2,6-disubstituted quinazolines, quinoxalines, quinolines and isoquinolines and methods of their use as inhibitors of raf kinase

Abstract

New substituted quinazoline, quinoxaline, quinoline and isoquinoline compounds, compositions and methods of inhibition of Raf kinase activity in a human or animal subject are provided. The new compounds compositions may be used either alone or in combination with at least one additional agent for the treatment of a Raf kinase mediated disorder, such as cancer.

1 . A method of inhibiting Raf kinase activity in a human or animal subject, comprising administering to the human or animal subject a composition comprising an amount of a compound of the following formula: 
       
         
           
           
               
               
           
         
         wherein, 
         Y is O or S; 
         A 1  is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, polycyclic aryl, polycyclic arylalkyl, heteroaryl, biaryl, heteroarylaryl, heteroaryl-heteroaryl, cycloalkylalkyl, cycloalkylaryl, heterocycloalkyl, heterocycloalkylalkyl, heterocycloaryl, arylalkyl, heteroarylalkyl, biarylalkyl, or heteroarylarylalkyl; 
         R 2  is NR 6 R 7  or hydroxyl; 
         R 3  and R 3′  are independently selected from hydrogen, halogen, loweralkyl, and loweralkoxy; 
         R 4  is hydrogen, hydroxyl or substituted or unsubstituted alkyl; and 
         R 6  and R 7  are independently selected from hydrogen, and substituted or unsubstituted alkyl, alkoxy, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and heteroarylalkyl; or R 6  and R 7  are taken together to form substituted or unsubstituted heterocyclo or heteroaryl; or 
         a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof, 
         effective to inhibit Raf kinase activity in the human or animal subject. 
       
     
     
         2 . A method for treating a cancer disorder in a human or animal subject, comprising administering to the human or animal subject a composition comprising an amount of a compound of the following formula: 
       
         
           
           
               
               
           
         
         wherein, 
         Y is O or S; 
         A 1  is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, polycyclic aryl, polycyclic arylalkyl, heteroaryl, biaryl, heteroarylaryl, heteroaryl-heteroaryl, cycloalkylalkyl, cycloalkylaryl, heterocycloalkyl, heterocycloalkylalkyl, heterocycloaryl, arylalkyl, heteroarylalkyl, biarylalkyl, or heteroarylarylalkyl; 
         R 2  is NR 6 R 7  or hydroxyl; 
         R 3  and R 3′  are independently selected from hydrogen, halogen, loweralkyl, and loweralkoxy; 
         R 4  is hydrogen, hydroxyl or substituted or unsubstituted alkyl; and 
         R 6  and R 7  are independently selected from hydrogen, and substituted or unsubstituted alkyl, alkoxy, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and heteroarylalkyl; or R 6  and R 7  are taken together to form substituted or unsubstituted heterocyclo or heteroaryl; or 
         a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof, 
         effective to inhibit Raf kinase activity in the human or animal subject. 
       
     
     
         3 . A method of  claim 2  which further comprises administering to the human or animal subject at least one additional agent for the treatment of cancer. 
     
     
         4 . A method of  claim 3  in which the at least one additional agent for the treatment of cancer is selected from irinotecan, topotecan, gemcitabine, 5-fluorouracil, leucovorin carboplatin, cisplatin, taxanes, tezacitabine, cyclophosphamide, vinca alkaloids, imatinib, anthracyclines, rituximab, trastuzumab, dacarbazine, aldesleukin, capecitabine, and Iressa (gefitinib). 
     
     
         5 . A method for treating a hormone dependent cancer disorder in a human or animal subject, comprising administering to the human or animal subject a composition comprising an amount of a compound of the following formula: 
       
         
           
           
               
               
           
         
         wherein, 
         Y is O or S; 
         A 1  is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, polycyclic aryl, polycyclic arylalkyl, heteroaryl, biaryl, heteroarylaryl, heteroaryl-heteroaryl, cycloalkylalkyl, cycloalkylaryl, heterocycloalkyl, heterocycloalkylalkyl, heterocycloaryl, arylalkyl, heteroarylalkyl, biarylalkyl, or heteroarylarylalkyl; 
         R 2  is NR 6 R 7  or hydroxyl; 
         R 3  and R 3′  are independently selected from hydrogen, halogen, loweralkyl, and loweralkoxy; 
         R 4  is hydrogen, hydroxyl or substituted or unsubstituted alkyl; and 
         R 6  and R 7  are independently selected from hydrogen, and substituted or unsubstituted alkyl, alkoxy, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and heteroarylalkyl; or R 6  and R 7  are taken together to form substituted or unsubstituted heterocyclo or heteroaryl; or 
         a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof, 
         effective to inhibit Raf kinase activity in the human or animal subject. 
       
     
     
         6 . A method of  claim 5  wherein the hormone dependent cancer is breast cancer or prostate cancer. 
     
     
         7 . A method of  claim 5  which further comprises administering to the human or animal subject at least one additional agent for the treatment of cancer. 
     
     
         8 . A method of  claim 7  in which the at least one additional agent for the treatment of cancer is selected from irinotecan, topotecan, gemcitabine, 5-fluorouracil, leucovorin carboplatin, cisplatin, taxanes, tezacitabine, cyclophosphamide, vinca alkaloids, imatinib, anthracyclines, rituximab, trastuzumab, dacarbazine, aldesleukin, capecitabine, and Iressa (gefitinib). 
     
     
         9 . A method for treating a hematological cancer disorder in a human or animal subject, comprising administering to the human or animal subject a composition comprising an amount of a compound of the following formula: 
       
         
           
           
               
               
           
         
         wherein, 
         Y is O or S; 
         A 1  is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, polycyclic aryl, polycyclic arylalkyl, heteroaryl, biaryl, heteroarylaryl, heteroaryl-heteroaryl, cycloalkylalkyl, cycloalkylaryl, heterocycloalkyl, heterocycloalkylalkyl, heterocycloaryl, arylalkyl, heteroarylalkyl, biarylalkyl, or heteroarylarylalkyl; 
         R 2  is NR 6 R 7  or hydroxyl; 
         R 3  and R 3′  are independently selected from hydrogen, halogen, loweralkyl, and loweralkoxy; 
         R 4  is hydrogen, hydroxyl or substituted or unsubstituted alkyl; and 
         R 6  and R 7  are independently selected from hydrogen, and substituted or unsubstituted alkyl, alkoxy, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and heteroarylalkyl; or R 6  and R 7  are taken together to form substituted or unsubstituted heterocyclo or heteroaryl; or 
         a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof, 
         effective to inhibit Raf kinase activity in the human or animal subject. 
       
     
     
         10 . A method of  claim 9  which further comprises administering to the human or animal subject at least one additional agent for the treatment of cancer. 
     
     
         11 . A method of  claim 10  in which the at least one additional agent for the treatment of cancer is selected from irinotecan, topotecan, gemcitabine, 5-fluorouracil, leucovorin carboplatin, cisplatin, taxanes, tezacitabine, cyclophosphamide, vinca alkaloids, imatinib, anthracyclines, rituximab, trastuzumab, dacarbazine, aldesleukin, capecitabine, and Iressa (gefitinib).