التفاصيل البيبلوغرافية
| العنوان: |
SUBSTITUTED BENZAZOLES AND METHODS OF THEIR USE AS INHIBITORS OF RAF KINASE |
| Document Number: |
20120288501 |
| تاريخ النشر: |
November 15, 2012 |
| Appl. No: |
13/556907 |
| Application Filed: |
July 24, 2012 |
| مستخلص: |
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. |
| Inventors: |
Amiri, Payman (Walnut Creek, CA, US); Fantl, Wendy (San Francisco, CA, US); Levine, Barry Haskell (Lafayette, CA, US); Poon, Daniel J. (Oakland, CA, US); Ramurthy, Savithri (Walnut Creek, CA, US); Renhowe, Paul A. (Danville, CA, US); Subramanian, Sharadha (San Ramon, CA, US); Sung, Leonard (Irvine, CA, US) |
| Assignees: |
Novartis Vaccines and Diagnostics, Inc. formerly known as Chiron Corporation (Emeryville, CA, US) |
| Claim: |
1. A compound of the formula (I): [chemical expression included] wherein X1 is ═N— and X2 is —S—, or X1 is —S— and X2 is ═N—; Y is O or S; A1 is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, polycyclic aryl, polycyclic arylalkyl, heteroaryl, biaryl, heteroarylaryl, heteroarylheteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, biarylalkyl, or heteroarylarylalkyl; A2 is substituted or unsubstituted heteroaryl; R1 is O or H, and R2 is NR5R6 or hydroxyl; or R1 is taken together with R2 to form a substituted or unsubstituted heterocycloalkyl or heteroaryl group; wherein, the dashed line represents a single or double bond; R3 is hydrogen, halogen, loweralkyl, or loweralkoxy; R5 and R6 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; and R7 is loweralkyl; or a pharmaceutically acceptable salt, ester or prodrug thereof. |
| Claim: |
2. A compound of claim 1 wherein Y is O. |
| Claim: |
3. A compound of claim 1 wherein A1 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. |
| Claim: |
4. A compound of claim 1 wherein A2 is substituted or unsubstituted pyridyl. |
| Claim: |
5. A compound of claim 1 wherein R1 is O and the dashed line represents a single or double bond. |
| Claim: |
6. A compound of claim 1 wherein R2 is NR5R6, R5 is hydrogen and R6 is selected from hydrogen, and substituted or unsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and heteroarylalkyl. |
| Claim: |
7. A compound of claim 1 wherein R1 is taken together with R2 to form a substituted or unsubstituted heterocycloalkyl or heteroaryl group. |
| Claim: |
8. A compound of the formula (V): [chemical expression included] wherein X is S; A1 is substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, polycyclic aryl, polycyclic arylalkyl, heteroaryl, biaryl, heteroarylaryl, heteroarylheteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, biarylalkyl, heteroarylarylalkyl; R1 is O and R2 is NR5R6; or R1 is taken together with R2 to form a substituted or unsubstituted heterocycloalkyl or heteroaryl group; wherein, the dashed line represents a single or double bond; R3 is hydrogen, halogen, loweralkyl, or loweralkoxy; R5 and R6 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. |
| Claim: |
9. A compound of claim 8 wherein A1 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. |
| Claim: |
10. A compound of claim 8 wherein R1 is O and the dashed line represents a single or double bond. |
| Claim: |
11. A compound of claim 8 wherein R2 is NR5R6, R5 is hydrogen and R6 is selected from hydrogen, and substituted or unsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and heteroarylalkyl. |
| Claim: |
12. A compound of claim 8 wherein R1 is taken together with R2 to form a substituted or unsubstituted heterocycloalkyl or heteroaryl group. |
| Claim: |
13. A compound of claim 8 wherein R3 is loweralkoxy. |
| Claim: |
14. A compound of claim 8 wherein R1 is O, R2 is NR5R6, R5 is H, and R6 is methyl. |
| Claim: |
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. |
| Claim: |
16. A composition of claim 15 which further comprises at least one additional agent for the treatment of cancer. |
| Claim: |
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. |
| Current U.S. Class: |
4241/331 |
| Current International Class: |
61; 07; 61; 61; 61; 61; 61; 61; 61; 61; 61; 07; 61 |
| رقم الانضمام: |
edspap.20120288501 |
| قاعدة البيانات: |
USPTO Patent Applications |