Quinazoline Derivatives as Antiproliferative Agents
AssigneeAstraZeneca AB
InventorsBernard Christophe Barlaam, Laurent Francois Andre Hennequin, Christopher Thomas Halsall
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Abstract
The invention concerns quinazoline derivatives of Formula I wherein each of R1a, R1b, R2, R3 and a have any of the meanings defined in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use as an antiproliferative agent in the prevention or treatment of tumours which are sensitive to inhibition of erbB receptor tyrosine kinases.
Claims18
1:
- A quinazoline derivative of the Formula I:
- wherein:
- one of R1a or R1b is a group of sub-formula (i)
- Q2-X1—Z-Q1-X2—O— (i)
- wherein:
- X1 is a direct bond or a methylene or ethylene group;
- X2 is a direct bond;
- Z is —C(O)—, —NR10—C(O)— (wherein R10 is H or (1-6C)alkyl), or —O—C(O)—;
- Q1 is piperidin-4-yl or piperidin-3-yl;
- Q2 is selected from furyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, furazanyl, thiadiazolyl, tetrazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, phthalazinyl, quinoxalinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, phenyl and naphthyl;
- and is optionally substituted by 1 or 2 substituents, which may be the same or different, selected from halogeno, hydroxy, nitro, amino, cyano, carbamoyl, (1-4C)alkyl, (1-4C)alkoxy, (2-4C)alkanoyl and (1-4C)alkylsulfonyl, (1-4C)alkylamino, di[(1-4C)alkyl]amino, N-[(1-4C)alkyl]carbamoyl, and N,N-di[(1-4C)alkyl]carbamoyl;
- and the other of R1a or R1b is a group R1 which is methoxy;
- R2 is hydrogen;
- and
- the group of sub-formula (ii)
- in formula (I) is 3-chloro-2-fluorophenyl;
- or a pharmaceutically acceptable salt thereof;
- subject to the following proviso;
- when Q2 is phenyl or naphthyl, then R1a is a group of sub-formula (i) defined above and R1b is the group R1 defined above.
(canceled)
The quinazoline derivative according to claim 1, wherein R1a is a group of sub-formula (i), and R1b is a group R1 as defined in claim 1.
The quinazoline derivative according to claim 1, wherein R1a is a group R1, and R1b is a group of sub-formula (i) as defined in claim 1.
5-11. (canceled)
The quinazoline derivative according to claim 1, wherein Z is —C(O)—.
The quinazoline derivative according to claim 1, wherein Z is selected from —NH—C(O)— and —O—C(O)—.
14-18. (canceled)
The quinazoline derivative according to claim 1 wherein Q2 is selected from furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, furazanyl, thiadiazolyl or tetrazolyl.
(canceled)
The quinazoline derivative according to claim 1, wherein Q2 is selected from quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, phthalazinyl, quinoxalinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl or purinyl.
The quinazoline derivative according to claim 1, wherein Q2 is selected from phenyl and naphthyl.
23-30. (canceled)
A compound as claimed in claim 1 selected from
- (1) N-(3-chloro-2-fluorophenyl)-7-methoxy-6-{[1-(pyridin-3-ylcarbonyl)piperidin-4-yl]oxy}quinazolin-4-amine;
- (2) N-(3-chloro-2-fluorophenyl)-7-methoxy-6-{[1-(pyridin-2-ylcarbonyl)piperidin-4-yl]oxy}quinazolin-4-amine;
- (3) N-(3-chloro-2-fluorophenyl)-6-{[1-(2-furoyl)piperidin-4-yl]oxy}-7-methoxyquinazolin-4-amine;
- (4) N-(3-chloro-2-fluorophenyl)-7-{[1-(pyridin-3-ylcarbonyl)piperidin-4-yl]oxy}-6-methoxyquinazolin-4-amine;
- (5) N-(3-chloro-2-fluorophenyl)-7-{[1-(2-furoyl)piperidin-4-yl]oxy}-6-methoxyquinazolin-4-amine;
- (6) N-(3-chloro-2-fluorophenyl)-7-methoxy-6-{[(3R)-1-(2-thienylacetyl)piperidin-3-yl]oxy}quinazolin-4-amine;
- (7) N-(3-chloro-2-fluorophenyl)-6-{[(3R)-1-isonicotinoylpiperidin-3-yl]oxy}-7-methoxyquinazolin-4-amine;
- (8) 6-({(3R)-1-[(2-aminopyridin-3-yl)carbonyl]piperidin-3-yl}oxy)-N-(3-chloro-2-fluorophenyl)-7-methoxyquinazolin-4-amine;
- (9) N-(3-chloro-2-fluorophenyl)-7-methoxy-6-{[(3R)-1-(1H-pyrrol-2-ylcarbonyl)piperidin-3-yl]oxy}quinazolin-4-amine;
- (10) N-(3-chloro-2-fluorophenyl)-7-methoxy-6-{[(3R)-1-(2-thienylcarbonyl)piperidin-3-yl]oxy}quinazolin-4-amine;
- (11) N-(3-chloro-2-fluorophenyl)-6-{[(3R)-1-(2-furoyl)piperidin-3-yl]oxy}-7-methoxyquinazolin-4-amine;
- (12) N-(3-chloro-2-fluorophenyl)-6-{[(3R)-1-(3-furoyl)piperidin-3-yl]oxy}-7-methoxyquinazolin-4-amine;
- (13) N-(3-chloro-2-fluorophenyl)-7-methoxy-6-{[(3R)-1-(3-thienylcarbonyl)piperidin-3-yl]oxy}quinazolin-4-amine;
- (14) N-(3-chloro-2-fluorophenyl)-7-methoxy-6-{[(3R)-1-(3-thienylacetyl)piperidin-3-yl]oxy}quinazolin-4-amine;
- (15) N-(3-chloro-2-fluorophenyl)-7-methoxy-6-({(3R)-1-[(1-methyl-1H-pyrrol-2-yl)carbonyl]piperidin-3-yl}oxy)quinazolin-4-amine;
- (16) N-(3-chloro-2-fluorophenyl)-7-methoxy-6-({(3R)-1-[(4-nitro-1H-pyrazol-1-yl)acetyl]piperidin-3-yl}oxy)quinazolin-4-amine;
- (17) N-(3-chloro-2-fluorophenyl)-7-methoxy-6-{[(3R)-1-(4-{N,N-dimethylcarbamoyl}-1H-pyrazol-1-ylacetyl)piperidin-3-yl]oxy}quinazolin-4-amine;
- (18) N-(3-chloro-2-fluorophenyl)-7-methoxy-6-{[(3R)-1-(4-cyano-1H-pyrazol-1-ylacetyl)piperidin-3-yl]oxy}quinazolin-4-amine;
- (19) 4-({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N-phenylpiperidine-1-carboxamide;
- (20) N-Benzyl-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidine-1-carboxamide;
- (21) 4-({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N-[4-(dimethylamino)phenyl]piperidine-1-carboxamide;
- (22) 4-({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N-(2-phenylethyl)piperidine-1-carboxamide;
- (23) 4-({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N-(3,4-dimethoxyphenyl)piperidine-1-carboxamide;
- (24) 4-({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N-(3-fluorophenyl)piperidine-1-carboxamide;
- (25) 4-({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N-2-thienylpiperidine-1-carboxamide;
- and
- (26) 4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N-3-thienylpiperidine-1-carboxamide.
32-33. (canceled)
35-36. (canceled)
A method for producing an anti-proliferative effect in warm-blooded animal in need of such treatment which comprises administering to said animal a quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt thereof;
- as defined in claim 1.
Dependencies are inferred from the claim text.