Novel Oxabispidine Compounds And Their Use In The Treatment Of Cardiac Arrhythmias

Abstract

There is provided compounds of formula I, wherein R 1 , R 2 , R 4 , R 41 to R 46 , A, B and G have meanings given in the description, which are useful in the prophylaxis and in the treatment of arrhythmias, in particular atrial and ventricular arrhythmias.

1 - 40 . (canceled) 
     
     
         41 . A compound of formula II, 
       
         
           
           
               
               
           
         
       
       wherein:
 G represents CH or N; 
 R 41  to R 46 , independently, represent H or C 1-3  alkyl; 
 A represents C 2-6  alkylene optionally interrupted by —S(O) 2 N(R 18a )— or —N(R)SO 2 — and/or optionally substituted by one or more substituents selected from —OH, halo, and amino; 
 R 18a  represents H or C 1-6  alkyl; 
 R 2  represents —S(O) 2 R 3a , —C(O)OR 3b , —C(O)R 3c , —C(O)N(R 3d )(R 3e ) or —S(O) 2 N(R 3f )(R 3g ); 
 R 3a  to R 3g , independently represent C 1-6  alkyl (optionally substituted by one or more substituents selected from halo, -E-aryl -E-Het 8 , —C(O)R 16a , —C(O)OR 16b  and —C(O)N(R 16c )R 16d ), aryl or Het 9 , or R 3c  and R 3d  to R 3g  independently represent H; 
 E represents, at each occurrence when used herein, a direct bond or C 1-4  alkylene; 
 Het 8  to Het 11 , independently, represent five- to twelve-membered heterocyclic groups containing one or more heteroatoms selected from oxygen, nitrogen and/or sulfur, which groups are optionally substituted by one or more substituents selected from —OH, oxo, halo, cyano, nitro, C 1-6  alkyl, C 1-6  alkoxy, aryl, aryloxy, —N(R 17a )R 17b , —C(O)R 17c , —C(O)OR 17d , —C(O)N(R 17e )R 17 , —N(R 17g )C(O)R 17h , —S(O) 2 N(R 17i )R 17j  and —N(R 17k )S(O) 2 R 17l ; 
 R 16a  to R 16d , independently, represent at each occurrence when used herein, H, C 1-6  alkyl (optionally substituted by one or more substituents selected from halo, aryl and Het 10 ), aryl, Het 11 , or R 16c  and R 16d  together represent C 3-6  alkylene, optionally interrupted by an O atom; 
 R 17a  to R 17l , independently, represent C 1-6  alkyl, aryl or R 17a  to R 17k  independently represent H; 
 B represents -Z 1 -{[C(O)] a C(H)(R 19a )} b —, -Z 2 -[C(O)] c N(R 19b )—, -Z 2 -S(O) n —, -Z 2 -N(R 18c )S(O) 2 —, -Z 2 -S(O) 2 N(R 18d )— or -Z 2 -O— (in which six groups Z 1  or Z 2  is attached to the nitrogen atom bearing R 2 ); 
 a, b, and c, independently, represent 0 or 1; 
 n represents 0, 1, or 2; 
 Z 1  represents a direct bond or C 1-4  alkylene, optionally interrupted by —N(R 18e )S(O) 2 — or —S(O) 2 N(R 18f )—; 
 Z 2  represents, at each occurrence when used herein, C 2-4  alkylene, optionally interrupted by —N(R 18g )S(O) 2 — or —S(O) 2 N(R 18h )—; 
 R 18c  to R 18h , independently, represent H or C 1-6  alkyl; 
 R 19a  represents H or, together with a single R 4  substituent at a position on the phenyl or pyridyl group that is ortho- to the position at which the group B is attached, R 19a  represents C 2-4  alkylene optionally interrupted or terminated by O, S or N(R 20 ); 
 R 19b  represents H, C 1-6  alkyl or, together with a single R 4  substituent at a position on the phenyl or pyridyl group that is ortho- to the position at which the group B is attached, R 19b  represents C 2-4  alkylene; 
 R 20  represents H or C 1-6  alkyl; 
 R 4  represents one or more optional substituents selected from —OH, cyano, halo, nitro, C 1-6  alkyl (optionally terminated by —N(H)C(O)OR 21a ), C 1-6  alkoxy, —N(R 22a )R 22b , —C(O)R 22c , —C(O)OR 22d , —C(O)N(R 22e )R 22f , —N(R 22g )C(O)R 22h , —N(R 22i )C(O)N(R 22j )R 22k , —N(R 22m )S(O) 2 R 21b , —S(O) 2 N(R 22n )R 22o , —S(O) 2 R 21c , —OS(O) 2 R 21d  and aryl, and an R 4  substituent in a position on the phenyl or pyridyl group that is ortho- to the position at which the group B is attached may 
 (i) together with R 19a , represent C 2-4  alkylene optionally interrupted or terminated by O, S or N(R 20 ), or 
 (ii) together with R 19b , represent C 2-4  alkylene; 
 R 21a  to R 21d , independently, represent C 1-6  alkyl; 
 R 22a  and R 22b , independently, represent H, C 1-6  alkyl or together represent C 3-6  alkylene, resulting in a four- to seven-membered nitrogen-containing ring; and 
 R 22c  to R 22o , independently, represent H or C 1-6  alkyl; 
 
       wherein each aryl and aryloxy group, unless otherwise specified, is optionally substituted; 
       or a protected derivative thereof. 
     
     
         42 . A compound of formula IV, 
       
         
           
           
               
               
           
         
       
       wherein:
 G represents CH or N; 
 R 41  to R 46 , independently, represent H or C 1-3  alkyl; 
 A represents C 2-6  alkylene optionally interrupted by —S(O) 2 N(R 18a )— or —N(R)S(O) 2 — and/or optionally substituted by one or more substituents selected from —OH, halo, and amino; 
 R 18a  represents H or C 1-6  alkyl; 
 R 2  represents —S(O) 2 R 3a , —C(O)OR 3b , —C(O)R 3c , —C(O)N(R 3d ) or —S(O) 2 N(R 3f )(R 3g ); 
 R 3a  to R 3g , independently, represent C 1-6  alkyl (optionally substituted by one or more substituents selected from halo, -E-aryl, -E-Het 8 , —C(O)R 16a , —C(O)OR 16b  and —C(O)N(R 16c )R 16d ), aryl or Het 9 , or R 3c  and R 3d  to R 3g  independently represent H; 
 E represents, at each occurrence when used herein, a direct bond or C 1-4  alkylene; 
 Het 8  to Het 11 , independently, represent five- to twelve-membered heterocyclic groups containing one or more heteroatoms selected from oxygen, nitrogen and/or sulfur, which groups are optionally substituted by one or more substituents selected from —OH, oxo, halo, cyano, nitro, C 1-6  alkyl, C 1-6  alkoxy, aryl, aryloxy, —N(R 17a )R 17b , —C(O)R 17c , —C(O)OR 17d , —C(O)N(R 17e )R 17 , —N(R 17g )C(O)R 17h , —S(O) 2 N(R 17i )R 17j  and —N(R 17k )S(O) 2 R 17l ; 
 R 16a  to R 16d , independently, represent at each occurrence when used herein, H, C 1-6  alkyl (optionally substituted by one or more substituents selected from halo, aryl and Het 10 ), aryl, Het 11 , or R 16c  and R 16d  together represent C 3-6  alkylene, optionally interrupted by an O atom; 
 R 17a  to R 17l , independently, represent C 1-6  alkyl, aryl or R 17a  to R 17k  independently represent H; 
 B represents -Z 1 -{[C(O)] a C(H)(R 19a )} b —, -Z 2 -[C(O)] c N(R 19b )—, -Z 2 -S(O) n —, -Z 2 -N(R 18c )S(O) 2 —, -Z 2 -S(O) 2 N(R 18d )— or -Z 2 -O— (in which six groups Z 1  or Z 2  is attached to the nitrogen atom bearing R 2 ); 
 a, b, and c, independently, represent 0 or 1; 
 n represents 0, 1, or 2; 
 Z 1  represents a direct bond or C 1-4  alkylene, optionally interrupted by —N(R 18e )S(O) 2 — or —S(O) 2 N(R 18f )—; 
 Z 2  represents, at each occurrence when used herein, C 2-4  alkylene, optionally interrupted by —N(R 18g )S(O) 2 — or —S(O) 2 N(R 18h )—; 
 R 18c  to R 18h , independently, represent H or C 1-6  alkyl; 
 R 19a  represents H or, together with a single R 4  substituent at a position on the phenyl or pyridyl group that is ortho- to the position at which the group B is attached, R 19a  represents C 2-4  alkylene optionally interrupted or terminated by O, S or N(R 20 ); 
 R 19b  represents H, C 1-6  alkyl or, together with a single R 4  substituent at a position on the phenyl or pyridyl group that is ortho- to the position at which the group B is attached, R 19b  represents C 2-4  alkylene; 
 R 20  represents H or C 1-6  alkyl; 
 R 4  represents one or more optional substituents selected from —OH, cyano, halo, nitro, C 1-6  alkyl (optionally terminated by —N(H)C(O)OR 21a ), C 1-6  alkoxy, —N(R 22a )R 22b , —C(O)R 22c , —C(O)OR 22d , —C(O)N(R 22e )R 22f , —N(R 22g )C(O)R 22h , —N(R 22i )C(O)N(R 22j )R 22k , —N(R 22m )S(O) 2 R 21b , —S(O) 2 N(R 22n )R 22o , —S(O) 2 R 21c , —OS(O)R 21d  and aryl, and an R 4  substituent in a position on the phenyl or pyridyl group that is ortho- to the position at which the group B is attached may 
 (i) together with R 19a , represent C 2-4  alkylene optionally interrupted or terminated by O, S or N(R 20 ), or 
 (ii) together with R 19b , represent C 2-4  alkylene; 
 R 21a  to R 21d , independently, represent C 1-6  alkyl; 
 R 22a  and R 22b , independently, represent H, C 1-6  alkyl or together represent C 3-6  alkylene, resulting in a four- to seven-membered nitrogen-containing ring; 
 R 22c  to R 22o , independently, represent H or C 1-6  alkyl; and 
 L 1  is a leaving group; 
 
       wherein each aryl and aryloxy group, unless otherwise specified, is optionally substituted; 
       or a protected derivative thereof. 
     
     
         43 . A compound of formula X, 
       
         
           
           
               
               
           
         
       
       wherein:
 R 41  to R 46 , independently, represent H or C 1-3  alkyl; 
 A represents C 2-6  alkylene optionally interrupted by —S(O) 2 N(R 18a )— or —N(R)SO 2 — and/or optionally substituted by one or more substituents selected from —OH, halo, and amino; 
 R 18a  represents H or C 1-6  alkyl; 
 R 2  represents —S(O) 2 R 3a , —C(O)OR 3b , —C(O)R 3c , —C(O)N(R 3d )(R 3e ) or —S(O) 2 N(R 3f )(R 3g ); 
 R 3a  to R 3g , independently, represent C 1-6  alkyl (optionally substituted by one or more substituents selected from halo, -E-aryl, -E-Het 8 , —C(O)R 16a , —C(O)OR 16b  and —C(O)N(R 16c )R 16d ), aryl or Het 9 , or R 3c  and R 3d  to R 3g  independently represent H; 
 E represents, at each occurrence when used herein, a direct bond or C 1-4  alkylene; 
 Het 1  to Het 11 , independently, represent five- to twelve-membered heterocyclic groups containing one or more heteroatoms selected from oxygen, nitrogen and/or sulfur, which groups are optionally substituted by one or more substituents selected from —OH, oxo, halo, cyano, nitro, C 1-6  alkyl, C 1-6  alkoxy, aryl, aryloxy, —N(R 17a )R 17b , —C(O)R 17c , —C(O)OR 17d , —C(O)N(R 17e )R 17f , —N(R 17g )C(O)R 17h , —S(O) 2 N(R 17i )R 17j  and —N(R 17k )S(O) 2 R 17 ; 
 R 16a  to R 16d , independently, represent at each occurrence when used herein, H, C 1-6  alkyl (optionally substituted by one or more substituents selected from halo, aryl and Het 10 ), aryl, Het 11 , or R 16c  and R 16d  together represent C 3-6  alkylene, optionally interrupted by an O atom; 
 R 17a  to R 17l , independently, represent C 1-6  alkyl, aryl or R 17a  to R 17k  independently represent H; 
 Z 2  represents, at each occurrence when used herein, C 2-4  alkylene, optionally interrupted by —N(R 18g )S(O) 2 N(R 18h )—; 
 R 18g  and R 18h , independently, represent H or C 1-6  alkyl; 
 R 1  represents C 1-12  alkyl (which alkyl group is optionally substituted by one or more groups selected from halo, cyano, nitro, aryl, Het 1 , —C(O)R 5a , —OR 5b , —N(R 6 )R 5c , —C(O)XR 7 , —C(O)N(R 8a )R 5d , —OC(O)N(R 8b )R 5e , —S(O) 2 R 9a , —S(O) 2 N(R 9b )R 9c , and —N(R 9b )S(O) 2 R 9d ); 
 X is O or S; 
 R 5a  to R 5e , independently, represent at each occurrence when used herein, H, C 1-6  alkyl (which latter group is optionally substituted by one or more substituents selected from —OH, halo, cyano, nitro, aryl, aryloxy, Het 2 , —S(O) 2 N(R 9b )R 9c  and —N(R 9b )S(O) 2 R 9d ), aryl or Het 3 , or R 5d  or R 5e , together with, respectively, R 8a  or R 8b , represent C 3-6  alkylene (which alkylene group is optionally interrupted by an O atom and/or is optionally substituted by one or more C 1-3  alkyl groups); 
 R 6  represents H, C 1-6  alkyl (optionally substituted by one or more substituents selected from —OH, halo, cyano, nitro, aryl, —S(O) 2 N(R 9b )R 9c  and —N(R 9b )S(O) 2 R 9d ), aryl, —C(O)R 10a , —C(O)OR 10b , —C(O)N(R 10c )R 10d  or —S(O) 2 R 10e ; 
 R 10a  to R 10e , independently, represent C 1-6  alkyl (optionally substituted by one or more substituents selected from —OH, halo, cyano, nitro and aryl), aryl, or R 10a , R 10c  or R 10d  represent H; 
 R 7  represents, at each occurrence when used herein, C 1-12  alkyl (optionally substituted by one or more substituents selected from —OH, halo, cyano, nitro, aryl, C 1-6  alkoxy, Het 4 , —S(O) 2 N(R 9b )R 9c  and —N(R 9b )S(O) 2 R 9d ); 
 R 8a  and R 8b  independently represent H, C 1-12  alkyl, C 1-6  alkoxy (which latter two groups are optionally substituted by one or more substituents selected from —OH, halo, cyano, nitro, C 1-4  alkyl, C 1-4  alkoxy, —S(O) 2 N(R 9b )R 9c  and —N(R 9b )S(O) 2 R 9d ), -D-aryl, -D-aryloxy, -D-Het 5 , -D-N(H)C(O)R 11a , -D-S(O) 2 R 12a , -D-C(O)R 11b , -D-C(O)OR 12b -D-C(O)N(R 11c )R 11d , or R 8a  or R 8b , together with, respectively R 5d  or R 5e , may represent C 3-6  alkylene (which alkylene group is optionally interrupted by an O atom and/or is optionally substituted by one or more C 1-3  alkyl groups); 
 R 9a  represents, at each occurrence when used herein, C 1-6  alkyl (optionally substituted by one or more substituents selected from —OH, halo, cyano, nitro, aryl, —S(O) 2 N(R 9b )R 9c  and —N(R 9b )S(O) 2 R 9d ) or aryl; 
 R 9b  represents, at each occurrence when used herein, H or C 1-6  alkyl 
 R 9c  and R 9d , independently, represent at each occurrence when used herein, C 1-6  alkyl (optionally substituted by one or more substituents selected from —OH, halo, cyano, nitro, aryl and Het 6 ), aryl or Het 7 , or R 9c  represents H; 
 R 11a  to R 11d , independently represent H, C 1-6  alkyl (optionally substituted by one or more substituents selected from —OH, halo, cyano, nitro, and aryl), aryl, or R 11c  and R 11d  together represent C 3-6  alkylene; 
 R 12a  and R 12b , independently, represent C 1-6  alkyl (optionally substituted by one or more substituents selected from —OH, halo, cyano, nitro and aryl), or aryl; and 
 D represents, at each occurrence when used herein, a direct bond or C 1-6  alkylene; 
 
       wherein each aryl and aryloxy group, unless otherwise specified, is optionally substituted; 
       or a protected derivative thereof. 
     
     
         44 . A compound of formula XIII, 
       
         
           
           
               
               
           
         
       
       wherein:
 R 41  to R 46 , independently, represent H or C 1-3  alkyl; 
 A represents C 2-6  alkylene optionally interrupted by —S(O) 2 N(R 18a )— or —N(R)S(O) 2 — and/or optionally substituted by one or more substituents selected from —OH, halo, and amino; 
 R 18a  represents H or C 1-6  alkyl; 
 R 2  represents —S(O) 2 R 3a , —C(O)OR 3b , —C(O)R 3c , —C(O)N(R 3d )(R 3e ) or —S(O) 2 N(R 3f )(R 3g ); 
 R 3a  to R 3g , independently, represent C 1-6  alkyl (optionally substituted by one or more substituents selected from halo, -E-aryl, -E-Het 8 , —C(O)R 16a , —C(O)OR 16b  and —C(O)N(R 16c )R 16d ), aryl or Het 9 , or R 3c  and R 3d  to R 3g  independently represent H; 
 E represents, at each occurrence when used herein, a direct bond or C 1-4  alkylene; 
 Het 1  to Het 11 , independently, represent five- to twelve-membered heterocyclic groups containing one or more heteroatoms selected from oxygen, nitrogen and/or sulfur, which groups are optionally substituted by one or more substituents selected from —OH, oxo, halo, cyano, nitro, C 1-6  alkyl, C 1-6  alkoxy, aryl, aryloxy, —N(R 17a )R 17b , —C(O)R 17c , —C(O)OR 17d , —C(O)N(R 17e )R 17f , —N(R 17g )C(O)R 17h , —S(O) 2 N(R 17i )R 17j  and —N(R 17k )S(O) 2 R 17l ; 
 R 16a  to R 16d , independently, represent at each occurrence when used herein, H, C 1-6  alkyl (optionally substituted by one or more substituents selected from halo, aryl and Het 10 ), aryl, Het 11 , or R 16c  and R 16d  together represent C 3-6  alkylene optionally interrupted by an O atom; 
 R 17a  to R 17l , independently, represent C 1-6  alkyl, aryl, or R 17a  to R 17k  independently represent H; 
 R 1  represents C 1-12  alkyl (which alkyl group is optionally substituted by one or more groups selected from halo, cyano, nitro, aryl, Het 1 , —C(O)R 5a , —OR 5b , —N(R 6 )R 5c , —C(O)XR 7 , —C(O)N(R 8a )R 5d , —OC(O)N(R 8b )R 5e , —S(O) 2 R 9a , —S(O) 2 N(R 9b )R 9c , and —N(R 9b )S(O) 2 R 9d ); 
 X is O or S; 
 R 5a  to R 5e , independently, represent at each occurrence when used herein, H, C 1-6  alkyl (which latter group is optionally substituted by one or more substituents selected from —OH, halo, cyano, nitro, aryl, aryloxy, Het 2 , —S(O) 2 N(R 9b )R 9c  and —N(R 9b )S(O) 2 R 9d ), aryl or Het 3 , or R 5d  or R 5e , together with, respectively, R 8a  or R 8b , may represent C 3-6  alkylene (which alkylene group is optionally interrupted by an O atom and/or is optionally substituted by one or more C 1-3  alkyl groups); 
 R 6  represents H, C 1-6  alkyl (optionally substituted by one or more substituents selected from —OH, halo, cyano, nitro, aryl, —S(O) 2 N(R 9b )R 9c  and —N(R 9b )S(O) 2 R 9d ), aryl, —C(O)R 10a , —C(O)OR 10b , —C(O)N(R 10c )R 10d  or —S(O) 2 R 10e ; 
 R 10a  to R 10e , independently, represent C 1-6  alkyl (optionally substituted by one or more substituents selected from —OH, halo, cyano, nitro and aryl), aryl, or R 10a , R 10c  or R 10d  represents H; 
 R 7  represents, at each occurrence when used herein, C 1-12  alkyl (optionally substituted by one or more substituents selected from —OH, halo, cyano, nitro, aryl, C 1-6  alkoxy, Het 4 , —S(O) 2 N(R 9b )R 9c  and —N(R 9b )S(O) 2 R 9d ); 
 R 8a  and R 8b  independently represent H, C 1-12  alkyl, C 1-6  alkoxy (which latter two groups are optionally substituted by one or more substituents selected from —OH, halo, cyano, nitro, C 1-4  alkyl, C 1-4  alkoxy, —S(O) 2 N(R 9b )R 9c  and —N(R 9b )S(O) 2 R 9d ), -D-aryl, -D-aryloxy, -D-Het 5 , -D-N(H)C(O)R 11a , -D-S(O) 2 R 12a , -D-C(O)R 11b , -D-C(O)OR 12b , -D-C(O)N(R 11c )R 11d , or R 8a  or R 8b , together with, respectively, R 5d  or R 5e , may represent C 3-6  alkylene (which alkylene group is optionally interrupted by an O atom and/or is optionally substituted by one or more C 1-3  alkyl groups); 
 R 9a  represents, at each occurrence when used herein, C 1-6  alkyl (optionally substituted by one or more substituents selected from —OH, halo, cyano, nitro, aryl, —S(O) 2 N(R 9b )R 9c  and —N(R 9b )S(O) 2 R 9d ) or aryl; 
 R 9b  represents, at each occurrence when used herein H, or C 1-6  alkyl; 
 R 9c  and R 9d , independently, represent at each occurrence when used herein, C 1-6  alkyl (optionally substituted by one or more substituents selected from —OH, halo, cyano, nitro, aryl and Het 6 ), aryl or Het 7  or R 9c  represents H; 
 R 11a  to R 11d , independently, represent H, C 1-6  alkyl (optionally substituted by one or more substituents selected from —OH, halo, cyano, nitro and aryl), aryl, or R 11c  and R 11d  together represent C 3-6  alkylene; 
 R 12a  and R 12b , independently, represent C 1-6  alkyl (optionally substituted by one or more substituents selected from —OH, halo, cyano, nitro and aryl) or aryl; and 
 D represents, at each occurrence when used herein, a direct bond or C 1-6  alkylene; 
 
       wherein each aryl and aryloxy group, unless otherwise specified, is optionally substituted; 
       or a protected derivative thereof. 
     
     
         45 . A compound of formula XVIII, 
       
         
           
           
               
               
           
         
       
       wherein:
 G represents CH or N; 
 R 41  to R 46 , independently, represent H or C 1-3  alkyl; 
 A represents C 2-6  alkylene optionally interrupted by —S(O) 2 N(R 18a )— or —N(R)SO 2 — and/or optionally substituted by one or more substituents selected from —OH, halo, and amino; 
 R 18a  represents H or C 1-6  alkyl; 
 R 2  represents —S(O) 2 R 3a , —C(O)OR 3b , —C(O)R 3c , —C(O)N(R 3d )(R 3e ) or —S(O) 2 N(R 3f )(R 3g ); 
 R 3a  to R 3g , independently, represent C 1-6  alkyl (optionally substituted by one or more substituents selected from halo, -E-aryl, -E-Het 8 , —C(O)R 16a , —C(O)OR 16b  and —C(O)N(R 16c )R 16d ), aryl or Het 9 , or R 3c  and R 3d  to R 3g  independently represent H; 
 E represents, at each occurrence when used herein, a direct bond or C 1-4  alkylene; 
 Het 1  to Het 11 , independently, represent five- to twelve-membered heterocyclic groups containing one or more heteroatoms selected from oxygen, nitrogen and/or sulfur, which groups are optionally substituted by one or more substituents selected from —OH, oxo, halo, cyano, nitro, C 1-6  alkyl, C 1-6  alkoxy, aryl, aryloxy, —N(R 17a )R 17b , —C(O)R 17c , —C(O)OR 17d , —C(O)N(R 17e )R 17f , —N(R 17g )C(O)R 17h , —S(O) 2 N(R 17i )R 17j  and —N(R 17k )S(O) 2 R 17l ; 
 R 16a  to R 16d , independently, represent at each occurrence when used herein, H, C 1-6  alkyl (optionally substituted by one or more substituents selected from halo, aryl and Het 10 ), aryl, Het 11 , or R 16c  and R 16d  together represent C 3-6  alkylene, optionally interrupted by an O atom; 
 R 17a  to R 17l , independently, represent C 1-6  alkyl, aryl or R 17a  to R 17k  independently represent H; 
 B represents -Z 1 -{[C(O)] a C(H)(R 19a )} b —, -Z 2 -[C(O)] c N(R 19b )—, -Z 2 -S(O) n —, -Z 2 -N(R 18c )S(O) 2 —, -Z 2 -S(O) 2 N(R 18d )— or -Z 2 -O— (in which six groups Z 1  or Z 2  is attached to the nitrogen atom bearing R 2 ); 
 a, b, and c, independently, represent 0 or 1; 
 n represents 0, 1, or 2; 
 Z 1  represents a direct bond or C 1-4  alkylene, optionally interrupted by —N(R 18e )S(O) 2 — or —S(O) 2 N(R 18f )—; 
 Z 2  represents, at each occurrence when used herein, C 2-4  alkylene, optionally interrupted by —N(R 18g )S(O) 2 — or —S(O) 2 N(R 18h )—; 
 R 18c  to R 18h , independently, represent H or C 1-6  alkyl; 
 R 19a  represents H or, together with a single R 4  substituent at a position on the phenyl or pyridyl group that is ortho- to the position at which the group B is attached, R 19a  represents C 2-4  alkylene optionally interrupted or terminated by O, S or N(R 20 ); 
 R 19b  represents H, C 1-6  alkyl or, together with a single R 4  substituent at a position on the phenyl or pyridyl group that is ortho- to the position at which the group B is attached, R 19b  represents C 2-4  alkylene; 
 R 20  represents H or C 1-6  alkyl; 
 R 4  represents one or more optional substituents selected from —OH, cyano, halo, nitro, C 1-6  alkyl (optionally terminated by —N(H)C(O)OR 21a ), C 1-6  alkoxy, —N(R 22a )R 22b , —C(O)R 22c , —C(O)OR 22d , —C(O)N(R 22e )R 22f , —N(R 22g )C(O)R 22h , —N(R 22i )C(O)N(R 22j )R 22k , —N(R 22m )S(O) 2 R 21b , —S(O) 2 N(R 22n )R 22o , —S(O) 2 R 21c , —OS(O) 2 R 21d  and aryl, and an R 4  substituent in a position on the phenyl or pyridyl group that is ortho- to the position at which the group B is attached may 
 (i) together with R 19a , represent C 2-4  alkylene optionally interrupted or terminated by O, S or N(R 20 ), or 
 (ii) together with R 19b , represent C 2-4  alkylene; 
 R 21a  to R 21d , independently, represent C 1-6  alkyl; 
 R 22a  and R 22b , independently, represent H, C 1-6  alkyl or together represent C 3-6  alkylene, resulting in a four- to seven-membered nitrogen-containing ring; 
 R 22c  to R 22o , independently, represent H or C 1-6  alkyl; 
 R 1a  represents C 1-12  alkylene, which group is optionally substituted by one or more substituents selected from halo, cyano, nitro, aryl, Het 1 , —C(O)R 5a , —OR 5b , —N(R 6 )R 5c , —C(O)XR 7 , —C(O)N(R 8a )R 5d , —OC(O)N(R 8b )R 5e , —S(O) 2 R 9a , —S(O) 2 N(R 9b )R 9c , and —N(R 9b )S(O) 2 R 9d ); 
 X is O or S; 
 R 5a  to R 5e , independently, represent at each occurrence when used herein, H, C 1-6  alkyl (which latter group is optionally substituted by one or more substituents selected from —OH, halo, cyano, nitro, aryl, aryloxy, Het 2 , —S(O) 2 N(R 9b )R 9c  and —N(R 9b )S(O) 2 R 9d ), aryl or Het 3 , or R 5d  or R 5e , together with, respectively, R 8a  or R 8b , may represent C 3-6  alkylene (which alkylene group is optionally interrupted by an O atom and/or is optionally substituted by one or more C 1-3  alkyl groups); 
 R 6  represents H, C 1-6  alkyl (optionally substituted by one or more substituents selected from —OH, halo, cyano, nitro, aryl, —S(O) 2 N(R 9b )R 9c  and —N(R 9b )S(O) 2 R 9d ), aryl, —C(O)R 10a , —C(O)OR 10b , —C(O)N(R 10c )R 10d  or —S(O) 2 R 10e ; 
 R 10a  to R 10e , independently, represent C 1-6  alkyl (optionally substituted by one or more substituents selected from —OH, halo, cyano, nitro and aryl), aryl, or R 10a , R 10c  or R 10d  represents H; 
 R 7  represents, at each occurrence when used herein, C 1-12  alkyl (optionally substituted by one or more substituents selected from —OH, halo, cyano, nitro, aryl, C 1-6  alkoxy, Het 4 , —S(O) 2 N(R 9b )R 9c  and —N(R 9b )S(O) 2 R 9d ); 
 R 8a  and R 8b  independently represent H, C 1-12  alkyl, C 1-6  alkoxy (which latter two groups are optionally substituted by one or more substituents selected from —OH, halo, cyano, nitro, C 1-4  alkyl, C 1-4  alkoxy, —S(O)N(R 9b )R 9c  and —N(R 9b )S(O) 2 R 9d ), -D-aryl, -D-aryloxy, -D-Het 5 , -D-N(H)C(O)R 11a , -D-S(O) 2 R 12a , -D-C(O)R 11b , -D-C(O)OR 12b -D-C(O)N(R 11c )R 11d , or R 8a  or R 8b , together with, respectively, R 5d  or R 5e , may represent C 3-6  alkylene (which alkylene group is optionally interrupted by an O atom and/or is optionally substituted by one or more C 1-3  alkyl groups); 
 R 9a  represents, at each occurrence when used herein, C 1-6  alkyl (optionally substituted by one or more substituents selected from —OH, halo, cyano, nitro, aryl, —S(O) 2 N(R 9b )R 9c  and —N(R 9b )S(O) 2 R 9d ) or aryl; 
 R 9b  represents, at each occurrence when used herein, H or C 1-6  alkyl; 
 R 9c  and R 9d , independently, represent at each occurrence when used herein, C 1-6  alkyl (optionally substituted by one or more substituents selected from —OH, halo, cyano, nitro, aryl and Het 6 ), aryl, or Het 7 , or R 9c  represents H; 
 R 11a  to R 11d , independently, represent H, C 1-6  alkyl (optionally substituted by one or more substituents selected from —OH, halo, cyano, nitro and aryl), aryl, or R 11c  and R 11d  together represent C 3-6  alkylene; 
 R 12a  and R 12b , independently, represent C 1-6  alkyl (optionally substituted by one or more substituents selected from —OH, halo, cyano, nitro and aryl) or aryl; and 
 D represents, at each occurrence when used herein, a direct bond or C 1-6  alkylene; 
 
       wherein each aryl and aryloxy group, unless otherwise specified, is optionally substituted; 
       or a protected derivative thereof. 
     
     
         46 . A compound of  claim 42  wherein:
 L 1  is selected from halo, alkanesulfonate, perfluoroalkanesulfonate, arenesulfonate, —OC(O)XR 7 , imidazole or R 23 O—;   R 23  represents C 1-10  alkyl or aryl, which groups are optionally substituted by one or more halo or nitro groups;   X is O or S; and   R 7  is C 1-12  alkyl (optionally substituted by one or more substituents selected from —OH, halo, cyano, nitro, aryl, C 1-6  alkoxy, Het 4 , —S(O) 2 N(R 9b )R 9c  and —N(R 9b )S(O) 2 R 9d )   R 9b  represents H or C 1-6  alkyl;   R 9c  and R 9d , independently, represent C 1-6  alkyl (optionally substituted by one or more substituents selected from —OH, halo, cyano, nitro, aryl and Het 6 ), aryl or Het 7 , or R 9c  represents H; and   Het 4 , Het 6 , and Het 7 , independently, represent five- to twelve-membered heterocyclic groups containing one or more heteroatoms selected from oxygen, nitrogen and/or sulfur, which groups are optionally substituted by one or more substituents selected from —OH, oxo, halo, cyano, nitro, C 1-6  alkyl, C 1-6  alkoxy, aryl, aryloxy, —N(R 17a )R 17b , —C(O)R 17c , —C(O)OR 17d , —C(O)N(R 17e )R 17f , —N(R 17g )C(O)R 17h , —S(O) 2 N(R 17i )R 17j  and —N(R 17k )S(O) 2 R 17l ;   
       or a protected derivative thereof.