2,6-disubstituted quinazolines, quinoxalines, quinolines and isoquinolines and methods of their use as inhibitors of Raf kinase

• US 7,691,866 B2
• Filed: 10/15/2004
• Issued: 04/06/2010
• Est. Priority Date: 10/16/2003
• Status: Expired due to Fees

• Current Assignee: Novartis Vaccines And Diagnostics Incorporated (Novartis Ag)
• Original Assignee: Novartis Vaccines And Diagnostics Incorporated (Novartis Ag)
• Inventors: Renhowe, Paul A., Subramanian, Sharadha, Ramurthy, Savithri
• Primary Examiner(s): Wilson; James O
• Assistant Examiner(s): TRUONG, TAMTHOM NGO
• Application Number:
  US10/966,358
• Publication Number:
  US 20050085482A1
• Time in Patent Office: 1,999 Days
• Field of Search: 514/266.21, 514/266.4, 544/284, 544/292
• US Class Current: 514/266.21
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C04B 35/632 Organic additives
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings

Abstract

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.

Claims

1. A compound of the formula (IV):

2. A compound of claim 1 wherein Y is O.

3. A compound of claim 1 wherein A₁ 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 A₁ is substituted or unsubstituted phenyl.

5. A compound of claim 4 wherein A₁ 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 A₁ 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 R₂ is NR₆R₇, R₆ is hydrogen and R₇ 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 R₃ is loweralkoxy.

9. A compound of claim 8 wherein R₃ is methoxy.

10. A compound of claim 1 wherein R₄ is hydrogen.

11. A compound of claim 1 wherein R₄ is loweralkyl.

12. A compound of claim 11 wherein R₄ is methyl.

13. A compound of claim 1 having the formula:

14. A compound of claim 1 wherein R₂ is NR₆R₇, R₆ is H, and R₇ 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).