Quinazoline Derivatives as Antiproliferative Agents

Abstract

The invention concerns quinazoline derivatives of Formula I wherein each of R 1a , R 1b , R 2 , R 3 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.

1 : A quinazoline derivative of the Formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 one of R 1a  or R 1b  is a group of sub-formula (i)
   Q 2 -X 1 —Z-Q 1 -X 2 —O—  (i)
 
 wherein: 
 X 1  is a direct bond or a methylene or ethylene group; 
 X 2  is a direct bond; 
 Z is —C(O)—, —NR 10 —C(O)— (wherein R 10  is H or (1-6C)alkyl), or —O—C(O)—; 
 Q 1  is piperidin-4-yl or piperidin-3-yl; 
 Q 2  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 R 1a  or R 1b  is a group R 1  which is methoxy; 
 R 2  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 Q 2  is phenyl or naphthyl, then R 1a  is a group of sub-formula (i) defined above and R 1b  is the group R 1  defined above. 
 
       
     
     
         2 . (canceled) 
     
     
         3 . The quinazoline derivative according to  claim 1 , wherein R 1a  is a group of sub-formula (i), and R 1b  is a group R 1  as defined in  claim 1 . 
     
     
         4 . The quinazoline derivative according to  claim 1 , wherein R 1a  is a group R 1 , and R 1b  is a group of sub-formula (i) as defined in  claim 1 . 
     
     
         5 - 11 . (canceled) 
     
     
         12 . The quinazoline derivative according to  claim 1 , wherein Z is —C(O)—. 
     
     
         13 . The quinazoline derivative according to  claim 1 , wherein Z is selected from —NH—C(O)— and —O—C(O)—. 
     
     
         14 - 18 . (canceled) 
     
     
         19 . The quinazoline derivative according to  claim 1  wherein Q 2  is selected from furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, furazanyl, thiadiazolyl or tetrazolyl. 
     
     
         20 . (canceled) 
     
     
         21 . The quinazoline derivative according to  claim 1 , wherein Q 2  is selected from quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, phthalazinyl, quinoxalinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl or purinyl. 
     
     
         22 . The quinazoline derivative according to  claim 1 , wherein Q 2  is selected from phenyl and naphthyl. 
     
     
         23 - 30 . (canceled) 
     
     
         31 . 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) 
     
     
         34 . A pharmaceutical composition which comprises a quinazoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined in any one of  claims 1 ,  3 ,  4 ,  12 ,  13 ,  19 ,  21 ,  22  and  31  in association with a pharmaceutically-acceptable diluent or carrier. 
     
     
         35 - 36 . (canceled) 
     
     
         37 . 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 .