Claims for Patent: 6,908,916

Summary for Patent: 6,908,916

Title:	C-5 modified indazolylpyrrolotriazines
Abstract:	The present invention provides compounds of formula I ##STR1## and pharmaceutically acceptable salts thereof. The formula I compounds inhibit tyrosine kinase activity of growth factor receptors such as HER1, HER2 and HER4 thereby making them useful as antiproliferative 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):	Mastalerz; Harold (Guilford, CT), Zhang; Guifen (Wallingford, CT), Tarrant; James G. (Hamden, CT), Vite; Gregory D. (Titusville, NJ)
Assignee:	Bristol Myers Squibb Company (Princeton, NJ)
Application Number:	10/294,281
Patent Claims:	1. A compound of formula I ##STR159## its enantiomers, diastereomers, or pharmaceutically acceptable salts, or solvates thereof, wherein R is selected from the group consisting of SR.sup.2, SOR.sup.2, SO.sub.2 R.sup.2, OR.sup.2, and NR.sup.3 R.sup.4 ; R.sup.1 is selected from the group consisting of aryl, substituted aryl, heterocyclo, and substituted heterocyclo; R.sup.2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, heterocyclo, and substituted heterocyclo; R.sup.3 and R.sup.4 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, and substituted heterocyclo; or R.sup.3 and R.sup.4 may together form an optionally substituted monocyclic 4-8 membered saturated or unsaturated carbocyclic or heterocyclic ring, or an optionally substituted bicyclic 7 to 12 membered saturated or unsaturated carbocyclic or heterocyclic ring. 2. The compound according to claim 1 wherein R.sup.1 is selected from the group consisting of benzene, fluoro substituted benzene and pyridine. 3. The compound according to claim 2 wherein R.sup.1 is a fluoro substituted benzene. 4. The compound according to claim 3 wherein R is an ether. 5. The compound according to claim 1 selected from the group consisting of: (5-[1,4]Diazepan-1-ylmethyl-pyrrolo[2,1-f][1,2,4]triazin-4-yl)-[1-(3-fluoro -benzyl)-1H-indazol-5-yl]-amine; [1-(3-Fluoro-benzyl)-1H-indazol-5-yl]-(5-imidazol-1-ylmethyl-pyrrolo[2,1-f] [1,2,4]triazin-4-yl)-amine; 1-{4-[1-(3-Fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazi n-5-ylmethyl}-piperidine-3-carboxylic acid amide; [1-(3-Fluoro-benzyl)-1H-indazol-5-yl]-[5-(4-methyl-piperazin-1-ylmethyl)-py rrolo[2,1-f][1,2,4]triazin-4-yl]-amine; 2-(4-{4-[1-(3-Fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]tri azin-5-ylmethyl}-piperazin-1-yl)-ethanol; 1-{4-[1-(3-Fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1f][1,2,4]triazin -5-ylmethyl}-(3R)-pyrrolidin-3-ol; (1-{4-[1-(3-Fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triaz in-5-ylmethyl}-piperidin-4-yl)-methanol; 1-{4-[1-(3-Fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazi n-5-ylmethyl}-piperidin-4-ol; (2R)-3-({4-[1-(3-Fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4] triazin-5-ylmethyl}-amino)-propane-1,2-diol; 2-({4-[1-(3-Fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triaz in-5-ylmethyl}-amino)-ethanol; 1-{4-[1-(3-Fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazi n-5-ylmethyl}-(3S)-pyrrolidin-3-ol; [1-(3-Fluoro-benzyl)-1H-indazol-5-yl]-[5-(4-cyanomethyl-cyclohexylmethyl)-p yrrolo[2,1-f][1,2,4]triazin-4-yl]-amine; [5-(3,5-Dimethyl-piperazin-1-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-4-yl]-[ 1-(3-fluoro-benzyl)-1H-indazol-5-yl]-amine; [1-(3-Fluoro-benzyl)-1H-indazol-5-yl]-[5-((3S)-3-methyl-piperazin-1-ylmethy l)-pyrrolo[2,1-f][1,2,4]triazin-4-yl]-amine; 4-{4-[1-(3-Fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazi n-5-ylmethyl}-piperazine-2-carboxylic acid amide; 4-{4-[1-(3-Fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazi n-5-ylmethyl}-piperazin-2-one; 2-({4-[1-(3-Fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triaz in-5-ylmethyl}-amino)-2-methyl-propane-1,3-diol; 2-({4-[1-(3-Fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triaz in-5-ylmethyl}-amino)-propane-1,3-diol; [1-(3-Fluoro-benzyl)-1H-indazol]-5-yl]-(5-piperazin-1-ylmethyl-pyrrolo[2,1- f][1,2,4]triazin-4-yl)amine; [1-(3-Fluoro-benzyl)-1H-indazol-5-yl]-{5-[4-(2-methoxy-ethylamino)-piperidi n-1-ylmethyl]-pyrrolo[2,1-f][1,2,4]triazin-4-yl}-amine; 1-{4-[1-(3-Fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazi n-5-ylmethyl}-[1,4]diazepan-5-one; [5-(4-Amino-piperidin-1-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-4-yl]-[1-(3- fluoro-benzyl)-1H-indazol-5-yl]-amine; (+)-[5-(cis-4-Amino-3-methyl-piperidin-1-ylmethyl)-pyrrolo[2,1-f][1,2,4]tri azin-4-yl]-[1-(3-fluoro-benzyl)-1H-indazol-5-yl]-amine; (+)-[5-(trans-4-Amino-3-methyl-piperidin-1-ylmethyl)-pyrrolo[2,1-f][1,2,4]t riazin-4-yl]-[1-(3-fluoro-benzyl)-1H-indazol-5-yl]-amine; 1-{4-[1-(3-Fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazi n-5-ylmethyl}-piperidin-4-one; (1-{4-[1-(3-Fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triaz in-5-ylmethyl}-(+)-[1,4]diazepan-6-ol; 1-{4-[1-(3-Fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazi n-5-ylmethyl}-(6R)-[1,4]diazepan-6-ol; 2-(1-{4-[1-(3-Fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]tri azin-ylmethyl}-piperidin-4-ylamino)-ethanol; [1-(3-Fluoro-benzyl)-1H-indazol-5-yl]-[5-(4-methylamino-piperidin-1-ylmethy l)-pyrrolo[2,1-f][1,2,4]triazin-4-yl]-amine; [5-(6,6-Difluoro-[1,4]diazepan-1-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-4-y l]-[1-(3-fluoro-benzyl)-1H-indazol-5-yl]-amine; (+)-[1-(3-Fluoro-benzyl)-1H-indazol-5-yl]-[5-(6-fluoro-[1,4]diazepan-1-ylme thyl)-pyrrolo[2,1-f][1,2,4]triazin-4-yl]-amine; 1-{4-[1-(3Fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazin -5-ylmethyl}-[1,4]diazepan-6-one; [1-(3-Fluoro-benzyl)-1H-indazol-5-yl]-[5-(piperidin-4-yloxymethyl)-pyrrolo[ 2,1-f][1,2,4]triazin-4-yl]-amine; 2-{4-[1-(3-Fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazi n-5-ylmethoxy}-ethanol; [1-(3-Fluoro-benzyl)-1H-indazol-5-yl]-[5-(piperidin-3-ylmethoxymethyl)-pyrr olo[2,1-f][1,2,4]triazin-4-yl]-amine; 3-{4-[1-(3-Fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazi n-5-ylmethoxy}-propane-1,2-diol; [5-(4-Amino-butoxymethyl)-pyrrolo[2,1-f][1,2,4]triazin-4-yl]-[1-(3-fluoro-b enzyl)-1H-indazol-5-yl]-amine; [5-(4-Amino-propoxymethyl)-pyrrolo[2,1-f][1,2,4]triazin-4-yl]-[1-(3-fluoro- benzyl)-1H-indazol-5-yl]-amine; ([1-(3-Fluoro-benzyl)-1H-indazol-5-yl]-[5-({2S}-morpholin-2-ylmethoxymethyl )-pyrrolo[2,1-f][1,2,4]triazin-4-yl]-amine; [trans-5-(4-Amino-cyclohexyloxymethyl)-pyrrolo[2,1-f][1,2,4]triazin-4-yl]-[ 1-(3-fluoro-benzyl)-1H-indazol-5-yl]-amine; [5-(2-Amino-ethoxymethyl)-pyrrolo[2,1-f][1,2,4]triazin-4-yl]-[1-(3-fluoro-b enzyl)-1H-indazol-5-yl]-amine; 3-{4-[1-(3-Fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazi n-5-ylmethoxy}-propan-1-ol; {5-[(3R)-3-Amino-pyrrolidin-1-ylmethy]-pyrrolo[2,1-f][1,2,4]triazin-4-yl}-[ 1-(3-fluoro-benzyl)-1H-indazol-5-yl]-amine; [5-(4-Amino-piperidin-1-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-4-yl]-[1-(3- fluoro-benzyl)-1H-indazol-5-yl]-amine; [1-(3-Fluoro-benzyl)-1H-indazol-5-yl]-[5-(piperidin-4-ylaminomethyl)-pyrrol o[2,1-f][1,2,4]triazin-4-yl]-amine; (+)-[1-(3-Fluoro-benzyl)-1H-indazol-5-yl]-[5-(piperidin-3-ylaminomethyl)-py rrolo[2,1-f][1,2,4]triazin-4-yl]-amine; [5-(4-Aminomethyl-piperidin-1ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-4-yl]-[ 1-(3-fluoro-benzyl)-1H-indazol-5-yl]-amine; and 2-(4-{4-[1-(3-Fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]tri azin-5-ylmethyl}-[1,4]diazepan-1-yl)-ethanol. 6. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier. 7. A pharmaceutical composition comprising a compound of claim 1 in combination with a pharmaceutically acceptable carrier and at least one other anti-cancer or cytotoxic agent formulated as a fixed dose. 8. The pharmaceutical composition of claim 7 wherein said anti-cancer or cytotoxic agent is selected from the group consisting of: tamoxifen, toremifen, raloxifene, droloxifene, iodoxifene, megestrol acetate, anastrozole, letrazole, borazole, exemestane; flutamide, nilutamide, bicalutamide, cyproterone acetate, goserelin acetate, luprolide, finasteride, herceptin, methotrexate, 5-fluorouracil, cytosine arabinoside, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, mithramycin, cisplatin, carboplatin, melphalan, chlorambucil, busulphan, cyclophosphamide, ifosfamide, nitrosoureas, thiotephan, vincristine, taxol, taxotere, etoposide, teniposide, amsacrine, irinotecan, topotecan and an epothilone. 9. A method for treating a proliferative disease, selected from the group consisting of psoriasis and rheumatoid arthritis, comprising administering to a warm-blooded species in need thereof, a therapeutically effective amount of a compound of claim 1.

Details for Patent 6,908,916

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2021-11-14
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2021-11-14