Piperidine derivatives as modulators of chemokine receptor ccr5

Abstract

Compounds of formula (I): compositions comprising them, processes for preparing them and their use in medical therapy (for example modulating CCR5 receptor activity in a warm blooded animal).

1 . A compound of formula (I): 
     
       
         
         
             
             
         
       
     
     wherein:
 A is absent or is (CH 2 ) 2 , and M is O, S, S(O) 2 ; or 
 A is (CH 2 ) 2 , and M is NR 1 ; 
 L is CH or N; 
 R 1  is hydrogen, C 1-6  alkyl [optionally substituted by phenyl {which itself optionally substituted by halo, C 1-4  alkyl, C 1-4  alkoxy, cyano, nitro, CF 3 , OCF 3 , (C 1-4  alkyl)C(O)NH, S(O) 2 NH 2 , C 1-4  alkylthio, S(O)(C 1-4  alkyl) or S(O) 2 (C 1-4  alkyl)} or heteroaryl {which itself optionally substituted by halo, C 1-4  alkyl, C 1-4  alkoxy, cyano, nitro, CF 3 , (C 1-4  alkyl)C(O)NH, S(O) 2 NH 2 , C 1-4  alkylthio, S(O)(C 1-4  alkyl) or S(O) 2 (C 1-4  alkyl)}], phenyl {optionally substituted by halo, C 1-4  alkyl, C 1-4  alkoxy, cyano, nitro, CF 3 , OCF 3 , (C 1-4  alkyl)C(O)NH, S(O) 2 NH 2 , C 1-4  alkylthio, S(O)(C 1-4  alkyl) or S(O) 2 (C 1-4  alkyl)}, heteroaryl {optionally substituted by halo, C 1-4  alkyl, C 1-4  alkoxy, cyano, nitro, CF 3 , (C 1-4  alkyl)C(O)NH, S(O) 2 NH 2 , C 1-4  alkylthio, S(O)(C 1-4  alkyl) or S(O) 2 (C 1-4  alkyl)}, S(O) 2 R 5 , S(O) 2 NR 6 R 7 , C(O)R 8 , C(O) 2 (C 1-6  alkyl), C(O) 2 (phenyl(C 1-2  alkyl)) or C(O)NHR 11 ; 
 R 2  is phenyl (optionally substituted by halo, CN or C 1-4  haloalkyl), thienyl or halothienyl; 
 R 3  is hydrogen or methyl; 
 R b  is hydrogen or C 1-3  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 1-6  alkyl [which is optionally substituted by halogen, CN, OH, C 1-4  alkoxy, S(C 1-4  alkyl), S(O)(C 1-4  alkyl), S(O) 2 (C 1-4  alkyl) or heterocyclyl {itself optionally substituted by C 1-6  alkyl [which is optionally substituted by oxo, halogen, OH, C 1-4  alkoxy, OCF 3 , C(O)(C 1-4  alkoxy), CN, C(O)NH 2 , C(O)NH(C 1-4  alkyl), C(O)N(C 1-4  alkyl) 2 , NH 2 , NH(C 1-4  alkyl) or N(C 1-4  alkyl) 2 ], C(O)(C 1-4  alkyl) [wherein the alkyl is optionally substituted by C 1-4  alkoxy or fluoro], benzyl [which is optionally substituted by halogen, C 1-4  alkyl, C 1-4  alkoxy, CF 3 , OCF 3 , cyano, nitro, S(C 1-4  alkyl), S(O)(C 1-4  alkyl) or S(O) 2 (C 1-4  alkyl)], C(O)(C 1-4  alkoxy), C(O)NH 2 , C(O)NH(C 1-4  alkyl), C(O)N(C 1-4  alkyl) 2  or S(O) 2 (C 1-4  alkyl) [wherein the alkyl is optionally substituted by fluoro]}], C 2-6  alkenyl, C 3-6  cycloalkyl, CN, C(O)NH 2 , C(O)NH(phenylC 1-2  alkyl), phenyl [which is optionally substituted by halogen, C 1-4  alkyl, C 1-4  alkoxy, CF 3 , OCF 3 , cyano, nitro, S(C 1-4  alkyl), S(O)(C 1-4  alkyl) or S(O) 2 (C 1-4  alkyl)] or benzyl [which is optionally substituted by halogen, C 1-4  alkyl, C 1-4  alkoxy, CF 3 , OCF 3 , cyano, nitro, S(C 1-4  alkyl), S(O)(C 1-4  alkyl) or S(O) 2 (C 1-4  alkyl)]; 
 where possible, a ring nitrogen of said heterocycle R 4  being optionally substituted by C 1-6  alkyl [optionally substituted by oxo, halogen, OH, C 1-4  alkoxy, OCF 3 , NH 2 , NH(C 1-4  alkyl), N(C 1-4  alkyl) 2 , S(C 1-4  alkyl), S(O)(C 1-4  alkyl), S(O) 2 (C 1-4  alkyl), C(O)(C 1-4  alkoxy), CONH 2 , CONH(C 1-4  alkyl), CON(C 1-4  alkyl) 2 , cyano, aryl {optionally substituted by halogen, C 1-4  alkyl, C 1-4  alkoxy, CF 3 , OCF 3 , cyano, nitro, S(C 1-4  alkyl), S(O)(C 1-4  alkyl) or S(O) 2 (C 1-4  alkyl)}, heteroaryl {optionally substituted by oxo, halogen, C 1-4  alkyl, C 1-4  alkoxy, CF 3 , OCF 3 , cyano, nitro, S(C 1-4  alkyl), S(O)(C 1-4  alkyl) or S(O) 2 (C 1-4  alkyl)}, heterocyclyl {optionally substituted by C 1-4  alkyl, aryl [optionally substituted by halogen, C 1-4  alkyl, C 1-4  alkoxy, CF 3 , OCF 3 , cyano, nitro, S(C 1-4  alkyl), S(O)(C 1-4  alkyl) or S(O) 2 (C 1-4  alkyl)], SO 2 NH(C 1-4  alkyl), SO 2 N(C 1-4  alkyl) 2 , CONH(C 1-4  alkyl), CON(C 1-4  alkyl) 2 , CO(C 1-4  alkyl), CO(aryl) [optionally substituted by halogen, C 1-4  alkyl, C 1-4  alkoxy, CF 3 , OCF 3 , cyano, nitro, S(C 1-4  alkyl), S(O)(C 1-4  alkyl) or S(O) 2 (C 1-4  alkyl)], SO 2 (aryl) [optionally substituted by halogen, C 1-4  alkyl, C 1-4  alkoxy, CF 3 , OCF 3 , cyano, nitro, S(C 1-4  alkyl), S(O)(C 1-4  alkyl) or S(O) 2 (C 1-4  alkyl)]}], C 3-6  cycloalkyl, CO(C 1-4  alkyl) [optionally substituted by halogen], CO(aryl) [optionally substituted by halogen, C 1-4  alkyl, C 1-4  alkoxy, CF 3 , OCF 3 , cyano, nitro, S(C 1-4  alkyl), S(O)(C 1-4  alkyl) or S(O) 2 (C 1-4  alkyl)], SO 2 (aryl) [optionally substituted by halogen, C 1-4  alkyl, C 1-4  alkoxy, CF 3 , OCF 3 , cyano, nitro, S(C 1-4  alkyl), S(O)(C 1-4  alkyl) or S(O) 2 (C 1-4  alkyl)], SO 2 (C 1-4  alkyl) [optionally substituted by fluorine], COO(C 1-6  alkyl), aryl [optionally substituted by halogen, C 1-4  alkyl, C 1-4  alkoxy, CF 3 , OCF 3 , cyano, nitro, S(C 1-4  alkyl), S(O)(C 1-4  alkyl) or S(O) 2 (C 1-4  alkyl)], heteroaryl [optionally substituted by oxo, halogen, C 1-4  alkyl, C 1-4  alkoxy, CF 3 , OCF 3 , cyano, nitro, S(C 1-4  alkyl), S(O)(C 1-4  alkyl) or S(O) 2 (C 1-4  alkyl)], CONH(C 1-4  alkyl), CONH(aryl) [optionally substituted by halogen, C 1-4  alkyl, C 1-4  alkoxy, CF 3 , OCF 3 , cyano, nitro, S(C 1-4  alkyl), S(O)(C 1-4  alkyl) or S(O) 2 (C 1-4  alkyl)], SO 2 NH(C 1-4  alkyl) or SO 2 N(C 1-4  alkyl) 2 ; 
 provided that when a ring nitrogen of said heterocycle R 4  is substituted by an alkyl group, said alkyl does not carry an oxo, halogen, OH, C 1-4  alkoxy, OCF 3 , NH 2 , NH(C 1-4  alkyl), N(C 1-4  alkyl) 2 , S(C 1-4  alkyl), S(O)(C 1-4  alkyl) or S(O) 2 (C 1-4  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, C 1-4  alkyl, C 1-4  alkoxy, CF 3 , OCF 3 , cyano, nitro, S(C 1-4  alkyl), S(O)(C 1-4  alkyl) or S(O) 2 (C 1-4  alkyl); and the nitrogen of said fused piperidine ring being optionally substituted by C 1-4  alkyl [which is optionally substituted by oxo, halogen, OH, C 1-4  alkoxy, OCF 3 , C(O)(C 1-4  alkoxy), CN, C(O)NH 2 , C(O)NH(C 1-4  alkyl), C(O)N(C 1-4  alkyl) 2 , NH 2 , NH(C 1-4  alkyl) or N(C 1-4  alkyl) 2 ], C(O)(C 1-4  alkyl) [wherein the alkyl is optionally substituted by C 1-4  alkoxy or halogen], benzyl [which is optionally substituted by halogen, C 1-4  alkyl, C 1-4  alkoxy, CF 3 , OCF 3 , cyano, nitro, S(C 1-4  alkyl), S(O)(C 1-4  alkyl) or S(O) 2 (C 1-4  alkyl)], C(O)(C 1-4  alkoxy), C(O)NH 2 , C(O)NH(C 1-4  alkyl), C(O)N(C 1-4  alkyl) 2  or S(O) 2 (C 1-4  alkyl) [wherein the alkyl is optionally substituted by fluoro]; 
 
 R 5  is C 1-6  alkyl [optionally substituted by halo, C 1-4  alkoxy, phenyl {which itself optionally substituted by halo, C 1-4  alkyl, C 1-4  alkoxy, cyano, nitro, CF 3 , OCF 3 , (C 1-4  alkyl)C(O)NH, S(O) 2 NH 2 , C 1-4  alkylthio, S(O)(C 1-4  alkyl) or S(O) 2 (C 1-4  alkyl)} or heteroaryl {which itself optionally substituted by halo, C 1-4  alkyl, C 1-4  alkoxy, cyano, nitro, CF 3 , (C 1-4  alkyl)C(O)NH, S(O) 2 NH 2 , C 1-4  alkylthio, S(O)(C 1-4  alkyl) or S(O) 2 (C 1-4  alkyl)}], C 3-7  cycloalkyl (optionally substituted by halo or C 1-6  alkyl), pyranyl, phenyl {optionally substituted by halo, C 1-4  alkyl, C 1-4  alkoxy, cyano, nitro, CF 3 , OCF 3 , (C 1-4  alkyl)C(O)NH, S(O) 2 NH 2 , C 1-4  alkylthio, S(O)(C 1-4  alkyl) or S(O) 2 (C 1-4  alkyl)}, heteroaryl {optionally substituted by halo, C 1-4  alkyl, C 1-4  alkoxy, cyano, nitro, CF 3 , (C 1-4  alkyl)C(O)NH, S(O) 2 NH 2 , C 1-4  alkylthio, S(O)(C 1-4  alkyl) or S(O) 2 (C 1-4  alkyl)} or a 5- or 6-membered nitrogen containing heterocyclic ring {optionally substituted by S(O) 2 (C 1-4  alkyl) or C(O)(C 1-4  alkyl)}; 
 R 8  and R 11  are, independently, hydrogen, C 1-6  alkyl [optionally substituted by halo, C 1-4  alkoxy, phenyl {which itself optionally substituted by halo, C 1-4  alkyl, C 1-4  alkoxy, cyano, nitro, CF 3 , OCF 3 , (C 1-4  alkyl)C(O)NH, S(O) 2 NH 2 , C 1-4  alkylthio, S(O)(C 1-4  alkyl) or S(O) 2 (C 1-4  alkyl)} or heteroaryl {which itself optionally substituted by halo, C 1-4  alkyl, C 1-4  alkoxy, cyano, nitro, CF 3 , (C 1-4  alkyl)C(O)NH, S(O) 2 NH 2 , C 1-4  alkylthio, S(O)(C 1-4  alkyl) or S(O) 2 (C 1-4  alkyl)}], C 3-7  cycloalkyl (optionally substituted by halo or C 1-6  alkyl), pyranyl, phenyl {optionally substituted by halo, C 1-4  alkyl, C 1-4  alkoxy, cyano, nitro, CF 3 , OCF 3 , (C 1-4  alkyl)C(O)NH, S(O) 2 NH 2 , C 1-4  alkylthio, S(O)(C 1-4  alkyl) or S(O) 2 (C 1-4  alkyl)}, heteroaryl {optionally substituted by halo, C 1-4  alkyl, C 1-4  alkoxy, cyano, nitro, CF 3 , (C 1-4  alkyl)C(O)NH, S(O) 2 NH 2 , C 1-4  alkylthio, S(O)(C 1-4  alkyl) or S(O) 2 (C 1-4  alkyl)} or a 5- or 6-membered nitrogen containing heterocyclic ring {optionally substituted by S(O) 2 (C 1-4  alkyl) or C(O)(C 1-4  alkyl)}; 
 R 6  and R 7  are, independently, hydrogen or C 1-4  alkyl; or together R 6  and R 7  join to form a 5- or 6-membered ring which is optionally substituted with C 1-4  alkyl or phenyl (wherein the phenyl ring is optionally substituted by halo, cyano, nitro, hydroxy, C 1-4  alkyl, C 1-4  alkoxy, S(O) m C 1-4  alkyl, S(O) 2 NH 2 , S(O) 2 NH(C 1-4  alkyl), S(O) 2 N(C 1-4  alkyl) 2 , NHS(O) 2 (C 1-4  alkyl), NH 2 , NH(C 1-4  alkyl), N(C 1-4  alkyl) 2 , NHC(O)NH 2 , C(O)NH 2 , C(O)NH(C 1-4  alkyl), NHC(O)(C 1-4  alkyl), CO 2 H, CO 2 (C 1-4  alkyl), C(O)(C 1-4  alkyl), CF 3 , CHF 2 , CH 2 F, CH 2 CF 3  or OCF 3 ); 
 R 9  and R 10  are, independently, hydrogen or C 1-6  alkyl; 
 
     or a pharmaceutically acceptable salt thereof. 
   
   
       2 . A compound of formula (I) as claimed in  claim 1  wherein L is CH. 
   
   
       3 . A compound of formula (I) as claimed in  claim 1  or  2  wherein M is NR 1 . 
   
   
       4 . A compound of formula (I) as claimed in  claim 3  wherein R 1  is C 1-6  alkyl, phenyl {optionally substituted by halo, C 1-4  alkyl, C 1-4  alkoxy, cyano, nitro, CF 3 , OCF 3 , (C 1-4  alkyl)C(O)NH, S(O) 2 NH 2 , C 1-4  alkylthio, S(O)(C 1-4  alkyl) or S(O) 2 (C 1-4  alkyl)}, S(O) 2 R 5  or C(O)R 5 ; wherein R 5  and R 8  are C 1-6  alkyl, CF 3 , C 3-7  cycloalkyl (optionally substituted by halo or C 1-6  alkyl), phenyl {optionally substituted by halo, C 1-4  alkyl, C 1-4  alkoxy, cyano, nitro, CF 3 , OCF 3 , (C 1-4  alkyl)C(O)NH, S(O) 2 NH 2 , C 1-4  alkylthio, S(O)(C 1-4  alkyl) or S(O) 2 (C 1-4  alkyl)} or a 5- or 6-membered nitrogen containing heterocyclic ring {optionally substituted by S(O) 2 (C 1-4  alkyl) or C(O)(C 1-4  alkyl)}. 
   
   
       5 . A compound of formula (I) as claimed in  claim 1  wherein R 2  is phenyl optionally substituted by fluoro, chloro or CF 3 . 
   
   
       6 . A compound of formula (I) as claimed in  claim 1  wherein R 3  is hydrogen. 
   
   
       7 . A compound of formula (I) as claimed in  claim 1  claims wherein R 9  is hydrogen. 
   
   
       8 . A compound of formula (I) as claimed in  claim 1  wherein R 10  is hydrogen. 
   
   
       9 . A compound of formula (I) as claimed in  claim 1  wherein R b  is hydrogen. 
   
   
       10 . A compound of formula (I) as claimed in  claim 1  wherein R 4  is 1,2,4-triazolyl, thiazolyl, 1,2,4-oxadiazolyl, piperidinyl, benzimidazolyl, 1,3-dihydro-2H-benzimidazolyl, benzotriazolyl or an imidazopyridinyl, each of which is unsubstituted or substituted by one or two of the same or different C 1-6  alkyl, C 3-6  cycloalkyl, CF 3 , CHF 2 , OH (which may tautomerise to the keto form), oxo (which may tautomerise to the hydroxy form), C 1-4  alkyl substituted by heterocyclyl (which is itself optionally substituted by S(O) 2 (C 1-4  alkyl)), S(O) 2 (C 1-4  alkyl), (C 1-4  alkyl)C(O), (C 1-4  haloalkyl)C(O), (C 1-4  alkoxy)C(O), C(O)NH 2 , C(O)NH(C 1-4  alkyl), C(O)NH(phenyl(C 1-2  alkyl)) or phenyl(C 1-2  alkyl); wherein the phenyl of the foregoing phenyl(C 1-2  alkyl) groups is optionally substituted by halo, C 1-4  alkyl, C 1-4  alkoxy, cyano or S(O) 2 (C 1-4  alkyl). 
   
   
       11 . A process for preparing a compound as claimed in  claim 1 , the process comprising reductive amination of a compound of formula (II): 
     
       
         
         
             
             
         
       
     
     with a compound of formula (III): 
     
       
         
         
             
             
         
       
     
     in the presence of NaBH(OAc) 3  (wherein Ac is C(O)CH 3 ) and acetic acid, in a suitable solvent, at room temperature. 
   
   
       12 . A pharmaceutical composition which comprises a compound as claimed in  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier. 
   
   
       13 - 14 . (canceled) 
   
   
       15 . A method of treating a CCR5 mediated disease state comprising administering to a patient in need of such treatment an effective amount of a compound as claimed in  claim 1 . 
   
   
       16 . A method of treating rheumatoid arthritis comprising administering to a patient in need of such treatment an effective amount of a compound as claimed in  claim 1 .