WO2005101989A2 - Piperidine derivatives as modulators of chemokine receptor ccr5 - Google Patents

Piperidine derivatives as modulators of chemokine receptor ccr5 Download PDF

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Publication number
WO2005101989A2
WO2005101989A2 PCT/SE2005/000574 SE2005000574W WO2005101989A2 WO 2005101989 A2 WO2005101989 A2 WO 2005101989A2 SE 2005000574 W SE2005000574 W SE 2005000574W WO 2005101989 A2 WO2005101989 A2 WO 2005101989A2
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Prior art keywords
alkyl
optionally substituted
alkoxy
cyano
nitro
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English (en)
French (fr)
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WO2005101989A3 (en
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Alan Faull
Howard Tucker
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AstraZeneca AB
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AstraZeneca AB
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Priority claimed from SE0401057A external-priority patent/SE0401057D0/xx
Priority claimed from SE0500057A external-priority patent/SE0500057D0/sv
Application filed by AstraZeneca AB filed Critical AstraZeneca AB
Priority to JP2007509422A priority Critical patent/JP2007533735A/ja
Priority to CA002562417A priority patent/CA2562417A1/en
Priority to MXPA06012045A priority patent/MXPA06012045A/es
Priority to BRPI0510126-3A priority patent/BRPI0510126A/pt
Priority to US11/587,330 priority patent/US7615555B2/en
Priority to AU2005235169A priority patent/AU2005235169B2/en
Priority to EP05734934A priority patent/EP1742934A2/en
Publication of WO2005101989A2 publication Critical patent/WO2005101989A2/en
Publication of WO2005101989A3 publication Critical patent/WO2005101989A3/en
Priority to IL178650A priority patent/IL178650A0/en
Anticipated expiration legal-status Critical
Priority to NO20065319A priority patent/NO20065319L/no
Priority to US12/562,651 priority patent/US20100010007A1/en
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Definitions

  • 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.
  • Pharmaceutically active piperidine derivatives are disclosed in WO01/87839, WO01/66525, WOOO/08013, WO99/38514 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 ofthe 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 chemokine superfamily can be divided into two main groups exhibiting characteristic structural motifs, the Cys-X-Cys (C-X-C, or ⁇ ) and Cys-Cys (C-C, or ⁇ ) families. These are distinguished on the basis ofa single amino acid insertion between the NH-proximal pair of cysteine residues and sequence similarity.
  • the C-X-C chemokines include several potent chemoattractants and activators of neutrophils such as interleukin-8 (LL-8) and neutrophil-activating peptide 2 (NAP-2).
  • the C-C chemokines include potent chemoattractants of monocytes and lymphocytes but not neutrophils such as human monocyte chemotactic proteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated on Activation, Normal T Expressed and Secreted), eotaxin and the macrophage inflammatory proteins l ⁇ and l ⁇ (MIP-lo- and MIP-1 ⁇ ).
  • the actions ofthe 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.
  • chemokines principally "regulated on activation normal T-cell expressed and secreted” (RANTES), macrophage inflammatory proteins (MIP) MlP-l ⁇ and MLP-l ⁇ and monocyte chemoattractant protein-2 (MCP-2).
  • RANTES normal T-cell expressed and secreted
  • MIP macrophage inflammatory proteins
  • MLP-l ⁇ monocyte chemoattractant protein-2
  • CCR5 is also a co-receptor for fflV-l 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 piperidine or tropane compound of formula (I):
  • A is absent or is (CH 2 ) 2 ; is CH orN; M is NR 1 , O, S, S(O) or S(O) 2 ;
  • R 1 is hydrogen, C ⁇ - 6 alkyl [optionally substituted by phenyl ⁇ which itself optionally substituted by halo, C ⁇ - 4 alkyl, C ⁇ - 4 alkoxy, cyano, nitro, CF 3 , OCF 3 , (C alkyl)C(O)NH, S(O) 2 NH 2 , C alkylthio, S(O)(C M alkyl) or S(O) 2 (C ⁇ - 4 alkyl) ⁇ or heteroaryl ⁇ which itself optionally substituted by halo, C ⁇ - 4 alkyl, C ⁇ - 4 alkoxy, cyano, nitro, CF 3 , (C alkyl)C(O)NH, S(O) 2 NH 2 , CM alkylthio, S(O)(C M alkyl) or S(O) 2 (C ⁇ - 4 alkyl) ⁇ ], phenyl ⁇ optionally substituted by halo, C ⁇ - 4 alkyl, C M alk
  • CM alkylthio S(0)(C w alkyl) or S(O) 2 (C alkyl) ⁇ , heteroaryl ⁇ optionally substituted by halo, CM alkyl, CM alkoxy, cyano, nitro, CF 3 , (C M alkyl)C(O)NH, S(O) 2 NH 2 , CM alkylthio, S(O)(C alkyl) or S(O) 2 (C ⁇ - 4 alkyl) ⁇ , S(O) 2 R 5 , S(O) 2 NR°R 7 , C(O)R 8 , C(O) 2 (C ⁇ -6 alkyl) (such as tert-butoxycarbonyl), C(O) 2 (phenyl(C ⁇ - 2 alkyl)) (such as benzyloxycarbonyl) or C(O)NHR n ;
  • R 2 is phenyl (optionally substituted by halo, CN or - 4 haloalkyl), thienyl or halothienyl;
  • R 3 is hydrogen or methyl;
  • R is hydrogen or C ⁇ - 3 alkyl;
  • R 4 is a five or six membered heterocycle containing at least one carbon atom, one to four nitrogen atoms and, optionally, one oxygen or sulphur atom, - a ring carbon of said heterocycle R 4 being optionally substituted by oxo, C ⁇ - 6 alkyl [which is optionally substituted by halogen, CN, OH, CM alkoxy, S(C ⁇ - 4 alkyl), S(O)(C ⁇ - 4 alkyl), S(O) (C ⁇ - 4 alkyl) or heterocyclyl ⁇ itself optionally substituted by C ⁇ - 6 alkyl [which is optionally substituted by oxo, halogen, OH, CM alkoxy, OCF
  • heteroaryl [optionally substituted by oxo, halogen, C M alkyl, C M alkoxy, CF 3 , OCF 3 , cyano, nitro, S(C alkyl), S(O)(C M alkyl) or S(O) 2 (C ⁇ - 4 alkyl)], CONH(C M alkyl), CONH(aryl) [optionally substituted by halogen, CM alkyl, C M alkoxy, CF 3 , OCF 3 , cyano, nitro, S(C alkyl), S(O)(C ⁇ - 4 alkyl) or S(O) 2 (C ⁇ - 4 alkyl)], SO 2 NH(C ⁇ .
  • alkyl substituent on the carbon attached to the ring nitrogen of said heterocycle R 4 ; the five or six membered heterocycle R 4 being optionally fused to a cyclohexane, piperidine, benzene, pyridine, pyridazine, pyrimidine or pyrazine ring; the ring carbon atoms of said fused cyclohexane, piperidine, benzene, pyridine, pyridazine, pyrimidine or pyrazine ring being optionally substituted by halogen, CM alkyl, C M alkoxy, CF 3 , OCF 3 , cyano, nitro, S(C ⁇ - 4 alkyl), S(O)(C ⁇ .
  • R 5 is C ⁇ - 6 alkyl [optionally substituted by halo (such as fluoro), CM alkoxy, phenyl ⁇ which itself optionally substituted by halo, C M alkyl, C M alkoxy, cyano, nitro, CF 3 , OCF 3 , (CM alkyl)C(O)NH, S(O) 2 NH 2 , CM alkylthio, S(0)(C M alkyl) or S(O) 2 (C M alkyl) ⁇ or heteroaryl ⁇ which itself optionally substituted by halo, C M alkyl, C M alkoxy, cyano, nitro, CF 3 , (C M alkyl)C(O)NH, S(O) 2 NH 2 , CM alkylthio, S(O)
  • R 6 and R 7 are, independently, hydrogen or C M alkyl; or together R 6 and R 7 join to form a 5- or 6-membered ring which is optionally substituted with C M alkyl or phenyl (wherein the phenyl ring is optionally substituted by halo, cyano, nitro, hydroxy, CM alkyl, C M alkoxy, S(O) m C ⁇ - 4 alkyl, S(O) 2 NH 2 , S(O) 2 NH(C ⁇ .
  • R 9 and R 10 are, independently, hydrogen or C ⁇ - 6 alkyl; or a pharmaceutically acceptable salt thereof.
  • Certain compounds ofthe 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 (adducts) such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate, j->-toluenesulphonate or formate.
  • Acid addition salt is, for example hydrochloride or formate.
  • the compounds ofthe invention may exist as a solvate (such as a hydrate) and the present invention covers all such solvates.
  • Halogen is, for example, chloro, fluoro or bromo; such as chloro or fluoro.
  • Alkyl groups and moieties are straight or branched chain and are, for example, methyl (sometimes abbreviated to Me), ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl or tert-butyl.
  • Alkyl substituted by halogen is, for example, CF 3 , CHF2, CH2F, CH 2 CF 3 or C2F 5 .
  • Cycloalkyl is for example, cyclopropyl, cyclopentyl or cyclohexyl.
  • N-Linked heterocyclyl is a nitrogen-linked, non-aromatic 3, 4, 5 or 6 membered ring optionally comprising one further heteroatom (selected from the group comprising nitrogen, oxygen and sulphur). It is, for example, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl.
  • a 5- or 6-membered nitrogen containing heterocyclic ring contains, for example, only one nitrogen atom, all other ring atoms being carbon. It is, for example, pyrrolidinyl or piperidinyl.
  • 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, thienyl (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, benztriazolyl, benzoxazolyl, benzthiazolyl, 1,2,3- benzothiadiazolyl, an imidazopyridinyl (such as imidazo[l,2a]pyridinyl), thieno[3,2- b]pyridin-6-yl, 1,2,3-benzoxadiazoly
  • Heteroaryl is, for example, pyridyl, pyrimidinyl, indolyl or benzimidazolyl.
  • the five membered heterocycle of R 4 is, for example, pyrazolyl, imidazolyl, 1,3- dihydro-2H-imidazol-2-one, imidazolidin-2-one, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl or thiazolyl (such as pyrazolyl, imidazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl or thiazolyl).
  • the six membered heterocycle of R 4 is, for example, piperidinyl or piperazinyl.
  • the five or six membered heterocycle of R is fused to a benzene or pyridine ring the resulting bicyclic is, for example, benzimidazolyl, 1,3-dihydro- 2H-benzimidazolyl, benztriazolyl, an imidazopyridinyl (such as imidazo[4,5c]pyridinyl), [such as benzimidazolyl, benztriazolyl or an imidazopyridinyl (such as imidazo[4,5c]pyridinyl)].
  • the resulting bicyclic is, for example, 4,5,6,7-tetrahydro-lH-benzimidazole, 4,5,6,7-tetrahydro- 3H-imidazo[4,5-c]pyridine or 4,5,6, 7-tetrahydro-lH-imidazo[4,5-c] ⁇ yridine.
  • CM Alkyl is, for example, benzyl, 2-phenylethyl or 1-phenyleth-l-yl.
  • C M Alkyl is, for example, pyridylmethyl or pyrimidinylmethyl.
  • NHC(O)Heteroaryl is, for example, NHC(O)pyridyl.
  • NHC(O)(C ⁇ - 4 Alkyl)phenyl is, for example, NHC(O)benzyl.
  • NHC(O)(C ⁇ - Alkyl)heteroaryl is, for example, NHC(O)CH 2 ⁇ yridyl.
  • NHS(O)2Heteroaryl is, for example, NHS(O)2pyridyl.
  • NHS(O)2(C ⁇ - Alkyl)phenyl is, for example, NHS(O) 2 benzyl.
  • NHS(O) 2 (C ⁇ - 4 Alkyl)heteroaryl is, for example, NHS(O) 2 CH 2 pyridyl.
  • NHC(O)NHheteroaryl is, for example, NHC(O)NHpyridyl.
  • NHC(O)NH(C ⁇ - Alkyl)phenyl is, for example, NHC(O)NHbenzyl.
  • NHC(O)NH(C ⁇ - 4 Alkyl)heteroaryl is, for example, NHC(O)NHCH 2 pyridyl.
  • the present invention provides a compound wherein R is hydrogen; and R 4 is a five membered heterocycle containing at least one carbon atom, one to four nitrogen atoms and, optionally, one oxygen or sulphur atom, said heterocycle being optionally substituted by oxo, C ⁇ .
  • the invention provides a compound wherein R 4 is a five or six membered heterocycle containing at least one carbon atom, one to four nitrogen atoms and, optionally, one oxygen or sulphur atom, - a ring carbon of said heterocycle R being optionally substituted by oxo, C ⁇ - 6 alkyl [which is optionally substituted by halogen, CN, OH, C M alkoxy, S(C ⁇ - 4 alkyl), S(O)(C ⁇ - alkyl), S(O) 2 (C ⁇ - 4 alkyl) or heterocyclyl ⁇ itself optionally substituted by C « alkyl [which is optionally substituted by oxo, halogen, OH, C M alkoxy, OCF 3 , C(O)(C M alkoxy), CN, C(O)NH , C(O)NH(C ⁇ - 4 alkyl), C(O)N(C M alkyl) 2 , NH 2 , NH(C ⁇ ⁇
  • the five or six membered heterocycle R 4 being optionally fused to a cyclohexane, piperidine, benzene, pyridine, pyridazine, pyrimidine or pyrazine ring; the ring carbon atoms of said fused cyclohexane, piperidine, benzene, pyridine, pyridazine, pyrimidine or pyrazine ring being optionally substituted by halogen, CM alkyl, C M alkoxy, CF 3 , OCF 3 , cyano, nitro, S(C ⁇ - 4 alkyl), S(O)(C ⁇ .
  • the present invention provides a compound wherein L is CH. In a further aspect the present invention provides a compound wherein M is O. In a still further aspect the invention provides a compound wherein M is NR 1 . In another aspect the present invention provides a compound wherein A is absent. In yet another aspect the present invention provides a compound wherein A is CH 2 CH 2 .
  • the invention provides a compound wherein R 1 is C ⁇ - 6 alkyl, phenyl ⁇ optionally substituted by halo, CM alkyl, C M alkoxy, cyano, nitro, CF 3 , OCF 3 , (C alkyl)C(O)NH, S(O) 2 NH 2 , C M alkylthio, S(O)(C M alkyl) or S(O) 2 (C M alkyl) ⁇ , S(O)2R 5 or C(O)R 8 ; wherein R 5 and R s are C ⁇ - 6 alkyl, CF 3 , C 3 .
  • the invention provides a compound wherein R 1 is S(O) 2 R 5 or C(O)R 8 ; wherein R 5 and R 8 are C ⁇ - 6 alkyl, CF 3 , C 3 .
  • cycloalkyl (optionally substituted by halo or C ⁇ -6 alkyl), phenyl ⁇ optionally substituted by halo, C alkyl, C M alkoxy, cyano, nitro, CF 3 , OCF 3 , (C M alkyl)C(O)NH, S(O) 2 NH 2 , C alkylthio, S(O)(C M alkyl) or S(O) 2 (C M alkyl) ⁇ or a 5- or 6-membered nitrogen containing heterocyclic ring ⁇ optionally substituted by S(O) 2 (CM alkyl) or C(O)(C M alkyl) ⁇ .
  • the invention provides a compound wherein R 1 is S(O) 2 R 5 ; wherein R 5 is C ⁇ - 6 alkyl, CF 3 , C 3 . 7 cycloalkyl (optionally substituted by halo or C ⁇ - 6 alkyl), phenyl ⁇ optionally substituted by halo, C M alkyl, C M alkoxy, cyano, nitro, CF 3 , OCF 3 , (C M alkyl)C(O)NH, S(O) 2 NH 2 , CM alkylthio, S(O)(C M alkyl) or S(O) 2 (C ⁇ - 4 alkyl) ⁇ or a 5- or 6- membered nitrogen containing heterocyclic ring ⁇ optionally substituted by S(O) 2 (C ⁇ - 4 alkyl) or C(O)(C alkyl) ⁇ .
  • the invention provides a compound wherein R 2 is phenyl optionally substituted by chloro, fluoro or CF 3 (for example phenyl, mono-chlorophenyl, mono-fluorophenyl or di-fluorophenyl; such as phenyl 3 -fluorophenyl or 3,5-difluorophenyI), thienyl or halothienyl (for example mono-chlorothienyl; such as 4-chlorothien-2-yl or 5- chlorothien-2-yl).
  • R 2 is phenyl, mono-chlorophenyl, mono-fluorophenyl or di-fluorophenyl (such as phenyl, 3 -fluorophenyl or 3,5-difluorophenyl) or thienyl.
  • R 2 is 3 -fluorophenyl or 3,5-difluorophenyl.
  • R 3 is hydrogen.
  • R 9 and R 10 are both hydrogen.
  • the invention provides a compound wherein R is hydrogen.
  • R 4 is 1,2,4-triazolyl, thiazolyl, 1,2,4-oxadiazolyl, imidazolyl, l,3-dihydro-2H-imidazolyl, 1,2,3-triazolyl or piperidinyl substituted as described above.
  • R 4 is 1,2,4-triazolyl, thiazolyl, 1,2,4-oxadiazolyl, piperidinyl, benzimidazolyl, l,3-dihydro-2H-benzimidazolyl, benzotriazolyl or an imidazopyridinyl (such as imidazo[4,5c]pyridinyl, l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridinyl or 4,5,6, 7-tetrahydro- 3H-imidazo[4,5-c]pyridinyl), each of which is unsubstituted or substituted by one or two of the same or different C e alkyl (for example C alkyl; such as methyl), CF 3 , OH (which may tautomerise to the keto form), oxo (which may tautomerise to the hydroxy form), C M alkyl substituted by heterocyclyl (which is itself optionally substitute
  • R is 1,2,4-triazolyl, thiazolyl, 1,2,4-oxadiazolyl, imidazolyl or 1,2,3-triazolyl substituted as described above.
  • R 4 is 1,2,4-triazolyl, thiazolyl, 1,2,4-oxadiazolyl, benzimidazolyl, benzotriazolyl or an imidazopyridinyl (such as imidazo[4,5c]pyridinyl), each of which is unsubstituted or substituted by one or two ofthe same or different C ⁇ - 6 alkyl (for example C M alkyl; such as methyl), CF 3 , OH (which may tautomerise to the keto form), S(O) 2 (C ⁇ - 4 alkyl), C(O)NH 2 , C(O)NH(phenyl(C ⁇ - 2 alkyl)) or phenyl(C ⁇ - 2 alkyl); wherein the phenyl ofthe for
  • R 4 is 1,2,4-triazolyl, thiazolyl, 1,2,4-oxadiazolyl, imidazolyl, l,3-dihydro-2H-imidazolyl, 1,2,3-triazolyl or piperidinyl substituted as described above.
  • R 4 is 1,2,4-triazolyl, thiazolyl, 1,2,4-oxadiazolyl, piperidinyl, benzimidazolyl, l,3-dihydro-2H-benzimidazolyl, benzotriazolyl or an imidazopyridinyl (such as imidazo[4,5c]pyridinyl, l,4,6,7-tetrahydro-5H-imidazo[4,5-c] ⁇ yridinyl or 4,5,6,7-tetrahydro- 3H-imidazo[4,5-c]pyridinyl), each of which is unsubstituted or substituted by one or two of the same or different C ⁇ - 6 alkyl (for example C alkyl; such as methyl), C 3 - 6 cycloalkyl, C ⁇ - haloalkyl (for example CF 3 or CHF 2 ), OH (which may tautomerise to the keto form), oxo (which may
  • R 4 is 1,2,4-triazolyl, thiazolyl, 1,2,4-oxadiazolyl, imidazolyl or 1,2,3-triazolyl substituted as described above.
  • R is 1,2,4-triazolyl, thiazolyl, 1,2,4-oxadiazolyl, benzimidazolyl, benzotriazolyl or an imidazopyridinyl (such as imidazo[4,5c]pyridinyl), each of which is unsubstituted or substituted by one or two ofthe same or different C ⁇ - 6 alkyl (for example C M alkyl; such as methyl), C 3 .
  • C M alkyl for example C M alkyl; such as methyl
  • L, R 1 and R 4 are as defined above; and R 2* is 0, 1 or 2 ofthe same or different moieties selected from the group comprising: halo (such as chloro or fluoro) or C M haloalkyl (such as CF 3 ).
  • halo such as chloro or fluoro
  • C M haloalkyl such as CF 3
  • the present invention provides a compound or formula (Id): wherein M, R 2 , R 4 , R 9 and R 10 are as defined above. In a further aspect M is oxygen. In yet another aspect the present invention provides a compound or formula (Id):
  • R 9 is hydrogen.
  • the present invention provides a compound or formula (le):
  • R° is heterocyclyl it is, for example
  • R d is C M alkyl ⁇ which is optionally substituted by oxo, halogen, OH, C M alkoxy, OCF 3 , C(O)O(d- 4 alkyl), CN, C(O)NH 2 , C(O)NH(d- 4 alkyl), C(O)N(C alkyl) 2 , phenyl (itself optionally substituted by S(O) 2 (d- 4 alkyl)), NH 2 , NH(d- 4 alkyl) or N(CM alkyl) 2 ⁇ , C(O)(C ⁇ - 4 alkyl) ⁇ wherein the alkyl is optionally substituted by C ⁇ - 4 alkoxy or fluoro ⁇ , C(O)O(C alkyl), C(O)NH 2 , C(O)NH(d- 4 alkyl), C(O)N(C ⁇ - 4 alkyl) 2 or S(O) 2 (d- 4 alkyl) ⁇ wherein the alkyl
  • R is d- alkyl ⁇ which is optionally substituted by oxo, halogen, OH, C alkoxy, OCF 3 , C(O)O(d- 4 alkyl), CN, C(O)NH 2 , C(O)NH(d- alkyl), C(O)N(CM alkyl) 2 , NH 2 , NH(d- 4 alkyl) or N(d- 4 alkyl) 2 ⁇ , C(O)(CM alkyl) ⁇ wherein the alkyl is optionally substituted by C ⁇ - alkoxy or fluoro ⁇ , C(O)O(d- 4 alkyl), C(O)NH 2 , C(O)NH(C ⁇ - 4 alkyl), C(O)N(C M alkyl) 2 or S(O) 2 (C M alkyl) ⁇ wherein the alkyl is optionally substituted by fluoro ⁇ ; provided that when R is an alkyl group substituted
  • the present invention provides a compound or formula (Ih): wherein R e is CM alkyl ⁇ which is optionally substituted by oxo, halogen, OH, d- 4 alkoxy, OCF 3 , C(O)O(d- alkyl), CN, C(O)NH 2 , C(O)NH(C ⁇ -4 alkyl), C(O)N(d- 4 alkyl) 2 , NH 2 , NH(Ci- 4 alkyl) or N(d- 4 alkyl) 2 ⁇ , C(O)(C ⁇ - 4 alkyl) ⁇ wherein the alkyl is optionally substituted by d- 4 alkoxy or fluoro ⁇ , C(O)O(C ⁇ - 4 alkyl), C(O)NH 2 , C(O)NH(d- 4 alkyl), C(O)N(d- 4 alkyl) 2 or S(O) 2 (C ⁇ - 4 alkyl) ⁇ wherein the alkyl is
  • R 2 , R and R 4 are as defined above.
  • the present invention provides a compound or formula (Ik): wherein R is d- 4 alkyl ⁇ which is optionally substituted by oxo, halogen, OH, C alkoxy, OCF 3 , C(O)O(d- 4 alkyl), CN, C(O)NH 2 , C(O)NH(C M alkyl), C(O)N(d- 4 alkyl) 2 , NH 2 , NH(C ⁇ -4 alkyl) or N(d- 4 alkyl) 2 ⁇ , C(O)(C ⁇ -4 alkyl) ⁇ wherein the alkyl is optionally substituted by d- alkoxy or fluoro ⁇ , C(O)O(C ⁇ - 4 alkyl), C(O)NH 2 , C(O)NH(d- 4 alkyl), C(O)N(d-4 alkyl) 2 or S(O) 2 (C ⁇ -4 alkyl
  • the present invention provides a compound wherein R 4 is triazolyl (for example 1,2,4-triazolyl) optionally substituted by d- 4 alkyl (such as methyl, ethyl, n- propyl or iso-propyl) or d- 4 alkyl substituted by halogen (such as CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 or dFs).
  • R 4 is:
  • R d is as defined above.
  • R d is d- 4 alkyl, C(O)(d- 4 alkyl) ⁇ wherein the alkyl is optionally substituted by d-4 alkoxy or fluoro ⁇ , C(O)O(C M lkyl), or S(O) 2 (d-4 alkyl) ⁇ wherein the alkyl is optionally substituted by fluoro ⁇ .
  • the present invention provides a compound of formula (I) wherein A is absent or (CH 2 ) 2 ; L is CH or N; M is NR 1 , O or S(O) 2 ; R 1 is phenyl (optionally substituted by halogen), S(O) 2 R or C(O)R ; R is phenyl (optionally substituted by halogen or CF 3 ); R 3 is hydrogen or d- 4 alkyl; R 4 is 1,2,4-triazolyl, 1,2,4-oxadiazolyl, imidazolyl, 1,2,3-triazolyl, l,3-dihydro-2H-imidazolyl, imidazolidinyl or piperidinyl ring ⁇ optionally substituted by oxo, C1-6 alkyl [itself optionally substituted by piperidinyl optionally substituted by S(O) 2 (d- 4 alkyl)], CF 3 , H 2 NC(O), S(O) 2 (
  • the present invention provides a compound of formula (I) wherein A is absent or (CH 2 ) 2 ; L is CH or N; M is NR 1 or O; R 1 is phenyl (optionally substituted by halogen), S(O) 2 R 5 or C(O)R 8 ; R 2 is phenyl (optionally substituted by halogen or CF 3 ); R is hydrogen; R is 1,2,4-triazolyl, 1,2,4-oxadiazolyl, imidazolyl, 1,2,3-triazolyl or l,3-dihydro-2H-imidazolyl ring ⁇ optionally substituted by oxo, C ⁇ - 6 alkyl, H 2 NC(O),
  • R 5 and R 8 are C M alkyl, phenyl (optionally substituted by halogen), CF 3 , C 3 - ⁇ j cycloalkyl (optionally substituted by halogen) or piperidinyl (optionally substituted by S(O) 2 (d- 4 alkyl), C(O)(d- 4 alkyl) or benzyloxycarbonyl); and R 9 and R 10 are, independently, hydrogen or d- 4 alkyl.
  • Table HI comprises compounds of formula (Ic):
  • Table V comprises compounds of formula (le):
  • Table VLt comprises compounds of formula (Ig):
  • Table VTLT comprises compounds of formula (Ih):
  • Table DC comprises compounds of formula (Ii):
  • Table X comprises compounds of formula (Ij):
  • Table XI comprises compounds of formula (Ik):
  • a compound ofthe invention can be prepared by reductive amination of a compound of formula (II):
  • a compound of formula (II), wherein L is CH, can be prepared as shown in Scheme 1 below.
  • a compound of formula (II), wherein L is N, can be prepared as shown in Scheme 2 below.
  • a compound of formula (HI) can be prepared by removal ofthe protecting group (PG) from a compound of formula (IN):
  • PG is a protecting group
  • X is N, N-oxide, CH or a carbon substituted by halogen, cyano, d- 4 alkyl, d- 4 alkoxy, CF 3 , OCF 3 , S(d- 4 alkyl), S(O)(CM alkyl) or S(O) 2 (d- 4 alkyl);
  • R is hydrogen, halogen, cyano, d- 4 alkyl, d- alkoxy, CF 3 , OCF 3 , S(C ⁇ - 4 alkyl), S(O)(C ⁇ - 4 alkyl) or S(O)2(d-4 alkyl); can be made by first reducing a compound of formula (Na):
  • Variants of compounds of formulae(INa) and (Na) in which the group X occupies an alternative position in the aromatic ring can be prepared in a similar manner.
  • a compound of formula (Na) can be prepared by coupling a compound of formula (Via):
  • LG is a leaving group (such as fluorine), with a compound of formula (VII):
  • a compound of formula (Via) can be made by nitration ofthe respective chloroheteroaryl or respective chloroheteroaryl N-oxide (followed by reduction to remove the N-oxide); or by chlorination of an oxo-nitro-heteroaryl (such as 3-nitropyridin-4- one).
  • a compound of formula (Vb) can be prepared from a compound of formula (VII) by reaction with an activated carboxylic acid or with a carbonyl chloride in the presence ofa base.
  • a compound of formula (IVc), wherein PG and R' are as defined above, can be prepared by first activating the acid of a compound of formula (Vc) and reacting with an N- hydrox -amidine RC( ⁇ OH) ⁇ H 2 , then by cyclisation under elevated temperature in a suitable solvent (such as dioxin).
  • a compound of formula (INd), wherein PG and R' are as defined above, can be prepared by addition of azide to a compound of formula (Nd) then by alkylation ofthe product and separation ofthe ⁇ l and ⁇ 2 isomers so formed (N2 isomer shown).
  • Compounds of formulae (INe) and (INf), wherein PG, R' and R" are as defined above, can be prepared by reaction of a compound of formula (Ve) with an alkyl hydrazine R' ⁇ H ⁇ H 2 .
  • a compound of formula (Ve) can be made by condensation of a compound of formula (Vie) with an ester R"C(O) 2 R* (wherein R* is C ⁇ - 6 alkyl).
  • a compound of formula (INg), wherein PG, R' and R" are as defined above, can be prepared by reaction of a compound of formula (Ng) with a 1,3-di-ketone R"C(O)CH 2 C(O)R ⁇
  • a compound ofthe invention can be prepared by alkylation of a compound of formula (N ⁇ i) or (Vina):
  • LG is a leaving group
  • the invention provides processes for preparing the compounds of the invention. Many ofthe intermediates in the processes are novel and these are provided as further features ofthe invention.
  • the compounds ofthe invention have activity as pharmaceuticals, in particular as modulators (such as agonists, partial agonists, inverse agonists or antagonists) of chemokine receptor (for example 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)).
  • modulators such as agonists, partial agonists, inverse agonists or antagonists
  • CCR5 chemokine receptor
  • AIDS Acquired Immunodeficiency Syndrome
  • the compounds ofthe present invention are also of value in inhibiting the entry of viruses (such as human immunodeficiency virus (HTV)) into target calls and, therefore, are of value in the prevention of infection by viruses (such as HIN), the treatment of infection by viruses (such as HIN) and the prevention and/or treatment of acquired immune deficiency syndrome (AIDS).
  • viruses such as human immunodeficiency virus (HTV)
  • HIN human immunodeficiency virus
  • AIDS acquired immune deficiency syndrome
  • a compound ofthe invention, or a pharmaceutically acceptable salt thereof for use in a method of treatment ofa warm blooded animal (such as man) by therapy (including prophylaxis).
  • a method for modulating chemokine receptor activity for example CCR5 receptor activity
  • chemokine receptor activity for example CCR5 receptor activity
  • a warm blooded animal such as man
  • a pharmaceutically acceptable salt thereof for example a medicament for the treatment of transplant rejection, respiratory disease, psoriasis or rheumatoid arthritis (such as rheumatoid 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 scrofulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis ⁇ ; and is particularly asthma or rhinitis].
  • COPD chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness) ⁇
  • the present invention provides the use of a compound ofthe invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in therapy (for example modulating chemokine receptor activity (such as CCR5 receptor activity (for example rheumatoid arthritis)) in a warm blooded animal, such as man).
  • chemokine receptor activity such as CCR5 receptor activity (for example rheumatoid arthritis)
  • a warm blooded animal such as man
  • the invention also provides a compound ofthe invention, or a pharmaceutically acceptable salt thereof, for use as a medicament, for example a medicament for the treatment of rheumatoid arthritis.
  • the present invention provides the use of a compound ofthe invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in therapy (for example modulating chemokine receptor activity (such as CCR5 receptor activity (for example rheumatoid arthritis)) in a warm blooded animal, such as man).
  • therapy for example modulating chemokine receptor activity (such as CCR5 receptor activity (for example rheumatoid arthritis)) in a warm blooded animal, such as man).
  • the invention further provides the use of a compound ofthe invention, or a pharmaceutically acceptable salt thereof, in the manufacture ofa medicament for use in the treatment of:
  • obstructive diseases of airways including: chronic obstructive pulmonary disease (COPD) (such as irreversible COPD); asthma ⁇ such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness) ⁇ ; bronchitis ⁇ such as eosinophilic bronchitis ⁇ ; acute, allergic, atrophic rhinitis or chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis; sarcoidosis
  • COPD chronic
  • AUograft rejection acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea; or chronic graft versus host disease; and/or
  • Alzheimer's disease multiple sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS), Lupus disorders (such as lupus erythematosus or systemic lupus), erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, leprosy (such as lepromatous leprosy), Peridontal disease, Sezary syndrome, idiopathic thrombocytopenia pupura or disorders ofthe menstrual cycle; in a warm blooded animal, such as man.
  • AIDS Acquired Immunodeficiency Syndrome
  • Lupus disorders such as lupus erythematosus or systemic lupus
  • erythematosus Hashimoto's thyroiditis
  • myasthenia gravis myasthenia gravis
  • type I diabetes nephrotic syndrome
  • the present invention further provides a method of treating a chemokine mediated disease state (for example 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 ofthe invention, or a pharmaceutically acceptable salt thereof.
  • a chemokine mediated disease state for example a CCR5 mediated disease state
  • a pharmaceutically acceptable salt thereof for example a pharmaceutical treatment of a warm blooded animal, such as man, in particular modulating chemokine receptor (for example CCR5 receptor) activity
  • said ingredient is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • the present invention provides a pharmaceutical composition which comprises a compound ofthe invention, or a pharmaceutically acceptable salt thereof (active ingredient), and a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a pharmaceutical composition which comprises a compound ofthe invention, or a pharmaceutically acceptable salt thereof (active ingredient), and a pharmaceutically acceptable adjuvant, diluent or carrier.
  • 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.
  • the pharmaceutical composition will comprise, for example, from 0.05 to 99 %w (per cent by weight), such as from 0.05 to 80 %w, for example from 0.10 to 70 %w (such as from 0J0 to 50 %w), of active ingredient, all percentages by weight being based on total composition.
  • compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by topical (such as to the lung and/or airways or to the skin), oral, rectal or parenteral administration.
  • topical such as to the lung and/or airways or to the skin
  • 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 this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule which contains between 0J mg and 1 g of active ingredient.
  • a pharmaceutical composition ofthe invention is one suitable for intravenous, subcutaneous or intramuscular injection.
  • Each patient may receive, for example, an intravenous, subcutaneous or intramuscular dose of O.Olmgkg "1 to lOOmgkg "1 ofthe compound, for example in the range of OJmgkg "1 to 20mgkg "1 of this invention, the composition being administered 1 to 4 times per day.
  • the intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection. Alternatively the intravenous dose may be given by continuous infusion over a period of time.
  • each patient will receive a daily oral dose which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day.
  • Buffers such as polyethylene glycol, polypropylene glycol, glycerol or ethanol or complexing agents such as hydroxy-propyl ⁇ - cyclodextrin 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 further relates to combination therapies or compositions wherein a compound ofthe invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound ofthe invention, or a pharmaceutically acceptable salt thereof, is administered concurrently (possibly in the same composition) or sequentially with an agent for the treatment of any one of the above disease states.
  • a compound ofthe invention can be combined with a TNF- ⁇ inhibitor (such as an anti-TNF monoclonal antibody (such as Remicade, CDP-870 and D.sub2.E.sub7.), or a TNF receptor immunoglobulin molecule (such as Enbrel.reg.)), a non-selective COX-1 / COX-2 inhibitor (such as piroxicam or diclofenac; a propionic acid such as naproxen, flubiprofen, fenoprofen, ketoprofen or ibuprofen; a fenamate such as mefenamic acid, indomethacin, sulindac or apazone; a pyrazolone such as phenylbutazone; or a salicylate such as aspirin), a COX-1 / COX-2 inhibitor
  • a non-selective COX-1 / COX-2 inhibitor such as piroxicam or diclofenac
  • the present invention still further relates to the combination of a compound of the invention together with: • a leukotriene biosynthesis inhibitor, a 5-lipoxygenase (5-LO) inhibitor or a 5- lipoxygenase activating protein (FLAP) antagonist, such as zileuton, ABT-761, fenleuton, tepoxalin, Abbott-79175, Abbott-85761, an N-(5-substituted)-thiophene-2- alkylsulfonamide, a 2,6-di-tert-butylphenol hydrazones, a methoxytetrahydropyran such as Zeneca ZD-2138, SB-210661, a pyridinyl-substituted 2-cyanonaphthalene compound such as L-739,010; a 2-cyanoquinoline compound such as L-746,530; an indole or quinoline compound such as MK-591, MK-886 or BAY x 100
  • LTE.sub4 selected from the group consisting of a phenothiazin-3-one such as L- 651,392; an amidino compound such as CGS-25019c; a benzoxalamine such as ontazolast; a benzenecarboximidamide such as BHL 284/260; or a compound such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro- 245913, iralukast (CGP 45715A) or BAY x 7195; • a PDE4 inhibitor including an inhibitor of the isoform PDE4D; • an antihistaminic H.subl .
  • a phenothiazin-3-one such as L- 651,392
  • an amidino compound such as CGS-25019c
  • a benzoxalamine such as ontazolast
  • a receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, astemizole, azelastine or chlorpheniramine; • a gastroprotective H.sub2. receptor antagonist; • an ⁇ .subl .- and ⁇ .sub2.-adrenoceptor agonist vasoconstrictor sympathomimetic agent, such as propylhexedrine, phenylephrine, phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride or ethylnorepinephrine hydrochloride; • an anticholinergic agent such as ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine; • a ⁇
  • NSAID's such as piroxicam or diclofenac, a propionic acid such as naproxen, flubiprofen, fenoprofen, ketoprofen or ibuprofen, a fenamate such as mefenamic acid, indomethacin, sulindac or apazone, a pyrazolone such as phenylbutazone, a salicylate such as aspirin, a COX-2 inhibitor such as celecoxib, valdecoxib, rofecoxib or etoricoxib, an analgesic or intra-articular therapy such as a corticosteroid or a hyaluronic acid such as hyalgan or synvisc, or a P2X7 receptor antagonist.
  • NSAID's such as piroxicam or diclofenac
  • a propionic acid such as naproxen, flubiprofen, fenoprofen, ketoprof
  • the present invention still further relates to the combination of a compound ofthe invention together with: (i) a tryptase inhibitor; (ii) a platelet activating factor (PAF) antagonist; (iii) an interleukin converting enzyme (ICE) inhibitor; (iv) an IMPDH inhibitor; (v) an adhesion molecule inhibitor including a VLA-4 antagonist; (vi) a cathepsin; (vii) a MAP kinase inhibitor; (viii) a glucose-6 phosphate dehydrogenase inhibitor; (ix) a kinin- B.subl. - and B.sub2.
  • a -receptor antagonist comprising: (x) an anti-gout agent, e.g., colchicine; (xi) a xanthine oxidase inhibitor, e.g., allopurinol; (xii) an uricosuric agent, e.g., probenecid, sulfinpyrazone or benzbromarone; (xiii) a growth hormone secretagogue; (xiv) a transforming growth factor (TGF ⁇ ); (xv) a platelet-derived growth factor (PDGF); (xvi) a fibroblast growth factor, e.g., basic fibroblast growth factor (bFGF); (xvii) a granulocyte macrophage colony stimulating factor (GM-CSF); (xviii) a capsaicin cream; (xix) a Tachykinin NK.subl.
  • an anti-gout agent e.g., colchicine
  • NKP-608C selected from the group consisting of NKP-608C; SB-233412 (talnetant); and D-4418;
  • an elastase inhibitors selected from the group consisting of UT- 77 and ZD-0892;
  • TACE TNF ⁇ converting enzyme inhibitor
  • iNOS induced nitric oxide synthase inhibitor
  • a chemoattractant receptor-homologous molecule expressed on TH2 cells a CRTH2 antagonist.
  • temperatures are given in degrees Celsius (°C); operations were carried out at room or ambient temperature, that is, at a temperature in the range of 18-25°C;
  • IsoluteTM SCX column a column containing benzenesulphonic acid (non-endcapped) obtained from International Sorbent Technology Ltd., 1st House, Duffryn Industial Estate, Ystrad Mynach, Hengoed, Mid Glamorgan, UK.
  • ArgonautTM PS-trw-amine scavenger resin this means a t -(2-aminoethyl)amine polystyrene resin obtained from Argonaut Technologies Inc., 887 Industrial Road, Suite G, San Carlos, California, USA.
  • (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.
  • Triethylamine 72 ⁇ l was added to a solution of 5-(methylsulfonyl)-l-[l-(3-phenyl-3- piperazin-l-ylpropyl)piperidin-4-yl]-lH-benzimidazole (100 mg) in dichloromethane (10 ml) followed by ethanesulphonyl chloride (20 ⁇ l) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with water (10 ml) and brine (10 ml) and dried.
  • Boc-piperazine (393 mg) was added to a mixture of triethylamine (0.59 ml), l-[l-(3- chloro-3-phenylpropyl)piperidin-4-yl]-5-(methylsulfonyl)-lH-benzimidazole (910 mg) and sodium iodide (250 mg) in dichloromethane (20 ml) and the mixture was stirred at room temperature for 8 days, washed with water (20 ml) and brine (20 ml), dried and evaporated to dryness.
  • Methanesulphonyl chloride (0.46 ml) was added to a solution of 3- ⁇ 4-[5- (methylsulfonyl)-lH-benzimidazol-l-yl]piperidin-l-yl ⁇ -l-phenylpropan-l-ol (2. Ig) and triethylamine (0.9 ml) in dichloromethane (30 ml) at 0 °C. The mixture was allowed to warm to room temperature and stirring was continued for 16 hours. The reaction mixture was washed with water (15 ml) and brine (15 ml) and dried. Removal ofthe solvent gave the title compound as an orange foam, yield 1.85g, M+ ⁇ 432.
  • 3-Chloropropiophenone (860 mg) was added to a mixture of 5-(methylsulfonyl)-l- piperidin-4-yl-lH-benzimidazole (1.395g) and potassium carbonate (1.38g) in DMF (30 ml) and stirred for 2 days.
  • EXAMPLE 2 This Example illustrates the preparation of l- ⁇ (lS)-3-[4-(3-isopropyl-5-methyl-4H- 1,2, 4-triazol-4-yl)piperidin-l-yl]-l-phenylpropyl ⁇ -4-(phenylsulfonyl)piperazine (Compound 1 Table IT).
  • Triethylamine (195 ⁇ l) and benzenesulphonylpiperazine (190 mg) were added to a solution of l-[(3R)-3-chloro-3-phenylpropyl]-4-(3-isopropyl-5-methyl-4H-l,2,4-triazol-4- yl)piperidine (252 mg) [Method G] in dichloromethane (7 ml) and the mixture was stirred for 9 days at room temperature.
  • PS-NCO (700 mg) was added and stirring was continued for 16 hours.
  • the reaction mixture was filtered and the filter cake was washed with 10% methanol in dichloromethane (2x20 ml).
  • EXAMPLE 3 This Example illustrates the preparation of l-(l- ⁇ (3i?)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl ⁇ piperidin-4-yl)-5-(methylsulfonyl)-lH-benzimidazole (Compound 5 Table ⁇ ).
  • Methanesulphonyl chloride (61 ⁇ l) was added to a solution of 4-(3-isopropyl-5- methyl-4H-l,2,4-triazol-4-yl)-l-(3-phenyl-3-piperidin-4-ylpropyl)pi ⁇ eridine (263 mg) [Method J] and triethylamine (178 ⁇ l) in dichloromethane (3 ml) at 0 °C. The mixture was allowed to warm to room temperature and stirring was continued for 2 hours. The reaction mixture was poured onto a lOg SCX column and washed with methanol and then 1M ammonia in methanol.
  • HATU 153 mg
  • diisopropylethylamine 139 ⁇ l
  • benzylamine 44 ⁇ l
  • 2-(l- ⁇ 3-[l-(methylsulfonyl)piperidin-4-yl]-3-phenylpropyl ⁇ piperidin-4-yl)- l,3-thiazole-4-carboxylic acid 192 mg
  • Dichloromethane 50 ml was added and the solution was washed with saturated ammonium chloride (2x25 ml), water (25 ml), brine (25 ml) and dried.
  • Lithium hydroxide (118 mg) was added to a solution of ethyl 2-(l- ⁇ 3-[l- (methylsulfonyl)piperidin-4-yl]-3-phenylpropyl ⁇ piperidin-4-yl)-l,3-thiazole-4-carboxylate (290 mg) in a mixture of water (1 ml) and THF (3 ml) and the mixture was stirred for 24 hours. Additional water (1 ml) was added and the mixture was acidified to pH 4 with 2M HCl and extracted with dichloromethane (2x50 ml). The combined extracts were dried and solvent removed to give the acid, yield 196 mg.
  • the ethyl 2-(l - ⁇ 3-[l -(methylsulfonyl)piperidin-4-yl]-3-phenylpropyl ⁇ piperidin-4-yl)- l,3-thiazole-4-carboxylate used as starting material was prepared by reductive amination of 3- [ 1 -(methy Isulfony l)piperidin-4-y 1] -3 -pheny Ipropanal (prepared following Method I using 4- benzoyl-N-methanesulphonylpiperidine as starting material) with ethyl 2-piperidin-4-y 1-1,3 - thiazole-4-carboxylate (Method K) as the amine component.
  • the resin was filtered and washed with 10% methanol in dichloromethane (10 ml) and the filtrate was evaporated to dryness.
  • the residue was purified by chromatography on silica (Isolute 20g) eluting with a solvent gradient of 5% methanol/ethyl acetate to 10% methanol/ethyl acetate to give the title compound as a white foam, yield 146 mg.
  • EXAMPLE 10 This Example describes the preparation of l-(l- ⁇ (3R)-3-(3,5-difluorophenyl)-3-[l- (methylsulphonyl)piperidin-4-yl]propyl ⁇ piperidin-4-yl)-3-[4-(methylsulphonyl)benzyl]-l,3- dihydro-2H-imidazol-2-one (Compound 6 Table V).
  • Argon was bubbled through a suspension of i-(l- ⁇ (3R)-3-(3,5-difluorophenyl)-3-[l- (methylsulphonyl)piperidin-4-yl]propyl ⁇ piperidin-4-yl)- 1 ,3 -dihydro-2H-imidazol-2-one (400 mg, Example 9), 4-methanesulphonylbromobenzene (193 mg), potassium phosphate (350 mg) and copper iodide (314 mg) in dioxane (25 ml) for 10 minutes and N, N'- dimethylethylenediamine (290 mg) was added.
  • EXAMPLE 12 This Example describes the preparation of l-(l- ⁇ (3R)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl ⁇ piperidin-4-yl)-3- ⁇ [l-(methylsulfonyl)piperidin-4- yl]methyl ⁇ -1 ,3-dihydro-2H-imidazol-2-one (Compound 8 Table V).
  • Step 1 Preparation of l-(l- ⁇ (3R)-3-(3,5-difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4- yl]propyl ⁇ piperidin-4-yl)-3-(piperidin-4-ylmethyl)- 1 ,3-dihydro-2H-imidazol-2-one
  • EXAMPLE 13 This Example describes the preparation of tert-butyl l'- ⁇ (3R)-3-(3,5-dif ⁇ uorophenyl)- 3-[l -(methylsulphonyl)piperidin-4-yl]propyl ⁇ -4,4'-bipiperidine-l -carboxylate (Compound 1 Table V ⁇ i).
  • EXAMPLE 14 This Example describes the preparation of l- ⁇ (3R)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl ⁇ -l'-(methylsulfonyl)-4, 4' -bipiperidine (Compound 3 Table V ⁇ i).
  • Methanesulphonyl chloride (49 mg) was added to a stirred solution of l- ⁇ (3R)-3-(3,5- difluorophenyl)-3-[l-(methylsulphonyl)piperidin-4-yl]propyl ⁇ -4,4'-bipiperidine trifluoroacetate (260 mg) [prepared from the title compound of Example 13 following the method described in Example 12, step 1] and triethylamine (88 mg) in dichloromethane (20 ml) and stirring was continued for 30 minutes. The reaction mixture was washed with 2M NaOH (2x20 ml), dried and evaporated to dryness.
  • EXAMPLE 15 This Example illustrates the preparation of 8- ⁇ (3R)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl ⁇ -3-exo-(3-isopropyl-5-methyl-4H-l,2,4-triazol-4-yl)-8- azabicyclo[3.2.1] octane (Compound 3 Table IV).
  • EXAMPLE 16 This Example illustrates the preparation of l-(l- ⁇ (3R)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl ⁇ piperidin-4-yl)-4,5,6,7-tetrahydro-lH-imidazo[4,5- c]pyridine. (Compound 1 Table NTI).
  • EXAMPLE 17 This Example illustrates the preparation of methyl l-(l- ⁇ (3R)-3-(3,5-difluorophenyl)- 3-[l-(methylsulfonyl)piperidin-4-yl]propyl ⁇ piperidin-4-yl)-l,4,6,7-tetrahydro-5H- imidazo[4,5-c]pyridine-5-carboxylate (Compound 5 Table VTI).
  • EXAMPLE 18 This Example illustrates the preparation of 5-acetyl-l-(l- ⁇ (3R)-3-(3,5- difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4-yl]propyl ⁇ piperidin-4-yl)-4,5,6,7- tetrahydro-lH-imidazo[4,5-c]pyridine (Compound 4 Table VT1).
  • EXAMPLE 19 This Example illustrates the preparation of l-(l- ⁇ (3R)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl ⁇ piperidin-4-yl)-5-isopropyl-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridine trifluoroacetate (Compound 6 Table VTI).
  • the resulting solution was left to stir at room temperature for 48 hours before being poured directly onto a silica cartridge and initially purified by column chromatography using a gradient of methanol in dichloromethane followed by further purification by reverse-phase ⁇ PLC using a gradient of (0.1% trifluoroacetic acid in acetonitrile) in (0.1% trifluoroacetic acid in water) giving the title compound (0J05g) as a white foam.
  • EXAMPLE 20 This Example illustrates the preparation of 1-(1- ⁇ (3R)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl ⁇ iperidin-4-yl)-5-[4-(methylsulfonyl)benzyl]-4,5,6,7- tetrahydro-lH-imidazo[4,5-c]pyridine trifluoroacetate (Compound 7 Table VII).
  • EXAMPLE 21 This Example illustrates the preparation of l-(l- ⁇ (3R)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl ⁇ piperidin-4-yl)-5-(3,3,3-trifluoropropanoyl)-4,5,6,7- tetrahydro-lH-imidazo[4,5-c]pyridine (Compound 3 Table N ⁇ ).
  • EXAMPLE 22 This Example illustrates the preparation of l-(l- ⁇ (3R)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl ⁇ piperidin-4-yl)-5-(methylsulfonyl)-4,5,6, 7-tetrahy dro- lH-imidazo[4,5-c]pyridine (Compound 2 Table Nil).
  • the aqueous portion was further extracted with dichloromethane, the combined organic portions were washed with brine then the combined organic portions were dried (MgSO 4 ) and solvents evaporated under reduced pressure before purification ofthe residues on an SCX ion- exchange cartridge, using as eluent dichloromethane then methanol then methanolic ammonia, giving the title compound (0J02g) as a white foam.
  • EXAMPLE 23 This Example illustrates the preparation of l-(l- ⁇ (3R)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl ⁇ piperidin-4-yl)-N-methyl-l,4,6,7-tetrahydro-5H- imidazo[4,5-c]pyridine-5-carboxamide (Compound 9 Table N ⁇ ).
  • EXAMPLE 24 This Example illustrates the preparation of 3-(l- ⁇ (3R)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propyl ⁇ piperidin-4-yl)-5-(methylsulfonyl)-4,5,6,7-tetrahydro- 3H-imidazo[4,5-c]pyridine (Compound 1 Table XI).
  • Step 1 Preparation of 3-(l- ⁇ (3R)-3-(3,5-difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4- yl]propyl ⁇ piperidin-4-yl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine.
  • reaction mixture was filtered and solvents evaporated under reduced pressure to give a brown gum which was purified by SCX ion-exchange chromatography, eluting with a gradient of methanol then methanolic ammonia in methanol to give the title compound (0.34g) as a pale yellow foam.
  • Step 2 To a solution of 3-(l- ⁇ (3R)-3-(3,5-difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4- yl]propyl ⁇ piperidin-4-yl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine (0J55g) in tetrahydrofuran (10ml) cooled to 0°C was added methanesulfonyl chloride (0.035g, 0.024ml) followed by triethylamine (0.034g, 0.0476ml).
  • EXAMPLE 25 This Example describes the preparation of 4- ⁇ (lR)-l-(3,5-difluorophenyl)-3-[4-(3- isopropyl-5-methyl-4H- 1 ,2,4-triazol-4-yl)piperidin- 1 -yl]butyl ⁇ - 1 - (methylsulphonyl)piperidine (Compound 1 Table IX).
  • EXAMPLE 27 This Example illustrates the preparation of methyl l-((3-exo)-8- ⁇ (3R)-3-(3,5- difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4-yl]propyl ⁇ -8-azabicyclo[3.2J]oct-3-yl)- 1,4,6, 7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (Compound 12 Table VI).
  • EXAMPLE 28 This Example illustrates the preparation of l- ⁇ S-ew-fc -S ⁇ R ⁇ S- ⁇ S- difluoropheny -S-tl ⁇ me ylsulfony piperidin ⁇ -yH ⁇ lH-imidazo[4,5-c]pyridine (Compound 28 Table VI).
  • Step 1 4-Amino-l-benzylpiperidine (87g) was added slowly during 20 minutes to a stirred mixture of 2-fluoro-5-methylsulphonyl-nitrobenzene (100g) and anhydrous sodium carbonate (35g) in 500mL DMSO, the internal temperature rose from 20°C to 50°C. The mixture was stirred at 90°C for 12 hours, then poured into ice/water and the yellow solid was filtered off, redissolved in dichloromethane, dried and evaporated to give 175g N-(l-benzylpiperidin-4- yl)-2-nitro-4-methylsulphonylaniline.
  • Step 2 The crude material from Step 1 (170g) was dissolved in 3 litres of methanol in a pressure vessel, 20g of moist 5%Pd7C catalyst was added and stirred under an atmosphere of hydrogen at 3 bar and 50°C for one hour. The reaction was cooled, filtered and evaporated to give 133g N-(l-benzylpiperidin-4-yl)-2-amino-4-methylsulphonylaniline as a brown solid.
  • Step 3 The crude material from Step 2 (130g) was stirred in 300mL trimethylorthoformate containing 4-toluenesulphonic acid (8g) at 90°C for one hour, and collecting the methanol distillate. The reaction was cooled and filtered to give 108g l-(l-benzylpiperidin-4-yl)-5- methylsulphonyl-lH-benzimidazole as a brown solid.
  • Step 4 The crude material from Step 3 (lOOg) was dissolved in 1 litre of methanol in a pressure vessel, 20g of moist 10% Pd/C catalyst and lOOmL acetic acid were added and stirred under an atmosphere of hydrogen at 5 bar and 50°C for 8 hours. The reaction was cooled, filtered and evaporated. The residue was dissolved in water and basified with sodium hydroxide solution, extracted into dichloromethane, dried and evaporated.
  • Step 1 To a solution ofthe 2-methyl-N-[l-(phenylmethyl)-4-piperidinyl]-propanamide (5.89g) in pyridine (11.2mL) and chloroform (15mL) at 0°C under argon was added phosophorus oxychloride (6.33mL). The mixture was allowed to warm to ambient temperature and stirred for 24 hours then evaporated. The residue was dissolved in chloroform (30mL) and acetic hydrazide (3.36g) added and the mixture heated at reflux for 5 hrs, diluted with saturated sodium hydrogen carbonate and extracted with dichloromethane, dried (MgSO 4 ) and evepourated.
  • Step 2 The N-benzylpiperidine triazole (3.03g) was dissolved in ethanol (50mL) and 20% palladium hydroxide (0.70g) and ammonium formate (3.22g) added and the mixture heated at reflux for 150 minutes. The suspension was filtered through celite and the filtrate evaporated to give the product as a yellow solid (2.20g).
  • Step 1 Preparation of tert-butyl 4- ⁇ [4-(methylsulfonyl)-3-nitrophenyl]amino ⁇ piperidine-l- carboxylate.
  • Step 2 Preparation of tert-butyl 4-[2-methyl-5-(methylsulfonyl)-lH-benzimidazol-l- yl]piperidine- 1 -carboxylate
  • a solution of tert-butyl 4- ⁇ [4-(methylsulfonyl)-3-nitrophenyl]amino ⁇ piperidine-l- carboxylate (2g) in methanol / acetic acid ( 100ml) was added trimethyl orthoacetate (0.7ml) followed by a catalytic amount of 10% palladium on carbon.
  • the resulting mixture was placed under a hydrogen atmosphere (3 bar) and heated to 80°C for 16 hours. The mixture was cooled, filtered and evaporated to dryness.
  • Step 3 Preparation of 2-methyl-5-(methylsulfonyl)-l -piperidin-4-yl- lH-benzimidazole
  • the title compound was prepared in a similar manner to Method O, Step 5.
  • NMR (d6 DMSO) 2.2 (m, 2 ⁇ ), 2.85 (m, 2H), 2.9 (s, 3H), 3J5 (m, 2H), 3.3 (s, 3H), 3.5 (m, 2H), 5.0 (m, IH), 8.0 (dd, IH), 8.3 9s, IH), 8.7 (d, IH), 9.2 (d, IH), 9.9 (m, IH).
  • Step 2 Acetyl chloride (86 ⁇ L, 1.21mmol) was added dropwise to methanol (0.5mL) and stirred for 10 minutes then added to tert-butyl 4- ⁇ 3-[4-(methylthio)benzyl]-l,2,4-oxadiazol- 5-yl ⁇ piperidine-l-carboxylate (237mg, 0.61mmol) in MeOH (5mL) and the mixture heated to 60°C for lhour and the solvents evaporated to give a the title compound as a yellow powder, (199mg, 100%); MS: 290 (MH+).
  • Step 1 tert-Butyl 4- ⁇ 3-[4-(methylthio)benzyl]-l,2,4-oxadiazol-5-yl ⁇ piperidine-l-carboxylate (3J0g, 7.96mmol) (Method E, Step 1) was dissolved in dichloromethane(lOOmL), at room temperature, under argon. 3-Chloroperbenzoic acid (60% wt, 6.87g, 23.88mmol) was added portionwise and stirred for 1 hour.
  • Step 2 Acetyl chloride (0.97mL, 11.86mmol) was added dropwise to methanol (lOmL), stirred for 10 minutes and tert-butyl 4- ⁇ 3-[4-(methylsulfonyl)benzyl]-l ,2,4-oxadiazol-5- yl ⁇ piperidine- 1 -carboxylate (2.50g, 5.93mmol) was added and the mixture heated to reflux for 2 hours.
  • Step 1 Potassium carbonate (276 mg) was added to a solution of (3S)-3-hydroxy-3- phenylpropyl 4-methylbenzenesulfonate (306 mg) and 4-(3-isopropyl-5-methyl-4H-l,2,4- triazol-4-yl)piperidine (208 mg) in dioxane (5 ml) and the mixture was heated and stirred at 100 °C for 11 hours. The reaction mixture was evaporated to dryness and the residue was partitioned between dichloromethane and water (20 ml of each). The organic layer was collected and washed with water (1 Oml), brine (1 Oml) and dried.
  • Step 2 Triethylamine (127 ⁇ l) was added to a solution of (lS)-3-[4-(3-t>r ⁇ -propyl-5-methyl- 4H-l,2,4-triazol-4-yl)piperidin-l-yl]-l-phenylpropan-l-ol (238 mg) in dichloromethane (3 ml) at 0 °C followed by methanesulphonyl chloride (61 ⁇ l). The reaction mixture was allowed to warm to room temperature and was stirred for 48 hours. The reaction mixture was diluted with an equal volume of dichloromethane and washed with saturated ammonium chloride (2x10 ml) and brine (10 ml) and dried. Evaporation ofthe solvent gave the title compound, yield 252 mg, M+ ⁇ 361.
  • Step 1 Preparation of (2E)-3-[l-(methylsulfonyl)piperidin-4-yl]acryloyl chloride.
  • Step 2 Preparation of (4R,5S)-l,5-dimethyl-3- ⁇ (2E)-3-[l-(methylsulfonyl) ⁇ i ⁇ eridin-4- yl]prop-2-enoyl ⁇ -4-phenylimidazolidin-2-one.
  • Lithium bis(trimethylsilyl)amide (8 ml ofa IM solution in THF) was added dropwise to a suspension of (4R,5S)-l,5-dimethyl-4-phenyl-2-imidazolidinone (1.52g) in THF (20 ml) under argon at -10°C.
  • the reaction mixture was stirred at -10°C for 10 minutes, allowed to warm to 0°C and maintained at this temperature for 10 minutes then cooled again to -10°C.
  • the solution ofthe acid chloride (2g dissolved in 10 ml of dichloromethane) prepared in Step 1 was added dropwise and the reaction mixture was allowed to warm to room temperature and washed with water (100 ml).
  • the aqueous extract was extracted with ethyl acetate (3x50 ml) and the ethyl acetate extracts were dried and the residue passed through a 90g Biotage column eluting with a solvent gradient (50% ethyl acetate/isohexane - 70% ethyl acetate/isohexane). Yield 1.89g.
  • Step 3 Preparation of (4S,5R)-l- ⁇ (3R)-3-(3,5-difluorophenyl)-3-[l- (methylsulfonyl)piperidin-4-yl]propanoyl ⁇ -3,4-dimethyl-5-phenylimidazolidin-2-one.
  • Step A TMEDA (11.6g) was added to a suspension of copper iodide (19.4g) in THF (240 ml) under argon and the mixture was stirred for 45 minutes then cooled to -70 °C. A solution of 3,5-difluorophenyl magnesium bromide in THF (201J ml ofa 0.5M solution in THF) was added over 10 minutes and the mixture was stirred at -70 °C for 30 minutes.
  • Step B Di-ra-butylboron triflate (100.7 ml of IM solution in dichloromethane) was added to a suspension of (4R,5S)-l,5-dimethyl-3- ⁇ (2E)-3-[l-(methylsulfonyl)piperidin-4-yl]prop-2- enoyl ⁇ -4-phenylimidazolidin-2-one (20.41g; Step 2) in THF maintained at -40 °C and stirring was continued for 10 minutes and the mixture was cooled to -70 °C and added via a cannula to the cuprate suspension prepared in step A.
  • the reaction mixture was stirred at -70 °C for 1 hour, allowed to warm to room temperature, then saturated ammonium chloride solution (200 ml) was added.
  • the THF was evaporated and ethyl acetate (200 ml) was added. Air was blown through this mixture for 1 hour.
  • the ethyl acetate layer was collected and the aqueous portion was extracted with ethyl acetate (2x100 ml).
  • the combined ethyl acetate extracts were washed with saturated ammonium chloride solution (2x100 ml), dried and evaporated to dryness.
  • Step 4 Preparation of (3i?)-3-(3,5-difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4- yl]propan-l-ol
  • Lithium borohydride (48 ml of 2M solution in THF) was added to a solution of (4S,5R)-l- ⁇ (3R)-3-(3,5-difluoro ⁇ henyl)-3-[l-(methylsulfonyl)pi ⁇ eridin-4-yl] ⁇ ro ⁇ anoyl ⁇ -3,4- dimethyl-5- ⁇ henylimidazolidin-2-one (25g) in THF (200 ml) and the mixture was heated at 70°C for 3 hours then allowed to cool to room temperature and stirring was continued for 16 hours. Ethanol was added carefully (20 ml) and the reaction mixture was acidified to pH 4 by addition of 2M HCl.
  • Step 5 Preparation of title compound Dess-Martin periodinane (lg) was added to a solution of (R) 3-(N-methanesulphonyl- piperidin-4-yl)-3-(3,5-difluorophenyl)propanol (0.8g) in dichloromethane (40 ml) and the mixture was stirred for 1.5 hours. The reaction mixture was washed with 2M NaOH (2x20 ml) and dried. The solution ofthe title compound in dichloromethane was used in subsequent reactions.
  • step 1 In a similar manner but starting from (2E)-3-[l-(trifluoromethylsulfonyl)piperidin-4- yl]acrylic acid in step 1 was prepared (3R)-3-(3,5-difluorophenyl)-3-[l- (trifluoromethylsulfonyl)piperidin-4-yl]propanal.
  • Step 1 Preparation of l-tert-butylcarbonyloxy-4-benzoy -piperidine
  • Step 2 Preparation of ethyl 3-phenyl-3-(l-tert-butylcarbonyloxypi ⁇ eridin-4-yl)acrylate
  • Step 3 Preparation of ethyl 3-phenyl-3-(l-tert-butylcarbonyloxypiperidin-4-yl)propionoate
  • Step 4 Preparation of 3-phenyl-3-(l-tert-butylcarbonyloxypiperidin-4-yl)propan-l-ol
  • Step 5 Preparation ofthe title compound To a solution of 3-phenyl-3-(l-tert-butylcarbonyloxypiperidin-4-yl)propan-l-ol (4.6g, 14.4mmol) in DCM (lOOmL) was added Dess-Martin periodinane (6Jg, 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.
  • Step 1 Preparation of tert-butyl 4- ⁇ 3-[4-(3-isopropyl-5-methyl-4H-l,2,4-triazol-4- yl)piperidin-l -yl]- 1 -phenylpropyl ⁇ piperidine- 1 -carboxylate
  • Step 2 Preparation ofthe title compound
  • the product from step 1 was dissolved in dichloromethane (1.5 ml) and trifluoroacetic acid (15 ml) was added and the mixture was allowed to stand for 1 hour.
  • the reaction mixture was evaporated to dryness and the residue was dissolved in 2M NaOH (50 ml) and this solution was extracted with dichloromethane (2x50 ml).
  • Step 1 Preparation of benzyl 4-[4-(ethoxycarbonyl)-l,3-thiazol-2-yl]piperidine-l- carboxylate
  • Step 2 Preparation of title compound The product from step 1 was added to 33% HBr in acetic acid (35 ml) and the mixture was stirred for 1 hour. A further aliquot of HBr in acetic acid was added and stirring was continued for 1 hour.
  • the reaction mixture was diluted with diethyl ether (100 ml) and the solids filtered.
  • the solid was dissolved in dichloromethane (100 ml) and triethylamine (2 ml) and MP-carbonate (lOg) were added and the mixture was stirred for 16 hours, filtered and the filtered resin was washed with a mixture of methanol/dichloromethane (1:9) (2x50 ml).
  • the residue obtained on removal ofthe solvent was subjected to the scavenging process two more times. Removal o the solvent gave the title compound as a yellow oil, yield 1.8g.
  • Step 2 Preparation of (4R,5S)-l,5-dimethyl-4-phenyl-3-[(2E)-3-(tetrahydro-2H- ⁇ yran-4- yl)prop-2-enoyl]imidazolin-2-one
  • Step A To a solution of (2E)-3-(tetrahydro-2H-pyran-4-yl)acrylic acid (2.76g) in anhydrous T ⁇ F (25ml) was added l-chloro-N,N-2-trimethyl-l-propenylamine (2.31ml) and the resulting mixture was stirred for 3 hours.
  • Step B To a suspension of (4R,5S)-l,5-dimethyl-4-phenyl-2-imidazidinone (3.32g) in T ⁇ F (25ml), cooled to 5°C, was added dropwise lithium bis(trimethylsilyl)amide (19.2ml ofa IM solution in T ⁇ F) under argon. The reaction mixture was stirred for 30 minutes before the addition ofthe solution ofthe acid chloride from Step A. The resulting mixture was stirred at room temperature for 18 hours. The reaction was quenched with 50% brine (100ml) and extracted with ethyl acetate (3x100ml) and the ethyl acetate extracts were dried and evaporated.
  • Step 3 Preparation of (4S,5R)-l-[(3R)-3-(3,5-difluorophenyl)-3-(tetrahydro-2H- ⁇ yran-4- yl)propanoyl]-3,4-dimethyl-5-phenylimidazolidin-2-one
  • Lithium borohydride (1.5ml of 2M solution in T ⁇ F) was added to a solution of (4S,5R)-l-[(3R)-3-(3,5-difluorophenyl)-3-(tetrahydro-2H-pyran-4-yl)propanoyl]-3,4- dimethyl-5-phenylimidazolidin-2-one (882mg) in anhydrous T ⁇ F (20ml) and the mixture was heated to 60°C for 2 hours. The reaction mixture was cooled and quenched with saturated ammonium chloride and ethyl acetate and stirred for 20 minutes. The organic layer was dried and evaporated to dryness.
  • Step 5 Preparation ofthe title compound Dess-Martin periodinane (628mg) was added to a solution of (3R)-3-(3,5- difluorophenyl)-3-(tetrahydro-2H-pyran-4-yl)propan-l-ol (345mg) in dichloromethane (lOml) and the mixture was stirred for 2 hours. The reaction mixture was washed with IN NaOH (10ml) and dried. The solution ofthe title compound in dichloromethane was used in subsequent reactions.
  • Step 5 Preparation of 8-benzyl-3-(3-isopropyl-5-methyl-4H-l,2,4-triazol-4-yl)-exo-8- azabicyclo[3.2J] octane
  • Step 6 Preparation of 3-(3-isopropyl-5-methyl-4H-l,2,4-triazol-4-yl)-exo-8- azabicyclo[3.2.1 ] octane
  • Step 2 Preparation of tert-butyl 4-[(4-nitro-l-oxidopyridin-3-yl)amino]piperidine-l- carboxylate.
  • 3-fluoro-4-nitropyridine-N-oxide 3.46g
  • tert-butyl 4- aminopiperidine-1 -carboxylate 2.745g
  • acetonitrile 150ml
  • anhydrous potassium carbonate 2.74g
  • Step 3 Preparation of tert-butyl 4-[(4-aminopyridin-3-yl)amino]piperidine-l-carboxylate
  • Step 4 Preparation of tert-butyl 4-(3H-imidazo[4,5-c]pyridine-3-yl)piperidine-l -carboxylate
  • Step 5 Preparation of 3-piperidin-4-yl-3H-imidazo[4,5-c]pyridine
  • a solution of tert-butyl 4-(3H ⁇ imidazo[4,5-c]pyridine-3-yl)piperidine-l- carboxylate (lJ2g) in 1,4 dioxan (10ml) was added 4M hydrochloric acid in dioxin (10ml) and the resulting mixture was stirred for 3 hours.
  • Diethyl ether (30ml) was added and the mixture was filtered and washed with diethyl ether (50ml) to give the title compound which was used without further purification. Yield l.lg.
  • Step 1 Preparation of l-benzyl-4-[3-me cthyl-5 ⁇ -(trifluoromethyl)-4H-l,2,4-triazol-4- yl]piperidine
  • Phosphorous oxychloride 13.0 ml was added dropwise to a mixture of N-(l- benzylpiperidin-4-yl)acetamide (10.75g) in chloroform (30 ml) containing pyridine (22.5 ml) at 0 °C under an argon atmosphere.
  • the reaction mixture was allowed to warm to room temperature and stirring was continued for 12 hours.
  • the reaction mixture was evaporated to dryness under vacuum and the residue was azeotroped with toluene (100 ml).
  • the residue obtained was dissolved in chloroform (30 ml), trifluoro acetic acid hydrazide (8.89g) was added and the mixture was heated under reflux for 4 hours.
  • the reaction mixture was allowed to cool and saturated aqueous sodium bicarbonate (100 ml) was added and the mixture was extracted with dichloromethane (3x100 ml) and the cobined extracts were dried. The residue obtained on removal ofthe solvent was stirred with 2M ⁇ C1 (65 ml) for 2 hours. The reaction mixture was evaporated to dryness and the residue partitioned between saturated aqueous potassium carbonate (100 ml) and dichloromethane (100 ml).
  • Step 2 Preparation ofthe title compound A solution of l-benzyl-4-[3-methyl-5-(trifluoromethyl)-4H-l,2,4-triazol-4- yl]piperidine (2.97g) in ethanol (45 ml) was hydrogenated under a hydrogen filled ballon using 20% palladium hydroxide on charcoal as catalyst.
  • Aminoacetaldehyde dimethylacetal (1.2g) was added to a solution of benzyl 4- isocyanatopiperidine-1 -carboxylate (3g) in T ⁇ F (100 ml) and the mixture was stirred for 3 hours. 20% Palladium on charcoal (500mg) was added and the mixture was hydrogenated under a hydrogen filled balloon. The catalyst was filtered through Celite and the residue was evaporated to dryness then dissolved in ethanol and subjected to repeat hydrogenation with fresh palladium on charcoal catalyst (500 mg). The catalyst was filtered through Celite and the residue was evaporated to dryness then dissolved in 2M ⁇ C1 (50 ml) and allowed to stand for 4 hours.
  • Step 1 Preparation of benzyl 4-(2-oxoimidazolidin-l-yl)piperidine-l -carboxylate
  • 2-Chloroethylisocyanate (2.23g) was added to a solution of benzyl 4-aminopiperidine- 1-carboxylate (5g) (CAS 120278-07-1) in THF (100 ml) and the mixture was stirred at room temperature for 1 hour. Lithium bis(trimethylsilyl)amide (21 ml of IM solution in THF) was added and stirring was continued for 16 hours. The clear solution was evaporated to dryness and the residue was dissolved in dichloromethane (50 ml) and the solution was washed with 2M HCl (2x50 ml) and dried.
  • Step 2 Preparation ofthe title compound A solution of benzyl 4-(2-oxoimidazolidin-l-yl)piperidine-l-carboxylate (3.2g) in ethanol (200 ml) was hydrogenated under a hydrogen filled balloon with 20% palladium on charcoal as catalyst. The catalyst was filtered and the filtrate evaporated to dryness to give the title compound as a white solid, yield 1.6g.
  • Step 1 Preparation of l-(l-benzylpiperidin-4-yl)-3-[4-(methylsulphonyl)benzyl]-l,3-dihydro- 2H-imidazol-2-one
  • Trimethylsilyl chloride was added to a suspension of potassium iodide (2.47g) in acetonitrile (40 ml) and the mixture was stirred for 1 hour.
  • a solution of benzyl 4- ⁇ 3-[4- (methylsulphonyl)benzyl]-2-oxo-2,3-dihydro-lH-imidazol-l-yl ⁇ piperidine-l-carboxylate (1.4g) in acetonitrile (10 ml) was added and stirring was continued for 8 hours.
  • the solvent was evaporated and the residuewas suspended in 2M NaO ⁇ and extracted with dichloromethane (4x50 ml). The combined dichloromethane extracts were dried and the solvent was evaporated.
  • the benzyl 4- ⁇ 3-[4-(methylsulphonyl)benzyl]-2-oxo-2,3-dihydro-lH-imidazol-l- yl ⁇ piperidine- 1 -carboxylate used as starting material was obtained by alkylation of benzyl 4- (2-oxo-2,3-dihydro-lH-imidazol-l-yl)piperidine-l-carboxylate (obtained by reaction of benzyl 4- isocyanatopiperidine-1 -carboxylate with aminoacetaldehyde dimethyl acetal as described in Method Q) following the method outlined in Example 10.
  • Step 2 Preparation ofthe title compound A solution of l-(l-benzylpiperidin-4-yl)-3-[4-(methylsulphonyl)benzyl]-l,3-dihydro- 2H-imidazol-2-one (1.2g) in ethanol was hydrogenated under a hydrogen filled balloon using 20% palladium on charcoal as catalyst. The catalyst was filtered and the filtrate evaporated to dryness to give the title compound, yield 0.6g, NMR CDC1 3 1.6-2 (m, 5 ⁇ ) 2.8 (m, IH) 3.05 (s, 3H) 3.2-4.5 (m, 7H) 4.45 (s, 2H) 7.5 (d, 2H) 7.9 (d, 2H).
  • Method T Method T
  • Step 2 Preparation of tert-butyl 3-oxo-8-azabicyclo[3.2J]octane-8-carboxylate
  • Step 3 Preparation of tert-butyl 3-e « o-(benzylamino)-8-azabicyclo[3.2J]octane-8- carboxylate
  • Step 4 Preparation of tert-butyl 3-e « ⁇ f ⁇ -amino-8-azabicyclo[3.2.1]octane-8-carboxylate
  • Step 5 Preparation of tert-butyl 3- ⁇ [4-(methylsulphonyl)-2-nitrophenyl]amino ⁇ -8-e «- - azabicyclo[3.2.1 ]octane-8-carboxylate.
  • Step 6 Preparation of l-e «t o-(8-azabicyclo[3.2J]oct-3-yl)-5-(methylsufonyl)-lH- benzamidazole
  • Step A To a solution of tert-butyl 3- ⁇ [4-(methylsulphonyl)-2-nitrophenyl]amino ⁇ -8- e «- o-azabicyclo[3.2J]octane-8-carboxylate (3.25g) and trimethyl orthoformate (4.2ml) in ethanol (100ml) was added acetic acid (1ml) and 10% palladium on carbon (100mg
  • Step B The product from Step A was dissolved in dioxane (20ml) and 4M ⁇ C1 (20ml) was added. The resulting mixture was stirred for 1 hour. Diethyl ether (50ml) was added and the mixture was filtered and washed with diethyl ether to give the title compound. MS 306 MH + .
  • Step 1 Preparation of 8-benzyl-N-[4-(methylsulphonyl)-2-nitrophenyl]-8-e o- azabicyclo [3.2J ] octan-3 -amine
  • Step 2 Preparation of l-(8-benzyl-8-exo-azabicyclo[3.2J]oct-3-yl)-5-(methylsufonyl)-lH- benzamidazole
  • Step A was prepared l-(8-benzyl-8-exo- azabicyclo[3.2J]oct-3-yl)-5-(methylsufonyl)-lH-benzamidazole as oil, which solidified on standing.
  • NMR CDC1 3 1.9 (m, 4 ⁇ ), 2.3 (m, 4H), 3.1 (s, 3H), 3.45 (m, 2H), 3.65 (s, 2H), 4.7 (m, IH), 7.4 (m, 5H), 7.65 (m, IH), 7.9 (m, IH), 8.2 (s, IH), 8.4 (s, IH).
  • Step 3 Preparation of l-exo-(8-azabicyclo[3.2J]oct-3-yl)-5-(methylsufonyl) ⁇ lH- benzamidazole
  • l-(8-benzyl-8-exo-azabicyclo[3.2J]oct-3-yl)-5-(methylsufonyl)-lH- benzamidazole (l.lg) in ethanol (50ml) was added 30% palladium on carbon (HOmg) followed by ammonium formate (l.lg) and the resulting mixture was heated to 90°C for 5 hours.
  • Step 1 Preparation of (4S,5R)-l-[(3R)-3-(3,5-difluoro ⁇ henyl)-3-(tetrahydro-2H-thio ⁇ yran-4- yl)propanoyl]-3,4-dimethyl-5-phenylimidazolidin-2-one.
  • Step 2 Preparation of (4S,5R)-1 -[(3R)-3-(3,5-difluoro ⁇ henyl)-3-(l ,1 -dioxidotetrahydro-2H- thiopyran-4-yl)propanoyl]-3,4-dimethyl-5-phenylimidazolidin-2-one.
  • Step 3 Preparation of (3R)-3-(3,5-difluorophenyl)-3-(lJ-dioxidotetrahydro-2H-thiopyran-4- yl)propan-l-ol
  • Step 4 Preparation of (3R)-3-(3,5-difluorophenyl)-3-(lJ-dioxidotetrahydro-2H-thiopyran-4- yl)propanal
  • Step 1 Preparation of tert-butyl 4 amino-4-methylpiperidine-l -carboxylate
  • diphenylphosphorylazide 3.72ml
  • triethylamine 2.4ml
  • Step 2 Using tert-butyl 4 amino -4-methylpiperidine-l -carboxylate as starting material and following the procedure outlined in Method C, Step 1 there is obtained tert-butyl 4-methyl-4-
  • Step 3 Preparation of ⁇ 4-[(3-exo)-8-azabicyclo[3.2J]oct-3-yl]-5-methyl-4H-l,2,4-triazol-3- yl ⁇ methanol
  • Step 1 Preparation of 1 -benzyl-4-(4H- 1 ,2,4-triazol-4-yl)piperidine
  • Step 2 Preparation of l-[4-(l-benzylpiperidin-4-yl)-4H-l,2,4-triazol-3-yl]ethanone
  • Step 3 Preparation of l-(4-piperidin-4-yl-4H-l,2,4-triazol-3-yl)ethanone
  • a suspension ofthe triazole (60mg), ammonium formate (120mg) and 20% palladium hydroxide on carbon (20mg) in ethanol (20ml) was refluxed for 2 hours.
  • the reaction mixture was filtered through a plug of Celite® and the filtrate concentrated under reduced pressure to give l-(4-piperidin-4-yl-4H-l,2,4-triazol-3-yl)ethanone as a clear oil (30mg).

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Cited By (13)

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WO2008034731A1 (en) * 2006-09-18 2008-03-27 F. Hoffmann-La Roche Ag Octahydropyrrolo [3, 4-c] pyrrole derivatives an their use as antiviral agents
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WO2008071927A1 (en) * 2006-12-11 2008-06-19 Astrazeneca Ab Piperidine derivative used for treating chemokine receptor 5 mediated diseases
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