Pyrazinone derivatives

Abstract

The present invention relates to pyrazinone derivatives of formula (I): wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as herein defined; processes for their preparation, pharmaceutical compositions containing them and their use in therapy.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  and R 2  are independently selected from H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo, CF 3 , and CN; 
 R 1a  is H; 
 R 3  is H; 
 R 4  is selected from H, methyl, ethyl, methoxy, ethoxy, Cl, Br, CN, phenyl, and CONH 2 , wherein said methyl is optionally substituted with NR 12 R 13 ; 
 R 5  is selected from heterocycloalkyl and NR 16 R 17 ; 
 R 6  is selected from H, alkyl, (C 1 -C 4 )alkoxy, and (C 3 -C 6 )cycloalkyl; 
 R 7  is selected from H, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, and (C 3 -C 6 )cycloalkyl; 
 R 16  is selected from H, aryl, (C 3 -C 7 )cycloalkyl and 
 
       
         
           
           
               
               
           
         
       
       wherein said (C 3 -C 7 )cycloalkyl may be optionally substituted with an aryl group;
 R 17  is selected from H, (C 1 -C 6 )alkyl, aryl, heteroaryl, heterocycloalkyl and (C 3 -C 7 )cycloalkyl, wherein said (C 1 -C 6 )alkyl may be optionally substituted with 1, 2 or 3 groups independently selected from (C 1 -C 6 )alkoxy, (C 3 -C 10 )cycloalkyl, heterocycloalkyl, heteroaryl and NR 20 R 21 ; 
 as to R 22  and R 23 :
 R 22  and R 23  are independent substituents such that:
 R 22  is selected from H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, OH, NR 29 R 30 , heterocycloalkyl and aryl, wherein said (C 1 -C 6 )alkyl may be optionally substituted with 1, 2 or 3 R 28  groups; and wherein said aryl may be optionally substituted with 1, 2 or 3 groups independently selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo, CF 3  and OH; and 
 R 23  is selected from H and (C 1 -C 6 )alkyl; or 
 
 
 R 22  and R 23 , together with the carbon atom to which they are attached, form a (C 3 -C 7 )cycloalkyl or heterocycloalkyl ring; 
 X is a bond or a (CR 24 R 25 ) n  group; 
 as to R 24  and R 25 :
 R 24  and R 25  are independently selected from H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, OH, heterocycloalkyl and NR 39 R 40 ; or 
 R 24  and R 25 , together with the carbon atom to which they are attached, form a heterocycloalkyl ring; 
 
 Z is an aryl or heteroaryl ring, wherein said aryl or heteroaryl ring is substituted with R 26  and R 27 ; 
 as to R 26  and R 27 :
 R 26  and R 27  are independent substituents such that:
 R 26  is selected from H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, OH, aryl, O-aryl, halo, heterocycloalkyl, O-heterocycloalkyl, heteroaryl, O-heteroaryl, cycloalkyl, O-cycloalkyl, S(O) p R 34 , NR 34 R 35  and CONR 34 R 35 , wherein said (C 1 -C 6 )alkyl or said (C 1 -C 6 )alkoxy may be optionally substituted with 1, 2 or 3 groups independently selected from halo, OH, heterocycloalkyl or NR 34 R 35 ; and 
 R 27  is selected from H, halo and (C 1 -C 6 )alkyl, wherein said (C 1 -C 6 )alkyl may be optionally substituted with 1, 2 or 3 halo groups; or 
 
 R 26  and R 27 , together, form a methylenedioxy group when attached to adjacent carbon atoms of the aryl or heteroaryl ring; 
 
 each occurrence of R 28  is independently selected from NR 29 R 30 , halo, CH 2 CF 3 , CF 3 , heterocycloalkyl, (C 1 -C 6 )alkoxy, OR 36 , COOR 42 , CONR 31 R 32  and SO 2 NR 37 R 38 ; 
 R 29  and R 30  are independently selected from H, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, SO 2 R 41  and C(O)R 41 , wherein said (C 1 -C 6 )alkyl may be optionally substituted with, OH, NR 56 R 57  or heterocycloalkyl; 
 as to R 31  and R 32 :
 R 31  and R 32  are independently selected from H, (C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl; or 
 R 31  and R 32 , together with the nitrogen atom to which they are attached, form a 4 to 7 membered ring, optionally containing a further heteroatom selected from NR 33 , S and O; 
 
 as to R 34  and R 35 :
 R 34  and R 35  are independently selected from H, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, C-linked heterocycloalkyl and C(O)O(C 1 -C 6 )alkyl, wherein said (C 1 -C 6 )alkyl may be optionally substituted by OH, halo, (C 1 -C 6 )alkoxy, NR 58 R 59 , C(O)OH and heterocycloalkyl; or 
 R 34  and R 35 , together with the nitrogen to which they are attached, form a 4 to 7 membered ring; 
 
 R 36  is selected from H, (C 1 -C 6 )alkyl and heterocycloalkyl, wherein said (C 1 -C 6 )alkyl may be optionally substituted with heterocycloalkyl; 
 R 12 , R 13 , R 20 , R 21 , R 33 , R 37 , R 38 , R 39 , R 40 , R 41  and R 42  are independently selected from H and (C 1 -C 6 )alkyl; 
 n is 1 or 2; 
 each occurrence of p is independently selected from 0, 1 or 2; 
 cycloalkyl is a non-aromatic carbocyclic ring, optionally fused to an aryl group, wherein said cycloalkyl ring optionally contains, where possible, up to 2 double bonds; and wherein, unless otherwise stated, said cycloalkyl may be optionally substituted with 1 or 2 substituents independently selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, OH, CN, CF 3 , halo and NR 43 R 44 ; 
 heterocycloalkyl is a C-linked or N-linked 3 to 9 membered non-aromatic, mono- or bi-cyclic ring, optionally fused to an aryl or heteroaryl group, wherein said heterocycloalkyl ring:
 contains:
 1 or 2 NR 45  atoms, 
 one N— atom, 
 one N— atom and one NR 45 , 
 one N— atom, one NR 45  and an S(O) p  or an O atom, 
 one N— atom and an S(O) p  or an O atom, 
 one S atom, or 
 one O atom; 
 
 optionally contains, where possible, 1 or 2 double bonds; and 
 is optionally substituted on carbon with 1 or 2 substituents independently selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, OH, CN, CF 3 , halo, ═O, NR 46 R 47 , —C(O)NR 46 R 47 , bivalent substituent —OCH 2 CH 2 O— (wherein the terminal oxygen atoms are attached to the same ring carbon atom), bivalent substituent —CH 2 NHCH 2 — (wherein the terminal carbon atoms are attached to the same ring carbon atom), a tetrahydro-1,1-dioxido-3-thienyl group, and aryl, wherein said (C 1 -C 6 )alkyl may be optionally substituted by aryl, (C 1 -C 6 )alkoxy or OH; and wherein each aryl group may be optionally substituted with (C 1 -C 6 )alkoxy (which in turn may be optionally substituted by NR 34 R 35 ), (C 1 -C 6 )alkyl, OH, CF 3  and halo; 
 
 aryl is an aromatic ring containing 6 or 10 carbon atoms; wherein, unless otherwise stated, said aryl may be optionally substituted with 1, 2 or 3 substituents independently selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, OH, halo, CN, CF 3  and NR 48 R 49 ; 
 heteroaryl is a 5, 6, 9 or 10 membered aromatic ring, containing from 1 or 2 N atoms and, optionally, an NR 50  atom, or one NR 50  atom and an S or an O atom, or one S atom, or one O atom; wherein, unless otherwise stated, said heteroaryl may be optionally substituted with 1, 2 or 3 substituents independently selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, OH, halo, CN, CF 3  and NR 51 R 52 ; 
 R 45  is selected from H, (C 1 -C 6 )alkyl, C(O)(C 1 -C 6 )alkyl, C(O)O(C 1 -C 6 )alkyl and aryl, wherein said (C 1 -C 6 )alkyl is optionally substituted with a group selected from (C 1 -C 3 )alkoxy, OH, halo, heterocycloalkyl and NR 29 R 30 ; and wherein said C(O)O(C 1 -C 6 )alkyl is optionally substituted with an aryl group; 
 R 50  is selected from H, (C 1 -C 6 )alkyl and C(O)O(C 1 -C 6 )alkyl, wherein said (C 1 -C 6 )alkyl may be optionally substituted with a group selected from (C 1 -C 3 )alkoxy, OH, halo, (C 3 -C 6 )cycloalkyl and NR 53 R 54 ; 
 R 43 , R 44 , R 46 , R 47 , R 48 , R 49 , R 51 , R 52 , R 53 , R 54 , R 56 , R 57  and R 59  are each independently selected from H and (C 1 -C 6 )alkyl; 
 R 58  is selected from H and (C 1 -C 6 )alkyl wherein said (C 1 -C 6 )alkyl may be optionally substituted with a group selected from (C 1 -C 3 )alkoxy and OH; or 
 a pharmaceutically acceptable salt thereof. 
 
     
     
         2 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is selected from H and F, and   R 2  is selected from (C 1 -C 4 )alkyl and F.   
     
     
         3 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4  is H. 
     
     
         4 . (canceled) 
     
     
         5 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
 R 16  is   
       
         
           
           
               
               
           
         
       
       and
 Z is an aryl ring substituted with R 26  and R 27 . 
 
     
     
         6 - 15 . (canceled) 
     
     
         16 . A compound according to  claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 4  is H. 
     
     
         17 . A compound according to  claim 2 , or a pharmaceutically acceptable salt thereof, wherein:
 R 16  is   
       
         
           
           
               
               
           
         
       
       and
 Z is an aryl ring substituted with R 26  and R 27 .