Quinazoline derivatives and pharmaceutical compositions containing them

Abstract

The invention relates to quinazoline derivatives of formula (1) wherein m is an integer from 1 to 2; R 1 represents hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, or —NR 5 R 6 (wherein R 5 and R 6 , which may be the same or different, each represents hydrogen or C 1-3 alkyl); R 2 represents hydrogen, hydroxy, halogeno, methoxy, amino or nitro; R 3 represents hydroxy, halogeno, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkanoyloxy, trifluoromethyl, cyano, amino or nitro; X 1 represents —O—, —CH 2 —, —S—, —SO—, —SO 2 —, —NR 7 CO—, —CONR 8 —, —SO 2 NR 9 —, —NR 10 SO 2 — or —NR 11 — (wherein R 7 , R 8 , R 9 , R 10 and R 11 each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl); R 4 represents an optionally substituted 5 or 6 membered saturated carbocyclic or heterocyclic group or a group which is alkenyl, alkynyl or optionally substituted alkyl, which alkyl group may contain a heteroatom linking group, which alkenyl, alkynyl or alkyl group may carry a terminal optionally substituted group selected from alkyl and a 5 or 6 membered saturated carbocyclic or heterocyclic group, and salts thereof; processes for their preparation, pharmaceutical compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof as active ingredient. The compounds of formula (I) and pharmaceutically acceptable salts thereof inhibit the effects of VEGF, a property of value in the treatment of a number of disease states including cancer and rheumatoid arthritis.

1 - 16 . (canceled)  
     
     
         17 . A method for producing an anti-cancer effect in a warm-blooded animal in need of such treatment which comprises administering to said animal an effective amount of a quinazoline derivative of formula I:  
       
         
           
           
               
               
           
         
       
       wherein: 
 m is an integer from 1 to 2;  
 R 1  represents hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, or —NR 5 R 6  (wherein R 5  and R 6 , which may be the same or different, each represents hydrogen or C 1-3 alkyl);  
 R 2  represents hydrogen, hydroxy, halogeno, methoxy, amino or nitro;  
 R 3  represents hydroxy, halogeno, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkanoyloxy, trifluoromethyl, cyano, amino or nitro;  
 X 1  represents —O—;  
 R 4  is selected from one of the following twelve groups: 
 1) C 1-5 alkylR 12  (wherein R 12  is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group is linked to C 1-5 alkyl through a carbon atom and which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, carbamoyl, C 1-4 alkylcarbamoyl, N,N-di(C 1-4 alkyl)carbamoyl, C 1-4 alkanoyl and C 1-4 alkoxycarbonyl) or C 1-5 alkylR 13  (wherein R 13  is a group selected from pyrrolidin-1-yl, imidazolidin-1-yl and thiomorpholino, which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, carbamoyl, C 1-4 alkylcarbamoyl, N,N-di(C 1-4 alkyl)carbamoyl, C 1-4 alkanoyl and C 1-4 alkoxycarbonyl);  
 2) C 2-5 alkenylR 14  (wherein R 14  is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, carbamoyl, C 1-4 alkylcarbamoyl, N,N-di(C 1-4 alkyl)carbamoyl, C 1-4 alkanoyl and C 1-4 alkoxycarbonyl);  
 3) C 2-5 alkynylR 15  (wherein R 15  is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, carbamoyl, C 1-4 alkylcarbamoyl, N,N-di(C 1-4 alkyl)carbamoyl, C 1-4 alkanoyl and C 1-4 alkoxycarbonyl);  
 4) C 1-5 alkylX 2 C 1-5 alkylX 3 R 16  (wherein X 2  and X 3  which may be the same or different are each —O—, —S—, —SO—, —SO 2 —, —NR 17 CO—, —CONR 18 —, —SO 2 NR 19 —, —NR 20 SO 2 — or —NR 21 — (wherein R 17 , R 18 , R 19 , R 20  and R 21  each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 16  represents hydrogen or C 1-3 alkyl) with the proviso that X 1  cannot be —CH 2 — when R 4  is C 1-5 alkylX 2 C 1-5 alkylX 3 R 16 ;  
 5) C 1-5 alkylX 4 COR 22  (wherein X 4  represents —O— or —NR 23 — (wherein R 23  represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 22  represents —NR 24 R 25  or —OR 26  (wherein R 24 , R 25  and R 26  which may be the same or different each represents hydrogen, C 1-4 alkyl or C 1-3 alkoxyC 2-3 alkyl));  
 6) C 1-5 alkylX 5 R 27  (wherein X 5  represents —O—, —S—, —SO—, —SO 2 —, —OCO—, —NR 28 CO—, —CONR 29 , —SO 2 R 30 —, —NR 31 SO 2 — or —NR 32 — (wherein R 28 , R 29 , R 30 , R 31  and R 32  each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) or X 5  is carbonyl, and R 27  represents cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which cyclopentyl, cyclohexyl or heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, carbamoyl, C 1-4 alkylcarbamoyl, N,N-di(C 1-4 alkyl)carbamoyl, C 1-4 alkanoyl and C 1-4 alkoxycarbonyl or R 27  is C 1-3 alkyl with the proviso that when R 27  is C 1-3 alkyl, X 5  is —S—, —SO—, —SO 2 —, —SO 2 NR 30 — or —NR 31 SO 2 — and X 1  is not —CH 2 —);  
 7) C 1-3 alkoxyC 2-4 alkyl provided that X 1  is —S—, —SO— or —SO 2 —;  
 8) C 1-5 alkylX 6 C 1-5 alkylR 33  (wherein X 6  represents —O—, —S—, —SO—, —SO 2 —, —NR 34 CO—, —CONR 35 —, —SO 2 NR 36 —, —NR 37 SO 2 — or —NR 38 — (wherein R 34 , R 35 , R 36 , R 37  and R 38  each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 33  represents cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which cyclopentyl, cyclohexyl or heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, carbamoyl, C 1-4 alkylcarbamoyl, N,N-di(C 1-4 alkyl)carbamoyl, C 1-4 alkanoyl and C 1-4 alkoxycarbonyl);  
 9) R 39  (wherein R 39  is a group selected from pyrrolidin-3-yl, piperidin-3-yl and piperidin-4-yl which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, carbamoyl, C 1-4 alkylcarbamoyl, N,N-di(C 1-4 alkyl)carbamoyl, C 1-4 alkanoyl and C 1-4 alkoxycarbonyl);  
 10) C 1-5 alkylR 40  (wherein R 40  is piperazin-1-yl which bears at least one substituent selected from C 1-4 alkanoyl, C 1-4 alkoxycarbonyl, C 1-4 hydroxyalkyl and —CONR 41 R 42  (wherein R 41  and R 42  each independently represents hydrogen or C 1-4 alkyl);  
 11) C 1-5 alkylR 43  (wherein R 43  is morpholino which may bear one or two substituents selected from oxo, C 1-4 alkyl, C 1-4 hydroxyalkyl, carbamoyl, C 1-4 alkylcarbamoyl, N,N-di(C 1-4 alkyl)carbamoyl, C 1-4 alkanoyl and C 1-4 alkoxycarbonyl) with the proviso that when R 4  is C 1-5 alkylR 43 , X 1  is —S—, —SO—, —SO 2 —, —SO 2 NR 9 — or —NR 10 SO 2 —; and  
 12) C 1-5 alkylR 44  (wherein R 44  is morpholino which bears at least one and optionally two substituents selected from oxo, C 1-4 alkyl, C 1-4 hydroxyalkyl, carbamoyl, C 1-4 alkylcarbamoyl, N,N-di(C 1-4 alkyl)carbamoyl, C 1-4 alkanoyl and C 1-4 alkoxycarbonyl);  
 or a pharmaceutically acceptable salt thereof.  
 
 
     
     
         18 . A method for inhibiting the effects of VEGF in a warm-blooded animal in need of such treatment which comprises administering to said animal an effective inhibiting amount of a quinazoline derivative of formula I:  
       
         
           
           
               
               
           
         
       
       wherein: 
 m is an integer from 1 to 2;  
 R 1  represents hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, or —NR R (wherein R 5  and R 6 , which may be the same or different, each represents hydrogen or C 1-3 alkyl);  
 R 2  represents hydrogen, hydroxy, halogeno, methoxy, amino or nitro;  
 R 3  represents hydroxy, halogeno, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkanoyloxy, trifluoromethyl, cyano, amino or nitro;  
 X 1  represents —O—;  
 R 4  is selected from one of the following twelve groups: 
 1) C 1-5 alkylR 12  (wherein R 12  is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group is linked to C 1-5 alkyl through a carbon atom and which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, carbamoyl, C 1-4 alkylcarbamoyl, N,N-di(C 1-4 alkyl)carbamoyl, C 1-4 alkanoyl and C 1-4 alkoxycarbonyl) or C 1-5 alkylR 3  (wherein R 13  is a group selected from pyrrolidin-1-yl, imidazolidin-1-yl and thiomorpholino, which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, carbamoyl, C 1-4 alkylcarbamoyl, N,N-di(C 1-4 alkyl)carbamoyl, C 1-4 alkanoyl and C 1-4 alkoxycarbonyl);  
 2) C 2-5 alkenylR 14  (wherein R 14  is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, carbamoyl, C 1-4 alkylcarbamoyl, N,N-di(C 1-4 alkyl)carbamoyl, C 1-4 alkanoyl and C 1-4 alkoxycarbonyl);  
 3) C 2-5 alkynylR 15  (wherein R 15  is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, carbamoyl, C 1-4 alkylcarbamoyl, N,N-di(C 1-4 alkyl)carbamoyl, C 1-4 alkanoyl and C 1-4 alkoxycarbonyl);  
 4) C 1-5 alkylX 2 C 1-5 alkylX 3 R 16  (wherein X 2  and X 3  which may be the same or different are each —O—, —S—, —SO—, —SO 2 —, —NR 17 CO—, —CONR 18 —, —SO 2 NR 19 —, —NR 2 SO 2 — or —NR 21 — (wherein R 17 , R 18 , R 19 , R 20  and R 21  each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 16  represents hydrogen or C 1-3 alkyl) with the proviso that X 1  cannot be —CH 2 — when R 4  is C 1-5 alkylX 2 C 1-5 alkylX 3 R 16 ;  
 5) C 1-5 alkylX 4 COR 22  (wherein X 4  represents —O— or —NR 23 — (wherein R 23  represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 22  represents —NR 24 R 25  or —OR 26  (wherein R 24 , R 25  and R 26  which may be the same or different each represents hydrogen, C 1-4 alkyl or C 1-3 alkoxyC 2-3 alkyl));  
 6) C 1-5 alkylX 5 R 27  (wherein X 5  represents —O—, —S—, —SO—, —SO 2 —, —OCO—, —NR 28 CO—, —CONR 29 —, —SO 2 NR 30 —, —NR 31 SO 2 — or —NR 32 — (wherein R 28 , R 29 , R 30 , R 31  and R 32  each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) or X 5  is carbonyl, and R 27  represents cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which cyclopentyl, cyclohexyl or heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, carbamoyl, C 1-4 alkylcarbamoyl, N,N-di(C 1-4 alkyl)carbamoyl, C 1-4 alkanoyl and C 1-4 alkoxycarbonyl or R 27  is C 1-3 alkyl with the proviso that when R 27  is C 1-3 alkyl, X 5  is —S—, —SO—, —SO 2 —, —SO 2 NR 30 — or —NR 31 SO 2 — and X 1  is not —CH 2 —);  
 7) C 1-3 alkoxyC 2-4 alkyl provided that X 1  is —S—, —SO— or —SO 2 —;  
 8) C 1-5 alkylX 6 C 1-5 alkylR 33  (wherein X 6  represents —O—, —S—, —SO—, —SO 2 —, —NR 34 CO—, CONR 35 —, —SO 2 NR 6 , NR 37 SO 2 — or —NR 38 — (wherein R 34 , R 35 , R 36 , R 37  and R 38  each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 33  represents cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which cyclopentyl, cyclohexyl or heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, carbamoyl, C 1-4 alkylcarbamoyl, N,N-di(C 1-4 alkyl)carbamoyl, C 1-4 alkanoyl and C 1-4 alkoxycarbonyl); 
 9) R 39  (wherein R 39  is a group selected from pyrrolidin-3-yl, piperidin-3-yl and piperidin-4-yl which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, carbamoyl, C 1-4 alkylcarbamoyl, N,N-di(C 1-4 alkyl)carbamoyl, C 1-4 alkanoyl and C 1-4 alkoxycarbonyl);  
 
 10) C 1-5 alkyl 40  (wherein R 40  is piperazin-1-yl which bears at least one substituent selected from C 1-4 alkanoyl, C 1-4 alkoxycarbonyl, C 1-4 hydroxyalkyl and —CONR 41 R 42  (wherein R 41  and R 42  each independently represents hydrogen or C 1-4 alkyl);  
 11) C 1-5 alkylR 43  (wherein R 43  is morpholino which may bear one or two substituents selected from oxo, C 1-4 alkyl, C 1-4 hydroxyalkyl, carbamoyl, C 1-4 alkylcarbamoyl, N,N-di(C 1-4 alkyl)carbamoyl, C 1-4 alkanoyl and C 1-4 alkoxycarbonyl) with the proviso that when R 4  is C 1-5 alkylR 43 , X 1  is —S—, —SO—, —SO 2 —, —SO 2 NR 9 — or —NR 10 SO 2 —; and  
 12) C 1-5 alkylR 44  (wherein R 44  is morpholino which bears at least one and optionally two substituents selected from oxo, C 1-4 alkyl, C 1-4 hydroxyalkyl, carbamoyl, C 1-4 alkylcarbamoyl, N,N-di(C 1-4 alkyl)carbamoyl, C 1-4 alkanoyl and C 1-4 alkoxycarbonyl);  
 or a pharmaceutically salt thereof.  
 
 
     
     
         19 . A method for inhibiting the effects of VEGF and EGF in a warm-blooded animal in need of such treatment which comprises administering to said animal an effective inhibiting amount of a quinazoline derivative of formula I as claimed in  claim 18  or a pharmaceutically acceptable salt thereof.  
     
     
         20 . A method for inhibiting the growth of a solid tumour of the colon, breast, prostate, lung or skin in a warm-blooded animal in need of such treatment which comprises administering to said animal an effective inhibiting amount of a quinazoline derivative of formula I:  
       
         
           
           
               
               
           
         
       
       wherein: 
 m is an integer from 1 to 2;  
 R 1  represents hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, or —NR 5 R 6  (wherein R 5  and R 6 , which may be the same or different, each represents hydrogen or C 1-3 alkyl);  
 R 2  represents hydrogen, hydroxy, halogeno, methoxy, amino or nitro;  
 R 3  represents hydroxy, halogeno, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkanoyloxy, trifluoromethyl, cyano, amino or nitro;  
 X 1  represents —O—;  
 R 4  is selected from one of the following twelve groups: 
 1) C 1-5 alkylR 12  (wherein R 12  is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group is linked to C 1-5 alkyl through a carbon atom and which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, carbamoyl, C 1-4 alkylcarbamoyl, N,N-di(C 1-4 alkyl)carbamoyl, C 1-4 alkanoyl and C 1-4 alkoxycarbonyl) or C 1-5 alkylR 13  (wherein R 13  is a group selected from pyrrolidin-1-yl, imidazolidin-1-yl and thiomorpholino, which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, carbamoyl, C 1-4 alkylcarbamoyl, N,N-di(C 1-4 alkyl)carbamoyl, C 1-4 alkanoyl and C 1-4 alkoxycarbonyl);  
 2) C 2-5 alkenylR 14  (wherein R 14  is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, carbamoyl, C 1-4 alkylcarbamoyl, N,N-di(C 1-4 alkyl)carbamoyl, C 1-4 alkanoyl and C 1-4 alkoxycarbonyl);  
 3) C 2-5 alkynylR 15  (wherein R 15  is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, carbamoyl, C 1-4 alkylcarbamoyl, N,N-di(C 1-4 alkyl)carbamoyl, C 1-4 alkanoyl and C 1-4 alkoxycarbonyl);  
 4) C 1-5 alkylX 2 C 1-5 alkylX 3 R 16  (wherein X 2  and X 3  which may be the same or different are each —O—, —S—, —SO—, —SO 2 —, —NR 17 CO—, —CONR 18 —, —SO 2 NR 19 —, —NR 2 SO 2 — or —NR 21 — (wherein R 17 , R 18 , R 19 , R 20  and R 21  each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 16  represents hydrogen or C 1-3 alkyl) with the proviso that X 1  cannot be —CH 2 — when R 4  is C 1-5 alkylX 2 C 1-5 alkylX 3 R 16 ;  
 5) C 1-5 alkylX 4 COR 22  (wherein X 4  represents —O— or —NR 23 — (wherein R 23  represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 22  represents —NR 24 R 25  or —OR 26  (wherein R 24 , R 25  and R 26  which may be the same or different each represents hydrogen, C 1-4 alkyl or C 1-3 alkoxyC 2-3 alkyl));  
 6) C 1-5 alkylX 5 R 27  (wherein X 5  represents —O—, —S—, —SO—, —SO 2 —, —OCO—, —NR 23 CO—, —CONR 21 —, —SO 2 NR 31 , —NR 31 SO 2 — or —NR 32 — (wherein R 28 , R 29 , R 30 , R 31  and R 32  each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) or X 5  is carbonyl, and R 27  represents cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which cyclopentyl, cyclohexyl or heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, carbamoyl, C 1-4 alkylcarbamoyl, N,N-di(C 4 alkyl)carbamoyl, C 1-4 alkanoyl and C 1-4 alkoxycarbonyl or R 27  is C 1-3 alkyl with the proviso that when R 27  is C 1-3 alkyl, X 5  is —S—, —SO—, —SO 2 —, —SO 2 NR 30  or —NR 31 SO 2 — and X 1  is not —CH 2 —);  
 7) C 1-3 alkoxyC 2-4 alkyl provided that X 1  is —S—, —SO— or —SO 2 —;  
 8) C 1-5 alkylX 6 C 1-5 alkylR 33  (wherein X 6  represents —O—, —S—, —SO—, —SO 2 —, —NR 34 CO—, CONR 35 , SO 2 NR 36 —, NR 37 SO 2 — or —NR 38 — (wherein R 34 , R 3 , R 36 , R 37  and R 3  each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 33  represents cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which cyclopentyl, cyclohexyl or heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, carbamoyl, C 1-4 alkylcarbamoyl, N,N-di(C 1-4 alkyl)carbamoyl, C 1-4 alkanoyl and C 1-4 alkoxycarbonyl);  
 9) R 39  (wherein R 39  is a group selected from pyrrolidin-3-yl, piperidin-3-yl and piperidin-4-yl which group may bear one or two substituents selected from oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, carbamoyl, C 1-4 alkylcarbamoyl, N,N-di(C 1-4 alkyl)carbamoyl, C 1-4 alkanoyl and C 1-4 alkoxycarbonyl);  
 10) C 1-5 alkylR 40  (wherein R 40  is piperazin-1-yl which bears at least one substituent selected from C 1-4 alkanoyl, C 1-4 alkoxycarbonyl, C 1-4 hydroxyalkyl and —CONR 41 R 42  (wherein R 41  and R 42  each independently represents hydrogen or C 1-4 alkyl);  
 11) C 1-5 alkylR 43  (wherein R 43  is morpholino which may bear one or two substituents selected from oxo, C 1-4 alkyl, C 1-4 hydroxyalkyl, carbamoyl, C 1-4 alkylcarbamoyl, N,N-di(C 1-4 alkyl)carbamoyl, C 1-4 alkanoyl and C 1-4 alkoxycarbonyl) with the proviso that when R 4  is C 1-5 alkylR 43 , X 1  is —S—, —SO—, —SO 2 —, —SO 2 NR 9 — or —NR 10 SO 2 —; and  
 12) C 1-5 alkylR 44  (wherein R 44  is morpholino which bears at least one and optionally two substituents selected from oxo, C 1-4 alkyl, C 1-4 hydroxyalkyl, carbamoyl, C 1-4 alkylcarbamoyl, N,N-di(C 1-4 alkyl)carbamoyl, C 1-4 alkanoyl and C 1-4 alkoxycarbonyl);  
 or a pharmaceutically acceptable salt thereof.  
 
 
     
     
         21 . The method according to  claim 20  wherein the tumour is of the colon.  
     
     
         22 . The method according to  claim 20  wherein the tumour is of the lung.