Quinazoline derivatives as angiogenesis inhibitors

• US 7,074,800 B1
• Filed: 02/08/2000
• Issued: 07/11/2006
• Est. Priority Date: 02/10/1999
• Status: Expired due to Term

• Current Assignee: Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Astrazeneca AB (Astrazeneca PLC)
• Inventors: Stokes, Elaine S E, Mckerrecher, Darren, Ple, Patrick, Hennequin, Laurent F A
• Primary Examiner(s): Raymond, Richard L.
• Application Number:
  US09/913,020
• Time in Patent Office: 2,345 Days
• Field of Search: 514/266.1, 514/266.21, 514/266.23, 514/266.3, 514/235.5, 514/235.8, 514/266.2, 544/283, 544/284, 544/287, 544/141, 544/122, 544/281, 544/121
• US Class Current: 514/266.2
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• 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 37/00 Drugs for immunological or allergic disorders
• 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 9/00 Drugs for disorders of the cardiovascular system
• 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: A61P 9/14 Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/56 : with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 239/88 : Oxygen atoms
• CPC Class Codes: C07D 239/94 : Nitrogen atoms
• CPC Class Codes: C07D 249/08 : 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/14 : containing three or more hetero rings
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems

Abstract

The invention relates to the use of compounds of formula (I), wherein ring C is an 8, 9, 10, 12 or 13-membered bicyclic or tricyclic moiety which optionally may contain 1–3 heteroatoms selected independently from O, N and S; Z is —O—, —NH—, —S—, —CH₂— or a direct bond; n is 0–5; m is 0–3; R² represents hydrogen, hydroxy, halogeno, cyano, nitro, trifluoromethyl, C_1-3alkyl, C_1-3alkoxy, C_1-3alkylsulphanyl, —NR³R⁴ (wherein R³ and R⁴, which may be the same or different, each represents hydrogen or C_1-3alkyl), or R⁵X¹— (wherein X¹ and R⁵ are as defined herein; R¹ represents hydrogen, oxo, halogeno, hydroxy, C_1-4alkoxy, C_1-4alkyl, C_1-4alkoxymethyl, C_1-4alkanoyl, C_1-4haloalkyl, cyano, amino, C_2-5alkenyl, C_2-5alkynyl, C_1-3alkanoyloxy, nitro, C_1-4alkanoylamino, C_1-4alkoxycarbonyl, C_1-4alkylsulphanyl, C_1-4alkylsulphinyl, C_1-4alkylsulphonyl, carbamoyl, N—C_1-4alkylcarbamoyl, N,N-di(C_1-4alkylcarbamoyl, aminosulphonyl, N—C_1-4alkylaminosulphonyl, N,N-di(C_1-4alkyl)aminosulphonyl, N—(C_1-4alkylsulphonyl)amino, N—(C_1-4alkylsulphonyl)-N—(C_1-4alkyl)amino, N,N-di(C_1-4alkylsulphonyl)amino, a C_3-7alkylene chain joined to two ring C carbon atoms, C_1-4alkanoylaminoC_1-4alkyl, carboxy or a group R⁵⁶X¹⁰ (wherein X¹⁰ and R⁵⁶ are as defined herein); and salts thereof, in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in warm-blooded animals, processes for the preparation of such compounds, pharmaceutical compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof as active ingredient and compounds of formula (I). The compounds of formula (I) and the pharmaceutically acceptable salts thereof inhibit the effects of VEGF, a property of value in the treatment of a number of disease states including cancer and rheumatoid arthritis.

Claims

1. A compound of the formula II:

2. A compound of the formula II according to claim 1 wherein R² represents hydroxy, halogeno, cyano, nitro, trifluoromethyl, C_1-3alkyl, amino or R⁵X¹—

, wherein X¹ is as defined in claim 1 and R⁵ is selected from one of the following twenty-two groups;

1) C_1-4alkyl which may be unsubstituted or which may be substituted with one or more groups selected from fluoro, chloro and bromo, or C_2-5alkyl which may be unsubstituted or substituted with one or more groups selected from hydroxy and amino;

2) C_2-3alkylX²C(O)R¹¹ (wherein X² is as defined in claim 1 and R¹¹ represents —

NR¹³R¹⁴ or —

OR¹⁵ (wherein R¹³, R¹⁴ and R¹⁵ which may be the same or different are each C_1-4alkyl or C_1-2alkoxyethyl));

3) C_2-4alkylX³R¹⁶ (wherein X³ is as defined in claim 1 and R¹⁶ is a group selected from C_1-3alkyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl, azetidinyl and tetrahydropyranyl, which C_1-3alkyl group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno and C_1-2 alkoxy and which cyclopentyl, cyclohexyl, pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl, azetidinyl or tetrahydropyranyl group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C_1-3cyanoalkyl, C_1-3alkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, C_1-2alkoxyC_1-3alkyl, C_1-2alkylsulphonylC_1-3alkyl, C_1-3alkoxycarbonyl, C_1-3alkylamino, di(C_1-3alkyl)amino, C_1-3alkylaminoC_1-3alkyl, di(C_1-3alkyl)aminoC_1-3alkyl, C_1-3alkylaminoC_1-3alkoxy, di(C_1-3alkyl)aminoC_1-3alkoxy and a group —

(—

O—

)_f(C_1-3alkyl)_gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic group selected from pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl, azetidinyl, morpholino and thiomorpholino, which cyclic group may bear one or more substituents selected from C_1-3alkyl));

4) C_2-3alkylX⁴C_2-3alkylX⁵R²² (wherein X⁴ and X⁵ are as defined in claim 1 and R²² represents hydrogen or C_1-3alkyl);

5) R²⁸ (wherein R²⁸ is as defined in claim 1);

6) C_1-4alkylR¹¹⁰ (wherein R¹¹⁰ is a group selected from pyrrolidinyl, piperazinyl, piperidinyl, imidazolidin-1-yl, azetidinyl, 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_1-4alkyl through a carbon atom and which group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C_1-3cyanoalkyl, C_1-3alkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, C_1-2alkoxyC_1-3alkyl, C_1-2alkylsulphonylC_1-3alkyl, C_1-3alkoxycarbonyl, C_1-3alkylamino, di(C_1-3alkyl)amino, C_1-3alkylaminoC_1-3alkyl, di(C_1-3alkyl)aminoC_1-3alkyl, C_1-3alkylaminoC_1-3alkoxy, di(C_1-3alkyl)aminoC_1-3alkoxy and a group —

(—

O—

)_f(C_1-3alkyl)_gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic group selected from pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl, azetidinyl, morpholino and thiomorpholino, which cyclic group may bear one or more substituents selected from C_1-3alkyl)) or C_2-4alkylR¹¹¹ (wherein R¹¹¹ is a group selected from morpholino, thiomorpholino, azetidin-1-yl, pyrrolidin-1-yl, piperazin-1-yl and piperidino which group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano, C_1-3cyanoalkyl, C_1-3alkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, C_1-2alkoxyC_1-3alkyl, C_1-2alkylsulphonylC_1-3alkyl, C_1-3alkoxycarbonyl, C_1-3alkylamino, di(C_1-3alkyl)amino, C_1-3alkylaminoC_1-3alkyl, di(C_1-3alkyl)aminoC_1-3alkyl, C_1-3alkylaminoC_1-3alkoxy, di(C_1-3alkyl)aminoC_1-3alkoxy and a group —

(—

O—

)_f(C_1-3alkyl)_gringD (wherein f is 0 or 1, g is 0 or 1 and ring D is a heterocyclic group selected from pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl, azetidinyl, morpholino and thiomorpholino, which cyclic group may bear one or more substituents selected from C_1-3alkyl));

7) C_3-4alkenylR¹¹² (wherein R¹¹² represents R¹¹⁰ or R¹¹¹ as defined herein);

8) C_3-4alkynylR¹¹² (wherein R¹¹² represents R¹¹⁰ or R¹¹¹ as defined herein);

9) R²⁹ (wherein R²⁹ is as defined in claim 1);

10) C_1-4alkylR²⁹ (wherein R²⁹ is as defined in claim 1);

11) 1-R²⁹prop-1-en-3-yl or 1-R²⁹but-2-en-4-yl (wherein R²⁹ is as defined in claim 1 with the proviso that when R⁵ is 1-R²⁹prop-1-en-3-yl, R²⁹ is linked to the alkenyl group via a carbon atom);

12) 1-R²⁹prop-1-yn-3-yl or 1-R²⁹but-2-yn-4-yl (wherein R²⁹ is as defined in claim 1 with the proviso that when R⁵ is 1-R²⁹prop-1-yn-3-yl, R²⁹ is linked to the alkynyl group via a carbon atom);

13) C_1-5alkylX⁶R²⁹ (wherein X⁶ and R²⁹ are as defined in claim 1);

14) 1-(R²⁹X⁷)but-2-en-4-yl (wherein X⁷ and R²⁹ are as defined in claim 1);

15) 1-(R²⁹X⁸)but-2-yn-4-yl (wherein X⁸ and R²⁹ are as defined in claim 1);

16) C_2-3alkylX⁹C_1-3alkylR²⁹ (wherein X⁹ and R²⁹ are as defined in claim 1);

17) C_2-3alkylX⁹C_1-3alkylR²⁸ (wherein X⁹ and R²⁸ are as defined in claim 1);

18) C_2-5alkenyl which may be unsubstituted or which may be substituted with one or more fluorine atoms or with one or two groups selected from hydroxy, fluoro, amino, C_1-4alkylamino, N,N-di(C_1-4alkyl)amino, aminosulphonyl, N—

C_1-4alkylaminosulphonyl and N,N-di(C_1-4alkyl)aminosulphonyl;

19) C_2-5alkynyl which may be unsubstituted or which may be substituted with one or more fluorine atoms or with one or two groups selected from hydroxy, fluoro, amino, C_1-4alkylamino, N,N-di(C_1-4alkyl)amino, aminosulphonyl, N—

C_1-4alkylaminosulphonyl and N,N-di(C_1-4alkyl)aminosulphonyl;

20) C_2-4alkenylX⁹C_1-3alkylR²⁸ (wherein X⁹ and R²⁸ are as defined in claim 1);

21) C_2-4alkynylX⁹C_1-3alkylR²⁸ (wherein X⁹ and R²⁸ are as defined in claim 1); and

22) C_1-3alkylR⁵⁴(C_1-3alkyl)_q(X⁹)_rR⁵⁵ (wherein X⁹, q, r, R⁵⁴ and R⁵⁵ are as defined in claim 1);

and additionally wherein any C_1-5alkyl, C_2-5alkenyl or C_2-5alkynyl group in R⁵X¹—

may bear one or more substituents selected from hydroxy, halogeno and amino.

3. A compound according to claim 1 wherein Zb is —

O—

.

4. A compound according to claim 1 wherein R¹ represents oxo, halogeno, hydroxy, C_1-2alkoxy, C_1-2alkyl, C_1-2alkoxymethyl, C_2-3alkanoyl, C_1-2haloalkyl, cyano, amino, C_2-4alkenyl, C_2-4alkynyl, C_2-3alkanoyloxy, nitro, C_2-3alkanoylamino, C_1-2alkoxycarbonyl, C_1-2alkylsulphanyl, C_1-2alkylsulphinyl, C_1-2alkylsulphonyl, carbamoyl, N—

C_1-2alkylcarbamoyl, N,N-di(C_1-2alkyl)carbamoyl, aminosulphonyl, N—

C_1-2alkylaminosulphonyl, N,N-di(C_1-2alkyl)aminosulphonyl, N—

(C_1-2alkylsulphonyl)amino, N—

(C_1-2alkylsulphonyl)-N—

(C_1-2alkyl)amino or a C_3-7alkylene chain joined to two ring C carbon atoms.

5. A compound according to claim 1 wherein n is 0, 1 or 2.

6. A compound according to claim 1 wherein Zb is —

O—

, with the proviso that R² is not substituted or unsubstituted C_1-5alkyl, halogeno, C_1-5alkoxy, C_2-5alkenyl, phenoxy or phenylC_1-5alkoxy.

7. A compound according to claim 1 selected from

6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(quinolin-7-yloxy)quinazoline,

7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxy-4-(quinolin-7-yloxy)quinazoline,

6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)-4-(quinolin-7-yloxy)quinazoline,

6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)-4-(quinolin-7-yloxy)quinazoline,

4-(4-chloroquinolin-7-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline,

6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(4-methylquinolin-7-yloxy)quinazoline,

6-methoxy-4-(4-methylquinolin-7-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline,

6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)-4-(quinolin-7-yloxy)quinazoline,

6-methoxy-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)-4-(quinolin-7-yloxy) quinazoline,

4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy) quinazoline,

4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline,

6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)-4-(2-trifluoromethylindol-5-yloxy) quinazoline,

6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)-4-(2-trifluoromethylindol-5-yloxy)quinazoline,

(R,S)-4-(3-fluoroquinolin-7-yloxy)-6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)quinazoline,

4-(indol-5-yloxy)-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline,

7-(3-N,N-dimethylaminopropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,

6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(2-morpholinoethoxy)ethoxy)quinazoline,

7-(2-(N,N-diethylamino)ethoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,

6-methoxy-7-(3-piperidinopropoxy)-4-(quinolin-7-yloxy)quinazoline,

4-(2-methylindol-5-yloxy)-7-(3-morpholinopropoxy)quinazoline,

4-(2-methylindol-5-yloxy)-7-(2-(piperidin-1-yl)ethoxy)quinazoline,

4-(2-methylindol-5-yloxy)-7-(2-(1H-1,2,4-triazol-1-yl)ethoxy)quinazoline,

6-methoxy-7-(3-piperidinopropoxy)-4-(6-trifluoromethylindol-5-yloxy)quinazoline,

7-(3-(methylsulphonyl)propoxy)-4-(2-methylindol-5-yloxy)quinazoline,

7-(3-(,N-dimethylamino)propoxy)-4-(2,3-dimethylindol-5-yloxy)-6-methoxy-quinazoline,

4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(1-methylpiperidin-3-ylmethoxy) quinazoline,

7-(2-(N,N-diethyl amino) ethoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline,

4-(indol-5-yloxy)-6-methoxy-7-(2-(piperidin-2-yl)ethoxy)quinazoline,

4-(indol-5-yloxy)-6-methoxy-7-(2-(piperidin-1-yl)ethoxy)quinazoline,

4-(indol-6-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline,

7-(3-(ethylsulphonyl)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,

6-methoxy-4-(3-methylindol-5-yloxy)-7-(3-piperidinopropoxy) quinazoline,

7-(2-hydroxy-3-piperidinopropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,

7-(2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,

6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(N-methylamino)ethoxy)quinazoline, and

7-(2-hydroxy-3-(isopropylamino)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,

or a salt thereof.

8. A compound according to claim 1 selected from

6-methoxy-7-(3-morpholinopropoxy)-4-(quinolin-7-yloxy)quinazoline,

6-methoxy-4-(2-methylindol-5-yloxy)-7-((1-methylpiperidin-4-yl)methoxy)quinazoline,

4-(indol-5-yloxy)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline,

4-(indol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline,

6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-methylsulphonylpropoxy)quinazoline,

7-((1-cyanomethyl)piperidin-4-ylmethoxy)-6-methoxy-4-(2-methylindol-5-yloxy) quinazoline,

6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-morpholinoethoxy)quinazoline,

6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-pyrrolidin-1-ylethoxy)quinazoline,

6-methoxy-4-(2-methylindol-5-yloxy)-7-(1-methylpiperidin-3-ylmethoxy)quinazoline,

6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-piperidinoethoxy)quinazoline,

6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(N-methyl-N-(4-pyridyl)amino)ethoxy) quinazoline,

6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-morpholinopropoxy)quinazoline,

6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)-4-(2-methylindol-5-yloxy)quinazoline,

6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(1H-1,2,4-triazol-1-yl)ethoxy)quinazoline,

6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(2-(4-methylpiperazin-1-yl)ethoxy)ethoxy)quinazoline,

6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-piperidinopropoxy)quinazoline,

4-(indol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline,

6-methoxy-7-(1-(2-methoxyethyl)piperidin-4-ylmethoxy)-4-(2-methylindol-5-yloxy)quinazoline,

6-methoxy-4-(2-methylindol-5-yloxy)-7-((2-(2-pyrrolidin-1-ylethyl)carbamoyl)vinyl)quinazoline,

6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-(4-methypiperazin-1-yl)propoxy)quinazoline,

6-methoxy-4-(2-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline,

6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(pip eridin-4-yloxy) ethoxy)quinazoline,

6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(N-methyl-N-methylsulphonylamino)ethoxy)quinazoline,

7-(2-(1-(2-cyanoethyl)piperidin-4-yloxy)ethoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,

4-(2-methylindol-5-yloxy)-7-(3-(pyrrolidin-yl)propoxy)quinazoline,

4-(2-methylindol-5-yloxy)-7-(3-(1,1-dioxothiomorpholino)propoxy)quinazoline,

4-(2-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline,

4-(indol-5-yloxy)-6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)quinazoline,

7-(3-(N,N-dimethylamino)prop oxy)-4-(indol-5-yloxy)-6-methoxyquinazoline,

7-(3-(N,N-diethylamino)propoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline,

7-(3-(1,1-dioxothiomorpholino)propoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline,

4-(indol-5-yloxy)-6-methoxy-7-(2-(4-pyridyloxy)ethoxy)quinazoline,

4-(indol-6-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline,

7-(1-(2-methoxyethyl)piperidin-4-ylmethoxy)-4-(2-methylindol-5-yloxy)quinazoline,

7-(2-hydroxy-3-morpholinopropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,

7-(2-(1-(2-methoxyethyl)piperidin-4-yl)ethoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,

7-(2-hydroxy-3-pyrrolidin-1-ylpropoxy)-6-methoxy-4-(2-methylindol-5-yloxy) quinazoline,

7-(3-(N,N-diethylamino)-2-hydroxypropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,

7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy) quinazoline,

6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(4-pyridyloxy)ethoxy)quinazoline,

4-(indol-5-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline,

(2R)-6-methoxy-(2-methyl-1H-indol-5-yloxy)-7-(2-hydroxy-3-piperidinopropoxy)quinazoline,

(5R)-6-methoxy-4-(2-methyl-1H-indol-5-yloxy)-7-(2-oxopyrrolidin-5-ylmethoxy)quinazoline,

4-(4-bromoindol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline,

6-methoxy-4-(2-methylindol-5-yloxy)-7-(1-(2-(pyrrolidin-1-yl)ethyl)-piperidin-4-ylmethoxy)quinazoline,

(2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline,

(2R)-7-(2-hydroxy-3-morpholinopropoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline,

(2R)-7-(2-hydroxy-3-piperidinopropoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline,

(2S)-7-(2-hydroxy-3-((N,N-diisopropyl)amino)propoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline,

(2S)-7-(2-hydroxy-3-piperidinopropoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline,

(2R)-7-(2-hydroxy-3-piperidinopropoxy)-6-methoxy-4-(3-methylindol-5-yloxy) quinazoline,

(2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline,

(2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,

(2R)-7-(2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy)6-methoxy-4-(2-methylindol-5-yloxy)quinazoline,

6-methoxy-4-(2-methylindol-5-yloxy)-7-(1-(2-morpholinoethyl)piperidin-4-ylmethoxy)quinazoline,

4-(3-fluoro-quinolin-7-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline,

4-(3-fluoro-quinolin-7-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline,

6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-4-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)quinazoline,

(2S)-6-methoxy-(2-methyl-1H-indol-5-yloxy)-7-(2-hydroxy-3-piperidinopropoxy)quinazoline, and

4-(6-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy) quinazoline,

or a salt thereof.

9. A compound according to claim 1 selected from

6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline,

4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline,

4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline,

4-(6-fluoroindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline,

4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline,

4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline,

4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy) quinazoline,

4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline,

4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline,

4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline,

4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(2-(1-methylpiperidin-4-yl)ethoxy)quinazoline,

(2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxyquinazoline, and

4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(2-(1-methylpiperidin-4-yl)ethoxy)quinazoline,

or a salt thereof.

10. A compound according to claim 1 in the form of a pharmaceutically acceptable salt.

11. A compound according to claim 1 wherein ring C is selected from indolyl and quinolinyl.

13. A compound according to claim 9 which is 6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline,

or a salt thereof.

14. A compound according to claim 9 which is 4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline,

or a salt thereof.

15. A compound according to claim 9 which is 4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline,

or a salt thereof.

16. A compound according to claim 9 which is 4-(6-fluoroindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline,

or a salt thereof.

17. A compound according to claim 9 which is 4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline,

or a salt thereof.

18. A compound according to claim 9 which is 4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline,

or a salt thereof.

19. A compound according to claim 9 which is 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline,

or a salt thereof.

20. A compound according to claim 9 which is 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline,

or a salt thereof.

21. A compound according to claim 9 which is 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline,

or a salt thereof.

22. A compound according to claim 9 which is 4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(2-(1-methylpiperidin-4-yl)ethoxy)quinazoline,

or a salt thereof.

23. A compound according to claim 9 which is (2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxyquinazoline,

or a salt thereof.

24. A compound according to claim 9 which is 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(2-(1-methylpiperidin-4-yl)ethoxy)quinazoline,

or a salt thereof.

25. A pharmaceutical composition which comprises as active ingredient a compound of formula II or a pharmaceutically acceptable salt thereof according to any one of claims 1–

3, 4–

9 and 11 in association with a pharmaceutically acceptable excipient or carrier.

26. A method for inhibiting VEGF receptor tyrosine kinase activity in a warm-blooded animal in need thereof comprising administering to said animal an inhibiting amount of a compound of the formula II as defined in any one of claims 1–

3, 4–

9 and 11 or a pharmaceutically acceptable salt thereof.

12. The compound 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy) quinazoline,

or a salt thereof.