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

Abstract

New substituted benzazole 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.

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows: 
     
         1 . A compound of the formula (I): 
       
         
           
           
               
               
           
         
         wherein, X 1  and X 3  are independently selected from N, —NR 4 —, —O— or —S—, wherein R 4  is hydrogen or loweralkyl, provided that at least one of X 1  and X 3  must be N or —NR 4 —; 
         X 2  is —NH— or —(CH 2 ) m —, wherein m is 0, 1, 2, 3 or 4; 
         A 1  is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, polycyclic aryl, polycyclic arylalkyl, heteroaryl, biaryl, heteroarylaryl, or heteroarylheteroaryl; 
         R 1  is hydrogen or substituted or unsubstituted loweralkyl, alkoxyalkyl, loweralkyloxy, amino, aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocycloalkyl, heteroarylalkyl, cycloalkyloweralkyl, heterocycloalkylloweralkyl, loweralkylheterocycloalkyl, arylloweralkyl, heteroarylloweralkyl, alkyloxyalkylheterocycloloweralkyl, or heteroarylloweralkyl; 
         R 2  is hydrogen or loweralkyl; 
         each R 3  and R 3 ′ are independently selected from hydrogen, halogen, hydroxy, cyano, loweralkyl, or loweralkoxy; and 
         p and q are independently 0, 1, 2 or 3; or 
         a pharmaceutically acceptable salt, ester or prodrug thereof. 
       
     
     
         2 . A compound of  claim 1  wherein X 1  is —NR 4 —. 
     
     
         3 . A compound of  claim 2  wherein R 4  is hydrogen. 
     
     
         4 . A compound of  claim 2  wherein R 1  is methyl. 
     
     
         5 . A compound of  claim 1  wherein X 2  is —NH—. 
     
     
         6 . A compound of  claim 1  wherein A 1  is selected from the group consisting of substituted or unsubstituted phenyl, pyridyl, pyrimidinyl, phenylalkyl, pyridylalkyl, pyrimidinylalkyl, heterocyclylcarbonylphenyl, heterocyclylphenyl, heterocyclylalkylphenyl, chlorophenyl, fluorophenyl, 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, alkylfluorophenyl, trifluoromethylchlorophenyl, trifluoromethylbromophenyl indenyl, 2,3-dihydroindenyl, tetralinyl, trifluorophenyl, (trifluoromethypthiophenyl, alkoxybiphenyl, morpholinyl, N-piperazinyl, N-morpholinylalkyl, piperazinylalkyl, cyclohexylalkyl, indolyl, 2,3-dihydroindolyl, 1-aceytl-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-fluoren-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′-bipiperi din-1′-yl, and (1,4′-bipiperidin-1′-ylcarbonyl)phenyl. 
     
     
         7 . A compound of  claim 1  wherein A 1  has the structure: 
       
         
           
           
               
               
           
         
         wherein R 5 , R 6 , R 7 , R 8  and R 9  are independently selected from hydrogen, halo, loweralkyl, cyano, hydroxy, haloloweralkyl, loweralkyloxy, haloloweralkyloxy, loweralkylthio, haloloweralkylthio, and substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. 
       
     
     
         8 . A compound of  claim 7  wherein R 5 , R 6 , R 7 , R 8  and R 9  are independently selected from hydrogen, chloro, fluoro, methyl, ethyl, propyl, iso-propyl, butyl, tert-butyl, cyano, hydroxy, methyloxy, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, acetyl, and substituted or unsubstituted phenyl, phenyloxy, furyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, trifluoromethylpiperidinyl, thiophenyl, piperazinyl, and morpholinyl. 
     
     
         9 . A compound of  claim 1  wherein R 1  has the structure: 
       
         
           
           
               
               
           
         
         wherein n is 0, 1, 2, 3 or 4; 
         r is 1 or 2; 
         X 4  is —CH— or N 
         R 10  and R 12  are independently selected from hydrogen, halo, loweralkyl, haloloweralkyl, hydroxyloweralkyl, loweralkyloxy, haloloweralkyloxy, loweralkyl sulfonyl, haloloweralkylsulfonyl, and substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and 
         R 11  is hydrogen, loweralkyl, haloloweralkyl, hydroxyloweralkyl, loweralkyloxy, haloloweralkyloxy, loweralkyloxyloweralkyl, and substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. 
       
     
     
         10 . A compound of  claim 9  wherein n is 1. 
     
     
         11 . A compound of  claim 9  wherein R 10  and R 12  are hydrogen or loweralkyl. 
     
     
         12 . A compound of  claim 9  wherein R 11  is loweralkyl. 
     
     
         13 . A compound of the formula (II): 
       
         
           
           
               
               
           
         
         wherein, X 2  is —NH— or —(CH 2 ) m —, wherein m is 0, 1, 2, 3 or 4; 
         A 1  is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, polycyclic aryl, polycyclic arylalkyl, heteroaryl, biaryl, heteroarylaryl, or heteroarylheteroaryl; 
         R 1  is hydrogen or substituted or unsubstituted loweralkyl, alkoxyalkyl, loweralkyloxy, amino, aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocycloalkyl, heteroarylalkyl, cycloalkyloweralkyl, heterocycloalkylloweralkyl, loweralkylheterocycloalkyl, arylloweralkyl, heteroarylloweralkyl, alkyloxyalkylheterocycloloweralkyl, or heteroarylloweralkyl; 
         R 2  is hydrogen or loweralkyl; 
         R 3  is hydrogen, halogen, loweralkyl, or loweralkoxy; and 
         R 4  is hydrogen or loweralkyl or 
         a pharmaceutically acceptable salt, ester or prodrug thereof. 
       
     
     
         14 . A compound of  claim 13  wherein R 4  is hydrogen. 
     
     
         15 . A compound of  claim 13  wherein R 4  is methyl. 
     
     
         16 . A compound of  claim 13  wherein X 2  is —NH—. 
     
     
         17 . A compound of  claim 13  wherein A 1  is selected from the group consisting of substituted or unsubstituted phenyl, pyridyl, pyrimidinyl, phenylalkyl, pyridylalkyl, pyrimidinylalkyl, heterocyclylcarbonylphenyl, heterocyclylphenyl, heterocyclylalkylphenyl, chlorophenyl, fluorophenyl, 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, alkylfluorophenyl, trifluoromethylchlorophenyl, trifluoromethylbromophenyl indenyl, 2,3-dihydroindenyl, tetralinyl, trifluorophenyl, (trifluoromethypthiophenyl, alkoxybiphenyl, morpholinyl, N-piperazinyl, N-morpholinylalkyl, piperazinylalkyl, cyclohexylalkyl, indolyl, 2,3-dihydroindolyl, 1-aceytl-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-fluoren-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, di alkylaminopyrrolidin-1-yl, 1,4′-bipiperidin-1′-yl, and (1,4′-bipiperidin-1′-ylcarbonyl)phenyl. 
     
     
         18 . A compound of  claim 13  wherein A 1  has the structure: 
       
         
           
           
               
               
           
         
         wherein R 5 , R 6 , R 7 , R 8  and R 9  are independently selected from hydrogen, halo, loweralkyl, cyano, hydroxy, haloloweralkyl, loweralkyloxy, haloloweralkyloxy, loweralkylthio, haloloweralkylthio, and substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. 
       
     
     
         19 . A compound of  claim 18  wherein R 5 , R 6 , R 7 , R 8  and R 9  are independently selected from hydrogen, chloro, fluoro, methyl, ethyl, propyl, iso-propyl, butyl, tert-butyl, cyano, hydroxy, methyloxy, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, acetyl, and substituted or unsubstituted phenyl, phenyloxy, furyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, trifluoromethylpiperidinyl, thiophenyl, piperazinyl, and morpholinyl. 
     
     
         20 . A compound of  claim 13  wherein R 1  has the structure: 
       
         
           
           
               
               
           
         
         wherein n is 0, 1, 2, 3 or 4; 
         r is 1 or 2; 
         X 4  is —CH— or N 
         R 10  and R 12  are independently selected from hydrogen, halo, loweralkyl, haloloweralkyl, hydroxyloweralkyl, loweralkyloxy, haloloweralkyloxy, loweralkylsulfonyl, haloloweralkylsulfonyl, and substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and 
         R 11  is hydrogen, loweralkyl, haloloweralkyl, hydroxyloweralkyl, loweralkyloxy, haloloweralkyloxy, loweralkyloxyloweralkyl, and substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. 
       
     
     
         21 . A compound of  claim 20  wherein n is 1. 
     
     
         22 . A compound of  claim 20  wherein R 10  and R 12  are hydrogen or loweralkyl. 
     
     
         26 . A compound of  claim 20  wherein R 11  is loweralkyl. 
     
     
         27 . A compound of the formula (III): 
       
         
           
           
               
               
           
         
         wherein, X 1  is —NR 4 —, —O— or —S—, wherein R 4  is hydrogen or loweralkyl; 
         X 2  is NH— or (CH 2 ) m —, wherein m is 0, 1, 2, 3 or 4; 
         A 1  is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, polycyclic aryl, polycyclic arylalkyl, heteroaryl, biaryl, heteroarylaryl, or heteroarylheteroaryl; 
         R 1  is hydrogen or substituted or unsubstituted loweralkyl, alkoxyalkyl, loweralkyloxy, amino, aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocycloalkyl, heteroarylalkyl, cycloalkyloweralkyl, heterocycloalkylloweralkyl, loweralkylheterocycloalkyl, arylloweralkyl, heteroarylloweralkyl, alkyloxyalkylheterocycloloweralkyl, or heteroarylloweralkyl; 
         R 2  is hydrogen or loweralkyl; and 
         R 3  is hydrogen, halogen, loweralkyl, or loweralkoxy; or 
         a pharmaceutically acceptable salt, ester or prodrug thereof. 
       
     
     
         28 . A compound of  claim 27  wherein X 1  is —NR 1 —. 
     
     
         29 . A compound of  claim 28  wherein R 4  is hydrogen. 
     
     
         30 . A compound of  claim 28  wherein R 4  is methyl. 
     
     
         31 . A compound of  claim 27  wherein X 2  is —NH—. 
     
     
         32 . A compound of  claim 27  wherein A 1  is selected from the group consisting of substituted or unsubstituted phenyl, pyridyl, pyrimidinyl, phenylalkyl, pyridylalkyl, pyrimidinylalkyl, heterocyclylcarbonylphenyl, heterocyclylphenyl, heterocyclylalkylphenyl, chlorophenyl, fluorophenyl, 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, alkylfluorophenyl, trifluoromethylchlorophenyl, trifluoromethylbromophenyl indenyl, 2,3-dihydroindenyl, tetralinyl, trifluorophenyl, (trifluoromethypthiophenyl, alkoxybiphenyl, morpholinyl, N-piperazinyl, N-morpholinylalkyl, piperazinylalkyl, cyclohexylalkyl, indolyl, 2,3-dihydroindolyl, 1-aceytl-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-fluoren-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′-bipiperi din-1′-yl, and (1,4′-bipiperidin-1′-ylcarbonyl)phenyl. 
     
     
         33 . A compound of  claim 30  wherein A 1  has the structure: 
       
         
           
           
               
               
           
         
         wherein R 5 , R 6 , R 7 , R 8  and R 9  are independently selected from hydrogen, halo, loweralkyl, cyano, hydroxy, haloloweralkyl, loweralkyloxy, haloloweralkyloxy, loweralkylthio, haloloweralkylthio, and substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. 
       
     
     
         34 . A compound of  claim 33  wherein R 5 , R 6 , R 7 , R 8  and R 9  are independently selected from hydrogen, chloro, fluoro, methyl, ethyl, propyl, iso-propyl, butyl, tert-butyl, cyano, hydroxy, methyloxy, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, acetyl, and substituted or unsubstituted phenyl, phenyloxy, furyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, trifluoromethylpiperidinyl, thiophenyl, piperazinyl, and morpholinyl. 
     
     
         34 . A compound of  claim 27  wherein R 1  has the structure: 
       
         
           
           
               
               
           
         
         wherein n is 0, 1, 2, 3 or 4; 
         r is 1 or 2; 
         X 4  is —CH— or N 
         R 10  and R 12  are independently selected from hydrogen, halo, loweralkyl, haloloweralkyl, hydroxyloweralkyl, loweralkyloxy, haloloweralkyloxy, loweralkylsulfonyl, haloloweralkylsulfonyl, and substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and 
         R 11  is hydrogen, loweralkyl, haloloweralkyl, hydroxyloweralkyl, loweralkyloxy, haloloweralkyloxy, loweralkyloxyloweralkyl, and substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. 
       
     
     
         35 . A compound of  claim 34  wherein n is 1. 
     
     
         36 . A compound of  claim 34  wherein R 10  and R 12  are hydrogen or loweralkyl. 
     
     
         37 . A compound of  claim 34  wherein R 11  is loweralkyl. 
     
     
         38 . A compound of the formula (IV): 
       
         
           
           
               
               
           
         
         wherein X 1  is —NR 4 —, —O— or —S—, wherein R 4  is hydrogen or loweralkyl; 
         A 1  is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, polycyclic aryl, polycyclic arylalkyl, heteroaryl, biaryl, heteroarylaryl, or heteroarylheteroaryl; 
         R 1  is hydrogen or substituted or unsubstituted loweralkyl, alkoxyalkyl, loweralkyloxy, amino, aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocycloalkyl, heteroarylalkyl, cycloalkyloweralkyl, heterocycloalkylloweralkyl, loweralkylheterocycloalkyl, arylloweralkyl, heteroarylloweralkyl, alkyloxyalkylheterocycloloweralkyl, or heteroarylloweralkyl; 
         R 2  is hydrogen or loweralkyl; and 
         R 3  is hydrogen, halogen, loweralkyl, or loweralkoxy; or 
         a pharmaceutically acceptable salt, ester or prodrug thereof. 
       
     
     
         39 . A compound of  claim 38  wherein X 1  is —NR 1 —. 
     
     
         40 . A compound of  claim 39  wherein R 4  is hydrogen. 
     
     
         41 . A compound of  claim 39  wherein R 4  is methyl. 
     
     
         42 . A compound of  claim 38  wherein A 1  is selected from the group consisting of substituted or unsubstituted phenyl, pyridyl, pyrimidinyl, phenylalkyl, pyridylalkyl, pyrimidinylalkyl, heterocyclylcarbonylphenyl, heterocyclylphenyl, heterocyclylalkylphenyl, chlorophenyl, fluorophenyl, 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, alkylfluorophenyl, trifluoromethylchlorophenyl, trifluoromethylbromophenyl indenyl, 2,3-dihydroindenyl, tetralinyl, trifluorophenyl, (trifluoromethyl)thiophenyl, alkoxybiphenyl, morpholinyl, N-piperazinyl, N-morpholinylalkyl, piperazinylalkyl, cyclohexylalkyl, indolyl, 2,3-dihydroindolyl, 1-aceytl-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-fluoren-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. 
     
     
         43 . A compound of  claim 38  wherein A 1  has the structure: 
       
         
           
           
               
               
           
         
         wherein R 5 , R 6 , R 7 , R 8  and R 9  are independently selected from hydrogen, halo, loweralkyl, cyano, hydroxy, haloloweralkyl, loweralkyloxy, haloloweralkyloxy, loweralkylthio, haloloweralkylthio, and substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. 
       
     
     
         44 . A compound of  claim 38  wherein R 5 , R 6 , R 7 , R 8  and R 9  are independently selected from hydrogen, chloro, fluoro, methyl, ethyl, propyl, iso-propyl, butyl, tert-butyl, cyano, hydroxy, methyloxy, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, acetyl, and substituted or unsubstituted phenyl, phenyloxy, furyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, trifluoromethylpiperidinyl, thiophenyl, piperazinyl, and morpholinyl. 
     
     
         45 . A compound of  claim 38  wherein R 1  has the structure: 
       
         
           
           
               
               
           
         
         wherein n is 0, 1, 2, 3 or 4; 
         r is 1 or 2; 
         X 4  is —CH— or N 
         R 10  and R 12  are independently selected from hydrogen, halo, loweralkyl, haloloweralkyl, hydroxyloweralkyl, loweralkyloxy, haloloweralkyloxy, loweralkylsulfonyl, haloloweralkylsulfonyl, and substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and 
         R 11  is hydrogen, loweralkyl, haloloweralkyl, hydroxyloweralkyl, loweralkyloxy, haloloweralkyloxy, loweralkyloxyloweralkyl, and substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. 
       
     
     
         46 . A compound of  claim 45  wherein n is 1. 
     
     
         47 . A compound of  claim 45  wherein R 10  and R 12  are hydrogen or loweralkyl. 
     
     
         48 . A compound of  claim 45  wherein R 11  is loweralkyl. 
     
     
         49 . A compound of the formula (V): 
       
         
           
           
               
               
           
         
         wherein R 1  is hydrogen or substituted or unsubstituted loweralkyl, alkoxyalkyl, loweralkyloxy, amino, aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocycloalkyl, heteroarylalkyl, cycloalkyloweralkyl, heterocycloalkylloweralkyl, loweralkylheterocycloalkyl, arylloweralkyl, heteroarylloweralkyl, alkyloxy-alkylheterocycloloweralkyl, or heteroarylloweralkyl; 
         R 2  is hydrogen or loweralkyl; 
         R 3  is hydrogen, halogen, loweralkyl, or loweralkoxy; 
         R 4  is hydrogen or loweralkyl; and 
         R 5 , R 6 , R 7 , R 8  and R 9  are independently selected from hydrogen, halo, loweralkyl, cyano, hydroxy, haloloweralkyl, loweralkyloxy, haloloweralkyloxy, loweralkylthio, haloloweralkylthio, and substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or 
         a pharmaceutically acceptable salt, ester or prodrug thereof. 
       
     
     
         50 . A compound of  claim 49  wherein R 4  is hydrogen. 
     
     
         51 . A compound of  claim 49  wherein R 4  is methyl. 
     
     
         52 . A compound of  claim 49  wherein R 5 , R 6 , R 7 , R 8  and R 9  are independently selected from hydrogen, chloro, fluoro, methyl, ethyl, propyl, iso-propyl, butyl, tert-butyl, cyano, hydroxy, methyloxy, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, acetyl, and substituted or unsubstituted phenyl, phenyloxy, furyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, trifluoromethylpiperidinyl, thiophenyl, piperazinyl, and morpholinyl. 
     
     
         53 . A compound of  claim 49  wherein R 1  has the structure: 
       
         
           
           
               
               
           
         
         wherein n is 0, 1, 2, 3 or 4; 
         r is 1 or 2; 
         X 4  is —CH— or N 
         R 10  and R 12  are independently selected from hydrogen, halo, loweralkyl, haloloweralkyl, hydroxyloweralkyl, loweralkyloxy, haloloweralkyloxy, loweralkylsulfonyl, haloloweralkylsulfonyl, and substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and 
         R 11  is hydrogen, loweralkyl, haloloweralkyl, hydroxyloweralkyl, loweralkyloxy, haloloweralkyloxy, loweralkyloxyloweralkyl, and substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. 
       
     
     
         54 . A compound of  claim 53  wherein n is 1. 
     
     
         55 . A compound of  claim 53  wherein R 10  and R 12  are hydrogen or loweralkyl. 
     
     
         56 . A compound of  claim 53  wherein R 11  is loweralkyl. 
     
     
         57 . A compound of the formula (VI): 
       
         
           
           
               
               
           
         
         R 2  is hydrogen or loweralkyl; 
         R 3  is hydrogen, halogen, loweralkyl, or loweralkoxy; 
         R 4  is hydrogen or loweralkyl; and 
         R 5 , R 6 , R 7 , R 8  and R 9  are independently selected from hydrogen, halo, loweralkyl, cyano, hydroxy, haloloweralkyl, loweralkyloxy, haloloweralkyloxy, loweralkylthio, haloloweralkylthio, and substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; 
         n is 0, 1, 2, 3 or 4; 
         R 10  and R 12  are independently selected from hydrogen, halo, loweralkyl, haloloweralkyl, hydroxyloweralkyl, loweralkyloxy, haloloweralkyloxy, loweralkylsulfonyl, haloloweralkylsulfonyl, and substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and 
         R 11  is hydrogen, loweralkyl, haloloweralkyl, hydroxyloweralkyl, loweralkyloxy, haloloweralkyloxy, loweralkyloxyloweralkyl, and substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl or 
         a pharmaceutically acceptable salt, ester or prodrug thereof. 
       
     
     
         58 . A compound of  claim 57  wherein A compound of  claim 49  wherein R 4  is hydrogen. 
     
     
         59 . A compound of  claim 57  wherein R 4  is methyl. 
     
     
         60 . A compound of  claim 57  wherein R 5 , R 6 , R 7 , R 8  and R 9  are independently selected from hydrogen, chloro, fluoro, methyl, ethyl, propyl, iso-propyl, butyl, tert-butyl, cyano, hydroxy, methyloxy, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, acetyl, and substituted or unsubstituted phenyl, phenyloxy, furyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, trifluoromethylpiperidinyl, thiophenyl, piperazinyl, and morpholinyl. 
     
     
         61 . A compound of  claim 57  wherein n is 1. 
     
     
         62 . A compound of  claim 57  wherein R 10  and R 12  are hydrogen or loweralkyl. 
     
     
         63 . The compound of  claim 57  which is 2-(4-ethylpiperazin-1-yl)-N-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}acetamide. 
     
     
         64 . A composition comprising an amount of a compound of  claim 1 ,  13 ,  27 ,  38 ,  49 ,  57  or  63  effective to inhibit Raf activity in a human or animal subject when administered thereto, together with a pharmaceutically acceptable carrier. 
     
     
         65 . A composition of  claim 64  which further comprises at least one additional agent for the treatment of cancer. 
     
     
         66 . A composition of  claim 65  in which the at least one additional agent for the treatment of cancer is selected from dacarbazine, irinotecan, topotecan, gemcitabine, 5-fluorouracil, leucovorin carboplatin, cisplatin, taxanes, tezacitabine, cyclophosphamide, vinca alkaloids, imatinib, anthracyclines, rituximab and trastuzumab. 
     
     
         67 . 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  claim 1 ,  13 ,  27 ,  38 ,  49 ,  57  or  63  effective to inhibit Raf kinase activity in the human or animal subject. 
     
     
         68 . 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  claim 1 ,  13 ,  27 ,  38 ,  49 ,  57  or  63  effective to inhibit Raf kinase activity in the human or animal subject. 
     
     
         69 . A method of  claim 68  wherein said cancer is melanoma, papillary thyroid cancer, cholangiocarcinoma, gallbladder carcinoma, colorectal cancer, lung cancer, pancreatic cancer, leukemia, prostate cancer, ovarian cancer, breast cancer, or lung cancer. 
     
     
         70 . A method of  claim 68  which further comprises administering to the human or animal subject at least one additional agent for the treatment of cancer. 
     
     
         71 . A method of  claim 70  in which the at least one additional agent for the treatment of cancer is selected from dacarbazine, irinotecan, topotecan, gemcitabine, 5-fluorouracil, leucovorin carboplatin, cisplatin, taxanes, tezacitabine, cyclophosphamide, vinca alkaloids, imatinib, anthracyclines, rituximab and trastuzumab. 
     
     
         72 . 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  claim 1 ,  13 ,  27 ,  38 ,  49 ,  57  or  63  effective to inhibit Raf kinase activity in the human or animal subject. 
     
     
         73 . A method of  claim 72  wherein the hormone dependent cancer is breast cancer or prostate cancer. 
     
     
         74 . A method of  claim 72  which further comprises administering to the human or animal subject at least one additional agent for the treatment of cancer. 
     
     
         75 . A method of  claim 74  in which the at least one additional agent for the treatment of cancer is selected from dacarbazine, irinotecan, topotecan, gemcitabine, 5-fluorouracil, leucovorin carboplatin, cisplatin, taxanes, tezacitabine, cyclophosphamide, vinca alkaloids, imatinib, anthracyclines, rituximab and trastuzumab. 
     
     
         76 . 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  claim 1 ,  13 ,  27 ,  38 ,  49 ,  57  or  63  effective to inhibit Raf kinase activity in the human or animal subject. 
     
     
         77 . A method of  claim 76  which further comprises administering to the human or animal subject at least one additional agent for the treatment of cancer. 
     
     
         78 . A method of  claim 77  in which the at least one additional agent for the treatment of cancer is selected from dacarbazine, irinotecan, topotecan, gemcitabine, 5-fluorouracil, leucovorin carboplatin, cisplatin, taxanes, tezacitabine, cyclophosphamide, vinca alkaloids, imatinib, anthracyclines, rituximab and trastuzumab. 
     
     
         79 . A compound of  claim 1 ,  13 ,  27 ,  38 ,  49 ,  57  or  63  for use as a pharmaceutical. 
     
     
         80 . Use of a compound of  claim 1 ,  13 ,  27 ,  38 ,  49 ,  57  or  63  in the manufacture of a medicament for the treatment of cancer.