Quinazoline derivatives as kinase inhibitors

Abstract

The Present invention relates to nitrogen-containing heterocyclic compounds and pharmaceutically acceptable salts thereof which have inhibitory activity on the phosphorylation of kinases, which inhibits the activity of such kinases. The invention is also related to a method of inhibiting kinases and treating disease states in a mammal by inhibiting the phosphorylation of kinases. In a particular aspect the present invention provides nitrogen-containing heterocyclic compounds and pharmaceutically acceptable salts thereof which inhibit phosphorylation of a PDGF receptor to hinder abnormal cell growth and cell wandering, and a method for preventing or treating cell-proliferative diseases such as arteriosclerosis, vascular reobstruction, cancer and glomerulosclerosis.

What is claimed is: 
     
         1 - 12 . (canceled) 
     
     
         13 . A compound selected from the group consisting of: 
       {4-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl]piperazinyl}-N-(4-naphthyloxyphenyl)carboxamide 
       
         
           
           
               
               
           
         
       
       {4-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl]piperazinyl}-N-(4-phenoxyphenyl)carboxamide 
       
         
           
           
               
               
           
         
       
       {4-[6-methoxy-7-(ethoxy)quinazolin-4-yl]piperazinyl}-N-(4-phenoxyphenyl)carboxamide 
       
         
           
           
               
               
           
         
       
       {4-[6-methoxy-7-(ethoxy)quinazolin-4-yl]piperazinyl}-N-(4-phenyecarboxamide 
       
         
           
           
               
               
           
         
       
       {4-[6-methoxy-7-(ethoxy)quinazolin-4-yl]piperazinyl}-N-(4-cyanophenyl)carboxamide 
       
         
           
           
               
               
           
         
       
       {4-[6-methoxy-7-(prop-2-enylethoxy)quinazolin-4-yl]piperazinyl}-N-(4-cyanophenyl)carboxamide 
       
         
           
           
               
               
           
         
       
       {4-[6-methoxy-7-(prop-2-enylethoxy)quinazolin-4-yl]piperazinyl}-N-(4-methylethoxyphenyl)carboxamide 
       
         
           
           
               
               
           
         
       
       [4-(6-methoxy-7-prop-2-enyloxyquinazolin-4-yl)piperazinyl]-N-(4-naphthyloxyphenyl)carboxamide 
       
         
           
           
               
               
           
         
       
       N-(4-indol-4-yloxyphenyl)[4-(6-methoxy-7-prop-2-enyloxyquinazolin-4-yl)piperazinyl]carboxamide 
       
         
           
           
               
               
           
         
       
       [4-(6-methoxy-7-prop-2-enyloxyquinazolin-4-yl)piperazinyl]-N-(4-phenoxyphenyl)carboxamide 
       
         
           
           
               
               
           
         
       
       N-(4-cyanophenyl)[4-(6-methoxy-7-prop-2-ynyloxyquinazolin-4-yl)piperazinyl]carboxamide 
       
         
           
           
               
               
           
         
       
       [4-(6-methoxy-7-prop-2-ynyloxyquinazolin-4-yl)piperazinyl]-N-(4-(methylethoxy)phenyl]carboxamide 
       
         
           
           
               
               
           
         
       
       [4-(6-methoxy-7-prop-2-ynyloxyquinazolin-4-yl)piperazinyl]-N-(4-naphthyloxyphenyl)carboxamide 
       
         
           
           
               
               
           
         
       
       N-(4-indol -4-yloxyphenyl)[4-(6-methoxy-7-prop-2-ynyloxy quinazolin-4-yl)piperazinyl]carboxamide 
       
         
           
           
               
               
           
         
       
       [4-(6-methoxy-7-prop-2-ynyloxyquinazolin-4-yl)piperazinyl]-N-(4-phenoxyphenyl)carboxamide 
       
         
           
           
               
               
           
         
       
       {4-[7-(2-hydroxy-3-piperidylpropoxy)-6-methoxyquinazolin-4-yl]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide 
       
         
           
           
               
               
           
         
       
       {4-[7-(2-fluoro-3-piperidylpropoxy)-6-methoxyquinazolin-4-yl]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide 
       
         
           
           
               
               
           
         
       
       [4-(6-methoxy-7-{3-[(2-methylpropyl)sulfonyl]propoxy}quinazolin-4-yl)piperazinyl]-N-[4-(methylethoxy)phenyl]carboxamide 
       
         
           
           
               
               
           
         
       
       (4-{6-methoxly-7-[3-(propylsulfonyl)propoxy]quinazolin-4-yl}piperazinyl)-N-[4-(methylethoxy)phenyl]carboxamide 
       
         
           
           
               
               
           
         
       
       methyl 4-({4-[6-methoxy-7-(3-pyrrolidinylpropoxy) quinazolin-4-yl]piperazinyl}carbonylamino)benzoate 
       
         
           
           
               
               
           
         
       
       N-(4-acetylphenyl){4-[6-methoxy-7-(3-pyrrolidinylpropoxy) quinazolin-4-yl]piperazinyl}carboxamide 
       
         
           
           
               
               
           
         
       
       N-(4-bromophenyl){4-[6-methoxy-7-(3-pyrrolidinylpropoxy) quinazolin-4-yl]piperazinyl}carboxamide 
       
         
           
           
               
               
           
         
       
       {4-[6-methoxy-7-(3-pyrrolidinylpropoxy)quinazolin-4-yl]piperazinyl}-N-[4-(trifluoromethyl)phenyl]carboxamide 
       
         
           
           
               
               
           
         
       
       {4-[6-methoxy-7-(3-pyrrolidinylpropoxy)quinazolin-4-yl]piperazinyl}-N-(4-methylphenyl)carboxamide 
       
         
           
           
               
               
           
         
       
       {4-[6-methoxy-7-(3-pyrrolidinylpropoxy)quinazolin-4-yl]piperazinyl}-N-[4-(methylsulfonyl)phenyl]carboxamide 
       
         
           
           
               
               
           
         
       
       N-(4-fluorophenyl){4-[6-methoxy-7-(3-pyrrolidinylpropoxy) quinazolin-4-yl]piperazinyl}carboxamide 
       
         
           
           
               
               
           
         
       
       4-({4-[6-methoxy-7-(3-pyrrolidinylpropoxy) quinazolin-4-yl]piperazinyl}carbonylamino)benzoic acid 
       
         
           
           
               
               
           
         
       
       and all pharmaceutically acceptable salts or hydrates thereof. 
     
     
         14 . A pharmaceutical composition comprising an effective amount of a nitrogen-containing heterocyclic compound according to  claim 13 , or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable diluent or carrier. 
     
     
         15 . A method of inhibiting phosphorylation of PDGF receptor in a patient comprising the step of administering a compound of  claim 14  and all pharmaceutically acceptable salts and hydrates thereof to the patient. 
     
     
         16 . A method for inhibiting abnormal cell growth and cell wandering in a patient and thereby preventing or treating a cell-proliferative disease, comprising the step of administering a composition according to  claim 14  to the patient. 
     
     
         17 . A method of inhibiting phosphorylation of PDGF receptor in a patient comprising the step of administering a compound of the formula: 
       
         
           
           
               
               
           
         
       
       wherein 
       R 1  is a member selected from the group consisting of:
 CN, —X, —CX 3 , —R 5 , —CO 2 R 5 , —C(O)R 5 , —SO 2 R 5 , —O—C 1-8 alkyl that is straight or branched chained, —O-phenyl, —O-naphthyl, —O-indolyl and —O-isoquinolinyl X is halogen; 
 
       R 5  is hydrogen or a C 1-8 alkyl that is straight or branched chained; 
       R 2  is —O-CH 3 ; 
       R 4  is a member selected from the group consisting of: 
       —O—CH 2 —CH═CH 2 , —O—CH 2 —C═CH, —O(CH 2 ) n —SO 2 —R 5  and —O—CH 2 —CH(R 6 )CH 2 —R 3 ; 
       R 6  is —OH, —X, or a C 1-8 alkyl that is straight or branched chained; 
       n is 2 or 3; 
       R 3  is a member selected from the group consisting of: 
       —OH, —O-CH 3 , —O-CH 2 —CH 3 , —NH 2 , —N(—CH 3 ) 2 , —NH(—CH 2 -phenyl), —NH(-phenyl), —CN 
       
         
           
           
               
               
           
         
         
           and all pharmaceutically acceptable salts and hydrates thereof to the patient. 
         
       
     
     
         18 . The method of  claim 17 , wherein R 1  is a member selected from the group consisting of CN, —O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl, —O-t-butyl, —O-isoamyl, 1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy, 5-indolyloxy, 5-isoquinolyloxy,
 and all pharmaceutically acceptable salts and hydrates of such compounds. 
 
     
     
         19 . The method of  claim 17  wherein the compound has the formula I(a) or formula I(b) as follows: 
       
         
           
           
               
               
           
         
       
       wherein 
       R 1  is a member selected from the group consisting of CN, —O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl, —O-t-butyl, —O-isoamyl, 1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy, 5-indolyloxy, 5-isoquinolyloxy,
 and all pharmaceutically acceptable salts and hydrates thereof. 
 
     
     
         20 . The method of  claim 17  wherein the compound has formula I(c) or formula I(d) as follows: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is a member selected from the group consisting of CN, —O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl, —O-t-butyl, —O-isoamyl, 1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy, 5-indolyloxy, 5-isoquinolyloxy, 
         and all pharmaceutically acceptable salts and hydrates of such compounds. 
       
     
     
         21 . The method of  claim 17  wherein the compound has formula I(e) or formula I(f) as follows: 
       
         
           
           
               
               
           
         
       
       wherein 
       R 1  is a member selected from the group consisting of CN, —O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl, —O-t-butyl, —O-isoamyl, 1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy, 5-indolyloxy, 5-isoquinolyloxy,
 and all pharmaceutically acceptable salts and hydrates of such compounds. 
 
     
     
         22 . A method for inhibiting abnormal cell growth and cell wandering in a patient and thereby preventing or treating a cell-proliferative disease, comprising the step of administering a compound of the formula: 
       
         
           
           
               
               
           
         
       
       wherein 
       R 1  is a member selected from the group consisting of:
 CN, —X, —X 3 , —R 5 , —CO 2 R 5 , —C(O)R 5 , —SO 2 R 5 , —O—C 1-8  alkyl that is straight or branched chained, —O-phenyl, —O-naphthyl, —O-indolyl and —O-isoquinolinyl X is halogen; 
 
       R 5  is hydrogen or a C 1-8 alkyl that is straight or branched chained; 
       R 2  is —O—CH 3 ; 
       R 4  is a member selected from the group consisting of : 
       —O—CH 2 —CH═CH 2 , —O—CH 2 —C═CH, —O(CH 2 ) n —SO 2 —R 5  and —O—CH 2 —CH(R 6 )CH 2 —R 3 ; 
       R 6  is —OH, —X, or a C 1-8 alkyl that is straight or branched chained; 
       n is 2 or 3; 
       R 3  is a member selected from the group consisting of: 
       —OH, —O-CH 3 , —O—CH 2 —CH 3 , —NH 2 , —N(—CH 3 ) 2 , —NH(—CH 2 -phenyl), —NH(-phenyl), —CN 
       
         
           
           
               
               
           
         
         and all pharmaceutically acceptable salts and hydrates thereof to the patient. 
       
     
     
         23 . The method of  claim 22 , wherein R 1  is a member selected from the group consisting of CN, —O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl, —O-t-butyl, —O-isoamyl, 1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy, 5-indolyloxy, 5-isoquinolyloxy,
 and all pharmaceutically acceptable salts and hydrates of such compounds. 
 
     
     
         24 . The method of  claim 22  wherein the compound has the formula I(a) or formula I(b) as follows: 
       
         
           
           
               
               
           
         
       
       wherein 
       R 1  is a member selected from the group consisting of CN, —O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl, —O-t-butyl, —O-isoamyl, 1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy, 5-indolyloxy, 5-isoquinolyloxy,
 and all pharmaceutically acceptable salts and hydrates thereof. 
 
     
     
         25 . The method of  claim 22  wherein the compound has formula I(c) or formula I(d) as follows: 
       
         
           
           
               
               
           
         
       
       wherein 
       R 1  is a member selected from the group consisting of CN, —O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl, —O-t-butyl, —O-isoamyl, 1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy, 5-indolyloxy, 5-isoquinolyloxy,
 and all pharmaceutically acceptable salts and hydrates of such compounds. 
 
     
     
         26 . The method of  claim 22  wherein the compound has formula I(e) 
       
         
           
           
               
               
           
         
       
       or formula I(f) as follows: 
       
         
           
           
               
               
           
         
       
       wherein 
       R 1  is a member selected from the group consisting of CN, —O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl, —O-t-butyl, —O-isoamyl, 1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy, 5-indolyloxy, 5-isoquinolyloxy,
 and all pharmaceutically acceptable salts and hydrates of such compounds. 
 
     
     
         27 . The method for treating cancer in a patient, comprising the step of administering a compound having the formula I(g) or formula I(h) as follows: 
       
         
           
           
               
               
           
         
       
       wherein 
       R 1  is a member selected from the group consisting of: CN, —O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl, —O-t-butyl, —O-isoamyl, 1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy, 5-indolyloxy, 5-isoquinolyloxy; 
       n is 2 or 3; 
       R 3  is a member selected from the group consisting of: 
       —OH, —O—CH 3 , —O—CH 2 —CH 3 , —NH 2 , —N(—CH 3 ) 2 , —NH(—CH 2 -phenyl), —NH(—phenyl), —CN 
       
         
           
           
               
               
           
         
         and all pharmaceutically acceptable salts and hydrates thereof. 
       
     
     
         28 . The method of  claim 27 , wherein R 1  is a member selected from the group consisting of CN, —O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl, —O-t-butyl, —O-isoamyl, 1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy, 5-indolyloxy, 5-isoquinolyloxy,
 and all pharmaceutically acceptable salts and hydrates of such compounds. 
 
     
     
         29 . The method of  claim 27 , wherein R 1  is a member selected from the group consisting of CN and —O -propyl, and all pharmaceutically acceptable salts and hydrates of such compounds. 
     
     
         30 . The method of  claim 27 , wherein R 3  is a member selected from the group consisting of piperidine, pyrrolidine, morpholine, piperazine, 4-methyl-piperidine and 2-methyl-piperidine and all pharmaceutically acceptable salts and hydrates of such compounds. 
     
     
         31 . The method of  claim 27 , wherein n is 3, and all pharmaceutically acceptable salts and hydrates of such compounds. 
     
     
         32 . The method according to  claim 27 , wherein the compound has the formula as follows: 
       
         
           
           
               
               
           
         
       
       {4-[6-methoxy-7-(3-piperidylpropoxy)quinazolin-4-yl]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide, and all pharmaceutically acceptable salts and hydrates thereof.