Claims for Patent: 9,598,400

Summary for Patent: 9,598,400

Title:	Substituted quinoline compounds and methods of use
Abstract:	The present invention provides novel substituted quinoline compounds, pharmaceutical acceptable salts and formulations thereof useful in modulating the protein tyrosine kinase activity, and in modulating cellular activities such as proliferation, differentiation, apoptosis, migration and invasion. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of hyperproliferative disorders in mammals, especially humans.
Inventor(s):	Xi; Ning (Newbury Park, CA)
Assignee:	CALITOR SCIENCES, LLC (Newbury Park, CA) SUNSHINE LAKE PHARMA CO., LTD. (Dongguan, Guangdong, CN)
Application Number:	14/824,096
Patent Claims:	1. A method of treating or lessening the severity of a proliferative disorder in a patient comprising administering to the patient a compound of Formula (I): ##STR00052## or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, wherein: R.sup.1 is hydroxy C.sub.2-6 alkoxy; R.sup.2 is H, alkoxy or hydroxyalkoxy; R.sup.3 is H or F; R.sup.4 is H, F, Cl,Br, I, CN, alkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or cycloalkylalkyl; and X is CH or N, wherein the proliferative disorder is metastatic cancer, colon cancer, gastric adenocarcinoma, bladder cancer, breast cancer, kidney cancer, liver cancer, lung cancer, thyroid cancer, cancer of the head and neck, prostate cancer, pancreatic cancer, cancer of the CNS, glioblastoma, a myeloproliferative disorder, atherosclerosis or lung fibrosis. 2. The method according to claim 1, wherein R.sup.2 is H or methoxy; R.sup.3 is H or F; and R.sup.4 is H, F, Cl, Br, I, CN, C.sub.1-3 haloalkyl, C.sub.2-5 heterocyclyl, C.sub.2-5 heterocyclyl C.sub.1-3 alkyl, C.sub.3-6 cycloalkyl, or C.sub.3-6 cycloalkyl C.sub.1-3 alkyl. 3. The method according to claim 1, wherein R.sup.2 is H or methoxy; R.sup.3 is H or F; R.sup.4 is H or F; and X is CH. 4. The method according to claim 1, wherein R.sup.2 is H; R.sup.3 is H or F; R.sup.4 is H; and X is CH. 5. The method of claim 1, wherein the compound has one of the following structures: ##STR00053## ##STR00054## ##STR00055## ##STR00056## or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof. 6. A method of treating or lessening the severity of a proliferative disorder in a patient comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I): ##STR00057## or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, wherein: R.sup.1 is hydroxy C.sub.2-6 alkoxy; R.sup.2 is H, alkoxy or hydroxyalkoxy; R.sup.3 is H or F; R.sup.4 is H, F, Cl, Br, I, CN, alkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or cycloalkylalkyl; and X is CH or N, wherein the proliferative disorder is metastatic cancer, colon cancer, gastric adenocarcinoma, bladder cancer, breast cancer, kidney cancer, liver cancer, lung cancer, thyroid cancer, cancer of the head and neck, prostate cancer, pancreatic cancer, cancer of the CNS, glioblastoma, a myeloproliferative disorder, atherosclerosis or lung fibrosis. 7. The method according to claim 6, wherein R.sup.2 is H; R.sup.3 is H or F; R.sup.4 is H; and X is CH. 8. The method according to claim 6, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof. 9. The method according to claim 8, wherein the pharmaceutical composition further comprises a therapeutic agent selected from a chemotherapeutic agent, an anti-proliferative agent, an agent for treating atherosclerosis, an agent for treating lung fibrosis, and combinations thereof. 10. The method according to claim 9, wherein the additional therapeutic agent is adriamycin, rapamycin, temsirolimus, everolimus, ixabepilone, gemcitabin, cyclophosphamide, dexamethasone, etoposide, fluorouracil, afatinib, alisertib, amuvatinib, axitinib, bosutinib, brivanib, cabozantinib, cediranib, crenolanib, crizotinib, dabrafenib, dacomitinib, dasatinib, danusertib, dovitinib, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, imatinib, iniparib, lapatinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motesanib, neratinib, niraparib, nilotinib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, saracatinib, saridegib, sorafenib, sunitinib, tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, vandetanib, veliparib, vemurafenib, vismodegib, volasertib, an interferon, carboplatin, topotecan, taxol, vinblastine, vincristine, temozolomide, tositumomab, trabedectin, belimumab, bevacizumab, brentuximab, cetuximab, gemtuzumab, ipilimumab, ofatumumab, panitumumab, ranibizumab, rituximab, tositumomab, trastuzumab or a combination thereof. 11. A method of inhibiting or modulating protein kinase activity in a biological sample comprising contacting a biological sample with a compound of Formula (I): ##STR00058## or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, wherein: R.sup.1 is hydroxy C.sub.2-6 alkoxy; R.sup.2 is H, alkoxy or hydroxyalkoxy; R.sup.3 is H or F; R.sup.4 is H, F, Cl, Br, I, CN, alkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or cycloalkylalkyl; and X is CH or N. 12. The method according to claim 11, wherein R.sup.2 is H; R.sup.3 is H or F; R.sup.4 is H; and X is CH. 13. The method of claim 11, wherein the protein kinases are receptor tyrosine kinases. 14. The method of claim 13, wherein the receptor tyrosine kinases are VEGFR, c-Met and/or Axl. 15. A method of inhibiting or modulating protein kinase activity in a biological sample comprising contacting a biological sample with a pharmaceutical composition comprising a compound of Formula (I): ##STR00059## or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, wherein: R.sup.1 is hydroxy C.sub.2-6 alkoxy; R.sup.2 is H, alkoxy or hydroxyalkoxy; R.sup.3 is H or F; R.sup.4 is H, F, Cl, Br, I, CN, alkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or cycloalkylalkyl; and X is CH or N. 16. The method according to claim 15, wherein R.sup.2 is H; R.sup.3 is H or F; R.sup.4 is H; and X is CH. 17. The method of claim 15, wherein the protein kinases are receptor tyrosine kinases. 18. The method of claim 17, wherein the receptor tyrosine kinases are VEGFR, c-Met and/or Axl.

Details for Patent 9,598,400

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2031-02-28
Idec Pharmaceuticals Corp.	RITUXAN	rituximab	Injection	103737	02/19/2002		2031-02-28
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2031-02-28
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2031-02-28