be accurately weighed out Samples arc placed in provided glass titration vessels. The weight of compound most be entered into me GLpKaControl software. Other parameters that need to be entered are; the molecular weight of the compound, assay type (aqueous, cosolvent), number of assays in the beaker (1 for aqueous titrations, 3 for cosolvent/mixed solvent titrations), formula (eg. X for a compound not present as a salt, or XHC1 for a compound introduced as a hydrochloride salt), expected number of pK«s (from known structure), minimum pH (1.80 for operational minimum of electrode), maximum pH (12.20 for operational maximum of electrode), first assay direction (low to high pH recommended for bases, high to low pH recommended for acids), starting aqueous phase volume (minimum 8.00 mL, typically 15.00 mL for purely aqueous titrations and 9.00 mL for mixed solvent titrations), and pH step between points (ApHMUO units recommended). If mixed solvent titrations are carried out on a compound, then additional information needs to be entered; assay direction for second and third titrations (see first assay direction), and additional water volume for second and third assays (automatically calculated when using the cosolvent weight percentage tool). A number of samples (maximum 48) are placed in the autosampler and the pertinent information for each titration (weight of compound, molecular weight etc.) downloaded to the GLpK« instrument from the dedicated PC. The "run assays" option on the GLpKa instrument is selected and the titration run proceeds. At the end of the run, the titration data is uploaded to the PC and analysed using the pKaLOGP software. The first sample to be analysed is the blank titration. Curve fitting procedures are used to fit the measured data to a theoretical curve allowing the derivation of the exact concentration of the HCI solution, and also the values of various parameters (four-plus parameters) which characterise the behaviour of the electrode as a function of pH. These data are then used in the subsequent analysis of the other samples. The rest of the samples are analysed using further curve fitting procedures that extract the pKas of the compound by fitting the observed data to a theoretical curve. For cosolvent titrations the observed pKas from each sample at different percentages of methanol are analysed using the Yasuda-Shedlovsky • , procedure in the pKaLOGP software which extraplotes the observed pKas to the true pKas in 100% aqueous solution. Method C: DPAS (Pro Probe Absorption Soectroscopvl Method This method determines pKas by measuring UV spectra of a compound as a function of pH. This method is most suitable for compounds where the ionising centre is situated close to an aromatic or conjugated system within the molecule such that a change in the extent of ionisation will lead to a change in the UV spectrum. Due to the good sensitivity of UV spectroscopy, this method is suitable for rather insoluble compounds. This method requires a blank titration to be run in just the same way as the potentiometric method. However, for the samples, two vials are required for each sample. Into one vial is placed a small amount of a DMSO solution of the compound (typically 50 ul of a 1.5 mM solution) along with some phosphate buffer to give some pH stability during the titration (typically 100 uL of an aqueous solution prepared from 0.2 g potassium dihydrogen orthophosphate and 100 mL 0.1 M KC1 solution). The titrator will then add water (typically 10 mL) to this solution and then carry out a pH titration while collecting UV spectra at each pH. The second vial should contain and equivalent volume of neat DMSO and an equivalent volume of phosphate buffer. The titrator will then add an equivalent volume of water to this solution and take a UV spectrum of it to act as a reference (this is actually done before the pH titration of the corresponding sample solution). Again the first sample to be analysed is the blank titration which allows determination of the exact HC1 concentration and the values of four-phis parameters. The pKaUV software is then used to extract the pKas of the compound from the 3 dimensional data (absorbance, wavelength, pH) that was collected during the titration. The software uses a complex algorithm (target factor analysis) to extract the UV spectrum of each protonation state of the molecule as well as each pKa of the molecule from the raw 3 dimensional data. The invention will now be illustrated by the following non-limiting Examples in which, unless stated otherwise: (i) when given, H NMR data is quoted and is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMSfyas anmtemalstandaixl,deterinmedat300MHzor400MHz ' (CISOCDj), methanol-D4 (CDsOD) or CDC13 as the solvent unless otherwise stated; (ii) mass spectra (MS) were run with an electron energy of 70 electron volts in the chemical ionisation (O) mode using a direct exposure probe; where indicated ionisation was effected by electron impact (El) or fast atom bombardment (FAB) or electrospray (ESI); where vahies for m/z are given, generally only ions which indicate the parent mass are reported, and unless otherwise stated the mass ion quoted is the positive mass ion (iii) the title and subtitle compounds of die examples and methods were named using the ACD/Index name program version 4.55 from Advanced Chemistry Development, Lie; (iv) unless stated otherwise, reverse phase HPLC was conducted using a Symmetry, NovaPak or Xterra reverse phase silica column; and (v) the following abbreviations are used: Step 1: 4-(3,4-Dichlorophenoxy)piperidme 4-Hydroxypiperidine (50 g) was added portionwise to a stirred suspension of potassium terf-butoxide (1 10.9 g) in THF (900 mL) at room temperature and under nitrogen. The mixture was heated at reflux and l-dichloro-4-fluorobenzene (98 g) added dropwise over 30 mm. The mixture was stirred at reflux for another 1 h then cooled down. to room temperature, dihrted with ethyl acetate (500 mL) and washed with water (500 mL). The organic phase was dihrted further wim ethyl acetate (500 mL) and extracted with 1M hydrochloric acid (200 mL). The aqueous extract was adjusted to over pH 10 by addition of a solution of sodium hydroxide and extracted twice wim terf-butylmethyl ether (750 mL). The organic extracts were dried over magnesium sulfate, filtered aixl concentrated under vacuum to yield the sub-tide compound as a dark oil which was used as such in the next step. MS (ESI+ve) 246/248 [M+Hf 'HNMR 6 (CDC13) 1.60-1.70 (2H, m), 1.97-2.03 (2H, m), 2.75 (2H, td), 3.15 (2H, dt), 4.29-437 (1H, m), 6.78 (1H, dd), 7.00 (1H, d), 7.31 (1H, d). Step 2: (25)- l-Azido-3-[4-(3,4-dichlorophenoxy)piperidin-l -yl]propan-2-oI (2ROxiran-2-ylmethyl 3-nitrobenzenesulfonate (21.1 g) in DMF (300 mL) was treated with triethylamine (22.6 mL) followed by 4-(3,4-dichlorophenoxy)-piperidine g). The mixture was stirred overnight at 60°C. Sodium azide (16 g) was added to the mixture and the reaction was stirred for a further 72 h. The solution was carefully concentrated under vacuum and the residue was diluted with water (600 mL), extracted with ethyl acetate (1 500 mL). The organic layer was washed twice with water (500 mL), then brine (200 mL) and concentrated under vacuum to afford an oil. Step 3: (2R)-l-Ammo-3-[43,4chlorophenoxy)piperidm-l-yl]propan-2-ol The oil from Step 2 was dissolved in wet tetrahydroforan (225 mL) and was treated with triphenylphosphine (53.3 g). The reaction was heated at 60 °C and stirred for 4 h. The solvent was removed under vacuum, the residue redissolved into 2N hydrochloric acid (IL) and the aqueous layer was extracted with ethyl acetate (3 x 700 mL). The aqueous phase was basified with aqueous 2 N sodium hydroxide solution and extracted with DCM (3 x IL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum. The crude material was purified by chromatography (8% 7N ammonia hi methanol/DCM) to give the title compound as a yellow oil (17 g). MS (APd+ve) 319/321 |M+H]+ 'HNMR 6 (COa3) 1.90-1.72 (2H, m), 2.06-1.91 (ZH, m), 2.46-2.21 (3H, mX 2.60- 2.49 (1H, m), 2.65 (1H, d), 2.72-2.61 (1H, m), 2.82 (1H, d), 2.94-2.84 (1H, m), 3.74-3.62 (1H, m), 4.0 (1H, app. sept), 6.75 (1H, dd), 7.00 (1H, d), 7.31 (1H, d). Preparation 2 3Haenty Prepared as described in Preparation 1 using 4-(2,4-dichloro-3-methylphenoxy)- piperidine. MS (APCI+ve) 333/335 [M+H]+ 'H NMR 6 (CDaOD) 1.92-1.75 (2H, m), 2.08-1.90 (2H, m), 2.72-2.57 (1H, m), 2.93-2.72 (4H, m), 3.35-3.24 (2H, m), 3.88-3.71 (1H, m), 4.54-4.37 (1H, m), 6.94 (2H, d), 7.25 (2H, d). Preparation 3 -[4-(3,4-Dichlorophenoxy)piperidin- l-yl]-3-methylamino-propan-2-ol A solution of 43,41icWorophenoxyH(2/2)xiran-2-ylmethyl]piperidine (1.0 g), prepared as described in Preparation 1, Step 2 and concentrated from DMF, and methylamine (2.56 mL 40% v/v aqueous) in ethanol (15 mL) was heated at 60 °C in a sealed vessel for 16 h. The solvent was evaporated at reduced pressure and the residue was purified by flash column chromatography ehiting with 8% 7M methanolic ammonia in DCM to give the title compound (0.875 g). MS (APCI+ve) 333/335 [M+Hf 'HNMR 5 (CDC13) 2.38-2.2 (3H, m), 2.46 (3H, s), 2.48-2.42 (2H, m), 2.54 (1H, dd), 2.56-2.51 (2H, m), 2.65 (1H, dd), 2.71-2.65 (2H, m), 2.91-2.86 (1H, m), 3.86-3.80 (1H, m), 4.32-4.26 (1H, m), 6.75 (1H, dd), 6.99 (1H, d), 7.31 (1H, d). Preparation 4 JV-{(2J2)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-6-oxo-2- (trifluoromethyl) - 1 ,6-dihydropyridine-3-carboxamide 6-Oxo-2-(trifluoromethyl)-l,6-dihydropyridine-3-carboxyKc acid (Organic Process Research and Development 1997, 1, 370 - 378; O.SOg) was dissolved in thionyl chloride (10 mL) and heated at reflux for 3 h. The solvent was evaporated and the residue was azeotroped with toluene (10 mL). The resultant pale yellow solid was dissolved in ethyl acetate (10 mL) and added dropwise to a solution of (2fll-amino-3-[4-(3,4- dichlorophenoxy)piperidin-l-yl]propan-2-ol (0.770 g) and triethylamine (1.68 mL) in DCM (25 mL). The mixture was stirred at room temperature for 18 h and the solvents were evaporated. The residue was dissolved in methanol (20 mL) and heated at reflux for 18 h. The solvents were evaporated and purification by RPHPLC (Novapak, 0.1% ammonium acetate / acetonitrile) afforded the title compound as a colourless solid (0.520 g). The title compound has pKa 5.9 (measured using method 6), and pKa 6.3 (calculated by ACD). MS (APCI+ve) 508/510 [M+Hf NMR 8 (CDjOD) 1.89 - 1.78 (2H, m), 2.10 - 1.99 (2H, m), 2.65 - 2.51 (4H, m), 2.99 - 2.87 (2H, m), 3.40 - 334 (1H, m), 3.48 (1H, dd), 4.04 - 3.96 (1H, m), 4.50 - 4.42 (1H, m), 6.84 (1H, d), 6.92 (1H, ddd), 7.14 (1H, dd), 7.41 (1H, dd), 7.75 (1H, d). Example! 6-Oxo-2-(trifhioromethyl)-l6-dihydropyjidQe-3arboxylic acid (0.100 g) was dissolved in thionyl chloride (2 mL) and heated at reflux for 3 h. The solvent was evaporated and the residue was azeotroped with toluene (5 mL). The resultant pale yellow solid was dissolved in tetrahydrofuran (2 mL) and added dropwise to a solution of (2/)-lamino- 3-[4-(24-dichloro-3-meUiylphenoxy)piperidin-l-yl]propan-2-ol (0.161 g, and triethylamine (0.337 mL) in DCM (5 mL). The mixture was stirred at room .temperature for 18h and the solvents were evaporated. The residue was dissolved in methanol (10 mL) and heated at reflux for 3 h. The solvents were evaporated and purification by RPHPLC (Symmetry, 0.1% ammonium acetate / acetonitrile) afforded the title compound as colourless solid (0.520 g). The title compound has pKa 6.3 (calculated using ACD). MS (APCI+ve) 522/524 [M+H]+ 'H NMR 5 (CDaOD) 1.97 - 2.23 (4H, m), 2.48 (3H, s)t 2.81 - 3.07 (4H, m), 3.12 - 324 (2H, m), 3.31 - 3.52 (2H, m), 4.08 - 4.18 (IH, m), 4.62 - 4.69 (IH, m), 6.89 (IH, d), 7.02 (IH, d), 7.31 (IH, d), 7.80 (IH, d). Example 3 5-Bromo-7V- {(2/Z)-3-[4-(3,4-diclilorophenoxy)piperidin-1 -yl]-2-hydroxypropyl}-6- oxo-2-(trifluoromeAyl)-l,6-dihydrqpyridine-3-carboxaiiiide Step 1: Ethyl 5-bromo-6xa-2trifluoromeyl)-l6ihydropyridine-3-carboxylate To a solution of ethyl 6-oxo-2-(trifluoromefliyl)-l,6-dihydropyridine-3-carboxylate (Organic Process Research and Development 1997,7,370 - 378; 0.10 g) in carbon tetrachloride was added 4nromosuccininride (0.083 g). The mixture was heated at 80 °C fcr 24 IL Evaporation and the purificatkm by f subtitle compound as a colourless solid (0.10 g). MS (ES -ve) 311/313 [M-H]' 'H NMR 5 (CDC13) 138 (3H, t), 439 (2H, q), 8.34 (IH, s) Step 2: 5-BTcmo-6-oxo-2-(trifluoromel)-l,6dihydropyridme-3-carboxylic acid Ethyl 5-bromo-6-oxo-2trifhionmethyl)-l,6-dihydropyridine-3-carboxylate (0.25 g) was suspended in 30% aqueous hydrochloric acid and heated at reflux for 4 days. Cooling and filtration gave the subtitle compound (0.210 g). !H NMR 6 (DMSO-de) 8.40 (IH, s), 13.40 (IH, s), 13.70 (IH, s). Step 3: 5-Bromo-JV-{(2J)-3-[4-(3,4-chlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-6- oxo-2-(trifluoromethyl)-l,6-dihydropyridine-3-carboxarnide Made by the method of Example 1 using 5-bromo-6-oxo-2-(trifhiorome1:b.yl)-l,6- dihydropyridine-3-carboxylic acid (0.10 g), thionyl chloride (2 mL), (2J2)-l-amino-3 (3,4-dichlorophenoxy)piperidin-l-yl]propan-2-ol (0.112 g) and triethylamine (0.244 mL) to yield the title compound as a colourless solid (0.096 g). The title compound has pKa 4.5 (calculated using ACD). MS (APCI-ve) 586 [M-Hp JHNMR 8 (CD3OD) 1.99 - 2.13 (2H, m), 2.14 - 2.28 (2H, m), 2.97 - 3.28 (4H, m), 3.30 - 3.50 (4H, m), 4.13 - 422 (IH, m), 4.63 - 4.70 (IH, m), 6.98 (IH, dd), 7.22 (IH, d), 7.44 (IH, d), 7.88 (IH, s). Example 4 iV-{(2/Z3-[43,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2,3- dihydro-2xo(trifluoromethyl)-5-thiazolecarboxarnide Cl Step 1:2,3-Dihydro-2-oxo-4-(tri£luoromeihyl)-5-fliiazolecarboxylic acid To a solution of ethyl 23-tihydro-2-oxo-4-(trifluoromethyI)-5-thiazolecarboxyIic acid (Bionet Research, 2.0 g) in THF (20 mL) was added a solution of lithium hydroxide (0.696 g) in water (20 mL). The mixture was stirred at 50° C for 72 h, cooled to room temperature and filtered. The filtrate was washed with ethyl acetate (10 mL), acidified to pH 3 using dilute hydrochloric acid and extracted with ethyl acetate (2 x 25 mL). The combined organic extractions were washed wife water (2 x 50 mL), saturated brine solution, dried (NaiSO, filtered and concentrated in vacua to give the subtitle compound as a colourless solid (1.583 g). MS (APCI-ve) 212 [M-H]' "C NMR 8 (CDC13) 171.3 (s), 161.1 (s), 129.8 (q, 39.8 Hz), 122.3 (q, 272.4 Hz), 115.1(q,3.0Hz). Step 2: A((2/gV3-f4"(3.4-Dichlorophenoxvpiperidin-l-vl1-2-hvdroxvpropvU-2.3- dihydro-2-oxo-4-(trifluoromethyl)-5-thiazolecarboxarmde Prepared as in Example 1 using 2,3-dihydro-2-oxo-4-(trifluorpmethyl)-5- thiazolecarboxylic acid to afford the title compound as a cream foam (0.183 g). The title compound has a pKa 4.7 (measured using Method B). MS (APCI-ve) 512/514 [M-H)]- H NMR 8 (CD3OD) 2.06 - 1.94 (2H, m), 2.22 - 2.08 (2H, m), 3.00 - 2.86 (2H, ddd), 3.14-3.00 (2H, m), 3.30 - 3.18 (2H, m), 3.42-3.32 (2H, ddd), 4.11 -4.03 (IH, m), 4.64 - 4.56 (IH, m), 6.94 (IH, dd), 7.18 (IH, d), 7.41 (IH, d). • Example 5 N- {(2S)-3-[4-(3 Achloropheno)piperidin-l-yl]-2-hyidroxypropyl} -JST-methyl-2- oxo(trifluoromethyl)-23-iihydro-l,3-thiazole-5-carboxamide Prepared as Example 1 using (2jR)-l-[4-(3,4-dichloropIienoxy)piperidin-l-yl]-3- . (memylamino)propan-2-ol (ISOmg, 0.45 mmol) and 2-oxo-4-(trifluoromethyl)-2,3- dihydro-13-thiazole-5-carboxylic acid (0.096 g) to yield the title compound as a colourless solid (0.085 g). The title compound has pKa 6.27 (calculated using ACD). MS (APCI+ve) 528/530 [M+H]+ 'HNMR 5 (DMSO-dfe 90 °C) 1.79 - 1.62 (2H, m), 2;03 - 1.88 (2H, m), 2.62 - 2.45 (2H, mX 23 - 2.82 (4H, m\ 3.00 (3H, s), 34 (1H, dd), 3.52 (1H, dd), 3.91 (1H, qointet), 4.45 (1H, septet), 6.96 (1H, dd), 7.20 (1H, d), 7.46 (1H, d). Example 6 methyl-2-oxo-4-(trifluoromethyl)-2,3-dihydro-l 3"thia2»le-5-carboxamide Prepared as Example 1 using (2/)-l-[4-(2,4-dichloro-3-methylphenoxy)piperidinl- yl]-3-(methylamino)propan-2-ol (0.156 g) and 2-oxo-4-(tritluoromethyl)-2-dihydrol, 3-thiazole-5-carboxylic acid (0.096 g) to yield the title compound as a colourless solid (0.091 g). The title compound has pKa 6.3 (calculated using ACD). MS (APCI+ve) 542/544 [M+Hf 'H NMR 5 (DMSO-de, 90 °C) 1.83 - 1.67 (2H, m), 2.01 -1.87 (2H, m), 2.41 (3H, s), 2.61 - 2.50 (2H, m), 2.93 - 2.78 (4H, m), 2.99 (3H, s), 3.24 (1H, dd), 3.52 (1H, dd), 3.91 (1H, quintet), 4.47 (1H, septet), 7.05 (1H, d), 7.31 (1H, d). -Soytr Example N- {(2/J)-3-[4-(3,4-Dichlorophenoxy)pq)eridin-1 -yl]-2-hydroxypropyl}-2-oxo-4- (pentafluoroethyl23-dibydro-13-thiazole-5-carboxamide Ethyl 2)xo-(pentafluorc«thyl2-dihydro-13-azole-5arboxylate (J.Het.Chem. 22 1985 1621-1630; 0.240 g) in THF (6 mL) was treated with lithium hydroxide (0. 120 g) in water (5 mL) and the mixture was heated at 50 °C for 4 d. The mixture was filtered and the residue was washed with water. The filtrate was washed with ethyl acetate. The aqueous layer was acidified with dilute hydrochloric acid and men extracted with ethyl acetate (3 x 50 mL). The organic extracts were washed with water and brine and men dried over sodium sulphate, filtered and evaporated to yield me subtitle compound as a solid (0.13 g). (pentafluoroefhyl)-23-lihydro-13-thiaz Prepared as Example 1 using (2R)-l-amino-3-[4-(3,4-dichlorophenoxy)piperidin-lyl] propan-2-ol (0.158 g) and 2xo(pentafhK)roethyl)-2,3-dihydro-l-thiazole-5- carboxylic acid (0.130 g) to yield the tide compound as a colourless solid (0.074 g). The title compound has pKa 6.1 (calculated using ACD). MS (APCI+ve) 564/566 [M+Hf 'H NMR oXDMSO-dj) 1.86 - 1.72 (2H, m), 2.08 - 1.96 (2H, m), 2.84 - 2.59 (4H, m), 3.10 - 2.90 (IH, m,obscured), 3.28 - 3.16 (3H, m), 3.85 (IH, quintet), 4.53 (IH, septet), 6.98 (IH, dd), 7.23 (IH, d), 7.47 (IH, d), 7.48 (IH, s). Example 8 N- {(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin- 1 -yl]-2-hydroxypropyl) -5-methyl- 1H-1 ,2,3-triazole-4-carboxamide Prepared as Example 1 using 5-memyl-lH-13-triazole-4-carbo7cylic acid - (Berichte 1963 96, 802 - 812; 0.060 g) to yield the title compound as a colourless solid (0.063 mg). The title compound has a pKa 7.5 (measured using Method B), and pKa 7.5 (calculated using ACD). MS (APCI+ve) 428/430[M+Hf 'HNMR 8 (DMSO-dc) 1.73 - 1.60 (2H, m), 1.97 -1.86 (2H, m), 2.41 - 2.28 (4H, m), 2.45 (3H, s), 2.79 - 2.67 (2H, m), 3.43 - 3.24 (2H, m), 3.78 (IH, quintet), 4.39 (IH, septet), 6.95 (IH, dd), 7.18 (IH, d), 7.44 (lH,d), 7.90 (IH, t), Example 9 W-{(2/9-3-[42,4-Dichloro-3Hme methyHH-l,3-triazole-carboxamide . Prepared as Example 1 using (2Jf)-l-amino-3-[4-(2,4-dichlon-3- memyhhenoxy)piperidin-l-yl]propan-2-ol (0.158 g) and 5-methyl-lH-l,2,3-triazole-4- carboxylic acid to yield the tide compound as a colourless solid (0.037 g). The title compound has a pKa 7.5 (calculated using ACD). MS (APCI+ve) 442/444 [M+Hf 'HNMR 6 (DMSO-de, 90 °C) 1.78 -1.65 (2H, m), 1.97 -1.86 (2H, m), 2.43 - 2.32 (4H, m), 2.41 (3H, s), 2.45 (3H, s), 2.79 - 2.67 (2H, m), 3.28 (IH, dt), 3.40 (IH, dt), 3.78 (IH, quintet), 4.43 (IH, septet), 7.03 (IH, d), 7.30 (IH, d), 7.89 (IH, t). Example 10 5yano-A/'-{(2)-3-[4-(3,4-dichlorophenoxy)piperidui-l-yl]-2-hydroxypropyl}-6- oxo-2-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide 5-Cyano-6-oxo-2-(trifluoromethyl)-l ,6-dihydropyridme-3-carboxylic acid (Farmaco 1997,52(5), 331 - 337; 0.115 g) was dissolved inthionyl chloride (3 mL) and . The solvent was evaporated and the residue was azeotroped with toluene (10 mL). The resultant solid was dissolved in THF (5 mL) and added dropwise to a solution of (2J)-l-[4-(3,4-dichlorophenoxy)-piperidin-l-yl]-3-methylamino-propan-2-ol (0. 1 50 g) and triethylamine (0.3 mL) in DCM (5 mL). The mixture was stirred at room temperature for 18 h and the solvents were evaporated. Purification by RPHPLC (Novapak, 0. 1% ammonium acetate / acetonitrile) and normal phase chromatography (NHs/methanol/DCM) afforded the title compound as a colourless solid (0. 123 g). The title compound has a pKa 3.4 (calculated using ACD). MS (APCI-Hre) 533/535 [M+Hf H NMR 5 (CDsOD) 2.13 - 1.99 (2H, m), 2.28 - 2.13 (2H, m), 3.10 (2H, dt), 3.34- 3.14(2H, m), 3.50-3.36(4H, m), 4.21-4.12 (IH, m), 4.71-4.63 (IH, m), 6.96 (IH, dd), 7.21 (IH, d), 7.42 (IH, d), 7.85 (IH, s). 1 1 5yano-Ar-{(2)-3-[4-(2,4cUoro-3-roethylphenoxy)piperidin-l-yl]-2- hydroxypropyl}"6-axo-2-(trifhic Prepared as Example 1 using (2R)-l-amino-3-[4-(2,4-dichloro-3- methylphenoxy)piperidm-l-yl]propan-2-ol to yield the title compound as a colourless solid (0.121 g). The title compound has a pKa 3.0 (measured using Method B), and pKa 3.4 (calculated using ACD). MS (APd+ve) 547/549 [M+H]+ 'H NMR 8 (DMSO-d6+ND4OD) 1.72 -1.61 (2H, m), 1.93 - 1.84 (2H, m), 2.37 - 2.24 (4H, m), 2.40 (3H, s), 2.72 - 2.63 (2H, m), 3.07 (IH, dd)3 3.23 (IH, dd), 3.71 (IH, quintet), 4.48 (IH, septet), 7.10 (IH, d), 7.34 (IH, d), 7.66 (IH, s). Example 12 5-Cyano-JV1{(2/Z3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-6- oxo-2-phenyl-1,6-dihydropyridine-3-carboxamide -l,6-dihydropyridine-3-carboxylic acid (European Journal of Medicinal Chemistry 24(5), 517 - 519,1989; 0.112 g) was dissolved in thionyl chloride (4 mL) and heated under reflux for 2 h. The solvent was removed in vacua and the residue was azeotroped with toluene (10 mL). The resultant pale yellow solid was dissolved in THF (4 mL) and added dropwise to a solution of (2/l-amino-3-[4-(3,4- dichlorophenoxy)piperidin-l-yl]propan-2-ol (0.150 g) and triethylamine (0.7 mL) in DCM (2 mL). The mixture was stirred at room temperature overnight and the volatiles were removed in vacuo. The residue was dissolved in acetonitrile (6 mL) and purification by RPHPLC (Novapak, 0.1% ammonium acetate / acetonitrile) afforded the tide compound as a white solid (0.025 g). The title compound has a pKa 3.0 (measured using Method B), and pKa 63 (calculated using ACD). MS (APCRve) 541/543 [M+Hf 'HNMR fcXDMSCW) 134 -1.64 (2H, m), 1.84 -1.95 (2H, m), 2.12 - 235 (4H, m), 2.62 - 2.73 (2H, m), 2.92 - 3.00 (1H, m), 3.11 - 3.20 (1H, m), 3.53 - 3.61 (1H, m), 4.38 - 4.49 (1H, m), 4.56 - 4.76 (1H, br s), 6.98 (1H, dd), 7.25 (1H, d), 7.42 - 7.53 (6H, m), 8.11 (lH,t),8.23(lH,s). Example 13 5-Cyano-A/"-{(2J)-3-[4-(2,4-dichloro-3-methylphenoxy)piperidin-l-yl]-2- hydroxypropyl}-6-oxo-2-phenyl-l,6dihydropyridine-3-carboxamide 5-Cyano-6-oxo-2-phenyl-l,6-dihydropyridine-3-carboxylic acid (European Journal of Medicinal Chemistry 24 (5), 517 - 519,1989; 0.112 g) was dissolved in thionyl chloride (4 mL) and heated under reflux for 2 h. The solvent was removed in vacuo and the residue was azeotroped with toluene (10 mL). The resultant pale yellow solid was dissolved in THF (4 mL) and added dropwise to a solution of (2/H-amino-3-[4-(2,4-dichloro-3- Mtethylphenoxy)piperidin-l-yl]propan-2-ol (0.150 g) and triethylamine (0.7 mL) in DCM (2 mL). The mixture was stirred at room temperature overnight and the volatiles were removed in vacuo. The residue was dissolved in acetonitrile (6 mL) and purification by KPHPLC (Novapak, 0.1% ammonium acetate / acetonitrile) afforded the title compound as a dry yellow powder (0.01 1 g). The title compound has a pKa 6.3 (calculated using ACD). MS (APCI+ve) 555/557 [M+H] 'HNMR SXCDCls) 1.92 - 2.01 (2H, m), 2.06 - 2.21 (3H, m), 2.47 (3H, s), 2.50 - 2.56 (2H, m), 2.76 - 2.83 (IH, m), 2.87 (IH, td), 2.96 - 3.05 (2H, m), 3.06 - 3.15 (IH, m), 3.35 - 3.43 (IH, m), 4.50 - 4.55 (IH, in), 6.33 - 6.39 (IH, m), 6.74 (IH, d), 7.22 (IH, d), 7.47 - 7.51 (5H, m), 7.51 - 7.57 (IH, m), 8.22 (IH, s) pxample 14 Stepl: 3-Memyl-2,6oxo-l,3,6-tetiydrcpyrinriduie-4-carboxylic acid The subtitle compound was synthesized according to the procedure described in Pharmazie 481993, H. 11 861 - 862. Step 2: JST-{(2)-3-[43,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-3-methyl- 2,6oxo-l)23,6-tetrahydropyrunidine-4-carboxamide 3-Memyl-2,6-dioxo-l,3,6-tetrahydropyrimidine-4-carboxylic acid (Pharmazie 48 1993, H. 11,861 - 862; 0.173 g) was dissolved in thionyl chloride (8 mL) and heated under reflux for 2 h. The solvent was removed in vacuo and the residue was azeotroped with toluene (10 mL). The resultant pale yellow solid was dissolved in THF (4 mL) and added dropwise to a solution of (2R)-l-amino-3-[4-(3,4-dichlorophenoxy)piperidin-lyl] propan-2-ol (0.325 g) and triethylamine (1.56 mL) in DCM (4.5 mL). The mixture was stirred at room temperature overnight and the volatiles were removed in vacuo. The was dissolved in acetonitrile (6 mL) and purification by RPHPLC (Novapak, 0.1% ammonium acetate / acetonitrile) followed by trituration with DCM afforded the title compound as a yellow powder (0.008 g). The title compound has a pKa 6.9 (calculated using ACD). MS (APCI+ve) 471/473 [M+Hf 'HNMR 8 (CD3OD) 126 - 136 (2H,m), 1.78 - 1.85 (2H,m), 1.99 - 2.05 (2H, m), 2.55 - 2.60 (2H, m), 2.83 - 2.95 (2H, m), 3.11 - 3.14 (1H, m), 3.32 (3H, s), 3.49 - 3.52 (1H, m), 3.89 - 4.01 (1H, m), 4.41 - 4.47 (1H, m), 5.58 (1H, s), 5.78 (1H, d), 6.88 - 6.91 (1H, m), 7.11 (1H, d) 7.38 (1H, d). Example 15 d Stepl: 2,64Hoxo-3;24ri3uoneiiy acid The subtitle compound was synthesised according to the procedure described in Pharmazie 481993, H. 11 861 - 862. Step 2: {(2/2)-3-[4-(3,4-Dichlcrophenoxy)piperidm-l-yi]-2-hydroxypropyl}-2,6-dioxo- 3-(2-trifluoroethyl)-l,2,3,6-tetrahydropyrimidmecarboxamide To a solution of (2JR)-l-amino-3-[4-(3,4-dichlorophenoxy)piperidm-l-yl]propan-2- ol (0.134 g) in dry DMF (3 mL), was added /MT-diisopropylethylamine (0.14 mL), 2,6- dioxo-3-(2,2-trifluoroethyl)-l,2)3,6-tetrahydropyrteidine-4-carboxylic acid (0.100 g) and HATU (0.178 g). The reaction mixture was stirred at 0 °C under an atmosphere of nitrogen for 20 min, then quenched with saturated sodium bicarbonate solution (10 mL), and allowed to stand overnight. The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organics were washed with brine (2x10 mL), dried over anhydrous magnesium sulfate, and the volatiles were removed in vacua to give an oil (0.205 g). Purification by RPHPLC (Novapak, 0.1% ammonium acetate / acetonitrile) afforded the title compound (0.028 g) as a dry yellow powder. fhe title compound has a pKa 5.9 (calculated using ACD). MS (APd+ve) 539/541(M+H)+ 'HNMR (CDsOD) S 1.83 - 1.68 (2H, m), 2.03 - 1.90 (2H, m), 2.29- 2.24(1H, m), 2.45 - 2.34 (IH, m), 2.69 - 2.51 (4H, m), 2.97 - 2.84 (2H, m), 3.03 (IH, quintet), 3.26 - 3.23 (IH, m), 3.34 - 3.32 (IH, m), 3.37 - 3.35 (IH, m), 3.90 (IH, quintet), 4.40 (IH, quintet), 5.39 (IH, s), 5.93 (IH, s), 6.82 (IH, dd), 7.04 (IH, d) 7.30 (IH, d). Example 16 5yano-2-clopropyl-JV[(2J2 hydroxypropyl]-! ,6-dihydro-6-oxo-3-pyridinecarboxamide o A stirred solution of 5-cyaix-2Kkypropyl-6xo-l6dihydropyridme-3- carboxytic acid (0.080 g) (J. Ued. Chem. 2002,45,1887) in thionyl chloride (2.5 mL) was heated at reflux for 2 h. Thionyl chloride was removed from the cooled solution in vacua. The residue was dissolved in THF (4 mL) and mis solution was added dropwise.atroom temperature to a solution of (2/)-l-amino-343,4ichlon)herK)xy)piperidin-lyl] propan-2-ol (0.125 g) and trietbylamine (0.7 mL) in DCM (2 mL) before stirring overnight The reaction mixture was concentrated in vacua and redissolved in 9:1 acetonitrile/water (4 mL) before subjecting to RPHPLC (gradient 0.1% ammonium acetate/acetonitrilc 95% to 50%) to yield a white solid (0.022 g). The title compound has a pKa 3.8 (measured using Method B), and pKa 7.5 (calculated using ACD). MS(ES+ve) 505/507 [M+Hf 'HNMR 8 (DMSO-de) 1.02 -1.08 (2H, m), 1.11 - 1.17 (2H, m), 1.57 - 1.68 (2H, m), 1.89 -1.97 (2H, m), 2.30 - 2.43 (4H, m), 2.53 - 2.61 (IH, m), 2.72 - 2.85 (2H, m), 3.05 - 3.14 (IH, m), 3.74 - 3.81 (IH, m), 4.42 - 4.49 (IH, m), 6.98 (IH, dd), 7.26 (IH, d), 7.50 (IH, d), 8.10 (IH, s), 8.32 (IH, t); resonance at -3.3 (IH, m) obscured by HDD. Example 17 5-Cyano-2-cyclopropyl-N-[(2R)-3-[4-(2,4-dichloro-3-methylphenoxy)-lpiperidinyl]- 2-hydroxypropyl]-l,6dihydro-6-oxo-3-pyridinecarboxamide The title compound has pKa 7.5 (calculated using ACD). MS (ES+ve) 519/521 [M+H]+ 'H NMR 8 (DMSO-dg) 1-00 -1.07 (2H, m), 1.10 - 1.17 (2H, m), 1.62 - 1.73 (2H, m), 1.86 -1.93 (2H, m), 2.30 - 2.39 (4H, m), 2.40 (3H, s), 2.52 - 2.61 (IH, m), 2.66 - 2.78 (2H, m), 3.04 - 3.13 (IH, m), 3.73 - 3.80 (IH, m), 4.46 - 4.54 (IH, m), 7.10 (IH, d), 7.35 (IH, d), 8.07 (IH, s), 8.29 (IH, t); resonance at -3.3 (IH, m) obscured by HDD. Example 18 N-{(2J)-3-[43,4-DicMoropheiKxy)piperi [(methylsulfonyl)amino]-4-(trifluoromettiyl)nicotinamide Stepl: 6XororAH(2K3-[43,4-dieM (trifluoromethyl)nicotinamide A solution of 4-trifluoromemyl-6-chloronicotinoyl chloride (0.585 g) hi THF (3 mL) was added dropwise at room temperature to a stirred solution of (2/)-l-amino-3-[4- (3,4-dichlorophenoxy)piperidin-l-yI]propan-2-ol (0.735 g) and triethylamine (0.7 mL) hi DCM (2 mL). After 18 h, the reaction mixture was concentrated in vacuo and subjected to flash column chromatography (eluent 96 : 4 dichloromethane/7 N ammonia hi methanol) to yield a yellow oil (1.02 g). A small amount (0.1 g) was redissolved in 9 : 1 acetonitrile/water (4 mL) and subjected to RPHPLC (gradient 0.1% ammonium acetate/acetonitrile 95% to 5%) to yield a white solid (0.025 g). MS (ES+ve) 526/528 [M+Hf H NMR S (CD3OD) 1.66 - 1.80 (2H, m), 1.87 - 2.00 (2H, m), 2.42 - 2.57 (4H, m), 2.76 - 2.90 (2H, m), 3.27 (IH, dd), 3.44 (IH, dd), 3.86 - 3.95 (IH, m), 4.30 - 4.41 (IH, m), 6.80 (IH, dd), 7.02 (IH, d), 7.29 (IH, d), 7.78 (IH, s), 8.56 (IH, s). Step 2: N- {(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl} -6- [(memylsulfonyl)amino]-4-(trifluoromethyl)nicotinamide m . A stared solution of 6-oit-JV-{(2/Z)-3-[4-(3,4-dichlorophenoxy)pipCTidin-l--yl]- 2-hydroxypropyl}-4-(trifluoromethyl)nicxtinamide (0.28 g), methanesulfonamide (0.12 g) and potassium carbonate (0.148 g) in AT-methyl-2-pyrrolidmone was heated under microwave irradiation (100 W) at 100°C for 15 min. The reaction mixture was concentrated in vacua and redissolved in 4 : 1 : 1 acetonitrile/ water/acetic acid (6 mL) and subjected to RPHPLC (gradient 0.1% ammonium acetate/acetonitrile 95% to 5%) to yield a white solid (0.025 g). The title compound has a pKa 53 (measured using Method B). MS (ES+ve) 585/587 [M+Hf 'H NMR oXCDaOD) 1.86 - 2.02 (2H, m), 2.06 - 2.20 (2H, m), 2.74 - 2.98 (4H, m), 3.07 - 3.22 (2H, m), 3.24 (3H, B), 3.36 - 3.56 (2H, m), 4.05 - 4.16 (1H, m), 4.52 - 4.62 (1H, m), 6.95 (1H, dd), 7.12 (1H, s), 7.18 (1H, d), 7.42 (1H, d), 8.44 (1H, s) o' II I I 0 s.F Stepl: Ethyl l-(4-memoxybenzyl5-[(2;Z£-Mfluoix carboxylate Sodium hydride (0.018 g) was added to a solution of 3,3-trifluoroethanol (0.060 mL) in dry DMF (1.5 mL). After stirring at room temperature for 30 min a solution of ethyl 5-chloro-l//-l,2,3-triazole-4-carboxylate (0.20 g, J.Chem. Sac. Perkin 1,1982, 627) in dry DMF (1 mL) was added. The mixture was heated at 80 °C for 18 h then cooled and partitioned between diethyl ether (50 mL) and water (50 mL). The aqueous layer was re-extracted with diethyl ether (2 x 50 mL) and the combined extracts were dried over anhydrous sodium sulfate. Concentration in vacua and chromatography on silica (0-50% gradient EtOAc / isohexane) gave the subtitle compound (0.127 g). MS (ES+ve) 376 [M+Hf 'H NMR oXCDCla) 1.44 (3H, t), 3.66 (2H, q), 3.78 (3H, s), 4.46 (2H, q), 5.62 (2H, s), 6.89-6.83 (2H, m), 7.29-7.24 (2H, m). Step 2: Ethyl 5-[(2trifhioroemyl)thio]-lH-l,23-triazole-carboxylate Ethyl H4-methoxybenzyl)-5-[(2-triiluoroemyl)thio]-l/f-l ,2,3-triazole-4- carboxylate (0.127 g) was dissolved in triflnoroacetic acid (2 mL) and heated at 65 °C for 4 h. The trifluoroacetic acid was evaporated in vacuo and the residue was azeotroped with toluene (3x10 mL) then dried under vacuum to afford the subtitle compound (0.086 g). MS(ES-ve)234[M-HF]' 'H NMR S(GDC13) 1.44 (3H, t), 3.89 (2H, q), 4.46 (2H, q). Step 3; 5-[(2-TrMuoroemyl)tMo]-lH-l-triazole-4-carboxylic acid Ethyl 5-[(2-trifluoroethyl)thio]-lr-l,3-triazole-4-carboxylate (0.086 g) was suspended in IN aqueous sodium hydroxide solution and heated at 70 °C for 3 h. The reaction mixture was filtered and men acidified with concentrated hydrochloric acid. Concentration in vacuo afforded a colourless solid which was washed with ice cold water to afford the subtitle compound (O.OSOg) MS(ES-ve) 226[M-HT 'HNMR SXDMSOd) 4.09-432 (2H, m), 13.51 (1H, &), 15.75 (1H, s). 5-[(2,2-Trifhioroemyl)thio]-l/f-13-triazole-4-carboxylic acid (0.080 g) was dissolved in DCM (2 mL) and treated with oxalyl chloride (0.060 mL) and DMF (1 drop). The solution was stirred at room temperature for 1 h then concentrated in vacuo and azeotroped with anhydrous toluene (5 mL). The residue was redissolved in dry THF and added dropwise to a stirred solution of (2R)-l-amino-3-[4-(3,4-dichlorophenoxy)piperidinl- yl]propan-2-ol (0.108 g) and triethylamine (0.142 mL) in DCM. The mixture was stirred for 1 h, the solvent was evaporated in vacuo and the product purified by RPHPLC (gradient 0.1% ammonium acetate/acetonitrile 50% to 5%). to afford the title compound as a colourless solid (0.058 g). The title compound has a pKa 5.2 (measured using Method B), and pKa 4.6 (calculated using ACD). MS (ES-fve) 528/530 [M+Hf 'HNMR 5(CD30D) L92 -1.84 (2H,m), 2.09 - 1.98 (2H, m), 2.92 - 2.72 (4H, m), 3.13 - 3.04 (2H, m), 3.42-3.32 (2H, m), 3.82 (2H, q), 4.03 - 3.97 (IH, m), 4.50 - 4.43 (IH, m), 6.83 (IH, dd), 7.07 (IH, d), 7.30 (IH, d). Example 20 4-[({(2/Q-3-[4-(3,4-Wchlorophenoxy)pir carbonylj-l-naphmoic acid cu d" sX/xX' To a solution of naphthalene-l,4-dicarboxylic acid (0.100 g), (2)-l-amino-3-[4- (3,4-dichlorophenoxy)piperidin-l-yl]propan-2-ol (0.147 g) and triethylamine (0.193 mL) in JV-methyl-2-pyroh'dinone (20 mL) was added PyBrOP (0258 g). The reaction mixture was stirred for 16 h and me solvent was removed in vacua. The residue was purified by RFHPLC (Symmetry, 0.1% ammonium acetate / acetonitrile) to afford the title compound as a colourless solid (0.050 g, 20%). The title compound has pKa 3.1 (calculated using ACD). MS (APCI+ve) 517/519 [M+Hf 'H NMR oXCCbOD) 2.02 - 2.30 (4H, m), 3.09 - 320 (2H, m), 3.22 - 330 (2H, m), 338 - 3.47 (2H, m), 3.51 - 3.67 (2H, m), 4.26 - 435 (IH, m), 4.66 - 4.73 (IH, m), 6.99 (IH, dd), 7.23 (IH, d), 7.45 (IH, d), 7.53 - 7.59 (2H, m), 7.64 (IH, d), 7.69 (IH, d), 8.23 - 826 (IH, m), 8.57 - 8.60 (IH, m). Example 21 A-{(2)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2- [(methylsulfonyl)amino]-4-(trifluoromethyI)- 1 3-thiazole-5-carboxamide O CF3 Step 1: 2-[(Methylsulfonyl)amino]-4-(trifluoromethyl)-l,3-thiazole-5-carboxylic acid To a stirred solution of ethyl-2-amino-4-(trifluoromethyl)-5-thiazole carboxylate (1.2 g) and triethylamine (2.1 mL) in THF (12 mL) was added methane sulfonic anhydride (1.74 g) in small portions at room temperature. After 2 h, the reaction mixture was concentrated in vacua and the residue was stirred in dioxane (5 mL) and aqueous 1 N NaOH (5 mL) for 16 h. The reaction mixture was concentrated in vacua and to the residue in water (20 mL) and THF (30 mL) was added lithium hydroxide monohydrate (1.8 g) before being heated at 50 °C for 12 h. To the cooled reaction mixture was added 1N aqueous hydrochloric acid (30 mL) and extracted into EtOAc (2 x 25 mL), dried over sodium sulfate, filtered, and concentrated in vacua. 'H NMR 5(DMSO-d6) 3.26 (3H, m). Step 2: N-{(2)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2- [(methylsulfonyl)ammo]-4trifluo A stirred solution of 2-[(memylsulfcmyl)amino](triiluoromethyl)-l,3-thiazole-5- carboxylic acid (0.145 g) in thioriyl chloride (3 mL) was heated at reflux for 2 h. Thionyl chloride was removed from the cooled solution in vacua. Hie residue was dissolved in THF (4 mL) and this solution was added dropwise at room temperature to a solution of (2K)-l-amino-3-[43,4HikMorophei»xy (0.144 g) and triethylamine (0.7 mL) in DCM (2 mL) before stirring overnight. The reaction mixture was concentrated m vocuo and redissolved in 9:1 acetonitrfle/water (4 mL) before being subjected to RPHPLC (Novapak, gradient 0.1 % ammonium acetate/acetonitrile 95% to 50%) to yield a white solid (0.028 g). Retention tune: 1.46 min (reverse phase analytical HPLC (Hewlett Packard Series 1100): Waters "Symmetry" C8 column 3.5um; 4.6 x 50mm column gradient 0.1% ammonium acetate/acetonitrile 75% to 5% in 3 min; flow 2mL/min). The title compound has a pKa 7.5 (measured using Method B). MS (ES+ve) 591/593 [M+Hf JH NMR 5(CD3OD) 1.88 - 2.04 (2H, m), 2.05 - 2.19 (2H, m), 2.82 (3H, s), 2.97 (1H, t), 3.10 (1H, d), 3.14 - 3.41 (4H, m), 4.05 - 4.14 (1H, m), 4.55 - 4.62 (1H, m), 6.87 (1H, dd), 7.12 (1H, d), 7.32 (1H, d), 2 resonances obscured. Example 22 A/"-{(2/)-3-[4-(4-Chloro-2-methylphenoxy)piperidin-l-yl3-2-hydroxypropyl}-2- oxo-4-(trifluoromethyl)-2,3-dihydro-1,3-thiazole-5-carboxamide O CF3 Prepared as Example 4 from (2/J)-l-amino-3-[4-(4-chloro-2-methylphenoxy)- piperidin-l-yl]propan-2-ol [WO2003068743(Al)] to give a whhe solid (0.046 g). Retention time: 1 .37 rain (reverse phase analytical HPLC (Hewlett Packard Series 1 100): Waters "Symmetry" C8 column 3.5pm; 4.6 \ 50mm column gradient 0.1% ammonium acetate/acetonitrile 75% to 5% in 3 min; flow 2mL/min). The title compound has pKa 6.1 (calculated using ACD). MS (ES4ve) 494/496 [M-f Hf 'H NMR 8(CD3OD) 1.97 - 2.10 (2H, m), 2.1 1 - 2.21 (2H, m), 2.22 (3H, s), 2.93 (1H, dd), 3.02 (1H, dd), 3.08 - 3.21 (2H, m), 3.2,1 - 3.30 (2H, m), 3.33 - 3.42 (2H, m), 4.06 - 4.13 (1H, m), 4.57 - 4.63 (1H, mfc 6.92 (1H, d), 7.11 (1H, dd), 7.15 (1H, d). [5-[({(ZR3-[4-(3,4-Iichloropbenoxy)piperidin-l-yl]-2- hydroxypropyl}aniino)carbonyl]-2K)xo-4trifluoroniemyl)py acid O CF3 Step 1:12-Memoxy-2-oxoemyl)-6xo-4trifmoromemyl)-l,6mydtepyridine-3- carboxylic acid To a stirred suspension of 6-oxo-4-(trifluoromemyl)-l,6-dihydropyridine-3- carboxylic acid (0.207 g) and potassium carbonate (0.553 g) in methanol (5 mL) was added methyl broraoacetate (0.104 mL) at room temperature. After 16 h, the reaction was not complete, so further methyl bromoacetate (0.15 mL) was added. After a further 16 h, the mixture was concentrated in vocuo before the addition of 1 N aqueous hydrochloric acid (30 mL) and extracted into ethyl acetate (3 x 25 mL), dried over Na2SC4, filtered, and concentrated in vacuo to leave a white solid (300 rag). MS (ES-ve) 278 [M-H] 'HNMR 5(DMSO-d6) 3.70 (3H, s), 4.88 (2H, s), 6.91 (1H, d), 8.68 (1H, d), 13.25 Step 2; Methyl [5-[({(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl2- hydroxypropyl}ainmo)carbonyl]-2xo-4trifluoromethyl)pyri A stirred solution of l-(2-methoxy-2-oxoefliyl)-6-oxo-4-(trifluoromethyl)-l,6- dihydropyridine-3-carboxylic acid (0.140 g) in ihionyl chloride (4 mL) was heated at reflux for 2 h. Thionyl chloride was removed from the cooled solution in vacua. The residue was dissolved in THF (4 mL) and this solution was added dropwise at room temperature to a solution of (2J)-l-amino-3-[4-(3,4-dichlorophenoxy)piperidin-lyl] propan-2-ol (0.144 g) and triethylamine (0.7 mL) in DCM (2 mL) before stirring overnight The reaction mixture was concentrated in vacua and used directly in the subsequent step. ,; - . - Step 3: r54(((2JV3-r4-G.4-DichloroDhenoxvpiperi carbonyl]-2xotrifliwrotnemyl)pyrid acid A solution of methyl [5-[({(2J3-[4-(3,4-dichlorophenoxy)piperidin-l-yl}-2- hydroxypropyl}aim)auixiryI]-2 (0.1 g) and tithram hydroxide (0.022 g) in THF (3 mL) and water (1 mL) was stored at room temperature for 16 h. The reaction mixture was concentrated in vacua and redissolved in 9 : 1 acetonitrile/water (4 mL), and acidified to pH 5 with acetic acid before being subjected to reverse phase HPLC (Novapak, gradient 0.1% ammonium acetate/acetonitrile 95% to 50%) to yield a white solid (0.032 g). Retention time: 1.29 min (reverse phase analytical HPLC (Hewlett Packard Series 1100): Waters "Symmetry" C8 column 3.5um; 4.6 x 50mm column gradient 0.1% ammonium acetate/acetonitrile 75% to 5% in 3 min; flow 2mL/min). The title compound has pKa 3.6 (calculated using ACD). !HNMR 8(CD3OD) 1.97 - 2.07 (2H, m), 2.08 - 2.23 (2H, m), 2.93 (IH, dd), 3.03 (IH, dd), 3.06 - 3.16 (2H, m), 3.21 - 3.29 (2H, m), 3.36 (IH, dd), 3.45 (IH, dd), 4.08 - 4.15 (IH, m), 4.58 (2H, d), 4.59 - 4.65 (IH, m), 6.85 (IH, s), 6.95 (IH, dd), 7.19 (IH, d), 7.41 (!H,d),8.07(lH,s). Examle 24 :-memylpbenoxy)piperidin-l-yl3-2-hydroxypropyl}-2- The title compound was prepared as Example 4 and was obtained as a white solid (0.10 g). The title compound has pKa 6.1 (calculated using ACD). MS (APd+ve) 528/530 [M+Hf 'HNMR 8(CD3OD) 1.87 - 2.02 (2H, m), 2.02 - 2.21 (2H, m), 2.25 (3H, s), 2.79 - 2.97 (2H, m), 2.97 - 3.20 (2H, m), 3.22 - 3.33 (4H, m), 4.00 (IH, td), 4.54 (IH, s), 6.87 (lH,d),7.21(lH,dd). Stepl: Methyl 4-(4-fluorophenyl)-2-oxo-2)3-dihydrorl,3-thiazole-5-carboxylate Prepared according to J.Het.Chem. 22,1985,1621-30 using methyl (2£)-3-amino- 3-(4-fluorophenyl)acrylate [Angew. Chem. 2003,42(8), 913-6]. Obtained as a yellow solid (3.67 g). Retention time: 2.62 min (reverse phase analytical HPLC (Hewlett Packard Series 1100): Waters "Symmetry" C8 column 3.5um; 4.6 x 50mm column gradient 0.1% ammonium acetate/acetonitrile 95% to 50% in 3 min; flow 2rnL/rnin). MS (ES-ve) 252 [M-HT Step 2: 4-(4-Fluorophenyl)-2-oxo-2,3-dihydro-l,3-thiazole-5-carboxylic acid Prepared as for Example 4. Obtained as pale yellow solid (0.38 g). MS (ES-f-ve) 240 [M+Hf 'HNMR 5(DMSO-d6) 724 - 7.33 (2H, m), 7.57 - 7.64 (2H, m), 12.10 (1H, s). fluorophenyl)-2-oxo-2,3-dihydro-l,3-tijiazole-5-carboxainide Prepared as Example 4. Obtained as white solid (0.06 g). The title compound has a pKa 7.4 (measured using Method 8). MS (APCI+ve) 538/540 [M-t-Hf JH NMR 6XDMSO-d6) 1.51 - 1.63 (2H, m), 1.83 - 1.93 (2H, m), 2.15 - 2.29 (4H, m), 2.59 - 2.71 (2H, m), 2.97 - 3.04 (1H, m), 3.15 - 3.21 (1H, m), 3.60 (1H, quintet), 4.42 (1H, septet), 4.60 (1H, s), 6.98 (1H, dd), 7.25 (1H, d), 7.26 - 734 (3H, m), 7.49 (1H, d), Ar-{(23-[43ADicWorophenoxy)pipeTidin-l-yl]-2-hydroxypropyl}-5-(4- F Step 1: Methyl 5-(4-fluorophenyl)-l/f-123-triazole-4-carboxylate Sodium (0.25 g) was added gradually to dry absolute ethanol (4.6 mL). Methyl 3- (4-fluorophenyl)-3-oxopropanoate (1.44 g) was added followed by 4-methoxybenzyl azide. The mixture was heated at reflux for 18 h and was then cooled and concentrated in vacuo. The mixture was poured into ice water and acidified with dilute hydrochloric acid. The resulting precipitate was filtered and dried to yield a yellow solid. This was heated at 65 °C in trifluoroacetic acid (8 mL) for 8 h. The mixture was concentrated in vacuo and azeotroped with toluene and then treated with ethyl acetate and filtered to yield the title compound as a yellow solid (0.5 g). Used without purification. Step 2; 5-(4-Fluorophenyl)-l-l,2,3-triazole-4-carboxylic acid Prepared as for Example 8. Obtained as a white solid. Retention time: 0.87 min (reverse phase analytical HPLC (Hewlett Packard Series 1100): Waters "Symmetry" C8 column 3.5um; 4.6 x 50mm column gradient 0.1% ammonium acetate/acetonitrile 95% to 50% in 3 min; flow 2mL/min). MS(BS-ve)206[M-HT Step_3: -{(2J3-[4-(3,4-Dikrophenoxy)piperidin-l-yl]-2-hydroxypropyl}-54- fluorophenyl)-l/f-l,3-triazole-4-carboxamide Prepared as Example 8. Obtained as white solid (0.10 g). The title compound has a pKa 6.1 (measured using Method B). MS (APd+ve) 508/510 [M+H]+ H NMR opMSO-dg) 1.59 - 1.70 (2H, m), 1.87 - 1.97 (2H, m), 2.28 - 2.46 (4H, m), 2.67 - 2.82 (2H, m), 3.24 - 3.41 (2H, m), 3.81 (IH, quintet), 4.45 (IH, septet), 4.86 (IH, sX 6 J8 (IH, dd), 7.26 (IH, t), 7.29 (2H, tt), 7.49 (IH, d), 7.99 - 8.04 (2H, m), 8.44 The title compound was obtained as a white solid (0.07 g). The title compound has pKa 6.1 (calculated using ACD). MS (APCI+ve) 505/507 [M+Hf 'HNMR 5(DMSO-d6) 1.69 - 1.82 (2H, m), 1.95 - 2.06 (2H, m), 2.51 - 2.67 (4H, m), 2.87 -2.95 (2H, m),3.15 - 3.29 (2H, m), 3.80 (IH, quintet),4.65 (IH, septet), 7.10 (IH, dd), 7.30 (IH, d), 7.52 (IH, s), 7.79 (IH, d). Example 28 -{(23-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2-oxo-4- (trifluoromethyl)-2,3-dihydro-l,3-thiazole-5-carboxamide The title compound -was obtained as a white solid (0.14 g). The title compound has pKla 6.1 (calculated using ACD). MS (APCI+ve) 514/516(M+H) 'H NMR SpMSO-cU 90 °C) 1.69-1 .82 (2H, m), 1.92 - 2.06 (2H, m), 2.52 - 2.75 (4H, m), 2.88 - 3.13 (2H, m), 3.83 (IH, quintet), 4.50 (IH, septet), 6.98 (IH, dd), 7.23 ), 7.47 (lH,d), 7.53 Example 29 J-{(25-3H[43-C1iloro-4anophenoxy)piperidm-l-yl]-2-hydroxypropyl} The title compound was obtained as a white solid (0.13 g). The tide compound has pKLa 6.3 (calculated using ACD). MS (APCI+ve) 519/521 [M+Hf JHNMRS(DMSO-d6 90 °C) 1.65 - 1.79 (2H, m), 1.91 - 2.03 (2H, m), 2.35 - 2.59 (4H obscured, m), 2.80 - 2.89 (2H obscured, m), 3.00 (3H obscured, s), 3.23 (IH, dd), 3.53 (IH, dd), 3.90 (IH, quintet), 4.62 CIH, septet), 7.09 (IH, dd), 7.30 (IH, d), 7.79 (IH, d). Example 30 JV-{(2/Z)-3-[4-(2,4-DicWoro-3-memylphenoxy)piperidm-l-yl]-2-hydroxypropyl}-2- oxotrifluoromethyl)-2,3-dihydro-l,3-thiazole-5-carboxarnide The title compound was obtained as a white solid (0.08 g). The title compound has pKa 6.1 (calculated using ACD). MS (APCI+ve) 528/530 [M+Hf 'HNMR 5(DMSO-d6) 1.74 - 1.87 (2H, m), 1.93 - 2.05 (2H, m), 2.41 (3H, s), 2.51 2.72 (4H, mX 2.88 - 2.98 (2H, m), 3.14 - 3.30 (2H, mX 3.82 (IH, quintet), 4.52 (IH, septet), 7.07 (IH, d), 7.32 (IH, d), 7.54 (IH, s). Examle 31 isopropyl-l/f-l,2,3-triazole-4-carboxamide Stepl: Ethyl 5-isopropyl-l//P-13-triazole-4-carboxylate Prepared as Example 8 using ethyl 4-methyl-3-oxopentanoate. Used without j purification. Step 2:5-wo-Pr()yH/f-l,2,3-triazole-4-carboxyUc acid Prepared as Example 8 to yield an amber oily solid. MS (ES+ve)156 [M+HT Retention time: 0.49 min (reverse phase analytical HPLC (Hewlett Packard Series 1100): Waters "Symmetry C8 column 3.5 um; 4.6 x 50mm column gradient 0.1% ammonium acetate/acetonitrile 95% to 50% in 3 min; flow 2mL/min). Step 3: jy-((2/gV3-r4-(3-chloro-4-cvanophenoxv')piperidin-l-vn-2-hvdroxypropyl}-Sisopropyl- ljy-l ,2,3-triazole-4-carboxamide The title compound was prepared as Example 8 and obtained as a white solid (0.04 g). The title compound has pKa 7.3 (calculated using ACD). MS (APCI+ve) 447/449 [M+H]+ 'H NMR 8(DMSO-d6 90 °C) 1.25 (6H, d), 1.64 - 1.74 (2H, m), 1.89 - 1.99 (2H, m), 2.30 - 2.43 (4H, m), 2.68 - 2.79 (2H, mX 3.29 (IH, dt), 3.39 (IH, dt), 3.65 (IH, septet), 3.78 (IH, quintet), 4.57 (IH, septet), 4.58 (IH, s), 7.08 (IH, dd), 7.28 (IH, d), 7.78 (IH, d), 7.96 (IH, s). Example 32 J\r-{(2iS3-[43Moro-4-cyariophenoxy)iperidin-l-yl]-2-hydroxypropyl}-5- isopropyl-AT-methyl- 1H-1 3-triazole-4-carboxainide The title compound was prepared as Example 8 and obtained as a white solid (0.03g). The title compound has pKa 8.O (calculated using ACD). MS (APCI-fve) 461/463 [M+H]+ 'HNMR&XDMSO) 1.22 (6H, d), 1.54 - IJO (2H, m), 1.83 - 1.95 (2H, m),2.19 - 239 (4H, m), 2.56 - 2.76 (2H, m), 3.09 (3H, s), 3.18 - 335 (2H, m), 3.68 (1H, dd), 3.87 (1H, s), 4.54 (1H, s), 7.07 (1H, dd), 7.26 (1H, s), 7.78 (1H, d). Examle 33 (2-trifhuroethyl2,3-dihydit)-l-thiazoIe-5-carboxamide Step 1: Benzyl 5,5,5-trifluoro-3-oxopentanoate 3,3,3-Trifluoropropanoic acid (5 g) hi dry THF (50 mL) was treated with N,Ncarbonyldiimidazole (7.6 g) and the mixture was stirred at room temperature for 6 h. 2,2- Dimethyl-l,3-dioxane-4,6-dione (5.63 g) and triethylamine (5.4 mL) were added and the mixture was stirred at room temperature for 18 h. Aqueous potassium hydrogen sulphate solution (10% w/v) was added and the mixture was extracted with diethyl ether. The organic layer was separated and washed -with water, then brine and dried over sodium sulphate and filtered. The solvent was concentrated in vacua to yield a pale yellow solid. Toluene was added, followed by benzyl alcohol. The mixture was heated at 80 °C for 6 h and was then concentrated in vacua. Purification by flash chromatography (eluent 5:95 ethyl acetate / isohexane) yielded the title compound as a beige solid (3.1 g). MS (ES-ve) 259 [M-H]' HNMR SXCDCIa) 3.41 (2H, q), 3.58 (2H, s), 5.19 (2H, s), 7.30 - 7.42 (5H, m). Step 2: Benzyl (2i3-anrino-5,5,5-trifliKropent-2-enoate Benzyl 5,5,5-trifluoro-3-oxopentanoate (2.1 g) in ethanol (15 mL) was treated with ammonium acetate (2 g). The mixture was heated at 80 °C for 1 8 h and was then concentrated in vacua. Water and DCM were added. The organic phase was separated and washed with sodium bicarbonate solution and water and then dried over sodium sulphate and filtered. The solvent was concentrated in vacua to yield the tide compound as a colourless oil (0.7 1 g). Retention time: 3.34 mm (reverse phase analytical HPLC (Hewlett Packard Series 1 100): Waters "Symmetry" C8 column 3.5urn; 4.6 x 50mm column gradient 0.1% ammonium acetate/acetonitrile 95% to 50% in 3 min; flow 2mL/min). MS258[M-HrCBS-). 'H NMR 8(GDd3) 3.41 (2H, q), 3.58 (2H, s), 5.19 (2H, s), 730 - 7.42 (5H, m). Step 3: Benzyl 2-0xcMH2A2-trifluoroethyI23 Prepared according to J.Het.Chem. 22, 1985, 1621-30 using benzyl (2£3-amino- 55-trifluoropent-2-enoate. Obtained as a pale yellow solid (0.61 g). Retention tune: 3.10 mm (reverse phase analytical HPLC (Hewlett Packard Series 1100): Waters "Symmetry" C8 column 3.5um; 4.6 x 50mm column gradient 0.1% ammonium acetate/acetonitrile 75% to 5% in 3 min; flow 2mL/min). MS 318 (ES-Hre) [M+Hf H NMR 8(CDC13) 3.93 (2H, q), 5.28 (2H, s), 7.33 - 7.42 (5H, m), 9.47 (1H, s). Step 4: 2-Oxo2,2-trMuoroethyl)-2,3ihydro-13-thiazole-5-»rboxylic acid Benzyl 2-oxc-(2-trifluoroethyl)-2,3-dihydro-l-ttiia2»le-5-carboxylate (0.6 g) in ethanol was treated with 5% palladium on carbon and hydrogenated at 3 bar for 8 days. After filtration, the solvent was evaporated to yield the title compound as a colourless Retention time: 0.37 min (reverse phase analytical HPLC (Hewlett Packard Series 1 100):Waters "Symmetry" C8 column 3.5um; 4.6 x 50mm column gradient 0.1% ammonium acetate/acetonitrile 95% to 50% in 3 min; flow 2mL/min). MS (ES-ve) 226 [M-H]' : N- {(2JK)3-[4-(3,4-Dichloropbenoxy)piperidin-l -yl]-2-hydroxypropyl}-2-oxo-4- (2,2,2-trifluoroethyl)-23~dihydro-13-1hiazole-5-carboxainide Prepared as Example 4. Obtained as a white solid (0.12g). The title compound has a pKa 6.6 (measured using Method B). MS (APd+ve) 528/530 [M+Hf 'HNMR&XDMSO-dfi) 1.56 -1.68 (2H, m), 1.86 - 1.96 (2H, m), 2.23 - 2.39 (4H, m), 2.65 - 2.79 (2H, m), 3.09 - 3.27 (2H, m), 3.73 (1H, quintet), 3.97 (2H, q), 4.44 (1H, septet), 4.75 (1H, s), 6.98 (1H, dd), 726 (1H, d), 7.49 (1H, d), 7.81 (1H, t). Example 34 N- {(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1 -yl]-2-hydroxypropyl} -2-oxo~4- pyridin-2-yl-23-dmydro-13-flu82»le-5-carboxamide Steol: Ethyl (2J5-3-ammo-3-pyridin-2-yl acrylate Prepared as Example 33 Step 2 using ethyl 3-oxo-3-pyridin-2-yrpropenoate to yield die title compound as a brown oil (2.5 g). Retention time: 2.92 rain (reverse phase analytical HPLC (Hewlett Packard Series 1100): Waters "Symmetry" C8 column 3.5um; 4.6 x 50mm column gradient 0.1% ammonium acetate/acetonitrile 95% to 50% in 3 min; flow 2mL/min). 'H NMR 5(CDC13) 1.32 (3H, t), 4.21 (2H, q), 5.34 (1H, s), 7.34 (1H, ddd), 7.75 (2H, td), 8.63 (1H, dt). Step 2: Ethyl 2-oxo-4-pyridin-2-yl-2,3-dihydro-l,3-thiazole-5-carboxylate Prepared according to J.Het.Chem. 22,1985,1621-30. MS(ES-fve)251[M+Hf JHNMR 6(DMSO-d6) 1.08 (3H, t), 4.09 (2H, q), 7.51 (1H, ddd), 7.82 (1H, dt), 7.92 (1H, td), 8.67 (1H, dq), 12.32 (1H, s). Step 3:2-Oxo-4-pyridin-2-yl-2,3-dihydro-l,3-thia2X)le-5-carboxyHc acid Prepared as for Example 4 to yield the title compound as a pale yellow solid. Retention time: 0.49 min (reverse phase analytical HPLC (Hewlett Packard Series 1100): Waters "Symmetry" C8 column 3.5um; 4.6 x 50mm column gradient 0.1% ammonium acetate/acetonitrile 95% to 50% in 3 min; flow 2mL/min). MS (ES+ve) 223 [M+Hf Stej:JV-{(2)-3-[43,4-IMchlorophenoxy)piperidm-l-yl]-2-hydroxypropyl}-2-ox pyridin-2-yl-2,3-dihydro-l ,3-thiazole-5-carboxamide Prepared as Example 15, Step 2 to yield the title compound as a white solid (0.032 g). The title compound has pKa 7.1 (calculated using ACD). MS (APCH-ve) 523/525(M+H)+ !H NMR 8(DMSO-ds) 1.52 -1.65 (2H, ni), 1.82 - 1.94 (2H, m), 2 JZO - 2.34 (4H, mX 2.61 - 2.73 (2H, mX 3.05 - 3.17 (IH, mX 3.42 (IH, dt), 3.72 (IH, quintetX 4.42 (IH, septet), 4.83 (IH, s), 6.97 (IH, dd), 725 (IH, d), 7.49 (IH, dX 7.56 (IH, dd), 7.85 (IH, d), 8.04 (IH, td), 8.71 (IH, dX 10.85 OH, s), 11.96 (IH, s). Example 35 4(2J9-34,4JicMonphen (pentafluoroethyl)-1,6-dihydropyridine-3-carboxamide Step 1: Ethyl 6-oxo-2-(pentafluoroethyl)-l,4,5,6-tetrahydropyridine-3-carboxylate A suspension of acrylamide (4.11 gX ethyl 494,5,5,5-pentafluoro-3-oxopentanoate (16.5 g) and-toluenesulphonic acid (0.120 g) in chlorobenzene (40 mL) was sonicated for 30 minutes then heated by microwave irradiation (150W, 120 °C) for 3 h. The reaction mixture was concentrated in vacua and subjected to flash column chromatography (eluent 1: 3 ethyl acetate/isohexane) to yield a colourless solid (0.697 g). MS(ES-ve)286[M-Hf 'H NMR 5(CDCb) 7.13 (s, 1H), 4.25 (q, J- 7.2 Hz, 2H), 2.79 - 2.73 (m, 2H), 2.62 - 2.57 (m, 2H), 1.30 (t, J= 7.1 Hz, 3H). Step 2: Ethyl 6-oxo-2-(pentafluoroethyl)-l,6-dihydropyridine-3-carboxylate A suspension of ethyl 6-oxo-2-(pentafluoroethyl)-l,4,5,6-tetrahydropyridine-3- carboxylate (0.690 g) and W-bromosuccinimide (0.427 g) in carbon tetrachloride (5 mL) was heated at 80 °C for 20 h. The reaction mixture -was concentrated in vacua and subjected to flash column chromatography (eluent 1 : 3 ethyl acetate/isohexane) to yield a colourless solid (0.30 g). MS (ES-ve) 284 [M-H]' 'HNMR 5(CDC13) 1.36 (3H, t), 4.37 (2H, q), 6.93 (1H, d), 7.90 (1H, d). : 6-)xo-2-||)entafhJoroethy acid ; A suspension of ethyl 6-oiXo-2-entafhioixethyO-l,6sJfliydropyridine-3- carboxylate (0300 g)in concentrated hydrochloric acid (10 mL) was heated at reflux for 20 h. The reaction mixture was cooled and a colourless solid filtered off (030 g). MS (ES-ve) 256 p-Hf 'H NMR 5(DMSOd6) 6.98 (1H, d), 8.04 (1H, d), 12.03 (1H, s). : AT- {(2/)-3-[43,4-Dichlor (pentafluoroethyl)-! ,6-dihydropyridine-3-carboxamide A stirred solution of 6-oxo-2entafluoroettiyl)-l,6-ihydropyridine-3-carboxylic acid (0.105 g) in thionyl chloride (5 mL) was heated at reflux for 3 h. Thionyl chloride was removed from the cooled solution in vacua. The residue was dissolved in THF (4 mL) and this solution was added drop wise at room temperature to a solution of (2/2)-l-amino-3-[4- (3,4-dichlorophenoxy)piperidin-l-yl]propan-2-ol (0.130 g) and triethylamine (0.4 mL) in DCM (5 mL) before stirring overnight The reaction mixture was concentrated in vacua and redissolved in 9 : 1 acetonitrile/water (4 mL) before subjecting to KPHPLC (gradient 0.1% ammonium acetate/acetonitrile 95% to 50%) to yield the title compound as a white solid (125mg). The title compound has pKa 6.3 (calculated using ACD). MS (ES+ve) 558/560 [M+Hf 'H NMR 8(CD3OD) 1.69 - 1.79 (2H, m), 1.90 - 1.99 (2H, m), 2.48 - 2.60 (4H, m), 2.81 -.91 (2H, m), 3.26 (IH, dd), 335 (IH, dd), 3.87 - 3.93 (IH, m), 4.34 - 4.39 (IH, m), 6.77 (IH, d), 6.81 (IH, dd), 7.02 (IH, d), 7.29 (IH, d), 7.64 (IH, d). Example 36 N- {(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-l -yl]-2-hydroxypropyl}-5- (methylthio)-l//-l,3-triazole-4-carboxamide To a stirred suspension of 5-(memylthio)-Lff-l-triazole-4-carboxylic acid [J. Chem. Soc. Perfdn. Trans. 11982,627] (0.085 g) in DCM (2 mL) was added oxalyl chloride (0.09 mL) men DMF (1 drop). The.reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated m vocuo and the residue was dissoh/edmTHF(2niL)aixtthissolim'onwasadde solution of (2/0-l-aniino-3-[4-(3,4-dicMoropheimy (0.169 g) and triethylamine (02 mL) in DCM (5 mL). After being stirred for 1 h the reaction mixture was concentrated in vacuo and redissolved inmethanol (4 mL) before being subjected to RPHPLC (gradient 0.1% ammonium acetate/acetonitrile 95% to 50%) to yield a white solid (0.091 g). The title compound has a pKa 5.5 (measured using Method B). MS (ES-Hre) 460/462 [M+H]+ 'H NMR 5(CT)3OD) 1.76 - 1.88 (2H, m), 1.93 - 2.06 (2H, m), 2.45 (3H, s), 2.63 - 2.77 (4H, m), 2.92 - 3.04 (2H, m), 3.35 (2H, t), 3.91 - 3.99 (IH, m), 4.38 - 4.46 (IH, m), 6.82 (IH, dd), 7.05 (IH, d), 7.30 (IH, d). Example 37 7V-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2-oxo- (trifluoromethyl)-2,3-dihydro-l,3-oxazole-5-carboxamide litnyl zxo-4triflu0rome1iiyl)-23-dydro-l,3-oxa2»le-5-carboxylate (0.3 g) [EP 0 027 020 Al] was treated with a solution of lithium hydroxide dissolved in 3 : 1 THF/ water (6 mL), and heated at 50 °C for 1 h. The reaction mixture was partitioned between water (10 mL) and dthyl acetate (10 mL). The aqueous phase was acidified to pH 3 using dilute hydrochloric acid, followed by extraction with ethyl acetate (3 x 10 mL). The organics were combined and washed with water (2 x 10 mL) and brine (10 mL), then dried (Na2SO4), filtered, and concentrated in vacua to leave the acid as an off white solid (0.175 g). Purification was carried out on amine resin by flushing with methanol to remove impurities, followed by 5 % formic acid in methanol to isolate the product A stirred solution of 2-oxo-4-(trifluoromeTOyl)-2,3-dihydro-l,3-oxazole-5- carboxylic acid (0.032 g) hi thionyl chloride (4 mL) was heated at reflux for 2 h. Excess thionyl chloride was removed from the cooled solution in vacua. The residue was dissolved in THF (2 mL) and this solution was added dropwise at room temperature to a solution of (2/)-l-aniino-3-[4,4Hfichkrophenoxyipcridin-l-yl]rxopan-2-ol (0.051 g) and triethylamme (0.24 mL) in DCM (1 mL) before being stirred overnight The reaction mixture was concentrated in VOCMO, and me residue was redissolved in acetonitrile containing 2-3 drops each of water, methanol and acetic acid before it was subjected to RPHPLC Novapak (gradient 0.1 % ammonium acetate/acetonftrile 95 % to 50 %), followed by normal phase elution with 3/17 mixture of 7 N NEb in methanol/ dichloromethane. This yielded the desired product as a yellow solid (0.016 g). The title compound has pKa 5.8 (calculated using ACD). MS (ES-ve) 498/496 [M-H]' 1HNMR8(CD3OD) 1.77 (s, 1H), 2.07 (s, 1H), 2.94-2.91 (m, 1H), 3.02 - 2.98 (m, 1H), 3.18 - 3.06 (m, 3H), 3.42 - 3.36 (m, 3H), 3.74 - 3.69 (m, 1H), 4.62 (quintet, 1H), 5.25 (s, 1H), 5.43 (s, 1H), 5.53 (s, 1H), 5.70 (s, 1H), 6.95 (dd, 2.8 Hz, 1H), 7.18 (d, 1H), 7.40 (d, 1H). Example 38 N- {(2/)-3-[4-(3,4-Dichlorophenoxy)piperidin-l -yl]-2-hydroxypropyl} -5- (trifluoromethyl)-1 H-1,2,3-triazole-4-carboxamide. Stepl: 5rifhioromethyl)-l/-l,3-triazole-4-carboxylic acid. Ethyl 5-(trifluoromelhyll/f-l,3-triazole-4-carboxylate (0.312 g) was stirred in aqueous N sodium hydroxide (3.8 mL) and heated under reflux for 90 min. The cooled solution was acidified with aqueous hydrochloric acid and extracted with ethyl acetate. The extracts were washed with brine then dried and evaporated to leave a colourless solid (0.226 g). MS (ES-ve) 180 [M-H]' Step 2: AT-{(2£3-[43,4-IWcUorophenoxy)pipOT Prepared by the method of Example 8 to give fee title compound (0.113 g). The title compound has a pKa 4.0 (measured using Method B). MS (APa+ve) 482/484/486 [M+Hf !H NMR oXCPjOD) 2.04 (4H, m), 2.99 (1H, m), 3.13 (3H, m), 3.32 (2H, m), 339 (2H, m), 4.10 (1H, m), 4.58 (1H, m), 6.88 (1H, dd), 7.13 (1H, d), 734 (1H, d). Example 39 N- {(2/)-3-[43,4-IM(Morophenoxy)piperidin-l-yl]-2-hydioxypropyl} -5- [methymethylsulfonyarainoJ-lJ-l-triazole-carboxamide. Step 1: Ethyl 5-amino-l-(4-methoxybenzyl)-l/r-l,2,3-tria2ole-4-carboxylate Ethyl cyanoacetate (1.96 mL) was added to a solution of sodium ethoxide, prepared from sodium (0.423 g) and ethanol (45 mL), and the solution was stirred for 30 min. A. solution of 4-methoxybenzylazide (3.0 g) hi ethanol (5 mL) was added dropwise and the mixture was heated under reflux for 5 h. The cooled mixture was poured into water and acidified with dilute hydrochloric acid then extracted with ethyl acetate. The extracts were washed with water, brine and evaporated. Purification by flash chromatography (ethyl acetate/ dichloromethane 1:9 then 15:85) gave the product as a pale yellow solid (0.85 g). MS(APCI-ve)275[M-Hf Step 2: l-(4-Me&O3ben2yl)-5-[(mettylsulfonyl)amino]-l/f-l,23-triazole-4-carboxylic acid Ethyl 5-amino-l-(4-meflioxyben2yl)-l/r-l,3-triazole-4-carboxykte (0.85 g) and methane sulphonyl chloride (0.72 mL) were stirred in pyridine (20 mL) for 4 d. Further methane sulphonyl chloride (0.72 mL) was added and stirring continued for 24 h. Further methane sulphonyl chloride (0.5 mL) was added and stirring continued for 24 h. The mixture was concentrated in vacua. The residue was suspended in dilute hydrochloric acid and extracted with ethyl acetate. The extracts were washed with dilute hydrochloric acid and water then evaporated. The residue was taken up in ethanol (70 mL) and 2 M sodium hydroxide solution (70 mL) and stared for 18h. The mixture was concentrated to about half volume and acidified with dilute hydrochloric acid. The mixture was extracted with ethyl acetate and the extracts were washed with water and brine, men dried and evaporated to leave a white solid (0.90 g). 'HNMR&XCDaOD) 3.15 (3H, s), 3.79 (3H, s), 5.63 (2H, s), 6.92 (2H, d), 7.32 (2H, d). Step 3: Methyl 14-memoxybenl)-5-[methyl(methylsulfonyl)arnino]-lf-l,2,3-triazole- 4-carboxylate l-(4-Memoxybenzyl)-5-[(memylsulfonyl)ammo]-l acid (0.9 g) and potassium carbonate (1.15 g) were stirred in dry DMF (10 mL). Methyl iodide (0.83 mL) was added and the mixture was stirred for 5 h. The mixture was poured onto water and extracted with ethyl acetate. The extracts were washed with dilute hydrochloric acid, water and brine then dried and evaporated. Purification by flash chromatography (ethyl acetate/ DCM 1:9) afforded the sub-titled compound as a brown solid (0.54 g). MS (APCI+ve) 355 [M+H]+ Step 4: Methyl 5-[methyl(methylsulfonyl)amino]-l//'-l,2,3-triazole-4-carboxylate Methyl H4-memoxybenzyl)-5-[memyl(methylsu 4-carboxylate (0.54 g) was stirred in trifluoroacetic acid (5 mL) at 60 °C for 6 h. The mixture was evaporated and the residue was co-evaporated with toluene. Purification by flash chromatoraphy (1 :49 methanol/ DCM) gave the subtitle compound as a gum (036 g). MS (APOH-ve) 235 [M+Hf Step 5: 5-[Methyl(methylsulfonyl)amino]-lF-13-triazole-4-carboxylic acid Methyl 5-[raethyl(methylsulfonyl)amino]-l/f-l,3-triazole-4-carboxylate (036 g) was stirred in THF (5 mL) with 2 N aqueous sodium hydroxide solution (1.7 mL) for 18 h. The mixture was concentrated in vacua. To the aqueous residue was added dilute acetic acid and this was extracted with ethyl acetate (2x15 mL). The extracts were washed with water and brine then dried and evaporated to leave the subtitle compound (0.07 g). MS (APd-ve)219 [M-Hf Step 6: -{(2tf!H4,4cMorophenoxy)piperidu [nyl(trethylsutfonyl)einir»]-l Prepared using 5-[methyl(methylsulfbny])am acid (0.07 g) by the method of Example 8 to give the title compound (05 g). The title compound has pKa 4.2 (calculated using ACD). MS (APCI-ve) 519 [M-Hf 'H NMR SXCDaOD) 1.95-2.06 (2H, m), 2.08-2.22 (2H, m), 2.94 (1H, m), 3.01 (1H, m), 3.06 (3H, s), 3.07-3.15 (1H, m), 3.18-3.29 (3H, m), 333 (3H, s), 3.49 (2H, d), 4.12 (1H, m), 4.60 (1H, m), 6.94 (1H, dd), 7.18 (1H, d), 7.41 (1H, d). Example 40 A-{(2R)-3-[4-(3-Chloro-4-cyano-2-methylphenoxy)piperidin-l-yl]-2- hydroxypropyl}-2-oxo-4-(Mfliu)romemyl)-23-dihydro-13-thiazole-5-carboxamide. Step 1: 2-Chloro-4-hydroxy-3-methylben2»nitrile A stirred solution of 4-bromo-3-chloro-2-methylphenol (0.427 g), zinc cyanide (0.271 g), andtetrakis[triphenylphosphine] palladium (0.056 g) in//-methyl-2- pyrrolidinone (5 mL) was heated under microwave irradiation (150 W) at 130 °C for 35 min. The reaction mixture was filtered through anhydrous magnesium sulfate, partitioned between 1:2 ethyl acetate/ diethyl ether (15 mL) and water (15 mL). The aqueous phase was re-extracted with 1:2 ethyl acetate/ diethyl ether (2 x 15 mL). The organics were combined, washed with water (2 x 20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacua. The compound was purified by column chromatography using 1: 9 ethyl acetate/ iso-hexane as eluent, to give the desired product as a peach coloured solid (174 mg, 54 %). Retention time: 1.60 min (reverse phase analytical HPLC (Hewlett Packard Series 1100): Waters "Symmetry" C8 column 3.Sum; 4.6 x 50mm column gradient 0.1% ammonium acetate/acetonitrile 75% to 5% in 3 min; flow 2mL/min). MS (ES-ve) 166/168 [M-Hf 'HNMR.S (CDjOD) 2.27 (s, 3H), 6.82 (d,/= 8.5 Hz, 1H), 7.44 (d, J- 8.8 Hz, 1H). Step 2: ferf-Butyl 43-chloro-4-yaiK-2-niemylpheiKx Prepared according to method in patent WO 0220484 Al. Retention time: 2.83 min (reverse phase analytical HPLC (Hewlett Packard Series 1100): Waters "Symmetry" C8 column 3.5um; 4.6 x 50mm column gradient 0.1% ammonium acetate/acetonitrile 75% to 5% in 3 min; flow 2mL/min). 'HNMR 5(CDC13) 1.48 (s, 9H), 1.86 - 1.75 (m, 2H), 1.99 - 1.89 (m, 2H), 2.32 (s, 3H), 3.51 - 3.42 (m, 2H), 3.65 - 3.57 (m, 2H), 4.64 - 4.57 (m, 1H), 6.80 (d, J= 8.7 Hz, 1H) ,7.49 (d, .7=8.7 Hz, 1H) Step 3: 2-Chloro-3-methyl-4-(piperidin-4-yloxy)benzonitrile Prepared according to Preparation 1, Step 2. Retention time: 1.17 min (reverse phase analytical HPLC (Hewlett Packard Series 1100): Waters "Symmetry" C8 column 3.5um; 4.6 x 50mm column gradient 0.1% ammonium acetate/acetonitrile 75% to 5% in 3 min; flow 2mL/mm). MS(ES+ve)251/253 [M+Hf 'HNMR SCCDQs) 1.80 - 1.70 (m, 2H), 2.06 - 1.96 (m, 2H), 2.32 (s, 3H), 2.83 - 2.75 (m, 2H), 3.18 - 3.09 (m, 2H), 4.54 - 4.47 (m, IH), 6.79 (d, ./= 8.9 Hz, IH), 7.47 (d, J = 8.7Hz,lH). Step 4: 4-({ 1 -[(2/)-3-Amino-2-hydroxypropyl]piperidin-4-yl} oxy)-2-chloro-3- methylbenzonitrile Prepared according to Preparation 1, Step 3. Retention time: 1.20 min (reverse phase analytical HPLC (Hewlett Packard Series 1 100): Waters "Symmetry" C8 column 3.5um; 4.6 x 50mm column gradient 0.1% ammonium acetate/acetonitrile 75% to 5% in 3 min; flow 2mL/min). MS (ES+ve) 324/326 fM+Hf 'HNMR 5(CDC13) 1.29 - 1.22 (m, 2H), 1.94 - 1.81 (m, 2H), 2.08 - 1.95 (m, 2H), 2.31 (s,.3H), 2.31 (s, 3H) 2.46 - 2.33 (m, 3H), 2.67 - 2.59 (m, 3H), 2.90 - 2.80 (m, 2H), 3.73 - 3.66 (m, IH), 4.51 - 4.44 (m, IH), 6.79 (d, J= 8.8 Hz, IH), 7.47 (d, J= 8.7 Hz, IH). Step 5: A{(2/)-3-[43-Chloro-4K(2-methylpbenoxy)piperidiil Prepared according to method for Example 4. Retention time: 1.18 min (reverse phase analytical HPLC (Hewlett Packard Series 1 100): Waters "Symmetry" C8 column 3.5m; 4.6 x 50mm column gradient 0.1% ammonium acetate/acetonitrile 75% to 5% in 3 min; flow 2mL/min). The title compound has a pKa of 4.7 (measured using Method B).and pKa 6.1 (calculated using ACD). MS (ES+ve) 519/521 [M+HT, (ES-ve) 517/519 [M-H]' 1E NMR 5 (DMSO-de) 1.81 - 1.91 (m, 2H), 2.02 - 2.10 (m, 2H), 2.33 (s, 3H), 2.54 - 2.70 (m, 4H), 2.88 - 2.95 (m, 2H), 3.24 - 3.31 (m, IH), 3.34 - 3.41 (m, IH), 3.87 (quintet, IH), 4.63 - 4.69 (m, IH), 7.17 (d, IH), 7.54 - 7.64 (m, IH), 7.68 (d, IH). Example 41 A{(2R)-3-[4-(3-Chloro-4-cyanophenoxy)piperidin-l-yl]-2-hydroxypropyl}-5- (trifluororaethyl)-l/f-l,2,3-triazole-4-carboxamide Prepared by the method of Example 31 to give the title compound (0.64 g). The title compound has pKa 2.1 (calculated using ACD). MS (APCI+ve) 473/475 [M+H]+ 'HNMR &XCD3OD) 2.39-2.67 (4H, m), 3.44 (1H, m), 3.55-3.90 (6H, m), 3.84 (1H, m), 7.45 (1H, dd), 7.65 (1H, d), 8.08 (1H, d). Example 42 2-Cloro-5-[({(2R)-3--[4-(3,4-dichloro-2-niethylphenoxy)piperidui-l-yl]-2- hydroxypropyl}amino)carbonyl]benzoic acid ov OH Stepl: 3-tert-Butyl 1 -methyl 4-chloroisophthalatc fert-Butyl 5-bromo-2-chlorobenzoate (1.9 g) (WO2003095430) was dissolved in raethanol (1 8ml) with //,-diisopropylethylamine (2 mL) and dichlorobis(triphenylphosphine)-palladium(II) (0.134 g). The mixture was carbonylated at 85 °C for 12 h. The cooled solution was evaporated and purified by flash chromatography, eluting with 5:95 ethyl acetate/isohexane, to yield the subtitle compound as a colourless oil (0.67 g). JH NMR 6(CDC13) 1.62 (9H, s), 3.94 (3H, s), 7.49 (1H, dd), 8.02 (1H, dd), 8.35 Step 2: 3-(ter/-Butoxycarbonyl)-4-chlorobenzoic acid 3-terf-Butyl 1 -methyl 4-chloroisophthalate (0.37 g) in THF (5 mL) was treated with lithium hydroxide (0.17 g) in water (5 mL) and the mixture was stirred for 18 h. The solvent was evaporated. Water and ethyl acetate were added. The aqueous extract was separated and acidified with dilute hydrochloric acid. The product was extracted into ethyl acetate. The solution was dried over sodium sulphate, filtered and the solvent was evaporated to yield the subtitle compound as a white solid (0.32 g). Retention time: 1.98 mm (reverse phase analytical HPLC (Hewlett Packard Series 1100): Waters "Symmetry" C8 column 3.Sum; 4.6 x 50mm column gradient 0.1% ammonium acetate/acetonitrile 95% to 50% in 3 min; flow 2mL/min). MS (ES-ve) 255 [M-H]' !H NMR oXDMSO-d) 1.56 (9H, s), 7.69 (IH, d), 8.03 (IH, dd), 8.18 (IH, d). Step 3: terf-Butyl 2-chloro-5-[({(2/3-[4K3,4-d1chloro-2-memylphenoxy)piperidm-l-yl]- 2-hydroxypropyl} amino)carbonyl]benzoate Prepared as for Example 15, Step 2 and the sub-titled compound was obtained as a colourless oil (0.14 g). Retention time: 2.93 min (reverse phase analytical HPLC (Hewlett Packard Series 1100): Waters "Symmetry" C8 column 3.5um; 4.6 x 50mm column gradient 0.1% ammonium acetate/acetonitrile 75% to 5% in 3 min; flow 2mL/nrin). MS (ES4ve) 571 [M+Hf Step 4:2-(oro-54(ir2V3-f443.4chloffC)-2-mcthvlphenoxvViperidin-l-vl]-2- hydroxypropyl}amino)carbonyl]benzoic acid fcrButy!2Moro-5-[({(2J3-[4,4ic 2-hydroxypropyl}ammo)carbonyl]benzoate (0.14 g) in DCM (5 mL) was treated with trifluoroacetic acid (1.5 mL) and the mixture was stirred for 1.5 h. The solvent was evaporated. The product was purified by RPHPLC (Symmetry, 0.1% ammonium acetate/acetonitrile) to yield the title compound as a white solid.(0.05g). The title compound has a measured pKa 2.3, and a calculated pKa 2.6 (calculated using ACD). MS (APCI-ve) 513/517[M-Hp 'H NMR 5(CD3OD -J-NaOD) 1.79 - 1.91 (2H, m), 1.98 - 2.09 (2H, m), 2.34 (3H, s), 2.47 - 2.58 (2H, m), 2.52 (2H, d), 2.75 - 2.87 (2H, m), 3.43 (IH, dd), 3.53 (IH, dd), 4.02 (IH, quintet), 4.44 - 4.53 (IH, m), 6.95 (IH, d), 7.31 (IH, d), 7.49 (IH, d), 7.77 (IH, dd), 7.96 (IH, d). Example 43 4loro-3-[({(2IO-3-[43,4chlaro-2-methylphenoxy)piperidin-l-yl3-2- hydroxypropyl}amino)caibQQyl]benzoic acid Stepl: Methyl 4-chloro-3-[({(2JR)-3-[4-(3,4-dichloro-2-meihylphenoxy)piperidin-l -yl]-2- hydroxypropyl} amino)carbonyl]benzoate Prepared as for Example 15, Step 2 using 2-chloro-5-(methoxycarbonyl)benzoic acid(FR2842805) and (2)-l-amino-3-[4-(3,4-dicbloro-2-methyIphenoxy)piperidin-lyl] propan-2-ol and was obtained as a colourless oil (0.1 g). Retention time: 2.42 min (reverse phase analytical HPLC (Hewlett Packard Series 1 100): Waters "Symmetry" C8 column 3.5um; 4.6 x 50mm column gradient 0.1% ammonium acetate/acetonitrile 75% to 5% in 3 min; flow 2mL/min). : , MS (ES-ve) 529/531 Step 2: 4-Chloro-3-r(l(2JV34443.4KiiAloro-2-methvtoheiK)Xvipcridin-l--vll-2- hydroxypropyl}amino)carbonyl]benzoic acid Prepared as for Example 23, Step 3 and obtained as white solid (0.022 g). The title compound has pKa 3.7 (calculated using ACD). MS (APd-ve) 513/517[M-H]- 'H NMR 5(CD3OD) 1.78 - 1.89 (2H, m), 1.97 - 2.08 (2H, m), 2.34 (3H, s), 2.47 2.62 (4H, m), 2.79 - 2.90 (2H, m), 3.49 (2H, ddd), 4.03 (IH, quintet), 4.46 (IH, septet), 6.95 (IH, d), 7.30 (IH, d), 7.48 (IH, d), 8.00 (IH, dd), 8.06 (IH, d). Example 44 4-Chloro-3-[2-({(2R)-3-[4-(3,4-dichloro-2-methylphenoxy)piperidin-l-yl]-2- hydroxypropyl} amino)-2-oxoethoxy3benzoic acid OOH o Step 1: Methyl 3-(2-terbutoxy-2-oxoethoxy)-4-chlorobenzoate Methyl 4-diloro-3-hydroxybemzoate [Chem. Pharm. Bull 1994,42(1 1)2365-9] (0.73 g), caesium carbonate (1.27 g) and tert butylbromoacetate (0.58 mL) in DMF (6 mL) were heated and stirred at 60 °C for 3 h. Water was added and the product was extracted into ethyl acetate. The extracts were dried over sodium sulphate, filtered and the solvent was evaporated. The resulting oil was purified by flash chromatography, using 1:10 ethyl acetate/isohexane as ehient, to yield the subtitle compound as a colourless oil (1.25 g). 'HNMR 5(CDC13) 1.49 (9H, s), 3.91 (3H, s), 4.66 (2H, s), 7.45 (1H, d), 7.48 (1H, d), 7.62 (1H, dd). Step 2: [2-Chloro-5-(meuioxycarbonyl)phenoxy]acetic acid Prepared as Example 42 Step 4 to yield the subtitle compound as an off white solid (0.18 g). :'H NMR 5(DMSOd«) 3.86 (3H, s), 4.93 (2H, s), 7.48 (1H, d), 7.56 (1H, dd) 7.62 ' (1H, d), 13.21 (1H, s). MS(E5-ve)243[M-Hr Step3: Methyl 4KMcro-H2-(C23-[4K3,4HlicUo 2-hydroxyprcpyl}amino)-2-oxoemoxy]benzoate Prepared as for Example 15 Step 2 using [2-Chloro-5-(methoxycarbonyl phenoxy]acetic acid and (2J)-l-amino-3-[4-(3,4-dichloro-2-methylphenoxy)piperidui-lylJpropan- 2-ol to yield the subtitle compound as a colourless oil (0.084 g). MS (ES-fve) 561/3 [M+HT Retention time: 2.58 mm (reverse phase analytical HPLC (Hewlett Packard Series 1 100): Waters "Symmetry" C8 column 3.5um; 4.6 x 50mm column gradient 0.1% ammonium acetate/acetonitrile 75% to 5% in 3 min; flow 2mL/min). Step4:4-Chloro-3-r2-(((2)-3-r4-(3.4cloro-2-niethvbhenoxv)piperidin-l-vl]-2- hy droxypropyl} amino)-2-oxoethoxy]benzoic acid Prepared as for Example 23, Step 3. The title compound was obtained as a white solid (0.02 g). The title compound has pKa 3.8 (calculated using ACD). MS (APCI-ve) 545/547[M-H]' 'H NMR 8(CD3OD) 1.98 - 2.13 (2H, m), 2.16 - 2.31 (2H, m), 2.34 (3H, s), 2.94 - 3.11 (2H, m), 3.15 - 3.26 (2H, m), 3.34 (2H, s), 3.40 (2H, d), 4.10 - 4.17 (1H, m), 4.64 - 4.70 (1H, m), 4.71 (2H, d), 6.99 (1H, d), 7.32 (1H, d), 7.41 (1H, d), 7.58 (1H, dd), 7.59 (1H, s). Example 45 (2-Chloro-5-[({(2/3-[4-(3,4-dichloro-2-mefliylphenoxy)piperidin-l-yl]-2- hydroxypropyl}amiao)carbonyl]phenoxy}aceticacid o Step 1: 3-(2-tert-Butoxy-2-oxoethoxy)-4-chlorobenzoic acid Methyl 32-/ert-butoxy-2xoethoxy)-4-chlorobenzoate (0.7g) in 9:1 tert butanolrwater was subjected to Antarctica B lipase for 6 d. Filtration and evaporation of die solvent yielded the subtitle compound as an off-white solid (0.6 g). MS(ES-ve)285[M-HT 'H NMR oXDMSOdj) 1.42 (9H, sX 4.8« (2H, sX 7.45 (1H, d), 7 J4 (1H, ddX 7.58 Step 2: fert-Butyl {2hloro-5-[({(2J3-[43,4-chloro-2-niethylphenoxy)piperidin-lyl]- 2-hydroxypropyl}amino)carbonyl]phenoxy}acetate Prepared as for Example 15, Step 2 using 3-(2-terf-butoxy-2-oxoethoxy)~4- chlorobenzoic acid and (2/)-l-amino-3-[4-(3,4-dichloro-2-methylphenoxy)piperidin-lyl] propan-2-ol to yield the subtitle compound as a colourless oil (0.14 g). MS (ES+ve) 603/5 [M+H]+ Retention time: 2.98 min (reverse phase analytical HPLC (Hewlett Packard Series 1100): Waters "Symmetry" C8 column 3.5um; 4.6 x 50mm column gradient 0.1% ammonium acetate/acetonitrile 75% to 5% in 3 min; flow 2mL/min). Step 3: {2-Chloro-5-[({(2/)-3-[4-(3,4-dichloro-2-methylphenoxy)piperidin-l-yl]-2- hydroxypropyl} amino)carbonyl]phenoxy} acetic acid Prepared as Example 42 Step 4 to yield the title compound as a white solid (0.085 g). The title compound has pKa 3.0 (calculated using ACD). MS (APCI-ve) 543/547[M-H]" !HNMR SXCDsODH-NaOD) 1.74 -1.86 (2H, m), 1.95 - 2.05 (2H, m), 2.31 (3H, s), 2.41 - 2.52 (4H, m), 2.74 - 2.84 (2H, m), 3.32 - 3.38 (1H, m), 3.50 (1H, dd), 3.98 (1H, quintet), 4.42 (1H, septet), 4.54 (2H, s), 6.91 (1H, d), 7.27 (1H, d), 7.37 (1H, dd), 7.38 (1H, s),7.44(lH,d). Example 46 3-[2-({(2/)-3-[4-(3,4-Dichloro-2-me1hylphenoxy)piperidin-l-yl]-2- hydimypropyi}amino)-2Hxoe1hoxy]benzoic acid Stepl: Methyl 3-[2{(23-[43,4chlcwo-2-me%lpbenoxy)piPeridin-l-yl]-2- Prepared as for Example 15, Step 2 using [3-(methoxycaibonyl)phenoxy]acetic acid [Asian Journal of Chemistry 1992,4(4)20-3] and (2l-amiiK)-3-[4-(3)4-dichloro-2- metiiylphenoxy)piperidin-l-yripropan-2-ol to yield the subtitle compound as a pale yellow oil (0.1 Ig). MS (ES+ve) 525/527 [M+HJ Retention time: 2.35 rain (reverse phase analytical HPLC (Hewlett Packard Series 1 100): Waters "Symmetry" C8 column 3.5pm; 4.6 x 50mm column gradient 0.1% ammonium acetate/acetonitrile 75% to 5% in 3 min; flow 2mL/min). Step2:3-r2-(((2JV3-r4-f3.4-Dichloro-2-methvlphenoxv)piperidin-l-vn-2- hydroxypropyl} amino)-2-oxoethoxy]benzoic acid Prepared as for Example 23, Step 3. The title compound was obtained as a white solid (0.049 g). The title compound has a measured pKa 2.6 and a calculated pKa 4.0 (calculated using ACD). MS (APCI-ve) 509/511[M-H]' 'HNMR5(CD30D + NaOD) 1.73 - 1.85 (2H, m), 1.94 - 2.03 (2H, m), 230 (3H, s), 2.33 - 2.47 (4H, m), 2.68 - 2.78 (2H, m), 3.32 - 3.44 (2H, m), 3.90 (IH, quintet), 4.37 4.46 (IH, m), 451 (2H, s), 6.92 (IH, d), 7.04 - 7.08 (IH, m), 724 - 734 (2H, m), 756 - 7.61 (2H, m). Example 47 (3-[({(2/)-3-[4-(3,4-Dichloro-2-ine%lphenoxy)piperidin-l-yl]-2- hydroxypropyl} amino)carbonyl]phenoxy} acetic acid COOH Step 1: ter/-Butyl {3-[({(2/3-[4-(3,4-dichloro-2-methylphenoxy)piperidin-l-yl]-2- hydroxypropyl}amirM)»rbonyl]phenoxy}acetate :: . Prepared as for Example 15 Step 2 using 3-(2-/«t-butoxy-2-oxoemoxy)benzoic acid [WO 00/78317 Al] and (2R)-l-amino-343,4ichIoit)-2-melhyhphenoxy)piPeridiQ- 1 -yl]propan-2-ol to yield me subtitle compound as a white solid (0.11 g). MS (ES+ve) 567/569 [M+Hf Retention time: 2.65 mm (reverse phase analytical HPLC (Hewlett Packard Series 1100): Waters "Symmetry" C8 column 3.5jim; 4.6 x 50mm column gradient 0.1% ammonium acetate/acetonitrile 75% to 5% in 3 min; flow 2mL/min). Step 2: {3-[({(2/3-[4-(3,4-Dichloro-2-methylphenoxy)piperidm-l-yl]-2- hydroxypropyl}amino)carbonyl]phenoxy}aceticacid Prepared as Example 42, Step 4 to yield the title compound as a white solid (0.063 The title compound has pKa 3.1 (calculated using ACD). MS (APCI+ve) 511/513 [M+Hf 'H NMR 5(CD3OD + NaOD) 1.75 -1.87 (2H, m), 1.96 - 2.05 (2H, m), 2.31 (3H, s), 2.42 -2.54 (4H,m), 2.75 - 2.85 (2H,m), 3.37 (IH, dd), 3.50 (IH, dd), 3.99 (IH, quintet), 4.47 (3H, s), 6.91 (IH, d), 7.08 - 7.12 (IH, m), 7.27 (IH, dd), 7.32 - 7.40 (3H, m). Example 48 Pharmacological Analysis: Calcium flux [Ca 2+]\ assay runnan eosinopnus Human eosmophils were isolated from EDTA anticoagulated peripheral blood as previously described (Hansel et al., /. Immwol. Methods, 1991,145.105-110). The cells were resuspended (5x106 ml'1) and loaded with SiM FLUO-3/AM + Pluronic F127 2.21/ml (Molecular Probes) in low potassium solution (LKS; NaCl 118mM, MgSO4 O.SmM, glucose 5.5mM, Na2CO3 8.5mM, KC15mM, HEPES 20mM, CaCl2 L8mM, BSA 0.1%, pH 7.4) for one hour at room temperature. After loading, cells were centrifuged at 200g for 5mm and resuspended in LKS at 2.5xl06 ml"1. The cells were then transferred to 96 well FLIPr plates (Poly-D-Lysine plates from Becton Dickinson pre-incubated with 5iM fibronectin for two h) at 25nl/well. The plate was centrifuged at 200g for 5min and the cells were washed twice with LKS (200ul; room temperature). A compound of the Examples was pre-dissolved in DMSO and added to a final concentration of 0.1%(v/v) DMSO. Assays were initiated by the addition of an AM . n- concentration of eotaxin and the transient increase in fluo-3 fluorescence (1& = 490nm and l&a=520nm) monitored using a FUPR (Fhtorometric Imaging Plate Reader, Molecular Devices, Sunnyvale, U.S.A.). Compounds of the Examples were found to be antagonists if the increase in fluorescence induced by eotaxin (a selective CCR3 agonist) was inhibited in a concentration dependent manner. The concentration of antagonist required to inhibit the fluorescence by 50% can be used to determine the ICso for the antagonist at the CCR3 receptor. Example 49 Human eosinophil chemotaxis Human eosinophils were isolated from EDTA anticoagulated peripheral blood as previously described (Hansel et al., /. Immunol Methods, 1991,145,105-110). The cells were resuspended at 10x106 ml"1 in RPMI containing 200 lU/ml penicillin, 200 |xg/ml streptomycin sulfate and supplemented with 10% HEFCS, at room temperature. Eosinophils (700 \A) were pre-incubated for 15 mins at 37° C with 7 |il of either vehicle or compound (lOOx required final concentration in 10% DMSO). The chemotaxis plate (ChemoTx, 3\xm pore, Neuroprobe) was loaded by adding 28 ul of a concentration of eotaxin 0.1 to lOOnM (a selective CCR3 agonist over this concentration range) containing a concentration of a compound according to the Examples or solvent to the lower wells of the chemotaxis plate. The filter was then placed over the wells and 25 1 of eosinophil suspension were added to the top of the filter. The plate was incubated for 1 hr at 37° C in a humidified incubator with a 95% air/5% COa atmosphere to allow chemotaxis. The medium, containing cells that had not migrated, was carefully aspirated from above the filter and discarded. The filter was washed once with phosphate buffered saline (PBS) containing 5 mM EDTA to remove any adherent cells. Cells that had migrated through the filter were pelleted by centrifugation (SOOxg for 5 mins at room temperature) and the filter removed and the supernatant transferred to each well of a 96-well plate (Costar). The pelleted cells were lysedby the addition of 28 nl of PBS containing 0.5% Triton xlOO followed by two cycles of freeze/thawing. The cell lysate was then added to the supernatant. The number of eosinophils migrating was quantified according to the method of Strath et al., J. ImmunoL Methods, 1985, 83,209 by measuring eosinophil perpxidase activity in the supernatant , Compounds of the Examples were found to be antagonists of eotaxin mediated human eosinophil chemotaxis if the concentration response to eotaxin was shifted tome right of the control curve. Measuring the concentration of eotaxin required to give 50% chemotaxis in the presence or absence of compounds enables the apparent affinity of the compounds at CCR3 to be calculated, or the assay can be used to determine activity of compounds at a set concentration of compound against a predifmed concentration of eotaxin. Example 50 Guinea-pig isolated trachea (See for example, Harrison, R.W.S., Carswell, H. & Young, J.M. (1984) European J. Pharmacol., 106,405-409.) Male albino Dunkm-Hartley guinea-pigs (250g) were killed by cervical dislocation and the whole trachea removed. After clearing the adherent connective tissue, the trachea was cut into six ring segments each three cartilage bands wide and then suspended in 20ml organ baths containing Krebs-Henseleit solution of the following composition (mM): NaCl 117.6, NaH2P04 0.9, NaHCO3 25.0, MgS04 1.2, KC1 5.4, CaCl2 2.6 and glucose 11.1. The buffer was maintained at 37°C and gassed with 5% COa in oxygen. Indomethacin (2.8|iM) was added to the Krebs solution to prevent development of smooth muscle tone due to the synthesis of cyclo-oxygenase products. The tracheal rings were suspended between two parallel tungsten wire hooks, one attached to an Ormed beam isometric force transducer and the other to a stationary support in the organ bath. Changes in isometric force were recorded on 2-channel Sekonic fiat bed chart recorders. Experimental protocols At the beginning of each experiment a force of Ig was applied to the tissues and this was reinstated over a 60 minute equilibration period until a steady resting tone was achieved. Subsequently, a cumulative histamine concentration effect (E/[A]) curve was constructed at 0.5 logio unit increments, in each tissue. The tissues were men washed and approximately 30 minutes later, test compound or vehicle (20% DMSO) was added. Following an incubation period of 60 minutes a second E/[A] curve was performed to histamine. Contraction responses were recorded as a percentage of the first curve maximum. Data analysis Experimental E/[A] curve data were analysed for the purposes of estimating the potencies (piAso] values) of histamine in the absence and presence of the test compound. Affinity (pAa) values of test compounds were subsequently calculated using the following equation: where r = [A]so in presence of test compound/[A]so hi absence of antagonist and [B] is the concentration of test compound. Compounds of the Examples were found to be HI antagonists. Example 51 Histamine HI receptor binding activity of compounds of the invention was assessed by competition displacement of InM [3H]-pyrilamine (Amersham, Bucks, .Product code TRKL 608, specific activity 30Ci/mmol) to 2jxg membranes prepared from recombinant CHO-K1 cells expressing the human HI receptor (Buroscreen SA, Brussels, Belgium, product code ES-390-M) in assay buffer (50mM Tris pH 7.4 containing 2mM MgCla, 250mM sucrose and lOOmM NaCl) for 1 hour at room temperature. The following compounds of the invention gave inhibition of [3H] pyrilimine We Claim: A N-(2-hydroxyprop-l-yl) piperidine derivative of formula (1): (Formula Removed) wherein: R' is phenyl optionally substituted by one or more halogen, cyano. C1-4 alkyl or C1-4 haloalkyl; R2 is hydrogen, C1-66 alkyl or C3.6 cycloalkyl; and, R2 is a group having an acidic NH or OH that is part of a ring or part of a substitucnt on a phenyl, napthyl or heterocyclyl ring such as herein described and has a calculated or measured pKa of 1.0 to 8.0; or a pharmaceutically acceptable salt thereof. 2. A compound of formula (I) as claimed in 1 wherein R' is a group having an Nil or 011 that have a calculated or measured pKa of 3 to 6.5. 3. A compound of formula (I) as claimed in claim 1 wherein R1 is phenyl substituted with one, two or three of: halogen, cyano or C1-4 alkyl. 4. A compound of formula (I) as claimed in claim 1 or claim 2 wherein R1 is phenyl substituted by one or more of chloro or methyl. 5. A compound of formula (I) as claimed in claim 3 wherein R1 is phenyl substituted by one or more fluoro. 6. A compound of formula (I) as claimed in claim 1 or claim 2 wherein R is 3.4-dichlorophenyl, 2-methyl-4-chlorophenyl, 3-methyl-2,4-dichlorophenyl, 2-methyl-3,4-dichlorophenyl or 2-methyl-3-chloro-4-cyanophenyl. 7. A compound of formula (1) as claimed in any one of the preceding claims wherein R2 is hydrogen. A compound of formula (I) as claimed in claim 1, wherein R has a heterocyclyl ring that is furyl, thienyl, pyrrolyl, 2,5-dihydropyrrolyl, thiazolyl, 2-oxo-2,3-dihydro-l.3-thiazolyl. isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl. triazolyl. pyridinyl or pyrimidinyl. A compound of formula (I) as claimed in any one of claims 1 to 8 wherein R' has an acidic NH that is part of a suitably substituted 2-oxo-thiazol-5-yl, 2-oxo-oxazol-5-yl. 2-oxo-imidazol-5-yl, lH-l,2,3-triazoI-4-yl, 4-oxo-lH-l,4-dihydropyridin-3-yl, 2,6-dioxo-lH-l,2,3,6-tetrahydropyrimidin-4-yl, 6-oxo-lH-l,6-dihydropyridin-3-yl or 2H-tctrazol-5-yl ring. A compound of formula (I) as claimed in claim 1, wherein the R3 has a heterocyclyl ring such as herein described that is substituted by fluoro, chloro, bromo. C1-4 alkyl. C3-4 cycloalkyl, C1-4 fluoroalkyl, S-R4 (wherein R4 is C1-64 alkyl, C1-4 fluoroalkyl or C3-6, cycloalkyl), cyano, S(O)2(C1-4 alkyl) or S(O)2NH(C1-4 alkyl). A compound of formula (I) as claimed in any one of claims 1 to 10 wherein R' is: 2-oxo-thiazol-5-yl having a C1-4 fluoroalkyl, a phenyl or napthyl group, a heterocyclyl group such as herein described or a group CH2S(O)2(C1-4 alkyl) in the 4-position; 2-oxo-oxazol-5-yl having a C1-4 fluoroalkyl or CH2S(O)2(C1-4 alkyl)} in the 4-position; lH-l,2,3-triazol-4-yl having a C1-4 alkyl, C1-6 cycloalkyl, C1-4 fluoroalkyl, S-R4 (wherein R4 is C1-4 alkyl, C1-4 fluoroalkyl or C3.6 cycloalkyl, NHS(O)2(C1-4 alkyl), N(C1-4 alkyl)S(O)2(C1-44 alkyl), a phenyl or napthyl group, a heterocyclyl group such as herein described or a group CH2S(O)2(C1-4 alkyl)in the 5-position; 4-oxo-lH-l,4-dihydropyridin-3-yl having a as C1-4 fluoroalkyl substituent in the 2- position; 2,6-dioxo-lH-l,2,3,6-tetrahydropyrimidin-4-yl having a C1-4 alkyl, C3-6 cycloalkyl or CH2(C1-33 fluoroalkyl) substituent in the 3-position; 6-oxo-lH-l,6-dihydropyridin-3-yl having a C1-4 fluoroalkyl, cyano or phenyl substituent in the 2-position and/or the 5-position; 6-oxo-lH-l,6-dihydropyridin-3-yl having CH2CO2H on the ring nitrogen and substituted in one or more other ring positions; 2H-tetrazol-5-yl; • a phenyl, CH2Ophenyl or naphthyl substituted by at least a CO2H. CIFCCMI or OCH2CO2H group; or, • an NHS(O)2( C1-64 alkyl) group on a substituted aromatic heterocyclyl ring such as herein described. 12. A compound of formula (I) as claimed in claim 11 wherein R3 is: • 2-oxo-thiazol-5-yl having a C1-64 fluoroalkyl, a phenyl or napthyl group, a heterocyclyl group such as herein described or a group CH2S(O)2(C1-4 alkyl) substituent in the 4-position; • lH-l,2,3-triazol-4-yl having a C1-44 alkyl, C3_6 cycloalkyl, C1-34 fluoroalkyl. S-R1 (wherein R4 is C1-4 alkyl, C1-4 fluoroalkyl or C3_6 cycloalkyl, NHS(O)2( C1-4 alkyl). N(C1-4 alkyl)S(O)2(C1-4 alkyl), a phenyl or napthyl group, a heterocyclyl group such as herein described or a group CH2S(O)2(C1-44 alkyl)substituent in the 5-position; or. • 6-oxo-lH-l,6-dihydropyridin-3-yl having C1-64 fluoroalkyl or cyano in the 2-position or the 5-position. 13. A compound of formula (I) as claimed in claim 12 wherein R' is: • 2-oxo-thiazol-5-yl having CF3 or C2F5 in the 4-position; • lH-l,2,3-triazol-4-yl having CF3. C2F5, SCF3, SCH2CF3 or SC2F5 (for example CI\ or SCH2CF3) in the 5-position; or, • 6-oxo-l H-l,6-dihydropyridin-3-yl having CF3 or C2F5 in the 2-position; or a pharmaceutical^ acceptable salt thereof. 14. A compound of formula (I) as claimed in claim 13 wherein R3 is 2-oxo-thia/.ol-5-\ I having CF3 or C2F5 in the 4-position; or a pharmaceutically acceptable salt thereof. 15. A compound of formula (1) as claimed in claim 1 which is: N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-6-oxo-2-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide; N-{(2R)-3-[4-(2,4-Dichloro-3-methylphenoxy)piperidin-l-yl]-2-hydroxypropyl}-6-oxo-2-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide; 5-Bromo-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-6-0X0-2-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide; N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2,3-dihydro-2- oxo-4-(trifluoromethyl)-5-thiazolecarboxamide; N- {(2S)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-N-mcthy 1-2-oxo- 4-(trinuoromethyl)-2,3-dihydro-1.3-thiazole-5-caiboxamide; N-{(2S')-3-f4-(2,4-Dichloro-3-methylphenoxy)piperidin-l-ylJ-2-hydroxypropyl}-N- methyl-2-oxo-4-(trifluoromethyl)-2,3-dihydro-l,3-thiazole-5-carboxamidc; N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2-0X0-4- (pentafluoroethyl)-2,3-dihydro-l,3-thiazole-5-carboxamide; N-{(2R)-3-[4-(3.4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-5-mcthyl-lH- 1,2,3-triazole-4-carboxamide; N-{(2R)-3-[4-(2,4-Dichloro-3-methylphenoxy)piperidin-l-yl|-2-hydroxypropyl}-5- methyl-]H-l,2.3-triazole-4-carboxamide; 5-Cyano-Af-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-6-0X0-2- (trifluoromethyl)-l,6-dihydropyridine-3-carboxamide; 5-Cyano-N-{(2R)-3-[4-(2,4-dichloro-3-methylphenoxy)piperidin-l-yl]-2- hydroxypropyl}-6-oxo-2-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamidc; 5-Cyano-Af-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-6-0X0-2- phenyl-l,6-dihydropyridine-3-carboxamide; 5-Cyano-N-{(2R)-3-[4-(2,4-dichloro-3-methylphenoxy)piperidin-l-yl]-2- hydroxypropyl}-6-oxo-2-phenyl-l,6-dihydropyridine-3-carboxamide; N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-3-methyl-2.6-dioxo- l,2,3,6-tetrahydropyrimidine-4-carboxamide; Af-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2.6-dioxo-3- (2?2,2-trifluoroethyl)-l,2,3,6-tetrahydropyrimidine-4-carboxamide; 5-Cyano-2-cyclopropyl-N-[(2R)-3-[4-(3,4-dichlorophenoxy)-1 -piperidinyl ]-2- hydroxypropy 1]-1,6-dihydro-6-oxo-3-pyridinecarboxamide; 5-Cyano-2-cyclopropyl-N-[(2R)-3-[4-(2,4-dichloro-3-methylphenoxy)-1 -piperidinyl ]-2- hydroxypropyl]-l,6-dihydro-6-oxo-3-pyridinecarboxamide; N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-6- [(methylsulfonyl)amino]-4-(trifluoromethyl)nicotinamide; N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-5-[(2,2,2- trifluoroethyl)thio]-lH-l,2,3-triazole-4-carboxamide; 4-[({(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}amino)- carbonyl]-1-naphthoic acid; N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2- [(methylsulfonyl)amino]-4-(trifluoromethyl)-l,3-thiazole-5-carboxamidc; N-{(2R)-3-[4-(4-Chloro-2-methylphenoxy)piperidin-l-yl]-2-liydroxypropyl}-2-oxo-4- (trifluoromethyl)-2,3-dihydro-l,3-thiazole-5-carboxamide; [5-[({(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2- hydroxypropyl}amino)carbonyl]-2-oxo-4-(trifluoroniethyl)pyridin-l(2H)-yl]acetic acid: N-{(2R)-3-[4-(3,4-Dichloro-2-metliylphenoxy)piperidin-l-yl]-2-liydroxypropyl}-2-oxo- 4-(trifluoromethyl)-2,3-dihydro-l,3-thiazole-5-carboxamide: N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-4-(4- fluorophenyl)-2-oxo-2,3-dihydro-1,3-thiazole-5-carboxamide; N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-5-(4- nuorophenyl)-lH-l,2,3-triazole-4-carboxamide; N-{(2R)-3-[4-(3-Chloro-4-cyanophenoxy)piperidin-l-yl]-2-hydroxypropyI}-2-oxo-4- (trifluoromethyl)-2,3-dihydro-1,3-thiazole-5-carboxamide; N-{(25)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2-0X0-4- (trifluoromethyl)-2,3-dihydro-l,3-thiazole-5-carboxamide; iV-{(25)-3-[4-(3-Chloro-4-cyanophenoxy)piperidin-l-yl]-2-hydroxypropyl}-N-methyl-2- oxo-4-(trifluoromethyl)-2,3-dihydro-l,3-thiazole-5-carboxamide; N-{(2JR)-3-[4-(2,4-Dichloro-3-methylphenoxy)piperidin-l-yl]-2-hydroxypropyl}-2-oxo- 4-(trifluoromethyI)-2,3-dihydro-l,3-thiazole-5-carboxamide; N-{(2R)-3-[4-(3-Chloro-4-cyanophenoxy)piperidin-l-yI]-2-hydroxypropyl}-5-isopropyl- lH-l,2,3-triazole-4-carboxamide; N-{(25)-3-[4-(3-Chloro-4-cyanophenoxy)piperidin-l-yl]-2-hydroxypropyl}-5-isoprop\l- N-methyl-1 H-1,2,3-triazole-4-carboxamide; N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2-oxo-4-(2.2.2- trifluoroethyl)-2.3-dihydro-1,3-thiazole-5-carboxamide; yV-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2-oxo-4-pyridin- 2-yl-2,3-dihydro-1,3-thiazole-5-carboxamide; N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-6-oxo-2- (pcntafluoroethyl)-1,6-dihydropyridine-3-carboxamide; N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-5-(methylthio)- lH-l,2,3-triazole-4-carboxamide; N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-l-yl]-2-hydroxypropyl}-2-oxo-4- (trifluoromethyl)-2,3-dihydro-l,3-oxazole-5-carboxamide; N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidiii-l-yl]-2-hydroxypropyl}-5- (trifluoromethyl)-lH-l,2,3-triazole-4-carboxamide; N-{(2R)-3-f4-(3,4-Dichlorophenoxy)piperidin-l-yl|-2-hydioxypropyl}-5-[mcthyl(methyl sulfonyl)amino]-lH-l,2,3-triazole-4-carboxamide; N-{(2R)-3-|4-(3-Chloro-4-cyano-2-methylphenoxy)piperidin-l-yI]-2-hydroxypropyl}-2- oxo-4-(trifluoromethyl)-2,3-dihydro-l,3-thiazole-5-carboxamidc; N-{(2R)-3-[4-(3-Chloro-4-cyanophenoxy)piperidin-l-yl]-2-hydroxypropyl}-5- (trifluoromethyl)-1H-1,2,3-triazole-4-carboxamide; 2-Chloro-5-f({(2R)-3-[4-(3,4-dichloro-2-methyIphenoxy)piperidin-l-yl]-2- hydroxypropyl}amino)carbonyl]benzoic acid; 4-Chloro-3-f({(2R)-3-[4-(3,4-dichloro-2-methylphenoxy)piperidin-l-yl]-2- liydroxypropyl}amino)carbonyl]benzoic acid; 4-Cliloro-3-[2-({(2R)-3-[4-(3,4-dichloro-2-methylphenoxy)pipciidin-l-yl]-2- hydroxypropyl}amino)-2-oxoethoxy]benzoic acid; {2-Chloro-5-[( {(2R)-3-[4-(3,4-dichloro-2-methylphenoxy)piperidin-1 -yl]-2- hydroxypropyl}amino)carbonyl]phenoxy}acetic acid; 3-[2-({(2R)-3-[4-(3.4-Dichloro-2-methylphenoxy)piperidin-l-yl|-2- hydroxypropyl}amino)-2-oxoethoxy]benzoic acid; or, {3-[({(2R)-3-[4-(3,4-DichIoro-2-methylphenoxy)piperidin-l-ylj-2- hydroxypropyl}amino)carbonyl]phenoxy}acetic acid; or a pharmaceutically acceptable salt thereof. 16. A process for preparing a compound as claimed in claim 1, the process comprising reacting a compound of formula (II): (Formula Removed) wherein R1 and R2 are as defined in claim 1, with a compound of formula (III): (Formula Removed) wherein L1 is a leaving group, and R is as defined in claim 1; in the presence of a base. optionally in the presence of a coupling agent; A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claim 1 alongvvith a pharmaceutically acceptable adjuvant, diluent or carrier as when used for the manufacture of a medicament for the treatment of the diseases such as herein described. A compound of formula (I) and a process for the preparation thereof substantially as herein described with reference to the foregoing examples.

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4201-DELNP-2006-Abstract-(10-02-2009).pdf

4201-DELNP-2006-Abstract-(19-09-2008).pdf

4201-delnp-2006-abstract.pdf

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