Pyrimidine compounds and their use as modulators of chemokine receptor activity

Abstract

The invention provides certain heterocyclic compounds, processes and intermediates used in their preparation, pharmaceutical compositions containing them and their use in therapy; in formula (I), A is a group of formula (a) or (b).

1 - 8 . (canceled)  
   
   
       9 . A process for the preparation of a pharmaceutical composition which comprises mixing a compound of formula (I)  
     
       
         
         
             
             
         
       
     
     in which: 
 A is a group of formula (a) or (b):  
                     
 R 1  represents a C 3 -C 7  carbocyclic, C 1 -C 8  alkyl C 2 -C 6  alkenyl or C 2 -C 6  alkynyl group, the latter four groups may be optionally substituted by one or more substituent groups independently selected from halogen atoms, —OR 4 , —NR 5 R 6 , —CONR 5 R 6 , —COOR 7 , —NR 8 COR 9 , —SR 10 , —SO 2 NR 5 R 6 , —NR 8 SO 2 R 10 , an aryl or heteroaryl group either of which can be optionally substituted by one or more substituents independently selected from halogen atoms, —OR 4 , —NR 5 R 6 , —CONR 5 R 6 , —COOR 7 , —NR 8 COR 9 , —SR 10 , —SO 2 R 10 , —SO 2 NR 5 R 6 , —NR 8 SO 2 R 10 , C 1 -C 6  alkyl or trifluoromethyl groups;  
 R 2  and R 3  each independently represent hydrogen, a C 3 -C 7  carbocyclic group, C 1 -C 8  alkyl, C 2 -C 6  alkenyl or C 2 -C 6  alkynyl group, the latter four groups may be optionally substituted by one or more substituent groups independently selected from halogen atoms, —OR 4 , —NR 5 R 6 —CONR 5 R 6 , —COOR 7 , —NR 8 COR 9 , —SR 10 , —SO 2 R 10 , —SO 2 NR 5 R 6 , —NR 8 SO 2 R 10    
 or  
 a 3-8 membered ring optionally containing one or more atoms selected from O, S, NR 8  and itself optionally substituted by C 1-3 -alkyl, halogen,  
 R 4  represents hydrogen, C 1 -C 6  alkyl or a phenyl group the latter two of which may be optionally substituted by one or more substituent groups independently selected from halogen atoms, phenyl, —OR 11  and —NR 12 R 13 ;  
 R 5 and R 6  independently represent a hydrogen atom or a C 1 -C 6  alkyl or phenyl group the latter two of which may be optionally substituted by one or more substituent groups independently selected from halogen atoms, phenyl, —OR 14  and —NR 15 R 16 , —CONR 15 R 16 , —NR 15 COR 16 , —SO 2 NR 15 R 16 , NR 15 SO 2 R 16    
 or  
 R 5  and R 6  together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring system optionally comprising a further heteroatom selected from oxygen and nitrogen atoms, which ring system may be optionally substituted by one or more substituent groups independently selected from phenyl, —OR 14 , —COOR 14 , —NR 15 R 16 , —CONR 15 R 16 , —NR 15 COR 16 , —SO 2 NR 15 R 16 , NR 15 SO 2 R 16  or C 1 -C 6  alkyl, itself optionally substituted by one or more substituents independently selected from halogen atoms and —NR 15 R 16  and —OR 17  groups;  
 R 10  represents a C 1 -C 6  alkyl group or phenyl group, each of which may be optionally substituted by one or more substituent groups independently selected from halogen atoms, phenyl, —OR 17  and —NR 15 R 16 ;  
 X is NH or CR 18 R 19 ;  
 Y is N or CR 18 ; and  
 each of R 7 , R 8 , R 9 , R 11 , R 12 , R 13 , R 14  R 15 , R 16 , R 17 , R 18 , R 19 independently represent a hydrogen atom, C 1 -C 6 , alkyl, or a phenyl group, or a pharmaceutically acceptable salt or solvate thereof, with a pharmaceutically acceptable adjuvant, diluent or carrier.  
 
   
   
       10 - 11 . (canceled)  
   
   
       12 . A method of treating a chemokine mediated disease wherein the chemokine binds to one or more chemokine receptors, which comprises administering to a patient a therapeutically effective amount of a compound of formula (I),  
     
       
         
         
             
             
         
       
     
     in which: 
 A is a group of formula (a) or (b):  
                     
 R 1  represents a C 3 -C 7  carbocyclic, C 1 -C 8  alkyl, C 2 -C 6  alkenyl or C 1 -C 6  alkynyl group, the latter four groups may be optionally substituted by one or more substituent groups independently selected from halogen atoms, —OR 4 , —NR 5 R 6 , —CONR 5 R 6 , —COOR 7 ,  
 —NR 8 COR 9 , —SR 10 , —SO 2 R 10 , —SO 2 NR 5 R 6 , —NR 8 SO 2 R 10 , an aryl or heteroaryl group either of which can be optionally substituted by one or more substituents independently selected from halogen atoms, cyano, nitro, —OR 4 , —NR 5 R 6 , —CONR 5 R 6 , —COOR 7 , —NR 8 COR 9 , —SR 10 , —SO 2 R 10 , —SO 2 NR 5 R 6 , —NR 8 SO 2 R 10 , C 1 -C 6  alkyl or trifluoromethyl groups;  
 R 2  and R 3  each independently represent hydrogen, a C 3 -C 7  carbocyclic group, C 1 -C 8  alkyl, C 2 -C 6  alkenyl or C 2 -C 6  alkynyl group, the latter four groups may be optionally substituted by one or more substituent groups independently selected from halogen atoms, —OR 4 , —NR 5 R 6 —CONR 5 R 6 , —COOR 7 , —NR 8 COR 9 , —SR 10 , —SO 2 R 10 , —SO 2 NR 5 R 6 , —NR 8 SO 2 R 10    
 or  
 a 3-8 membered ring optionally containing one or more atoms selected from O, S, NR 8  and itself optionally substituted by C 1-3 -alkyl, halogen,  
 R 4  represents hydrogen, C 1 -C 6  alkyl or a phenyl group the latter two of which may be optionally substituted by one or more substituent groups independently selected from halogen atoms, phenyl, —OR 11  and —NR 12 R 13 ;  
 R 5  and R 6  independently represent a hydrogen atom or a C 1 -C 6  alkyl or phenyl group the latter two of which may be optionally substituted by one or more substituent groups independently selected from halogen atoms, phenyl, —OR 14  and —NR 15 R 16 , —CONR 15 R 16 , —NR 15 COR 16 , —SO 2 NR 15 R 16 , NR 15 SO 2 R 16    
 or  
 R 5  and R 6  together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring system optionally comprising a further heteroatom selected from oxygen and nitrogen atoms, which ring system may be optionally substituted by one or more substituent groups independently selected from phenyl, —OR 14 , —COOR 14 ,  
 —NR 15 R 16 , —CONR 15 R 16 , —NR 15 COR 16 , —SO 2 NR 15 R 16 , NR 15 SO 2 R 16  or C 1 -C 6  alkyl, itself optionally substituted by one or more substituents independently selected from halogen atoms and —NR 15 R 16  and —OR 17  groups;  
 R 10  represents a C 1 -C 6  alkyl group or phenyl group, each of which may be optionally substituted by one or more substituent groups independently selected from halogen atoms, phenyl, —OR 17  and —NR 15 R 16 ;  
 X is NH or CR 18 R 19 ;  
 Y is N or CR 18 ; and  
 each of R 7 , R 8 , R 9 , R 11 , R 12 , R 13 , R 14  R 15 , R 16 , R 17 , R 18 , R 19  independently represent a hydrogen atom, C 1 -C 6 , alkyl, or a phenyl group, or a pharmaceutically acceptable salt or solvate thereof.  
 
   
   
       13 . The method according to  claim 12  in which the chemokine receptor belongs to the CXC chemokine receptor subfamily is the CXCR2 receptor.  
   
   
       14 . The method according to  claim 12  in which the chemokine receptor is the CXCR2 receptor.  
   
   
       15 . A method of 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),  
     
       
         
         
             
             
         
       
     
     in which: 
 A is a group of formula (a) or (b):  
                     
 R 1  represents a C 3 -C 7  carbocyclic, C 1 -C 8  alkyl, C 2 -C 6  alkenyl or C 2 -C 6  alkynyl group, the latter four groups may be optionally substituted by one or more substituent groups independently selected from halogen atoms, —OR 4 , —NR 5 R 6 , —CONR 5 R 6 , —COOR 7 , —NR 8 COR 9 , —SR 10 , —SO 2 R 10 , —SO 2 NR 5 R 6 , —NR 8 SO 2 R 10 , an aryl or heteroaryl group either of which can be optionally substituted by one or more substituents independently selected from halogen atoms, cyano, nitro —OR 4 , —NR 5 R 6 , —CONR 5 R 6 , —COOR 7 , —NR 8 COR 9 , —SR 10 , —SO 2 R 10 , —SO 2 NR 5 R 6 , —NR 8 SO 2 R 10 , C 1 -C 6  alkyl or trifluoromethyl groups;  
 R 2  and R 3  each independently represent hydrogen a C 3 -C 7  carbocyclic group, C 1 -C 8  alkyl, C 2 -C 6  alkenyl or C 2 -C 6  alkynyl groups the latter four groups may be optionally substituted by one or more substituent groups independently selected from halogen atoms, —OR 4 , —NR 5 R 6 —CONR 5 R 6 , —COOR 7 , —NR 8 COR 9 , —SR 10 , —SO 2 R 10 , —SO 2 NR 5 R 6 , —NR 8 SO 2 R 10    
 or  
 a 3-8 membered ring optionally containing one or more atoms selected from O, S, NR 8  and itself optionally substituted by C 1-3 -alkyl, halogen,  
 R 4  represents hydrogen, C 1 -C 6  alkyl or a phenyl group the latter two of which may be optionally substituted by one or more substituent groups independently selected from halogen atoms, phenyl, —OR 11  and —NR 12 R 13 ;  
 R 5  and R 6  independently represent a hydrogen atom or a C 1 -C 6  alkyl or phenyl group the latter two of which may be optionally substituted by one or more substituent groups independently selected from halogen atoms, phenyl, —OR 14  and —NR 15 R 16 , —CONR 15 R 16 , —NR 15 COR 16 , —SO 2 NR 15 R 16 , NR 15 SO 2 R 16    
 or  
 R 5  and R 6  together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring system optionally comprising a further heteroatom selected from oxygen and nitrogen atoms, which ring system may be optionally substituted by one or more substituent groups independently selected from phenyl, —OR 14 , —COOR 14 , —NR 15 R 16 , —CONR 15 R 16 , —NR 15 COR 16 , —SO 2 NR 15 R 16 , NR 15 SO 2 R 16  or C 1 -C 6  alkyl, itself optionally substituted by one or more substituents independently selected from halogen atoms and —NR 15 R 16  and —OR 17  groups;  
 R 10  represents a C 1 -C 6  alkyl group or phenyl group each of which may be optionally substituted by one or more substituent groups independently selected from halogen atoms, phenyl, —OR 17  and —NR 15 R 16 ;  
 X is NH or CR 18 R 19 ;  
 Y is N or CR 18 ; and  
 each of R 7 , R 8 , R 9 , R 11 , R 12 , R 13 , R 14  R 15 , R 16 , R 17 , R 18 , R 19  independently represent a hydrogen atom, C 1 -C 6 , alkyl, or a phenyl group or a pharmaceutically acceptable salt or solvate thereof.  
 
   
   
       16 . The method according to  claim 15 , wherein the disease is psoriasis.  
   
   
       17 . A method according to  claim 15 , wherein the disease is psoriasis.  
   
   
       18 . The method according to  claim 15 , wherein the disease is a disease in which angiogenesis is associated with raised CXCR2 chemokine levels.  
   
   
       19 . The method according to  claim 15 , wherein the disease is COPD.