Claims for Patent: 8,748,626

Summary for Patent: 8,748,626

Title:	Oxazole and thiazole compounds as KSP inhibitors
Abstract:	Disclosed are new substituted oxazole and thiazole compounds of Formula (I) and pharmaceutically acceptable salts, esters or prodrugs thereof, compositions of the derivatives together with pharmaceutically acceptable carriers, and uses thereof: ##STR00001##
Inventor(s):	Barsanti; Paul A. (Pleasant Hill, CA), Ding; Yu (Union City, CA), Han; Wooseok (San Ramon, CA)
Assignee:	Novartis AG (Basel, CH)
Application Number:	13/640,561
Patent Claims:	1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof: ##STR00090## wherein: R.sup.1 is selected from the group consisting of alkyl, branched alkyl, and substituted alkyl; R.sup.2 is selected from the group consisting of hydrogen, alkyl, and substituted alkyl; R.sup.3 is selected from the group consisting of -L.sub.1-A.sup.1, wherein L.sup.1 is selected from the group consisting of --C(O)--, --C(S)--, --S(O)--, and --S(O).sub.2-- and A.sup.1 is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, and NR.sup.8R.sup.9; R.sup.4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl, and optionally substituted pyrrolidinyl; X is O or S; R.sup.6 is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, all of which may be optionally substituted with --(R.sup.10).sub.m where R.sup.10 is as defined herein, m is 1, 2, 3, or 4, and each R.sup.10 may be the same or different when m is 2, 3, or 4; R.sup.7 is -L.sup.2-A.sup.2 wherein L.sup.2 is C.sub.1-C.sub.5 alkylene and A.sup.2 is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, and substituted heterocycloalkyl; R.sup.8 is selected from the group consisting of hydrogen and alkyl; R.sup.9 is selected from the group consisting of hydrogen, hydroxy, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, and substituted heterocycloalkyl; or R.sup.8 and R.sup.9 together with the nitrogen atom pendent thereto join to form a heterocycloalkyl or substituted heterocycloalkyl; R.sup.10 is selected from the group consisting of cyano, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, --CF.sub.3, alkoxy, substituted alkoxy, halo, and hydroxy; and R.sup.11 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, --SO.sub.2alkyl, and --SO.sub.2substituted alkyl. 2. A compound of claim 1, wherein R.sup.1 is alkyl. 3. A compound of claim 1, wherein R.sup.2 is C.sub.1-4 alkyl or H. 4. A compound of claim 3, wherein R.sup.2 is H. 5. A compound of claim 4, wherein R.sup.1 is i-propyl, or t-butyl. 6. A compound of claim 5, wherein R.sup.3 is selected from -L.sup.1-A.sup.1, wherein L.sup.1 is selected from the group consisting of --C(O)--, --C(S)--, --S(O)--, and --S(O).sub.2-- and A.sup.1 is selected from the group consisting of alkyl, and substituted alkyl. 7. A compound of claim 6, wherein R.sup.3 is selected from -L.sup.1-A.sup.1, wherein L.sup.1 is --C(O)--, and A.sup.1 is substituted alkyl. 8. A compound of claim 7, wherein R.sup.4 is selected from the group consisting of hydrogen, alkyl, and substituted alkyl. 9. A compound of claim 8, wherein R.sup.4 is substituted alkyl or --CH.sub.2-fluoropyrrolidinyl. 10. A compound of claim 9, wherein R.sup.3 is selected from -L.sup.1-A.sup.1, wherein L.sup.1 is --C(O)--, and A.sup.1 is --CH(CH.sub.3)OH. 11. A compound of claim 10, wherein R.sup.4 is --(CH.sub.2).sub.2--CH(CH.sub.2F)NH.sub.2, or --CH.sub.2-3-fluoropyrrolidinyl. 12. A compound of claim 11, wherein R.sup.6 is selected from the group consisting of aryl, and heteroaryl, all of which are optionally substituted with --(R.sup.10).sub.m where m is 1, 2, 3, or 4, and each R.sup.10 may be the same or different when m is 2, 3, or 4; and R.sup.7 is -L.sup.2-A.sup.2 wherein L.sup.2 is C.sub.1-C.sub.2 alkylene and A.sup.2 is selected from the group consisting of aryl, and heteroaryl. 13. A compound of claim 12, wherein R.sup.6 represents aryl substituted with two R.sup.10 groups. 14. A compound of claim 12, wherein R.sup.6 represents phenyl substituted with two fluorine atoms. 15. A compound of claim 13, wherein R.sup.7 represents --CH.sub.2-aryl. 16. A compound of claim 14 wherein R.sup.7 represents --CH.sub.2-phenyl. 17. A compound selected from ##STR00091## ##STR00092## 18. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier. 19. The composition of claim 18 further comprising at least one additional agent for the treatment of cancer. 20. The composition of claim 19, wherein the additional agent for the treatment of cancer is selected from the group consisting of irinotecan, topotecan, gemcitabine, imatinib, 5-fluorouracil, leucovorin, carboplatin, cisplatin, docetaxel, paclitaxel, tezacitabine, cyclophosphamide, vinca alkaloids, anthracyclines, rituximab, and trastuzumab. 21. A method of treating a colon cancer or breast cancer mediated, at least in part, by kinesin spindle protein (KSP) in a mammalian patient in need of such treatment comprising administering to the mammalian patient a therapeutically effective amount of a compound of claim 1. 22. A method for inhibiting KSP in a mammalian patient, wherein said method comprises administering to the patient an effective KSP-inhibiting amount of a compound of claim 1. 23. A compound of claim 1 selected from: ##STR00093## 24. A method of treating a colon cancer or breast cancer mediated, at least in part, by KSP in a mammalian patient in need of such treatment, comprising administering to the mammalian patient a therapeutically effective amount of the pharmaceutical composition of claim 18.

Details for Patent 8,748,626

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