Title of Invention	"A PIPERIDINE COMPOUND"
Abstract	A piperidine compound of formula (I): wherein L is CH or N; M is CH or N; provided that L and M are not both CH; R1 is hydrogen, C1-6 alky1[optionally substituted by phenyl {which itself optionally substituted by halo}], S(O)2R6, S(O)2NHR7, C(0)R7, C(O)2(C1-6 alkyl) or C(O)NHR7; and when M is CH R1 can also be NHS(O)2R6, NHS{O)2NHR7, NHC(O)R7 or NHC{O)NHR7; R2 is phenyl or heteroaryl, either of which is optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, S{0)n(C1-4 alkyl),nitro, cyano or CF3; R3 is hydrogen or C1-4 alkyl; R4 is hydrogen, methyl, ethyl, allyl or cyclopropyl; R5 is phenyl, heteroaryl, phenyl (C1-2)alkyl or heteroaryl(C1-2)alkyl; wherein the phenyl and heteroaryl rings are optionally substituted by halo, cyano, nitro, hydroxy, C1-4 alkyl, C1-4 alkoxy, S(0)kC1-4alkyl, S(0)2NR8R9, NHS(0)2(C1-4 alkyl), NH2, NH(C1-4alkyl), N(C1-4alkyl)2, NHC(0)NH2, C(0)NH2, C(0)NH(C1-4alkyl), NHC(0)(C1-4alkyl), CO2H, C02(C1-4 alkyl), C{0) (C1-4 alkyl), CF3, CHF2, CH2F, CH2CF3 or OCF3; k, m and n are, independently, 0, 1 or 2; R6 is C1-6 alkyl [optionally substituted by phenyl { which itself optionally substituted by halo}], C3-7 cycloalkyl, phenyl {optionally substituted by halo}; R7 is hydrogen, C1-6 alkyl [optionally substituted by phenyl { which itself optionally substituted by halo}], C3-7 cycloalkyl, phenyl {optionally substituted by halo}; R8 and R9 are, independently, hydrogen or C1-4alkyl, or together with a nitrogen or oxygen atom, may join to form a 5- or 6-membered ring which is optionally substituted with C1-4alkyl, C(0)H or C(0)(C1-4alkyl); or a pharmaceutically acceptable salt thereof or a solvate thereof.

Title of Invention

"A PIPERIDINE COMPOUND"

Abstract

A piperidine compound of formula (I): wherein L is CH or N; M is CH or N; provided that L and M are not both CH; R1 is hydrogen, C1-6 alky1[optionally substituted by phenyl {which itself optionally substituted by halo}], S(O)2R6, S(O)2NHR7, C(0)R7, C(O)2(C1-6 alkyl) or C(O)NHR7; and when M is CH R1 can also be NHS(O)2R6, NHS{O)2NHR7, NHC(O)R7 or NHC{O)NHR7; R2 is phenyl or heteroaryl, either of which is optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, S{0)n(C1-4 alkyl),nitro, cyano or CF3; R3 is hydrogen or C1-4 alkyl; R4 is hydrogen, methyl, ethyl, allyl or cyclopropyl; R5 is phenyl, heteroaryl, phenyl (C1-2)alkyl or heteroaryl(C1-2)alkyl; wherein the phenyl and heteroaryl rings are optionally substituted by halo, cyano, nitro, hydroxy, C1-4 alkyl, C1-4 alkoxy, S(0)kC1-4alkyl, S(0)2NR8R9, NHS(0)2(C1-4 alkyl), NH2, NH(C1-4alkyl), N(C1-4alkyl)2, NHC(0)NH2, C(0)NH2, C(0)NH(C1-4alkyl), NHC(0)(C1-4alkyl), CO2H, C02(C1-4 alkyl), C{0) (C1-4 alkyl), CF3, CHF2, CH2F, CH2CF3 or OCF3; k, m and n are, independently, 0, 1 or 2; R6 is C1-6 alkyl [optionally substituted by phenyl { which itself optionally substituted by halo}], C3-7 cycloalkyl, phenyl {optionally substituted by halo}; R7 is hydrogen, C1-6 alkyl [optionally substituted by phenyl { which itself optionally substituted by halo}], C3-7 cycloalkyl, phenyl {optionally substituted by halo}; R8 and R9 are, independently, hydrogen or C1-4alkyl, or together with a nitrogen or oxygen atom, may join to form a 5- or 6-membered ring which is optionally substituted with C1-4alkyl, C(0)H or C(0)(C1-4alkyl); or a pharmaceutically acceptable salt thereof or a solvate thereof.

Full Text	The present invention relates to a piperidine compound. The present invention relates to heterocyclic derivatives having pharmaceutical activity, to processes for preparing such derivatives, to pharmaceutical compositions comprising such derivatives and to the use of such derivatives as active therapeutic agents. PharmaceuticaHy active piperidine derivatives are disclosed in PCT/SEO1/01053, EP-Al-1013276, WO00/08013, W099/38514 and WO99/04794. 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 well as 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 chemokme 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 )3) families. These are distinguished on the basis of a single ammo 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 neurrophil-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 (Regulaced on Activation, Normal T Expressed and Secreted), eotaxin and the macrophage inflammatory proteins lα and 1ß (MTP-lα and MTP-1ß). 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. The CCR5 receptor is expressed on T-lymphocytes, monocytes, macrophages, dendritic cells, microglia and other cell types. These detect and respond to several chemokines, principally "regulated on activation normal T-cell expressed and secreted" (RANTES), macrophage inflammatory proteins (MIP) MEP-lα and MIP-1ß and monocyte chemoattractant protein-2 (MCP-2) This results in the recruitment of cells of the immune system to sites of disease In many diseases it is the cells expressing CCR5 which contribute, directly or indirectly, to tissue damage Consequently, inhibiting the recruitment of these cells is beneficial in a wide range of diseases CCR5 is also a co-receptor for HIV-1 and other viruses, allowing these viruses to enter cells. Blocking the receptor with a CCR5 antagonist or inducing receptor internalisation with a CCR5 agonist protects cells from viral infection The present invention provides a compound of formula (I) wherein L is CH or N, M is CH or N, provided that L and M are not both CH; R1 is hydrogen, C1-6 alkyl [optionally substituted by phenyl {which itself optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, mtro, CF3, OCF3, (C1-4 alkyl)C(0)NH, S(0)2NH2, C1-4 alkylthio, S(0)(C1-4 alkyl) or S(0)2(C1-4 alkyl)} or heteroaryl {which itself optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, intro, CF3. (C1-4 alkyl)C(0)NH, S(0)2NH2, C1-4 alkylthio, S(0)(C1-4 alkyl) or S(0)2(C1-4 alkyl))], phenyl {optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, mtro, CF3, OCF3, (C1-4 alkyl)C(0)NH, S(0)2NH2, C1-4 alkylthio, S(0)(C1-4 alkyl) or S(0)2(C14 alkyl)), heteroaryl {optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, mtro, CF3, (C1-4 alkyl)C(0)NH. S(0)2NH2 C1-4 alkylthio, S(0)(C1-4 alkyl) or S(0)2(C1-4 alkyl)), S(0)2R6, S(O)2NR10Ru, C(0)R7, C(0)2(C1-6 alkyl) (such as tert-butoxycarbonyl), C(0)2(phenyl(C1-2 alkyl)) (such as benzyloxycarbonyl) or C(0)NHR7, and when M is CH R1 can also be NHS(0)2R6, NHS(0)2NHR7, NHC(0)R7 or NHC(0)NHR7, R is phenyl or heteroaryl, either of which is optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, S(0)„(C1-4 alkyl), mtro, cyano or CF3, R is hydrogen or C1-4 alkyl, R4 is hydrogen, methyl, ethyl, ally] or cyclopropyl, R5 is phenyl, heteroaryl, phenylNH, heteroarylNH, phenyl(Ci.2)alkyl. heteroaryl(C1-62)alkyl, phenyl(C1-2 alkyl)NH or heteroaryl(C1-2 alkylJNH, wherein the phenyl and heteroaryl rings of R5 are optionally substituted by halo, cyano, nitro, hydroxy, C1-4 alkyl, C1-4 alkoxy, S(0)IC(C1-4 alkyl), S(0)2NR8R9, NHS(0)2(Ci.4 alkyl), NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, NHC(0)NH2, C(0)NH2, C(0)NH(C1-4 alkyl), NHC(0)(C1-4 alkyl), C02H, C02(C1-4 alkyl), C(0)(C1-4 alkyl), CF3, CHF2, CH2F, CH2CF3 or OCF3, k, m and n are, independently, 0, 1 or 2, R6 is C1-6 alkyl [optionally substituted by halo (such as fluoro), C1-4alkoxy, phenyl {which itself optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, 0CF3, (C1-4 alkyl)C(0)NH, S(0)2NH2, C1-4alkylthio, S(0)(C1-4 alkyl) or S(0)2(C1-4 alkyl)} or heteroaryl {which itself optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, (C1-4 alkyl)C(0)NH, S(0)2NH2, C1-4 alkylthio, S(0)(C1-4 alkyl) or S(0)2(C1-4 alkyl)}], C3-7 cycloalkyl, pyranyl, phenyl (optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, OCF3, (C1-4 alkyl)C(0)NH, S(0)2NH2, C1-4 alkylthio, S(0)(C1-4 alkyl) or S(0)2(Ci-4 alkyl)} or heteroaryl {optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, (C1-4 alkyl)C(0)NH, S(0)2NH2, C1-4 alkylthio, S(0)(C1-4 alkyl) 01 S(0)2(C1-4 alkyl)}, R7 is hydrogen, C1-6 alkyl {optionally substituted by halo (such as fluoro), C1-4 alkoxy, phenyl (which itself optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, OCF3, (C1-4 aIkyl)C(0)NH, S(0)2NH2, C1-4 alkylthio, S(0)(C1-4 alkyl) or S(0)2(C1-4 alkyl)} 01 heteroaryl {which itself optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, (C1-4 alkyl)C(0)NH, S(0)2NH2, C1-4 alkylthio, S(0)(C1-4 alkyl) or S(0)2(C1-4 alkyl)}], C3.7 cycloalkyl, pyranyl, phenyl {optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, OCF3, (C1-4 alkyl)C(0)NH, S(0)2NH2, C1-4 alkylthio, S(0)(C1-4 alkyl) or S(0)2(C,. 4 alkyl)] or heteroaryl {optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, (C1-4 alkyl)C(0)NH, S(0)2NH2, C1-4 alkylthio, S(0)(C1-4 alkyl) or S(0)2(C1-4 alkyl)}, R and R are, independently, hydrogen or C1-4 alkyl, or together with a nitrogen or oxygen atom, may join to form a 5- or 6-membered ring which is optionally substituted with C1-4 alky], C(0)H or C(0)(C1-4 alkyl), R10 and Rn are, independently, hydrogen or C1-4 alkyl, or may join to form a 5- or 6-membered ring which is optionally substituted with C1-4 alkyl or phenyl (wherein the phenyl nng is optionally substituted by halo, cyano, nitro, hydroxy, C1-4 alkyl, C1-4 alkoxy, S(0)mC1-4 alkyl, S(0)2NH2, S(0)2NH(C1-4 alkyl), S(0)2N(C1-4 alkyl)2, NHS(0)2(C1-4 alkyl), NH2, NH(Ci-4 alkyl), N(C1-4 alkyl)2, NHC(0)NH2, C(0)NH2, C(0)NH(C1-4 alkyl), NHC(0)(C1-4 alkyl), C02H, C02(C1-4 alkyl), C(0)(C1-4 alkyl), CF3, CHF2, CH2F, C,H2CF3 or 0CF3); or a pharmaceutically acceptable salt thereof or a solvate thereof; provided that when R1 is hydrogen or unsubstituted alkyl, R4 is hydrogen, methyl or ethyl, L is CH and M is N, then the phenyl or heteroaryl part of R5 is substituted by one of: S(0)kCi„4 alkyl, NHC(0)NH2, C(0)(C1-4 alkyl), CHF2, CH2F, CH2CF3 or OCF3, and optionally further substituted by one or more of halo, cyano, nitro, hydroxy, C1-4 alkyl, C1-4 alkoxy, S(0)icC1-4 alkyl, S(0)2NR8R9, NHS(0)2(C1-4 alkyl), NH2) NH(C1-4 alkyl), N(C1-4 alkyl)2, NHC(0)NH2, C(0)NH2, C(0)NH(C1-4 alkyl), NHC(0)(C1-4 alkyl), C02H, C02(C1-4alkyl), C(0)(C1-4 alkyl), CF3, CFfF2, CH2F, CH2CF3 or OCF3 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, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate or p-toluenesulphonate The compounds of the invention may exist as solvates (such as hydrates) and the present invention covers all such solvates Alkyl groups and moieties are straight or branched chain and are, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl or tert-butyl Methyl is sometimes abbreviated to Me herembelow Fluoroalkyl includes, for example, one to six, such as one to three, fluorine atoms, and comprises, for example, a CF3 group Fluoroalkyl is, for example, CF3 or CH2CF3 Cycloalkyl is, for example, cyclopropyl, cyclopentyl or cyclohexyl. Phenyl(C1-2 alkyl)aikyl is, for example, benzyl, l-(phenyl)eth-l-yl or l-(phenyl)eth-2- Heteroaryl(C1-2 alkyl)alkyl is, for example, pyridinylmethyl, pyrimidinylmethyl or 1-(pyndmyl)eth-2-yl. Phenyl(C1-2 alkyl)NH is, for example, benzylamino Heteroaryl(C1-2 alkyl)NH is, for example, pyndinylCH2NH, pynmidinylCH2NH or pyndinylCH(CH3)NH Heteroaryl is an aromatic 5 or 6 membered ring, optionally fused to one or more other rings, comprising at least one heteroatom selected from the group comprising nitrogen, oxygen and sulphur, or an N-oxide thereof, or an S-oxide or S-dioxide thereof Heteroaryl is, for example, furyl, threnyl (also known as thiophenyl), pyrrolyl, thiazolyl, isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, [l,2,4]-triazolyl, pyridinyl, pyrimidinyl, indolyl, benzo[b]furyl (also known as benzfuryl), benz[b]thienyl (also known as benzthienyl or benzthiophenyl), indazolyl, benzimidazolyl, benztnazolyl, benzoxazolyl, benzthiazolyl, 1,2,3-benzothiadiazolyl, an rmidazopyridinyl (such as irxudazo[l,2a]pyndinyl), thieno[3,2-b]pyndin-6-yl, 1,2,3-benzoxadiazolyI (also known as benzo[l,2,3]thiadiazolyl), 2,1,3-benzothiadiazolyl, benzofurazan (also known as 2,1,3-benzoxadiazolyl), quinoxalinyl, a pyrazolopyndine (for example lH-pyrazolo[3,4-b]pyndmyl), quinolinyl, isoquinolinyl, a naphthyndinyl (for example [l,6]naphthyridinyl or [l,8]naphthyndinyl), a benzothiazinyl or dibenzothiophenyl (also known as dibenzothienyl); or an N-oxide thereof, or an S-oxide or S-dioxide thereof Heteroaryl can also be pyrazinyl. Heteroaryl is, for example, pyndinyl, pyrimidinyl, indolyl or benzimidazolyl. In one particular aspect the present invention provides a compound of formula (I) wherein L is CH or N; M is CH or N, provided that L and M are not both CH, R1 is hydrogen, C1-6 alkyl [optionally substituted by phenyl {which itself optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, C1-4 alkylthio, S(0)(C1-4 alkyl) or S(0)2(C1-4 alkyl)} or heteroaryl {which itself optionally substituted by halo, C1-4 alky], C1-4 alkoxy, cyano, nitro, CF3, C1-4 alkylthio, S(0)(C1-4 alkyl) or S(0)2(C1-4 alkyl)}], phenyl {optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, C1-4 alkylthio, S(0)(C1-4 alkyl) or S(0)2(C1-4 alkyl)}, heteroaryl {optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, C1-4 alkylthio, S(0)(C1-4 alkyl) or S(0)2(C1-4 alkyl)}, S(0)2R6, S(0)2NHR7, C(0)R7, C(0)2(C1-6 alkyl) or C(0)NHR7; and when M is CH R1 can also be NHS(0)2R6, NHS(0)2NHR7, NHC(0)R7 or NHC(0)NHR7, R2 is phenyl or heteroaryl, either of which is optionally substituted in the ortho or meta position by halo, C1-4 alkyl, C1-4 alkoxy, S(0)„(C1-4 alkyl), nitro, cyano or CF3; R3 is hydrogen or C1-4 alkyl, R4 is hydrogen, methyl, ethyl, ally] or cyclopropyl; R5 is phenyl, heteroaryl, phenylNH, heteroarylNH, phenyl(C1-2)alkyl, heteroaryl(C1-2)alkyl, phenyl(C1-2 alkyl)NH or heteroary](C1-2 alkyl)NH. wherein the phenyl and heteroaryl rings of R5 are optionally substituted by halo, cyano, nitro, hydroxy, C1-4 alkyl, C1-4 alkoxy, S(0)kC1-4 alkyl, S(0)2NRsR9, NHS(0)2(C1-4 alkyl), NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, NHC(0)NH2) C(0)NH2, C(0)NH(Ci.4 alkyl), NHC(0)(C1-4 alkyl), C02H, C02(C1-4 alkyl), C(0)(C1-4 alkyl), CF3, CHF2, CH2F, CH2CF3 or OCF3; R8 and R9 are, independently, hydrogen or C1-4 alkyl, or together with a nitrogen or oxygen atom, may join to form a 5- or 6- membered ring which is optionally substituted with C1-4 alkyl, C(0)H or C(0)(C1-4 alkyl), k and n are, independently, 0, 1 or 2, R6 is C1-6 alkyl [optionally substituted by phenyl {which itself optionally substituted by halo, Cw alkyl, C1-4 alkoxy, cyano, mtro, CF3, C1-4 alkylthio, S(0)(C1-4 alkyl) or S(0)2(C1-4 alkyl)} or heteroaryl {which itself optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, C1-4 alkylthio, S(0)(C1-4 alkyl) or S(0)2(C1-4 alkyl))], C3-7 cycloalkyl, phenyl {optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, , mtro, CF3, C1-4 alkylthio, S(0)(C1-4 alkyl) or S(0)2(C1-4 alkyl)) or heteroaryl {optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, INtro, CF3, C1-4 alkylthio, S(0)(C1-4alkyl) or S(0)2(C1-4 alkyl)}, R7 is hydrogen, C1-6 alkyl [optionally substituted by phenyl {which itself optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, C1-4 alkylthio, S(0)(C1-4 alkyl) or S(0)2(C1-4 alky!)} or heteroaryl {which itself optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, C1-4 alkylthio, S(0)(C1-4 alkyl) or S(0)2(C1-4 alkyl)}], C3-7 cycloalkyl, phenyl {optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, C1-4 alkylthio, S(0){C1-4 alkyl) or S(0)2(C1-4 alkyl)} or heteroaryl {optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, C1-4 alkylthio, S(0)(C1-4 alkyl) or S(0)2(C1-4 alkyl)}, or a pharmaceutically acceptable salt thereof or a solvate thereof, provided that when R1 is hydrogen or unsubstituted alkyl, R4 is hydrogen, methyl or ethyl, L is CH and M is N, then the phenyl or heteroaryl part of Rs is substituted by one of: S(0)kC1-4 alkyl, NHC(0)NH2, C(0)(C1-4alkyl), CHF2, CH2F, CH2CF3 or OCF3, and optionally further substituted by one or more of halo, cyano, nitro, hydroxy, C1-4 alkyl, C1-4alkoxy, S(0)kC1-4 alkyl, S(0)2NRRR9, NHS(0)2(C1-4 alkyl), NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, NHC(0)NH2, C(0)NH2, C(0)NH(C,.4 alkyl), NHC(0)(C1-4 alkyl), C02H, C02(C,4 alkyl), C(0)(C1-4 alkyl), CF3, CHF2, CH2F, CH2CF3 or OCF3 In another aspect the present invention provides a compound of the invention wherein when L and M are both N, and R1 is hydrogen, C1-4 alkyl or phenyl (the phenyl being substituted with 0, 1 or 2 substituents selected from the list consisting of. fluoro, chloro, C1-4 alkyl, C1-4 alkoxy, cyano, CF3, OCF3, (C1-4 alkyl)C(0)NH and S(0)2NH2), then the phenyl or heteroaryl moiety of R5 carries a S(0)2(C1-4 alkyl) substituent, and, optionally, one or more further substituents In a further aspect of the invention heteroaryl is pyrrolyl, thRenyl, imidazolyl, thiazolyl, isoxazolyl, pyridinyl, pynmidinyl, pyrazINyl or quINohnyl In another aspect M is N and L is CH or N In yet another aspect L and M are both N In a further aspect L is CH and M is N. In a still further aspect L is N and M is CH In another aspect of the invention R1 is hydrogen, C1-6 alkyl [optionally substituted by phenyl {which itself optionally substituted by halo}], S(0)2R6, S(0)2NHR7, C(0)R7, C(0)2(C1-6 alkyl) or C(0)NHR7; and when M is CH R! can also be NHS(0)2R6, NHS(0)2NHR7, NHC(0)R7 or NHC(0)NHR7; R6 is Q.6 alkyl [optionally substituted by phenyl {which itself optionally substituted by halo}], C3.7 cycloalkyl, phenyl {optionally substituted by halo}; and R7 is hydrogen, C1-6 alkyl [optionally substituted by phenyl {which itself optionally substituted by halo}], C3-7 cycloalkyl, phenyl {optionally substituted by halo}. In another aspect of the invention R1 is C1-6 alkyl [substituted by phenyl {which itself optionally substituted by halo}], S(0)2R6, S(0)2NHR7, C(0)R7, C(0)2(C1-6 alkyl) or C(0)NHR7, and when M is CH R1 can also be NHS(0)2R6, NHS(0)2NHR7, NHC(0)R7 or NHC(0)NHR7; R6 is C1-6alkyl [optionally substituted by phenyl {which itself optionally substituted by halo]], C3.7 cycloalkyl, phenyl {optionally substituted by halo); and R7 is hydrogen, C1-6alkyl [optionally substituted by phenyl {which itself optionally substituted by halo}], C3-7 cycloalkyl, phenyl {optionally substituted by halo} In a further aspect of the invention R1 is S(0)2R6, C(0)R7, C(0)2(Ci.6 alkyl) or C(0)NHR7, and when M is CH R1 can also be NHS(0)2R6 or NHC(0)R7, and R6 and R7 are as defined above In another aspect of the invention R1 is hydrogen, C1-6 alkyl [optionally substituted by phenyl {which itself optionally substituted by halo}], S(0)2R6, C(0)R7, C(0)2(C1-6 alkyl) or C(0)NHR7, and when M is CH R1 can also be NHS(0)2R6 or NHC(0)R7; R6 is C1-6alkyl [optionally substituted by phenyl {which itself optionally substituted by halo}], C3.7 cycloalkyl, phenyl {optionally substituted by halo}, and R7 is hydrogen, C1-6 alkyl [optionally substituted by phenyl {which itself optionally substituted by halo}], C3-7 cycloalkyl, phenyl {optionally substituted by halo}. In a further aspect R1 is phenyl (optionally substituted by halo (for example fluoro), C1-4 alkyl (for example methyl), C1-4 alkoxy (for example methoxy), CF3 or OCF3), S(0)2(C1-4 alkyl) (for example S(0)2CH3, S(0)2CH2CH3 or S(0)2CH(CH3)z), S(0)2(C1-4 fluoroalkyl) (for example S(0)2CF3 or S(0)2CH2CF3), S(0)2phenyl (optionally substituted (such as mono-substituted) by halo (for example chloro), cyano, C1-4 alkyl, C1-4 alkoxy, CF3, OCF3, S(0)2(Q. 4 alkyl) (for example S(0)2CH3 or S(0)2CH2CH2CH3) or S(0)2(C1-4 fluoroalkyl) (for example S(0)2CH2CF3)), benzyl (optionally substituted by halo (for example chloro or fluoro), Q.4 alkyl, C1-4 alkoxy (for example methoxy), CF3 or OCF3), benzoyl (optionally substituted by halo (for example chloro or fluoro), C1-4 alkyl (for example methyl), C1-4 alkoxy, CF3 or OCF3), C(0)NHphenyl (optionally substituted by halo (for example fluoro), C1-4 alkyl, C1-4 alkoxy, CF3 or OCF3), S(0)2thiophenyl, CH2pyridINyl, CH2quinolinyl or CH3tmazolyl In yet another aspect R1 is phenyl (optionally substituted (such as mono-substituted) by halo (for example fluoro), C1-4 alkyl (for example methyl) or C1-4 alkoxy (for example methoxy)), S(0)2(C1-4 alkyl) (for example S(0)2CH3, S(0)2CH2CH3 or S(0)2CH(CH3)2), S(0)2(C1-4 fluoroalkyl) (for example S(0)2CF3 or S(0)2CH2CF3), S(0)2phenyl (optionally substituted (such as mono-substituted) by halo (for example chloro), cyano, CF3, OCF3, S(0)2(C1-4 alkyl) (for example S(0)2CH3 or S(0)2CH2CH2CH3) or S(0)2(C1-4 fluoroalkyl) (for example S(0)2CH2CF3)), benzyl (optionally substituted by halo (for example chloro or fluoro) or C1-4 alkoxy (for example methoxy)), benzoyl (optionally substituted by halo (for example chloro or fluoro) or C1-4 alkyl (for example methyl)), C(0)NHphenyl (optionally substituted by halo (for example fluoro)), S(0)2thiophenyl, CH2pyndinyl, CH2quinolmyl or CH2thiazolyl In a further aspect R is phenyl (optionally substituted (such as mono-substituted) by halo (for example fluoro) or C1-4 alkyl (for example methyl)), S(0)2(C1-4 alkyl) (for example S(0)2CH3, S(0)2CH2CH3 or S(0)2CH(CH3)2), S(0)2(C1-4 fluoroalkyl) (for example S(0)2CF3 or S(0)2CH2CF3), S(0)2phenyl (optionally substituted (such as mono-substituted) by CF3, OCF3 or S(0)2(C1-4 alkyl) (for example S(0)2CH3)), benzyl (optionally substituted by halo (for example chloro or fluoro) or C1-4 alkoxy (for example methoxy)), benzoyl (optionally substituted by halo (for example chloro or fluoro)), C(0)NHphenyl (optionally substituted by , halo (for example fluoro)), CH2pyndinyl, CH2qumohnyl or CH2thiazolyl In a still further aspect R1 is hydrogen, C1-6 alkyl [optionally substituted by phenyl {which itself optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, OCF3, (C1-4 alkyl)C(0)NH, S(0)2NH2 or S(0)2(C1-4 alkyl)} or heteroaryl (which itself optionally substituted by halo, C1-4 alkyl or (C1-4 alkyl)C(O)NH)], phenyl (optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, OCF3, (C1-4 alkyl)C(0)NH, S(0)2NH2 or S(0)2(C1-4 alkyl)}, heteroaryl (optionally substituted by halo, C1-4 alkyl or (C1-4 alkyl)C(0)NH}, S(0)2R6, S(O)2NR,0Rn, C(0)R7 or C(0)NHR7, and when M is CH R1 can also be NHC(0)R7; R6 is C1-6 alkyl [optionally substituted by halo (such as fluoro), phenyl (which itself optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, OCF3, (C1-4 alkyl)C(0)NH, S(0)2NH2 or S(0)2(C1-4 alkyl)} or heteroaryl (which itself optionally substituted by halo, C1-4 alkyl or (C1-4 alkyl)C(O)NH)], phenyl (optionally substituted by halo, C1-4 aikyl, C1-4 alkoxy, cyano, nitro, CF3, OCF3, (C1-4 alkyl)C(0)NH, S(0)2NH2 or S(0)2(C1-4 aikyl)} or heteroaryl {optionally substituted by halo, C1-4 alkyl or (C1-4 alkyl)C(0)NH}, R7 is hydrogen, C1-6alkyl [optionally substituted by halo (such as fluoro), C1. 4 alkoxy, phenyl {which itself optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, iutro, CF3) OCF3, (C1-4 alkyl)C(0)NH, S(0)2NH2 or S(Oh(C1-4 alkyl)} or heteroaryl {which itself optionally substituted by halo, C1-4 alkyl or (C1-4 alkyl)C(O)NH)], C3-7 cycloalkyl, pyranyl, phenyl {optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, OCF3, (C1-4 alkyl)C(0)NH, S(0)2NH2 or S(0)2(C1-4alkyl)] or heteroaryl {optionally substituted by halo, C1-4 alkyl or (C1-4 alkyl)C(0)NH}, and, R10 and Rn are, independently, hydrogen or C1-4 alkyl In a further aspect R1 is phenyl (optionally substituted (such as mono-substituted) by halo (for example fluoio) orC1-4 alkyl (for example methyl)), S(0)2(C1-4 alkyl) (for example S(0)2CH3 or S(0)2CH2CH3), S(0)2(Ci 4 fluoroalkyl) (for example S(0)2CF3), S(0)2phenyl (optionally substituted (such as mono-substituted) by CF3 or OCF3), benzyl, benzoyl (optionally substituted by halo (for example chloro or fluoro)) or C(0)NHphenyl (optionally substituted by halo (for example fluoro)) In yet another aspect of the invention R2 is phenyl or heteroaryl, either of which is optionally substituted in the ortho or meta position by halo, C1-4 alkyl, C1-4 alkoxy, S(0)„(C1-4 alkyl), nitro, cyano or CF3, wherein n is 0, 1 01 2, for example 0 or 2 (Ortho and meta positions are ortho and meta relative to the position of attachment of that ring to the structure of formula (I)) In a still further aspect R2 is optionally substituted phenyl (such as optionally substituted by halo-{such as chloro or fluoro), cyano, methyl, ethyl, methoxy, ethoxy or CF3). In one aspect the substitution is on the ortho or meta position of the phenyl ring. In another aspect R2 is optionally substituted phenyl (such as optionally substituted by halo or CF3). For example R2 is 3-fluorophenyl, 3-chlorophenyl, 4-fluorophenyl or 4-CF3-phenyl In a further aspect R2 is phenyl, 3-fluoiophenyl, 4-fluorophenyl, 3-chlorophenyl, 3,4-difluorophenyl or 3,5-difluorophenyl. In another aspect R2 is phenyl, 3-fluorophenyl, 4-fluorophenyl, 3,4-difiuorophenyl or 3,5-difluorophenyl In a still further aspect of the invention R" is phenyl or 3-fluorophenyl In another aspect of the invention R3 is hydrogen or methyl In a further aspect of the invention when R3 is C1-4 alkyl (such as methyl) the carbon to which R3 is attached has the R absolute configuration In yet another aspect of the invention R3 is hydiogen In a further aspect offhe invention R4 is ethyl. In a still further aspect the present invention provides a compound of the invention wherein R5 is phenyl(C1-2)alkyl, pheny(C1-2 alkyl)NH, phenyl, heteroaryl or heteroaryl(C1. 2)alkyl, wherein the phenyl and heteroaryl rings are optionally substituted by halo, cyano, nitro, hydroxy, C1-4 alkyl, C1-4 alkoxy, S(0)kC1-4alkyl, S(0)2NR8R9, NHS(0)2(C1-4alkyl), NH2> NH(C1-4 alkyl), N(C1-4 alkyl)2, NHC(0)NH2, C(0)NH2, C(0)NH(C1-4 alkyl), NHC(0)(C1-4 alkyl), C02H, C02(C1-4 alkyl), C(0)(C1-4 alkyl), CF3, CHF2, CH2F, CH2CF3 or OCF3; and R8 and R9 are, independently, hydrogen or C1-4 alkyl, or together with a nitrogen or oxygen atom, may join to form a 5- or 6-membered ring which is optionally substituted with C1-4lkyl, C(0)H or C(0)(C1-4 alkyl); and k is 0, I or 2 (for example, 2). In another aspect the invention provides a compound of the invention wherein R is phenyl(C1-2)alkyl or phenyl(C1-2 alkyl)NH, wherein the phenyl rings of R5 are optionally substituted by halo, cyano, nitro, hydroxy, C1-4 alkyl, C1-4alkoxy, S(0)KC1-4 alkyl, S(0)2NR8R9, NHS(0)2(C1-4 alkyl), NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, NHC(0)NH2, C(0)NH2, C(0)NH(C1-4 alkyl), NHC(0)(C1-4alkyl), C02H, C02(C1-4 alkyl), C(0)(C1-4 alkyl), CF3, CHF2, CH2F, CH2CF3 or OCF3, R8 and R9 are, independently, hydrogen or C1-4 alkyl, or together with a nitrogen or oxygen atom, may join to form a 5- or 6-membered ring which is optionally substituted with C1-4 alkyl, C(0)H or C(0)(C1-4 alkyl), and k is 0, I or 2. In a still further aspect of the invention R5 is phenyl, heteroaryl, phenyl(Ci_2)alkyl or heteroaryl(C].2)alkyl, wherein the phenyl and heteroaryl rings are optionally substituted by halo, cyano, nitro, hydroxy, C1-4 alkyl, C1-4 alkoxy, S(0)kC1-4 alkyl, S(Q)2NR8R9, NHS(0)2(C1-4 alkyl), NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, NHC(0)NH2, C(0)NH2, C(0)NH(C1-4 alkyl), NHC(0)(C1-4 alkyl), C02H, C02(C1-4 alkyl), C(0)(C1-4 alkyl), CF3, CHF2, CH2F, CH2CF3 or OCF3, k is 0, 1 or 2, and R8 and R9 aRe, independently, hydrogen or C1-4 alkyl, or together with a nitrogen or oxygen atom, may join to form a 5- or 6-membered ring which is optionally substituted with C1-4 alkyl, C(0)H or C(0)(C1-4 alkyl) In another aspect R5 is phenyl or benzyl, wherein the aromatic rings are optionally substituted by halo, cyano, nitro, hydroxy, C1-4 alkyl, C1-4 alkoxy, S(0)ICC1-4 alkyl, S(0)2NR8R9, NHS(0)2(C1-4 alkyl), NH2, NH(Cw alkyl), N(C1-4 alkyl)2, NHC(0)NH2, C(0)NH2, C(0)NH(C1-4 alkyl), NHC(0)(C1-4 alkyl), C02H, C02(C1-4 alkyl), C(0)(C1-4 alkyl), CF3, CHF2, CH2F, CH2CF3 or OCF3, k is 0, 1 or 2, and R8 and R9 are, independently, hydrogen or C1-4 alkyl, or together with a nitrogen or oxygen atom, may join to form a 5- or 6-membered ring which is optionally substituted with C1-4 alkyl, C(0)H or C(0)(C1-4 alkyl). In a further aspect R5 is phenyl or benzyl; wherein the aromatic rings are optionally substituted by halo, cyano, nitro, hydroxy, C1-4 alkyl, C1-4 alkoxy, S(0)2C1-4 alkyl, S(0)2NR8R9, NHS(0)2(C1-4 alkyl), NH2, NH(Cm alkyl), N(Cm alkyl)2, NHC(0)NH2> C(0)NH2, C(0)NH(C,.4 alkyl), NHC(0)(Cm alkyl), C02H, C02(CM alkyl), C(0)(Cm alkyl), CF3, and R8 and R9 are, independently, hydrogen or CM alkyl In another aspect R5 is NHCH2phenyl wherein the phenyl ring is optionally substituted by halo, cyano, nitro, hydroxy,C1-4 alkyl, C1-4 alkoxy, S(0)2C1-4 alkyl, S(0)2NR8R9, NHS(0)2(C1-4 alkyl), NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2) NHC(0)NH2; C(0)NH2, C(0)NH(C1-4 alkyl), NHC(0)(C1-4 alkyl), C02H, C02(C1-4 alkyl), C(0)(C1-4 alkyl), CF3, and R8 and R9 are, independently, hydrogen or Cm alkyl In yet another aspect R5 is benzyl wherein the phenyl ring is optionally substituted by halo, cyano, nitro, hydroxy, C1-4 alkyl, C1-4 alkoxy. S(0)2C1-4 alkyl, S(0)2NR8R9, NHS(0)2(C1-4 alkyl), NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, NHC(0)NH2, C(0)NH2) C(0)NH(Cm alkyl), NHC(0)(CM alkyl), C02H, C02(CM alkyl), C(0)(C,.4 alkyl), CF3. and R8 and R9 aie, independently, hydrogen or C1-4 alkyl In another aspect R5 is NHCH2phenyl wherein the aromatic ring is optionally substituted by halo (such as fluoro, chloro or bromo), cyano, C1-4 alkyl (such as methyl), C1-4 alkoxy (such as methoxy) or S(0)2C1-4 alkyl (such as S(0)2CH3) In yet another aspect R5 is benzyl wherein the aromatic ring is optionally substituted by halo (such as fluoro, chloro or bromo), cyano. C1-4 alkyl (such as methyl), C1-4 alkoxy (such as methoxy) or S(0)2C1-4 alkyl (such as S(0)2CH3). In a still further aspect Rs is phenyl or benzyl, wherein the aromatic ring is substituted (for example in the para-position) by S(0)2C1-4 alkyl and the ring is optionally further substituted by halo, cyano, nitro, hydroxy, C1-4 alkyl or C1-4 alkoxy. In another aspect R5 is NHCH2phenyl or benzyl, wherein the aromatic ring is substituted (for example in the para-position) by S(0)2C1-4 alkyl (such as S(0)2CH3) and the ring is optionally further substituted by halo, cyano, nitro, hydroxy, C1-4 alkyl or C1-4 alkoxy. In another aspect R is NHCH2phenyl wherein the aromatic ring is substituted (for example in the para-position) by S(0)2C1-4 alkyl (such as S(0)2CH3), RJ is, for example NHCH2(4-S(0)2CH3-C6H4) In another aspect R is benzyl, wherein the aromatic ring is substituted (for example m the para-position) by S(0)2C1-4 alkyl (such as S(0)2CH3), R5 is, for example CH2(4-S(0)2CH3-C6H4) The carbon labelled ^ in the representation of formula (I) shown below, is always chiral (Formula Removed) When L is N the carbon labelled ^ has, for example, the S absolute configuration. When L is CH the carbon labelled ^ has, for example, the R absolute configuration. In another aspect the present invention provides a compound of formula (la)' (Formula Removed) wherein L, M and R1 are as defined above In a further aspect the present invention provides a compound of formula (lb): (Formula Removed) wherein L, M and R1 are as defined above; and R is hydrogen, one or two fluorine atoms, S(0)n(C1-4 alkyl) or C1-4 alkoxy; and n is 0, 1 or 2 (for example, 2) In another aspect the present invention provides a compound of formula (Ic). (Formula Removed) wherein L, M and R1 are as defined above, and R is hydrogen, one or two fluorine atoms, S(O)n(C1-4 alkyl) or C1-4 alkoxy, and n is 0, 1 or 2 (for example, 2). In a still further aspect the present invention provides a compound of formula (Id) (Formula Removed) wherein L, M and R1 are as defined above; R is hydrogen, one or two fluorine atoms, S(O)„(C1-4 alkyl) or C1-4 alkoxy; X is NHCH2, NH or CH2; n is 0, 1 or 2 (for example, 2), and R* is halo (such as fluoio, chloro or bromo), cyano, C1-4 alkyl (such as methyl), C1-4 alkoxy (such as methoxy) or S(O)2C1-4 alkyl (such as S(O)2CH3). In another aspect the present invention provides a compound of formula (Ie): (Formula Removed) wherein L, M and R1 are as defined above In yet another aspect the present invention provides a compound of formula (If) (Formula Removed) wherein L, M, X and R are as defined above In a still further aspect the present invention provides a compound of formula wherein R5 is as defined above The compounds listed in Tables I to VI lllusti ate the invention TABLET Table I comprises compounds of formula (lb) Table H Table II comprises compounds of formula (lei (Table Removed) Table II (Table Removed) Table III comprises compounds of formula (Id)(Table Removed) Table IV Table IV comprises compounds of formula (Ie) (Table Removed) (Table Removed) Table VI Table VI comprises compounds of formula (Ig) Table V Table V comprises compounds of formula (If). (Table Removed) In yet another aspect the invention provides each individual compound listed in the tables above The compounds of formula (I), (la), (lb), (Ic), (Id). (Ie), (If) and (Ig) can be prepared as shown below (for example in Schemes 2 and 3, with Scheme 1 showing the preparation of an intermediate.) In Schemes 1 to 3 PG is a protecting Group; Ac is acetyl; Boc is tert-butoxycarbonyl, Bn is benzyl, Bz is benzoyl; DIBAL is diisobutylalummium hydride, Et is ethyl, Ms is mesyl, and, TFA is tnfluoroacetic acid wherein R2, R3, R4 and R5 are as defined above, with a compound of formula (III) (Table Removed) A compound of the invention wherein L is N can be prepared by reacting a compound of formula (IT). (Formula Removed) wherein R1 is as defined above, in the presence of sodium iodide rand a suitable base (for example a tri(C1-6alkyl)armne such as tnethylamine or Hunig's base), in a suitable solvent (such as a chlorinated solvent, for example dichloromethane) and, for example, at a room temperature (for example 10-30°C) A compound of the invention wherein L is CH can be prepared by reacting a compound of formula (IV): (Formula Removed) wherein R2, R3, R4 and R5 are as defined above, with, depending on the compound of the invention it is desired to make: a) an acid of formula R1CO2H in the presence of a suitable coupling agent (for example PyBrOP [bromo-tns-pyrrolidino-phosphonium hexafluorophosphate] or HATU) in the presence of a suitable base (such as a tn(C1-6 alkyl)amme, for example dnsopropylethylamine) in a suitable solvent (for example iV-methylpyrrolidinone or a chlorinated solvent, such as dichloromethane) at room temperature (for example 10-30°C), b) an acid chloride of formula R'C(0)C1 or sulphonyl chlonde of formula R1S(O)2Cl, in the piesence of a suitable base (such as a tri(C1-6 alkyl)amine, for example tnethylamine or diisopropylethylamine) in a suitable solvent (for example a chlorinated solvent, such as dichloromethane) at room temperature (for example 10-30°C), or, c) an aldehyde of formula R'CHO in the presence of NaBH(OAc)3 (wherein Ac is C(O)CH3) and acetic acid, in a suitable solvent (such as a C1-6aliphatic alcohol, for example ethanol) at room temperature (for example 10-30°C) Alternatively, a compound of the invention can be prepared by coupling a compound of formula (V)- (Formula Removed) wherein L, M, R1, R2, R3 and R4 are as defined above, with- a) an acid of formula R5C02H in the presence of a suitable coupling agent (for example PyBrOP or HATU) in the presence of a suitable base (such as a tri(C1-6 alkyl)amine, for example diisopropylethylamine) in a suitable solvent (for example N-methylpyrrolidmone or a chlorinated solvent, such as dichloromethane) at room temperature (for example 10-30°C), or, b) an acid chloride of formula R5C(0)C1, in the presence of a suitable base (such as a tri(C1-6 alkyl)amine, for example triethylamme or diisopropylethylamine) in a suitable solvent (for example a chlorinated solvent, such as dichloromethane) at room temperature (for example 10-30°C) The starting materials for these processes are either commercially available or can be prepared by literature methods, adapting literature methods or by following or adapting Methods herein described In a further aspect the invention provides an intermediate of formula (V). In a still further aspect the invention provides processes for preparing the compounds of formula (I), (la), (lb), (Ic), (Id), (Ie), (If) and (Ig). Many of the intermediates in the processes are novel and these are provided as further features of the invention The compounds of the invention have activity as pharmaceuticals, in particular as modulators (such as agonists, partial agonists, inverse agonists or antagonists) of chemokine receptor (especially CCR5) 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 (AIDS)) The compounds of the present invention are also of value in inhibiting the entry of viruses (such as human immunodeficiency virus (HIV)) into target calls and, therefore, are of value in the prevention of infection by viruses (such as HIV), the treatment of infection by viruses (such as HIV) and the prevention and/or treatment of acquired immune deficiency syndrome (AIDS) According to a further feature of the invention there is provided a compound of the formula (I), (la), (lb), (Ic), (Id), (Ie), (If) or (Ig) (such as (I) or (la)), or a pharmaceutically acceptable salt thereof or a solvate 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 chemokme receptor activity (especially CCR5 receptor activity) 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 present invention, or a pharmaceutically acceptable salt thereof or a solvate thereof The present invention also provides the use of a compound of the formula (I), (la), (lb), (Ic), (Id), (Ie), (If) or (Ig) (such as (I) or (la)), or a pharmaceutically acceptable salt thereof or a solvate thereof, as a medicament, especially a medicamenl for the treatment of transplant rejection, respiratory disease, psoriasis or rheumatoid arthritis (especially iheumatoid arthritis). [Respiratory disease is, for example, COPD, 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 {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 scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis), and is particularly asthma or rhinitis]. In another aspect the present invention provides the use of a compound of the formula (I), (la), (lb), (Ic), (Id), (Ie), (If) or (Ig) (such as (I) or (la)), or a pharmaceutically acceptable salt thereof or a solvate thereof, in the manufacture of a medicament for use in therapy (for example modulating chemokme receptor activity (especially CCR5 receptor activity (especially rheumatoid arthritis)) in a warm blooded animal, such as man) The invention also provides a compound of the formula (I), (la), (lb), (Ic), (Id), (Ie), (If) or (Ig) (such as (I) or (la)), or a pharmaceutically acceptable salt thereof or a solvate thereof, for use as a medicament, especially a medicament for the treatment of rheumatoid arthritis In another aspect the present invention provides the use of a compound of the formula (I), (la), (lb), (Ic), (Id), (Ie), (If) or (Ig) (such as (I) or (la)), or a pharmaceutic ally acceptable salt thereof or a solvate thereof, in the manufacture of a medicament for use in therapy (for example modulating chemokme receptor activity (especially CCR5 receptor activity (especially rheumatoid arthritis)) in a warm blooded animal, such as man). The invention further provides the use of a compound of formula (I), (la), (lb), (Ic), (Id), (le), (If) or (Ig) (such as (I) or (la)), 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 chrome ihinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis, sarcoidosis; farmer's lung and related diseases; nasal polyposis; fibroid lung or ldiopamic interstitial pneumonia, (2) (bone and joints) arthndes including rheumatic, infectious, autoimmune, seronegative spondyloarthropathies (such as ankylosing spondylitis, psoriatic arthritis or Reiter's disease), Behcet'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, vascuhtides erythemas, cutaneous eosinophilias, uveitis, Alopecia areata or vernal conjunctivitis, (4) (gastrointestinal tract) Coeliac disease, proctitis, eosinophilic gastro-ententis, 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 oi cornea, or chronic graft versus host disease; and/or 26 (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, eosmophiha fascitis, hyper IgE syndrome, leprosy (such as lepromatous leprosy), Pendontal disease, Sezary syndrome, idiopathic thrombocytopenia pupura or disorders of the menstrual cycle; in a warm blooded animal, such as man The present invention further provides a method of treating a chemokine mediated disease state (especially a CCR5 mediated disease state) 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), (la), (lb), (Ic), (Id), (le), (If) or (Ig) (such as (I) or (la)), or a pharmaceutically acceptable salt thereof or solvate thereof In order to use a compound of the invention, or a pharmaceutically acceptable salt thereof or solvate thereof, for the therapeutic treatment of a warm blooded animal, such as man, m particular modulating chemokine receptor (for example CCR5 receptor) activity, said ingiedient 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), (la), (lb), (Ic), (Id), (le), (If) or (Ig) (such as (I) or (la)), or a pharmaceutically acceptable salt thereof or a solvate thereof (active ingredient), and a pharmaceutically acceptable adjuvant, diluent or earner. 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 carrier Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0 05 to 99 %w (per cent by weight), more preferably from 0 05 to 80 %w, still more preferably from 0 10 to 70 %w, and even more preferably 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 skm), 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, (lipid) emulsions, dispersible powders, suppositories,.ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions. A suitable pharmaceutical composition of tins invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule which contains between 0.lmg and lg 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 0lmgkg"1 to l00mgkg"1 of the compound, preferably in the range of 0.lmgkg"1 to 20mgkg"' 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 ieceive a daily oral dose which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day The following illustrate representative pharmaceutical dosage forms containing the compound of formula (I), (la), (lb), (Ic), (Id), (Ie), (If) or (lg) (such as (I) or (la)), or a pharmaceutically acceptable salt thereof or a solvent thereof (hereafter Compound X), for therapeutic or prophylactic use in humans. (a) (Table Removed) Buffers, pharmaceutically-acceptable cosolvents such as polyethylene glycol, polypropylene glycol, glycerol or ethanol or complexmg agents such as hydroxy-propyl ß-cyclodextrm may be used to aid formulation. The above formulations may be obtained by conventional procedures well known in the-pharmaceutical art The tablets (a)-(c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate. The invention will now be illustrated by the following non-limiting Examples in which, unless stated otherwise- (i) temperatures are given in degrees Celsius (°C), operations were earned out at room or ambient temperature, that is, at a temperature in the range of 18-25°C, (li) organic solutions were dried over anhydrous magnesium sulfate, evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600-4000 Pascals; 4 5-30 mm Hg) with a bath temperature of up to 60CC, (in) chromatography unless otherwise stated means flash chromatography on silica gel; thin layer chromatography (TLC) was carried out on silica gel plates; where a "Bond Elut" column is referred to, this means a column containing lOg or 20g of silica of 40 micron particle size, the silica being contained in a 60ml disposable syringe and supported by a porous disc, obtained from Varian, Harbor City, California, USA under the name "Mega Bond Elut ST' Where an "Isolute™ SCX column" is referred to, this means a column containing benzenesulphonic acid (non-endcapped) obtained from International Sorbent Technology Ltd , 1st House, Duffryn Industial Estate, Ystrad Mynach, Hengoed, Mid Glamorgan, UK. Where "Argonaut™ PS-tris-amine scavenger resin" is referred to, this means a tns-(2-ammoethyl)amine polystyrene resin obtained from Argonaut Technologies Inc., 887 Industrial Road, Suite G, San Carlos, California, USA (IV) IN general, the course of reactions was followed by TLC and reaction times are given for illustration only, (v) yields, when given, are for illustration only and are not necessarily those which can be obtained by diligent process development, preparations were repeated if more material was required; (vi) when given, JH 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 (TMS) as an internal standard, determined at 300 MHz using perdeuterio DMSO (CD3SOCD3) as the solvent unless otherwise stated, coupling constants (J) are given m Hz, (vii) chemical symbols have their usual meanings; SI units and symbols are used, (viii) solvent ratios are given in percentage by volume, (IX) mass spectra (MS) were run with an electron energy of 70 electron volts in the chemical lonisation (APCI) mode using a direct exposure probe, where indicated ionisation was effected by electrospray (ES); where values 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 - (M+H)+, (x) LCMS characterisation was performed using a pair of Gilson 306 pumps with Gilson 233 XL sampler and Waters ZMD4000 mass spectrometer The LC comprised water symmetry 4 6x50 column C18 with 5 micron particle size The eluents were- A, water with 0 05% formic acid and B, acetonitrile with 0 05% formic acid The eluent gradient went from 95% A to 95% B in 6 minutes. Where indicated ionisation was effected by electrospray (ES), where values for m/z are given, generally only ions which indicate the parenl mass are reported, and unless otherwise stated the mass ion quoted is the positive mass ion - (M+H)+ and (xi) the following abbreviations are used- DMSO dimethyl sulfoxide; DMF N-dimethylformarnide, DCM dichloromethane, THF tetrahydrofuran; DIPEA N-N-drisopropylethylamine, NMP N-methylpyrrolidmone; HATU 0-(7-Azabenzotnazol- l-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate, HBTU 0-(7-Benzotnazol-l -yl)-N,N,N,N-tetramethyluronium hexafluorophosphate; Boc tert-butoxycarbonyl MeOH methanol; EtOH ethanol, and EtOAc ethyl acetate. EXAMPLE 1 This Example illustrates the preparation of N-[l-(3-phenyl-3-[4-methylprperazin-l-yl]propyl)-piperidin-4-yl]-N-ethyl-4-methnesulfonylphenylacetamide (Compound No. 6 of Table I) To a solution of 1-methylpiperazme (42µL, 0 38mmol) m DCM (l0mL) was added triethylamine (0.1 mL, 0.72mmol) then N-[l-(3-phenyl-3-chloropropyl)-pjpendm-4-yl]-N-elhyl-4-methanesulfonylphenylacetamide (Method A, 180mg, 0 38mmol) and sodium iodide (50mg) The resulting mixture was stirred at room temperature for 48h then washed with water and brine, dried (MgSO4) and evaporated The residue was purified by eluting through a 20g Bond Elut with 10% methanol in ethyl acetate then methanol then 1% triethylamine in methanol to give the title compound (58mg), NMR 1 2 (t, 1H), 1 3 (t, 2H), 1 4 (m, 1H), 1 6 (m, 2H), 1 8 (m, 4H), 1 9 (m,2 H), 2 1 (m, 2H), 2 2 (s, 3H), 2 4 (m, 8H), 2 9 (m, 2H), 3 0 (s, 3H), 3.3 (m, 2H), 3 8 (s, 2H), 7 2 (m, 2H), 7 4 (m, 2H), 7 9 (d, 2H), MS 541 The procedure described in Example 1 can be repeated using different secondary amines (such as 4-formylpiperazine, 4-isobutyrylpiperazine or 4-benzylpreridme) in place of 1 -methyl piperazme EXAMPLE 2 This Example illustrates the preparation of N-[l-(3-phenyl-3-[pipeiidin-4-yl]propyl)-pipendin-4-yl]-N-ethyl-4-methanesulfonylphenylacetamide (Compound No 17 of Table I) N--[l-(3-Phenyl-3-[l-tert-butylcarbonyloxypipendin-4-yl]propyl)-pipendin-4-yl]-N--ethyl-4-methanesulfonylphenylacetanude (Example 3,4g) was dissolved in trifluoroacetic aud (25mL) and the resulting mixture was stirred at room temperature for 2h The mixture was evaporated and the residue azeotroped with toluene The resulting material was stirred with 2M aqueous sodium hydroxide (25mL) and the resulting mixture extracted with DCM (8 x 25mL) The combined extracts were dried and evaporated to give the title compound (2.5g), MS 526 EXAMPLE 3 This Example illustrates the preparation of N-[l-(3-phenyl-3-[l-tert-butylcarbonyloxy-piperidm-4-yl]propyl)-pipendin-4-yl]-N-ethyl-4-methanesulfonylphenylacetamide (Compound No. 23 of Table I) To a solution of 3-phenyl-3-(l-tert-butylcarbonyloxypipendin-4-yl)propionaldehyde (Method C; 14.4mmol) m DCM (l00mL) was added N--(4-pipendinyl)-N-ethyl-4-methanesulfonylphenylacetamide (Method B, 4 6g, 14.4mmol) and the resulting mixture was stirred at room temperature for 30mm Sodium tnacetoxyborohydnde (3 05g, 14.4mmol) was added and the resulting mixture was stirred at room temperature for 2h. The reaction mixture was washed with 2M aqueous sodium hydroxide (3 x 25mL), dried and eluted through a 50g SCX cartridge with DCM (3 x 25mL), ethyl acetate (4 x 25mL), methanol (4 x 25mL) and finally 1M ammonia in methanol (4 x 50mL) to yield crude product which was purified by silica gel chromatography (eluent: ethyl acetate then 10% methanol m ethyl acetate) to yield the title compound (4 2g); MS: 626 EXAMPLE 4 This Example illustrates the preparation of N-[l-(3-phenyl-3-[1-methylpipendm-4-y]]propyl)-pipeiidin-4-yl]-.N-ethyl-4-methanesulfonylphenylacetamide (Compound No 26 of Table I) To a mixture of N-l-(3-phenyl-3-[piperidin-4-yl]propyl)-piperidin-4~yl]-N~etbyl-4-methanesulfonylphenylacetamide (Example 2, 250mg, 4 76mmol) and formaldehyde (0 2mL, 37% aqueous) in DCM (l0mL) was added sodium triacetoxyborohydnde (9.52mmol) and the resulting mixture was stirred at room temperature for 18h The mixtuie was washed with 2M aqueous sodium hydroxide (l0mL) and eluted through a l0g SCX cartridge with DCM (2 x l0mL), methanol (2 x l0mL) and finally 1M ammonia in methanol (4 x l0mL) affording the title compound (172mg), MS. 540 The procedure described in Example 4 can be repeated using different aldehydes (such as acetaldehyde and benzaldehyde) in place of formaldehyde EXAMPLE 5 This Example illustrates the preparation of N-[1-(3-phenyl-3-[l -acetylpipendin-4-yi]propyl)-piperidin-4-yl]-N-ethyl-4-rnethanesulfonylphenyIacetarnide (Compound No 21 of Table I) To a mixture of N--[l-(3-phenyl-3-[pipendm-4-yl]propyl)-pipendjn-4-yl]-N-ethyl-4-methanesulfonylphenylacetamide (Example 2, 250mg, 4 76mmol) and tnethylamine (48mg, 4 76mmol) in DCM was added acetyl chloride (37mg, 4 76mmol) The resulting mixture was stirred at room temperature for 18h, washed with saturated aqueous sodium bicarbonate solution (l0mL), dried and eluted through a l0g SCX cartridge with DCM (2 x l0mL), methanol (4 x l0mL) and finally 1M ammonia in methanol (4 x l0mL) affording the title compound (180mg); MS 568 The procedure described in Example 5 can be repeated using different acid chlorides (such as phenylacetyl chloride and 4-chlorobenzoyl chloride) or sulfonyl chlorides (such as methane sulfonyl chloride) in place of acetyl chloride. EXAMPLE 6 This Example illustrates the preparation of N-[1(3-phenyl-3-[l-cyclohexylamino-carbonylpipendm-4-yl]propyl)-piperidin-4-yl]-N--ethyl-4-methanesulfonylphenylacetamide (Compound No 22 of Table 1) To a mixture of N-[l-(3-phenyl-3-[prperidin-4-yl]propyl)-pipendin-4-yl]-N--ethyl-4-methanesulfonylphenylacetamide (Example 2, 250mg, 4 76mmol) and DCM (l0mL) was added cyclohexyl isocyanate (59mg, 4.6mmol) and the resulting mixture was stirred at room temperature for 18h. The mixture was eluted through a l0g SCX cartridge with DCM (4 x lOmL), methanol (2 x l0mL) and finally 1M ammonia in methanol (4 x l0mL) affording the title compound (300mg), MS 651 EXAMPLE 7 N-[l-(3-phenyl-3-[4-(2-chlorophenyJsulphonyl)piperazin-l-yl]piopyl)-pipendm-4-yl]-N-ethyl-4-methanesulphonylphenylacetamide (Compound number 150 of Table 1) 2-Chlorophenylsulphonyl chloride (40.1 mg) was added to a solution of N-[l-(3-phenyl-3-[piperazm-l-yl]propyl)-pipendm-4-yl]-N-ethyl-4-methanesulphonylphenyl-acelarrude (100 mg) and triethylamme (53 µl) m dichloromethane (5 ml) and the mixture was stirred for 1 hour The reaction mixture was washed with water, brine and dried.The solvent was removed and the residue was chromatographed on a lOg silica Bond-Elut column eluted with a solvent gradient (ethyl acetate-20% methanol/ethylacetate) to give the title compound, yield 90mg MET 701 The N-[l-(3-phenyl-3-[piperazin-l-yl]propyl)-pipendin-4-yl]-N-ethyl-4-methanesulphonylphenylacetamide (Compound 86 of Table 1) used as starting material was prepared following the method described in Example 2 using the appropriate (1-tert-butyloxycarbonyl)-piperazme analogue The N-[l-(3-phenyl-3-[l-tert-butyloxycarbonylpiperazin-l-yl]propyl)-pipendin-4-yl]-N-ethyl-4-methanesulphonylphenylacetamide (Compound 152 of Table l)used as starting material was prepared following the method described in example 1 using (1-tert-butyloxycarbonyl)prperazine as the amine component EXAMPLE 8 (R or S) N-[l-(3-phenyl-3-[(4-{2,2,2-tnfluoroethylsulphonyl-piperazinyl}propyl)-piperidm-4-yl]-N-ethyl-4-methanesulphonylphenylacetamide. (Compound number 15 of Table 2) Triethylamine (50 µl) was added to a solution of (R or S) N-[l-(3-phenyl-3 -piperazinyl}propyl)-pipendm-4-yl]-N-ethyl-4-methanesulphonylphenylacetamide ( 175 mg) in dichloromethane (5 ml) followed by 2,2,2-tnfluoroethanesulphonyl chloride (37 µl) and the mixture was stirred at room temperature for 14 hours. The reaction mixture was washed with water and dried The residue obtained-on removal of the solvent was chromatographed on a 20g silica Bond-Elut column eluted with a solvent gradient (ethyl acetate - 40% methanol/ethyl acetate) to give the title compound as a white foam, yield 79 mg, MH+ 673. NMR (CDCl3) : 1.2 (t, 1H), 1.3 (t, 2H), 1 4 (m, 1H), 1 6-1.8 (m,8H), 2 I (m,2H), 2.25 (m, 1H), 2 5 (m, 4H), 2 9 (m, 2H), 3 0 (s, 3H), 3 3 (m, 5H), 3 4 (m, 1H), 3 6 (q, 2H), 3 8 (m, 2H), 7 2 (m, 2H), 7 3 (m, 3H), 7 4 (m, 2H), 7.9 (d, 2H) EXAMPLE 9 (R or S) N-[l-(3-phenyl-3~(Boc-piperazmyl}propyl)-pipendin-4-yl]-N-ethyl-4-methanesulphonylpheny 1 acetarrude (R or S) N-[l-(3-phenyl-3-chloropropyl)-pipendin-4-yl]-N-ethyl-4-methanesulphonylphenylacetanude (594 mg) was added to a solution of tnethylamme ( 0 35 ml) and Boc-piperazme (233 mg) in dichloromethane (10 ml) at room temperature and the mixture was stirred for 14 hours The reaction mixture was added to a 20g silica Bond-Elut column and was eluted with a solvent gradient (ethyl acetate - 40% methanol/ethyl acetate) to give the title compound as a foam, yield 440 mg, MH4 627. (R or S) N-[l-(3-phenyl-3-chloropropyl)-piperidin-4-yl]-N-ethyl-4-methanesulphonylphenylacetamide (Formula Removed) Methanesulphonyl chloride (0 5 ml) was added to a stirred mixture of S N-[l-(3-phenyl-3-hydroxypropyl)-pipendm-4-yl]-N-ethyl-4-methanesulphonylphenylacetairude (2 7g) and triethylamine (1 64 ml) in dichloromethane (50 ml) at 0°C and the mixture was stirred at ambient temperature for 15 hours The reaction mixture was washed with water and dried Removal of the solvent gave the title compound as an orange foam, yield 2.4g, MH+ 477. (S) N-[l-(3-phenyl-3-hydroxypropyl)-pipendm-4-yl]-N-ethyl-4-rnethanesulphonylphenylacetarnide (Formula Removed) (S) l-Phenyl-3-(4-toluenesulphonyloxy)propan-l-ol (5g) was added to a mixture of N-(pipendin-4-yl)-N-ethyl-4-methanesulphonylphenylacetarmde (5 3g) and potassium carbonate (2 71g) in DMF (100 ml) and the mixture was stirred and heated at 80-90 °C for 6 hours The leaction mixture was allowed to cool and was evaporated to dryness The residue obtained was dissolved in dichloromethane (50 ml) and was washed with water and dried. The solvent was removed and the residue was passed down a 90g silica Bond-Elut column eluted with a solvent gradient ( ethyl acetate- 20% methanol/ethyl acetate) to give the title compound, yield 2.7g, MH+ 459 NMR (CDCI3) 1 2 (t, 1H), 1 3 (t,2H), 1.6 (m, 2H), 1 75 (m, 3H), 1.85 (m, 3H), 2 2 (m, 1H), 2.55-2 7 (m, 2H), 3 0 (s, 3H), 3 1 - 3 2 (m, 2H), 3.3(q, 2H), 3.8(m, 2H), 4.9 (ra, 1H), 7 3 (m, 5H), 7 45 (d, 2H), 7 9 (d, 2Hj (S) l-Phenyl-3-(4-toluenesulphonyloxy)propan-l-ol is a known compound (CAS No 156453-52-0) EXAMPLE 10 (R or S) N-[l-(3-phenyl-3 -prperazmyl}propyl)-prperidin-4-yl]-N-ethyl-4-methanesulphonylphenyl acetarmde Trifluoroacetic acid ( 5 ml) was added to a solution of (R or S) N-[l-(3-phenyl-3 ( Boc-piperazinyl}propyl)-pipendin-4-yl]-N-ethyl-4-methanesulphonylphenylacetamide (440 mg) in dichloromethane (10 ml) and the mixture was stirred for 1 hour The reaction mixture was concentrated and the residue was dissolved in 2M aqueous sodium hydroxide and extracted twice with dichloromethane (10 ml each bine). The combined extracts were dried and evaporated to give the title compound as a foam, yield 370 mg, MH+ 527 EXAMPLE 11 (R) N-[l-(3-phenyl-3-(l-(4-chlorobenzoylpipendin-4-yl)propyl}pipendin-4-yl]-N-ethyl-4-rnethanesulphonylphenylacetarmde. (Compound number 26 of Table 2) To a mixture of (R) Ar-[l-3-phenyl-3-[pipendin-4-yl]propyl)-piperidm-4-yl]-N-ethyl-4-methanesulphonylphenylacetamide (330 mg) and MP carbonate resin (670 mg of 2.8 mM/g material) in dichloromethane (10 ml) was added 4-chlorobenzoyl chloride (111 mg) and the mixture was stirred at room temperature for 15 hours The reaction mixture was filtered and MP 4-toluenesulphomc acid resin ( Ig) was added to the filtrate and stirred for 30 minutes The reaction mixture was filtered and the resin was washed successively with dichloromethane (4X10 ml), 1M MeOH/NH3 (3X10 ml) The combined washings were evaporated to dryness and the residue was passed through a silica Bond-Elut column eluted with a solvent gradient (ethyl acetate-20% methanol m ethyl acetate) to give the title compound, yield 121 mg NMR (DMSOd6) 0 8-2 2 (m, 6H) 1 2-1 5 (m, 4H) 1 5-2 1 (m, 13H) 2 4 (m, 1H) 2.7 (m, 3H) 3.3 (m, 4H) 3 8 (d, 2H) 7-7 5 (m, 11H) 7 8 (d, 2H) Analytical HPLC on a Chiralcel OJ column (250mm x 4.6 mm) eluted with methanol showed that the chural purity was >99% (R)7V-[l-3-phenyl-3-[piperidin-4-yl]propyl)-pipendin-4-yl]-N-ethyl-4-methanesulphonylphenylacetamide (Compound number 35 of Table 2) (Formula Removed) A solution of (R) N-[l-(3-phenyl-3-{ l-(benzyloxycarbonylpipendm-4-yl)propyl}pipendin-4-yl]-N-elhyl-4-methanesulphonylphenylacetamide (1 5g) methanol (100 ml) containing 20% Palladium/carbon catalyst (200 mg) was hydrogenated under a hydrogen-filled balloon. The catalyst was filtered and the filtrate evaporated to dryness to give the title compound, yield 1 lg MS (MH+) 526. (R)N-[l-(3-phenyl-3-{l-(benzyloxycarbonylpipendin-4-yl)propyl}piperidin-4-yl]-N-ethyl-4-methanesulphonylphenylacetanude (Compound number 24 of Table 2). Sodium tnacetoxyborohydride (890 mg) was added to a solution of (R) 3-phenyl-3-(benzyloxycarbonylpipendin-4-yl)propionaldehyde (1 49g) and N-(4-pipendinyl)-N-ethyl4-methanesulphonylphenylacetarmde (1 4g) in dichloromethane (25 ml) and the mixture was stirred for 1 hour The reaction mixture was washed with 2M NaOH (2X50 ml) and dried. The solvent was removed and the residue was passed down a silica Bond-Elut column eluted with a solvent gradient (ethyl acetate-20% methanol/ethyl acetate) to give the title compound, yield 1.5g MS(MH+)660 (R) 3-phenyl-3-(benzyloxycarbonylpipendm-4-yl)propionaldehyde Dess-Martin penodinane (1,1,1 -triacetoxy-1,1-dihydro-1,2-benziodoxol-3(lH)-one) (1.8g) was added to a solution of (R) 3-phenyl-3-(benzyloxycarbonylpipendin-4-yl)propanol m dichloromethane (25 ml) and the mixture was stirred for 1 hour, washed with 2M NaOH (2X20 ml) and dried The dichloromethane solution containing the title compound was used directly in the next stage (R) 3 -phenyl-3 -(benzyloxycarbonylpiperidin-4-yl)propanol Lithium aluminium hydride (9 46 ml of 1M LAH in THF) was added dropwise to a solution of (R) 3-[3-phenyl-3-(benzyloxycarbonylpiperidm-4-yl)propionyl]-(4R,5S)-1,5-dimethyl-4-phenyl-2-imidazohdinone (5 lg) in THF (100 ml) at such a rate that the temperature did not exceed 0°C. The reaction mixture was stirred at -5°C for 10 minutes and 2M NaOH was added (10 ml). The reaction mixture was filtered through Cehte and the filtrate was evaporated to dryness The residue was dissolved in dichloromethane (20 ml) and dried The residue obtained on removal of the solvent was passed through a Bond-Elut column eluted with a solvent gradient (isohexane-60% ethyl acetate/isohexane) to give the title compound , yield 1.6g. MS (MH+) 354. 3-[(R) 3-phenyl-3-(benzyloxycarbonylpipendm-4-yl)propionyl]-(4R,5S)-1,5-dimethyl-4-phenyl-2-imidazolidmone (Formula Removed) TMEDA (2 4g) was added to a suspension of cuprous iodide (4.02g) in THF (100 ml) and the mixture was stirred at room temperature for 30 minutes The reaction mixture was cooled to -78 °C and phenylmagnesium bromide (11 69 ml of a 1M solution in THF) was added and the mixture was stirred at -78 °C for 30 minutes Dibutylboron tnflate (11 69 ml, 1M solution m diethyl ether) was added to a solution of 3-[3-(benzyloxycarbonylpipendin-4-yl)acryloyl]-(4R,5S)-l,5-dimethyl-4-phenyl-2-imidazoIidmone (4 9g) in THF (50 ml) and this mixture was added dropwise over 10 minutes to the solution of the cuprate reagent The reaction mixture was stirred at -78 °C for 1 hour then allowed to warm to ambient temperature The solvent was evaporated, the residue was dissolved in ethyl acetate and filtered through silica (l00g). The ethyl acetate solution was washed with 2M HC1 (1X100 ml), dried and evaporated to dryness The residue was passed down a Bond-Elut column AS-eluted with a mixture of ethyl acetate and isohexane (1 • 1) to give the title compound as a single diastereoisomer by NMR Yield 5.1g. NMR (DMSOd6) 0.5 (d, 3H) 0.8-1.1 (m 2H) 1 3 (d, 1H) 1 7 (m, 2H) 2 6 (m, 5H) 2.85-3.1 (m, 4H) 5.05 (s, 2H) 5.2 (d, 1H) 6.8 (m, 2H) 7.1-7 5 (m, 13H) 3-[3-(benzyloxycarbonylpiperidin-4-yl)acryloyl]-(4R,5S)-l,5-dimethyl-4-phenyl-2-lmidazohdinone (Formula Removed) l-Chloro-N,N,2-tnmethyl-l-propenylamine (1 37g) was added dropwise over 10 minutes to a solution of 3-(benzyloxycarbonylpiperidin-4~yl)propenoic acid (2 5g) in THF (20 ml) and the mixture was stirred for 1 5 hours Lithium bis(tnmethylsilyl)amide (8 65 ml)was added to a solution of (4R,5S)-l,5-dimethyl-4-phenyl-2-imidazolidinone (1 64g) in THF (20 ml) at -10 °C and the mixture was stirred at -10 °C for 10 minutes, allowed to warm to 0 °C and then cooled again to -10 °C. The acid chloride solution (prepared above) was added dropwise and the mixture was allowed to warm to room temperature The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (3X50 ml) The combined extracts were dried, evaporated to dryness and the residue was chromatographed on a Bond-Elut column eluted with an ethyl acetate/isohexane mixture (1 1) to give the title compound, yield 3.6g NMR (DMSOd6) : 0 6 (d, 3H) 0 95 (d, 1H) 1 2 (m, 2H) 1 55 (m, 2H) 2.4 (m 1H) 2 3 (s, 3H) 2.8 (m, 2H) 3 95 (m, 3H) 5 (s, 2H) 5.3 (d, 1H) 6 9 (m, 1H) 7 1 (m, 2H) 7.2-7 4 (m, 8H) 3-(benzyloxycarbonylpiperidin-4-yl)propenoic acid A mixture of N-benzyloxycarbonyl-4-formylpipendine (10g), malonic acid (4 2), pyridine (4 ml) and pipendine (0 4 ml) was heated at 100 °C for 2 hours The reaction mixture was allowed to cool and was diluted with ethyl acetate (100 ml) The solution was washed with 2M HC1 (2X100 ml), dried and evaporated to dryness The residue was triturated with isohexane to give the title compound, yield 13.5g NMR (DMSOd6) 1 2 (m, 2H) 1.7 (m, 2H) 2 35 (m, 1H) 2.85 (m, 2H) 4"(d, 2H) 5.05 (s, 2H) 5.75 (d, 1H) 6 75 (m, 1H) 7 35 (m, 5H) 12 25 (broad peak, 1H) EXAMPLE 12 N-[ 1 -3 - [(3 -fluorophenyI)-3 - [ 1 -phenylpiperidin-4-yl] propyl)-pipendin-4-yl] -N-ethyl-4-methanesulphonylphenylacetamide (Compound number 145 of Table 1) 2M NaOH was added to a suspension of N-[1-[3-(3-fluorophenyl-3-[plperidin-4-yI]propyl)-prperidin-4-yl]-N-ethyl-4-methanesulphonylphenylacetamide di-hydrochlonde salt (0.85 g) in dichloromethane (25 ml) and the mixture was stirred until a clear solution was obtained. The dichloromethane solution was dried and filtered To this dichloromethane solution was added benzeneboromc acid (330 mg), tnethylamine (280 mg) and cupnc acetate (276 mg). The reaction mixture was stirred for 15 hours, washed with water and filtered through a Chem Elute cartridge. The dichloromethane filtrate was washed with 2M NaOH (3X20 ml), dried and poured on to a 20g SCX cartridge and eluted with methanol (6X20 ml) and 1M ammonia in methanol (6X20 ml) The combined ammonia washings were evaporated and the residue obtained was chromatographed on a Bond-Elut column eluted with a solvent gradient (ethyl acetate-20% methanol/ethyl acetate to give the title compound, yield 179 mg The N--[l-3(3-fluorophenyl-3-[prperidin-4-yl]propyl)-piperidm-4-yl]-N--ethyl-4-methanesulphonylphenylacetarmde di-hydrochlonde salt (Compound number 87 of Table 1) used as starting material was prepared following the procedmes of Example 3 and Method C. EXAMPLE 13 Racermic N-[l-(3-(3-fluorophenyl)-3-[4-(4-methanesulphonyl)phenylsulphonyl)piperazm-l-yl]propyl)-pipendin-4-yl]-N-ethyl-4-methanesulphonylphenylacetamide (78 mg) (Compound number 59 of Table 1) was separated into its single enantiomers by chromatography on a Gilson preparative HPLC using a 50 mm 20(im Chiracel OD column eluted with a mixture of ethanol.isohexane (9' 1). Less polar isomer, yield 20mg (Compound number 16 of Table 2) More polar isomer, yield 22 mg (Compound number 17 of Table 2) EXAMPLE 14 Nl-[l-(3-phenyl)-3-{l-(ethanesulphonylpipendin-4-yl)propyljpipendin-4-yl]-Nl-ethyl-N3-4-methanesulphonylphenylmethyl urea. (Compound number 7 of Table 3) 4-Methanesulphonylphenylmethyl isocyanate ( 99 mg) in THF (10 ml) was added to 4-N-ethyl- [l-(3-phenyl)-3-{ l-(ethanesulphonylpipendm-4-yl)propyl}pipendine (200 mg) and the mixture was allowed to stand at room temperature for 16 hours The reaction mixture was poured on to a 5g SCX cartridge and was eluted with dichloromethane (3X10 ml), methanol (3X10 ml) and methanohc ammonia (1M, 3X10 ml) The methanolic ammonia washings were evaporated and the residue was dissolved in dichloromethane (20 ml) and isocyanate resin (200mg) was added The mixture was stirred for 16 hours, Filtered and the Filtrate was evaporated to dryness The residue obtained was chromatographed on a Bond-Elut column eluted with a solvent gradient (ethyl acetate-25% methanol/ethyl acetate) to give the title compound, yield 37 mg MS (MH+) 633 4- N-ethyl- [l-(3-phenyl)-3-{ l-(ethanesulphonylpipendm-4-yl)propyl}piperidine (Formula Removed) A mixture of N-ethyl-N- [l-(3-phenyl)-3-{ l-(ethanesulphonylpiperidin-4-yl)propyl}piperidin-4-yl]-carbamic acid benzyl ester (5g) and 10% Palladium on carbon (2g) in ethanol (200ml) was hydrogenated under a hydrogen filled balloon The catalyst was filtered and the filtrate evaporated to dryness to give the title compound, yield 2 78g. N-ethyl-N- [l-(3-phenyl)-3-{ l-(ethanesulphonylpipendin-4-yl)propyl}piperidm-4-yl]-carbamic acid benzyl ester. (Formula Removed) thanesulphonyl chloride (2.3g) was added to a solution of N-ethyl-N- [l-(3-phenyl)-3-{pipendin-4-yl)propyl}pipendin-4-yl]-carbamic acid benzyl ester di-hydrochlonde (8 5g) and triethylamine (4.8g) in dichloromethane (200 ml) maintained at 0 °C. The reaction mixture was allowed to warm to room temperature and was stirred for 4 hours. The reaction mixture was washed with 2M NaOH (2X100 ml), dried and evaporated to dryness. The residue was chromatographed on a Bond-Elut column eluted with a solvent gradient (ethyl acetate-20% methanol/ethyl acetate) to give the title compound, yield 5g NMR (DMSOd6): 1 (t, 3H) 1 1 (t, 3H) 1.3-3 (m, 14H) 2 2 (m, 1H) 2 55-2 9 (m, 5H) 2.95 (q, 2H) 3.1(q, 2H) 3 4-3 7 (m, 3H) 5.05 (s, 2H) 7.1-7 4 (m, 10H) MS (MH+) 556 N-ethyl-N-[l-(3-phenyl)-3-{piperidin-4-yl)propyl}piperidm-4-yl]-carbamic acid benzyl ester di-hydrochloride HC1 in dioxan (50 ml of 4M) was added to N-ethyl-N- [l-(3-phenyl)-3-{ 1-tert-butyloxycarbonylpiperidin-4-yl)propyl}piperidin-4-yl]-carbamic acid benzyl ester (26g) at 0 °C the mixture was allowed to warm to room temperature and was stirred for 2 hours The reaction mixture was diluted with diethyl ether (200ml) and the precipitated solid di-hydrochlonde salt was filtered and dried (hygroscopic) Yield 17g MS (MH+) 464. N-ethyl-N- [l-(3-phenyl)-3-{l-tert-butyloxycarbonylpipendm-4-yl)propyl}pipendin-4-yl]-carbamic acid benzyl ester A solution of 3-phenyl-3-(l-tert-butylcxycarbonylpiperidin 4-yl)propionaldehyde (7 8 g) [prepared following the method described in Example 11] in dichloromethane (200 ml) was added to a mixture of N-ethyl-N-piperidin-4-ylcarbamic acid benzyl ester hydrochloride (7.4g) (CAS No 220395-87-9) and sodium acetate (2 17g) m ethanol (50ml) and stirred for 30 minutes. Sodium tnacetoxyborohydride (5 2g) was added in small portions over 15 minutes and staring was continued for 2 hours Aqueous NaOH (2M, 200 ml) was added dropwise, the dichloromethane layer was collected and washed with 2M NaOH (2X100 ml), dried and evaporated to dryness to give the title compound, yield 26g NMR (DMSOd6) 1 (t, 3H) 1.35 (s, 9H) 1.4-2 (m, 14H) 2.3(m, 2H) 2 6-2 7 (m, 4H) 3 15 (q, 2H) 3 4-4 (m, 3H) 5 05 (s, 2H) 7 1-72 (m, 10H) MS (MIT") 563 4-methanesulphonylphenylmethyl isocyanate Diphenylphosphoryl azide (260 mg) was added to a mixture of 4-methanesulphonylphenylacetic acid (200mg) and tnethylamine (191 mg) in THF (20 ml) and the reaction mixture was heated under reflux for 4 hours, the reaction mixture was cooled and used directly for the next stage. Method A N-[1-(3-Phenyl-3-chloropropyl)-piperidin-4-yl]-N-ethyl-4-methanesulfonylphenylacetanude Step 1 Preparation of N-l-(3-phenyl-3-oxopropyl)-pipendm-4-yl]-N-ethyl-4-melhanesulfonylphenylacetamide To a solution of N-(4-pipendinyl)-N-ethyl-4-methanesulfonylphenylacetamide (Method B; 3 24g, l0mmol) in DMF (50mL) was added potassium carbonate (2 76g, 20mmol) followed by 3-chloropropiophenone (1 85g, 1 lmmol). The resulting mixture was stirred at room temperature for 18h then evaporated. The residue was dissolved in DCM and the resulting solution washed with water (4 x l0mL) and brine (l0mL), dried (MgS04) and evaporated to give the crude product which was purified by elutmg through a 50g Bond Elut with 10% methanol in ethyl acetate to afford the sub-titled compound (2 4g, 53%), NMR (CDC13) 1 1 (t, 1H), 1 2 (m, 2H), 1 6 (m, 6H), 2.2 (m, 1H), 2 8 (m, 2H), 3.0 (m, 5H), 3 2 (m, 2H), 3 3 (m, 2H), 3 8 (m, 2H), 7 4 (m, 5H), 7 9 (m, 4H), MS' 457 Step 2, Preparation of N-[l-(3-phenyl-3-hydroxypropyl)-pipendin-4-yl]-N--ethyl-4-methanesulfonylphenylacetamide To a solution of N--[l-(3-phenyl-3-oxopropyl)-pipendin-4-yl]-N--ethyl-4-methanesulfonylphenylacetarmde (912mg, 2mmol) m ethanol (20mL) at 0°C was added sodium borohydride (76mg, 2mmol) The resulting mixture was stirred at room temperature for 30mm then evaporated. The residue was dissolved in DCM and the resulting solution washed with water (2 x 5mL) and brine (5mL), dried (MgSO4) and evaporated to give the subtitled compound (812mg, 87%), NMR (CDC13)- 1.1 (t, 1H), 1 2 (m, 2H), 1.6 (m , 8H), 2.0 (m, 1H), 2 2 (m, 1H) 2 6 (m, 2H), 3.0 (s ,3H), 3 2 (m, 2 H), 3 3 (m , 2H), 3.8 (m, 2H), 4 9 (d, 1H), 7 3 (m, 5H), 7 4 (d, 2H), 7 9 (d, 2H), MS 459 Step 31 Preparation of the title compound To a mixture of N-[l-(3-phenyl-3-hydroxypropyl)-pipendin-4-yl]-N-ethyl-4-methanesulfonylphenylacetamide (400mg, 0 87mmol) and tnethylamine (0 24mL, 1 04mmo]) in DCM (l0mL) at 0°C was added methane sulfonyl chloride (67µL, 0 87mmol) The resulting mixture was stirred at room temperature for 30min. then evaporated. The residue was purified by eluting through a 20g Bond Elut to give the title compound (180mg, 44%), NMR (CDC13) 1.1 (t, 1H), 1.2 (m, 2H), 1 6 (m . 7H), 2.2 (m, 2H), 2.4 (m, 2H), 2.8 (m, 2H), 3 0 (s, 3H), 3 3 (m, 2H), 3.8 (m, 2H), 5 0 (m, 1H), 7 3 (m, 5H), 7 4 (d, 2H), 7.9 (d, 2H), MS: 477 Method B N-(4-Piperidinyl)-N-ethyl-4-methanesulfonylphenylacetamide Step 1' Preparation of l-phenylmethyl-4-ethylaminopiperidine dihydrochlonde To a solution of l-phenylmetliyl-4-piperidone (25.0g, 132mmol) in THF (250mL) was added ethylamme hydrochloride (12.0g, 147 mol) and methanol (50mL) and the resulting mixture stirred at room temperature for l0min Sodium triacetoxyborohydnde (40g, 189mmol) was added portionwise and the resulting mixture stirred at 100m temperature for Ih. 2M Sodium hydroxide solution (250mL) was added and the resulting mixture extracted with diethyl ether The organic extracts were dried (K2CO3) and evaporated to give 1-phenylmethyl-4-ethylaminopipendine as an oil This was dissolved in ethanol (500mL) and concentrated hydrochloric acid (20mL) was added The resulting crystals were collected, washed with diethyl ether and dried giving the sub-titled compound as a solid (38 g), NMR (CDCI3) 1 10 (t, 3H), 1 40 (m, 2H), 1 83 (m, 2H), 2.02 (m, 2H), 2 65 (q, 2H), 2.85 (m, 2H), 3.50 (s, 2H), 3 75 (m, IH), 7.2 - 7 4 (m, 5H); MS. 219 (MH+). Step 2: Preparation of N-(l-Phenylmethyl-4-pipendmyl)-A'-ethyl-4-methanesulfonylphenylacetamide To a solution of l-phenylmethyl-4-ethylammopipendine dihydrochlonde (32.0g, 1 lOmmol) in DCM (500mL) was added N,N-dusopropylethylamine (60mL) with stirring to ensure complete dissolution. 4-Methanesulfonylphenylacetic acid (25 0g, 117mmol), 4-dimethylaminopyndme (20g) and dicyclohexylcarbodnirude (25 0g, 121mmol) were added and the resulting mixture was stirred at room temperature for 20h The precipitate was removed by filtration and the resulting solution was washed successively with 2N aqueous HCl, water and IN aqueous NaOH, dried (MgSO4) and evaporated The residue was purified by silica gel chromatography (eluent. 10% MeOH/ethyl acetate) to afford the sub-titled compound (35 g, 76%), NMR' 1.00 and 1.14 (t, 3H), 1 45 and 1 70 (m, 2H), 1.95 (br m, 2H), 2.80 (br m, 2H), 3 18 (s, 3H), 3 20 and 3.33 (q, 2H), 3 45 (s, 2H), 3 80 and 3.87 (s, 2H), 3.70 and 4.10 (m, 1H), 7 2 - 7.3 (m, 5H), 7 48 (m, 2H), 7.82 (m, 2H); MS. 415 (MH+) Step 3' Preparation of the title compound To a solution of N-(l-phenylmethyl-4-piperidinyl)-N-ethyl-4-methanesulfonylphenyl-acetarrude (34g, 82mmol) in ethanol (600mL) was added ammonium formate (40g). The mixture was purged with argon and 30% Pd on carbon (4 2g) was added The resulting mixture was stirred at reflux for 4h, then allowed to cool and filtered through diatomaceous earth The filtrate was evaporated to give a thick oil which solidified on standing to yield the title compound (24 9g, 94%), NMR. 1.02 and 1 15 (t, 3H), 1 4 -1.6 (br m, 4H), 2.45 (m, 2H), 2 93 (br m, 2H), 3 18 (s, 3H), 3 20 and 3.32 (q, 2H), 3 72 and 4 18 (m, 1H), 3.80 and 3.87 (s, 2H), 7 50 (m, 2H), 7 85 (m, 2H), MS. 325 (MH+) Method C 3-Phenyl-3-(l-tert-butylcarbonyloxyprperidin-4-yl)propionaldehyde Step 1 Preparation of l-tert-butylcarbonyloxy-4-benzoylpipendme To a solution of 4-benzoylpiperidme (6g, 26 5mmol) in 2M aqueous sodium hydroxide (26 5mL) was added di-tert-butyl dicarbonate (5 79g, 26 5mmol) and the resulting mixture was stirred at room temperature for 18h. The solid product was isolated by filtration and dried under vacuum at 40°C giving the sub-titled compound (7g), NMR. 1 3-1.4 (m, 11H) 1 7 (m, 2H) 2 9 (m, 2H) 3 6 (m, 1H) 3 95 (m, 2H) 7 5-7 6 (m, 3H) 7.95 (d, 2H) Step 2 Preparation of ethyl 3-phenyl-3-(l-tert-butylcarbonyloxypipendin-4-yl)acrylate To a solution of triethylphosphonoacetate (6.2g, 27mmol) in THF (l00mL) at0°C was added lithium bis(tnmethylsilyl)amide (32.5mL, 1M, 32 5mmol). The resulting mixture was stirred at 0°C for 20rrun l-tert-Butylcarbonyloxy-4-benzoylpiperidine (7g, 25mmol) was added and the resulting mixture was stirred at room temperature for 48h The mixture was evaporated and the residue dissolved in ethyl acetate (200mL). The solution was washed with 2M hydrochloric acid (2 x 100mL), dried and evaporated giving the sub-titled compound Step 3 Preparation of ethyl 3-phenyl-3-( 1 -tert-butylcarbonyloxypipendin-4-yl)propionoate Ethyl 3-phenyl-3-(l-tert-butylcarbonyloxypiperidin-4-yl)acrylate (-25mmol) was dissolved in ethanol (200mL) and the solution purged with argon 20% Palladium hydroxide (2g) was added and the resulting mixture was stirred at room temperature under an atmosphere of hydrogen (balloon) for 72h. The mixture was purged with argon, filtered and the filtrate evaporated. The crude product was purified by silica gel chromatography (eluent: isohexane then 35% ethyl acetate in isohexane) to give the sub-titled compound (5 3g) Step 4. Preparation of 3-phenyl-3-(l-tert-butylcarbonyloxypipendin-4-yl)propan-l-ol To a solution of ethyl 3-phenyl-3-(l-tert-butylcarbonyloxypipendin-4-yl)propronoate (5.3g, 14 6mmol) m THF (l00mL) was added lithium aluminium hydride (14 6mL, 1M, 14.6mmol) dropwise over 20mm. The resulting mixture was stirred at 0°C for lh. 2M aqueous sodium hydroxide (20mL) was added dropwise The mixture was filtered through Celite®, washing with ethyl acetate (3 x 25mL) The filtrate and washings were combined and evaporated The residue was dissolved in ethyl acetate (l00mL) and the resulting solution washed with water (3 x 50mL), dried and evaporated to give the sub-titled compound (4.6g), NMR. 0 9-1 (m, 2H) 1.25 (m, 1H) 1 35 (s, 9H) 1 5-2 (m, 5H) 2 6 (m, 2H) 3.1 (m, 2H) 3.8-4 (m, 2H) 4 2 (t, 1H) Step 5 Preparation of the title compound To A solution of 3-phenyi-3-(4-l-tert-butyicarbonyloxypipendin-4-yl)propan-l-ol (4 6g, 14 4mmol) in DCM (l00mL) was added Dess-Martm penodinane (6.1g, 14 6mmol) and the resulting mixture was stirred at room temperature for 2h The mixture was washed with 2M aqueous sodium hydroxide (3 x 50mL), dried and evaporated to give the title compound Method D N~(tert-butoxycarbonylpipendin-4-yl]-N-ethyl-4-methanesulphonylphenylacetarrude (Formula Removed) To a solution of 4-methylsulfonylphenylacetic acid (16 lg) in toluene (200ml) under argon was added diphenylphosphoryl azide (16 2ml) and triethylamine (10.4ml). The mixture was heated at 90 °C for 3 hours and then allowed to cool The tert-butyl-l-oxo-4-arninoethyl-prpendine [CAS 264905-39-7] (17.10g) in toluene (100ml) was added and the mixture stined far 18 hours and then partitioned with EtOAc/H20 (500ml/400ml), filtered and the organic layer separated and washed with sat NaHC03 solution (2 x 300ml), brine (300ml), dried over MgSCU, filtered and evaporated. The resulting brown oil was purified on silica using a gradient elution of 0 to 3% MeOH in EtOAc to give the title compound as a yellow solid (7.10g), NMR (DMSO)- 1 4 (t, 3H), 1 40 (s, 9H), 1 52 (m, 4H), 2.73 (m, 2H), 3 15 (m, 5H), 4.02 (m, 3H), 4 32 (d, 2H), 6.89 (t, 1H), 7 43 (d, 2H), 7 87 (d, 2H) MS 340 (MH+ - Boc) N-(pipendin-4-yl]-N-ethyl-4-methanesulphonylphenylacetamide (Formula Removed) The pipendme (6 84g) was dissolved in DCM (39ml) and TFA (39ml) was added slowly The mixture was allowed to stand for 40 minutes and then evaporated The residue was dissolved in 2M NaOH and extracted with DCM (3x150ml) and the extracts dried over MgSO4, filtered and evaporated to give the title compound as a yellow solid (5.00g), NMR (DMSO)- 1.05 (t, 3H), 1 41 (m, 4H), 2 42 (m, 2H), 2 96 (d, 2H), 3 20 (m, 5H), 3.90 (quint, 1H), 4 29 (d, 2H), 6.84 (t, 1H), 7 43 (d, 2H), 7 85 (d, 2H), MS 340 (MH4). Method E N-[l-(3-[3,4-di-fluorophenyl]-3-hydroxypropyl)-pipendin-4-yl]-N-ethyl-4-methanesulphonylphenylacetamide (Formula Removed) A solution of sodium borohydnde (7 7 mg) in ethanol (1 ml) was added to a solution of N-t 1 -(3-[3,4-difluorophenyl]-3-ketopropyl)-piperidm-4-yl]-N-ethyl-4-methanesulphonylphenylacetamide (0 25g) in ethanol (3 2 ml) at 0°C under argon and the reaction allowed to warm to room temperature over 20 hours The reaction was quenched with bnne, extracted three times with ether and the combined extracts dried. The filtrate was then concentrated to a clear oil, yield 0 21 g MS (MH+) 495 N [l-(3-[3,4-difluorophenyl]~3-ketopropyl)-pipendm-4-yl]-N-ethyl-4-methanesulphonylphenylacetarmde (Formula Removed) DBU was added to a solution of pipendin-4-yl]-N-ethyl-4-methanesulphonylphenylacetamide (CAS number 374725-04-9) (320 mg) and 3,4-difluorophenylvmyl ketone (654 mg) in dicholoromethane (9 ml) under argon and the reaction mixture stirred for 36 hours The reaction mixture was concentrated in vacuo and purified using flash column chromatography on silica eluting with a solvent gradient (methanol 10-15%, methanol in dicholormethane), yield 250 mg, MH+ 493. 3,4-difluorophenyl vinyl ketone. Dess martin penodmane (3 18 g) was added to a solution of 3,4-difluorovmyl alcohol (CAS number 149946-84-9) (1 18 g) in dicholoromethane (22 ml) at 0°C under argon and the reaction mixture allowed to stir for 1 hour The mixture was put directly on to a column for purification via flash column chromatography elutmg with a gradient (ethyl acetate - 10%, ethyl acetate and isohexane) yield 654 mg NMR (CDCl3) 6 0 (d, 1H), 6 50 (d, 1H), 7 10 (dd, 1H), 7 30 (m, 1H), 7 80 (m, 2H) EXAMPLE 15 The ability of compounds to inhibit the binding of RANTES was assessed by an in vitro radioligand binding assay Membranes were prepared from Chinese hamster ovary cells which expressed the recombinant human CCR5 receptor These membranes were incubated with 0.1 nM iodinated RANTES, scintillation proximity beads and various conSScentrations of the compounds of the invention in 96-well plates. The amount of iodinated RANTES bound to the receptor was determined by scintillation counting Competition curves were obtained for compounds and the concentration of compound which displaced 50% of bound iodinated RANTES was calculated (IC50) Preferred compounds of formula (I) have an IC50 of less than 50jxM EXAMPLE 16 The ability of compounds to inhibit the binding of MlP-lα was assessed by an in vitro radioligand binding assay Membranes were prepared from Chinese hamster ovary cells which expressed the recombinant human CCR5 receptor These membranes were incubated with 0.lnM iodinated MlP-lα, scintillation proximity beads and various concentrations of the compounds of the invention in 96-well plates The amount of iodinated MTP-lα bound to the receptor was determined by scintillation counting Competition curves were obtained for compounds and the concentration of compound which displaced 50% of bound iodinated MJP-lα was calculated (IC50). Preferred compounds of formula (I) have an IC50 of less than 50UM Results from this test for certain compounds of the invention are presented in Table II In Table II the results are presented as Pic50 values A Pic50 value is the negative log (to base 10) of the IC50 result, so an IC50 of lµM (that is 1 x 10'6M) gives a Pic50 of 6. If a compound was tested more than once then the data below is an average of the probative tests results. Table VII (Table Removed) SCHEME 1 (Scheme Removed) Conditions a) Reductive amination (R4NH2, NaBH(OAc)3) b) Amide formation (R5C02H, coupling agent or R5COCI, base) c) Urea formation (isocyanate) d) H2, Pd (PG is Bn or Bz) e) HCI or TFA (PG is Boc) SCHEME 2 (Scheme Removed) Conditions a) Alkyl halide, base b) R2C(=0)CH2, R3CHO, AcOH c) R2C(=0)CH=CHR3 d) Reduction then MsCI, base e) Cyclic amine, base, Nal SCHEME 3 (Scheme Removed) Conditions a) (i) (EtO)2P(=0)CH2CO2Et, base, (il) hydtogenation (e.g Pd(OH)2, H2) b) Reduction (e g. LiAIH4) (R3 is H) c) (i) Reduction to aldehyde (e.g DIBAL-H), (n) R3MgBr d) Oxidation (e g Dess-Martin periodinane) e) (i) MeONHMe, AIMe3, (ii) Reduction (R3 is H) or R3MgBr f) Reductive animation (NaBH(OAc)3, AcOH) g) HCI or TFA h) Amide formation (acid & coupling reagent or acid halide, base) i) Sulfonamide formation (sulfonyl chloride, base) j) Reductive amination (aldehyde, NaBH(OAc)3) WE CLAIM: 1. A piperidine compound of formula (I): (Formula Removed) wherein L is CH or N; M is CH or N; provided that L and M are not both CH; R1 is hydrogen, C1-6 aikyl[optionally substituted by phenyl {which itself optionally substituted by halo}], S(O)2R6, S(O)2NHR7, C(O)R7, C(O)2(C1-6 alkyl) or C(O)NHR7; and when M is CH R1 can also be NHS(O)2R6, NHS(O)2NHR7, NHC(O)R7 or NHC(O)NHR7; R2 is phenyl or heteroaryl, either of which is optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, S(O)n(C1-4 alkyl),nitro, cyano or CF3; R3 is hydrogen or C1-4 alkyl; R4 is hydrogen, methyl, ethyl, allyl or cyclopropyl; R5 is phenyl, heteroaiyl, phenyl (C1-2)alkyl or heteroaryl(C1-2)alkyl; wherein the phenyl and heteroaryl rings are optionally substituted by halo, cyano, nitro, hydroxy, C1-4 alkyl, C1-4 alkoxy, S(O)kC1-4alkyl, S{O)2NR8R9, NHS(O)2(C1-4 alkyl), NH2, NH(C1-4alkyl), N(C1-4alkyl)2, NHC(O)NH2, C{0)NH2, C(O)NH(C1-4alkyl), NHC(O)(C1-4alkyl), CO2H, C02(C1-4 alkyl), C(O) (C1-4 alkyl), CF3, CHF2, CH2F, CH2CF3 or OCF3; k, m and n axe, independently, 0, 1 or 2; R6 is C1-6 alkyl [optionally substituted by phenyl { which itself optionally substituted by halo}], C3-7 cycloalkyl, phenyl {optionally substituted by halo}; R7 is hydrogen, C1-6 alkyl [optionally substituted by phenyl { which itself optionally substituted by halo}], C3-7 cycloalkyl, phenyl {optionally substituted by halo}; R8 and R9 are, independently, hydrogen or C1-4alkyl, or together with a nitrogen or oxygen atom, may join to form a 5- or 6-membered ring which is optionally substituted with C1-4alkyl, C(0)H or C{0)(C1-4alkyl); or a pharmaceutically acceptable salt thereof or a solvate thereof; provided that when R1 is hydrogen or unsubstituted alkyl, R4 is hydrogen, methyl or ethyl, L is CH and M is N, then the phenyl or heteroaryl part of R5 is substituted by one of: S(0)kC1-4alkyl, NHC(0)NH2, C(0)(C1-4alkyl), CHF2, CH2F, CH2CF3 or OCF3, and optionally further substituted by one or more of halo, cyano, nitro, hydroxyl, C1-4alkyl , C1-4alkoxy, S{O)kC1-4alkyl, S(O)2NR8R9, NHS(O)2(C1-4 alkyl), NH2, NH(C1-4alkyl), N(C1-4alkyl)2, NHC(O)NH2, C(O)NH2, C(O)NH(C1-4alkyl), NHC{O)(C1-4alkyl), CO2H, CO2(C1-4 alkyl), C(O)(C1-4 alkyl), CF3, CHF2, CH2F, CH2CF3 or OCF3; 2. A compound as claimed in claim 1, wherein L is CH. 3. A compound as claimed in claim 1 or 2, wherein M is N. 4. A compound as claimed in claim 1, 2 or 3, wherein R2 is phenyl optionally substituted by halo. 5. A compound as claimed in claim 1, 2, 3 or 4 wherein R3 is hydrogen or methyl. 6. A compound as claimed in claim 1, 2, 3, 4 or 5 wherein R4 is ethyl.

Full Text

The present invention relates to a piperidine compound.
The present invention relates to heterocyclic derivatives having pharmaceutical activity, to processes for preparing such derivatives, to pharmaceutical compositions comprising such derivatives and to the use of such derivatives as active therapeutic agents.
PharmaceuticaHy active piperidine derivatives are disclosed in PCT/SEO1/01053, EP-Al-1013276, WO00/08013, W099/38514 and WO99/04794.
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 well as 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 chemokme 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 )3) families. These are distinguished on the basis of a single ammo 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 neurrophil-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 (Regulaced on Activation, Normal T Expressed and Secreted), eotaxin and the macrophage inflammatory proteins lα and 1ß (MTP-lα and MTP-1ß).
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.
The CCR5 receptor is expressed on T-lymphocytes, monocytes, macrophages, dendritic cells, microglia and other cell types. These detect and respond to several
chemokines, principally "regulated on activation normal T-cell expressed and secreted" (RANTES), macrophage inflammatory proteins (MIP) MEP-lα and MIP-1ß and monocyte chemoattractant protein-2 (MCP-2)
This results in the recruitment of cells of the immune system to sites of disease In many diseases it is the cells expressing CCR5 which contribute, directly or indirectly, to tissue damage Consequently, inhibiting the recruitment of these cells is beneficial in a wide range of diseases
CCR5 is also a co-receptor for HIV-1 and other viruses, allowing these viruses to enter cells. Blocking the receptor with a CCR5 antagonist or inducing receptor internalisation with a CCR5 agonist protects cells from viral infection
The present invention provides a compound of formula (I)
wherein
L is CH or N, M is CH or N, provided that L and M are not both CH; R1 is hydrogen, C1-6 alkyl [optionally substituted by phenyl {which itself optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, mtro, CF3, OCF3, (C1-4 alkyl)C(0)NH, S(0)2NH2, C1-4 alkylthio, S(0)(C1-4 alkyl) or S(0)2(C1-4 alkyl)} or heteroaryl {which itself optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, intro, CF3. (C1-4 alkyl)C(0)NH, S(0)2NH2, C1-4 alkylthio, S(0)(C1-4 alkyl) or S(0)2(C1-4 alkyl))], phenyl {optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, mtro, CF3, OCF3, (C1-4 alkyl)C(0)NH, S(0)2NH2, C1-4 alkylthio, S(0)(C1-4 alkyl) or S(0)2(C14 alkyl)), heteroaryl {optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, mtro, CF3, (C1-4 alkyl)C(0)NH. S(0)2NH2 C1-4 alkylthio, S(0)(C1-4 alkyl) or S(0)2(C1-4 alkyl)), S(0)2R6, S(O)2NR10Ru, C(0)R7, C(0)2(C1-6 alkyl) (such as tert-butoxycarbonyl), C(0)2(phenyl(C1-2 alkyl)) (such as benzyloxycarbonyl) or C(0)NHR7, and when M is CH R1 can also be NHS(0)2R6, NHS(0)2NHR7, NHC(0)R7 or NHC(0)NHR7,
R is phenyl or heteroaryl, either of which is optionally substituted by halo, C1-4 alkyl, C1-4
alkoxy, S(0)„(C1-4 alkyl), mtro, cyano or CF3,
R is hydrogen or C1-4 alkyl, R4 is hydrogen, methyl, ethyl, ally] or cyclopropyl,
R5 is phenyl, heteroaryl, phenylNH, heteroarylNH, phenyl(Ci.2)alkyl. heteroaryl(C1-62)alkyl, phenyl(C1-2 alkyl)NH or heteroaryl(C1-2 alkylJNH, wherein the phenyl and heteroaryl rings of R5 are optionally substituted by halo, cyano, nitro, hydroxy, C1-4 alkyl, C1-4 alkoxy, S(0)IC(C1-4
alkyl), S(0)2NR8R9, NHS(0)2(Ci.4 alkyl), NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, NHC(0)NH2, C(0)NH2, C(0)NH(C1-4 alkyl), NHC(0)(C1-4 alkyl), C02H, C02(C1-4 alkyl), C(0)(C1-4 alkyl), CF3, CHF2, CH2F, CH2CF3 or OCF3, k, m and n are, independently, 0, 1 or 2,
R6 is C1-6 alkyl [optionally substituted by halo (such as fluoro), C1-4alkoxy, phenyl {which itself optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, 0CF3, (C1-4 alkyl)C(0)NH, S(0)2NH2, C1-4alkylthio, S(0)(C1-4 alkyl) or S(0)2(C1-4 alkyl)} or heteroaryl {which itself optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, (C1-4
alkyl)C(0)NH, S(0)2NH2, C1-4 alkylthio, S(0)(C1-4 alkyl) or S(0)2(C1-4 alkyl)}], C3-7 cycloalkyl, pyranyl, phenyl (optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, OCF3, (C1-4 alkyl)C(0)NH, S(0)2NH2, C1-4 alkylthio, S(0)(C1-4 alkyl) or S(0)2(Ci-4 alkyl)} or heteroaryl {optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, (C1-4 alkyl)C(0)NH, S(0)2NH2, C1-4 alkylthio, S(0)(C1-4 alkyl) 01 S(0)2(C1-4 alkyl)}, R7 is hydrogen, C1-6 alkyl {optionally substituted by halo (such as fluoro), C1-4 alkoxy, phenyl (which itself optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, OCF3, (C1-4 aIkyl)C(0)NH, S(0)2NH2, C1-4 alkylthio, S(0)(C1-4 alkyl) or S(0)2(C1-4 alkyl)} 01 heteroaryl {which itself optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, (C1-4 alkyl)C(0)NH, S(0)2NH2, C1-4 alkylthio, S(0)(C1-4 alkyl) or S(0)2(C1-4 alkyl)}], C3.7 cycloalkyl, pyranyl, phenyl {optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, OCF3, (C1-4 alkyl)C(0)NH, S(0)2NH2, C1-4 alkylthio, S(0)(C1-4 alkyl) or S(0)2(C,. 4 alkyl)] or heteroaryl {optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, (C1-4 alkyl)C(0)NH, S(0)2NH2, C1-4 alkylthio, S(0)(C1-4 alkyl) or S(0)2(C1-4 alkyl)}, R and R are, independently, hydrogen or C1-4 alkyl, or together with a nitrogen or oxygen atom, may join to form a 5- or 6-membered ring which is optionally substituted with C1-4
alky], C(0)H or C(0)(C1-4 alkyl),
R10 and Rn are, independently, hydrogen or C1-4 alkyl, or may join to form a 5- or 6-membered ring which is optionally substituted with C1-4 alkyl or phenyl (wherein the phenyl nng is optionally substituted by halo, cyano, nitro, hydroxy, C1-4 alkyl, C1-4 alkoxy, S(0)mC1-4
alkyl, S(0)2NH2, S(0)2NH(C1-4 alkyl), S(0)2N(C1-4 alkyl)2, NHS(0)2(C1-4 alkyl), NH2, NH(Ci-4 alkyl), N(C1-4 alkyl)2, NHC(0)NH2, C(0)NH2, C(0)NH(C1-4 alkyl), NHC(0)(C1-4
alkyl), C02H, C02(C1-4 alkyl), C(0)(C1-4 alkyl), CF3, CHF2, CH2F, C,H2CF3 or 0CF3); or a pharmaceutically acceptable salt thereof or a solvate thereof;
provided that when R1 is hydrogen or unsubstituted alkyl, R4 is hydrogen, methyl or ethyl, L is CH and M is N, then the phenyl or heteroaryl part of R5 is substituted by one of: S(0)kCi„4 alkyl, NHC(0)NH2, C(0)(C1-4 alkyl), CHF2, CH2F, CH2CF3 or OCF3, and optionally further substituted by one or more of halo, cyano, nitro, hydroxy, C1-4 alkyl, C1-4 alkoxy, S(0)icC1-4 alkyl, S(0)2NR8R9, NHS(0)2(C1-4 alkyl), NH2) NH(C1-4 alkyl), N(C1-4 alkyl)2, NHC(0)NH2, C(0)NH2, C(0)NH(C1-4 alkyl), NHC(0)(C1-4 alkyl), C02H, C02(C1-4alkyl), C(0)(C1-4 alkyl), CF3, CFfF2, CH2F, CH2CF3 or OCF3
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, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate or p-toluenesulphonate
The compounds of the invention may exist as solvates (such as hydrates) and the present invention covers all such solvates
Alkyl groups and moieties are straight or branched chain and are, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl or tert-butyl Methyl is sometimes abbreviated to Me herembelow
Fluoroalkyl includes, for example, one to six, such as one to three, fluorine atoms, and comprises, for example, a CF3 group Fluoroalkyl is, for example, CF3 or CH2CF3
Cycloalkyl is, for example, cyclopropyl, cyclopentyl or cyclohexyl.
Phenyl(C1-2 alkyl)aikyl is, for example, benzyl, l-(phenyl)eth-l-yl or l-(phenyl)eth-2-
Heteroaryl(C1-2 alkyl)alkyl is, for example, pyridinylmethyl, pyrimidinylmethyl or 1-(pyndmyl)eth-2-yl.
Phenyl(C1-2 alkyl)NH is, for example, benzylamino Heteroaryl(C1-2 alkyl)NH is, for example, pyndinylCH2NH, pynmidinylCH2NH or pyndinylCH(CH3)NH
Heteroaryl is an aromatic 5 or 6 membered ring, optionally fused to one or more other rings, comprising at least one heteroatom selected from the group comprising nitrogen,
oxygen and sulphur, or an N-oxide thereof, or an S-oxide or S-dioxide thereof Heteroaryl is, for example, furyl, threnyl (also known as thiophenyl), pyrrolyl, thiazolyl, isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, [l,2,4]-triazolyl, pyridinyl, pyrimidinyl, indolyl, benzo[b]furyl (also known as benzfuryl), benz[b]thienyl (also known as benzthienyl or benzthiophenyl), indazolyl, benzimidazolyl, benztnazolyl, benzoxazolyl, benzthiazolyl, 1,2,3-benzothiadiazolyl, an rmidazopyridinyl (such as irxudazo[l,2a]pyndinyl), thieno[3,2-b]pyndin-6-yl, 1,2,3-benzoxadiazolyI (also known as benzo[l,2,3]thiadiazolyl), 2,1,3-benzothiadiazolyl, benzofurazan (also known as 2,1,3-benzoxadiazolyl), quinoxalinyl, a pyrazolopyndine (for example lH-pyrazolo[3,4-b]pyndmyl), quinolinyl, isoquinolinyl, a naphthyndinyl (for example [l,6]naphthyridinyl or [l,8]naphthyndinyl), a benzothiazinyl or dibenzothiophenyl (also known as dibenzothienyl); or an N-oxide thereof, or an S-oxide or S-dioxide thereof Heteroaryl can also be pyrazinyl. Heteroaryl is, for example, pyndinyl, pyrimidinyl, indolyl or benzimidazolyl.
In one particular aspect the present invention provides a compound of formula (I) wherein L is CH or N; M is CH or N, provided that L and M are not both CH, R1 is hydrogen, C1-6 alkyl [optionally substituted by phenyl {which itself optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, C1-4 alkylthio, S(0)(C1-4 alkyl) or S(0)2(C1-4 alkyl)} or heteroaryl {which itself optionally substituted by halo, C1-4 alky], C1-4 alkoxy, cyano, nitro, CF3, C1-4 alkylthio, S(0)(C1-4 alkyl) or S(0)2(C1-4 alkyl)}], phenyl {optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, C1-4 alkylthio, S(0)(C1-4 alkyl) or S(0)2(C1-4 alkyl)}, heteroaryl {optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, C1-4 alkylthio, S(0)(C1-4 alkyl) or S(0)2(C1-4 alkyl)}, S(0)2R6, S(0)2NHR7, C(0)R7, C(0)2(C1-6 alkyl) or C(0)NHR7; and when M is CH R1 can also be NHS(0)2R6, NHS(0)2NHR7, NHC(0)R7 or NHC(0)NHR7, R2 is phenyl or heteroaryl, either of which is optionally substituted in the ortho or meta position by halo, C1-4 alkyl, C1-4 alkoxy, S(0)„(C1-4 alkyl), nitro, cyano or CF3; R3 is hydrogen or C1-4 alkyl, R4 is hydrogen, methyl, ethyl, ally] or cyclopropyl; R5 is phenyl, heteroaryl, phenylNH, heteroarylNH, phenyl(C1-2)alkyl, heteroaryl(C1-2)alkyl, phenyl(C1-2 alkyl)NH or heteroary](C1-2 alkyl)NH. wherein the phenyl and heteroaryl rings of R5 are optionally substituted by halo, cyano, nitro, hydroxy, C1-4 alkyl, C1-4 alkoxy, S(0)kC1-4 alkyl, S(0)2NRsR9, NHS(0)2(C1-4 alkyl), NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, NHC(0)NH2) C(0)NH2, C(0)NH(Ci.4 alkyl), NHC(0)(C1-4 alkyl), C02H, C02(C1-4 alkyl), C(0)(C1-4 alkyl), CF3, CHF2, CH2F, CH2CF3 or OCF3; R8 and R9 are, independently, hydrogen or C1-4 alkyl, or together with a nitrogen or oxygen atom, may join to form a 5- or 6-
membered ring which is optionally substituted with C1-4 alkyl, C(0)H or C(0)(C1-4 alkyl), k and n are, independently, 0, 1 or 2, R6 is C1-6 alkyl [optionally substituted by phenyl {which itself optionally substituted by halo, Cw alkyl, C1-4 alkoxy, cyano, mtro, CF3, C1-4 alkylthio, S(0)(C1-4 alkyl) or S(0)2(C1-4 alkyl)} or heteroaryl {which itself optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, C1-4 alkylthio, S(0)(C1-4 alkyl) or S(0)2(C1-4
alkyl))], C3-7 cycloalkyl, phenyl {optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, , mtro, CF3, C1-4 alkylthio, S(0)(C1-4 alkyl) or S(0)2(C1-4 alkyl)) or heteroaryl {optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, INtro, CF3, C1-4 alkylthio, S(0)(C1-4alkyl) or S(0)2(C1-4 alkyl)}, R7 is hydrogen, C1-6 alkyl [optionally substituted by phenyl {which itself optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, C1-4 alkylthio, S(0)(C1-4 alkyl) or S(0)2(C1-4 alky!)} or heteroaryl {which itself optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, C1-4 alkylthio, S(0)(C1-4 alkyl) or S(0)2(C1-4
alkyl)}], C3-7 cycloalkyl, phenyl {optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, C1-4 alkylthio, S(0){C1-4 alkyl) or S(0)2(C1-4 alkyl)} or heteroaryl {optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, C1-4 alkylthio, S(0)(C1-4 alkyl) or S(0)2(C1-4 alkyl)}, or a pharmaceutically acceptable salt thereof or a solvate thereof, provided that when R1 is hydrogen or unsubstituted alkyl, R4 is hydrogen, methyl or ethyl, L is CH and M is N, then the phenyl or heteroaryl part of Rs is substituted by one of: S(0)kC1-4
alkyl, NHC(0)NH2, C(0)(C1-4alkyl), CHF2, CH2F, CH2CF3 or OCF3, and optionally further substituted by one or more of halo, cyano, nitro, hydroxy, C1-4 alkyl, C1-4alkoxy, S(0)kC1-4 alkyl, S(0)2NRRR9, NHS(0)2(C1-4 alkyl), NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, NHC(0)NH2, C(0)NH2, C(0)NH(C,.4 alkyl), NHC(0)(C1-4 alkyl), C02H, C02(C,4 alkyl), C(0)(C1-4 alkyl), CF3, CHF2, CH2F, CH2CF3 or OCF3
In another aspect the present invention provides a compound of the invention wherein when L and M are both N, and R1 is hydrogen, C1-4 alkyl or phenyl (the phenyl being substituted with 0, 1 or 2 substituents selected from the list consisting of. fluoro, chloro, C1-4
alkyl, C1-4 alkoxy, cyano, CF3, OCF3, (C1-4 alkyl)C(0)NH and S(0)2NH2), then the phenyl or heteroaryl moiety of R5 carries a S(0)2(C1-4 alkyl) substituent, and, optionally, one or more further substituents
In a further aspect of the invention heteroaryl is pyrrolyl, thRenyl, imidazolyl, thiazolyl, isoxazolyl, pyridinyl, pynmidinyl, pyrazINyl or quINohnyl
In another aspect M is N and L is CH or N
In yet another aspect L and M are both N
In a further aspect L is CH and M is N.
In a still further aspect L is N and M is CH
In another aspect of the invention R1 is hydrogen, C1-6 alkyl [optionally substituted by phenyl {which itself optionally substituted by halo}], S(0)2R6, S(0)2NHR7, C(0)R7, C(0)2(C1-6 alkyl) or C(0)NHR7; and when M is CH R! can also be NHS(0)2R6, NHS(0)2NHR7, NHC(0)R7 or NHC(0)NHR7; R6 is Q.6 alkyl [optionally substituted by phenyl {which itself optionally substituted by halo}], C3.7 cycloalkyl, phenyl {optionally substituted by halo}; and R7 is hydrogen, C1-6 alkyl [optionally substituted by phenyl {which itself optionally substituted by halo}], C3-7 cycloalkyl, phenyl {optionally substituted by halo}.
In another aspect of the invention R1 is C1-6 alkyl [substituted by phenyl {which itself optionally substituted by halo}], S(0)2R6, S(0)2NHR7, C(0)R7, C(0)2(C1-6 alkyl) or C(0)NHR7, and when M is CH R1 can also be NHS(0)2R6, NHS(0)2NHR7, NHC(0)R7 or NHC(0)NHR7; R6 is C1-6alkyl [optionally substituted by phenyl {which itself optionally substituted by halo]], C3.7 cycloalkyl, phenyl {optionally substituted by halo); and R7 is hydrogen, C1-6alkyl [optionally substituted by phenyl {which itself optionally substituted by halo}], C3-7 cycloalkyl, phenyl {optionally substituted by halo}
In a further aspect of the invention R1 is S(0)2R6, C(0)R7, C(0)2(Ci.6 alkyl) or C(0)NHR7, and when M is CH R1 can also be NHS(0)2R6 or NHC(0)R7, and R6 and R7 are as defined above
In another aspect of the invention R1 is hydrogen, C1-6 alkyl [optionally substituted by phenyl {which itself optionally substituted by halo}], S(0)2R6, C(0)R7, C(0)2(C1-6 alkyl) or C(0)NHR7, and when M is CH R1 can also be NHS(0)2R6 or NHC(0)R7; R6 is C1-6alkyl [optionally substituted by phenyl {which itself optionally substituted by halo}], C3.7 cycloalkyl, phenyl {optionally substituted by halo}, and R7 is hydrogen, C1-6 alkyl [optionally substituted by phenyl {which itself optionally substituted by halo}], C3-7 cycloalkyl, phenyl {optionally substituted by halo}.
In a further aspect R1 is phenyl (optionally substituted by halo (for example fluoro), C1-4 alkyl (for example methyl), C1-4 alkoxy (for example methoxy), CF3 or OCF3), S(0)2(C1-4 alkyl) (for example S(0)2CH3, S(0)2CH2CH3 or S(0)2CH(CH3)z), S(0)2(C1-4 fluoroalkyl) (for example S(0)2CF3 or S(0)2CH2CF3), S(0)2phenyl (optionally substituted (such as mono-substituted) by halo (for example chloro), cyano, C1-4 alkyl, C1-4 alkoxy, CF3, OCF3, S(0)2(Q. 4 alkyl) (for example S(0)2CH3 or S(0)2CH2CH2CH3) or S(0)2(C1-4 fluoroalkyl) (for example S(0)2CH2CF3)), benzyl (optionally substituted by halo (for example chloro or fluoro), Q.4
alkyl, C1-4 alkoxy (for example methoxy), CF3 or OCF3), benzoyl (optionally substituted by halo (for example chloro or fluoro), C1-4 alkyl (for example methyl), C1-4 alkoxy, CF3 or OCF3), C(0)NHphenyl (optionally substituted by halo (for example fluoro), C1-4 alkyl, C1-4
alkoxy, CF3 or OCF3), S(0)2thiophenyl, CH2pyridINyl, CH2quinolinyl or CH3tmazolyl
In yet another aspect R1 is phenyl (optionally substituted (such as mono-substituted) by halo (for example fluoro), C1-4 alkyl (for example methyl) or C1-4 alkoxy (for example methoxy)), S(0)2(C1-4 alkyl) (for example S(0)2CH3, S(0)2CH2CH3 or S(0)2CH(CH3)2), S(0)2(C1-4 fluoroalkyl) (for example S(0)2CF3 or S(0)2CH2CF3), S(0)2phenyl (optionally substituted (such as mono-substituted) by halo (for example chloro), cyano, CF3, OCF3, S(0)2(C1-4 alkyl) (for example S(0)2CH3 or S(0)2CH2CH2CH3) or S(0)2(C1-4 fluoroalkyl) (for example S(0)2CH2CF3)), benzyl (optionally substituted by halo (for example chloro or fluoro) or C1-4 alkoxy (for example methoxy)), benzoyl (optionally substituted by halo (for example chloro or fluoro) or C1-4 alkyl (for example methyl)), C(0)NHphenyl (optionally substituted by halo (for example fluoro)), S(0)2thiophenyl, CH2pyndinyl, CH2quinolmyl or CH2thiazolyl
In a further aspect R is phenyl (optionally substituted (such as mono-substituted) by halo (for example fluoro) or C1-4 alkyl (for example methyl)), S(0)2(C1-4 alkyl) (for example S(0)2CH3, S(0)2CH2CH3 or S(0)2CH(CH3)2), S(0)2(C1-4 fluoroalkyl) (for example S(0)2CF3 or S(0)2CH2CF3), S(0)2phenyl (optionally substituted (such as mono-substituted) by CF3, OCF3 or S(0)2(C1-4 alkyl) (for example S(0)2CH3)), benzyl (optionally substituted by halo (for example chloro or fluoro) or C1-4 alkoxy (for example methoxy)), benzoyl (optionally substituted by halo (for example chloro or fluoro)), C(0)NHphenyl (optionally substituted by , halo (for example fluoro)), CH2pyndinyl, CH2qumohnyl or CH2thiazolyl
In a still further aspect R1 is hydrogen, C1-6 alkyl [optionally substituted by phenyl {which itself optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, OCF3, (C1-4 alkyl)C(0)NH, S(0)2NH2 or S(0)2(C1-4 alkyl)} or heteroaryl (which itself optionally substituted by halo, C1-4 alkyl or (C1-4 alkyl)C(O)NH)], phenyl (optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, OCF3, (C1-4 alkyl)C(0)NH, S(0)2NH2 or S(0)2(C1-4 alkyl)}, heteroaryl (optionally substituted by halo, C1-4 alkyl or (C1-4
alkyl)C(0)NH}, S(0)2R6, S(O)2NR,0Rn, C(0)R7 or C(0)NHR7, and when M is CH R1 can also be NHC(0)R7; R6 is C1-6 alkyl [optionally substituted by halo (such as fluoro), phenyl (which itself optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, OCF3, (C1-4 alkyl)C(0)NH, S(0)2NH2 or S(0)2(C1-4 alkyl)} or heteroaryl (which itself optionally substituted by halo, C1-4 alkyl or (C1-4 alkyl)C(O)NH)], phenyl (optionally substituted by
halo, C1-4 aikyl, C1-4 alkoxy, cyano, nitro, CF3, OCF3, (C1-4 alkyl)C(0)NH, S(0)2NH2 or S(0)2(C1-4 aikyl)} or heteroaryl {optionally substituted by halo, C1-4 alkyl or (C1-4
alkyl)C(0)NH}, R7 is hydrogen, C1-6alkyl [optionally substituted by halo (such as fluoro), C1. 4 alkoxy, phenyl {which itself optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, iutro, CF3) OCF3, (C1-4 alkyl)C(0)NH, S(0)2NH2 or S(Oh(C1-4 alkyl)} or heteroaryl {which itself optionally substituted by halo, C1-4 alkyl or (C1-4 alkyl)C(O)NH)], C3-7 cycloalkyl, pyranyl, phenyl {optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, OCF3, (C1-4 alkyl)C(0)NH, S(0)2NH2 or S(0)2(C1-4alkyl)] or heteroaryl {optionally substituted by halo, C1-4 alkyl or (C1-4 alkyl)C(0)NH}, and, R10 and Rn are, independently, hydrogen or C1-4 alkyl
In a further aspect R1 is phenyl (optionally substituted (such as mono-substituted) by halo (for example fluoio) orC1-4 alkyl (for example methyl)), S(0)2(C1-4 alkyl) (for example S(0)2CH3 or S(0)2CH2CH3), S(0)2(Ci 4 fluoroalkyl) (for example S(0)2CF3), S(0)2phenyl (optionally substituted (such as mono-substituted) by CF3 or OCF3), benzyl, benzoyl (optionally substituted by halo (for example chloro or fluoro)) or C(0)NHphenyl (optionally substituted by halo (for example fluoro))
In yet another aspect of the invention R2 is phenyl or heteroaryl, either of which is optionally substituted in the ortho or meta position by halo, C1-4 alkyl, C1-4 alkoxy, S(0)„(C1-4
alkyl), nitro, cyano or CF3, wherein n is 0, 1 01 2, for example 0 or 2 (Ortho and meta positions are ortho and meta relative to the position of attachment of that ring to the structure of formula (I))
In a still further aspect R2 is optionally substituted phenyl (such as optionally substituted by halo-{such as chloro or fluoro), cyano, methyl, ethyl, methoxy, ethoxy or CF3). In one aspect the substitution is on the ortho or meta position of the phenyl ring.
In another aspect R2 is optionally substituted phenyl (such as optionally substituted by halo or CF3). For example R2 is 3-fluorophenyl, 3-chlorophenyl, 4-fluorophenyl or 4-CF3-phenyl In a further aspect R2 is phenyl, 3-fluoiophenyl, 4-fluorophenyl, 3-chlorophenyl, 3,4-difluorophenyl or 3,5-difluorophenyl. In another aspect R2 is phenyl, 3-fluorophenyl, 4-fluorophenyl, 3,4-difiuorophenyl or 3,5-difluorophenyl In a still further aspect of the invention R" is phenyl or 3-fluorophenyl
In another aspect of the invention R3 is hydrogen or methyl In a further aspect of the invention when R3 is C1-4 alkyl (such as methyl) the carbon to which R3 is attached has the R absolute configuration In yet another aspect of the invention R3 is hydiogen
In a further aspect offhe invention R4 is ethyl.
In a still further aspect the present invention provides a compound of the invention wherein R5 is phenyl(C1-2)alkyl, pheny(C1-2 alkyl)NH, phenyl, heteroaryl or heteroaryl(C1. 2)alkyl, wherein the phenyl and heteroaryl rings are optionally substituted by halo, cyano, nitro, hydroxy, C1-4 alkyl, C1-4 alkoxy, S(0)kC1-4alkyl, S(0)2NR8R9, NHS(0)2(C1-4alkyl), NH2> NH(C1-4 alkyl), N(C1-4 alkyl)2, NHC(0)NH2, C(0)NH2, C(0)NH(C1-4 alkyl), NHC(0)(C1-4 alkyl), C02H, C02(C1-4 alkyl), C(0)(C1-4 alkyl), CF3, CHF2, CH2F, CH2CF3 or OCF3; and R8 and R9 are, independently, hydrogen or C1-4 alkyl, or together with a nitrogen or oxygen atom, may join to form a 5- or 6-membered ring which is optionally substituted with C1-4lkyl, C(0)H or C(0)(C1-4 alkyl); and k is 0, I or 2 (for example, 2).
In another aspect the invention provides a compound of the invention wherein R is phenyl(C1-2)alkyl or phenyl(C1-2 alkyl)NH, wherein the phenyl rings of R5 are optionally substituted by halo, cyano, nitro, hydroxy, C1-4 alkyl, C1-4alkoxy, S(0)KC1-4 alkyl, S(0)2NR8R9, NHS(0)2(C1-4 alkyl), NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, NHC(0)NH2, C(0)NH2, C(0)NH(C1-4 alkyl), NHC(0)(C1-4alkyl), C02H, C02(C1-4 alkyl), C(0)(C1-4 alkyl), CF3, CHF2, CH2F, CH2CF3 or OCF3, R8 and R9 are, independently, hydrogen or C1-4 alkyl, or together with a nitrogen or oxygen atom, may join to form a 5- or 6-membered ring which is optionally substituted with C1-4 alkyl, C(0)H or C(0)(C1-4 alkyl), and k is 0, I or 2.
In a still further aspect of the invention R5 is phenyl, heteroaryl, phenyl(Ci_2)alkyl or heteroaryl(C].2)alkyl, wherein the phenyl and heteroaryl rings are optionally substituted by halo, cyano, nitro, hydroxy, C1-4 alkyl, C1-4 alkoxy, S(0)kC1-4 alkyl, S(Q)2NR8R9, NHS(0)2(C1-4 alkyl), NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, NHC(0)NH2, C(0)NH2, C(0)NH(C1-4 alkyl), NHC(0)(C1-4 alkyl), C02H, C02(C1-4 alkyl), C(0)(C1-4 alkyl), CF3, CHF2, CH2F, CH2CF3 or OCF3, k is 0, 1 or 2, and R8 and R9 aRe, independently, hydrogen or C1-4 alkyl, or together with a nitrogen or oxygen atom, may join to form a 5- or 6-membered ring which is optionally substituted with C1-4 alkyl, C(0)H or C(0)(C1-4 alkyl)
In another aspect R5 is phenyl or benzyl, wherein the aromatic rings are optionally substituted by halo, cyano, nitro, hydroxy, C1-4 alkyl, C1-4 alkoxy, S(0)ICC1-4 alkyl, S(0)2NR8R9, NHS(0)2(C1-4 alkyl), NH2, NH(Cw alkyl), N(C1-4 alkyl)2, NHC(0)NH2, C(0)NH2, C(0)NH(C1-4 alkyl), NHC(0)(C1-4 alkyl), C02H, C02(C1-4 alkyl), C(0)(C1-4 alkyl), CF3, CHF2, CH2F, CH2CF3 or OCF3, k is 0, 1 or 2, and R8 and R9 are, independently, hydrogen or C1-4 alkyl, or together with a nitrogen or oxygen atom, may join to form a 5- or 6-membered ring which is optionally substituted with C1-4 alkyl, C(0)H or C(0)(C1-4 alkyl).
In a further aspect R5 is phenyl or benzyl; wherein the aromatic rings are optionally substituted by halo, cyano, nitro, hydroxy, C1-4 alkyl, C1-4 alkoxy, S(0)2C1-4 alkyl, S(0)2NR8R9, NHS(0)2(C1-4 alkyl), NH2, NH(Cm alkyl), N(Cm alkyl)2, NHC(0)NH2> C(0)NH2, C(0)NH(C,.4 alkyl), NHC(0)(Cm alkyl), C02H, C02(CM alkyl), C(0)(Cm alkyl), CF3, and R8 and R9 are, independently, hydrogen or CM alkyl
In another aspect R5 is NHCH2phenyl wherein the phenyl ring is optionally substituted by halo, cyano, nitro, hydroxy,C1-4 alkyl, C1-4 alkoxy, S(0)2C1-4 alkyl, S(0)2NR8R9, NHS(0)2(C1-4 alkyl), NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2) NHC(0)NH2; C(0)NH2, C(0)NH(C1-4 alkyl), NHC(0)(C1-4 alkyl), C02H, C02(C1-4 alkyl), C(0)(C1-4 alkyl), CF3, and R8 and R9 are, independently, hydrogen or Cm alkyl
In yet another aspect R5 is benzyl wherein the phenyl ring is optionally substituted by halo, cyano, nitro, hydroxy, C1-4 alkyl, C1-4 alkoxy. S(0)2C1-4 alkyl, S(0)2NR8R9, NHS(0)2(C1-4 alkyl), NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, NHC(0)NH2, C(0)NH2) C(0)NH(Cm alkyl), NHC(0)(CM alkyl), C02H, C02(CM alkyl), C(0)(C,.4 alkyl), CF3. and R8 and R9 aie, independently, hydrogen or C1-4 alkyl
In another aspect R5 is NHCH2phenyl wherein the aromatic ring is optionally substituted by halo (such as fluoro, chloro or bromo), cyano, C1-4 alkyl (such as methyl), C1-4
alkoxy (such as methoxy) or S(0)2C1-4 alkyl (such as S(0)2CH3)
In yet another aspect R5 is benzyl wherein the aromatic ring is optionally substituted by halo (such as fluoro, chloro or bromo), cyano. C1-4 alkyl (such as methyl), C1-4 alkoxy (such as methoxy) or S(0)2C1-4 alkyl (such as S(0)2CH3).
In a still further aspect Rs is phenyl or benzyl, wherein the aromatic ring is substituted (for example in the para-position) by S(0)2C1-4 alkyl and the ring is optionally further substituted by halo, cyano, nitro, hydroxy, C1-4 alkyl or C1-4 alkoxy.
In another aspect R5 is NHCH2phenyl or benzyl, wherein the aromatic ring is substituted (for example in the para-position) by S(0)2C1-4 alkyl (such as S(0)2CH3) and the ring is optionally further substituted by halo, cyano, nitro, hydroxy, C1-4 alkyl or C1-4 alkoxy.
In another aspect R is NHCH2phenyl wherein the aromatic ring is substituted (for example in the para-position) by S(0)2C1-4 alkyl (such as S(0)2CH3), RJ is, for example NHCH2(4-S(0)2CH3-C6H4)
In another aspect R is benzyl, wherein the aromatic ring is substituted (for example m the para-position) by S(0)2C1-4 alkyl (such as S(0)2CH3), R5 is, for example CH2(4-S(0)2CH3-C6H4)
The carbon labelled ^ in the representation of formula (I) shown below, is always
chiral
(Formula Removed)
When L is N the carbon labelled ^ has, for example, the S absolute configuration. When L is CH the carbon labelled ^ has, for example, the R absolute configuration.
In another aspect the present invention provides a compound of formula (la)'
(Formula Removed) wherein L, M and R1 are as defined above
In a further aspect the present invention provides a compound of formula (lb):
(Formula Removed)
wherein L, M and R1 are as defined above; and R is hydrogen, one or two fluorine atoms, S(0)n(C1-4 alkyl) or C1-4 alkoxy; and n is 0, 1 or 2 (for example, 2)
In another aspect the present invention provides a compound of formula (Ic).
(Formula Removed)
wherein L, M and R1 are as defined above, and R is hydrogen, one or two fluorine atoms, S(O)n(C1-4 alkyl) or C1-4 alkoxy, and n is 0, 1 or 2 (for example, 2).
In a still further aspect the present invention provides a compound of formula (Id)
(Formula Removed)
wherein L, M and R1 are as defined above; R is hydrogen, one or two fluorine atoms, S(O)„(C1-4 alkyl) or C1-4 alkoxy; X is NHCH2, NH or CH2; n is 0, 1 or 2 (for example, 2), and R* is halo (such as fluoio, chloro or bromo), cyano, C1-4 alkyl (such as methyl), C1-4 alkoxy (such as methoxy) or S(O)2C1-4 alkyl (such as S(O)2CH3).
In another aspect the present invention provides a compound of formula (Ie):
(Formula Removed)
wherein L, M and R1 are as defined above
In yet another aspect the present invention provides a compound of formula (If)
(Formula Removed)
wherein L, M, X and R are as defined above
In a still further aspect the present invention provides a compound of formula
wherein R5 is as defined above
The compounds listed in Tables I to VI lllusti ate the invention
TABLET
Table I comprises compounds of formula (lb)
Table H
Table II comprises compounds of formula (lei (Table Removed)

Table II (Table Removed)

Table III comprises compounds of formula (Id)(Table Removed)

Table IV Table IV comprises compounds of formula (Ie) (Table Removed)

(Table Removed)
Table VI Table VI comprises compounds of formula (Ig)
Table V Table V comprises compounds of formula (If).
(Table Removed)
In yet another aspect the invention provides each individual compound listed in the tables above
The compounds of formula (I), (la), (lb), (Ic), (Id). (Ie), (If) and (Ig) can be prepared as shown below (for example in Schemes 2 and 3, with Scheme 1 showing the preparation of an intermediate.) In Schemes 1 to 3 PG is a protecting Group; Ac is acetyl; Boc is tert-butoxycarbonyl, Bn is benzyl, Bz is benzoyl; DIBAL is diisobutylalummium hydride, Et is ethyl, Ms is mesyl, and, TFA is tnfluoroacetic acid
wherein R2, R3, R4 and R5 are as defined above, with a compound of formula (III)
(Table Removed)
A compound of the invention wherein L is N can be prepared by reacting a compound of formula (IT).
(Formula Removed)
wherein R1 is as defined above, in the presence of sodium iodide rand a suitable base (for example a tri(C1-6alkyl)armne such as tnethylamine or Hunig's base), in a suitable solvent (such as a chlorinated solvent, for example dichloromethane) and, for example, at a room temperature (for example 10-30°C)
A compound of the invention wherein L is CH can be prepared by reacting a compound of formula (IV):
(Formula Removed)
wherein R2, R3, R4 and R5 are as defined above, with, depending on the compound of the invention it is desired to make:
a) an acid of formula R1CO2H in the presence of a suitable coupling agent (for example PyBrOP [bromo-tns-pyrrolidino-phosphonium hexafluorophosphate] or HATU) in the presence of a suitable base (such as a tn(C1-6 alkyl)amme, for example dnsopropylethylamine) in a suitable solvent (for example iV-methylpyrrolidinone or a chlorinated solvent, such as dichloromethane) at room temperature (for example 10-30°C),
b) an acid chloride of formula R'C(0)C1 or sulphonyl chlonde of formula R1S(O)2Cl, in the piesence of a suitable base (such as a tri(C1-6 alkyl)amine, for example tnethylamine or diisopropylethylamine) in a suitable solvent (for example a chlorinated solvent, such as dichloromethane) at room temperature (for example 10-30°C), or,
c) an aldehyde of formula R'CHO in the presence of NaBH(OAc)3 (wherein Ac is C(O)CH3) and acetic acid, in a suitable solvent (such as a C1-6aliphatic alcohol, for example ethanol) at room temperature (for example 10-30°C)
Alternatively, a compound of the invention can be prepared by coupling a compound of formula (V)-
(Formula Removed)
wherein L, M, R1, R2, R3 and R4 are as defined above, with-
a) an acid of formula R5C02H in the presence of a suitable coupling agent (for example PyBrOP or HATU) in the presence of a suitable base (such as a tri(C1-6 alkyl)amine, for example diisopropylethylamine) in a suitable solvent (for example N-methylpyrrolidmone or a chlorinated solvent, such as dichloromethane) at room temperature (for example 10-30°C), or,
b) an acid chloride of formula R5C(0)C1, in the presence of a suitable base (such as a tri(C1-6 alkyl)amine, for example triethylamme or diisopropylethylamine) in a suitable solvent (for example a chlorinated solvent, such as dichloromethane) at room temperature (for example 10-30°C)
The starting materials for these processes are either commercially available or can be prepared by literature methods, adapting literature methods or by following or adapting Methods herein described
In a further aspect the invention provides an intermediate of formula (V).
In a still further aspect the invention provides processes for preparing the compounds of formula (I), (la), (lb), (Ic), (Id), (Ie), (If) and (Ig). Many of the intermediates in the processes are novel and these are provided as further features of the invention
The compounds of the invention have activity as pharmaceuticals, in particular as modulators (such as agonists, partial agonists, inverse agonists or antagonists) of chemokine receptor (especially CCR5) 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 (AIDS))
The compounds of the present invention are also of value in inhibiting the entry of viruses (such as human immunodeficiency virus (HIV)) into target calls and, therefore, are of
value in the prevention of infection by viruses (such as HIV), the treatment of infection by viruses (such as HIV) and the prevention and/or treatment of acquired immune deficiency syndrome (AIDS)
According to a further feature of the invention there is provided a compound of the formula (I), (la), (lb), (Ic), (Id), (Ie), (If) or (Ig) (such as (I) or (la)), or a pharmaceutically acceptable salt thereof or a solvate 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 chemokme receptor activity (especially CCR5 receptor activity) 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 present invention, or a pharmaceutically acceptable salt thereof or a solvate thereof
The present invention also provides the use of a compound of the formula (I), (la), (lb), (Ic), (Id), (Ie), (If) or (Ig) (such as (I) or (la)), or a pharmaceutically acceptable salt thereof or a solvate thereof, as a medicament, especially a medicamenl for the treatment of transplant rejection, respiratory disease, psoriasis or rheumatoid arthritis (especially iheumatoid arthritis). [Respiratory disease is, for example, COPD, 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 {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 scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis), and is particularly asthma or rhinitis].
In another aspect the present invention provides the use of a compound of the formula (I), (la), (lb), (Ic), (Id), (Ie), (If) or (Ig) (such as (I) or (la)), or a pharmaceutically acceptable salt thereof or a solvate thereof, in the manufacture of a medicament for use in therapy (for example modulating chemokme receptor activity (especially CCR5 receptor activity (especially rheumatoid arthritis)) in a warm blooded animal, such as man)
The invention also provides a compound of the formula (I), (la), (lb), (Ic), (Id), (Ie), (If) or (Ig) (such as (I) or (la)), or a pharmaceutically acceptable salt thereof or a solvate thereof, for use as a medicament, especially a medicament for the treatment of rheumatoid arthritis
In another aspect the present invention provides the use of a compound of the formula (I), (la), (lb), (Ic), (Id), (Ie), (If) or (Ig) (such as (I) or (la)), or a pharmaceutic ally acceptable salt thereof or a solvate thereof, in the manufacture of a medicament for use in therapy (for example modulating chemokme receptor activity (especially CCR5 receptor activity (especially rheumatoid arthritis)) in a warm blooded animal, such as man).
The invention further provides the use of a compound of formula (I), (la), (lb), (Ic), (Id), (le), (If) or (Ig) (such as (I) or (la)), 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 chrome ihinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis, sarcoidosis; farmer's lung and related diseases; nasal polyposis; fibroid lung or ldiopamic interstitial pneumonia,
(2) (bone and joints) arthndes including rheumatic, infectious, autoimmune, seronegative spondyloarthropathies (such as ankylosing spondylitis, psoriatic arthritis or Reiter's disease), Behcet'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, vascuhtides erythemas, cutaneous eosinophilias, uveitis, Alopecia areata or vernal conjunctivitis,
(4) (gastrointestinal tract) Coeliac disease, proctitis, eosinophilic gastro-ententis, 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 oi cornea, or chronic graft versus host disease; and/or
26 (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, eosmophiha fascitis, hyper IgE syndrome, leprosy (such as lepromatous leprosy), Pendontal disease, Sezary syndrome, idiopathic thrombocytopenia pupura or disorders of the menstrual cycle; in a warm blooded animal, such as man
The present invention further provides a method of treating a chemokine mediated disease state (especially a CCR5 mediated disease state) 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), (la), (lb), (Ic), (Id), (le), (If) or (Ig) (such as (I) or (la)), or a pharmaceutically acceptable salt thereof or solvate thereof
In order to use a compound of the invention, or a pharmaceutically acceptable salt thereof or solvate thereof, for the therapeutic treatment of a warm blooded animal, such as man, m particular modulating chemokine receptor (for example CCR5 receptor) activity, said ingiedient 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), (la), (lb), (Ic), (Id), (le), (If) or (Ig) (such as (I) or (la)), or a pharmaceutically acceptable salt thereof or a solvate thereof (active ingredient), and a pharmaceutically acceptable adjuvant, diluent or earner. 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 carrier Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0 05 to 99 %w (per cent by weight), more preferably from 0 05 to 80 %w, still more preferably from 0 10 to 70 %w, and even more preferably 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 skm), 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, (lipid) emulsions, dispersible
powders, suppositories,.ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions.
A suitable pharmaceutical composition of tins invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule which contains between 0.lmg and lg 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 0lmgkg"1 to l00mgkg"1 of the compound, preferably in the range of 0.lmgkg"1 to 20mgkg"' 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 ieceive a daily oral dose which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day
The following illustrate representative pharmaceutical dosage forms containing the compound of formula (I), (la), (lb), (Ic), (Id), (Ie), (If) or (lg) (such as (I) or (la)), or a pharmaceutically acceptable salt thereof or a solvent thereof (hereafter Compound X), for therapeutic or prophylactic use in humans.

(a)
(Table Removed)
Buffers, pharmaceutically-acceptable cosolvents such as polyethylene glycol, polypropylene glycol, glycerol or ethanol or complexmg agents such as hydroxy-propyl ß-cyclodextrm may be used to aid formulation.
The above formulations may be obtained by conventional procedures well known in the-pharmaceutical art The tablets (a)-(c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.
The invention will now be illustrated by the following non-limiting Examples in which, unless stated otherwise-
(i) temperatures are given in degrees Celsius (°C), operations were earned out at room or ambient temperature, that is, at a temperature in the range of 18-25°C, (li) organic solutions were dried over anhydrous magnesium sulfate, evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600-4000 Pascals; 4 5-30 mm Hg) with a bath temperature of up to 60CC,
(in) chromatography unless otherwise stated means flash chromatography on silica gel; thin layer chromatography (TLC) was carried out on silica gel plates; where a "Bond Elut" column is referred to, this means a column containing lOg or 20g of silica of 40 micron particle size, the silica being contained in a 60ml disposable syringe and supported by a porous disc, obtained from Varian, Harbor City, California, USA under the name "Mega Bond Elut ST' Where an "Isolute™ SCX column" is referred to, this means a column containing benzenesulphonic acid (non-endcapped) obtained from International Sorbent Technology Ltd , 1st House, Duffryn Industial Estate, Ystrad Mynach, Hengoed, Mid Glamorgan, UK. Where "Argonaut™ PS-tris-amine scavenger resin" is referred to, this means a tns-(2-ammoethyl)amine polystyrene resin obtained from Argonaut Technologies Inc., 887 Industrial Road, Suite G, San Carlos, California, USA
(IV) IN general, the course of reactions was followed by TLC and reaction times are given for illustration only,
(v) yields, when given, are for illustration only and are not necessarily those which can be obtained by diligent process development, preparations were repeated if more material was required;
(vi) when given, JH 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 (TMS) as an internal standard, determined at 300 MHz using perdeuterio DMSO (CD3SOCD3) as the solvent unless otherwise stated, coupling constants (J) are given m Hz, (vii) chemical symbols have their usual meanings; SI units and symbols are used, (viii) solvent ratios are given in percentage by volume,
(IX) mass spectra (MS) were run with an electron energy of 70 electron volts in the chemical lonisation (APCI) mode using a direct exposure probe, where indicated ionisation was effected by electrospray (ES); where values 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 - (M+H)+,
(x) LCMS characterisation was performed using a pair of Gilson 306 pumps with Gilson 233 XL sampler and Waters ZMD4000 mass spectrometer The LC comprised water symmetry 4 6x50 column C18 with 5 micron particle size The eluents were- A, water with 0 05% formic acid and B, acetonitrile with 0 05% formic acid The eluent gradient went from 95% A to 95% B in 6 minutes. Where indicated ionisation was effected by electrospray (ES), where values for m/z are given, generally only ions which indicate the parenl mass are reported, and unless otherwise stated the mass ion quoted is the positive mass ion - (M+H)+ and (xi) the following abbreviations are used-
DMSO dimethyl sulfoxide;
DMF N-dimethylformarnide,
DCM dichloromethane,
THF tetrahydrofuran;
DIPEA N-N-drisopropylethylamine,
NMP N-methylpyrrolidmone;
HATU 0-(7-Azabenzotnazol- l-yl)-N,N,N,N-tetramethyluronium
hexafluorophosphate,
HBTU 0-(7-Benzotnazol-l -yl)-N,N,N,N-tetramethyluronium
hexafluorophosphate;
Boc tert-butoxycarbonyl
MeOH methanol;
EtOH ethanol, and
EtOAc ethyl acetate.
EXAMPLE 1
This Example illustrates the preparation of N-[l-(3-phenyl-3-[4-methylprperazin-l-yl]propyl)-piperidin-4-yl]-N-ethyl-4-methnesulfonylphenylacetamide (Compound No. 6 of Table I)
To a solution of 1-methylpiperazme (42µL, 0 38mmol) m DCM (l0mL) was added triethylamine (0.1 mL, 0.72mmol) then N-[l-(3-phenyl-3-chloropropyl)-pjpendm-4-yl]-N-elhyl-4-methanesulfonylphenylacetamide (Method A, 180mg, 0 38mmol) and sodium iodide (50mg) The resulting mixture was stirred at room temperature for 48h then washed with water and brine, dried (MgSO4) and evaporated The residue was purified by eluting through a 20g Bond Elut with 10% methanol in ethyl acetate then methanol then 1% triethylamine in methanol to give the title compound (58mg), NMR 1 2 (t, 1H), 1 3 (t, 2H), 1 4 (m, 1H), 1 6 (m, 2H), 1 8 (m, 4H), 1 9 (m,2 H), 2 1 (m, 2H), 2 2 (s, 3H), 2 4 (m, 8H), 2 9 (m, 2H), 3 0 (s, 3H), 3.3 (m, 2H), 3 8 (s, 2H), 7 2 (m, 2H), 7 4 (m, 2H), 7 9 (d, 2H), MS 541
The procedure described in Example 1 can be repeated using different secondary amines (such as 4-formylpiperazine, 4-isobutyrylpiperazine or 4-benzylpreridme) in place of 1 -methyl piperazme
EXAMPLE 2
This Example illustrates the preparation of N-[l-(3-phenyl-3-[pipeiidin-4-yl]propyl)-pipendin-4-yl]-N-ethyl-4-methanesulfonylphenylacetamide (Compound No 17 of Table I)
N--[l-(3-Phenyl-3-[l-tert-butylcarbonyloxypipendin-4-yl]propyl)-pipendin-4-yl]-N--ethyl-4-methanesulfonylphenylacetanude (Example 3,4g) was dissolved in trifluoroacetic aud (25mL) and the resulting mixture was stirred at room temperature for 2h The mixture was evaporated and the residue azeotroped with toluene The resulting material was stirred with 2M aqueous sodium hydroxide (25mL) and the resulting mixture extracted with DCM (8 x 25mL) The combined extracts were dried and evaporated to give the title compound (2.5g), MS 526
EXAMPLE 3
This Example illustrates the preparation of N-[l-(3-phenyl-3-[l-tert-butylcarbonyloxy-piperidm-4-yl]propyl)-pipendin-4-yl]-N-ethyl-4-methanesulfonylphenylacetamide (Compound No. 23 of Table I)
To a solution of 3-phenyl-3-(l-tert-butylcarbonyloxypipendin-4-yl)propionaldehyde (Method C; 14.4mmol) m DCM (l00mL) was added N--(4-pipendinyl)-N-ethyl-4-methanesulfonylphenylacetamide (Method B, 4 6g, 14.4mmol) and the resulting mixture was stirred at room temperature for 30mm Sodium tnacetoxyborohydnde (3 05g, 14.4mmol) was added and the resulting mixture was stirred at room temperature for 2h. The reaction mixture was washed with 2M aqueous sodium hydroxide (3 x 25mL), dried and eluted through a 50g SCX cartridge with DCM (3 x 25mL), ethyl acetate (4 x 25mL), methanol (4 x 25mL) and finally 1M ammonia in methanol (4 x 50mL) to yield crude product which was purified by silica gel chromatography (eluent: ethyl acetate then 10% methanol m ethyl acetate) to yield the title compound (4 2g); MS: 626
EXAMPLE 4
This Example illustrates the preparation of N-[l-(3-phenyl-3-[1-methylpipendm-4-y]]propyl)-pipeiidin-4-yl]-.N-ethyl-4-methanesulfonylphenylacetamide (Compound No 26 of Table I)
To a mixture of N-l-(3-phenyl-3-[piperidin-4-yl]propyl)-piperidin-4~yl]-N~etbyl-4-methanesulfonylphenylacetamide (Example 2, 250mg, 4 76mmol) and formaldehyde (0 2mL, 37% aqueous) in DCM (l0mL) was added sodium triacetoxyborohydnde (9.52mmol) and the resulting mixture was stirred at room temperature for 18h The mixtuie was washed with 2M aqueous sodium hydroxide (l0mL) and eluted through a l0g SCX cartridge with DCM (2 x l0mL), methanol (2 x l0mL) and finally 1M ammonia in methanol (4 x l0mL) affording the title compound (172mg), MS. 540
The procedure described in Example 4 can be repeated using different aldehydes (such as acetaldehyde and benzaldehyde) in place of formaldehyde
EXAMPLE 5
This Example illustrates the preparation of N-[1-(3-phenyl-3-[l -acetylpipendin-4-yi]propyl)-piperidin-4-yl]-N-ethyl-4-rnethanesulfonylphenyIacetarnide (Compound No 21 of Table I)
To a mixture of N--[l-(3-phenyl-3-[pipendm-4-yl]propyl)-pipendjn-4-yl]-N-ethyl-4-methanesulfonylphenylacetamide (Example 2, 250mg, 4 76mmol) and tnethylamine (48mg, 4 76mmol) in DCM was added acetyl chloride (37mg, 4 76mmol) The resulting mixture was stirred at room temperature for 18h, washed with saturated aqueous sodium bicarbonate solution (l0mL), dried and eluted through a l0g SCX cartridge with DCM (2 x l0mL), methanol (4 x l0mL) and finally 1M ammonia in methanol (4 x l0mL) affording the title compound (180mg); MS 568
The procedure described in Example 5 can be repeated using different acid chlorides (such as phenylacetyl chloride and 4-chlorobenzoyl chloride) or sulfonyl chlorides (such as methane sulfonyl chloride) in place of acetyl chloride.
EXAMPLE 6
This Example illustrates the preparation of N-[1(3-phenyl-3-[l-cyclohexylamino-carbonylpipendm-4-yl]propyl)-piperidin-4-yl]-N--ethyl-4-methanesulfonylphenylacetamide (Compound No 22 of Table 1)
To a mixture of N-[l-(3-phenyl-3-[prperidin-4-yl]propyl)-pipendin-4-yl]-N--ethyl-4-methanesulfonylphenylacetamide (Example 2, 250mg, 4 76mmol) and DCM (l0mL) was added cyclohexyl isocyanate (59mg, 4.6mmol) and the resulting mixture was stirred at room temperature for 18h. The mixture was eluted through a l0g SCX cartridge with DCM (4 x lOmL), methanol (2 x l0mL) and finally 1M ammonia in methanol (4 x l0mL) affording the title compound (300mg), MS 651
EXAMPLE 7
N-[l-(3-phenyl-3-[4-(2-chlorophenyJsulphonyl)piperazin-l-yl]piopyl)-pipendm-4-yl]-N-ethyl-4-methanesulphonylphenylacetamide (Compound number 150 of Table 1)
2-Chlorophenylsulphonyl chloride (40.1 mg) was added to a solution of N-[l-(3-phenyl-3-[piperazm-l-yl]propyl)-pipendm-4-yl]-N-ethyl-4-methanesulphonylphenyl-acelarrude (100 mg) and triethylamme (53 µl) m dichloromethane (5 ml) and the mixture was
stirred for 1 hour The reaction mixture was washed with water, brine and dried.The solvent was removed and the residue was chromatographed on a lOg silica Bond-Elut column eluted with a solvent gradient (ethyl acetate-20% methanol/ethylacetate) to give the title compound, yield 90mg MET 701
The N-[l-(3-phenyl-3-[piperazin-l-yl]propyl)-pipendin-4-yl]-N-ethyl-4-methanesulphonylphenylacetamide (Compound 86 of Table 1) used as starting material was prepared following the method described in Example 2 using the appropriate (1-tert-butyloxycarbonyl)-piperazme analogue
The N-[l-(3-phenyl-3-[l-tert-butyloxycarbonylpiperazin-l-yl]propyl)-pipendin-4-yl]-N-ethyl-4-methanesulphonylphenylacetamide (Compound 152 of Table l)used as starting material was prepared following the method described in example 1 using (1-tert-butyloxycarbonyl)prperazine as the amine component
EXAMPLE 8
(R or S) N-[l-(3-phenyl-3-[(4-{2,2,2-tnfluoroethylsulphonyl-piperazinyl}propyl)-piperidm-4-yl]-N-ethyl-4-methanesulphonylphenylacetamide. (Compound number 15 of Table 2)
Triethylamine (50 µl) was added to a solution of (R or S) N-[l-(3-phenyl-3 -piperazinyl}propyl)-pipendm-4-yl]-N-ethyl-4-methanesulphonylphenylacetamide ( 175 mg) in dichloromethane (5 ml) followed by 2,2,2-tnfluoroethanesulphonyl chloride (37 µl) and the mixture was stirred at room temperature for 14 hours. The reaction mixture was washed with water and dried The residue obtained-on removal of the solvent was chromatographed on a 20g silica Bond-Elut column eluted with a solvent gradient (ethyl acetate - 40% methanol/ethyl acetate) to give the title compound as a white foam, yield 79 mg, MH+ 673. NMR (CDCl3) : 1.2 (t, 1H), 1.3 (t, 2H), 1 4 (m, 1H), 1 6-1.8 (m,8H), 2 I (m,2H), 2.25 (m, 1H), 2 5 (m, 4H), 2 9 (m, 2H), 3 0 (s, 3H), 3 3 (m, 5H), 3 4 (m, 1H), 3 6 (q, 2H), 3 8 (m, 2H), 7 2 (m, 2H), 7 3 (m, 3H), 7 4 (m, 2H), 7.9 (d, 2H)
EXAMPLE 9
(R or S) N-[l-(3-phenyl-3~(Boc-piperazmyl}propyl)-pipendin-4-yl]-N-ethyl-4-methanesulphonylpheny 1 acetarrude
(R or S) N-[l-(3-phenyl-3-chloropropyl)-pipendin-4-yl]-N-ethyl-4-methanesulphonylphenylacetanude (594 mg) was added to a solution of tnethylamme ( 0 35 ml) and Boc-piperazme (233 mg) in dichloromethane (10 ml) at room temperature and the mixture was stirred for 14 hours The reaction mixture was added to a 20g silica Bond-Elut column and was eluted with a solvent gradient (ethyl acetate - 40% methanol/ethyl acetate) to give the title compound as a foam, yield 440 mg, MH4 627.
(R or S) N-[l-(3-phenyl-3-chloropropyl)-piperidin-4-yl]-N-ethyl-4-methanesulphonylphenylacetamide
(Formula Removed)
Methanesulphonyl chloride (0 5 ml) was added to a stirred mixture of S N-[l-(3-phenyl-3-hydroxypropyl)-pipendm-4-yl]-N-ethyl-4-methanesulphonylphenylacetairude (2 7g) and triethylamine (1 64 ml) in dichloromethane (50 ml) at 0°C and the mixture was stirred at ambient temperature for 15 hours The reaction mixture was washed with water and dried Removal of the solvent gave the title compound as an orange foam, yield 2.4g, MH+ 477.
(S) N-[l-(3-phenyl-3-hydroxypropyl)-pipendm-4-yl]-N-ethyl-4-rnethanesulphonylphenylacetarnide
(Formula Removed)
(S) l-Phenyl-3-(4-toluenesulphonyloxy)propan-l-ol (5g) was added to a mixture of N-(pipendin-4-yl)-N-ethyl-4-methanesulphonylphenylacetarmde (5 3g) and potassium carbonate (2 71g) in DMF (100 ml) and the mixture was stirred and heated at 80-90 °C for 6 hours The leaction mixture was allowed to cool and was evaporated to dryness The residue obtained
was dissolved in dichloromethane (50 ml) and was washed with water and dried. The solvent was removed and the residue was passed down a 90g silica Bond-Elut column eluted with a solvent gradient ( ethyl acetate- 20% methanol/ethyl acetate) to give the title compound, yield 2.7g, MH+ 459 NMR (CDCI3) 1 2 (t, 1H), 1 3 (t,2H), 1.6 (m, 2H), 1 75 (m, 3H), 1.85 (m, 3H), 2 2 (m, 1H), 2.55-2 7 (m, 2H), 3 0 (s, 3H), 3 1 - 3 2 (m, 2H), 3.3(q, 2H), 3.8(m, 2H), 4.9 (ra, 1H), 7 3 (m, 5H), 7 45 (d, 2H), 7 9 (d, 2Hj
(S) l-Phenyl-3-(4-toluenesulphonyloxy)propan-l-ol is a known compound (CAS No 156453-52-0)
EXAMPLE 10
(R or S) N-[l-(3-phenyl-3 -prperazmyl}propyl)-prperidin-4-yl]-N-ethyl-4-methanesulphonylphenyl acetarmde
Trifluoroacetic acid ( 5 ml) was added to a solution of (R or S) N-[l-(3-phenyl-3 ( Boc-piperazinyl}propyl)-pipendin-4-yl]-N-ethyl-4-methanesulphonylphenylacetamide (440 mg) in dichloromethane (10 ml) and the mixture was stirred for 1 hour The reaction mixture was concentrated and the residue was dissolved in 2M aqueous sodium hydroxide and extracted twice with dichloromethane (10 ml each bine). The combined extracts were dried and evaporated to give the title compound as a foam, yield 370 mg, MH+ 527
EXAMPLE 11
(R) N-[l-(3-phenyl-3-(l-(4-chlorobenzoylpipendin-4-yl)propyl}pipendin-4-yl]-N-ethyl-4-rnethanesulphonylphenylacetarmde. (Compound number 26 of Table 2)
To a mixture of (R) Ar-[l-3-phenyl-3-[pipendin-4-yl]propyl)-piperidm-4-yl]-N-ethyl-4-methanesulphonylphenylacetamide (330 mg) and MP carbonate resin (670 mg of 2.8 mM/g material) in dichloromethane (10 ml) was added 4-chlorobenzoyl chloride (111 mg) and the mixture was stirred at room temperature for 15 hours The reaction mixture was filtered and MP 4-toluenesulphomc acid resin ( Ig) was added to the filtrate and stirred for 30 minutes The reaction mixture was filtered and the resin was washed successively with dichloromethane (4X10 ml), 1M MeOH/NH3 (3X10 ml) The combined washings were evaporated to dryness and the residue was passed through a silica Bond-Elut column eluted with a solvent gradient (ethyl acetate-20% methanol m ethyl acetate) to give the title compound, yield 121 mg NMR (DMSOd6) 0 8-2 2 (m, 6H) 1 2-1 5 (m, 4H) 1 5-2 1 (m, 13H)
2 4 (m, 1H) 2.7 (m, 3H) 3.3 (m, 4H) 3 8 (d, 2H) 7-7 5 (m, 11H) 7 8 (d, 2H) Analytical HPLC on a Chiralcel OJ column (250mm x 4.6 mm) eluted with methanol showed that the chural purity was >99%
(R)7V-[l-3-phenyl-3-[piperidin-4-yl]propyl)-pipendin-4-yl]-N-ethyl-4-methanesulphonylphenylacetamide (Compound number 35 of Table 2)
(Formula Removed)
A solution of (R) N-[l-(3-phenyl-3-{ l-(benzyloxycarbonylpipendm-4-yl)propyl}pipendin-4-yl]-N-elhyl-4-methanesulphonylphenylacetamide (1 5g) methanol (100 ml) containing 20% Palladium/carbon catalyst (200 mg) was hydrogenated under a hydrogen-filled balloon. The catalyst was filtered and the filtrate evaporated to dryness to give the title compound, yield 1 lg MS (MH+) 526.
(R)N-[l-(3-phenyl-3-{l-(benzyloxycarbonylpipendin-4-yl)propyl}piperidin-4-yl]-N-ethyl-4-methanesulphonylphenylacetanude (Compound number 24 of Table 2).
Sodium tnacetoxyborohydride (890 mg) was added to a solution of (R) 3-phenyl-3-(benzyloxycarbonylpipendin-4-yl)propionaldehyde (1 49g) and N-(4-pipendinyl)-N-ethyl4-methanesulphonylphenylacetarmde (1 4g) in dichloromethane (25 ml) and the mixture was stirred for 1 hour The reaction mixture was washed with 2M NaOH (2X50 ml) and dried. The solvent was removed and the residue was passed down a silica Bond-Elut column eluted with a solvent gradient (ethyl acetate-20% methanol/ethyl acetate) to give the title compound, yield 1.5g MS(MH+)660
(R) 3-phenyl-3-(benzyloxycarbonylpipendm-4-yl)propionaldehyde
Dess-Martin penodinane (1,1,1 -triacetoxy-1,1-dihydro-1,2-benziodoxol-3(lH)-one) (1.8g) was added to a solution of (R) 3-phenyl-3-(benzyloxycarbonylpipendin-4-yl)propanol m dichloromethane (25 ml) and the mixture was stirred for 1 hour, washed with 2M NaOH
(2X20 ml) and dried The dichloromethane solution containing the title compound was used directly in the next stage
(R) 3 -phenyl-3 -(benzyloxycarbonylpiperidin-4-yl)propanol
Lithium aluminium hydride (9 46 ml of 1M LAH in THF) was added dropwise to a solution of (R) 3-[3-phenyl-3-(benzyloxycarbonylpiperidm-4-yl)propionyl]-(4R,5S)-1,5-dimethyl-4-phenyl-2-imidazohdinone (5 lg) in THF (100 ml) at such a rate that the temperature did not exceed 0°C. The reaction mixture was stirred at -5°C for 10 minutes and 2M NaOH was added (10 ml). The reaction mixture was filtered through Cehte and the filtrate was evaporated to dryness The residue was dissolved in dichloromethane (20 ml) and dried The residue obtained on removal of the solvent was passed through a Bond-Elut column eluted with a solvent gradient (isohexane-60% ethyl acetate/isohexane) to give the title compound , yield 1.6g. MS (MH+) 354.
3-[(R) 3-phenyl-3-(benzyloxycarbonylpipendm-4-yl)propionyl]-(4R,5S)-1,5-dimethyl-4-phenyl-2-imidazolidmone
(Formula Removed)
TMEDA (2 4g) was added to a suspension of cuprous iodide (4.02g) in THF (100 ml) and the mixture was stirred at room temperature for 30 minutes The reaction mixture was cooled to -78 °C and phenylmagnesium bromide (11 69 ml of a 1M solution in THF) was added and the mixture was stirred at -78 °C for 30 minutes Dibutylboron tnflate (11 69 ml, 1M solution m diethyl ether) was added to a solution of 3-[3-(benzyloxycarbonylpipendin-4-yl)acryloyl]-(4R,5S)-l,5-dimethyl-4-phenyl-2-imidazoIidmone (4 9g) in THF (50 ml) and this mixture was added dropwise over 10 minutes to the solution of the cuprate reagent The reaction mixture was stirred at -78 °C for 1 hour then allowed to warm to ambient temperature The solvent was evaporated, the residue was dissolved in ethyl acetate and filtered through silica (l00g). The ethyl acetate solution was washed with 2M HC1 (1X100 ml), dried and evaporated to dryness The residue was passed down a Bond-Elut column
AS-eluted with a mixture of ethyl acetate and isohexane (1 • 1) to give the title compound as a single diastereoisomer by NMR Yield 5.1g. NMR (DMSOd6) 0.5 (d, 3H) 0.8-1.1 (m 2H) 1 3 (d, 1H) 1 7 (m, 2H) 2 6 (m, 5H) 2.85-3.1 (m, 4H) 5.05 (s, 2H) 5.2 (d, 1H) 6.8 (m, 2H) 7.1-7 5 (m, 13H)
3-[3-(benzyloxycarbonylpiperidin-4-yl)acryloyl]-(4R,5S)-l,5-dimethyl-4-phenyl-2-lmidazohdinone
(Formula Removed)
l-Chloro-N,N,2-tnmethyl-l-propenylamine (1 37g) was added dropwise over 10 minutes to a solution of 3-(benzyloxycarbonylpiperidin-4~yl)propenoic acid (2 5g) in THF (20 ml) and the mixture was stirred for 1 5 hours Lithium bis(tnmethylsilyl)amide (8 65 ml)was added to a solution of (4R,5S)-l,5-dimethyl-4-phenyl-2-imidazolidinone (1 64g) in THF (20 ml) at -10 °C and the mixture was stirred at -10 °C for 10 minutes, allowed to warm to 0 °C and then cooled again to -10 °C. The acid chloride solution (prepared above) was added dropwise and the mixture was allowed to warm to room temperature The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (3X50 ml) The combined extracts were dried, evaporated to dryness and the residue was chromatographed on a Bond-Elut column eluted with an ethyl acetate/isohexane mixture (1 1) to give the title compound, yield 3.6g NMR (DMSOd6) : 0 6 (d, 3H) 0 95 (d, 1H) 1 2 (m, 2H) 1 55 (m, 2H) 2.4 (m 1H) 2 3 (s, 3H) 2.8 (m, 2H) 3 95 (m, 3H) 5 (s, 2H) 5.3 (d, 1H) 6 9 (m, 1H) 7 1 (m, 2H) 7.2-7 4 (m, 8H)
3-(benzyloxycarbonylpiperidin-4-yl)propenoic acid
A mixture of N-benzyloxycarbonyl-4-formylpipendine (10g), malonic acid (4 2), pyridine (4 ml) and pipendine (0 4 ml) was heated at 100 °C for 2 hours The reaction mixture was allowed to cool and was diluted with ethyl acetate (100 ml) The solution was washed with 2M HC1 (2X100 ml), dried and evaporated to dryness The residue was triturated with isohexane to give the title compound, yield 13.5g NMR (DMSOd6) 1 2 (m, 2H) 1.7 (m, 2H)
2 35 (m, 1H) 2.85 (m, 2H) 4"(d, 2H) 5.05 (s, 2H) 5.75 (d, 1H) 6 75 (m, 1H) 7 35 (m, 5H) 12 25 (broad peak, 1H)
EXAMPLE 12
N-[ 1 -3 - [(3 -fluorophenyI)-3 - [ 1 -phenylpiperidin-4-yl] propyl)-pipendin-4-yl] -N-ethyl-4-methanesulphonylphenylacetamide (Compound number 145 of Table 1)
2M NaOH was added to a suspension of N-[1-[3-(3-fluorophenyl-3-[plperidin-4-yI]propyl)-prperidin-4-yl]-N-ethyl-4-methanesulphonylphenylacetamide di-hydrochlonde salt (0.85 g) in dichloromethane (25 ml) and the mixture was stirred until a clear solution was obtained. The dichloromethane solution was dried and filtered To this dichloromethane solution was added benzeneboromc acid (330 mg), tnethylamine (280 mg) and cupnc acetate (276 mg). The reaction mixture was stirred for 15 hours, washed with water and filtered through a Chem Elute cartridge. The dichloromethane filtrate was washed with 2M NaOH (3X20 ml), dried and poured on to a 20g SCX cartridge and eluted with methanol (6X20 ml) and 1M ammonia in methanol (6X20 ml) The combined ammonia washings were evaporated and the residue obtained was chromatographed on a Bond-Elut column eluted with a solvent gradient (ethyl acetate-20% methanol/ethyl acetate to give the title compound, yield 179 mg
The N--[l-3(3-fluorophenyl-3-[prperidin-4-yl]propyl)-piperidm-4-yl]-N--ethyl-4-methanesulphonylphenylacetarmde di-hydrochlonde salt (Compound number 87 of Table 1) used as starting material was prepared following the procedmes of Example 3 and Method C.
EXAMPLE 13 Racermic N-[l-(3-(3-fluorophenyl)-3-[4-(4-methanesulphonyl)phenylsulphonyl)piperazm-l-yl]propyl)-pipendin-4-yl]-N-ethyl-4-methanesulphonylphenylacetamide (78 mg) (Compound number 59 of Table 1) was separated into its single enantiomers by chromatography on a Gilson preparative HPLC using a 50 mm 20(im Chiracel OD column eluted with a mixture of ethanol.isohexane (9' 1). Less polar isomer, yield 20mg (Compound number 16 of Table 2) More polar isomer, yield 22 mg (Compound number 17 of Table 2)
EXAMPLE 14
Nl-[l-(3-phenyl)-3-{l-(ethanesulphonylpipendin-4-yl)propyljpipendin-4-yl]-Nl-ethyl-N3-4-methanesulphonylphenylmethyl urea. (Compound number 7 of Table 3)
4-Methanesulphonylphenylmethyl isocyanate ( 99 mg) in THF (10 ml) was added to 4-N-ethyl- [l-(3-phenyl)-3-{ l-(ethanesulphonylpipendm-4-yl)propyl}pipendine (200 mg) and the mixture was allowed to stand at room temperature for 16 hours The reaction mixture was poured on to a 5g SCX cartridge and was eluted with dichloromethane (3X10 ml), methanol (3X10 ml) and methanohc ammonia (1M, 3X10 ml) The methanolic ammonia washings were evaporated and the residue was dissolved in dichloromethane (20 ml) and isocyanate resin (200mg) was added The mixture was stirred for 16 hours, Filtered and the Filtrate was evaporated to dryness The residue obtained was chromatographed on a Bond-Elut column eluted with a solvent gradient (ethyl acetate-25% methanol/ethyl acetate) to give the title compound, yield 37 mg MS (MH+) 633
4- N-ethyl- [l-(3-phenyl)-3-{ l-(ethanesulphonylpipendm-4-yl)propyl}piperidine
(Formula Removed)
A mixture of N-ethyl-N- [l-(3-phenyl)-3-{ l-(ethanesulphonylpiperidin-4-yl)propyl}piperidin-4-yl]-carbamic acid benzyl ester (5g) and 10% Palladium on carbon (2g) in ethanol (200ml) was hydrogenated under a hydrogen filled balloon The catalyst was filtered and the filtrate evaporated to dryness to give the title compound, yield 2 78g.
N-ethyl-N- [l-(3-phenyl)-3-{ l-(ethanesulphonylpipendin-4-yl)propyl}piperidm-4-yl]-carbamic acid benzyl ester.
(Formula Removed)
thanesulphonyl chloride (2.3g) was added to a solution of N-ethyl-N- [l-(3-phenyl)-3-{pipendin-4-yl)propyl}pipendin-4-yl]-carbamic acid benzyl ester di-hydrochlonde (8 5g) and triethylamine (4.8g) in dichloromethane (200 ml) maintained at 0 °C. The reaction mixture was allowed to warm to room temperature and was stirred for 4 hours. The reaction mixture was washed with 2M NaOH (2X100 ml), dried and evaporated to dryness. The residue was chromatographed on a Bond-Elut column eluted with a solvent gradient (ethyl acetate-20% methanol/ethyl acetate) to give the title compound, yield 5g NMR (DMSOd6): 1 (t, 3H) 1 1 (t, 3H) 1.3-3 (m, 14H) 2 2 (m, 1H) 2 55-2 9 (m, 5H) 2.95 (q, 2H) 3.1(q, 2H) 3 4-3 7 (m, 3H) 5.05 (s, 2H) 7.1-7 4 (m, 10H) MS (MH+) 556
N-ethyl-N-[l-(3-phenyl)-3-{piperidin-4-yl)propyl}piperidm-4-yl]-carbamic acid benzyl ester di-hydrochloride
HC1 in dioxan (50 ml of 4M) was added to N-ethyl-N- [l-(3-phenyl)-3-{ 1-tert-butyloxycarbonylpiperidin-4-yl)propyl}piperidin-4-yl]-carbamic acid benzyl ester (26g) at 0 °C the mixture was allowed to warm to room temperature and was stirred for 2 hours The reaction mixture was diluted with diethyl ether (200ml) and the precipitated solid di-hydrochlonde salt was filtered and dried (hygroscopic) Yield 17g MS (MH+) 464.
N-ethyl-N- [l-(3-phenyl)-3-{l-tert-butyloxycarbonylpipendm-4-yl)propyl}pipendin-4-yl]-carbamic acid benzyl ester
A solution of 3-phenyl-3-(l-tert-butylcxycarbonylpiperidin 4-yl)propionaldehyde (7 8 g) [prepared following the method described in Example 11] in dichloromethane (200 ml) was added to a mixture of N-ethyl-N-piperidin-4-ylcarbamic acid benzyl ester hydrochloride (7.4g) (CAS No 220395-87-9) and sodium acetate (2 17g) m ethanol (50ml) and stirred for 30 minutes. Sodium tnacetoxyborohydride (5 2g) was added in small portions over 15 minutes and staring was continued for 2 hours Aqueous NaOH (2M, 200 ml) was added dropwise, the dichloromethane layer was collected and washed with 2M NaOH (2X100 ml), dried and evaporated to dryness to give the title compound, yield 26g NMR (DMSOd6) 1 (t, 3H) 1.35 (s, 9H) 1.4-2 (m, 14H) 2.3(m, 2H) 2 6-2 7 (m, 4H) 3 15 (q, 2H) 3 4-4 (m, 3H) 5 05 (s, 2H) 7 1-72 (m, 10H) MS (MIT") 563
4-methanesulphonylphenylmethyl isocyanate
Diphenylphosphoryl azide (260 mg) was added to a mixture of 4-methanesulphonylphenylacetic acid (200mg) and tnethylamine (191 mg) in THF (20 ml) and the reaction mixture was heated under reflux for 4 hours, the reaction mixture was cooled and used directly for the next stage.
Method A
N-[1-(3-Phenyl-3-chloropropyl)-piperidin-4-yl]-N-ethyl-4-methanesulfonylphenylacetanude Step 1 Preparation of N-l-(3-phenyl-3-oxopropyl)-pipendm-4-yl]-N-ethyl-4-melhanesulfonylphenylacetamide
To a solution of N-(4-pipendinyl)-N-ethyl-4-methanesulfonylphenylacetamide (Method B; 3 24g, l0mmol) in DMF (50mL) was added potassium carbonate (2 76g, 20mmol) followed by 3-chloropropiophenone (1 85g, 1 lmmol). The resulting mixture was stirred at room temperature for 18h then evaporated. The residue was dissolved in DCM and the resulting solution washed with water (4 x l0mL) and brine (l0mL), dried (MgS04) and evaporated to give the crude product which was purified by elutmg through a 50g Bond Elut with 10% methanol in ethyl acetate to afford the sub-titled compound (2 4g, 53%), NMR (CDC13) 1 1 (t, 1H), 1 2 (m, 2H), 1 6 (m, 6H), 2.2 (m, 1H), 2 8 (m, 2H), 3.0 (m, 5H), 3 2 (m, 2H), 3 3 (m, 2H), 3 8 (m, 2H), 7 4 (m, 5H), 7 9 (m, 4H), MS' 457
Step 2, Preparation of N-[l-(3-phenyl-3-hydroxypropyl)-pipendin-4-yl]-N--ethyl-4-methanesulfonylphenylacetamide
To a solution of N--[l-(3-phenyl-3-oxopropyl)-pipendin-4-yl]-N--ethyl-4-methanesulfonylphenylacetarmde (912mg, 2mmol) m ethanol (20mL) at 0°C was added sodium borohydride (76mg, 2mmol) The resulting mixture was stirred at room temperature for 30mm then evaporated. The residue was dissolved in DCM and the resulting solution washed with water (2 x 5mL) and brine (5mL), dried (MgSO4) and evaporated to give the subtitled compound (812mg, 87%), NMR (CDC13)- 1.1 (t, 1H), 1 2 (m, 2H), 1.6 (m , 8H), 2.0 (m, 1H), 2 2 (m, 1H) 2 6 (m, 2H), 3.0 (s ,3H), 3 2 (m, 2 H), 3 3 (m , 2H), 3.8 (m, 2H), 4 9 (d, 1H), 7 3 (m, 5H), 7 4 (d, 2H), 7 9 (d, 2H), MS 459
Step 31 Preparation of the title compound
To a mixture of N-[l-(3-phenyl-3-hydroxypropyl)-pipendin-4-yl]-N-ethyl-4-methanesulfonylphenylacetamide (400mg, 0 87mmol) and tnethylamine (0 24mL, 1 04mmo]) in DCM (l0mL) at 0°C was added methane sulfonyl chloride (67µL, 0 87mmol) The resulting mixture was stirred at room temperature for 30min. then evaporated. The residue was purified by eluting through a 20g Bond Elut to give the title compound (180mg, 44%), NMR (CDC13) 1.1 (t, 1H), 1.2 (m, 2H), 1 6 (m . 7H), 2.2 (m, 2H), 2.4 (m, 2H), 2.8 (m, 2H), 3 0 (s, 3H), 3 3 (m, 2H), 3.8 (m, 2H), 5 0 (m, 1H), 7 3 (m, 5H), 7 4 (d, 2H), 7.9 (d, 2H), MS: 477
Method B
N-(4-Piperidinyl)-N-ethyl-4-methanesulfonylphenylacetamide
Step 1' Preparation of l-phenylmethyl-4-ethylaminopiperidine dihydrochlonde
To a solution of l-phenylmetliyl-4-piperidone (25.0g, 132mmol) in THF (250mL) was added ethylamme hydrochloride (12.0g, 147 mol) and methanol (50mL) and the resulting mixture stirred at room temperature for l0min Sodium triacetoxyborohydnde (40g, 189mmol) was added portionwise and the resulting mixture stirred at 100m temperature for Ih. 2M Sodium hydroxide solution (250mL) was added and the resulting mixture extracted with diethyl ether The organic extracts were dried (K2CO3) and evaporated to give 1-phenylmethyl-4-ethylaminopipendine as an oil This was dissolved in ethanol (500mL) and concentrated hydrochloric acid (20mL) was added The resulting crystals were collected, washed with diethyl ether and dried giving the sub-titled compound as a solid (38 g), NMR (CDCI3) 1 10 (t, 3H), 1 40 (m, 2H), 1 83 (m, 2H), 2.02 (m, 2H), 2 65 (q, 2H), 2.85 (m, 2H), 3.50 (s, 2H), 3 75 (m, IH), 7.2 - 7 4 (m, 5H); MS. 219 (MH+).
Step 2: Preparation of N-(l-Phenylmethyl-4-pipendmyl)-A'-ethyl-4-methanesulfonylphenylacetamide
To a solution of l-phenylmethyl-4-ethylammopipendine dihydrochlonde (32.0g, 1 lOmmol) in DCM (500mL) was added N,N-dusopropylethylamine (60mL) with stirring to ensure complete dissolution. 4-Methanesulfonylphenylacetic acid (25 0g, 117mmol), 4-dimethylaminopyndme (20g) and dicyclohexylcarbodnirude (25 0g, 121mmol) were added and the resulting mixture was stirred at room temperature for 20h The precipitate was removed by filtration and the resulting solution was washed successively with 2N aqueous
HCl, water and IN aqueous NaOH, dried (MgSO4) and evaporated The residue was purified by silica gel chromatography (eluent. 10% MeOH/ethyl acetate) to afford the sub-titled compound (35 g, 76%), NMR' 1.00 and 1.14 (t, 3H), 1 45 and 1 70 (m, 2H), 1.95 (br m, 2H), 2.80 (br m, 2H), 3 18 (s, 3H), 3 20 and 3.33 (q, 2H), 3 45 (s, 2H), 3 80 and 3.87 (s, 2H), 3.70 and 4.10 (m, 1H), 7 2 - 7.3 (m, 5H), 7 48 (m, 2H), 7.82 (m, 2H); MS. 415 (MH+)
Step 3' Preparation of the title compound
To a solution of N-(l-phenylmethyl-4-piperidinyl)-N-ethyl-4-methanesulfonylphenyl-acetarrude (34g, 82mmol) in ethanol (600mL) was added ammonium formate (40g). The mixture was purged with argon and 30% Pd on carbon (4 2g) was added The resulting mixture was stirred at reflux for 4h, then allowed to cool and filtered through diatomaceous earth The filtrate was evaporated to give a thick oil which solidified on standing to yield the title compound (24 9g, 94%), NMR. 1.02 and 1 15 (t, 3H), 1 4 -1.6 (br m, 4H), 2.45 (m, 2H), 2 93 (br m, 2H), 3 18 (s, 3H), 3 20 and 3.32 (q, 2H), 3 72 and 4 18 (m, 1H), 3.80 and 3.87 (s, 2H), 7 50 (m, 2H), 7 85 (m, 2H), MS. 325 (MH+)
Method C
3-Phenyl-3-(l-tert-butylcarbonyloxyprperidin-4-yl)propionaldehyde Step 1 Preparation of l-tert-butylcarbonyloxy-4-benzoylpipendme
To a solution of 4-benzoylpiperidme (6g, 26 5mmol) in 2M aqueous sodium hydroxide (26 5mL) was added di-tert-butyl dicarbonate (5 79g, 26 5mmol) and the resulting mixture was stirred at room temperature for 18h. The solid product was isolated by filtration and dried under vacuum at 40°C giving the sub-titled compound (7g), NMR. 1 3-1.4 (m, 11H) 1 7 (m, 2H) 2 9 (m, 2H) 3 6 (m, 1H) 3 95 (m, 2H) 7 5-7 6 (m, 3H) 7.95 (d, 2H)
Step 2 Preparation of ethyl 3-phenyl-3-(l-tert-butylcarbonyloxypipendin-4-yl)acrylate
To a solution of triethylphosphonoacetate (6.2g, 27mmol) in THF (l00mL) at0°C was added lithium bis(tnmethylsilyl)amide (32.5mL, 1M, 32 5mmol). The resulting mixture was stirred at 0°C for 20rrun l-tert-Butylcarbonyloxy-4-benzoylpiperidine (7g, 25mmol) was added and the resulting mixture was stirred at room temperature for 48h The mixture was evaporated and the residue dissolved in ethyl acetate (200mL). The solution was washed with 2M hydrochloric acid (2 x 100mL), dried and evaporated giving the sub-titled compound
Step 3 Preparation of ethyl 3-phenyl-3-( 1 -tert-butylcarbonyloxypipendin-4-yl)propionoate
Ethyl 3-phenyl-3-(l-tert-butylcarbonyloxypiperidin-4-yl)acrylate (-25mmol) was dissolved in ethanol (200mL) and the solution purged with argon 20% Palladium hydroxide (2g) was added and the resulting mixture was stirred at room temperature under an atmosphere of hydrogen (balloon) for 72h. The mixture was purged with argon, filtered and the filtrate evaporated. The crude product was purified by silica gel chromatography (eluent: isohexane then 35% ethyl acetate in isohexane) to give the sub-titled compound (5 3g)
Step 4. Preparation of 3-phenyl-3-(l-tert-butylcarbonyloxypipendin-4-yl)propan-l-ol
To a solution of ethyl 3-phenyl-3-(l-tert-butylcarbonyloxypipendin-4-yl)propronoate (5.3g, 14 6mmol) m THF (l00mL) was added lithium aluminium hydride (14 6mL, 1M, 14.6mmol) dropwise over 20mm. The resulting mixture was stirred at 0°C for lh. 2M aqueous sodium hydroxide (20mL) was added dropwise The mixture was filtered through Celite®, washing with ethyl acetate (3 x 25mL) The filtrate and washings were combined and evaporated The residue was dissolved in ethyl acetate (l00mL) and the resulting solution washed with water (3 x 50mL), dried and evaporated to give the sub-titled compound (4.6g), NMR. 0 9-1 (m, 2H) 1.25 (m, 1H) 1 35 (s, 9H) 1 5-2 (m, 5H) 2 6 (m, 2H) 3.1 (m, 2H) 3.8-4 (m, 2H) 4 2 (t, 1H)
Step 5 Preparation of the title compound
To A solution of 3-phenyi-3-(4-l-tert-butyicarbonyloxypipendin-4-yl)propan-l-ol (4 6g, 14 4mmol) in DCM (l00mL) was added Dess-Martm penodinane (6.1g, 14 6mmol) and the resulting mixture was stirred at room temperature for 2h The mixture was washed with 2M aqueous sodium hydroxide (3 x 50mL), dried and evaporated to give the title compound
Method D
N~(tert-butoxycarbonylpipendin-4-yl]-N-ethyl-4-methanesulphonylphenylacetarrude
(Formula Removed)
To a solution of 4-methylsulfonylphenylacetic acid (16 lg) in toluene (200ml) under argon was added diphenylphosphoryl azide (16 2ml) and triethylamine (10.4ml). The mixture was heated at 90 °C for 3 hours and then allowed to cool The tert-butyl-l-oxo-4-arninoethyl-prpendine [CAS 264905-39-7] (17.10g) in toluene (100ml) was added and the mixture stined far 18 hours and then partitioned with EtOAc/H20 (500ml/400ml), filtered and the organic layer separated and washed with sat NaHC03 solution (2 x 300ml), brine (300ml), dried over MgSCU, filtered and evaporated. The resulting brown oil was purified on silica using a gradient elution of 0 to 3% MeOH in EtOAc to give the title compound as a yellow solid (7.10g), NMR (DMSO)- 1 4 (t, 3H), 1 40 (s, 9H), 1 52 (m, 4H), 2.73 (m, 2H), 3 15 (m, 5H), 4.02 (m, 3H), 4 32 (d, 2H), 6.89 (t, 1H), 7 43 (d, 2H), 7 87 (d, 2H) MS 340 (MH+ - Boc)
N-(pipendin-4-yl]-N-ethyl-4-methanesulphonylphenylacetamide
(Formula Removed)
The pipendme (6 84g) was dissolved in DCM (39ml) and TFA (39ml) was added slowly The mixture was allowed to stand for 40 minutes and then evaporated The residue was dissolved in 2M NaOH and extracted with DCM (3x150ml) and the extracts dried over MgSO4, filtered and evaporated to give the title compound as a yellow solid (5.00g), NMR (DMSO)- 1.05 (t, 3H), 1 41 (m, 4H), 2 42 (m, 2H), 2 96 (d, 2H), 3 20 (m, 5H), 3.90 (quint, 1H), 4 29 (d, 2H), 6.84 (t, 1H), 7 43 (d, 2H), 7 85 (d, 2H), MS 340 (MH4).
Method E
N-[l-(3-[3,4-di-fluorophenyl]-3-hydroxypropyl)-pipendin-4-yl]-N-ethyl-4-methanesulphonylphenylacetamide
(Formula Removed)
A solution of sodium borohydnde (7 7 mg) in ethanol (1 ml) was added to a solution of N-t 1 -(3-[3,4-difluorophenyl]-3-ketopropyl)-piperidm-4-yl]-N-ethyl-4-methanesulphonylphenylacetamide (0 25g) in ethanol (3 2 ml) at 0°C under argon and the reaction allowed to warm to room temperature over 20 hours The reaction was quenched with bnne, extracted three times with ether and the combined extracts dried. The filtrate was then concentrated to a clear oil, yield 0 21 g MS (MH+) 495
N [l-(3-[3,4-difluorophenyl]~3-ketopropyl)-pipendm-4-yl]-N-ethyl-4-methanesulphonylphenylacetarmde
(Formula Removed)
DBU was added to a solution of pipendin-4-yl]-N-ethyl-4-methanesulphonylphenylacetamide (CAS number 374725-04-9) (320 mg) and 3,4-difluorophenylvmyl ketone (654 mg) in dicholoromethane (9 ml) under argon and the reaction mixture stirred for 36 hours The reaction mixture was concentrated in vacuo and purified using flash column chromatography on silica eluting with a solvent gradient (methanol 10-15%, methanol in dicholormethane), yield 250 mg, MH+ 493.
3,4-difluorophenyl vinyl ketone.
Dess martin penodmane (3 18 g) was added to a solution of 3,4-difluorovmyl alcohol (CAS number 149946-84-9) (1 18 g) in dicholoromethane (22 ml) at 0°C under argon and the reaction mixture allowed to stir for 1 hour The mixture was put directly on to a column for purification via flash column chromatography elutmg with a gradient (ethyl acetate - 10%,
ethyl acetate and isohexane) yield 654 mg NMR (CDCl3) 6 0 (d, 1H), 6 50 (d, 1H), 7 10 (dd, 1H), 7 30 (m, 1H), 7 80 (m, 2H)
EXAMPLE 15
The ability of compounds to inhibit the binding of RANTES was assessed by an in vitro radioligand binding assay Membranes were prepared from Chinese hamster ovary cells which expressed the recombinant human CCR5 receptor These membranes were incubated with 0.1 nM iodinated RANTES, scintillation proximity beads and various conSScentrations of the compounds of the invention in 96-well plates. The amount of iodinated RANTES bound to the receptor was determined by scintillation counting Competition curves were obtained for compounds and the concentration of compound which displaced 50% of bound iodinated RANTES was calculated (IC50) Preferred compounds of formula (I) have an IC50 of less than 50jxM
EXAMPLE 16
The ability of compounds to inhibit the binding of MlP-lα was assessed by an in vitro radioligand binding assay Membranes were prepared from Chinese hamster ovary cells which expressed the recombinant human CCR5 receptor These membranes were incubated with 0.lnM iodinated MlP-lα, scintillation proximity beads and various concentrations of the compounds of the invention in 96-well plates The amount of iodinated MTP-lα bound to the receptor was determined by scintillation counting Competition curves were obtained for compounds and the concentration of compound which displaced 50% of bound iodinated MJP-lα was calculated (IC50). Preferred compounds of formula (I) have an IC50 of less than 50UM
Results from this test for certain compounds of the invention are presented in Table II In Table II the results are presented as Pic50 values A Pic50 value is the negative log (to base 10) of the IC50 result, so an IC50 of lµM (that is 1 x 10'6M) gives a Pic50 of 6. If a compound was tested more than once then the data below is an average of the probative tests results.
Table VII (Table Removed)

SCHEME 1 (Scheme Removed)

Conditions
a) Reductive amination (R4NH2, NaBH(OAc)3)
b) Amide formation (R5C02H, coupling agent or R5COCI, base)
c) Urea formation (isocyanate)
d) H2, Pd (PG is Bn or Bz)
e) HCI or TFA (PG is Boc)
SCHEME 2 (Scheme Removed)

Conditions
a) Alkyl halide, base
b) R2C(=0)CH2, R3CHO, AcOH
c) R2C(=0)CH=CHR3
d) Reduction then MsCI, base
e) Cyclic amine, base, Nal
SCHEME 3 (Scheme Removed)

Conditions
a) (i) (EtO)2P(=0)CH2CO2Et, base, (il) hydtogenation (e.g Pd(OH)2, H2)
b) Reduction (e g. LiAIH4) (R3 is H)
c) (i) Reduction to aldehyde (e.g DIBAL-H), (n) R3MgBr
d) Oxidation (e g Dess-Martin periodinane)
e) (i) MeONHMe, AIMe3, (ii) Reduction (R3 is H) or R3MgBr
f) Reductive animation (NaBH(OAc)3, AcOH)
g) HCI or TFA
h) Amide formation (acid & coupling reagent or acid halide, base) i) Sulfonamide formation (sulfonyl chloride, base) j) Reductive amination (aldehyde, NaBH(OAc)3)

WE CLAIM:
1. A piperidine compound of formula (I):
(Formula Removed)
wherein
L is CH or N; M is CH or N; provided that L and M are not both CH;
R1 is hydrogen, C1-6 aikyl[optionally substituted by phenyl {which itself optionally substituted by halo}], S(O)2R6, S(O)2NHR7, C(O)R7, C(O)2(C1-6 alkyl) or C(O)NHR7; and when M is CH R1 can also be NHS(O)2R6, NHS(O)2NHR7, NHC(O)R7 or NHC(O)NHR7;
R2 is phenyl or heteroaryl, either of which is optionally substituted by halo, C1-4 alkyl, C1-4 alkoxy, S(O)n(C1-4 alkyl),nitro, cyano or CF3;
R3 is hydrogen or C1-4 alkyl;
R4 is hydrogen, methyl, ethyl, allyl or cyclopropyl;
R5 is phenyl, heteroaiyl, phenyl (C1-2)alkyl or heteroaryl(C1-2)alkyl; wherein the phenyl and heteroaryl rings are optionally substituted by halo, cyano, nitro, hydroxy, C1-4 alkyl, C1-4 alkoxy, S(O)kC1-4alkyl, S{O)2NR8R9, NHS(O)2(C1-4 alkyl), NH2, NH(C1-4alkyl), N(C1-4alkyl)2, NHC(O)NH2, C{0)NH2, C(O)NH(C1-4alkyl), NHC(O)(C1-4alkyl), CO2H, C02(C1-4 alkyl), C(O) (C1-4 alkyl), CF3, CHF2, CH2F, CH2CF3 or OCF3;
k, m and n axe, independently, 0, 1 or 2;
R6 is C1-6 alkyl [optionally substituted by phenyl { which itself optionally substituted by halo}], C3-7 cycloalkyl, phenyl {optionally substituted by halo};
R7 is hydrogen, C1-6 alkyl [optionally substituted by phenyl { which itself optionally substituted by halo}], C3-7 cycloalkyl, phenyl {optionally substituted by halo};
R8 and R9 are, independently, hydrogen or C1-4alkyl, or together with a nitrogen or oxygen atom, may join to form a 5- or 6-membered ring which is optionally substituted with C1-4alkyl, C(0)H or C{0)(C1-4alkyl); or a pharmaceutically acceptable salt thereof or a solvate thereof;
provided that when R1 is hydrogen or unsubstituted alkyl, R4 is hydrogen, methyl or ethyl, L is CH and M is N, then the phenyl or heteroaryl part of R5 is substituted by one of: S(0)kC1-4alkyl, NHC(0)NH2, C(0)(C1-4alkyl), CHF2, CH2F, CH2CF3 or OCF3, and optionally further substituted by one or more of halo, cyano, nitro, hydroxyl, C1-4alkyl , C1-4alkoxy, S{O)kC1-4alkyl, S(O)2NR8R9, NHS(O)2(C1-4 alkyl), NH2, NH(C1-4alkyl), N(C1-4alkyl)2, NHC(O)NH2, C(O)NH2, C(O)NH(C1-4alkyl), NHC{O)(C1-4alkyl), CO2H, CO2(C1-4 alkyl), C(O)(C1-4 alkyl), CF3, CHF2, CH2F, CH2CF3 or OCF3;
2. A compound as claimed in claim 1, wherein L is CH.
3. A compound as claimed in claim 1 or 2, wherein M is N.
4. A compound as claimed in claim 1, 2 or 3, wherein R2 is phenyl optionally substituted by halo.
5. A compound as claimed in claim 1, 2, 3 or 4 wherein R3 is hydrogen or methyl.
6. A compound as claimed in claim 1, 2, 3, 4 or 5 wherein R4 is ethyl.

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Patent Number

228338

Indian Patent Application Number

912/DELNP/2004

PG Journal Number

08/2009

Publication Date

20-Feb-2009

Grant Date

02-Feb-2009

Date of Filing

08-Apr-2004

Name of Patentee

AstraZeneca AB

Applicant Address

S-151 85 Sodertalje, SWEDEN.

Inventors:

#	Inventor's Name	Inventor's Address
1	HOWARD TUCKER	AstraZeneca R&D Alderly, Alderley Park, Macclesfield, Cheshire SK10 4TG, ENGLAND.

PCT International Classification Number

C07D 401/06

PCT International Application Number

PCT/SE02/02055

PCT International Filing date

2002-11-12

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	0103818-1	2001-11-15	U.K.