Quinazoline derivatives

Abstract

The invention concerns quinazoline derivatives of Formula I: wherein each of R 1 , X 1 , R 2 , R 3 , R 5 , n and m have any of the meanings defined in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use as an antiproliferative agent in the prevention or treatment of tumours which are sensitive to inhibition of EGF and erbB receptor tyrosine kinases.

1 . A method for producing an anti-proliferative effect in a warm-blooded animal in need of such treatment which comprises administering to said animal a quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein
 n is 0, 1, 2 or 3, 
 each R 5  is independently selected from halogeno, cyano, nitro, hydroxy, amino, carboxy, sulfamoyl, trifluoromethyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylsulfamoyl, and N,N-di-[(1-6C)alkyl]sulfamoyl, C(O)NR 6 R 7  where R 6  and R 7  are independently selected from hydrogen, optionally substituted (1-6C)alkyl, optionally substituted (3-8C)cycloalkyl or optionally substituted aryl, or R 6  and R 7  together with the nitrogen to which they are attached form an optionally substituted heterocyclic ring which may contain additional heteroatoms; 
 X 1  is a direct bond or O; 
 R 1  is selected from hydrogen and (1-6C)alkyl, wherein the (1-6C)alkyl group is optionally substituted by one or more substituents, which may be the same or different, selected from hydroxy and halogeno, and/or a substituent selected from amino, nitro, carboxy, cyano, halogeno, (1-6C)alkoxy, hydroxy(1-6C)alkoxy, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, carbamoyl, N-(1-6C)alkylcarbamoyl, N,N di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino, (1-6C)alkoxycarbonyl, sulfamoyl, N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino; 
 m is 0, 1, 2 or 3; 
 R 2  is hydrogen or (1-6C)alkyl; and 
 R 3  is (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl or (1-6C)alkoxy, any of which can be optionally substituted on a carbon atom by a (1-6C)alkoxy, amino, (1-6C)alkylamino, di-(1-6C)alkylamino, or a group S(O) s (1-6C)alkyl where s is 0, 1 or 2, or a saturated 5 or 6 membered heterocyclic ring which optionally contains additional heteroatoms selected from oxygen, sulfur or NR 8  where R 8  is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkylsulfonyl or (1-6C)alkylcarbonyl; 
 
       or R 2  and R 3  together with the nitrogen atom to which they are attached form a saturated 5 or 6 membered heterocyclic ring which optionally contains additional heteroatoms selected from oxygen, S, SO or S(O) 2  or NR 8  where R 8  is as defined above; 
       provided that the quinazoline derivative is not:
 4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(dimethylamino)carbonyl]-piperidin-4-yl-oxy}-7-methoxy-quinazoline; 
 4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yl-oxy}-7-methoxy-quinazoline; 
 4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yl-oxy}-quinazoline; 
 4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(dimethylamino)carbonyl]-piperidin-4-yl-oxy}-quinazoline; 
 4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(diethylamino)carbonyl]-piperidin-4-yl-oxy}-7-methoxy-quinazoline; 
 4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperidin-4-yl-oxy}-7-methoxy-quinazoline; 
 4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(pyrrolidin-1-yl)carbonyl]-piperidin-4-yl-oxy}-7-methoxy-quinazoline; 
 4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(4-methyl-piperazin-1-yl)carbonyl]-piperidin-4-yl-oxy}-7-methoxy-quinazoline; 
 4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yl-oxy}-7-ethoxy-quinazoline; 
 4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yl-oxy}-7-(2-methoxy-ethoxy)-quinazoline; 
 4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yl-oxy}-7-methoxy-quinazoline; 
 4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(ethylamino)carbonyl]-piperidin-4-yl-oxy}-7-methoxy-quinazoline; 
 4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(isopropylamino)carbonyl]-piperidin-4-yl-oxy}-7-methoxy-quinazoline; 
 4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(dimethylamino)carbonylmethyl]-piperidin-4-yl-oxy}-quinazoline; 
 4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(morpholin-4-yl)carbonylmethyl]-piperidin-4-yl-oxy}-quinazoline; 
 4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(dimethylamino)carbonylmethyl]-piperidin-4-yl-oxy}-7-methoxy-quinazoline; 
 4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(morpholin-4-yl)carbonylmethyl]-piperidin-4-yl-oxy}-7-methoxy-quinazoline; 
 4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(methylamino)carbonylmethyl]-piperidin-4-yl-oxy}-7-methoxy-quinazoline; 
 4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(dimethylamino)carbonylmethyl]-piperidin-4-yl-oxy}-7-methoxy-quinazoline; 
 4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(pyrrolidin-1-yl)carbonylmethyl]-piperidin-4-yl-oxy}-7-methoxy-quinazoline; 
 4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(morpholin-4-yl)carbonylmethyl]-piperidin-4-yl-oxy}-7-methoxy-quinazoline; 
 4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(methylamino)carbonyl]-piperidin-4-yl-oxy}-7-methoxy-quinazoline; 
 4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(2-methoxyethyl)amino)carbonyl]-piperidin-4-yl-oxy}-7-methoxy-quinazoline; 
 4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl)amino)carbonyl]-piperidin-4-yl-oxy}-7-methoxy-quinazoline; 
 4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(3-methoxypropyl)amino)carbonyl]-piperidin-4-yl-oxy}-7-methoxy-quinazoline; 
 4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(N-methyl-N-3-methoxypropyl)amino)carbonyl]-piperidin-4-yl-oxy}-7-methoxy-quinazoline; 
 4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(morpholin-4-yl)carbonylethyl]-piperidin-4-yl-oxy}-7-methoxy-quinazoline; or 
 4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(morpholin-4-yl)carbonylpropyl]-piperidin-4-yl-oxy}-7-methoxy-quinazoline; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         2 . The method of  claim 1 , wherein n is 1, 2 or 3. 
     
     
         3 . The method of  claim 1 , wherein each group R 5  is a halogeno group. 
     
     
         4 . The method of  claim 1 , wherein R 5  is a group positioned at an ortho-(2-) position on the benzene ring to which it is attached. 
     
     
         5 . The method of  claim 1 , wherein in the Formula I, the group of sub-formula (i): 
       
         
           
           
               
               
           
         
       
       is a group of sub-formula (ii): 
       
         
           
           
               
               
           
         
       
       wherein (a) one of R 10  or R 12  is hydrogen and the other is halogeno, and R 11  is halogeno, or (b) R 10  is halogeno, R 11  is halogeno and R 12  is selected from hydrogen or halogeno, or (c) R 10  is fluoro, R 11  is chloro, and R 12  is selected hydrogen or fluoro. 
     
     
         6 . The method of  claim 5 , wherein one of R 10  or R 12  is hydrogen and the other is fluoro, and R 11  is chloro. 
     
     
         7 . The method of  claim 5 , wherein R 10  is fluoro, R 11  is chloro, and R 12  is fluoro. 
     
     
         8 . The method of  claim 1 , wherein X 1  is oxygen. 
     
     
         9 . The method of  claim 1 , wherein R 1  is selected from hydrogen, (1-6C)alkyl and (1-6C)alkoxy(1-6C)alkyl, wherein any (1-6C)alkyl group in R 1  optionally bears one or more hydroxy or halogeno substituents 
     
     
         10 . The method of  claim 1 , wherein R 1 —X 1 — is selected from hydrogen, methoxy, ethoxy and 2-methoxyethoxy. 
     
     
         11 . The method of  claim 1  of Formula IA: 
       
         
           
           
               
               
           
         
       
       wherein R 2 , R 3  and m are as defined in  claim 1 , R 10 , R 11  and R 12  are as defined in any one of  claims 10  to  13 , and R 13  is selected from hydrogen, methoxy, ethoxy and 2-methoxyethoxy. 
     
     
         12 . The method of  claim 1  of Formula IB or IC: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein R 2 , R 3  and m are as defined in  claim 1  and R 13  is selected from hydrogen, methoxy, ethoxy and 2-methoxyethoxy. 
     
     
         13 . The method of  claim 1 , wherein m is 0 or 1. 
     
     
         14 . The method of  claim 1 , wherein R 2  is hydrogen or (1-3C)alkyl. 
     
     
         15 . The method of  claim 1 , wherein R 3  is (1-6C)alkyl. 
     
     
         16 . The method of  claim 1 , wherein the quinazoline derivative according to  claim 1 , which is selected from the group consisting of:
 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[1-(N-methylcarbamoylmethyl)piperidin-4-yl]-oxy}quinazoline;   4-(3-chloro-2-fluoroanilino)-6-{[1-(N,N-dimethylcarbamoylmethyl)piperidin-4-yl]oxy}-7-methoxyquinazoline;   4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[1-(morpholin-4-ylcarbonylmethyl)piperidin-4-yl]oxy}-quinazoline;   4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[1-(pyrrolidin-1-ylcarbonyl)piperidin-4-yl]oxy}quinazoline;   4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[1-(N-methylcarbamoyl)piperidin-4-yl]oxy}quinazoline;   4-(3-chloro-2-fluoroanilino)-6-{[1-(N-(2-dimethylaminoethyl)carbamoyl)piperidin-4-yl]oxy}-7-methoxyquinazoline;   4-(3-chloro-2-fluoroanilino)-6-{[1-(N,N-dimethylcarbamoyl)piperidin-4-yl]oxy}7-methoxy-quinazoline;   4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[1-(morpholin-4-ylcarbonyl)piperidin-4-yl ]oxy}quinazoline;   4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[1-(N-[2-pyrrolidin-1-ylethyl]carbamoyl) piperidin-4-yl]oxy}quinazoline;   4-(3-chloro-2,4-difluoroanilino)-7-methoxy-6-{[1-(N-methylcarbamoylmethyl)piperidin-4-yl]oxy}quinazoline;   4-(3-chloro-2-fluoroanilino)-6-{[1-(N-ethylcarbamoylmethyl)piperidin-4-yl]oxy}-7-methoxyquinazoline;   4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[1-(N-[2-(pyrrolidin-1-yl)ethyl]carbamoylmethyl)piperidin-4-yl]oxy}quinazoline;   4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[1-(N-(2-methoxyethyl)carbamoylmethyl)piperidin-4-yl]oxy}quinazoline;   4-(3-chloro-2-fluoroanilino)-6-{[1-(N-(2-dimethylaminoethyl)carbamoylmethyl)piperidin-4-yl]oxy}-7-methoxyquinazoline;   4-(3-chloro-2-fluoroanilino)-7-methoxy-6-({1-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]piperidin-4-yl}oxy)quinazoline;   4-(3-chloro-2-fluoroanilino)-7-methoxy-6-({1-[2-(piperazin-1-yl)-2-oxoethyl]piperidin-4-yl}oxy)quinazoline; and   4-(3-chloro-2,4-difluoroanilino)-7-methoxy-6-({1-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]piperidin-4-yl}oxy)quinazoline; or a pharmaceutically acceptable salt thereof.