Claims for Patent: 7,501,430

Summary for Patent: 7,501,430

Title:	RAF inhibitors and their uses
Abstract:	The present invention provides imidazooxazole and imidazothiazole compounds and their synthesis. The compounds of the present invention are capable of inhibiting the activity of RAF kinase, such as B-RAF.sup.V600E. The compounds are useful for the treatment of cell proliferative disorders such as cancer.
Inventor(s):	Lapierre; Jean-Marc (Pelham, NH), Namdev; Nivedita D. (Westford, MA), Ashwell; Mark A. (Carlisle, MA), France; Dennis S. (Carlisle, MA), Wu; Hui (Malden, MA), Hutchins; Patrick M. (Denver, CO), Tandon; Manish (Framingham, MA), Liu; Yanbin (Acton, MA), Link; Jeff S. (Londonderry, NH), Ali; Syed M. (North Andover, MA), Brassard; Chris J. (Somerville, MA), Nicewonger; Robb B. (Tyngsboro, MA), Filikov; Anton (Stoneham, MA), Carazza; Rebecca J. (Winchester, MA)
Assignee:	ArQule, Inc. (Woburn, MA)
Application Number:	11/785,163
Patent Claims:	1. A compound of formula II, or pharmaceutically acceptable salts thereof: ##STR00466## wherein X is O, S(O).sub.p; m is an integer from 1 to 3; n is an integer from 1 to 3; p is an integer from 0 to 2; Z is hydrogen, a bond, --C(O)--, --C(O)NR.sub.11--, --S(O).sub.2--, --C(O)NH--S(O).sub.2--, or CH(OH)--CH.sub.2--Y--, wherein Y is CH.sub.2, O, S, NH, or a bond; R.sub.1 is --(CH.sub.2).sub.0-3--C(O)NR.sub.6R.sub.7, --NR.sub.8SO.sub.2R.sub.9, --NR.sub.8C(O)NR.sub.6R.sub.7, --NR.sub.8C(S)NR.sub.6R.sub.7, --OSO.sub.2NR.sub.6R.sub.7, --C(N--OH)NH.sub.2, --C(N--OH)R.sub.8, --CH.sub.2OR.sub.8, --OC(O)NR.sub.6R.sub.7, --SR.sub.9, or --C(O)NR.sub.8SO.sub.2R.sub.9; R.sub.2 is hydrogen, --(CH.sub.2).sub.0-3--C(O)NR.sub.6R.sub.7, --NR.sub.8SO.sub.2R.sub.9, --NR.sub.8C(O)NR.sub.6R.sub.7, --NR.sub.8C(S)NR.sub.6R.sub.7, --OSO.sub.2NR.sub.6R.sub.7, --C(N--OH)NH.sub.2, --C(N--OH)R.sub.8, --CH.sub.2OR.sub.8, --OC(O)NR.sub.6R.sub.7, --SR.sub.9, or --C(O)NR.sub.8SO.sub.2R.sub.9, or R.sub.1 and R.sub.2, taken together, may form a ring; R.sub.3 and R.sub.4 are independently hydrogen, substituted or unsubstituted lower alkyl, --COOH, --COOR.sub.8, or --C(O)NR.sub.10R.sub.11; each R.sub.6 and each R.sub.7 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclyl, or R.sub.6 and R.sub.7, taken together, may form a ring; each R.sub.8 is independently hydrogen, or substituted or unsubstituted lower alkyl; each R.sub.9 is independently substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl; R.sub.10 is substituted or unsubstituted lower alkyl, or substituted or unsubstituted aryl; R.sub.11 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl, or R.sub.11, taken together with R.sub.10, may form a ring; R.sub.12 is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl; and R.sub.13 is independently selected from the group consisting of hydrogen, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 fluoro-substituted alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8 fluoro-substituted cycloalkyl, aryl, halogen-substituted aryl, heteroaryl, and halogen-substituted heteroaryl. 2. The compound of claim 1 wherein R.sub.3 and R.sub.4 are hydrogen. 3. The compound of claim 1 wherein R.sub.13 is hydrogen. 4. The compound of claim 1 wherein m+n=4, if m is not equal to n, then the preferred configuration is R. 5. The compound of claim 1 wherein Z is --S(O).sub.2-- and R.sub.12 is 4-chlorophenyl, 4-fluorophenyl, 4-cyanophenyl, methyl, or cyclopropyl. 6. The compound of claim 1 wherein the compound of formula II is selected from the group consisting of 3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin- -4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl carbamate, 3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin- -4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl sulfamate, 3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin- -4-yl]imidazo[2,1-b][1,3]oxazol-6-yl}phenyl sulfamate, 3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin- -4-yl]imidazo[2,1-b][1,3]oxazol-6-yl}phenyl carbamate, and (1E)-1-(3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)p- yrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl)ethanone oxime. 7. A compound selected from the group consisting of 3-[5-(2-{[1-(cyclopropylsulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)imid- azo[2,1-b][1,3]thiazol-6-yl]phenol, 3-[5-(2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)imidazo[2- ,1-b][1,3]thiazol-6-yl]phenol, 3-[5-(2-{[1-(cyclopropylsulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)imid- azo[2,1-b][1,3]oxazol-6-yl]phenol, 3-[5-(2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)imidazo[2- ,1-b][1,3]oxazol-6-yl]phenol, 5-[5-(2-{[1-(cyclopropylsulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)imid- azo[2,1-b][1,3]thiazol-6-yl]-2-fluorophenol, and 3-[5-(2-{[(3R)-1-(cyclopropylsulfonyl)piperidin-3-yl]amino}pyrimidin-4-yl- )imidazo[2,1-b][1,3]oxazol-6-yl]phenol. 8. A pharmaceutical composition comprising a compound as claimed in claim 1 or claim 7 or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers or excipients. 9. The pharmaceutical composition of claim 8 further comprising a second chemotherapeutic agent. 10. The pharmaceutical composition of claim 9, wherein said second chemotherapeutic agent is selected from the group consisting of tamoxifen, raloxifene, anastrozole, exemestane, letrozole, cisplatin, carboplatin, paclitaxel, cyclophosphamide, lovastatin, minosine, gemcitabine, araC, 5-fluorouracil, methotrexate, docetaxel, goserelin, vincristin, vinblastin, nocodazole, teniposide, etoposide, epothilone, navelbine, camptothecin, daunonibicin, dactinomycin, mitoxantrone, amsacrine, doxorubicin, epirubicin, idarubicin imatanib, gefitinib, erlotinib, sorafenib, sunitinib malate, trastuzumab, rituximab, cetuximab, and bevacizumab.

Details for Patent 7,501,430

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2026-04-17
Idec Pharmaceuticals Corp.	RITUXAN	rituximab	Injection	103737	02/19/2002		2026-04-17
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2026-04-17
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2026-04-17