Substituted benzazoles and methods of their use as inhibitors of Raf kinase
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.
1. A compound of the formula (I):
wherein, X 1 and X 3 are selected from N and —NR 4 —, wherein R 4 is hydrogen or loweralkyl, provided that one of X 1 and X 3 must be N and the other of X 1 and X 3 must be —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 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 4 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-chiorophenyl, alkylbeuzoate, alkoxyphenyl, dialkoxyphenyl, dialkyiphenyl, trialkytphenyl, 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.
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 0,1,2,3or 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.
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 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, (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.
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, 3or4;
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.
23. A compound of claim 20 wherein R 11 is loweralkyl.
24. A compound of the formula (IV):
wherein X 1 is —NR 4 —, 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 thereof.
25. A compound of claim 24 wherein R 4 is hydrogen.
26. A compound of claim 24 wherein R 4 is methyl.
27. A compound of claim 24 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.
28. A compound of claim 24 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.
29. A compound of claim 24 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.
30. A compound of claim 24 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, halotoweralkyloxy, 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.
31. A compound of claim 30 wherein n is 1.
32. A compound of claim 30 wherein R 10 and R 12 are hydrogen or loweralkyl.
33. A compound of claim 30 wherein R 11 is loweralkyl.
34. 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, heterocycloalkyl-loweralkyl, 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 thereof.
35. A compound of claim 34 wherein R 4 is hydrogen.
36. A compound of claim 34 wherein R 4 is methyl.
37. A compound of claim 34 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, trilluoromethyl, trifluoromethoxy, trifluoromethylthio, acetyl, and substituted or unsubstituted phenyl, phenyloxy, furyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, trifluoromethylpiperidinyl, thiophenyl, piperazinyl, and morpholinyl.
38. A compound of claim 34 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.
39. A compound of claim 38 wherein n is 1.
40. A compound of claim 38 wherein R 10 and R 12 are hydrogen or loweralkyl.
41. A compound of claim 38 wherein R 11 is loweralkyl.
42. 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, haloloweralkyl sulfonyl, 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 thereof.
43. A compound of claim 42 wherein R 4 is hydrogen.
44. A compound of claim 42 wherein R 4 is methyl.
45. A compound of claim 42 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.
46. A compound of claim 42 wherein n is 1.
47. A compound of claim 42 wherein R 10 and R 12 are hydrogen or loweralkyl.
48. The compound of claim 42 which is 2-(4-ethylpiperazin-1-yl)-N-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino }-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2yl}acetamide.