1. A quinazoline derivative of the formula I:
wherein:
m is 0, 1 or 2;
each R1, which may be the same or different, is selected from hydroxy, (1-6C)alkoxy, (3-7C)cycloalkyl-oxy and (3-7C)cycloalkyl-(1-6C)alkoxy,
wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more halogeno or (1-6C)alkyl substituents, or a substituent selected from hydroxy and (1-6C)alkoxy,
R2 is hydrogen or (1-4C)alkyl;
n is 0, 1, 2, 3 or 4;
each R3, which may be the same or different, is selected from cyano, halogeno, (1-4C)alkyl, trifluoromethyl, (1-4C)alkoxy, (2-4C)alkenyl and (2-4C)alkynyl;
X1 is selected from O, S, SO, SO2, N(R7), CH(OR7), CON(R7), N(R7)CO, SO2N(R7), N(R7)SO2, OC(R7)2, C(R7)2O, SC(R7)2, C(R7)2S, CO, C(R7)2N(R7) and N(R7)C(R7)2,
each R7, which may be the same or different, is hydrogen or (1-6C)alkyl;
Q1 is aryl, or heteroaryl,
wherein Q1 optionally bears one or more substituents, which may be the same or different, selected from halogeno, hydroxy, (1-4C)alkyl and (1-4C)alkoxy;
wherein any CH2 or CH3 group within -X1-Q1 optionally bears on each said CH2 or CH3 group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, (1-4C)alkoxy, (1-4C)alkylamino and di-(1-4C)alkylamino;
R4, R4a, R5 and R5a, which may be the same or different, are selected from hydrogen and (1-6C)alkyl, or
R4 and R4a together with the carbon atom to which they are attached form a (3-7C)cycloalkyl ring, or
R5 and R5a together with the carbon atom to which they are attached form a (3-7C)cycloalkyl ring,
wherein any CH2 or CH3 group within any of R4, R4a, R5 and R5a optionally bears on each said CH2 or CH3 group one or more halogeno substituents or a substituent selected from hydroxy, cyano, (1-6C)alkoxy, amino, (2-6C)alkanoyl, (1-6C)alkylamino and di-(1-6C)alkylamino;
R6 is selected from hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-6C)alkyl, heterocyclyl and heterocyclyl-(1-6C)alkyl,
wherein any heterocyclyl group within an R6 substituent optionally bears one or more substituents, 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)alkylamino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula:
X3\u2014R10;
X3 is a direct bond or is selected from O, CO, SO2 and N(R11);
R11 is hydrogen or (1-4C)alkyl;
R10 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)alkylamino-(1-4C)alkyl,
wherein any heterocyclyl group within an R6 substituent optionally bears 1 or 2 oxo or thioxo substituents; and
wherein any CH2 or CH3 group within a R6 substituent, other than a CH2 group within a heterocyclyl group, optionally bears on each said CH2 or CH3 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)alkylamino, N-(1-6C)alkylcarbamoyl, N,N-di-(1-6C)alkylcarbamoyl, (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)alkylsulfamoyl, (1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino;
A is selected from hydrogen, a group of the formula Z-(CR12R13)p\u2014 and R14;
p is 1, 2, 3, or 4;
each R12 and R13, which may be the same or different, is selected from hydrogen, (1-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl,
or an R12 and an R13 group attached to the same carbon atom form a (3-7C)cycloalkyl or (3-7C)cycloalkenyl ring,
wherein any CH2 or CH3 group within any of R12 and R13, optionally bears on each said CH2 or CH3 group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, cyano, (1-6C)alkyl, (1-6C)alkoxy, amino, (2-6C)alkanoyl, (1-6C)alkylamino and di-(1-6C)alkylamino;
Z is selected from hydrogen, OR15, NR16R17, (1-6C)alkylsulfonyl, (1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino;
each of R15, R16 and R17, which may be the same or different, is selected from hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl and (1-6C)alkoxycarbonyl,
or Z is a group of the formula: Q2-X4\u2014;
X4 is selected from O, N(R18), SO2 and SO2N(R18);
R18 is hydrogen or (1-6C)alkyl;
Q2 is (3-7C)cycloalkyl, (3-7C)cycloalkenyl or heterocyclyl;
R14 is selected from hydrogen, OR19 and NR16R17;
R19 is selected from (1-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl, and wherein R16 and R17 are as defined above,
or R14 is a group of the formula: Q3-X5\u2014;
X5 is selected from O and N(R20);
R20 is hydrogen or (1-6C)alkyl;
Q3 is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-6C)alkyl, heterocyclyl and heterocyclyl-(1-6C)alkyl,
or R14 is Q4;
Q4 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,
wherein adjacent carbon atoms in any (2-6C)alkylene chain within a Z or R14 substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO2, N(R21), CO, \u2014C\u2550C\u2014 and \u2014C\u2261C\u2014;
R21 is hydrogen or (1-6C)alkyl,
wherein any heterocyclyl group within a Z or R14 substituent optionally bears one or more substituents, 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)alkylamino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula:
\u2014X6\u2014R22;
X6 is a direct bond or is selected from O, CO, SO2 and N(R23);
R23 is hydrogen or (1-4C)alkyl;
R22 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)alkylamino-(1-4C)alkyl,
wherein any heterocyclyl group within a Z or R14 substituent optionally bears 1 or 2 oxo or thioxo substituents, and
wherein any CH2 or CH3 group within a Z or R14 group, other than a CH2 group within a heterocyclyl ring, optionally bears on each said CH2 or CH3 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)alkylamino, N-(1-6C)alkylcarbamoyl, N,N-di-(1-6C)alkylcarbamoyl, (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)alkylsulfamoyl, (1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino;
or a pharmaceutically acceptable salt thereof.
2. A quinazoline derivative according to claim 1, wherein:
m is 0, 1 or 2;
each R1, which may be the same or different, is selected from hydroxy, (1-6C)alkoxy, (3-7C)cycloalkyl-oxy and (3-7C)cycloalkyl-(1-6C)alkoxy,
wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more halogeno or (1-6C)alkyl substituents, or a substituent selected from hydroxy and (1-6C)alkoxy,
R2 is hydrogen or (1-4C)alkyl;
n is 0, 1, 2, 3 or 4;
each R3, which may be the same or different, is selected from halogeno, (1-4C)alkyl, trifluoromethyl, (1-4C)alkoxy, (2-4C)alkenyl and (2-4C)alkynyl;
X1 is selected from O, S, SO, SO2, N(R7), CH(OR7), CON(R7), N(R7)CO, SO2N(R7), N(R7)SO2, OC(R7)2, C(R7)2O, SC(R7)2, C(R7)2S, CO, C(R7)2N(R7) and N(R7)C(R7)2,
each R7, which may be the same or different, is hydrogen or (1-6C)alkyl;
Q1 is aryl, or heteroaryl,
wherein Q1 optionally bears one or more substituents, which may be the same or different, selected from halogeno, hydroxy, (1-4C)alkyl and (1-4C)alkoxy,
wherein any CH2 or CH3 group within \u2014X1-Q1 optionally bears on each said CH2 or CH3 group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, (1-4C)alkoxy, (1-4C)alkylamino and di-(1-4C)alkylamino;
R4, R4a, R5 and R5a, which may be the same or different, are selected from hydrogen and (1-6 C)alkyl, or
R4 and R4a together with the carbon atom to which they are attached form a (3-7C)cycloalkyl ring, or
R5 and R5a together with the carbon atom to which they are attached form a (3-7C)cycloalkyl ring,
wherein any CH2 or CH3 group within any of R4, R4a, R5 and R5a optionally bears on each said CH2 or CH3 group one or more halogeno substituents or a substituent selected from hydroxy, cyano, (1-6C)alkoxy, amino, (2-6C)alkanoyl, (1-6C)alkylamino and di-(1-6C)alkylamino;
R6 is selected from hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-6C)alkyl, heterocyclyl and heterocyclyl-(1-6C)alkyl, and
wherein any heterocyclyl group within an R6 substituent optionally bears one or more substituents, 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)alkylamino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula:
\u2014X3\u2014R10;
X3 is a direct bond or is selected from O, CO, SO2 and N(R11),
R11 is hydrogen or (1-4C)alkyl, and R10 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)alkylamino-(1-4C)alkyl,
wherein any heterocyclyl group within an R6 substituent optionally bears 1 or 2 oxo or thioxo substituents; and
wherein any CH2 or CH3 group within a R6 substituent, other than a CH2 group within a heterocyclyl group, optionally bears on each said CH2 or CH3 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)alkylamino, N-(1-6C)alkylcarbamoyl, N,N-di-(1-6C)alkylcarbamoyl, (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)alkylsulfamoyl, (1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino;
A is selected from hydrogen, a group of the formula Z-(CR12R13)p\u2014 and R14;
p is 1, 2, 3, or 4,
each R12 and R13, which may be the same or different, is selected from hydrogen, (1-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl,
or an R12 and an R13 group attached to the same carbon atom form a (3-7C)cycloalkyl or (3-7C)cycloalkenyl ring,
wherein any CH2 or CH3 group within any of R12 and R13, optionally bears on each said CH2 or CH3 group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, cyano, (1-6C)alkyl, (1-6C)alkoxy, amino, (2-6C)alkanoyl, (1-6C)alkylamino and di-(1-6C)alkylamino,
Z is selected from hydrogen, OR15, NR16R17, (1-6C)alkylsulfonyl, (1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino,
each of R15, R16 and R17, which may be the same or different, is selected from hydrogen, (1-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl,
or Z is a group of the formula: Q2-X4\u2014;
X4 is selected from O, N(R18), SO2 and SO2N(R18);
R18 is hydrogen or (1-6C)alkyl;
Q2 is (3-7C)cycloalkyl, (3-7C)cycloalkenyl or heterocyclyl;
R14 is selected from hydrogen, OR19 and NR16R17;
R19 is selected from (1-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl, and wherein R16 and R17 are as defined above,
or R14 is a group of the formula: Q3-X5\u2014;
X5 is selected from O and N(R20), wherein R20 is hydrogen or (1-6C)alkyl;
Q3 is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl -(1-6C)alkyl, heterocyclyl and heterocyclyl-(1-6C)alkyl,
or R14 is Q4 wherein Q4 is (3-7C)cycloalkyl, (3-7C)cycloalkenyl or heterocyclyl,
wherein adjacent carbon atoms in any (2-6C)alkylene chain within a Z or R14 substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO2, N(R21), CO, \u2014C\u2550C\u2014 and \u2014C\u2261C\u2014;
R21 is hydrogen or (1-6C)alkyl,
wherein any heterocyclyl group within a Z or R14 substituent optionally bears one or more substituents, 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)alkylamino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula:
\u2014X6\u2014R22;
X6 is a direct bond or is selected from O, CO, SO2 and N(R23);
R23 is hydrogen or (1-4C)alkyl;
R22 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)alkylamino-(1-4C)alkyl,
wherein any heterocyclyl group within a Z or R14 substituent optionally bears 1 or 2 oxo or thioxo substituents, and
wherein any CH2 or CH3 group within a Z or R14 group, other than a CH2 group within a heterocyclyl ring, optionally bears on each said CH2 or CH3 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)alkylamino, N-(1-6C)alkylcarbamoyl, N,N-di-(1-6C)alkylcarbamoyl, (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)alkylsulfamoyl, (1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino;
or a pharmaceutically acceptable salt thereof.
3. A quinazoline derivative according to claim 1, wherein R4, R4a, R5 and R5a, which may be the same or different, are selected from hydrogen and (1-6C)alkyl, and wherein any CH2 or CH3 group within any of R4, R4a, R5 and R5a optionally bears on each said CH2 or CH3 group one or more halogeno substituents or a substituent selected from hydroxy, cyano, (1-6C)alkoxy, amino, (2-6C)alkanoyl, (1-6C)alkylamino and di-(1-6C) alkylamino.
4. A quinazoline derivative according to claim 1, wherein m is 0.
5. A quinazoline derivative according to claim 1, wherein R2 is hydrogen.
6. A quinazoline derivative according to claim 1, wherein n is 0, 1 or 2 and, when present, at least one R3 is in a meta-position (3-position) relative to the nitrogen of the anilino group in formula I.
7. A quinazoline derivative according to claim 1, wherein n is 1 and R3 is selected from halogeno and (1-4C)alkyl.
8. A quinazoline derivative according to claim 7, wherein R3 is chloro.
9. A quinazoline derivative according to claim 7, wherein R3 is methyl.
10. A quinazoline derivative according to claim 1, wherein X1 is selected from O, S, OC(R7)2, SC(R7)2, SO, SO2, N(R7), CO and N(R7)C(R7)2 wherein each R7, which may be the same or different, is selected from hydrogen or (1-6C)alkyl.
11. A quinazoline derivative according to claim 1, wherein X1 is selected from O, S and OC(R7)2 wherein each R7 is, independently, hydrogen or (1-4C)alkyl.
12. A quinazoline derivative according to claim 1, wherein X1 is OCH2.
13. A quinazoline derivative according to claim 1, wherein
Q1 is selected from phenyl and a 5- or 6-membered monocyclic heteroaryl ring, which ring contains 1, 2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, and
wherein Q1 optionally bears one or more substituents, which may be the same or different, selected from halogeno, hydroxy, (1-4C)alkyl (1-4C)alkoxy,
wherein any CH2 or CH3 group within \u2014X1-Q1 optionally bears on each said CH2 or CH3 group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, (1-4C)alkoxy, (1-4C)alkylamino and di-(1-4C)alkylamino.
14. A quinazoline derivative according to claim 1, wherein Q1 is selected from phenyl, pyridyl, pyrazinyl, 1,3-thiazolyl, 1H-imidazolyl, 1H-pyrazolyl, 1, 3-oxazolyl and isoxazolyl.
15. A quinazoline derivative according to claim 1,
wherein
R6 is selected from hydrogen, (1-3C)alkyl, (2-3C)alkenyl, (2-3C)alkynyl, (3-5C)cycloalkyl, (3-5C)cycloalkyl-(1-3C)alkyl, heterocyclyl and heterocyclyl-(1-3C)alkyl,
wherein any heterocyclyl group within R6 is a 4, 5, 6 or 7 membered monocyclic saturated or partially saturated heterocyclyl ring containing 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur, which heterocyclyl group is linked to the group to which it is attached by a ring carbon atom,
wherein any heterocyclyl group within an R6 substituent optionally bears one or more substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, 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)alkylamino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula:
\u2014X3\u2014R10;
X3 is a direct bond or is selected from O and N(R11);
R11 is hydrogen or (1-4C)alkyl;
R10 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)alkylamino-(1-4C)alkyl,
wherein any heterocyclyl group within an R6 substituent optionally bears 1 or 2 oxo substituents;
and wherein any CH2 or CH3 group within a R6 substituent, other than a CH2 group within a heterocyclyl group, optionally bears on each said CH2 or CH3 group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, amino, (1-6C)alkoxy, (1-6C)alkylamino and di-(1-6C)alkylamino.
16. A quinazoline derivative according to claim 15, wherein R6 is (1-3C)alkyl, and wherein any CH2 or CH3 group within a R6 substituent, other than a CH2 group within a heterocyclyl group, optionally bears on each said CH2 or CH3 group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, amino, (1-6C)alkoxy, (1-6C)alkylamino and di-(1-6C)alkylamino.
17. A quinazoline derivative according to claim 1,
wherein
A is selected from a group of the formula Z-(CR12R13)p\u2014 and R14;
p is 1, 2 or 3;
each R12 and R13, which may be the same or different, is selected from hydrogen and (1-6C)alkyl,
wherein any CH2 or CH3 group within any of R12 and R13 optionally bears on each said CH2 or CH3 group one or more halogeno substituents or a substituent selected from hydroxy and (1-6C)alkoxy,
Z is selected from hydrogen, OR15, NR16R17 and (1-6C)alkylsulfonyl;
each of R15, R16 and R17, which may be the same or different, is selected from hydrogen, (1-6C)alkyl and (1-6C)alkoxycarbonyl;
R14 is selected from OR19 and NR16R17;
R19 is selected from (1-6C)alkyl and wherein R16 and R17 are as defined above,
or R14 is Q4
Q4 is (3-7C)cycloalkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl,
wherein any heterocyclyl group within a Z or R14 substituent optionally bears one or more substituents, which may be the same or different, selected from halogeno, hydroxy, (1-6C)alkyl and (1-6C)alkoxy, and
wherein any CH2 or CH3 group within a Z or R14 group, other than a CH2 group within a heterocyclyl ring, optionally bears on each said CH2 or CH3 group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy and (1-6C)alkoxy.
18. A quinazoline derivative selected from one or more of the following:
N-{2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)anilino}quinazolin-5-yl)oxyethyl}-2-methoxy-N -methylacetamide;
N-{2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)anilino}quinazolin-5-yl)oxyethyl}-2-(dimethylamino)-N-methylacetamide;
N-{(2R)-2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)anilino}quinazolin-5-yl)oxypropyl}-2-methoxy-N-methylacetamide);
2-hydroxy-N-methyl-N-{2-(4-{3-methyl-4-(pyrazin-2-ylmethoxy)anilino}quinazolin-5-yl)oxyethyl}acetamide;
2-hydroxy-N-methyl-N-{2-(4-{3-methyl-4-(1,3-thiazol-4-ylmethoxy)anilino}quinazolin-5-yl)oxyethyl}acetamide;
2-hydroxy-N-methyl-N-(2-{4-(3-methyl-4-(5-methylisoxazol-3-yl)methoxyanilino)quinazolin -5-yloxy}ethyl)acetamide;
N-{(2R)-2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)anilino}quinazolin-5-yl)oxypropyl}-2-methoxyacetamide;
N-(2-{4-(3-chloro-4-(6-methylpyridin-2-yl)methoxyanilino)quinazolin-5-yloxy}ethyl)-2-hydroxy-N-methylacetamide;
N-((2R)-2-{4-(3-chloro-4-(6-methylpyridin-2-yl)methoxyanilino)quinazolin-5-yloxy}propyl) -2-hydroxy-N-methylacetamide;
N-(2-{4-(3-chloro-4-(6-methylpyridin-2-yl)methoxyanilino)quinazolin-5-yloxy}ethyl)-N -methylacetamide;
N-(2-{4-(3-chloro-4-(2-fluorobenzyl)oxyanilino)quinazolin-5-yloxy}ethyl)-N -methylacetamide;
N-(2-{4-(3-chloro-4-(3-fluorobenzyl)oxyanilino)quinazolin-5-yloxy}ethyl)-N -methylacetamide;
N-{2-(4-{3-chloro-4-(1,3-thiazol-4-ylmethoxy)anilino}quinazolin-5-yl)oxyethyl}-N -methylacetamide;
N-{2-(4-{3-chloro-4-(pyrazin-2-ylmethoxy)anilino}quinazolin-5-yl)oxyethyl}-N -methylacetamide;
N-{(2R)-2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)anilino}quinazolin-5-yl)oxypropyl}-2-hydroxyacetamide;
N-{2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)anilino}quinazolin-5-yl)oxyethyl}-N -methylacetamide;
2-hydroxy-N-methyl-N-{2-(4-{3-methyl-4-(pyridin-2-ylmethoxy)anilino}quinazolin-5-yl)oxyethyl}acetamide;
N-{(1R)-2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)anilino}quinazolin-5-yl)oxy-1-methylethyl}acetamide;
N-{(1R)-2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)anilino}quinazolin-5-yl)oxy-1-methylethyl}-2-hydroxyacetamide;
N-{2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)anilino}quinazolin-5-yl)oxyethyl}-2-hydroxy-N -methylacetamide;
N-(2-{4-(3-chloro-4-(3-fluorobenzyl)oxyanilino)quinazolin-5-yloxy}ethyl)-2-hydroxy-N -methylacetamide;
N-{2-(4-{3-chloro-4-(1,3-thiazol-4-ylmethoxy)anilino}quinazolin-5-yl)oxyethyl}-2-hydroxy-N -methylacetamide;
N-{2-(4-{3-chloro-4-(pyrazin-2-ylmethoxy)anilino}quinazolin-5-yl)oxyethyl}-2-hydroxy-N -methylacetamide;
N-{2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)anilino}quinazolin-5-yl)oxyethyl}acetamide;
N-{(2R)-2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)anilino}quinazolin-5-yl)oxypropyl}acetamide;
N-{(2R)-2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)anilino}quinazolin-5-yl)oxypropyl}-2-hydroxy-N-methylacetamide;
N-{(2R)-2-(4-{3-chloro-4-(pyrazin-2-ylmethoxy)anilino}quinazolin-5-yl)oxypropyl}-2-hydroxy-N-methylacetamide;
N-((2R)-2-{4-(3-chloro-4-(3-fluorobenzyl)oxyanilino)quinazolin-5-yloxy}propyl)-2-hydroxy -N-methylacetamide;
N-{(2R)-2-(4-{3-chloro-4-(1,3-thiazol-4-ylmethoxy)anilino}quinazolin-5-yl)oxypropyl}-2-hydroxy-N-methylacetamide;
N-{(2R)-2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)anilino}quinazolin-5-yl)oxypropyl}-N -methylacetamide;
N-{2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}-N -ethylacetamide;
N-{2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}-N-ethyl -2-hydroxyacetamide;
N-{2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}-N -propylacetamide;
N-{2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}-2-hydroxy-N-propylacetamide;
N-{2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}-N -isopropylacetamide;
N-{2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}-2-hydroxy-N-isopropylacetamide;
N-allyl-N-{2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}acetamide;
N-allyl-N-{2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}-2-hydroxyacetamide;
N-{2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}-N -cyclopropylacetamide;
N-{2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}-N -cyclopropyl-2-hydroxyacetamide;
N-{2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}-N -(cyclopropylmethyl)acetamide;
N-{2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}-N -(cyclopropylmethyl)-2-hydroxyacetamide;
N-{2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}-N -cyclobutylacetamide;
N-{2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}-N -cyclobutyl-2-hydroxyacetamide;
N-{2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}-N-(1-methylpiperidin-4-yl)acetamide;
N-{2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}-N -(tetrahydro-2H-pyran-4-yl)acetamide;
N-{2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}-2-hydroxy-N-(tetrahydro-2H-pyran-4-yl)acetamide;
N-{2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}-N-(2-hydroxyethyl)acetamide;
N-{2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}-2-hydroxy-N-(2-hydroxyethyl)acetamide;
N-{2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}-N-(2-methoxyethyl)acetamide;
N-{2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}-2-hydroxy-N-(2-methoxyethyl)acetamide;
N-{2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}-N-prop-2-yn-1-ylacetamide;
N-{2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}-2-hydroxy-N-prop-2-yn-1-ylacetamide;
N-{2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}-2-hydroxy-N-methylpropanamide;
N-{2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}-N -methyl-tetrahydrofuranyl-2-carboxamide;
N-{2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}-N,1-dimethylprolinamide;
N-{2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}-2-hydroxy-N,2-dimethylpropanamide;
N-{2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}-1-hydroxy-N-methylcyclopropanecarboxamide;
N1-{2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}-N1,N2-dimethylglycinamide;
N-{2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}-3-hydroxy-N,2,2-trimethylpropanamide;
N-{2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}-3-hydroxy-N-methylpropanamide;
N-{(2S)-2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxypropyl}acetamide;
N-{(2S)-2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxypropyl}-2-hydroxyacetamide;
N1-{(2S)-2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxypropyl}-N2,N2-dimethylglycinamide;
N-{(2S)-2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxypropyl}-2-methoxyacetamide;
N-{(2S)-2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxypropyl}-2-(methylsulfonyl)acetamide;
N-{2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}-2-hydroxyacetamide;
N1-{2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}-N2,N2-dimethylglycinamide;
N-{2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}-2-methoxyacetamide;
N-{2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}-2-(methylsulfonyl)acetamide;
N-{(2S)-2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxypropyl}-N -methylacetamide;
N-{(2S)-2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxypropyl}-2-hydroxy-N-methylacetamide;
N1-{(2S)-2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxypropyl}-N1,N2,N2-trimethylglycinamide;
N-{(2S)-2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxypropyl}-2-methoxy-N-methylacetamide;
N-{(2S)-2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxypropyl}-N -methyl-2-(methylsulfonyl)acetamide;
N-{(2R)-2-(4-{3-chloro-4-(pyrazin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxypropyl}-N-methylacetamide;
N-{(2R)-2-(4-{3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenylamino}quinazolin-5-yl)oxypropyl}-N-methylacetamide;
N-((2R)-2-{4-({3-chloro-4-(3-fluorobenzyl)oxyphenyl}amino)quinazolin-5-yloxy}propyl)-N -methylacetamide;
N-((2R)-2-{4-({3-chloro-4-(2-fluorobenzyl)oxyphenyl}amino)quinazolin-5-yloxy}propyl)-N -methylacetamide;
N-{(1R)-2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxy-1-methylethyl}-2-hydroxy-N-methylacetamide;
N-{(1R)-2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxy-1-methylethyl}-N-methylacetamide;
N-{(1S)-2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxy-1-methylethyl}-2-hydroxy-N-methylacetamide;
N-{(1S)-2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxy-1-methylethyl}-N-methylacetamide;
N-{(1S)-2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxy-1-methylethyl}-2-methoxy-N-methylacetamide;
N-{(1S)-2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxy-1-methylethyl}-2-hydroxyacetamide;
N-{(1S)-2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxy-1-methylethyl}acetamide;
N1-{(1S)-2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxy-1-methylethyl}-N2,N2-dimethylglycinamide;
N1-{(2R)-2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxypropyl}-N2,N2-dimethylglycinamide;
(2S)-N-{2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}-2,4-dihydroxybutanamide;
(2R)-N-{2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}-2,4-dihydroxybutanamide;
(2R)-N-{(2R)-2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxypropyl}-2,4-dihydroxybutanamide;
(2S)-N-{(2R)-2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxypropyl}-2,4-dihydroxybutanamide;
(2R)-N-{(2S)-2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxypropyl}-2,4-dihydroxybutanamide;
(2S)-N-{(2S)-2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxypropyl}-2,4-dihydroxybutanamide;
(2S)-N-{(1R)-2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxy-1-methylethyl}-2,4-dihydroxybutanamide;
(2R)-N-{(1R)-2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxy-1-methylethyl}-2,4-dihydroxybutanamide;
(2R)-N-{2-(4-{3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}-2,4-dihydroxybutanamide;
(2S)-N-{2-(4-{3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}-2,4-dihydroxybutanamide;
(2R)-N-{(1R)-2-(4-{3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenylamino}quinazolin-5-yl)oxy-1-methylethyl}-2,4-dihydroxybutanamide;
(2S)-N-{(1R)-2-(4-{3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenylamino}quinazolin-5-yl)oxy-1-methylethyl}-2,4-dihydroxybutanamide;
N-methyl-N-{2-(4-{3-methyl-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}acetamide;
N-methyl-N-{2-(4-{3-methyl-4-(1,3-thiazol-4-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}acetamide;
N-methyl-N-(2-{4-({3-methyl-4-(5-methylisoxazol-3-yl)methoxyphenyl}amino)quinazolin-5-yloxy}ethyl)acetamide;
2-hydroxy-N-methyl-N-{2-(4-{3-methyl-4-(1,3-thiazol-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}acetamide;
2-hydroxy-N-{2-(4-{3-methyl-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}acetamide;
2-hydroxy-N-{2-(4-{3-methyl-4-(1,3-thiazol-4-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}acetamide;
N-{2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxy-1,1-dimethylethyl}-2-hydroxyacetamide;
2-hydroxy-N-{(2R)-2-(4-{3-methyl-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxypropyl}acetamide;
2-hydroxy-N-{(2R)-2-(4-{3-methyl-4-(1,3-thiazol-4-ylmethoxy)phenylamino}quinazolin-5-yl)oxypropyl}acetamide;
N-((2R)-2-{4-({4-(3-fluorobenzyl)oxy-3-methylphenyl}amino)quinazolin-5-yloxy}propyl)-2-hydroxyacetamide;
2-hydroxy-N-{(2R)-2-(4-{3-methyl-4-(1,3-thiazol-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxypropyl}acetamide;
N-{(2R)-2-(4-{3-methyl-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxypropyl}acetamide;
N-{(2R)-2-(4-{3-methyl-4-(1,3-thiazol-4-ylmethoxy)phenylamino}quinazolin-5-yl)oxypropyl}acetamide;
N-((2R)-2-{4-({4-(3-fluorobenzyl)oxy-3-methylphenyl}amino)quinazolin-5-yloxy}propyl)acetamide;
N-{(2R)-2-(4-{3-methyl-4-(1,3-thiazol-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxypropyl}acetamide;
2-hydroxy-N-methyl-N-{(2R)-2-(4-{3-methyl-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxypropyl}acetamide;
2-hydroxy-N-methyl-N-{(2R)-2-(4-{3-methyl-4-(1,3-thiazol-4-ylmethoxy)phenylamino}quinazolin-5-yl)oxypropyl}acetamide;
2-hydroxy-N-methyl-N-((2R)-2-{4-({3-methyl-4-(5-methylisoxazol-3-yl)methoxyphenyl}amino)quinazolin-5-yloxy}propyl)acetamide;
N-methyl-N-{(1R)-1-methyl-2-(4-{3-methyl-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}acetamide;
N-methyl-N-{(1R)-1-methyl-2-(4-{3-methyl-4-(1,3-thiazol-4-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}acetamide;
N-{(1R)-2-(4-{3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenylamino}quinazolin-5-yl)oxy-1-methylethyl}-2-hydroxy-N-methylacetamide;
2-hydroxy-N-methyl-N-{(1R)-1-methyl-2-(4-{3-methyl-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}acetamide;
2-hydroxy-N-methyl-N-{(1R)-1-methyl-2-(4-{3-methyl-4-(1,3-thiazol-4-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}acetamide;
N-{(2R)-2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxypropyl}-1-hydroxy-N-methylcyclopropanecarboxamide;
(2S)-N-{(2R)-2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxypropyl}-2-hydroxy-N-methylpropanamide;
N-{(2R)-2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxypropyl}-2-hydroxy-N,2-dimethylpropanamide;
(2R)-N-{(2R)-2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxypropyl}-2-hydroxy-N-methylpropanamide;
(2R)-N-{(2R)-2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxypropyl}-2-methoxy-N-methylpropanamide;
2-hydroxy-N-methyl-N-((2R)-2-{4-({3-methyl-4-(6-methylpyridin-3-yl)oxyphenyl}amino)quinazolin-5-yloxy}propyl)acetamide;
N-methyl-N-((2R)-2-{4-({3-methyl-4-(6-methylpyridin-3-yl)oxyphenyl}amino)quinazolin-5-yloxy}propyl)acetamide;
N1,N2,N2-trimethyl-N1-((2R)-2-{4-({3-methyl-4-(6-methylpyridin-3-yl)oxyphenyl}amino)quinazolin-5-yloxy}propyl)glycinamide;
N-methyl-N-((2R)-2-{4-({3-methyl-4-(6-methylpyridin-3-yl)oxyphenyl}amino)quinazolin-5-yloxy}propyl)-2-pyrrolidin-1-ylacetamide;
N-methyl-N-((2R)-2-{4-({3-methyl-4-(6-methylpyridin-3-yl)oxyphenyl}amino)quinazolin-5-yloxy}propyl)-2-morpholin-4-ylacetamide;
N-methyl-N-((2R)-2-{4-({3-methyl-4-(6-methylpyridin-3-yl)oxyphenyl}amino)quinazolin-5-yloxy}propyl)-2-(4-methylpiperazin-1-yl)acetamide;
2-hydroxy-N-methyl-N-((2S)-2-{4-({3-methyl-4-(6-methylpyridin-3-yl)oxyphenyl}amino)quinazolin-5-yloxy}propyl)acetamide;
N-methyl-N-((2S)-2-{4-({3-methyl-4-(6-methylpyridin-3-yl)oxyphenyl}amino)quinazolin-5-yloxy}propyl)acetamide;
N-methyl-N-((2S)-2-{4-({3-methyl-4-(6-methylpyridin-3-yl)oxyphenyl}amino)quinazolin-5-yloxy}propyl)-2-pyrrolidin-1-ylacetamide;
(2S)-2,4-dihydroxy-N-((2R)-2-{4-({3-methyl-4-(6-methylpyridin-3-yl)oxyphenyl}amino)quinazolin-5-yloxy}propyl)butanamide;
(2S)-4-bromo-2-hydroxy-N-((2R)-2-{4-({3-methyl-4-(6-methylpyridin-3-yl)oxyphenyl}amino)quinazolin-5-yloxy}propyl)butanamide;
N-(2-chloroethyl)-N\u2032-((2R)-2-{4-({3-methyl-4-(6-methylpyridin-3-yl)oxyphenyl}amino)quinazolin-5-yloxy}propyl)urea;
2-hydroxy-N-methyl-N-((1R)-1-methyl-2-{4-({3-methyl-4-(6-methylpyridin-3-yl)oxyphenyl}amino)quinazolin-5-yloxy}ethyl)acetamide;
N-methyl-N-((1R)-1-methyl-2-{4-({3-methyl-4-(6-methylpyridin-3-yl)oxyphenyl}amino)quinazolin-5-yloxy}ethyl)acetamide;
2-hydroxy-N-methyl-N-((1S)-1-methyl-2-{4-({3-methyl-4-(6-methylpyridin-3-yl)oxyphenyl}amino)quinazolin-5-yloxy}ethyl)acetamide;
N-methyl-N-((1S)-1-methyl-2-{4-({3-methyl-4-(6-methylpyridin-3-yl)oxyphenyl}amino)quinazolin-5-yloxy}ethyl)acetamide;
methyl-{2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}methylcarbamate;
N-{2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}-N,N\u2032-dimethylurea;
N\u2032-(2-chloroethyl)-N-{2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxyethyl}-N-methylurea;
N-{(2R)-2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxypropyl}-N\u2032-methylurea;
((R)-2-{4-3-chloro-4-(pyridin-2-ylmethoxy)phenylaminoquinazolin-5-yloxy}propylcarbamoyl)methylmethylcarbamic acid tert-butyl ester;
N1-{(2R)-2-(4-{3-chloro-4-(pyridin-2-ylmethoxy)phenylamino}quinazolin-5-yl)oxypropyl}-N2-methylglycinamide;
2-hydroxy-N-methyl-N-(2-{4-({3-methyl-4-(6-methylpyridin-3-yl)oxyphenyl}amino)quinazolin-5-yloxy}ethyl)acetamide;
N-methyl-N-(2-{4-({3-methyl-4-(6-methylpyridin-3-yl)oxyphenyl}amino)quinazolin-5-yloxy}ethyl)acetamide; and
N-{2-(4-{3-chloro-4-(1-methyl-1-pyridin-2-ylethoxy)phenylamino}quinazolin-5-yl)oxyethyl}-N-methylacetamide;
or a pharmaceutically acceptable salt thereof.
19. A pharmaceutical composition which comprises a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, as defined in claim 1 or claim 18 in association with a pharmaceutically-acceptable diluent or carrier.
20. A process for the preparation of a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, as defined in claim 1 which comprises:
a) the coupling, optionally in the presence of a suitable base, of a quinazoline of the formula II:
\u2003wherein R1, R2, R3, R4, R4a, R5, R5a, R6, X1, Q1, m, and n have any of the meanings defined in claim 1 except that any functional group is optionally protected, with a carboxylic acid of the formula III, or a reactive derivative thereof:
A-COOH\u2003\u2003III
\u2003wherein A has any of the meanings defined in claim 1 except that any functional group is optionally protected; or
(b) for the preparation of those compounds of the formula I wherein X1 is OC(R7)2, SC(R7)2 or N(R7)C(R7)2, the reaction, conveniently in the presence of a suitable base, of a quinazoline of the formula IV:
\u2003wherein X1a is O, S or N(R7) and R1, R2, R3, R4, R4a, R5, R5a, R6, R7, A, m, and n have any of the meanings defined in claim 1 except that any functional group is optionally protected, with a compound of the formula V or a salt thereof:
Q1-C(R7)2-L1\u2003\u2003V
\u2003wherein L1 is a suitable displaceable group and Q1 and R7 have any of the meanings defined in claim 1 except that any functional group is optionally protected; or
(c) for the preparation of those compounds of the formula I wherein A is R14 and R14 is NHR17 or Q3-X5\u2014 (wherein R17 and Q3 are as defined in claim 1 and X5 is NH), the coupling of a quinazoline of the formula II as defined above in (a) with an isocyanate of the formula IIIa:
A-NCO\u2003\u2003IIIa
\u2003wherein A is R14 as previously defined in this section except that any functional group is optionally protected; or
(d) the reaction of a quinazoline of the formula II wherein R6 is hydrogen:
\u2003wherein R1, R2, R3, R4, R4a, R5, R5a, X1, Q1, m, and n have any of the meanings defined in claim 1 except that any functional group is optionally protected, with \u03b1-hydroxy-\u03b3-butyrolactone wherein any functional group is optionally protected; or
(e) the coupling of a quinazoline of the formula VI:
\u2003wherein R1, R4, R4a, R5, R5a, R6, A and m have any of the meanings defined in claim 1 except that any functional group is optionally protected, with a compound of the formula IIb:
\u2003wherein R2, R3, X1, Q1 and n have any of the meanings defined in claim 1 except that any functional group is optionally protected;
(f) for the preparation of those compounds of the formula I wherein X1 is O and Q1 is 2-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 2-pyrazinyl or 3-pyridazinyl, reacting, optionally in the presence of a suitable base and a suitable catalyst, of a quinazoline of the formula VII:
\u2003wherein R1, R2, R3, R4, R4a, R5, R5a, R6, A, m and n have any of the meanings defined in claim 1 except that any functional group is optionally protected, with 2-bromopyridine, 4-bromopyridine, 2-chloropyrimidine, 4-chloropyrimidine, 2-chloropyrazine or 3-chloropyridazine; or
(g) for the preparation of those compounds of the formula I wherein A is Z-(CR12R13)p\u2014, wherein Z is NR16R17, the reaction, conveniently in the presence of a suitable base, of a quinazoline of the formula VIII:
\u2003wherein L1 is a suitable displaceable group and R1, R2, R3, R4, R4a, R5, R5a, R6, R12, R13, X1, Q1, m, n and p have any of the meanings defined in claim 1 except that any functional group is optionally protected, with a compound of the formula IXa, or a reactive derivative thereof:
H\u2014NR16R17\u2003\u2003IXa
\u2003wherein R16 and R17 have any of the meanings defined in claim 1 except that any functional group is optionally protected;
and thereafter, optionally;
(i) removing any protecting group that is present;
(ii) forming a pharmaceutically acceptable salt.
21. A method for treating a breast tumour in a warm-blooded animal in need of such treatment, which comprises administering to the animal an effective amount of a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, according to claim 1.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. An electric power system comprising:
a weather data input means for inputting weather data, temperature, atmospheric pressure and weather, at predetermined time intervals, in the district of an operating transmission line;
a digital processing unit;
a memory means for storing said transmission line data that shows relations between a corona discharge start voltage and weather conditions at each transmission line, and processed data by said digital processing unit; and
a power system analysis means,
wherein said digital processing unit calculates the corona discharge start voltage at said transmission line by the data on weather forecasts and said transmission line data,
if the calculated corona discharge start voltage is lower than a normal transmission voltage of the line, a countermeasure transmission voltage that is recorded in said memory means in advance is selected to set a transmission voltage of the transmission line or stop transmitting electric power on the transmission line, and
if the calculated corona discharge start voltage is above the normal transmission voltage of the line, the normal transmission voltage is selected as the set transmission voltage of the transmission line, and
wherein said power system analysis means analyzes loads of apparatuses of the power system.
2-11. (canceled)
12. The electric power system as claimed in claim 1,
wherein the calculation of the corona discharge start voltage by said digital processing unit is executed as follows:
(1) the transmission line is an object for which a corona discharge is to be suppressed,
(2) said digital processing unit reads data to determine whether past data should be used or not, and if the past data should be used, the past data recorded in said memory means is used for the corona discharge start voltage, and
(3) if the past data cannot be used, the corona discharge start voltage at the transmission line is calculated by substituting the weather forecast data and the transmission data in an equation.
13. The electric power system comprising:
a corona discharge detection means;
a digital processing unit;
a memory means for storing transmission line data and processed data by said digital processing unit;
a power system analysis means;
a weather detecting means; and
a transmitter,
wherein said digital processing unit stops a corona discharge in a short time by lowering a transmission voltage of a transmission line that generates the corona discharge, or stops transmitting electric power in the transmission line when said corona discharge detection means detects a corona discharge, and
wherein said power system analysis means adjusts loads of apparatuses in the electric power system.
14. The electric power system as claimed in claim 13,
wherein said digital processing unit stores weather conditions in said memory means before and after occurrence of a corona discharge, and
changes the transmission voltage to a previous one, when weather conditions are assumed not to generate a corona discharge.
15. The electric power system as claimed in claim 13,
wherein said corona discharge detection means is an ultraviolet light detecting device.
16. The electric power system as claimed in claim 13,
wherein said corona discharge detection means is an ultraviolet light detecting device that detects ultraviolet light of a wavelength 100 nm to 320 nm.
17. The electric power system as claimed in claim 13,
wherein said digital processing unit restores the previous transmission voltage on a predetermined time after lowering the transmission voltages.
18. An electric power system operating method comprising:
inputting weather data, temperature, atmospheric pressure and weather at predetermined time intervals;
calculating a corona discharge start voltage at a transmission line and deciding a set transmission voltage of the transmission line by a digital processing unit;
storing transmission line data and processed data in memory means by a digital processing unit; and
analyzing loads of apparatuses of the power system by a power system analysis means.
19. The electric power system operating method as claimed in claim 18,
wherein the calculating the corona discharge start voltage includes:
(1) judging whether or not the transmission line is an object for which a corona discharge is to be suppressed,
(2) deciding whether past data should be used or not, and if the past data should be used, the past data recorded in said memory means is used for the corona discharge start voltage,
(3) calculating the corona discharge start voltage at the transmission line by substituting weather forecast data and the transmission data in an equation, if the past data cannot be used.
20. An electric power system operating method comprising:
detecting a corona discharge on a transmission line;
stopping the corona discharge in a short time by lowering a transmission voltage of a transmission line that generates the corona discharge, or stopping transmitting electric power in the transmission line;
adjusting loads of apparatuses in the electric power system; and
operating the apparatuses under an adjusted condition for supplying electric power.
21. The electric power system operating method as claimed in claim 20, further comprising:
storing weather conditions in a memory means before and after occurrence of a corona discharge; and
changing the transmission voltage to a previous one, when weather conditions are assumed not to generate a corona discharge.