2,6-disubstituted quinazolines, quinoxalines, quinolines and isoquinolines and methods of their use as inhibitors of Raf kinase
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 compound of the formula (IV):
wherein,
Y is O or S;
A 1 is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, polycyclic aryl, polycyclic arylalkyl, heteroaryl, biaryl, heteroarylaryl, heteroarylheteroaryl, 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, or 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.
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, phenylalkyl, pyridyl, pyrimidinyl, pyridylalkyl, pyrimidinylalkyl, alkylbenzoate, thiophene, thiophene-2-carboxylate, indenyl, 2,3-dihydroindenyl, tetralinyl, trifluorophenyl, (trifluoromethyl)thiophenyl, morpholinyl, N-piperazinyl, N-morpholinylalkyl, piperazinylalkyl, cyclohexylalkyl, indolyl, 2,3-dihydroindolyl, 1-aceytl-2,3-dihydroindolyl, cycloheptyl, bicyclo[2.2.1]hept-2-yl, pyrrolidinyl, pyrrolidin-1-yl, pyrrolidin-1-ylalkyl, 4-amino(imino)methylphenyl, isoxazolyl, indazolyl, adamantyl, bicyclohexyl, quinuclidinyl, imidazolyl, benzimidazolyl, imidazolylphenyl, phenylimidazolyl, pthalamido, napthyl, naphthalenyl, benzophenone, anilinyl, anisolyl, quinolinyl, quinolinonyl, phenylsulfonyl, phenylalkylsulfonyl, 9H-flouren-1-yl, piperidin-1-yl, piperidin-1-ylalkyl, cyclopropyl, cyclopropylalkyl, furanyl, N-methylpiperidin-4-yl, pyrrolidin-4-ylpyridinyl, 4-diazepan-1-yl, hydroxypyrrolidn-1-yl, dialkylaminopyrrolidin-1-yl, and 1,4′-bipiperidin-1′-yl.
4. A compound of claim 1 wherein A 1 is substituted or unsubstituted phenyl.
5. A compound of claim 4 wherein A 1 is substituted phenyl selected from the group consisting of substituted or unsubstituted hydroxyphenyl, hydroxyalkylphenyl, alkylphenyl, dialkylphenyl, trialkylphenyl, alkoxyphenyl, dialkoxyphenyl, alkoxyalkylphenyl, halophenyl, dihalophenyl, halo alkylphenyl, haloalkoxyphenyl, alkylbalophenyl, alkoxyhalophenyl, alkylthiophenyl, aminophenyl, nitrophenyl, acetylphenyl, sulfamoylphenyl, biphenyl, alkoxybiphenyl, cyclohexylphenyl, phenyloxyphenyl, dialkylaminophenyl, morpholinylphenyl, heterocyclylcarbonylphenyl, heterocyclylphenyl, heterocyclylalkylphenyl, furanylphenyl, (1,4′-bipiperidin-1′-ylcarbonyl)phenyl, pyrimidin-5-ylphenyl, and quinolidinylphenyl.
6. A compound of claim 5 wherein A 1 is substituted phenyl selected from the group consisting of chlorophenyl, fluorophenyl, bromophenyl, iodophenyl, dichlorophenyl, difluorophenyl, dibromophenyl, fluorochlorophenyl, bromochlorophenyl, trifluoromethylphenyl, trifluoromethoxyphenyl, alkylbromophenyl, trifluoromethylbromophenyl, alkylchlorophenyl, trifluoromethylchlorophenyl, alkylfluorophenyl, and trifluoromethylfluorophenyl.
7. A compound of claim 1 wherein R 2 is NR 6 R 7 , R 6 is hydrogen and R 7 is selected from hydrogen, and substituted or unsubstituted alkyl, alkoxy, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and heteroarylalkyl.
8. A compound of claim 1 wherein R 3 is loweralkoxy.
9. A compound of claim 8 wherein R 3 is methoxy.
10. A compound of claim 1 wherein R 4 is hydrogen.
11. A compound of claim 1 wherein R 4 is loweralkyl.
12. A compound of claim 11 wherein R 4 is methyl.
13. A compound of claim 1 having the formula:
or a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof.
14. A compound of claim 1 wherein R 2 is NR 6 R 7 , R 6 is H, and R 7 is methyl.
15. A composition comprising an amount of a compound of claim 1 or 13 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, trastuzumab, dacarbazine, aldesleukin, capecitabine, and Iressa (gefitinib).