Quinazoline derivatives

Abstract

The invention concerns quinazoline derivatives of Formula I wherein each of Q 1 , Z, R 1 and Q 2 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 erbB receptor tyrosine kinases.

1 . A quinazoline derivative of the Formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 G 1  and G 2  each independently is halogeno; 
 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)alkanesulponylamino and  N -(1-6C)alkyl-(1-6C)alkanesulfonylamino; 
 X 2  is a direct bond or [CR 2 R 3 ] m , wherein m is an integer from 1 to 6, 
 and each of R 2  and R 3  independently is selected from hydrogen, hydroxy, (1-4C)alkyl and hydroxy(1-4C)alkyl; 
 Q 1  is (3-7C)cycloalkyl or heterocyclyl, wherein Q 1  optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, acryloyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (1-6C)alkylthio, (2-6C)alkenylthio, (2-6C)alkynylthio, (1-6C)alkylsulfinyl, (2-6C)alkenylsulfinyl, (2-6C)alkynylsulfinyl, (1-6C)alkylsulfonyl, (2-6C)alkenylsulfonyl, (2-6C)alkynylsulfonyl, (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, sulfamoyl,  N -(1-6C)alkylsulfamoyl,  N , N -di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino,  N -(1-6C)alkyl-(1-6C)alkanesulfonylamino, carbamoyl(1-6C)alkyl,  N -(1-6C)alkylcarbamoyl(1-6C)alkyl,  N , N -di-[(1-6C)alkyl]carbamoyl(1-6C)alkyl, sulfamoyl(1-6C)alkyl,  N -(1-6C)alkylsulfamoyl(1-6C)alkyl,  N , N -di-[(1-6C)alkyl]sulfamoyl(1-6C)alkyl, (2-6C)alkanoyl(1-6C)alkyl, (2-6C)alkanoyloxy(1-6C)alkyl, (2-6C)alkanoylamino(1-6C)alkyl,  N -(1-6C)alkyl-(2-6C)alkanoylamino(1-6C)alkyl and (1-6C)alkoxycarbonyl(1-6C)alkyl, or from a group of the formula:
   Q 2 -X 3 —
 
 
 
       wherein X 3  is CO and Q 2  is heterocyclyl,
 and wherein Q 2  optionally bears 1 or 2 substituents, which may be the same or different, selected from halogeno, hydroxy, (1-4C)alkyl, (2-4C)alkanoyl and (1-4C)alkylsulfonyl, 
 and wherein any (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl and (2-6C)alkanoyl group within Q 1  optionally bears one or more substituents which may be the same or different selected from halogeno, hydroxy and (1-6C)alkyl and/or optionally a substituent selected from cyano, nitro, carboxy, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, hydroxy(1-6C)alkoxy, (1-4C)alkoxy(1-6C)alkoxy, (2-6C)alkanoyl, (2-6C)alkanoyloxy and NR a R b , wherein R a  is hydrogen or (1-4C)alkyl and R b  is hydrogen or (1-4C)alkyl, and wherein any (1-4C)alkyl in R a  or R b  optionally bears one or more substituents, which may be the same or different, selected from halogeno and hydroxy and/or optionally a substituent selected from cyano, nitro, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, hydroxy(1-4C)alkoxy and (1-2C)alkoxy(1-4C)alkoxy, 
 or R a  and R b  together with the nitrogen atom to which they are attached form a 4, 5 or 6 membered ring, which optionally bears 1 or 2 substituents, which may be the same or different, on an available ring carbon atom selected from halogeno, hydroxy, (1-4C)alkyl and (1-3C)alkylenedioxy, and may optionally bear on any available ring nitrogen a substituent (provided the ring is not thereby quaternised) selected from (1-4C)alkyl, (2-4C)alkanoyl and (1-4C)alkylsulfonyl, 
 and wherein any (1-4C)alkyl or (2-4C)alkanoyl group present as a substituent on the ring formed by R a  and R b  together with the nitrogen atom to which they are attached optionally bears one or more substituents, which may be the same or different, selected from halogeno and hydroxy and/or optionally a substituent selected from (1-4C)alkyl and (1-4C)alkoxy; 
 and wherein any heterocyclyl group within the Q 1 -X 2 — group optionally bears 1 or 2 oxo (═O) or thioxo (═S) substituents; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         2 . A quinazoline derivative of the Formula I according to  claim 1  wherein each of R 1 , G 1 , G 2 , X 1  and X 2  has any of the meanings defined in  claim 1 ; and
 Q 1  is a non-aromatic saturated or partially saturated 3 to 7 membered monocyclic heterocyclyl ring with 1 ring nitrogen heteroatom and optionally 1 or 2 heteroatoms selected from nitrogen and sulfur, which ring is linked to the group X 2 —O— by a ring carbon atom, and wherein Q 1  optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carbamoyl, acryloyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (1-6C)alkylthio, (2-6C)alkenylthio, (2-6C)alkynylthio, (1-6C)alkylsulfinyl, (2-6C)alkenylsulfinyl, (2-6C)alkynylsulfinyl, (1-6C)alkylsulfonyl, (2-6C)alkenylsulfonyl, (2-6C)alkynylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,  N -(1-6C)alkylcarbamoyl,  N , N -di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoylamino,  N -(1-6C)alkyl-(2-6C)alkanoylamino, sulfamoyl,  N -(1-6C)alkylsulfamoyl,  N , N -di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino,  N -(1-6C)alkyl-(1-6C)alkanesulfonylamino, carbamoyl(1-6C)alkyl,  N -(1-6C)alkylcarbamoyl(1-6C)alkyl,  N , N -di-[(1-6C)alkyl]carbamoyl(1-6C)alkyl, sulfamoyl(1-6C)alkyl,  N -(1-6C)alkylsulfamoyl(1-6C)alkyl,  N , N -di-[(1-6C)alkyl]sulfamoyl(1-6C)alkyl, (2-6C)alkanoyl(1-6C)alkyl, (2-6C)alkanoyloxy(1-6C)alkyl, (2-6C)alkanoylamino(1-6C)alkyl and N-(1-6C)alkyl-(2-6C)alkanoylamino(1-6C)alkyl, or from a group of the formula:
   Q 2 -X 3 —
 
 
 
       wherein X 3  is CO and Q 2  is a heterocyclyl group selected from morpholino and a 4, 5 or 6-membered monocyclic heterocyclyl group containing 1 nitrogen heteroatom and optionally 1 or 2 heteroatoms selected from sulfur and nitrogen,
 and wherein Q 2  optionally bears 1 or 2 substituents, which may be the same or different, selected from halogeno, hydroxy, (1-4C)alkyl, (2-4C)alkanoyl and (1-4C)alkylsulfonyl, 
 and wherein any (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl and (2-6C)alkanoyl group within Q 1  optionally bears one or more substituents, which may be the same or different, selected from halogeno, hydroxy and (1-6C)alkyl and/or optionally a substituent selected from cyano, nitro, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, hydroxy(1-6C)alkoxy, (1-4C)alkoxy(1-6C)alkoxy, (2-6C)alkanoyl, (2-6C)alkanoyloxy and NR a R b , wherein R a  is hydrogen or (1-4C)alkyl and R b  is hydrogen or (1-4C)alkyl, and wherein any (1-4C)alkyl in R a  or R b  optionally bears one or more substituents, which may be the same or different, selected from halogeno and hydroxy and/or optionally a substituent selected from cyano, nitro, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, hydroxy(1-4C)alkoxy and (1-2C)alkoxy(1-4C)alkoxy, 
 or R a  and R b  together with the nitrogen atom to which they are attached form a 4, 5 or 6 membered ring, which optionally bears 1 or 2 substituents, which may be the same or different, on an available ring carbon atom selected from halogeno, hydroxy, (1-4C)alkyl and (1-3C)alkylenedioxy, and may optionally bear on any available ring nitrogen a substituent (provided the ring is not thereby quaternised) selected from (1-4C)alkyl, (2-4C)alkanoyl and (1-4C)alkylsulfonyl, 
 and wherein any (1-4C)alkyl or (2-4C)alkanoyl group present as a substituent on the ring formed by R a  and R b  together with the nitrogen atom to which they are attached optionally bears one or more substituents, which may be the same or different, selected from halogeno and hydroxy and/or optionally a substituent selected from (1-4C)alkyl and (1-4C)alkoxy; 
 and wherein any heterocyclyl group within the Q 1 -X 2 — group optionally bears 1 or 2 oxo (═O) or thioxo (═S) substituents; 
 provided that when X 2  is [CH 2 ], m is an integer from 1 to 6, and Q 1  is a pyrrolidinyl or piperidinyl group substituted at the 1-position by a (2-4C)alkyl or (2-5C)alkanoyl group, then the (2-4C)alkyl or (2-5C)alkanoyl group at the 1-position on Q 1  is not substituted by a 2-oxo-morpholino group. 
 
     
     
         3 . A quinazoline derivative of the Formula I according to  claim 1  wherein each of R 1 , G 1 , G 2 , X 1  and X 2  has any of the meanings defined in  claim 1 ; and
 Q 1  is (3-7C)cycloalkyl or heterocyclyl, wherein Q 1  optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, (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, sulfamoyl,  N -(1-6C)alkylsulfamoyl,  N , N -di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino,  N -(1-6C)alkyl-(1-6C)alkanesulfonylamino, 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, (2-6C)alkanoyloxy(1-6C)alkyl, (2-6C)alkanoylamino(1-6C)alkyl,  N -(1-6C)alkyl-(2-6C)alkanoylamino(1-6C)alkyl and (1-6C)alkoxycarbonyl(1-6C)alkyl, 
 and wherein any (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl and (2-6C)alkanoyl group within Q 1  optionally bears one or more substituents, which may be the same or different, selected from halogeno, hydroxy and (1-6C)alkyl and/or optionally a substituent selected from cyano, nitro, carboxy, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, hydroxy(1-6C)alkoxy and NR a R b , wherein R a  is hydrogen or (1-4C)alkyl and R b  is hydrogen or (1-4C)alkyl, 
 or R a  and R b  together with the nitrogen atom to which they are attached form a 4, 5 or 6 membered ring; 
 and wherein any heterocyclyl group within the Q 1 -X 2 — group optionally bears 1 or 2 oxo (═O) or thioxo (═S) substituents; 
 
     
     
         4 . A quinazoline derivative of the Formula I according to  claim 1  wherein each of R 1 , G 1 , G 2 , X 1  and X 2  has any of the meanings defined in  claim 1 ; and
 Q 1  is a non-aromatic saturated or partially saturated 4, 5 or 6 membered monocyclic heterocyclyl ring with 1 or 2 ring nitrogen heteroatom(s), which ring is linked to the group X 2 —O— by a ring carbon atom, and wherein Q 1  optionally bears 1 or 2 substituents, which may be the same or different, selected from halogeno, cyano, nitro, hydroxy, carbamoyl, acryloyl, (1-6C)alkyl, (1-6C)alkylthio, (2-6C)alkenylthio, (2-6C)alkynylthio, (1-6C)alkylsulfinyl, (2-6C)alkenylsulfinyl, (2-6C)alkynylsulfinyl, (1-6C)alkylsulfonyl, (2-6C)alkenylsulfonyl, (2-6C)alkynylsulfonyl,  N -(1-6C)alkylcarbamoyl,  N , N -di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, sulfamoyl,  N -(1-6C)alkylsulfamoyl,  N , N -di-[(1-6C)alkyl]sulfamoyl, carbamoyl(1-6C)alkyl,  N -(1-6C)alkylcarbamoyl(1-6C)alkyl,  N , N -di-[(1-6C)alkyl]carbamoyl(1-6C)alkyl, sulfamoyl(1-6C)alkyl,  N -(1-6C)alkylsulfamoyl(1-6C)alkyl,  N , N -di-[(1-6C)alkyl]sulfamoyl(1-6C)alkyl, (2-6C)alkanoyl(1-6C)alkyl, (2-6C)alkanoyloxy(1-6C)alkyl, (2-6C)alkanoylamino(1-6C)alkyl and  N -(1-6C)alkyl-(2-6C)alkanoylamino(1-6C)alkyl, or from a group of the formula:
   Q 2 -X 3 —
 
 
 wherein X 3  is CO and Q 2  is a heterocyclyl group selected from morpholino, piperidinyl, piperazinyl and pyrrolidinyl 
 and wherein Q 2  optionally bears 1 or 2 substituents, which may be the same or different, selected from halogeno, hydroxy, (1-4C)alkyl, (2-4C)alkanoyl and (1-4C)alkylsulfonyl, 
 and wherein any (1-6C)alkyl, or (2-6C)alkanoyl group within Q 1  optionally bears 1 or 2 substituents, which may be the same or different, selected from halogeno, hydroxy and (1-6C)alkyl and/or optionally a substituent selected from cyano, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkanoyl, (2-6C)alkanoyloxy and NR a R b , wherein R a  is hydrogen or (1-4C)alkyl and R b  is hydrogen or (1-4C)alkyl, and wherein any (1-4C)alkyl in R a  or R b  optionally bears one or more substituents, which may be the same or different, selected from halogeno and hydroxy and/or optionally a substituent selected from cyano, and (1-4C)alkoxy, 
 or R a  and R b  together with the nitrogen atom to which they are attached form a 4, 5 or 6 membered ring which does not contain oxygen, which ring optionally bears 1 or 2 substituents, which may be the same or different, on an available ring carbon atom selected from halogeno, hydroxy, (1-4C)alkyl and (1-3C)alkylenedioxy, and may optionally bear on any available ring nitrogen a substituent (provided the ring is not thereby quaternised) selected from (1-4C)alkyl, (2-4C)alkanoyl and (1-4C)alkylsulfonyl, 
 and wherein any (1-4C)alkyl or (2-4C)alkanoyl group present as a substituent on the ring formed by R a  and R b  together with the nitrogen atom to which they are attached optionally bears one or more substituents, which may be the same or different, selected from halogeno and hydroxy and/or optionally a substituent selected from (1-4C)alkyl and (1-4C)alkoxy; 
 and wherein any heterocyclyl group within the Q 1 -X 2 — group optionally bears 1 or 2 oxo (═O) or thioxo (═S) substituents. 
 
     
     
         5 . A quinazoline derivative of the Formula I according to  claim 1  wherein each of R 1 , G 1 , G 2 , X 1  and X 2  has any of the meanings defined in  claim 1 ; and
 Q 1  is selected from pyrrolidinyl and piperidinyl linked to the group X 2 —O— by a ring carbon atom and wherein the pyrrolidinyl or piperidinyl group is optionally substituted by 1 or 2 groups selected from halogeno, cyano, hydroxy, carbamoyl, (1-6C)alkyl, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl,  N -(1-6C)alkylcarbamoyl,  N , N -di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, sulfamoyl,  N -(1-6C)alkylsulfamoyl,  N , N -di-[(1-6C)alkyl]sulfamoyl, carbamoyl(1-6C)alkyl,  N -(1-6C)alkylcarbamoyl(1-6C)alkyl,  N , N -di-[(1-6C)alkyl]carbamoyl(1-6C)alkyl, sulfamoyl(1-6C)alkyl,  N -(1-6C)alkylsulfamoyl(1-6C)alkyl,  N , N -di-[(1-6C)alkyl]sulfamoyl(1-6C)alkyl and (2-6C)alkanoyl(1-6C)alkyl, or from a group of the formula:
   Q 2 -X 3 —
 
 
 wherein X 3  is CO and Q 2  is a heterocyclyl group selected from morpholino, piperidino, piperazin-1-yl, pyrrolidin-1-yl and pyrrolidin-2-yl, 
 and wherein Q 2  optionally bears 1 or 2 substituents, which may be the same or different, selected from halogeno, hydroxy, (1-4C)alkyl, (2-4C)alkanoyl and (1-4C)alkylsulfonyl, 
 and wherein any (1-6C)alkyl, or (2-6C)alkanoyl group within Q 1  optionally bears 1 or 2 substituents, which may be the same or different, selected from halogeno, hydroxy and (1-6C)alkyl and/or optionally a substituent selected from cyano, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkanoyl, (2-6C)alkanoyloxy and NR a R b , wherein R a  is hydrogen or (1-4C)alkyl and R b  is hydrogen or (1-4C)alkyl, and wherein any (1-4C)alkyl in R a  or R b  optionally bears one or more substituents, which may be the same or different, selected from halogeno and hydroxy and/or optionally a substituent selected from cyano, and (1-4C)alkoxy, 
 or R a  and R b  together with the nitrogen atom to which they are attached form a ring selected from pyrrolidin-1-yl, piperidino and piperazin-1-yl, which ring optionally bears 1 or 2 substituents, which may be the same or different, on an available ring carbon atom selected from halogeno, hydroxy, (1-4C)alkyl and methylenedioxy, and may optionally bear on any available ring nitrogen a substituent (provided the ring is not thereby quaternised) selected from (1-4C)alkyl, (2-4C)alkanoyl and (1-4C)alkylsulfonyl, 
 and wherein any (1-4C)alkyl or (2-4C)alkanoyl group present as a substituent on the ring formed by R a  and R b  together with the nitrogen atom to which they are attached optionally bears one or more substituents, which may be the same or different, selected from halogeno and hydroxy and/or optionally a substituent selected from (1-4C)alkyl and (1-4C)alkoxy; 
 and wherein any heterocyclyl group within the Q 1 -X 2 — group optionally bears 1 or 2 oxo (═O) substituents. 
 
     
     
         6 . A quinazoline derivative of the Formula I according to any one of the preceding claims wherein X 2  is a direct bond or CH 2 . 
     
     
         7 . A quinazoline derivative of the Formula I according to  claim 1  wherein each of R 1 , G 1 , G 2  and X 1  has any of the meanings defined in  claim 1 ; and
 Q 1 -X 2  is selected from pyrrolidin-2-ylmethyl, pyrrolidin-3-yl, pyrrolidin-3-ylmethyl, piperidin-4-yl, piperidin-4-ylmethyl and piperidin-3-yl wherein Q 1  is substituted by 1 or 2 groups, which may be the same or different, selected from carbamoyl, (1-4C)alkyl, (1-4C)alkylsulfonyl,  N -(1-4C)alkylcarbamoyl,  N , N -di-[(1-4C)alkyl]carbamoyl, (2-4C)alkanoyl, sulfamoyl,  N -(1-4C)alkylsulfamoyl,  N , N -di-[(1-4C)alkyl]sulfamoyl, carbamoyl(1-3C)alkyl,  N -(1-4C)alkylcarbamoyl(1-3C)alkyl,  N , N -di-[(1-4C)alkyl]carbamoyl(1-3C)alkyl, (2-4C)alkanoyl(1-3C)alkyl, amino(2-4C)alkanoyl, (1-4C)alkylamino-(2-4C)alkanoyl,  N , N -di-[(1-4C)alkyl]amino-(2-4C)alkanoyl, (2-4C)alkanoyloxy-(2-4C)alkanoyl, amino(1-3C)alkylsulfonyl,  N -(1-4C)alkylamino-(1-3C)alkylsulfonyl,  N , N -di[(1-4)alkyl]amino(1-3C)alkylsulfonyl, pyrrolidin-1-yl-(2-4C)alkanoyl, 3,4-methylenedioxypyrrolidin-1-yl-(2-4C)alkanoyl, piperidino-(2-4C)alkanoyl, piperazin-1-yl-(2-4C)alkanoyl, morpholino-(2-4C)alkanoyl and a group of the formula:
   Q 2 -X 3 —
 
 
 wherein X 3  is CO and Q 2  is selected from pyrrolidin-1-yl, pyrrolidin-2-yl, morpholino and piperidino, 
 and wherein any pyrrolidin-1-yl, pyrrolidin-2-yl, morpholino, piperidino or piperazin-1-yl group within a substituent on Q 1  or which is represented by Q 2  optionally bears one or two substituents, which may be the same or different, selected from hydroxy, (1-4C)alkyl, (2-4C)alkanoyl and halogeno, 
 and wherein any (2-4C)alkanoyl group in a substituent on Q 1  optionally bears one or two substituents, which may be the same or different, selected from hydroxy and (1-3C)alkyl, 
 and wherein any (1-4C)alkyl group in a substituent on Q 1  optionally bears one or two substituents, which may be the same or different, selected from hydroxy, (1-4C)alkoxy and halogeno, 
 and wherein any heterocyclyl group within the Q 1 -X 2 — group optionally bears an oxo (═O) substituent. 
 
     
     
         8 . A quinazoline derivative of the Formula I according to  claim 1  wherein each of R 1 , G 1 , G 2  and X 1  has any of the meanings defined in  claim 1 ; and
 Q 1 -X 2  is selected from pyrrolidin-3-yl, piperidin-4-yl and piperidin-3-yl, wherein Q 1  is substituted at the 1-position by a group selected from (1-4C)alkyl, (1-4C)alkylsulfonyl, (2-4C)alkanoyl, (2-4C)alkanoyl(1-3C)alkyl, amino(2-4C)alkanoyl, (1-4C)alkylamino-(2-4C)alkanoyl,  N , N -di-[(1-4C)alkyl]amino-(2-4C)alkanoyl, (2-4C)alkanoyloxy-(2-4C)alkanoyl, amino(1-3C)alkylsulfonyl,  N -(1-4C)alkylamino-(1-3C)alkylsulfonyl,  N , N -di[(1-4)alkyl]amino(1-3C)alkylsulfonyl, pyrrolidin-1-yl-(2-4C)alkanoyl, 3,4-methylenedioxypyrrolidin-1-yl-(2-4C)alkanoyl, piperidino-(2-4C)alkanoyl, piperazin-1-yl-(2-4C)alkanoyl, morpholino-(2-4C)alkanoyl and a group of the formula:
   Q 2 -X 3 —
 
 
 wherein X 3  is CO and Q 2  is pyrrolidin-2-yl, 
 and wherein any pyrrolidin-1-yl, pyrrolidin-2-yl, morpholino, piperidino or piperazin-1-yl group within a substituent on Q 1  or which is represented by Q 2  optionally bears one or two substituents, which may be the same or different, selected from hydroxy, (1-4C)alkyl, (2-4C)alkanoyl and halogeno, 
 and wherein any (2-4C)alkanoyl group in a substituent on Q 1  optionally bears one or two substituents, which may be the same or different, selected from hydroxy and (1-3C)alkyl, 
 and wherein any (1-4C)alkyl group in a substituent on Q 1  optionally bears one or two substituents, which may be the same or different, selected from hydroxy, (1-4C)alkoxy and halogeno, 
 and wherein any heterocyclyl group within the Q 1 -X 2 — group optionally bears an oxo (═O) substituent. 
 
     
     
         9 . A quinazoline derivative of the Formula I according to  claim 1  wherein each of R 1 , G 1 , G 2  and X 1  has any of the meanings defined in  claim 1 ; and
 Q 1 -X 2  is a group of the formula A: 
 
       
         
           
           
               
               
           
         
       
       wherein:
 R 4  is selected from carbamoyl,  N -(1-6C)alkylcarbamoyl,  N , N -di-[(1-6C)alkyl]carbamoyl and a group of the formula:
   Q 2 -X 3 —
 
 
 wherein X 3  is CO and Q 2  is a heterocyclyl group selected from a 4, 5 or 6-membered monocyclic heterocyclyl group containing 1 nitrogen heteroatom and optionally 1 or 2 heteroatoms selected from sulfur, oxygen and nitrogen, 
 and wherein Q 2  is attached to X 3  by a ring nitrogen atom, 
 and wherein Q 2  optionally bears one or more substituents, which may be the same or different, selected from halogeno, hydroxy, (1-4C)alkyl and (2-4C)alkanoyl, 
 and wherein any (1-6C)alkyl or (2-6C)alkanoyl group within R 4  optionally bears one or more substituents, which may be the same or different, selected from halogeno, hydroxy and (1-6C)alkyl and/or optionally a substituent selected from cyano, nitro, (2-8C)alkenyl, (2-8C)alkynyl and (1-6C)alkoxy, 
 R 5  is selected from hydrogen, (1-6C)alkyl, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (2-6C)alkanoyl, carbamoyl(1-6C)alkyl,  N -(1-6C)alkylcarbamoyl(1-6C)alkyl,  N , N -di-[(1-6C)alkyl]carbamoyl(1-6C)alkyl, sulfamoyl(1-6C)alkyl,  N -(1-6C)alkylsulfamoyl(1-6C)alkyl,  N , N -di-[(1-6C)alkyl]sulfamoyl(1-6C)alkyl and (2-6C)alkanoyl(1-6C)alkyl, 
 and wherein any (1-6C)alkyl or (2-6C)alkanoyl group within R 5  optionally bears one or more substituents, which may be the same or different, selected from halogeno, hydroxy and (1-6C)alkyl and/or optionally a substituent selected from cyano, nitro, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy and NR a R b , wherein R a  is hydrogen or (1-4C)alkyl and R b  is hydrogen or (1-4C)alkyl, and wherein any (1-4C)alkyl in R a  or R b  optionally bears one or more substituents, which may be the same or different, selected from halogeno and hydroxy and/or optionally a substituent selected from cyano, nitro and (1-4C)alkoxy, 
 or R a  and R b  together with the nitrogen atom to which they are attached form a 4, 5 or 6 membered ring, which optionally bears 1 or 2 substituents, which may be the same or different, on an available ring carbon atom selected from halogeno, hydroxy, (1-4C)alkyl and (1-3C)alkylenedioxy, and may optionally bear on any available ring nitrogen a substituent (provided the ring is not thereby quaternised) selected from (1-4C)alkyl and (2-4C)alkanoyl, 
 and wherein any (1-4C)alkyl or (2-4C)alkanoyl group present as a substituent on the ring formed by R a  and R b  together with the nitrogen atom to which they are attached optionally bears one or more substituents, which may be the same or different, selected from halogeno and hydroxy and/or optionally a substituent selected from (1-4C)alkyl and (1-4C)alkoxy, 
 and wherein any heterocyclyl group within the Q 1 -X 2 — group optionally bears 1 or 2 oxo (═O) or thioxo (═S) substituents. 
 
     
     
         10 . A quinazoline derivative of the Formula I according to  claim 1  wherein each of R 1 , G 1 , G 2  and X 1  has any of the meanings defined in  claim 1 ; and
 Q 1 -X 2  is a group of the formula A: 
 
       
         
           
           
               
               
           
         
       
       wherein:
 R 4  is selected from  N , N -di-[(1-4C)alkyl]carbamoyl and a group of the formula:
   Q 2 -X 3 —
 
 
 
       wherein X 3  is CO and Q 2  is selected from pyrrolidin-1-yl, morpholino and piperidino,
 and wherein Q 2  optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, methyl and oxo, 
 and wherein any (1-4C)alkyl group within R 4  optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro and hydroxy and/or optionally a substituent selected from methoxy, 
 R 5  is selected from hydrogen, methyl, ethyl, isopropyl, isobutyl and cycloproplymethyl, 
 and wherein any (1-4C)alkyl group within R 5  optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro and hydroxy, and/or optionally a substituent selected from methoxy. 
 
     
     
         11 . A quinazoline derivative of the Formula I according to  claim 1  wherein R 1 —X 1  is selected from hydrogen, (1-6C)alkoxy and (1-4C)alkoxy(1-6C)alkoxy, and wherein any (1-6C)alkoxy group within R 1 X 1  optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from hydroxy, fluoro and chloro. 
     
     
         12 . A quinazoline derivative of the Formula I according to  claim 1  wherein G 1  is fluoro and G 2  is chloro. 
     
     
         13 . A quinazoline derivative of the Formula I according to  claim 1  wherein R 1 —X 1  is selected from hydrogen and (1-4C)alkoxy. 
     
     
         14 . A quinazoline derivative of the Formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1 —X 1  is (1-4C)alkoxy; 
 Q 1 -X 2  is a group of the formula A: 
 
       
         
           
           
               
               
           
         
       
       wherein:
 R 4  is N,N-dimethylcarbamoyl or morpholinocarbonyl; 
 R 5  is hydrogen or methyl; 
 G 1  is fluoro; and 
 G 2  is chloro; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         15 . A quinazoline derivative of the Formula I according to  claim 1  selected from:
 4-(3-Chloro-2-fluoroanilino)-6-{[1-(methylsulfonyl)piperidin-4-yl]oxy}-7-methoxyquinazoline; and 
 6-{[1-(carbamoylmethyl)piperidin-4-yl]oxy}-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline; 
 
       or a pharmaceutically acceptable acid addition salt thereof. 
     
     
         16 . A quinazoline derivative of the Formula I according to  claim 1  selected from:
 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[(1-methylpyrrolidin-3-yl)oxy]quinazoline; 
 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[(piperidin-4-yl)oxy]quinazoline; 
 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[(piperidin-4-yl)methoxy]quinazoline; 
 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[(1-methylpiperidin-4-yl)oxy]quinazoline; 
 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[(1-methylpiperidin-4-yl)methoxy]quinazoline; 
 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[2-(1-methylpiperidin-4-yl)ethoxy]quinazoline; 
 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{[1-(2-methoxyethyl)piperidin-4-yl]oxy}quinazoline; 
 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{[1-(2-methoxyethyl)piperidin-4-yl]methoxy}quinazoline; 
 4-(3-Chloro-2-fluoroanilino)-6-{[1-(methylsulfonyl)piperidin-4-yl]methoxy}-7-methoxyquinazoline; 
 6-{[1-(carbamoylmethyl)piperidin-4-yl]methoxy}-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline; 
 4-(3-Chloro-2-fluoroanilino)-6-{[1-(cyanomethyl)piperidin-4-yl]oxy}-7-methoxyquinazoline; 
 4-(3-Chloro-2-fluoroanilino)-6-{[1-(cyanomethyl)piperidin-4-yl]methoxy}-7-methoxyquinazoline; 
 4-(3-Chloro-2-fluoroanilino)-6-[(1-cyanopiperidin-4-yl)methoxy]-7-methoxyquinazoline; 
 6-(1-acetylpiperidin-4-yloxy)-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline; 
 4-(3-chloro-2-fluoroanilino)-6-[1-(N,N-dimethylaminoacetyl)piperidin-4-yloxy]-7-methoxyquinazoline; 
 6-[1-(N,N-dimethylsulfamoyl)piperidin-4-yloxy]-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline; 
 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[1-(morpholinoacetyl)piperidin-4-yloxy]quinazoline; 
 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[1-(pyrrolidin-1-ylacetyl)piperidin-4-yloxy]quinazoline; 
 4-(3-chloro-2-fluoroanilino)-6-{1-[3-(dimethylamino)propylsulfonyl]piperidin-4-yloxy}-7-methoxyquinazoline; 
 4-(3-chloro-2-fluoroanilino)-6-[1-(methylsulfonyl)piperidin-3-yloxy]-7-methoxyquinazoline; 
 4-(3-chloro-2-fluoroanilino)-6-[(3R)-1-(methylsulfonyl)piperidin-3-yloxy]-7-methoxyquinazoline; 
 4-(3-chloro-2-fluoroanilino)-6-[(3S)-1-(methylsulfonyl)piperidin-3-yloxy]-7-methoxyquinazoline; 
 6-(1-acetylpiperidin-3-yloxy)-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline; 
 4-(3-chloro-2-fluoroanilino)-6-[(2S,4S)-2-(N,N-dimethylcarbamoyl)pyrrolidin-4-yloxy]-7-methoxyquinazoline; 
 4-(3-chloro-2-fluoroanilino)-6-[(2S,4S)-2-(N,N-dimethylcarbamoyl)-1-methylpyrrolidin-4-yloxy]-7-methoxyquinazoline; 
 4-(3-chloro-2-fluoroanilino)-6-[1-(N,N-dimethylaminoacetyl)piperidin-3-yloxy]-7-methoxyquinazoline; 
 4-(3-chloro-2-fluoroanilino)-6-[(3R)-1-(N,N-dimethylaminoacetyl)piperidin-3-yloxy]-7-methoxyquinazoline; 
 4-(3-chloro-2-fluoroanilino)-6-[(3S)-1-(N,N-dimethylaminoacetyl)piperidin-3-yloxy]-7-methoxyquinazoline; 
 4-(3-chloro-2-fluoroanilino)-6-[1-(hydroxyacetyl)piperidin-3-yloxy]-7-methoxyquinazoline; 
 6-[1-(acetoxyacetyl)piperidin-3-yloxy]-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline; 
 4-(3-chloro-2-fluoroanilino)-6-[(3R)-1-(methylsulfonyl)pyrrolidin-3-yloxy]-7-methoxyquinazoline; 
 4-(3-chloro-2-fluoroanilino)-6-[(3S)-1-(methylsulfonyl)pyrrolidin-3-yloxy]-7-methoxyquinazoline; 
 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-methylsulfonylpyrrolidin-2-yl]methoxy}quinazoline; 
 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2R)-1-methylsulfonylpyrrolidin-2-yl]methoxy}quinazoline; 
 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[1-(methylsulfonyl)pyrrolidin-3-yl]methoxy}quinazoline; 
 4-(3-chloro-2-fluoroanilino)-6-[(3R)-1-methylpyrrolidin-3-yloxy]-7-methoxyquinazoline; 
 4-(3-chloro-2-fluoroanilino)-6-[(3S)-1-methylpyrrolidin-3-yloxy]-7-methoxyquinazoline; 
 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}quinazoline; 
 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(1-methylpyrrolidin-3-yl)methoxy]quinazoline; 
 6-[(3R)-1-acetylpyrrolidin-3-yloxy]-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline; 
 6-{[(2S)-1-acetylpyrrolidin-2-yl]methoxy}-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline; 
 6-{[(2R)-1-acetylpyrrolidin-2-yl]methoxy}-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline; 
 6-[(1-acetylpyrrolidin-3-yl)methoxy]-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline; 
 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(3S)-1-(N,N-dimethylsulfamoyl)pyrrolidin-3-yloxy]quinazoline; 
 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(morpholinoacetyl)pyrrolidin-2-yl]methoxy}quinazoline; 
 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(hydroxyacetyl)pyrrolidin-2-yl]methoxy}quinazoline; 
 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-3-yloxy)quinazoline; 
 4-(3-chloro-2-fluoroanilino)-6-[(2S,4R)-2-(N,N-dimethylcarbamoyl)-1-methylpyrrolidin-4-yloxy]-7-methoxyquinazoline; 
 4-(3-chloro-2-fluoroanilino)-6-[(2R,4R)-2-(N,N-dimethylcarbamoyl)-1-methylpyrrolidin-2-yloxy]-7-methoxyquinazoline; 
 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(N-methylaminoacetyl)pyrrolidin-2-yl]methoxy}quinazoline; 
 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(N,N-dimethylaminoacetyl)pyrrolidin-2-yl]methoxy}quinazoline; 
 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(pyrrolidin-1-ylacetyl)pyrrolidin-2-yl]methoxy}quinazoline; 
 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(2RS,4R)-1-methyl-2-(morpholinocarbonyl)pyrrolidin-4-yloxy]quinazoline; 
 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(3S)-piperidin-3-yloxy]quinazoline; 
 6-[(3S)-1-acetylpiperidin-3-yloxy]-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline; 
 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(3S)-1-(methylsulfonyl)piperidin-3-yloxy]quinazoline; 
 4-(3-chloro-2-fluoroanilino)-6-{(3S)-1-[(dimethylamino)acetyl]piperidin-3-yloxy}-7-methoxyquinazoline; 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[1-(pyrrolidin-1-ylacetyl)piperidin-3-yloxy]quinazoline; 
 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(3S)-1-(pyrrolidin-1-ylacetyl)piperidin-3-yloxy]quinazoline; 
 4-(3-chloro-2-fluoroanilino)-6-{[(2S)-1-(3,4-methylenedioxypyrrolidin-1-ylacetyl)pyrrolidin-2-yl]methoxy}-7-methoxyquinazoline; 
 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(1-methylpiperazin-4-ylacetyl)pyrrolidin-2-yl]methoxy}quinazoline; 
 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(1-methylpiperazin-4-ylacetyl)pyrrolidin-2-yl]methoxy}quinazoline; 
 4-(3-chloro-2-fluoroanilino)-6-[(3R)-1-(hydroxyacetyl)pyrrolidin-3-yloxy]-7-methoxyquinazoline; 
 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(2-hydroxyisobutyryl)pyrrolidin-2-yl]methoxy}quinazoline; 
 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{1-[(2S)-1-methylpyrrolidin-2-ylcarbonyl]piperidin-3-yloxy}quinazoline; 
 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[1-(N,N-dimethylcarbamoylmethyl)piperidin-3-yloxy]quinazoline; 
 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[1-(3,3-difluoropyrrolidin-1-ylacetyl)piperidin-3-yloxy]quinazoline; 
 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{1-[[(3R)-3-hydroxypyrrolidin-1-yl]acetyl]piperidin-3-yloxy}quinazoline; 
 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{[1-(4-methyl-3-oxopiperazin-1-yl)acetyl]piperidin-3-yloxy}quinazoline; 
 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{1-[(4-acetylpiperazin-1-yl)acetyl]piperidin-3-yloxy}quinazoline; and 
 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2R)-1-methylpyrrolidin-2-yl]methoxy}quinazoline; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         17 . A pharmaceutical composition which comprises a quinazoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined in  claim 1  in association with a pharmaceutically-acceptable diluent or carrier. 
     
     
         18 . 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, as defined in  claim 1 . 
     
     
         19 . A compound of the formula B or a salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein Y is hydrogen or a displaceable group; and
 R 1 , X 1 , G 1  and G 2  are as defined in  claim 1 .