Substituted benzazoles and methods of their use as inhibitors of raf kinase

Abstract

New substituted benz-azole 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 compound of the formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         X 1  is ═N— and X 2  is —S—, or X 1  is —S— and X 2  is ═N—; 
         Y is O or S; 
         A 1  is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, polycyclic aryl, polycyclic arylalkyl, heteroaryl, biaryl, heteroarylaryl, heteroarylheteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, biarylalkyl, or heteroarylarylalkyl; 
         A 2  is substituted or unsubstituted heteroaryl; 
         R 1  is O or H, and R 2  is NR 5 R 6  or hydroxyl; or R 1  is taken together with R 2  to form a substituted or unsubstituted heterocycloalkyl or heteroaryl group; wherein, the dashed line represents a single or double bond; 
         R 3  is hydrogen, halogen, loweralkyl, or loweralkoxy; 
         R 5  and R 6  are independently selected from hydrogen, and substituted or unsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and heteroarylalkyl; or R 5  and R 6  are taken together to form substituted or unsubstituted heterocyclo or heteroaryl; and 
         R 7  is loweralkyl; 
         or a pharmaceutically acceptable salt, ester or prodrug thereof. 
       
     
     
         2 . A compound of  claim 1  wherein Y is O. 
     
     
         3 . A compound of  claim 1  wherein A 1  is selected from the group consisting of substituted or unsubstituted phenyl, pyridyl, pyrimidinyl, phenylalkyl, pyridylalkyl, pyrimidinylalkyl, heterocyclocarbonylphenyl, heterocyclophenyl, heterocycloalkylphenyl, chlorophenyl, flourophenyl, bromophenyl, iodophenyl, dihalophenyl, nitrophenyl, 4-bromophenyl, 4-chlorophenyl, alkylbenzoate, alkoxyphenyl, dialkoxyphenyl, dialkylphenyl, trialkylphenyl, thiophene, thiophene-2-carboxylate, alkylthiophenyl, trifluoromethylphenyl, acetylphenyl, sulfamoylphenyl, biphenyl, cyclohexylphenyl, phenyloxyphenyl, dialkylaminophenyl, alkylbromophenyl, alkylchlorophenyl, alkylflourophenyl, triflouromethylchlorophenyl, triflouromethylbromophenyl indenyl, 2,3-dihydroindenyl, tetralinyl, triflourophenyl, (triflouromethyl)thiophenyl, alkoxybiphenyl, morpholinyl, N-piperazinyl, N-morpholinylalkyl, piperazinylalkyl, cyclohexylalkyl, indolyl, 2,3-dihydroindolyl, 1-aceyt1-2,3-dihydroindolyl, cycloheptyl, bicyclo [2.2.1]hept-2-yl, hydroxyphenyl, hydroxyalkylphenyl, pyrrolidinyl, pyrrolidin-1-yl, pyrrolidin-1-ylalkyl, 4-amino(imino)methylphenyl, isoxazolyl, indazolyl, adamantyl, bicyclohexyl, quinuclidinyl, imidazolyl, benzimidazolyl, imidazolylphenyl, phenylimidazolyl, pthalamido, napthyl, benzophenone, anilinyl, anisolyl, quinolinyl, quinolinonyl, phenylsulfonyl, phenylalkylsulfonyl, 9H-flouren-1-yl, piperidin-1-yl, piperidin-1-ylalkyl, cyclopropyl, cyclopropylalkyl, pyrimidin-5-ylphenyl, quinolidinylphenyl, furanyl, furanylphenyl, N-methylpiperidin-4-yl, pyrrolidin-4-ylpyridinyl, 4-diazepan-1-yl, hydroxypyrrolidn-1-yl, dialkylaminopyrrolidin-1-yl, 1,4′-bipiperidin-1′-yl, and (1,4′-bipiperidin-1′-ylcarbonyl)phenyl. 
     
     
         4 . A compound of  claim 1  wherein A 2  is substituted or unsubstituted pyridyl. 
     
     
         5 . A compound of  claim 1  wherein R 1  is O and the dashed line represents a single or double bond. 
     
     
         6 . A compound of  claim 1  wherein R 2  is NR 5 R 6 , R 5  is hydrogen and R 6  is selected from hydrogen, and substituted or unsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and heteroarylalkyl. 
     
     
         7 . A compound of  claim 1  wherein R 1  is taken together with R 2  to form a substituted or unsubstituted heterocycloalkyl or heteroaryl group. 
     
     
         8 . A compound of the formula (V): 
       
         
           
           
               
               
           
         
         wherein X is S; 
         A 1  is substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, polycyclic aryl, polycyclic arylalkyl, heteroaryl, biaryl, heteroarylaryl, heteroarylheteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, biarylalkyl, heteroarylarylalkyl; 
         R 1  is O and R 2  is NR 5 R 6 ; or R 1  is taken together with R 2  to form a substituted or unsubstituted heterocycloalkyl or heteroaryl group; wherein, the dashed line represents a single or double bond; 
         R 3  is hydrogen, halogen, loweralkyl, or loweralkoxy; 
         R 5  and R 6  are independently selected from hydrogen, and substituted or unsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and heteroarylalkyl; or R5 and R6 are taken together to form substituted or unsubstituted heterocyclo or heteroaryl; or 
         a pharmaceutically acceptable salt, ester or prodrug thereof. 
       
     
     
         9 . A compound of  claim 8  wherein A 1  is selected from the group consisting of substituted or unsubstituted phenyl, pyridyl, pyrimidinyl, phenylalkyl, pyridylalkyl, pyrimidinylalkyl, heterocyclocarbonylphenyl, heterocyclophenyl, heterocycloalkylphenyl, chlorophenyl, flourophenyl, bromophenyl, iodophenyl, dihalophenyl, nitrophenyl, 4-bromophenyl, 4-chlorophenyl, alkylbenzoate, alkoxyphenyl, dialkoxyphenyl, dialkylphenyl, trialkylphenyl, thiophene, thiophene-2-carboxylate, alkylthiophenyl, trifluoromethylphenyl, acetylphenyl, sulfamoylphenyl, biphenyl, cyclohexylphenyl, phenyloxyphenyl, dialkylaminophenyl, alkylbromophenyl, alkylchlorophenyl, alkylflourophenyl, triflouromethylchlorophenyl, triflouromethylbromophenyl indenyl, 2,3-dihydroindenyl, tetralinyl, triflourophenyl, (triflouromethyl)thiophenyl, alkoxybiphenyl, morpholinyl, N-piperazinyl, N-morpholinylalkyl, piperazinylalkyl, cyclohexylalkyl, indolyl, 2,3-dihydroindolyl, 1-aceyt1-2,3-dihydroindolyl, cycloheptyl, bicyclo[2.2.1]hept-2-yl, hydroxyphenyl, hydroxyalkylphenyl, pyrrolidinyl, pyrrolidin-1-yl, pyrrolidin-1-ylalkyl, 4-amino(imino)methylphenyl, isoxazolyl, indazolyl, adamantyl, bicyclohexyl, quinuclidinyl, imidazolyl, benzimidazolyl, imidazolylphenyl, phenylimidazolyl, pthalamido, napthyl, benzophenone, anilinyl, anisolyl, quinolinyl, quinolinonyl, phenylsulfonyl, phenylalkylsulfonyl, 9H-flouren-1-yl, piperidin-1-yl, piperidin-1-ylalkyl, cyclopropyl, cyclopropylalkyl, pyrimidin-5-ylphenyl, quinolidinylphenyl, furanyl, furanylphenyl, N-methylpiperidin-4-yl, pyrrolidin-4-ylpyridinyl, 4-diazepan-1-yl, hydroxypyrrolidn-1-yl, dialkylaminopyrrolidin-1-yl, 1,4′-bipiperidin-1′-yl, and (1,4′-bipiperidin-1′-ylcarbonyl)phenyl. 
     
     
         10 . A compound of  claim 8  wherein R 1  is O and the dashed line represents a single or double bond. 
     
     
         11 . A compound of  claim 8  wherein R 2  is NR 5 R 6 , R 5  is hydrogen and R 6  is selected from hydrogen, and substituted or unsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and heteroarylalkyl. 
     
     
         12 . A compound of  claim 8  wherein R 1  is taken together with R 2  to form a substituted or unsubstituted heterocycloalkyl or heteroaryl group. 
     
     
         13 . A compound of  claim 8  wherein R 3  is loweralkoxy. 
     
     
         14 . A compound of  claim 8  wherein R 1  is O, R 2  is NR 5 R 6 , R 5  is H, and R 6  is methyl. 
     
     
         15 . A composition comprising an amount of a compound of  claim 1  effective to inhibit Raf activity in a human or animal subject when administered thereto, together with a pharmaceutically acceptable carrier. 
     
     
         16 . A composition of  claim 15  which further comprises at least one additional agent for the treatment of cancer. 
     
     
         17 . A composition of  claim 16  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 and trastuzumab.