Claims for Patent: 6,869,952

Summary for Patent: 6,869,952

Title:	Pyrrolo[2,1-f][1,2,4]triazine inhibitors of kinases
Abstract:	The present invention provides compounds of formula I, ##STR1## and pharmaceutically acceptable salts thereof. The formula I compounds inhibit the tyrosine kinase activity of growth factor receptors such as VEGFR-2 and FGFR-1, thereby making them useful as anti-cancer agents. The formula I compounds are also useful for the treatment of other diseases associated with signal transduction pathways operating through growth factor receptors.
Inventor(s):	Bhide; Rajeev S. (Princeton Junction, NJ), Cai; Zhen-Wei (Belle Mead, NJ), Qian; Ligang (Hopewell, NJ), Barbosa; Stephanie (Lambertville, NJ)
Assignee:	Bristol Myers Squibb Company (Princeton, NJ)
Application Number:	10/623,171
Patent Claims:	1. A compound or a pharmaceutically acceptable salt thereof selected from the group consisting of 4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin -6-ol, 1-[4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methy-pyrrolo[2,1-f][1,2,4]tria zin-6-yloxy]-4-(aminosulfonyl)aminobutan-2-ol, N-{3-[4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methy-pyrrolo[2,1-f][1,2,4]t riazin-6-yloxy]-2-Hydroxy-propyl}-methanesulfonamide, (2S)-3-[4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methy-pyrrolo[2,1-f][1,2,4 ]triazin-6-yloxy]-propane-1,2-diol, (2R)-3-[4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4 ]triazin-6-yloxy]-propane-1,2-diol, (2R)-1-[4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4 ]triazin-6-yloxy]-propan-2-ol, (2S)-1-[4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4 ]triazin-6-yloxy]-propan-2-ol, (2R)1-[4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4] triazin-6-yloxy]-3-methoxy-propan-2-ol, (2S)-1-[4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4 ]triazin-6-yloxy]-3-methoxy-propan-2-ol, 2-[4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]tria zin-6-yloxy]-ethanol, N-{2-[4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methyl-pyrrolo[2,1-f][1,2,4] triazin-6-yloxy)-ethyl}-methanesulfonamide, (2R)-1-[4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methy-pyrrolo[2,1-f][1,2,4 ]triazin-6-yloxy]-4-methanesulfonyl-butan-2-ol, (2S)-1-[4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methy-pyrrolo[2,1-f][1,2,4 ]triazin-6-yloxy]-4-methanesulfonyl-butan-2-ol, 5-Methyl-4-(2-methyl-1H-indol-5-yloxy)-6-(3-piperidin-1-ylpropoxy)-pyrrolo[ 2,1-f][1,2,4]triazine, 4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methyl-6-(2-piperidin-4-yl-ethoxy) -pyrrolo[2,1-f][1,2,4]triazine, 4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methyl-6-(3-pyridin-4-yl-propoxy)- pyrrolo[2,1-f][1,2,4]triazine, {1-[4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methyl-pyrrolo[2,1-f][1,2,4]tr iazin-6-yloxymethyl]-3-methanesulfonyl-propyl}-dimethyl-amine, 2-[4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]tria zin-6-yloxy]-1-methylethylamine, {2-[4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]tri azin-6-yloxy]-1-methylethyl}-methylamine, 4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methyl-6-(morpholin-2-ylmethoxy)-p yrrolo[2,1-f][1,2,4]triazine, [(1R), 2S]-2-Dimethylaminopropionic acid-[2-[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f]-[1, 2,4]triazin-6-yloxy]]-1-methylethyl ester, [(1R),2S]-2-Amino-4-methylpentanoic acid [2-[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]tr iazin-6-yloxy]]-1-methylethyl ester, [(1R),2S]-2-Aminopropionic acid2-[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4 ]triazin-6-yloxy]-1-methylethyl ester, 4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-(3-methanesulfonyl-propoxy)-5-meth yl-pyrrolo[2,1-f][1,2,4]triazine, and N-{3-[4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methyl-pyrrolo[2,1-f][1,2,4] triazin-6-yloxy]-propyl}-methanesulfonamide. 2. A compound or a pharmaceutically acceptable salt thereof selected from the group consisting of 4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin -6-ol, (2S)-3-[4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methy-pyrrolo[2,1-f][1,2,4 ]triazin-6-yloxy]-propane-1,2-diol, (2R)-3-[4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo(2,1-f][1,2,4 ]triazin-6-yloxy]-propane-1,2-diol, (2R)-1-[4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4 ]triazin-6-yloxy]-propan-2-ol, (2S)-1-[4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4 ]triazin-6-yloxy]-propan-2-ol, (2R)1-[4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4] triazin6-yloxy]-3-methoxy-propan-2-ol, (2S)-1-[4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4 ]triazin-6-yloxy]-3-methoxy-propan-2-ol, 5-Methyl-4-(2-methyl-1H-indol-5-yloxy)-6-(3-piperidin-1-ylpropoxy)-pyrrolo[ 2,1-f][1,2,4]triazine, 4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methyl-6-(2-piperidin-4-yl-ethoxy) -pyrrolo[2,1-f][1,2,4]triazine, 2-[4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4[tria zin-6-yloxy]-1-methylethylamine, [(1R),2S]-2-Dimethylaminopropionic acid-[2-[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f]-[1, 2,4]triazin-6-yloxy]]-1-methylethyl ester, [(1R),2S]-2-Amino-4-methylpentanoic acid [2-[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]tr iazin-6-yloxy]]-1-methylethyl ester, [(1R),2S]-2-Aminopropionic acid 2-[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]tri azin-6-yloxy]-1-methylethyl ester, 4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-(3-methanesulfonyl-propoxy)-5-meth yl-pyrrolo[2,1-f][1,2,4]triazine, and N-{3-[4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methyl-pyrrolo[2,1-f][1,2,4] triazin-6-yloxy]-propyl}-methanesulfonamide. 3. A pharmaceutical composition comprising at least one of the compounds of claim 1 and a pharmaceutically acceptable carrier therefor. 4. A pharmaceutical composition comprising at least one of the compounds of claim 2 and a pharmaceutically acceptable carrier thereof. 5. A pharmaceutical composition comprising at least one or more compounds of claim 1 in combination with a pharmaceutically acceptable carrier and at least one additional anti-cancer or cytotoxic agent. 6. A pharmaceutical composition comprising at least one or more compound of claim 2 in combination with a pharmaceutically acceptable carrier and at least one additional anti-cancer or cytotoxic agent. 7. The pharmaceutical composition of claim 3, wherein said anti-cancer or cytotoxic agent is selected from the group consisting of: linomide, inhibitors of integrin .alpha.v.beta.3 function, angiostatin, razoxane, tamoxifen, toremifene, raloxifene, droloxifene, iodoxifene, megestrol acetate, anastrozole, letrozole, borazole, exemestane, flutamide, nilutamide, bicalutamide, cyproterone acetate, gosereline acetate, leuprolide, finasteride, herceptin, metalloproteinase inhibitors, inhibitors of urokinase plasminogen activator receptor function, growth factor antibodies, growth factor receptor antibodies, bevacizumab, cetuximab, tyrosine kinase inhibitors, serine/threonine kinase inhibitors, methotrexate, 5-fluorouracil, purine, adenosine analogues, cytosine arabinoside, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, mithramycin, cisplatin, carboplatin, nitrogen mustard, melphalan, chlorambucil, busulphan, cyclophosphamide, ifosfamide, nitrosoureas, thiotepa, vincristine, paclitaxel, docetaxel, epothilone analogs, discodermolide analogs, eleutherobin analogs, etoposide, teniposide, amsacrine, topotecan, irinotecan, flavopyridols, proteasome inhibitors including bortezomib and biological response modifiers.

Details for Patent 6,869,952

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Microbix Biosystems Inc.	KINLYTIC	urokinase	For Injection	021846	01/16/1978		2022-07-19
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2022-07-19
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2022-07-19
Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	02/12/2004		2022-07-19
Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	03/28/2007		2022-07-19
Genentech, Inc.	AVASTIN	bevacizumab	Injection	125085	02/26/2004		2022-07-19