Oxindolylquinazoline derivatives as angiogenesis inhibitors

• US 6,294,532 B1
• Filed: 05/03/2000
• Issued: 09/25/2001
• Est. Priority Date: 08/22/1997
• Status: Expired due to Fees

• Current Assignee: Astrazeneca UK Limited (Astrazeneca PLC)
• Original Assignee: Zeneca Incorporated (Astrazeneca PLC)
• Inventors: Hennequin, Laurent Francois Andre, Thomas, Andrew Peter, Lohmann, Jean-Jacques Marcel, Ple, Patrick
• Primary Examiner(s): Kifle, Bruck
• Application Number:
  US09/486,051
• Time in Patent Office: 510 Days
• Field of Search: 544/116, 544/117, 544/284, 544/280, 544/58.2, 514/233.8, 514/234.2, 514/234.5, 514/259, 514/258, 514/228.2, 514/228.5
• US Class Current: 514/228.2
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

The invention relates to compounds of formula (I)

and salts thereof as further defined herein, wherein ring Z is a 6-membered heterocyclic ring containing 1 to 3 nitrogen atoms, and the use of such compounds and salts to inhibit the effects of VEGF and FGF, and in the treatment of a number of disease states including cancer and rheumatoid arthritis.

Claims

1. A compound of the formula I:

wherein;

ring Z is a 6-membered heterocyclic ring containing 1 to 3 nitrogen atoms with the proviso that the group at the 4-position of the quinazoline ring is not a substituted or unsubstituted group selected from 4,5,7-triazaoxindol-3-yl and 4,6,7-triazaoxindol-3-yl;

R¹ represents hydrogen, C_1-4alkyl, C_1-4alkoxymethyl, di(C_1-4alkoxy)methyl or C_1-4alkanoyl;

R² represents hydroxy, halogeno, C_1-3alkyl, C_1-3alkoxy, C_1-3alkanoyloxy, trifluoromethyl, 2,2,2-trifluoroethyl, cyano, amino, nitro, C_2-4alkanoyl, C_1-4alkanoylamino, C_1-4alkoxycarbonyl, C_1-4alkylthio, C_1-4alkylsulphinyl, C_1-4alkylsulphonyl, carbamoyl, N-C_1-4alkylcarbamoyl, N,N-di(C_1-4alkyl)carbamoyl, aminosulphonyl,

N-C_1-4alkyl-aminosulphonyl, N,N-di(C_1-4alkyl)aminosulphonyl or

C_1-4alkylsulphonylamino or R² is selected from one of the following four groups;

1) R⁴X¹ wherein X¹ represents a direct bond, —

O—

, —

NR⁵—

, C_1-3alkyl, C_2-4alkanoyl, —

CONR⁶R⁷—

, —

SO₂NR⁸R⁹—

or —

SO₂R¹⁰—

(wherein R⁵, R⁶ and R⁸, each independently represents hydrogen or C_1-2alkyl and R⁷, R⁹ and R¹⁰ each independently represents C_1-4alkyl and wherein R⁴ is linked to R⁷, R⁹ or R¹⁰) and R⁴ represents phenyl or a 5 or 6-membered heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may be saturated or unsaturated and which phenyl or heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C_1-3alkyl, C_1-3alkoxy, C_1-3alkanoyloxy, trifluoromethyl, cyano, amino, nitro and C_1-4alkoxycarbonyl;

2) X²C_2-4alkylX³C_1-3alkyl (wherein X² is —

O—

or —

NR¹¹—

(wherein R¹¹ is hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and X³ is —

O—

, —

NR¹²—

, —

S—

, —

SO—

or —

SO₂—

(wherein R¹² is hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl);

3) C_1-2alkylX⁴C_2-3alkylX⁵C_1-3alkyl (wherein X⁴ and X⁵ which may be the same or different are each —

O—

, —

S—

, —

SO—

, —

SO₂—

or —

NR¹³—

(wherein R¹³ is hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl); and

4) C_1-3alkylX⁶C_1-3alkyl (wherein X⁶ is —

O—

, —

S—

, —

SO—

, —

SO₂—

or —

NR¹⁴—

(wherein R¹⁴ is hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl);

n is an integer from 0 to 3;

m is an integer from 0 to 4; and

R³ represents hydroxy, halogeno, nitro, trifluoromethyl, C_1-3alkyl, cyano, amino or R¹⁵X⁷, wherein X⁷ represents a direct bond, —

O—

, —

CH₂—

, —

S—

, —

SO—

, —

SO₂—

, —

NR¹⁶CO—

, —

CONR¹⁷—

, —

SO₂NR¹⁸—

, —

NR¹⁹SO₂—

or —

NR²⁰—

(wherein R¹⁶, R¹⁷, R¹⁸, R¹⁹ and R²⁰ each independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl), and R¹⁵ is selected from one of the following seventeen groups;

1) hydrogen or C_1-5alkyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro and amino;

2) C_1-5alkylX⁸COR²¹, wherein X⁸ represents —

O—

or —

NR²²—

(in which R²² represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R²² represents C_1-3alkyl, —

NR²³R²⁴—

or —

OR²⁵—

(wherein R²³, R²⁴ and R²⁵ which may be the same or different each represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl);

3) C_1-5alkylX⁹R²⁶, wherein X⁹ represents —

O—

, —

S—

, —

SO—

, —

SO₂—

, —

OCO—

, —

NR²⁷CO—

, —

CONR²⁸—

, —

SO₂NR²⁹—

, —

NR³⁰SO₂—

or —

NR³¹—

(wherein R²⁷, R²⁸, R²⁹, R³⁰ and R³¹ each independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R²⁶ represents hydrogen, C_1-3alkyl, cyclopentyl, cyclohexyl or a 5 or 6-membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which C_1-3alkyl group may bear one or two substituents selected from oxo, hydroxy, halogeno and C_1-4alkoxy and which cyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C_1-4alkyl, C_1-4hydroxyalkyl and C_1-4alkoxy;

4) C_1-5alkylX¹⁰C_1-5alkylX¹¹R³², wherein X¹⁰ and X¹¹ which may be the same or different are each —

O—

, —

S—

, —

SO—

, —

SO₂—

, —

NR³³CO—

, —

CONR³⁴—

, —

SO₂NR³⁵—

, —

NR³⁶SO₂—

or —

NR³⁷—

(wherein R³³, R³⁴, R³⁵, R³⁶ and R³⁷ each independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R³² represents hydrogen or C_1-3alkyl;

5) R³⁸, wherein R³⁸ is a 5 or 6-membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C_1-4alkyl, C_1-4hydroxyalkyl and C_1-4alkoxy;

6) C_1-5alkylR³⁸, wherein R³⁸ is as defined herein;

7) C_2-5alkenylR³⁸, wherein R³⁸ is as defined herein;

8) C_2-5alkynylR³⁸, wherein R³⁸ is as defined herein;

9) R³⁹, wherein R³⁹ represents a pyridone group, a phenyl group or a 5 or 6-membered aromatic heterocyclic group with 1 to 3 heteroatoms selected from O, N and S, which pyridone, phenyl or heterocyclic group may carry up to 5 substituents selected from hydroxy halogeno, amino, C_1-4alkyl, C_1-4alkoxy, C_1-4hydroxyalkyl, C_1-4aminoalkyl, C_1-4alkylamino, C_1-4hydroxyalkoxy, carboxy, trifluoromethyl, cyano, —

CONR⁴⁰R⁴¹ and —

NR⁴²COR⁴³—

(wherein R⁴⁰, R⁴¹, R⁴² and R⁴³, which may be the same or different, each represents hydrogen, C_1-4alkyl or C_1-3alkoxyC_2-3alkyl);

10) C_1-5alkylR³⁹, wherein R³⁹ is as defined herein;

11) C_2-5alkenylR³⁹, wherein R³⁹ is as defined herein;

12) C_2-5alkynylR³⁹, wherein R³⁹ is as defined herein;

13) C_1-5alkylX¹²R³⁹, wherein X¹² represents —

O—

, —

S—

, —

SO—

, —

SO₂—

, —

NR⁴⁴CO—

, —

CONR⁴⁵—

, —

SO₂NR⁴⁶—

, —

NR⁴⁷SO₂—

or —

NR⁴⁸—

(wherein R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷ and R⁴⁸ each independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R³⁹ is as defined herein;

14) C_2-5alkenylX¹³R³⁹, wherein X¹³ represents —

O—

, —

S—

, —

SO—

, —

SO₂—

, —

NR⁴⁹CO—

, —

CONR⁵⁰—

, —

SO₂NR⁵¹—

, —

NR⁵²SO₂—

or —

NR⁵³—

(wherein R⁴⁹, R⁵⁰, R⁵¹, R⁵² and R⁵³ each independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R³⁹ is as defined herein;

15) C_2-5alkynylX¹⁴R³⁹, wherein X¹⁴ represents —

O—

, —

S—

, —

SO—

, —

SO₂—

, —

NR⁵⁴CO—

, —

CONR⁵⁵—

, —

SO₂NR⁵⁶—

, —

NR⁵⁷SO₂—

or —

NR⁵⁸—

(wherein R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷ and R⁵⁸ each independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R³⁹ is as defined herein;

16) C_1-3alkylX¹⁵C_1-3alkylR³⁹, wherein X¹⁵ represents —

O—

, —

S—

, —

SO—

, —

SO₂—

, —

NR⁵⁹CO—

, —

CONR⁶⁰—

, —

SO₂NR⁶¹—

, —

NR⁶²SO₂—

or —

NR⁶³—

(wherein R⁵⁹, R⁶⁰, R⁶¹, R⁶² and R⁶³ each independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R³⁹ is as defined herein); and

17) C_1-3alkylX¹⁵C_1-3alkylR³⁸, wherein X¹⁵ and R³⁸ are as defined herein;

and salts thereof.

2. A compound as claimed in claim 1 wherein ring Z is a 6-membered heterocyclic ring containing 1 or 2 nitrogen atoms with the proviso that where R² is a group R⁴X¹, X¹ is not C_2-4alkanoyl or —

SO₂R¹⁰— and

R⁴ is not optionally substituted phenyl or an optionally substituted 5 or 6-membered unsaturated heterocyclic ring.

3. A compound as claimed in claim 1 or 2 wherein R¹ is hydrogen.

4. A compound as claimed in claim 1 or 2 wherein R² is halogeno, C_1-2alkyl, C_1-2alkoxy, trifluoromethyl, 2,2,2-trifluoroethyl, cyano, nitro, C_1-3alkanoylamino, C_1-3alkylsulphonyl, carbamoyl, N-C_1-3alkylcarbamoyl, N,N-di(C_1-3alkyl)carbamoyl, aminosulphonyl, N-C_1-3alkylaminosulphonyl, N,N-di(C_1-3alkyl)aminosulphonyl or C_1-3alkylsulphonylamino or R is selected from one of the following four groups:

1) R⁴X¹ wherein X¹ represents —

O—

, —

NR⁵—

, C_1-3alkyl, —

CONR⁶R⁷—

or —

SO₂NR⁸R⁹—

(wherein R⁵, R⁶, and R⁸, each independently represents hydrogen or C_1-2alkyl and R⁷ and R9 each independently represents C_1-3alkyl and wherein R⁴ is linked to R⁷ or R⁹) and R⁴ represents a 5 or 6-membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear two oxo substituents on a ring sulphur heteroatom;

2) X²C_2-3alkylX³methyl, wherein X² is —

O—

or —

NR¹¹—

(wherein R¹¹ is hydrogen or C_1-2alkyl) and X³ is —

O—

, —

NR¹²—

or —

SO₂—

(wherein R¹² is hydrogen or C_1-2alkyl);

3) C_1-2alkylX⁴C_2-3alkylX⁵methyl, wherein X⁴ and X⁵ which may be the same or different are each —

NR¹³—

or —

SO₂—

(wherein R¹³ is hydrogen or C_1-2alkyl); and

4) C_1-2alkylX⁶C_1-2alkyl, wherein X⁶ is —

O—

, —

NR¹⁴—

or —

SO₂—

(wherein R¹⁴ is hydrogen or C_1-2alkyl).

5. A compound as claimed in claim 1 or 2 wherein R³ is hydroxy, halogeno, nitro, trifluoromethyl, C_1-3alkyl, cyano, amino or R¹⁵X⁷ wherein X⁷ is as defined in claim 1 and R¹⁵ is selected from one of the following fifteen groups:

1) C_1-3alkyl which may be unsubstituted or substituted with one or more fluorine atoms, or C_2-3alkyl which may be unsubstituted or substituted with one or two groups selected from hydroxy and amino;

2) 2-(3,3-dimethylureido)ethyl, 3-(3,3-dimethylureido)propyl, 2-(3-methylureido)ethyl, 3-(3-methylureido)propyl, 2-ureidoethyl, 3-ureidopropyl, 2-(N,N-dimethylcarbamoyloxy)ethyl, 3-(N,N-dimethylcarbamoyloxy)propyl, 2-(N-methylcarbamoyloxy)ethyl, 3-(N-methylcarbamoyloxy)propyl, 2-(carbamoyloxy)ethyl, 3-(carbamoyloxy)propyl;

1

3) C_2-3alkylX⁹R²⁶, wherein X⁹ is as defined in claim 1 and R²⁶ is a group selected from C_1-2alkyl, cyclopentyl, cyclohexyl, pyrrolidinyl and piperidinyl which group is linked to X⁹ through a carbon atom and which C_1-2alkyl group may bear one or two substituents selected from hydroxy, halogeno and C_1-2alkoxy and which cyclopentyl, cyclohexyl, pyrrolidinyl or piperidinyl group may carry one substituent selected from oxo, hydroxy, halogeno, C_1-2alkyl, C_1-2hydroxyalkyl and C_1-2alkoxy;

4) C_2-3alkylX¹⁰C_2-3alkylX¹¹R³², wherein X¹⁰ and X¹¹ arc as defined in claim 1 and R³² represents hydrogen or C_1-2alkyl;

5) R³⁸, wherein R³⁸ is as defined in claim 1;

6) C_1-2alkylR⁶⁷ (wherein R⁶⁷ is a group selected from pyrrolidinyl, piperazinyl, piperidinyl, 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl and 1,3-dithian-2-yl, which group is linked to C_1-2alkyl through a carbon atom and which group may carry one substituent selected from oxo, hydroxy, halogeno, C_1-2alkyl, C_1-2hydroxyalkyl and C_1-2alkoxy) or C_2-3akylR⁶⁸ (wherein R⁶⁸ is a group selected from morpholino, thiomorpholino, piperidino, piperazin-1-yl and pyrrolidin-1-yl which group may carry one or two substituents selected from oxo, hydroxy, halogeno, C_1-2alkyl, C_1-2hydroxyalkyl and C_1-2alkoxy);

7) R³⁹, wherein R³⁹ is as defied in claim 1;

8) C₄alkylR³⁹, wherein R³⁹ is as defined in claim 1;

9) 1-R³⁹but-2-en-4-yl, wherein R³⁹ is as defined in claim 1;

10) 1-R³⁹but-2-yn-4-yl, wherein R³⁹ is as defined in claim 1;

11) C_2-4alkylX¹²R³⁹, wherein X¹² and R³⁹ are as defined in claim 1;

12) 1-(R³⁹X¹³)but-2-en-4-yl, wherein X¹³ and R³⁹ are as defined in claim 1;

13) 1-(R³⁹X¹⁴)but-2-yn-4-yl, wherein X¹⁴ and R³⁹ are as defined in claim 1;

14) ethylX¹⁵methylR³⁹, wherein X¹⁵ and R³⁹ are as defined in claim 1; and

15) ethylX¹⁵methylR³⁸, wherein X¹⁵ and R³⁸ are as defined in claim 1.

13. A compound as claimed in claim 6 or 7 wherein R^5a is selected from one of the following fifteen groups:

1) C_1-3alkyl which may be unsubstituted or substituted with one or more fluorine atoms, or C_2-3alkyl which may be unsubstituted or substituted with one or two groups selected from hydroxy and amino;

2) 2-(3,3-dimethylureido)etlhyl, 3-(3,3-dimethylureido)propyl, 2-(3-methylureido)ethyl, 3-(3-methylureido)propyl, 2-ureidoethyl, 3-ureidopropyl, 2-(N,N-dimethylcarbamoyloxy)ethyl, 3-(N,N-dimethylcarbamoyloxy)propyl, 2-(N-methylcarbamoyloxy)ethyl, 3-(N-methylcarbamoyloxy)propyl, 2-(carbamoyloxy)ethyl, 3-(carbamoyloxy)propyl;

3) C_2-3alkylX^4aR^24a, wherein X^4a is as defined in claim 6 and R^24a is a group selected from C_1-2alkyl, cyclopentyl, cyclohexyl, pyrrolidinyl and piperidinyl which group is linked to X^4a through a carbon atom and which C_1-2alkyl group may bear one or two substituents selected from hydroxy, halogeno and C_1-2alkoxy and which cyclopentyl, cyclohexyl, pyrrolidinyl or piperidinyl group may carry one substituent selected from oxo, hydroxy, halogeno, C_1-2alkyl, C_1-2hydroxyalkyl and C_1-2alkoxy;

4) C_2-3alkylX^5aC_2-3alkylX^6aR^30a, wherein X^5a and X^6a are as defined in claim 6 and R^30a represents hydrogen or C_1-2alkyl;

5) R^36a, wherein R^36a is as defined in claim 6;

6) C_1-2alkylR^65a (wherein R^65a is a group selected from pyrrolidinyl, piperazinyl, piperidinyl, 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl and 1,3-dithian-2-yl, which group is linked to C_1-2alkyl through a carbon atom and which group may carry one substituent selected from oxo, hydroxy, halogeno, C_1-2alkyl, C_1-2hydroxyalkyl and C_1-2alkoxy) or C_2-3alkylR^66a (wherein R^66a is a group selected from morpholino, thiomorpholino, piperidino, piperazin-1-yl and pyrrolidin-1-yl which group may carry one or two substituents selected from oxo, hydroxy, halogeno, C_1-2alkyl, C_1-2hydroxyalkyl and C_1-2alkoxy);

7) R^37a, wherein R^37a is as defined in claim 6;

8) C_1-4alkylR^37a, wherein R^37a is as defined in claim 6;

9) 1-R^37abut-2-en-4-yl, wherein R^37a is as defined in claim 6;

10) 1-R^37abut-2-yn-4-yl, wherein R^37a is as defined in claim 6;

11) C_2-4alkylX^7aR^37a, wherein X^7a and R^37a are as defined in claim 6;

12) 1-(R^37aX^8a)but-2-en-4-yl, wherein X^8a and R^37a are as defined in claim 6;

13) 1-(R^37aX^9a)but-2-yn-4-yl, wherein X^9a and R^37a are as defined in claim 6;

14) ethylX^10amethylR^37a, wherein X^10a and R^37a are as defined in claim 6; and

15) ethylX^10amethylR^36a, wherein X^10a and R^36a are as defined in claim 6.

18. A compound as claimed in any one of claims 1, 6, 14, 15, 16 and 17 in the form of a pharmaceutically acceptable salt.

19. A process for the preparation of a compound of formula I or salt thereof, as defined in claim 1, which comprises:

(a) the reaction of a compound of the formula III;

 

wherein R³ and m are as defined in claim 1 and L¹ is a displaceable moiety, with a compound of the formula IV;

 

wherein R¹, R² ring Z and n are as defined in claim 1, whereby to obtain compounds of the formula I and salts thereof;

(b) the deprotection of a compound of formula V;

 

wherein R², R³, n, ring Z and m are as defined in claim 1 and P¹ represents a protecting group;

(c) the reduction and cyclisation of a compound of formula VI;

 

wherein R², R³, m, ring Z and n are as defined in claim 1 and Y represents cyano, carboxy or C_1-4alkoxycarbonyl;

(d) for the preparation of those compounds of formula I and salts thereof wherein at least one of the R² groups is hydroxy, the deprotection of a compound of formula VII;

 

wherein R¹, R², R³, n, ring Z and m are as defined in claim 1, P² represents a phenolic hydroxy protecting group and p1 is an integer from 1 to 3 equal to the number of protected hydroxy groups and such that n−

p1 is equal to the number of R² substituents which are not protected hydroxy;

(e) for the preparation of those compounds of formula I and salts thereof wherein at least one R³ is R¹⁵X⁷ wherein R¹⁵ is as defined in claim 1 and X⁷ is —

O—

, —

S—

, —

SO₂—

, —

CONR¹⁷, —

SO₂NR¹⁸—

or —

NR²⁰—

(wherein R¹⁷, R¹⁸ and R²⁰ each independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) the reaction of a compound of the formula VIII;

 

wherein R¹, R², R³, n, ring Z and X⁷ are as defined in claim 1 and s is an integer from 0 to 3, with a compound of formula IX;

20. A pharmaceutical composition which comprises as active ingredient a compound as claimed in any one of claims 1, 6, 14, 15, 16 and 17, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient or carrier.

21. A method for producing an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal in need of such treatment which comprises administering to said animal an effective amount of a compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof.

22. A method for the treatment, in a warm blooded animal in need thereof, of a primary or recurrent solid tumor that is dependent on VEGF and/or FGF for its growth and spread, said method comprising administering to said animal an effective amount of a compound as claimed in any one of claims 1, 6, 14, 15, 16 and 17, or a pharmaceutically acceptable salt thereof.

23. The method of claim 22, wherein said tumor is a tumor of the colon, breast, prostate, lung, vulva or skin.

6. A compound of the formula Ia:

wherein;

ring Z is a 5 or 6-membered heterocyclic ring containing 1 to 3 nitrogen atoms with the proviso that the group at the 4-position of the quinazoline ring is not a substituted or unsubstituted group selected from 4,5,7-triazaoxindol-3-yl and 4,6,7-triazaoxindol-3-yl;

R¹ represents hydrogen, C_1-4alkyl, C_1-4alkoxymethyl, di(C_1-4alkoxy)methyl or C_1-4alkanoyl;

R² represents hydroxy, halogeno, C_1-3alkyl, C_1-3alkoxy, C_1-3alkanoyloxy, trifluoromethyl, 2,2,2-trifluoroethyl, cyano, amino, nitro, C_2-4alkanoyl, C_1-4alkanoylamino, C_1-4alkoxycarbonyl, C_1-4alkylthio, C_1-4alkylsulphinyl, C_1-4alkylsulphonyl, carbamoyl, N-C_1-4alkylcarbamoyl, N,N-di(C_1-4alkyl)carbamoyl, aminosulphonyl, N-C_1-4alkyl-aminosulphonyl, N,N-di(C_1-4alkyl)aminosulphonyl or C_1-4alkylsulphonylamino or R² is selected from one of the following four groups;

1) R⁴X¹ wherein X¹ represents a direct bond, —

O—

, —

NR⁵—

, C_1-3alkyl, C_2-4alkanoyl, —

CONR⁶R⁷—

, —

SO₂NR⁸R⁹—

or —

SO₂R¹⁰—

(wherein R⁵, R⁶ and R⁸, each independently represents hydrogen or C_1-2alkyl and R⁷, R⁹ and R¹⁰ each independently represents C_1-4alkyl and wherein R⁴ is linked to R⁷, R⁹ or R¹⁰) and R⁴ represents phenyl or a 5 or 6-membered heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may be saturated or unsaturated and which phenyl or heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C_1-3alkyl, C_1-3alkoxy, C_1-3alkanoyloxy, trifluoromethyl, cyano, amino, nitro and C_1-4alkoxycarbonyl;

2) X²C_2-4alkylX³C_1-3alkyl (wherein X² is —

O—

or —

NR¹¹—

(wherein R¹¹ is hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and X³ is —

O—

, —

NR¹²—

, —

S—

, —

SO—

or —

SO₂—

(wherein R¹² is hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl);

3) C_1-2alkylX⁴C_2-3alkylX⁵C_1-3alkyl (wherein X⁴ and X⁵ which may be the same or different are each —

O—

, —

S—

, —

SO—

, —

SO₂—

or —

NR¹³—

(wherein R¹³ is hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl); and

4) C_1-3alkylX⁶C_1-3alkyl (wherein X⁶ is —

O—

, —

S—

, —

SO—

, —

SO₂—

or —

NR¹⁴—

(wherein R¹⁴ is hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl);

is an integer from 0 to 3;

R^3a represents hydrogen, hydroxy, methoxy, amino, nitro or halogeno;

R^4a represents hydrogen, hydroxy, halogeno, cyano, nitro, trifluoromethyl, C_1-3alkyl, C_1-3alkoxy, C_1-3alkylthio, —

NR^6aR^7a—

(wherein R^6a and R^7a, which may be the same or different, each represents hydrogen or C_1-3alkyl), or a group R⁸a(CH₂)_taX^2a (wherein R^8a is a 5 or 6-membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C_1-4alkyl, C_1-4hydroxyalkyl and C_1-4alkoxy, ta is an integer from 0 to 4 and X^2a represents a direct bond, —

O—

, —

CH₂—

, —

S—

, —

SO₂—

, —

SO₂—

, —

NR^9aCO—

, —

CONR^10a—

, —

SO₂NR^11a—

, —

NR^12aSO₂—

or —

NR^13a—

(wherein R^9a, R^10a, R^11a, R^12a and R^13a each independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl));

X^1a represents a direct bond, —

O—

, —

CH₂—

, —

S—

, —

SO—

, —

SO₂—

, —

NR^14aCO—

, —

CONR^15a—

, —

SO₂NR^16a—

, —

NR^17aSO₂—

or —

NR^18a—

(wherein R^14a, R^15a, R^16a, R^17a and R^18a each independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl);

R^5a is selected from one of the following seventeen groups;

1) hydrogen or C_1-5alkyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro and amino;

2) C_1-5alkylX^3aCOR^19a, wherein X^3arepresents —

O—

or —

NR^20a—

(in which R^20a represents hydrogen, C_1-3 alkyl or C_1-3 alkoxyC_2-3alkyl) and R^19a represents C_1-3alkyl, —

NR^21aR^22a—

or —

OR^23a—

(wherein R^21a, R^22a and R^23a which may be the same or different each represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl);

3) C_1-5alkylX^4aR^24a, wherein X^4a represents —

O—

, —

S—

, —

SO—

, —

SO₂—

, —

OCO—

, —

NR^25aCO—

, , —

CONR^26a—

, —

SO₂NR^27a—

, —

NR^28aSO₂—

or —

NR^29a—

(wherein R^25a R^26a, R^27a, R^28a and R^29a each independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R^24a represents hydrogen, C_1-3alkyl, cyclopentyl, cyclohexyl or a 5 or 6-membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which C_1-3alkyl group may bear one or two substituents selected from oxo, hydroxy, halogeno and C_1-4alkoxy and which cyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C_1-4alkyl, C_1-4hydroxyalkyl and C_1-4alkoxy;

4) C_1-5alkylX^5aC_1-5alkylX^6aR^30a, wherein X^5a and X^6a which may be the same or different are each —

O—

, —

S—

, —

SO—

, —

SO₂—

, —

NR^31aCO—

, —

CONR^32a—

, —

SO₂NR^33a—

, —

NR^34aSO₂—

or —

NR^35a—

(wherein R^31a, R^32a, R^33a, R^34a and R^35a each independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R^30a represents hydrogen or C_1-3alkyl;

5) R^36a, wherein R^36a is a 5 or 6-membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C_1-4alkyl, C_1-4hydroxyalkyl and C_1-4alkoxy;

6) C_1-5alkylR^36a, wherein R^36a is as defined herein;

7) C_2-5alkynylR^36a, wherein R^36a is as defined herein;

8) C_2-5alkenylR^36a, wherein R^36a is as defined herein;

9) R^37a, wherein R^37a represents a pyridone group, a phenyl group or a 5 or 6-membered aromatic heterocyclic group with 1 to 3 hetcroatoms selected from O, N and S, which pyridone, phenyl or heterocyclic group may carry up to 5 substituents selected from hydroxy, halogeno, amino, C_1-4alkyl, C_1-4alkoxy, C_1-4hydroxyalkyl, C_1-4aminoalkyl, C_1-4alkylamino, C_1-4hydroxyalkoxy, carboxy, trifluoromethyl, cyano, —

CONR^38aR^39a and —

NR^40aCOR^41a—

(wherein R^38a, R^39a, R^40a and R^41a, which may be the same or different, each represents hydrogen, C_1-4alkyl or C_1-3alkoxyC_2-3alkyl);

10) C_1-5alkylR^37a, wherein R^37a is as defined herein;

11) C_2-5 alkenyR^37a, wherein R^37a is as defined herein;

12) C_2-5 alkynylR^37a, wherein R^37a is as defined herein;

13) C_1-5alkyX^7aR^37a, wherein X^7a represents —

O—

, —

S—

, —

SO—

, —

SO₂—

, —

NR^42aCO—

, —

CONR^43a—

, —

SO₂NR^44a—

, —

NR^45aSO₂—

or —

NR^46a—

(wherein R^42a, R^43a, R^44a, R^45a and R^46a each independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R^37a is as defined herein;

14) C_2-5alkenylX^8aR^37a, wherein X^8a represents —

O—

, —

S—

, —

SO—

, —

SO₂—

, —

NR^47aCO—

, —

CONR^48a—

, —

SO₂NR^49a—

, —

NR^50aSO₂—

or —

NR^51a—

(wherein R^47a, R^48a, R^49a, R^50a and R^51a each independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R^37a is as defined herein;

15) C_2-5alkynylX^9aR^37a, wherein X^9a represents —

O—

, —

S—

, —

SO—

, —

SO₂—

, —

NR^52aCO—

, —

CONR^53a—

, —

SO₂NR^54a—

, —

NR^55aSO₂—

or —

NR^56a—

(wherein R^52a, R^53a, R^54a, R^55a and R^56a each independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R^37a is as defined herein;

16) C_1-3alkylX^10aC_1-3alkylR^37a, wherein X^10a represents —

O—

, —

S—

, —

SO—

, —

SO₂—

, NR^57aCO—

, —

CONR^58a, —

SO₂NR^59a—

, —

NR^60aSO₂—

or —

NR^61a—

(wherein R^57a, R^58a, R^59a, R^60a and R^61a each independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl) and R^37a is as defined herein; and

17) C_1-3alkylX^10aC_1-3alkylR^36a, wherein X^10a and R^36a are as defined herein.

7. A compound as claimed in claim 6 wherein ring Z is a 6-membered heterocyclic ring containing 1 or 2 nitrogen atoms with the proviso that where R² is a group R⁴X¹, X¹ is not C_2-4alkanoyl or —

SO₂R¹⁰— and

R⁴ is not optionally substituted phenyl or an optionally substituted 5 or 6-membered unsaturated heterocyclic ring.

8. A compound as claimed in claim 6 or 7 wherein R¹ is hydrogen.

9. A compound as claimed in claim 6 or 7 wherein R² is halogeno, C_1-2alkyl, C_1-2alkoxy, trifluoromethyl, 2,2,2-trifluoroethyl, cyano, nitro, C_1-3alkanoylamino, C_1-3alkylsulphonyl, carbamoyl, N-C_1-3alkylcarbamoyl, N,N-di(C_1-3alkyl)carbamoyl, aminosulphonyl, N-C_1-3alkylaminosulphonyl, N,N-di(C_1-3alkyl)aminosulphonyl or C_1-3alkylsulphonylamino or R² is selected from one of the following four groups:

1) R⁴X¹, wherein X¹ represents —

O—

, —

NR⁵—

, C_1-3alkyl, —

CONR⁶R⁷—

or —

SO₂NR⁸R⁹—

(wherein R⁵, R⁶, and R⁸, each independently represents hydrogen or C_1-2alkyl and R⁷ and R⁹ each independently represents C_1-3alkyl and wherein R⁴ is linked to R⁷ or R⁹) and R⁴ represents a 5 or 6-membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear two oxo substituents on a ring sulphur heteroatom;

2) X²C_2-3alkylX³methyl, wherein X² is —

O—

or —

NR¹¹—

(wherein R¹¹ is hydrogen or C_1-2alkyl) and X³ is —

O—

, —

NR¹²or —

SO₂—

(wherein R¹² is hydrogen or C_1-2alkyl);

3) C_1-2alkylX⁴C_2-3alkylX⁵methyl, wherein X⁴ and X⁵ which may be the same or different are each —

NR¹³—

or —

SO₂—

(wherein R¹³ is hydrogen or C_1-2alkyl); and

4) C_1-2alkylX⁶C_1-2alkyl, wherein X⁶ is —

O—

, —

NR¹⁴—

or —

SO₂—

(wherein R¹⁴ is hydrogen or C_1-2alkyl).

10. A compound as claimed in claim 6 or 7 wherein R³, is hydrogen.

11. A compound as claimed in claim 6 or 7 wherein R^4a is hydrogen, hydroxy, cyano, nitro, trifluoromethyl, methyl, ethyl, methoxy, ethoxy or a group R^8a (CH₂)_taX^2a, wherein R^8a is a group selected from pyrrolidinyl, piperazinyl, piperidinyl, morpholino and thiomorpholino which group may carry one or two substituents selected from oxo, hydroxy, halogeno, C_1-2alkyl, C_1-2hydroxyalkyl and C_1-2alkoxy, X^2a is —

O—

, —

S—

, —

NR^9aCO—

, —

NR^12aSO₂—

(wherein R^9a and R^12a each independently represents hydrogen or C^1-2alkyl) or NH, and ta is an integer from 1 to 3.

12. A compound as claimed in claim 6 or 7 herein X^1a is —

O—

, —

S—

, —

NR^14aCO—

, —

NR^17aSO₂—

(wherein R^14a and R^17a each independently represents hydrogen or C_1-2alkyl) or NH.

14. A compound of the formula Ib:

wherein;

R^1b represents hydrogen;

R^2b represents halogeno, C_1-2alkyl, C_1-2alkoxy, trifluoromethyl, 2,2,2-trifluoroethyl, cyano, nitro, C_1-3alkanoylamino, C_1-3alkylsulphonyl, carbamoyl, N-C_1-3alkylcarbamoyl, N,N-di(C_1-3alkyl)carbamoyl, aminosulphonyl, N-C_1-3alkylaminosulphonyl, N,N-di(C_1-3alkyl)-aminosulphonyl or C_1-3alkylsulphonylamino or R^2b is selected from one of the following four groups;

1) R^6bX^2b, wherein X^2b represents —

O—

, −

NR^7b—

, C_1-3alkyl, —

CONR^8bR^9b—

or —

SO₂NR^10bR^11b—

(wherein R^7b, R^8b, and R^10b, each independently represents hydrogen or C_1-2alkyl and R^9b and R^11b each independently represents C_1-3alkyl and wherein R^6b is linked to R^9b or R^11b) and R^6b represents a 5 or 6-membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear two oxo substituents on a ring sulphur heteroatom;

2) X^3bC_2-3alkylX^4bmethyl, wherein X^3b is —

O—

or —

NR^12b—

(wherein R^12b is hydrogen or C_1-2alkyl) and X^4b is —

O—

, —

NR^13b—

or —

SO₂—

(wherein R^13b is hydrogen or C_1-2alkyl);

3) C_1-2alkylX^5bC^2-3alkylX^6bmethyl, wherein X^5b and X^6b which may be the same or different are each —

NR^14b—

or —

SO₂—

(wherein R^14b is hydrogen or C_1-2alkyl); and

4) C_1-2alkylX^7bC_1-2alkyl, wherein X^7b is —

O—

, —

NR^15b or —

SO₂—

(wherein R^15b is hydrogen or C_1-2alkyl);

nb is an integer from 0 to 2;

ring Zb is a 6-membered aromatic heterocyclic ring containing 1 or 2 nitrogen atoms such that the substituent at the 4-position of the quinazoline ring is selected from the groups 7-azaoxindol-3-yl and 5,7-diazaoxindol-3-yl which group bears (R^2b)_nb as defined herein;

R^2b is attached at the 5- and/or 6-positions of the heteroaromatic oxindole ring, but if R^2b is fluoro it can be attached at the 4-, 5-, 6- or 7-position(s) of the heteroaromatic oxindole ring;

R^3b represents hydrogen;

R^4b represents hydrogen, hydroxy, cyano, nitro, trifluoromethyl, methyl, methoxy or a group R^16b(CH₂)_tbX^8b, wherein R^16b represents a group selected from pyrrolidinyl, piperazinyl, piperidinyl, morpholino and thiomorpholino which group may carry one or two substituents selected from oxo, hydroxy, halogeno, C_1-2alkyl, C_1-2hydroxyalkyl and C_1-2alkoxy, tb is an integer from 1 to 3 and Xsb represents —

O—

, —

S—

, —

NR^17bCO—

, —

NR^18bSO₂—

(wherein R^17b and R^18b each independently represents hydrogen or C_1-2alkyl) or NH;

X^1b represents —

O—

or —

NR^19bCO—

(wherein R^19b represents hydrogen or C_1-2alkyl); and

R^5b represents methyl, ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-(N,N-dimethylsulphamoyl)ethyl, 2-(N-methylsulphamoyl)ethyl, (1,3-dioxolan-2-yl)methyl, 2-(1,3-dioxolan-2-yl)ethyl, 2-(2-methoxyethylamino)ethyl, 2-(2-hydroxyethylamino)ethyl, 3-(2-methoxyethylamino)propyl, 3-(2-hydroxyethylamino)propyl, 2-(1,2,4-triazol-1-yl)ethyl, 2-(1,2,4-triazol-4-yl)ethyl, 3-(1,2,4-triazol-1-yl)propyl, 3-(1,2,4-triazol-4-yl)propyl, 2-(4-pyridyloxy)ethyl, 3-(4-pyridyloxy)propyl, 2-(4-pyridylamino)ethyl, 3-(4-pyridylamino)propyl, 2-(2-methylimidazol-1-yl)ethyl, 3-(2-methylimidazol-1-yl)propyl, 2-(5-methyl-1,2,4-triazol-1-yl)ethyl, 3-(5-methyl-1,2,4-triazol-1-yl)propyl, morpholino, N-methylpiperazinyl, piperazinyl, 2-(N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2-(piperazin-1-yl)ethyl, 3-(piperazin-1-yl)propyl, 2-(pyrrolidin-1-yl)ethyl, 3-(pyrrolidin-1-yl)propyl, 2-methoxyethyl, 3-methoxypropyl, 2-(imidazol-1-yl)ethyl, 2-(1,2,3-triazol-1-yl)ethyl, 2-(1,2,3-triazol-2-yl)ethyl, 3-(imidazol-1-yl)propyl, 3-(1,2,3-triazol-1-yl)propyl, 3-(1,2,3-triazol-2-yl)propyl, 2-thiomorpholinoethyl, 3-thiomorpholinopropyl, 2-(1,1-dioxothiomorpholino)ethyl, 3-(1,1-dioxothiomorpholino)propyl, 2-(2-methoxyethoxy)ethyl, 2-(4-methylpiperazin-1-yl)ethyl, 3-(4-methylpiperazin-1-yl)propyl, 3-(methylsulphinyl)propyl, 3-(methylsulphonyl)propyl, ²-(methylsulphinyl)ethyl or 2-(methylsulphonyl)ethyl.

15. A compound selected from:

4-(7-azaoxindol-3-yl)-6-methoxy-7-(3-morpholinopropoxy)quinazoline;

4-(7-azaoxindol-3-yl)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline;

4-(5,7-diaza-6-methyloxindol-3-yl)-7-(3-morpholinopropoxy)quinazoline; and

4-(4-aza-6-trifluoromethyloxindol-3-yl) 6-methoxy-7-(3-morpholinopropoxy)quinazoline;

and salts thereof.

16. A compound selected from:

4-(5,7-diaza-6-methyloxindol-3-y)-7-(3-(1,1-dioxothiomorpholino)propoxy)quinazoline;

4-(7-aza-6-chlorooxindol-3-yl)-7-(3-morpholinopropoxy)quinazoline;

4-(7-azaoxindol-3-yl)-7-(4-morpholinobut-2-en-1-yloxy)quinazoline; and

4-(5,7-diaza-6-methyloxindol-3-yl)-7-(3-methylsulphonylpropoxy)quinazoline;

and salts thereof.

17. A compound selected from:

4-(5,7-diaza-6-methyloxindol-3-yl)-7-(3-morpholinopropoxy)quinazoline;

4-(7-azaoxindol-3-yl)-7-(2-(2-methoxyethoxy)ethoxy)quiiazoline; and

4-(7-azaoxindol-3-yl)-7-(3-morpholinopropoxy)quinazoline;

and salts thereof.