Substituted piperidine compounds useful as modulators of chemokine receptor activity

Abstract

The invention provides compounds of formula (I): wherein R 1 , R 2 , R 3 , R 6 , Z, Q, m, n, X 1 , X 2 , X 3 , X 4 and T are as defined in the specification, processes for their preparation, pharmaceutical compositions containing them, and their use in therapy, especially for the treatment of chemokine receptor related diseases and conditions.

1 . A compound of formula (I):  
     
       
         
         
             
             
         
       
     
     wherein 
 Z is CR 4 R 5 , C(O) or CR 4 R 5 -Z 1 ;  
 Z 1  is C 1-4  alkylene, C 2-4  alkenylene or C(O)NH;  
 R 1  represents a C 1 -C 12  alkyl group optionally substituted by one or more substituents independently selected from cyano, hydroxyl, C 1 -C 6  alkoxy, C 1 -C 6  alkylthio, C 3-7  cycloalkyl, C 1 -C 6  alkoxycarbonyl and phenyl (itself optionally substituted by one or more of halogen, nitro, cyano, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, phenyl(C 1 -C 6  alkyl), C 1 -C 6  alkoxy, C 1 -C 6  haloalkoxy, S(O) 2 (C 1 -C 6  alkyl), C(O)NH 2 , carboxy or C 1 -C 6  alkoxycarbonyl); or  
 R 1  represents C 2 -C 6  alkenyl optionally substituted by phenyl (itself optionally substituted by one or more of halogen, nitro, cyano, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, phenyl(C 1 -C 6  alkyl), C 1 -C 6  alkoxy, C 1 -C 6  haloalkoxy, S(O) 2 (C 1 -C 6  alkyl), C(O)NH 2 , carboxy or C 1 -C 6  alkoxycarbonyl); or  
 R 1  represents a 3- to 14-membered saturated or unsaturated ring system which optionally comprises up to two ring carbon atoms that form carbonyl groups and which optionally further comprises up to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulphur, wherein the ring system is optionally substituted by one or more substituents independently selected from: halogen, cyano, nitro, oxo, hydroxyl, C 1 -C 8  alkyl, C 1 -C 6  hydroxyalkyl, C 1 -C 6  haloalkyl, C 1-6  alkoxy(C 1 -C 6  alkyl), C 3 -C 7  cycloalkyl(C 1 -C 6  alkyl), C 1 -C 6  alkylthio(C 1 -C 6  alkyl), C 1 -C 6  alkylcarbonyloxy(C 1 -C 6  alkyl), C 1 -C 6  alkylS(O) 2 (C 1 -C 6  alkyl), aryl(C 1 -C 6  alkyl), heterocyclyl(C 1 -C 6  alkyl), arylS(O) 2 (C 1 -C 6  alkyl), heterocyclylS(O) 2 (C 1 -C 6  alkyl), aryl(C 1 -C 6  alkyl)S(O) 2 , heterocyclyl(C 1 -C 6  alkyl)S(O) 2 , C 2 -C 6  alkenyl, C 1 -C 6  alkoxy, carboxy-substituted C 1 -C 6  alkoxy, C 1 -C 6  haloalkoxy, C 1 -C 6  hydroxyalkoxy, C 1 -C 6  alkylcarboxy-substituted C 1 -C 6  alkoxy, aryloxy, heterocyclyloxy, C 1 -C 6  alkylthio, C 3 -C 7  cycloalkyl(C 1 -C 6  alkylthio), C 3 -C 6  alkynylthio, C 1 -C 6  alkylcarbonylamino, C 1 -C 6  haloalkylcarbonylamino, SO 3 H, —NR 7 R 8 , —C(O)NR 23 R 24 , S(O) 2 NR 18 R 19 , S(O) 2 R 20 , R 25 C(O), carboxyl, C 1 -C 6  alkoxycarbonyl, aryl and heterocyclyl; wherein the foregoing aryl and heterocyclyl moieties are optionally substituted by one or more of halogen, oxo, hydroxy, nitro, cyano, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, phenyl(C 1 -C 6  alkyl), C 1 -C 6  alkoxy, C 1 -C 6  haloalkoxy, S(O) 2 (C 1 -C 6  alkyl), C(O)NH 2 , carboxy or C 1 -C 6  alkoxycarbonyl;  
 m is 0 or 1;  
 Q represents an oxygen or sulphur atom or a group NR 9 , C(O), C(O)NR 9 , NR 9 C(O) or CH═CH;  
 n is 0, 1, 2, 3, 4, 5 or 6 provided that when n is 0, then m is 0;  
 each R 2  and R 3  independently represents a hydrogen atom or a C 1 -C 4  alkyl group, or (CR 2 R 3 ) n  represents C 3 -C 7  cycloalkyl optionally substituted by C 1 -C 4  alkyl;  
 T represents a group NR 10 , C(O)NR 10 , NR 11 C(O)NR 10  or C(O)NR 10 NR 11 ;  
 X 1 , X 2 , X 3  and X 4  are, independently, CH 2 , CHR 12  {wherein each R 12  is, independently, C 1 -C 4  alkyl or C 3 -C 7  cycloalkyl(C 1 -C 4  alkyl)} or C═O; or, when they are CHR 12 , the R 12  groups of X 1  and X 3  or X 4 , or, X 2  and X 3  or X 4  join to form a two or three atom chain which is CH 2 CH 2 , CH 2 CH 2 CH 2 , CH 2 OCH 2  or CH 2 SCH 2 ; provided always that at least two of X 1 , X 2 , X 3  and X 4  are CH 2 ;  
 R 4  and R 5  each independently represent a hydrogen atom or a C 1 -C 4  alkyl group;  
 R 6  is aryl or heterocyclyl, both optionally substituted by one or more of: halogen, cyano, nitro, oxo, hydroxyl, C 1 -C 8  alkyl, C 1 -C 6  hydroxyalkyl, C 1 -C 6  haloalkyl, C 1-6  alkoxy(C 1 -C 6  alkyl), C 3 -C 7  cycloalkyl(C 1 -C 6  alkyl), C 1 -C 6  alkylthio(C 1 -C 6  alkyl), C 1 -C 6  alkylcarbonyloxy(C 1 -C 6  alkyl), C 1 -C 6  alkylS(O) 2 (C 1 -C 6  alkyl), aryl(C 1 -C 6  alkyl), heterocyclyl(C 1 -C 6  alkyl), arylS(O) 2 (C 1 -C 6  alkyl), heterocyclylS(O) 2 (C 1 -C 6  alkyl), aryl(C 1 -C 6  alkyl)S(O) 2 , heterocyclyl(C 1 -C 6  alkyl)S(O) 2 , C 2 -C 6  alkenyl, C 1 -C 6  alkoxy, carboxy-substituted C 1 -C 6  alkoxy, C 1 -C 6  haloalkoxy, C 1 -C 6  hydroxyalkoxy, C 1 -C 6  alkylcarboxy-substituted C 1 -C 6  alkoxy, aryloxy, heterocyclyloxy, C 1 -C 6  alkylthio, C 3 -C 7  cycloalkyl(C 1 -C 6  alkylthio), C 3 -C 6  alkynylthio, C 1 -C 6  alkylcarbonylamino, C 1 -C 6  C 6  haloalkylcarbonylamino, SO 3 H, —NR 16 R 17 , —C(O)NR 21 R 22 , S(O) 2 NR 13 R 14 , S(O) 2 R 15 , R 26 C(O), carboxyl, C 1 -C 6  alkoxycarbonyl, aryl and heterocyclyl; wherein the foregoing aryl and heterocyclyl moieties are optionally substituted by one or more of halogen, nitro, cyano, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, phenyl(C 1 -C 6  alkyl), C 1 -C 6  alkoxy, C 1 -C 6  haloalkoxy, S(O) 2 (C 1 -C 6  alkyl), C(O)NH 2 , carboxy or C 1 -C 6  alkoxycarbonyl;  
 R 7 , R 8 , R 9 , R 10 , R 11 , R 13 , R 14 , R 16 , R 17 , R 18 , R 19 , R 21 , R 22 , R 23  and R 24  are, independently hydrogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 1 -C 6  hydroxyalkyl, C 3 -C 7  cycloalkyl, C 3 -C 7  cycloalkyl(C 1 -C 4  alkyl) or phenyl(C 1 -C 6  alkyl); and,  
 R 15  and R 20  are, independently, C 1 -C 6  alkyl, C 1 -C 6  hydroxyalkyl, C 3 -C 6  cycloalkyl, C 3 -C 7  cycloalkyl(C 1 -C 4  alkyl) or C 1 -C 6  alkyl optionally substituted by phenyl;  
 R 25  and R 26  are, independently, C 1 -C 6  alkyl or phenyl (optionally substituted by one or more of halogen, nitro, cyano, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, phenyl(C 1 -C 6  alkyl), C 1 -C 6  alkoxy, C 1 -C 6  haloalkoxy, S(O) 2 (C 1 -C 6  alkyl), C(O)NH 2 , carboxy or C 1 -C 6  alkoxycarbonyl);  
 or a pharmaceutically acceptable salt thereof, or solvate thereof, or a solvate of a salt thereof; provided that when T is C(O)NR 10  and R 1  is optionally substituted phenyl then n is not 0.  
 
   
   
       2 . A compound according to  claim 1 , wherein Q represents a sulphur atom or a group NH, C(O) or NHC(O).  
   
   
       3 . A compound according to  claim 1 , wherein T represents a group NH, C(O)NH or NHC(O)NH.  
   
   
       4 . A compound according to  claim 1 , wherein X 1 , X 2 , X 3  and X 4  are all CH 2 .  
   
   
       5 . A compound as defined in any one of Examples 1 to 416.  
   
   
       6 . A process for the preparation of a compound of formula (I) as defined in  claim 1  which comprises: 
 (a) when n is at least 1, the CR 2 R 3  group attached directly to T is CHR 3  and T is NR 10 , reacting a compound of general formula                          wherein n′ is 0 or an integer from 1 to 3 and R 1 , R 2 , R 3 , m and Q are as defined in formula (I), with a compound of general formula                          or a salt thereof, wherein X 1 , X 2 , X 3 , X 4 , Z, R 6  and R 10  are as defined in formula (I), in the presence of a reducing agent; or    (b) when n is at least 1, the CR 2 R 3  group attached directly to T is C(C 1 -C 4  alkyl) 2  and T is NR 10 , reacting a compound of general formula                          wherein n′ is 0 or an integer from 1 to 3, R 2′  and R 3′  each independently represent a C 1 -C 4  alkyl group, and R 1 , R 2 , R 3 , R 10 , m and Q are as defined in formula (I), with a compound of general formula                          wherein X 1 , X 2 , X 3 , X 4 , Z and R 6  are as defined in formula (I), in the presence of a reducing agent; or    (c) when T is C(O)NR 10 , reacting a compound of general formula                          wherein R 1 , R 2 , R 3 , Q, m and n are as defined in formula (I), with a compound of formula (III) or a salt thereof as defined in (a) above; or    (d) when m is 1 and Q is NR 9 , reacting a compound of general formula (VII), R 1 -L 1 , wherein L 1  represents a leaving group (e.g. a halogen atom) and R 1  is as defined in formula (I), with a compound of general formula                          or a salt thereof, wherein n, T, X 1 , X 2 , X 3 , X 4 , Z, R 2 , R 3 , R 6  and R 9  are as defined in formula (I); or    (e) when at least one of R 4  and R 5  represents a hydrogen atom, reacting a compound of general formula                          or a salt thereof, wherein R 1 , R 2 , R 3 , Q, m, n, X 1 , X 2 , X 3 , X 4  and T are as defined in formula (I), with a compound of general formula (X), R 6 —C(O)—R 20 , wherein R 20  represents a hydrogen atom or a C 1 -C 4  alkyl group and R 6  is as defined in formula (I), in the presence of a reducing agent; or    (f) reacting a compound of formula (IX) as defined in (e) above, with a compound of general formula                          wherein L 2  represents a leaving group (e.g. a halogen atom) and Z and R 6  are as defined in formula (I); or    (g) when T is NR 10 , reacting a compound of general formula      R 1 -(Q) m -(CR 2 R 3 ) n -L 3    (XII)    wherein L represents a leaving group (e.g. a halogen atom) and R 1 , R 2 , R 3 , m, n and Q are as defined in formula (I), with a compound of formula (III) or a salt thereof as defined in (a) above; or    (h) when T is NHC(O)NR 10 , reacting a compound of general formula      R 1 -(Q) m -(CR 2 R 3 ) n —N═C═O   (XIII)    wherein R 1 , R 2 , R 3 , Q, m and n are as defined in formula (I), with a compound of formula (III) or a salt thereof as defined in (a) above; or    (i) when T is C(O)NH, Z is CH 2 , n is 1, R 2  and R 3  are hydrogen or C 1 -C 4  alkyl and Q is oxygen or sulphur, reacting a compound of formula (XIV):                          wherein Hal is a suitable halogen, R 2 , R 3 , X 1 , X 2 , X 3 , X 4 , Z and R 6  are as defined in formula (I), with R 1 OH or R 1 SH in the presence of a suitable base;    and optionally after (a), (b), (c), (d), (e), (f), (g), (h) or (i) forming a pharmaceutically acceptable salt or solvate of the compound of formula (I) obtained.    
   
   
       7 . A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in  claim 1  and a pharmaceutically acceptable adjuvant, diluent or carrier.  
   
   
       8 . A process for the preparation of a pharmaceutical composition as claimed in  claim 7  which comprises mixing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, with a pharmaceutically acceptable adjuvant, diluent or carrier.  
   
   
       9 . (canceled)  
   
   
       10 . A method of treating a disease wherein the modulation of a chemokine receptor is beneficial comprising administering a compound of formula (I),  
     
       
         
         
             
             
         
       
     
     wherein 
 Z is CR 4 R 5 , C(O) or CR 4 R 5 -Z l ;  
 Z 1  is C 1-4  alkylene, C 2-4  alkenylene or C(O)NH;  
 R 1  represents a C 1 -C 12  alkyl group optionally substituted by one or more substituents independently selected from cyano, hydroxyl, C 1 -C 6  alkoxy, C 1 -C 6  alkylthio, C 3-7  cycloalkyl, C 1 -C 6  alkoxycarbonyl and phenyl (itself optionally substituted by one or more of halogen, nitro, cyano, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, phenyl(C 1 -C 6  alkyl), C 1 -C 6  alkoxy, C 1 -C 6  haloalkoxy, S(O) 2 (C 1 -C 6  alkyl), C(O)NH 2 , carboxy or C 1 -C 6  alkoxycarbonyl); or  
 R 1  represents C 2 -C 6  alkenyl optionally substituted by phenyl (itself optionally substituted by one or more of halogen, nitro, cyano, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, phenyl(C 1 -C 6  alkyl), C 1 -C 6  alkoxy, C 1 -C 6  haloalkoxy, S(O) 2 (C 1 -C 6  alkyl), C(O)NH 2 , carboxy or C 1 -C 6  alkoxycarbonyl); or  
 R 1  represents a 3- to 14-membered saturated or unsaturated ring system which optionally comprises up to two ring carbon atoms that form carbonyl groups and which optionally further comprises up to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulphur, wherein the ring system is optionally substituted by one or more substituents independently selected from: halogen, cyano, nitro, oxo, hydroxyl, C 1 -C 8  alkyl, C 1 -C 6  hydroxyalkyl, C 1 -C 6  haloalkyl, C 1 - 6  alkoxy(C 1 -C 6  alkyl), C 3 -C 7  cycloalkyl(C 1 -C 6  alkyl), C 1 -C 6  alkylthio(C 1 -C 6  alkyl), C 1 -C 6  alkylcarbonyloxy(C 1 -C 6  alkyl), C 1 -C 6  alkylS(O) 2 (C 1 -C 6  alkyl), aryl(C 1 -C 6  alkyl), heterocyclyl(C 1 -C 6  alkyl), arylS(O) 2 (C 1 -C 6  alkyl), heterocyclylS(O) 2 (C 1 -C 6  alkyl), aryl(C 1 -C 6  alkyl)S(O) 2 , heterocyclyl(C 1 -C 6  alkyl)S(O) 2 , C 2 -C 6  alkenyl, C 1 -C 6  alkoxy, carboxy-substituted C 1 -C 6  alkoxy, C 1 -C 6  haloalkoxy, C 1 -C 6  hydroxyalkoxy, C 1 -C 6  alkylcarboxy-substituted C 1 -C 6  alkoxy, aryloxy, heterocyclyloxy, C 1 -C 6  alkylthio, C 3 -C 7  cycloalkyl(C 1 -C 6  alkylthio), C 3 -C 6  alkynylthio, C 1 -C 6  alkylcarbonylamino, C 1 -C 6  haloalkylcarbonylamino, SO 3 H, —NR 7 R 8 , —C(O)NR 23 R 24 , S(O) 2 NR 18 R 19 , S(O) 2 R 20 , R 25 C(O), carboxyl, C 1 -C 6  alkoxycarbonyl, aryl and heterocyclyl; wherein the foregoing aryl and heterocyclyl moieties are optionally substituted by one or more of halogen, oxo, hydroxy, nitro, cyano, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, phenyl(C 1 -C 6  alkyl), C 1 -C 6  alkoxy, C 1 -C 6  haloalkoxy, S(O) 2 (C 1 -C 6  alkyl), C(O)NH 2 , carboxy or C 1 -C 6  alkoxycarbonyl;  
 m is 0 or 1;  
 Q represents an oxygen or sulphur atom or a group NR 9 , C(O), C(O)NR 9 , NR 9 C(O) or CH═CH;  
 n is 0, 1, 2, 3, 4, 5 or 6 provided that when n is 0, then m is 0;  
 each R 2  and R 3  independently represents a hydrogen atom or a C 1 -C 4  alkyl group, or (CR 2 R 3 ) n  represents C 3 -C 7  cycloalkyl optionally substituted by C 1 -C 4  alkyl;  
 T represents a group NR 10 , C(O)NR 10 , NR 11 C(O)NR 10  or C(O)NR 10 NR 11 ;  
 X 1 , X 2 , X 3  and X 4  are, independently, CH 2 , CHR 12  {wherein each R 12  is, independently, C 1 -C 4  alkyl or C 3 -C 7  cycloalkyl(C 1 -C 4  alkyl)} or C═O; or, when they are CHR 12 , the R 12  groups of X 1  and X 3  or X 4 , or, X 2  and X 3  or X 4  join to form a two or three atom chain which is CH 2 CH 2 , CH 2 CH 2 CH 2 , CH 2 OCH 2  or CH 2 SCH 2 ; provided always that at least two of X 1 , X 2 , X 3  and X 4  are CH 2 ;  
 R 4  and R 5  each independently represent a hydrogen atom or a C 1 -C 4  alkyl group;  
 R 6  is aryl or heterocyclyl, both optionally substituted by one or more of: halogen, cyano, nitro, oxo, hydroxyl, C 1 -C 8  alkyl, C 1 -C 6  hydroxyalkyl, C 1 -C 6  haloalkyl, C 1-6  alkoxy(C 1 -C 6  alkyl), C 3 -C 7  cycloalkyl(C 1 -C 6  alkyl), C 1 -C 6  alkylthio(C 1 -C 6  alkyl), C 1 -C 6  alkylcarbonyloxy(C 1 -C 6  alkyl), C 1 -C 6  alkylS(O) 2 (C 1 -C 6  alkyl), aryl(C 1 -C 6  alkyl), heterocyclyl(C 1 -C 6  alkyl), arylS(O) 2 (C 1 -C 6  alkyl), heterocyclylS(O) 2 (C 1 -C 6  alkyl), aryl(C 1 -C 6  alkyl)S(O) 2 , heterocyclyl(C 1 -C 6  alkyl)S(O) 2 , C 2 -C 6  alkenyl, C 1 -C 6  alkoxy, carboxy-substituted C 1 -C 6  alkoxy, C 1 -C 6  haloalkoxy, C 1 -C 6  hydroxyalkoxy, C 1 -C 6  alkylcarboxy-substituted C 1 -C 6  alkoxy, aryloxy, heterocyclyloxy, C 1 -C 6  alkylthio, C 3 -C 7  cycloalkyl(C 1 -C 6  alkylthio), C 3 -C 6  alkynylthio, C 1 -C 6  alkylcarbonylamino, C 1 -C 6  haloalkylcarbonylamino, SO 3 H, —NR 16 R 17 , —C(O)NR 21 R 22 , S(O) 2 NR 13 R 14 , S(O) 2 R 15 , R 26 C(O), carboxyl, C 1 -C 6  alkoxycarbonyl, aryl and heterocyclyl; wherein the foregoing aryl and heterocyclyl moieties are optionally substituted by one or more of halogen, nitro, cyano, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, phenyl(C 1 -C 6  alkyl), C 1 -C 6  alkoxy, C 1 -C 6  haloalkoxy, S(O) 2 (C 1 -C 6  alkyl), C(O)NH 2 , carboxy or C 1 -C 6  alkoxycarbonyl;  
 R 7 , R 8 , R 9 , R 10 , R 11 , R 13 , R 14 , R 16 , R 17 , R 18 , R 19 , R 21 , R 23  and R 24  are, independently hydrogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 1 -C 6  hydroxyalkyl, C 3 -C 7  cycloalkyl, C 3 -C 7  cycloalkyl(C 1 -C 4  alkyl) or phenyl(C 1 -C 6  alkyl); and,  
 R 15  and R 20  are, independently, C 1 -C 6  alkyl, C 1 -C 6  hydroxyalkyl, C 3 -C 6  cycloalkyl, C 3 -C 7  cycloalkyl(C 1 -C 4  alkyl) or C 1 -C 6  alkyl optionally substituted by phenyl;  
 R 25  and R 26  are, independently, C 1 -C 6  alkyl or phenyl (optionally substituted by one or more of halogen, nitro, cyano, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, phenyl(C 1 -C 6  alkyl), C 1 -C 6  alkoxy, C 1 -C 6  haloalkoxy, S(O) 2 (C 1 -C 6  alkyl), C(O)NH 2 , carboxy or C 1 -C 6  alkoxycarbonyl);  
 or a pharmaceutically acceptable salt thereof, or solvate thereof, or a solvate of a salt thereof.  
 
   
   
       11 . The method of  claim 10 , comprising treating an inflammatory disease in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or solvate thereof, or a solvate of a salt thereof.