Quinazoline derivatives as tyrosine kinase inhibitors

Abstract

The invention concerns quinazoline derivatives of the Formula I: wherein each of R 1 , R 2 , W, X 1 , X 2 , Z, a and b are as defined in the description; processes for their preparation; pharmaceutical compositions containing them and their use in the manufacture of a medicament for providing an anti-proliferative effect. The quinazoline derivatives of Formula I are expected to be useful in the treatment of diseases such as certain cancers mediated by erbB receptor tyrosine kinases, particularly EGFR tyrosine kinase.

1 . A quinazoline derivative of the Formula I: 
     
       
         
         
             
             
         
       
     
     wherein:
 R 1  is selected from hydrogen, hydroxy, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, or from a group of the formula:
   Q 2 -X 3 - 
 
 
     wherein X 3  is a direct bond or is O, and Q 2  is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl,
 and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R 1  substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO 2 , N(R 3 ), CO, CH(OR 3 ), CON(R 3 ), N(R 3 )CO, SO 2 N(R 3 ), N(R 3 )SO 2 , CH═CH and C≡C wherein R 3  is hydrogen or (1-6C)alkyl, 
 and wherein any CH 2 ═CH— or HC≡C— group within a R 1  substituent optionally bears at the terminal CH 2 ═ or HC≡ position a substituent selected from halogeno, carboxy, carbamoyl, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl and di-[(1-6C)alkyl]amino-(1-6C)alkyl or from a group of the formula:
   Q 3 -X 4 - 
 
 
     wherein X 4  is a direct bond or is selected from CO and N(R 4 )CO, wherein R 4  is hydrogen or (1-6C)alkyl, and Q 3  is heterocyclyl or heterocyclyl-(1-6C)alkyl,
 and wherein any CH 2  or CH 3  group within a R 1  substituent, other than a CH 2  group within a heterocyclyl ring, optionally bears on each said CH 2  or CH 3  group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, oxo, thioxo, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, 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, N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, or from a group of the formula:
   -X 5 -Q 4    
 
 
     wherein X 5  is a direct bond or is selected from O, S, SO, SO 2 , N(R 5 ), CO, CH(OR 5 ), CON(R 5 ), N(R 5 )CO, SO 2 N(R 5 ), N(R 5 )SO 2 , C(R 5 ) 2-0 , C(R 5 ) 2 S and C(R 5 ) 2 N(R 5 ), wherein R 5  is hydrogen or (1-6C)alkyl, and Q 4  is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl,
 and wherein any heterocyclyl group within a substituent on R 1  optionally bears one or more substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, formyl, mercapto, sulfamoyl, (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)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino, and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, or from a group of the formula:
   -X 6 -R 6    
 
 
     wherein X 6  is a direct bond or is selected from O, N(R 7 ) and C(O), wherein R 67  is hydrogen or (1-6C)alkyl, and R 6  is halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, carboxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl, (2-6C)alkanoylamino-(1-6C)alkyl, (1-6C)alkoxycarbonylamino-(1-6C)alkyl, carbamoyl-(1-6C)alkyl, N-(1-6C)alkylcarbamoyl-(1-6C)alkyl, N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkyl, (2-6C)alkanoyl-(1-6C)alkyl or (1-6C)alkoxycarbonyl-(1-6C)alkyl,
 and wherein any heterocyclyl group within a substituent on R 1  optionally bears 1 or 2 oxo or thioxo substituents; 
 b is 1, 2, 3, 4 or 5; 
 each R 2 , which may be the same or different, is selected from halogeno, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, 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)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino and a group of the formula:
   -X 7 -R 8    
 
 
     wherein X 7  is a direct bond or is selected from O and N(R 9 ), wherein R 9  is hydrogen or (1-6C)alkyl, and R 8  is halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl, (2-6C)alkanoylamino-(1-6C)alkyl or (1-6C)alkoxycarbonylamino-(1-6C)alkyl;
 Q′ is piperidinyl; 
 a is 0, 1, 2, 3 or 4; 
 each W, which may be the same or different, is selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, oxo, amino, formyl, mercapto, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula:
   -X 8 -R 10    
 
 wherein X 8  is a direct bond or is selected from O, CO, SO 2  and N(R 11 ), wherein R 11  is hydrogen or (1-6C)alkyl, and R 10  is halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, N-(1-6C)alkylamino-(1-6C)alkyl or N,N-di-[(1-6C)alkyl]amino-(1-6C)alkyl; 
 X 1  is selected from CO and SO 2 ; 
 X 2  is a group of the formula:
   —(CR 12 R 13 ) p -(Q 5 ) m -(CR 14 R 15 ) q - 
 
 wherein m is 0 or 1,p is 0, 1, 2, 3 or 4 and q is 0, 1, 2, 3 or 4, 
 each of R 12 , R 13 , R 14  and R 15 , which may be the same or different, is selected from hydrogen, (1-6C)alkyl, amino, (1-6C)alkylamino and di-[(1-6C)alkyl]amino, and Q 5  is selected from (3-7C)cycloalkylene and (3-7C)cycloalkenylene, 
 and wherein any CH 2  or CH 3  group within an X 2  group, optionally bears on each said CH 2  or CH 3  group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, cyano; amino, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino; 
 Z is selected from hydroxy, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxy, (1-6C)alkylsulfonyl, (1-6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino and a group of the formula:
   Q 6 -X 9 - 
 
 wherein X 9  is a direct bond or is selected from O, N(R 16 ), SO 2  and SO 2 N(R 16 ), wherein R 16  is hydrogen or (1-6C)alkyl, and Q 6  is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-4C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-4C)alkyl, heterocyclyl or heterocyclyl-(1-4C)alkyl; 
 provided that when X 9  is a direct bond, Q 6  is heterocyclyl, 
 and provided that when m, p and q are all 0, then Z is heterocyclyl, 
 and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a Z substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO 2 , N(R 17 ), Co, —C≡C— and —C≡C— wherein R 17  is hydrogen or (1-6C)alkyl, 
 and wherein and wherein any CH 2  or CH 3  group within any Z group, other than a CH 2  group within a heterocyclyl ring, optionally bears on each said CH 2  or CH 3  group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, 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, N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, 
 and wherein any heterocyclyl group within a Z substituent optionally bears one or more substitutents which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, mercapto, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula:
   -X 10 -R 18    
 
 wherein X 10  is a direct bond or is selected from O, CO, SO 2  and N(R 19 ), wherein R 19  is hydrogen or (1-4C)alkyl, and R 18  is halogeno-(1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cyano-(1-4C)alkyl, amino-(1-4C)alkyl, N-(1-4C)alkylamino-(1-4C)alkyl and N,N-di-[(1-4C)alkyl]amino-(1-4C)alkyl; provided that: 
 when the 4-anilino group in Formula I is 4-bromo-2-fluoroanilino or 4-chloro-2-fluoroanilino and R 1  is hydrogen or (1-3C)alkoxy, then a is 0 and Z is selected from hydroxy, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxy, (1-6C)alkylsulfonyl, (1-6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, and a group of the formula Q 6 -X 9 -; 
 
     or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof. 
   
   
       2 . A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to  claim 1  wherein:
 R 1  is selected from hydrogen, hydroxy, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, or from a group of the formula:
   Q 2 -X 3 - 
   
     wherein X 3  is a direct bond or is O, and Q 2  is heterocyclyl or heterocyclyl-(1-6C)alkyl,
 and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R 1  substituent are optionally separated by the insertion into the chain of a group selected from O, N(R 3 ), CON(R 3 ), N(R 3 )CO, CH═CH and C≡C wherein R 3  is hydrogen or (1-6C)alkyl, 
 and wherein any CH 2 ═CH— or HC≡C— group within a R 1  substituent optionally bears at the terminal CH 2 ═ or HC≡ position a substituent selected from carbamoyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl and di-[(1-6C)alkyl]amino-(1-6C)alkyl 
 and wherein any CH 2  or CH 3  group within a R 1  substituent, other than a CH 2  group within a heterocyclyl ring, optionally bears on each said CH 2  or CH 3  group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, amino, cyano, carbamoyl, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl and N,N-di-[(1-6C)alkyl]carbamoyl, or from a group of the formula
   -X 5 -Q 4    
 
 
     wherein X 5  is a direct bond or is selected from O, N(R 5 ), CON(R 5 ), N(R 5 )CO and C(R 5 ) 2 O, wherein R 5  is hydrogen or (1-6C)alkyl, and Q 4  is heterocyclyl or heterocyclyl-(1-6C)alkyl,
 and wherein any heterocyclyl group within a substituent on R 1  optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, hydroxy, amino, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, or from a group of the formula:
   X 6 -R 6    
 
 
     wherein X 6  is a direct bond or is selected from O and N(R 7 ), wherein R 7  is hydrogen or (1-6C)alkyl, and R 6  is halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl and di-[(1-6C)alkyl]amino-(1-6C)alkyl,
 and wherein any heterocyclyl group within a substituent on R 1  optionally bears 1 or 12 oxo substituents. 
 
   
   
       3 . A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to  claim 1  wherein:
 R 1  is selected from hydrogen, hydroxy, (1-4C)alkoxy, hydroxy-(2-4C)alkoxy, (1-3C)alkoxy-(2-4C)alkoxy or from a group of the formula:
   Q 2 -X 3 - 
   
     wherein X 3  is O, and Q 2  is azetidin-1-yl-(2-4C)alkyl, pyrrolidin-1-yl-(2-4C)alkyl, piperidino-(2-4C)alkyl, piperazino-(2-4C)alkyl or morpholino-(2-4C)alkyl, and wherein any heterocyclyl group within a substituent on R 1  optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, hydroxy, amino, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylsulfonyl, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, and (2-4C)alkanoyl,
 and wherein any heterocyclyl group within a substituent on R 1  optionally bears 1 oxo substituent. 
 
   
   
       4 . A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to  claim 1  wherein R 1  is (1-3C)alkoxy. 
   
   
       5 . A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to  claim 1  wherein:
 b is 1, 2 or 3; and   each R 2 , which may be the same or different, is selected from fluoro, chloro, bromo, (1-4C)alkyl, (2-4C)alkenyl and (2-4C)alkynyl.   
   
   
       6 . A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to  claim 1  wherein:
 b is 1, 2 or 3 and one R 2  is at the meta (3-) position on the anilino group in Formula I and is halogeno.   
   
   
       7 . A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to  claim 1  wherein the anilino group at the 4-position on the quinazoline ring in the compound of Formula I is selected from 3-chloro-2-bromoanilino, 3-chloro-2-fluoroanilino, 3-ethynylanilino and 3-bromoanilino. 
   
   
       8 . A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to  claim 1  wherein: 
     X 2  is a group of the formula —(CR 12 R 13 ) q —(CR 12aa R 13aa )—, wherein
 q is 1, 2 or 3, 
 each of R 12 , R 13  and R 13aa , which may be the same or different, is selected from hydrogen and (1-6C)alkyl, 
 R 12aa  is selected from amino, (1-6C)alkylamino and di-[(1-6C)alkyl]amino, and wherein any CH 2  or CH 3  group within an X 2  group, optionally bears on each said CH 2  or 
 CH 3  group one or more halogeno substituents, 
 
     and wherein any CH 2  group which is attached to 2 carbon atoms or any CH 3  group which is attached to a carbon atom within a X 2  substituent optionally bears on each said CH 2  or CH 3  group a substituent selected from hydroxy, amino, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino. 
   
   
       9 . A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to  claim 1  wherein: 
     X 2  is a group of the formula —(CR 12 R 13 ) q -, wherein
 q is 1, 2, 3 or 4, 
 each of R 12  and R 13 , which may be the same or different, is selected from hydrogen and (1-6C)alkyl, provided that at least one of the R 12  or R 13  groups in X 2  is (1-6C)alkyl, 
 and wherein any CH 2  or CH 3  group within an X 2  group, optionally bears on each said CH 2  or CH 3  group one or more halogeno substituents, 
 and wherein any CH 2  group which is attached to 2 carbon atoms or any CH 3  group which is attached to a carbon atom within a X 2  substituent optionally bears on each said CH 2  or CH 3  group a substituent selected from hydroxy, and (1-6C)alkoxy. 
 
   
   
       10 . A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to  claim 1  wherein:
 X 2  is selected from a group of the formula —CH 2 —, —CH 2 CH 2 —, —(CHR 12a )-, —(CHR 12a CH 2 )—, —(C(R 12a ) 2 CH 2 )—, —(CH 2 C(R 12a ) 2 )- and —(CH 2 CHR 12a )—,   wherein each R 12a , which may be the same or different, is (1-4C)alkyl.   
   
   
       11 . A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to  claim 1  wherein:
 Z is selected from hydroxy, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxy, hydroxy-(2-6C)alkoxy, (1-4C)alkoxy-(2-6C)alkoxy and a group of the formula:
   Q 6 -X 9 - 
   wherein X 9  is a direct bond and Q 6  is heterocyclyl,   and provided that when m, p and q are all 0, then Z is heterocyclyl linked to X 1  by a ring carbon atom,   and wherein any heterocyclyl group in Z is selected from azetidinyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl, oxepanyl, pyrrolidinyl, morpholinyl, piperidinyl, homopiperidinyl, piperazinyl and homopiperazinyl,   and wherein and wherein any CH 2  or CH 3  group within a Z group, other than a CH 2  group within a heterocyclyl ring, optionally bears on each said CH 2  or CH 3  group one or more halogeno or (1-4C)alkyl substituents or a substituent selected from hydroxy and (1-4C)alkoxy,   and wherein any heterocyclyl group within a Z substituent optionally bears one or more substitutents which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylsulfonyl, (1-4C)alkylamino, di-[(1-4C)alkyl]amino and (2-4C)alkanoyl.   
   
   
       12 . A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to  claim 1  wherein:
 Z is hydroxy or (1-4C)alkoxy; and   the sum of m+p+q is at least 1.   
   
   
       13 . A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to  claim 1  wherein:
 X 2  is selected from a group of the formula —CH 2 —, —CH 2 CH 2 —, —(CHR 12a )-, —(CHR 12a CH 2 )—, —(C(R 12a ) 2 CH 2 )—, —(CH 2 C(R 12a ) 2 )- and —(CH 2 CHR 12a )—,   wherein each R 12a , which may be the same or different, is (1-4C)alkyl; and   Z is hydroxy or (1-4C)alkoxy.   
   
   
       14 . A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to  claim 1  wherein:
 Q 1  is piperidin-4-yl;   a is 0 or 1; and   W is selected from halogeno, hydroxy, (1-3C)alkyl and (1-3C)alkoxy.   
   
   
       15 . A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to  claim 1  wherein X 1  is CO. 
   
   
       16 . A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to  claim 1  wherein:
 R 1  is selected from hydrogen, (1-6C)alkoxy, cyclopropyl-(1-4C)alkoxy, cyclobutyl-(1-4C)alkoxy, cyclopentyl-(1-4C)alkoxy, cyclohexyl-(1-6C)alkoxy, tetrahydrofuranyl-(1-4C)alkoxy and tetrahydropyranyl-(1-4C)alkoxy,   and wherein any CH 2  or CH 3  group within a R 1  substituent optionally bears on each said CH 2  or CH 3  group one or more halogeno substituents, or a substituent selected from hydroxy and (1-4C)alkoxy;   b is 1, 2 or 3;   each R 2 , which may be the same or different, is selected from halogeno, cyano, hydroxy, trifluoromethyl, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl and (1-4C)alkoxy;   Q 1  is piperidin-4-yl;   a is 0, 1 or 2;   each W, which may be the same or different, is selected from halogeno, trifluoromethyl, hydroxy, oxo, (1-6C)alkyl, (1-6C)alkoxy, and from a group of the formula:
   -X 8 -R 10    
   wherein X 8  is a direct bond or is O, and R 10  is halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl or (1-6C)alkoxy-(1-6C)alkyl;   X 1  is CO;   X 2  is a group selected from (3-6C)cycloalkylene, —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —(CR 12 R 13 ), —(CR 12 R 13 CH 2 )— and —(CH 2 CR 12 R 13  )-,   wherein each of R 12  and R 13 , which may be the same or different, is selected from hydrogen, (1-4C)alkyl, hydroxy-(1-4C)alkyl, and (1-3C)alkoxy-(1-4C)alkyl, provided that R 12  and R 13  are not both hydrogen,   and wherein any CH 2  group within a (3-6C)cycloalkylene group in X 2 , optionally bears on each said CH 2  or group one or more (1-4C)alkyl substituents or a substituent selected from hydroxy, (1-4C)alkoxy, hydroxy-(1-4C)alkyl, and (1-3C)alkoxy-(1-4C)alkyl; and   Z is selected from hydroxy and (1-4C)alkoxy;   
     provided that:
 when the 4-anilino group in Formula I is 4-bromo-2-fluoroanilino or 4-chloro-2-fluoroanilino, R 1  is hydrogen or (1-3C)alkoxy, and X 1  is CO, then a is 0. 
 
   
   
       17 . A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to  claim 1  wherein:
 the 4-anilino group on the quinazoline ring in Formula I is selected from 3-chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, 3-bromoanilino and 3-ethynylanilino;   R 1  is selected from (1-4C)alkoxy, hydroxy-(2-4C)alkoxy, (1-3C)alkoxy-(2-4C)alkoxy or from a group of the formula:
   Q 2 -X 3 - 
   wherein X 3  is O, and Q 2  is azetidin-1-yl-(2-4C)alkyl, pyrrolidin-1-yl-(2-4C)alkyl, piperidino-(2-4C)alkyl, piperazino-(2-4C)alkyl or morpholino-(2-4C)alkyl, and wherein any heterocyclyl group within a substituent on R 1  optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, hydroxy, amino, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino and di-[(1-4C)alkyl]amino;   Z is hydroxy or (1-4C)alkoxy;   Q 1  is piperidin-4-yl;   a is 0 or 1;   each W, which may be the same or different is selected from hydroxy, (1-3C)alkyl and (1-3C)alkoxy;   X 1  is CO;   X 2  is selected from a group of the formula —(CHR 12 a)- and —(CH 2 CHR 12b )—,   wherein R 12a  is (1-4C)alkyl,   and wherein R 12b  is selected from amino, (1-4C)alkylamino and di-[(1-4C)alkyl]-amino.   
   
   
       18 . A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to  claim 1  of the Formula Id: 
     
       
         
         
             
             
         
       
       wherein: 
       R 1b  is (1-4C)alkoxy, 
       and wherein any CH 2  or CH 3  group within a R 1b  substituent optionally bears on each said CH 2  or CH 3  group one or more halogeno substituents, or any CH 2  or CH 3  group within a R 1  which is not attached to an oxygen atom optionally bears on each said CH 2  or CH 3  group a substituent selected from hydroxy and (1-3C)alkoxy; 
       X 2b  is selected from a group of the formula —CH 2 —, —CH 2 CH 2 —, —(CHR 12 )—, —(CHR 12 CH 2 )— and —(CH 2 CHR 12 )— 
       wherein R 12  is selected from (1-3C)alkyl, hydroxy-(1-3C)alkyl and (1-3C)alkoxy-(1-3C)alkyl; and 
       Z 2  is selected from hydroxy, (1-3C)alkoxy, hydroxy-(2-3C)alkoxy, (1-3C)alkoxy-(2-3C)alkoxy, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 1,3-dioxolanyl, tetrahydropyranyl and 1,4-dioxanyl; 
       and wherein any heterocyclyl group within Z 2 -X 2b  optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, (1-3C)alkyl, (1-3C)alkoxy and (2-3C)alkanoyl; 
     
     or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof. 
   
   
       19 . A quinazoline derivative according to  claim 18 , or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, wherein Z 2  is hydroxy and R 12  is (1-3C)alkyl; 
   
   
       20 . A quinazoline derivative according to  claim 18 , or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, wherein: R 1b  is (1-3C)alkoxy; and 
     the group Z 2 -X 2b - is selected from hydroxymethyl, methoxymethyl, (S)-1-hydroxyethyl, (R)-1-hydroxyethyl, (S)-1-methoxyethyl and (R)-1-methoxyethyl. 
   
   
       21 . A quinazoline derivative of the Formula I according to  claim 1  selected from: 
     N-(3-chloro-2-fluorophenyl)-7-({1-[(dimethylamino)acetyl]piperidin-4-yl}oxy)-6-methoxyquinazolin-4-amine; 
     N-(3-chloro-2-fluorophenyl)-6-methoxy-7-({1-[(2-methoxyethoxy)acetyl]piperidin-4-yl}oxy)quinazolin-4-amine; 
     N-(3-chloro-2-fluorophenyl)-6-methoxy-7-{[1-(methoxyacetyl)piperidin-4-yl]oxy}quinazolin-4-amine; 
     2-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-2-oxoethanol; 
     N-(3-chloro-2-fluorophenyl)-7-{[1-(ethoxyacetyl)piperidin-4-yl]oxy}-6-methoxyquinazolin-4-amine; 
     N-(3-chloro-2-fluorophenyl)-6-methoxy-7-{[1-(3-methoxypropanoyl)piperidin-4-yl]oxy}quinazolin-4-amine; 
     3-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-3-oxopropan-1-ol; 
     (2S)-1-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol; 
     (2S,3S)-1-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-3-methyl-1-oxopentan-2-ol; 
     4-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-2-methyl-4-oxobutan-2-ol; 
     N-(3-chloro-2-fluorophenyl)-6-methoxy-7-{[1-(tetrahydrofuran-2-ylcarbonyl)piperidin-4-yl]oxy}quinazolin-4-amine; 
     3-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-2,2-dimethyl-3-oxopropan-1-ol; 
     (3R,5S)-1-acetyl-5-{[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]carbonyl}pyrrolidin-3-ol; and 
     N-(3-chloro-2-fluorophenyl)-6-methoxy-7-({1-[(4-methylpiperazin-1-yl)acetyl]piperidin-4-yl}oxy)quinazolin-4-amine; 
     and pharmaceutically acceptable salts, and pharmaceutically acceptable esters thereof. 
   
   
       22 . A quinazoline derivative of the Formula I according to  claim 1  selected from: 
     N-(3-Chloro-2-fluorophenyl)-6-methoxy-7-{[1-(methoxyacetyl)piperidin-4-yl]oxy}quinazolin-4-amine; 
     2-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-2-oxoethanol; 
     N-(3-chloro-2-fluorophenyl)-7-{[1-(ethoxyacetyl)piperidin-4-yl]oxy}-6-methoxyquinazolin-4-amine; 
     (2S)-1-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol; 
     3-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-2,2-dimethyl-3-oxopropan-1-ol; 
     (2S)-1-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-3,3-dimethyl-1-oxobutan-2-ol; 
     N-(3-chloro-2-fluorophenyl)-6-methoxy-7-{[1-(1-methyl-L-prolyl)piperidin-4-yl]oxy}quinazolin-4-amine; 
     N-(3-chloro-2-fluorophenyl)-6-methoxy-7-({1-[(2S)-tetrahydrofuran-2-ylcarbonyl]piperidin-4-yl}oxy)quinazolin-4-amine; 
     (2R)-1-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol; 
     N-(3-chloro-2-fluorophenyl)-6-methoxy-7-({1-[(2S)-2-methoxypropanoyl]piperidin-4-yl}oxy)quinazolin-4-amine; 
     N-(3-chloro-2-fluorophenyl)-6-methoxy-7-({1-[(2R)-2-methoxypropanoyl]piperidin-4-yl}oxy)quinazolin-4-amine; 
     (2R)-3-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-2-(dimethylamino)-3-oxopropan-1-ol; 
     (2S)-1-[4-({4-[(3-chloro-4-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol; 
     (2S)-1-[4-({4-[3-bromoanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol; 
     (2S)-1-[4-({4-[3-bromo-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol; 
     (2R)-1-[4-({4-[3-bromo-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol; and 
     (2R)-1-[4-({4-[3-bromoanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol; 
     and pharmaceutically acceptable-salts, and pharmaceutically acceptable esters thereof. 
   
   
       23 . A quinazoline derivative of the Formula I according to  claim 1 , or a pharmaceutically acceptable salt thereof. 
   
   
       24 . A pharmaceutical composition which comprises a quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to  claim 1 , in association with a pharmaceutically acceptable diluent or carrier. 
   
   
       25 - 29 . (canceled) 
   
   
       30 . A method for producing an anti-proliferative 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 the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, as defined in  claim 1 . 
   
   
       31 . A method for the prevention or treatment of those tumours in a warm-blooded animal which are sensitive to inhibition of EGFR tyrosine kinases, that are involved in the signal transduction steps which lead to the proliferation and/or survival of tumour cells which comprises administering to said animal an effective amount of a quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, as defined in  claim 1 . 
   
   
       32 . A method for providing a selective EGFR tyrosine kinase inhibitory effect in a warm-blooded animal which comprises administering to said animal an effective amount of a quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, as defined in  claim 1 . 
   
   
       33 . A method for treating a cancer in a warm-blooded animal, in need of such treatment, which comprises administering to said animal an effective amount of a quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, as defined in  claim 1 . 
   
   
       34 . A process for the preparation of a quinazoline derivative of the Formula I as defined in  claim 1  which comprises: 
     Process (a):
 for the preparation of compounds of the Formula I wherein X 1  is CO, the coupling of a quinazoline of the formula II or a salt thereof: 
 
     
       
         
         
             
             
         
       
       wherein R 1 , R 2 , W, a, b and Q 1  are as defined in  claim 1  except that any functional group is optionally protected with an acid of the formula III, or a reactive derivative thereof:
   Z-X 2 —COOH  III 
 
       wherein Z and X 2  are as defined in  claim 1 , except that any functional group is optionally protected; 
     
     or 
     Process (b) the reaction of a quinazoline of the formula II or a salt thereof, as defined in relation to Process (a), with a compound of the formula IV:
   Z-X 2 -X 1 -L 1   IV 
 wherein L 1  is a displaceable group and Z, X 1  and X 2  are as defined in  claim 1 , except that any functional group is optionally protected; 
 
     or 
     Process (c) for the preparation of those quinazoline derivatives of the Formula I wherein Z is linked to X 2  by nitrogen, the reaction of a compound of the formula V: 
     
       
         
         
             
             
         
       
       wherein L 2  is a displaceable group and R 1 , R 2 , W, X 1 , X 2 , a, b and Q 1  are as defined in  claim 1 , except that any functional group is optionally protected, with a compound of the formula ZH, wherein Z is as hereinbefore defined, except that any functional group is optionally protected; or 
     
     Process (d)
 for the preparation of those quinazoline derivatives which carry a mono- or di-(1-6C)alkylamino group, the reductive amination of the corresponding quinazoline derivative of the Formula I which contains an N—H group using formaldehyde or a (2-6C)alkanolaldehyde; 
 
     or 
     Process (e)
 for the preparation of those quinazoline derivatives of the Formula I wherein R 1  is hydroxy, the cleavage of a quinazoline derivative of the Formula I wherein R 1  is a (1-6C)alkoxy group; or 
 
     Process (f)
 for the preparation of those quinazoline derivatives of the Formula I wherein R 1  is linked to the quinazoline ring by an oxygen atom, by coupling a compound of the Formula 
 
     VI: 
     
       
         
         
             
             
         
       
       wherein R 2 , W, X 1 , X 2 , Z, a, b and are as defined in  claim 1  except that any functional group is optionally protected with a compound of the formula R 1′ OH, wherein the group R 1′ O is one of the oxygen linked groups as defined for R 1  in  claim 1 , except that any functional group is optionally protected; 
       and thereafter, optionally (in any order): 
     
     (i) converting a quinazoline derivative of the Formula I into another quinazoline derivative of the Formula I; 
     (ii) removing any protecting group that is present; and 
     (iii) forming a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester of the quinazoline derivative of the Formula I. 
   
   
       35 . A quinazoline derivative of the Formula II: 
     
       
         
         
             
             
         
       
     
     wherein:
 R 1  is selected from hydrogen, hydroxy, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, or from a group of the formula:
   Q 2 -X 3 - 
 
 
     wherein X 3  is a direct bond or is O, and Q 2  is (3-7C)cycloalkyl, (3-7C)-cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-6C)alkyl, heterocyclyl or heterocycyl-(1-6C)alkyl,
 and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R 1  substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO 2 , N(R 3 ), CO, CH(OR 3 ), CON(R 3 ), N(R 3 )CO, SO 2 N(R 3 ), N(R 3 )SO 2 , CH═CH and C≡C wherein R 3  is hydrogen or (1-6C)alkyl, 
 and wherein any CH 2 ═CH— or HC≡C— group within a R 1  substituent optionally bears at the terminal CH 2 ═ or HC≡ position a substituent selected from halogeno, carboxy, carbamoyl, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, amino-(1-6C)alkyl. (1-6C)alkylamino-(1-6C)alkyl and di-[(1-6C)alkyl]amino-(1-6C)alkyl or from, a group of the formula:
   Q 3 -X 4 - 
 
 
     wherein X 4  is a direct bond or is selected from CO and N(R 4 )CO, wherein R 4  is hydrogen or (1-6C)alkyl, and Q 3  is heterocycyl or heterocyclyl-(1-6C)alkyl,
 and wherein any CH 2  or CH 3  group within a R 1  substituent, other than a CH 2  group within a heterocyclyl ring, optionally bears on each said CH 2  or CH 3  group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino carboxy, carbamoyl, sulfamoyl, oxo, thioxo, (1-6C)alkoxy(1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]carbamoyl, (1-6C)alkoxycarbonyl, 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, N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkalesulfonylamino, or from a group of the formula:
   -X 5 -Q 4    
 
 
     wherein X 5  is a direct bond or is selected from O, S, SO, N(R 5 ), CO, CH(OR 5 ), CON(R 5 ), N(R 5 )CO, SO 2 N(R 5 ), N(R 5 )SO 2 , C(R 5 ) 2 O, C(R 5 ) 2 S and C(R 5 ) 2 N(R 5 ), wherein R 5  is hydrogen or (1-6C)alkyl and Q 4  is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl,
 and wherein any heterocyclyl group within a substituent on R 1  optionally bears one or more substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, formyl, mercapto, sulfamoyl, (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)alkylcarbamoyl. N,N-di-[(1-6C)alkyl]carbamoyl, N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino. N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino, and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, or from a group of the formula:
   -X 6 -R 6    
 
 
     wherein X 6  is a direct bond or is selected from O, N(R 7 ) and C(O), wherein R 7  is hydrogen or (1-6C)alkyl, and R 6  is halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, carboxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl, (2-6C)alkanoylamino-(1-6C)alkyl, (1-6C)alkoxycarbonylamino-(1-6C)alkyl, carbamoyl-(1-6C)alkyl, N-(1-6C)alkylcarbamoyl-(1-6C)alkyl N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkyl, (2-6C)alkanoyl-(1-6C)alkyl or (1-6C)alkoxycarbonyl-(1-6C)alkyl,
 and wherein any heterocyclyl group within a substituent on R 1  optionally bears 1 or 2 oxo or thioxo substituents; 
 Q 1  is piperidinyl; 
 a is 0, 1, 2, 3 or 4; 
 each W, which may be the same or different, is selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, oxo, amino, formyl, mercapto, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylthio. (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula:
   -X 8 -R 10    
 
 wherein X 8  is a direct bond or is selected from O, CO, SO 2  and N(R 11 ) wherein R 11  is hydrogen or (1-6C)alkyl, and R 10  is halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl. N-(1-6C)alkylamino-(1-6C)alkyl or N,N-di-[(1-6C)alkyl]amino-(1-6C)alkyl; 
 
     R 2c  and R 2d , which may be the same or different are halogeno; 
     or a salt thereof. 
   
   
       36 . The method according to  claim 33  wherein said cancer is selected from lung cancer, non-small cell lung cancer, breast cancer, head and neck cancer, gastric cancer, colorectal cancer and ovarian cancer. 
   
   
       37 . A method for treating psoriasis in a warm-blooded animal in need of such treatment, which comprises administering to said animal an effective amount of a quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, as defined in  claim 1 .