Claims for Patent: 8,415,382

Summary for Patent: 8,415,382

Title:	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.
Inventor(s):	Costales; Abran (El Cerrito, CA), Hansen; Teresa (Danville, CA), Levine; Barry H. (Lafayette, CA), McBride; Christopher (Oakland, CA), Poon; Daniel J. (Oakland, CA), Ramurthy; Savithri (Walnut Creek, CA), Renhowe; Paul A. (Danville, CA), Shafer; Cynthia M. (El Sobrante, CA), Subramanian; Sharadha (San Ramon, CA), Verhagen; Joelle (Richmond, CA)
Assignee:	Novartis Vaccines and Diagnostics, Inc. (Emeryville, CA)
Application Number:	12/205,028
Patent Claims:	1. A composition comprising an amount of a compound of formula (I): ##STR00586## wherein, X.sub.1 and X.sub.3 are selected from N and --NR.sub.4--, wherein R.sub.4 is hydrogen or loweralkyl, provided that one of X.sub.1 and X.sub.3 must be N and the other of X.sub.1 and X.sub.3 must be --NR.sub.4--; X.sub.2 is --NH-- or --(CH.sub.2)hd m--, wherein m is 0, 1, 2, 3 or 4; A.sub.l is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, polycyclic aryl, polycyclic arylalkyl, heteroaryl, biaryl, heteroarylaryl, or heteroarylheteroaryl; R.sub.1 is hydrogen or substituted loweralkyl, or substituted or unsubstituted alkoxyalkyl, loweralkyloxy, amino, aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocycloalkyl, heteroarylalkyl, cycloalkyloweralkyl, heterocycloalkyl -loweralkyl, loweralkylheterocycloalkyl, arylloweralkyl, heteroarylloweralkyl, alkyloxy -alkylheterocycloloweralkyl, or heteroarylloweralkyl; R.sub.2 is hydrogen or loweralkyl; each R.sub.3 and R.sub.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 that is effective to inhibit Raf kinase activity in a human or animal subject when administered thereto, together with a pharmaceutically acceptable carrier. 2. A composition of claim 1 which further comprises at least one additional agent for the treatment of cancer selected from dacarbazine, irinotecan, topotecan, gemcitabine, 5-fluorouracil, leucovorin, carboplatin, cisplatin, taxanes, tezacitabine, cyclophosphamide, vinca alkaloids, imatinib, anthracyclines, rituximab, and trastuzumab. 3. 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 effective to inhibit Raf kinase activity in the human or animal subject, wherein said cancer disorder is melanoma, papillary thyroid cancer, cholangiocarcinoma, gallbladder carcinoma, colorectal cancer, pancreatic cancer, chronic myelogenous leukemia, prostate cancer, ovarian cancer, breast cancer, or lung cancer. 4. A method of claim 3 which further comprises administering to the human or animal subject at least one additional agent for the treatment of cancer. 5. A method of claim 4 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. 6. The composition of claim 1, wherein X.sub.1 of the compound of formula (I) is --NR.sub.4--. 7. The composition of claim 6, wherein R.sub.4 is hydrogen. 8. The composition of claim 6, wherein R.sub.4 is methyl. 9. The composition of claim 1, wherein X.sub.2 of the compound of formula (I) is --NH--. 10. The composition of claim 1, wherein A.sub.1 of the compound of formula (I) 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-acetyl-2,3-dihydroindolyl, cycloheptyl, bicyclo[2.2.1]hept-2-yl, hydroxyphenyl, hydroxyalkyiphenyl, pyrrolidinyl, pyrrolidin-l-yl, pyrrolidin-1-ylalkyl, 4- amino(imino)methylphenyl, isoxazolyl, indazolyl, adamantyl, bicyclohexyl, quinuclidinyl, imidazolyl, benzimidazolyl, imidazolylphenyl, phenylimidazolyl, phthalamido, napthyl, benzophenone, anilinyl, anisolyl, quinolinyl, quinolinonyl, phenylsulfonyl, phenylalkylsulfonyl, 9H-fluoren-l-yl, piperidin-l-yl, piperidin-l-ylalkyl, cyclopropyl, cyclopropylalkyl, pyrimidin-5- ylphenyl, quinolidinylphenyl, furanyl, furanylphenyl, N-methylpiperidin-4-yl, 4-diazepan-l-yl, hydroxypyrrolidin-l-yl, dialkylaminopyrrolidin-l-yl, 1,4'- bipiperidin-l'-yl, and (1,4'-bipiperidin-1'-ylcarbonyl)phenyl. 11. The composition of claim 1, wherein A.sub.1 of the compound of formula (I) has the structure: ##STR00587## wherein R.sub.5, R.sub.6, R.sub.7, R.sub.8 and R.sub.9 are independently selected from hydrogen, halo, loweralkyl, cyano, hydroxy, haloloweralkyl, loweralkyloxy, haloloweralkyloxy, loweralkylthio, haloloweralkylthio, and substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. 12. The composition of claim 11, wherein R.sub.5, R.sub.6, R.sub.7, R.sub.8 and R.sub.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. 13. The composition of claim 1, wherein R.sub.1 of the compound of formula (I) has the structure: ##STR00588## wherein n is 0, 1, 2, 3 or 4; r is 1 or 2; X.sub.4 is --CH-- or N; R.sub.10 and R.sub.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.sub.11 is hydrogen, loweralkyl, haloloweralkyl, hydroxyloweralkyl, loweralkyloxy, haloloweralkyloxy, loweralkyloxyloweralkyl, and substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. 14. The composition of claim 13, wherein n of the compound of formula (I) is 1. 15. The composition of claim 13, wherein R.sub.10 and R.sub.12 of the compound of formula (I) are hydrogen or loweralkyl. 16. The composition of claim 13, wherein R.sub.11 of the compound of formula (I) is loweralkyl.

Details for Patent 8,415,382

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2039-02-26
Idec Pharmaceuticals Corp.	RITUXAN	rituximab	Injection	103737	02/19/2002		2039-02-26
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2039-02-26
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2039-02-26
Genentech, Inc.	RITUXAN HYCELA	rituximab and hyaluronidase human	Injection	761064	06/22/2017		2039-02-26
Genentech, Inc.	HERCEPTIN HYLECTA	trastuzumab and hyaluronidase-oysk	Injection	761106	02/28/2019		2039-02-26