Claims for Patent: 7,345,046

Summary for Patent: 7,345,046

Title:	Heteroaryl-fused pyrimidinyl compounds as anticancer agents
Abstract:	Heteroaryl-fused pyrimidinyl compounds, pharmaceutically acceptable salts, and prodrugs thereof; compositions that include a pharmaceutically acceptable carrier and one or more of the heteroaryl-fused pyrimidinyl compounds, either alone or in combination with at least one additional therapeutic agent. Methods of using the heteroaryl-fused pyrimidinyl compounds, either alone or in combination with at least one additional therapeutic agent, in the prophylaxis or treatment of proliferative diseases.
Inventor(s):	Wang; Weibo (Moraga, CA), Lagniton; Liana Marie (Berkeley, CA), Constantine; Ryan N. (Oakland, CA), Burger; Matthew T. (Albany, CA)
Assignee:	Chiron Corporation (Emeryville, CA)
Application Number:	10/850,429
Patent Claims:	1. A compound having the formula: ##STR00028## wherein Q is thienyl; X is O or S; R.sub.1 is hydrogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, alkylsulfonyl, or arylsulfonyl; R.sub.2 is hydrogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, alkylsulfonyl, arylsulfonyl, alkylcarboxy, aminocarboxy, aminocarbonyl, or alkylsulfonamido; or COR.sub.7, CO.sub.2R.sub.7, CONR.sub.8R.sub.9, S(O).sub.mR.sub.10, or SO.sub.2NR.sub.11R.sub.12; R.sub.3 is cyano, substituted or unsubstituted arylsulfonyl, or CONR.sub.8R.sub.9; R.sub.4 is hydrogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl; or L-R.sub.13, wherein L is a C1-C10 saturated or unsaturated branched or unbranched carbon chain comprising one or more methylene groups, wherein one or more methylene groups are optionally independently replaced by O, N, or S; and wherein L is optionally substituted with one or two oxo groups and one or more C1-C10 branched or unbranched alkyl optionally substituted by one or more halogen atoms; R.sub.5 is hydrogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or heterocyclyl; or COR.sub.7, CO.sub.2R.sub.7, CONR.sub.8R.sub.9, or SO.sub.(m)R.sub.10; R.sub.6 is hydrogen, halogen, hydroxy, nitro, amino, cyano, alkoxy, alkylthio, methylenedioxy, or haloalkoxy; or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylamino, dialkylamino, alkylsulfonyl, arylsulfonyl, alkylcarboxy, carboxyamino, carboxyamido, aminocarboxy, aminocarbonyl, or alkylsulfonamido; R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.11, and R.sub.12 are independently selected from hydrogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl; or R.sub.8 and R.sub.9, or R.sub.11 and R.sub.12 taken together form a 3- to 7-membered carbocyclic or heterocyclic ring; R.sub.13 is amino, alkylamino, or dialkylamino; or substituted or unsubstituted guanidino or heterocyclyl; m=0, 1, or 2; and n=0, 1, 2, or 3; or the tautomers or pharmaceutically acceptable salts thereof. 2. A compound of claim 1, wherein substituted alkyl comprises arylalkyl, heteroarylalkyl, heterocyclyalkyl, aminoalkyl, alkylaminoalkyl, dialkyaminoalkyl, or sulfonamidoalkyl. 3. A compound of claim 1, wherein X is O. 4. A compound of claim 1, wherein R.sub.1 is arylalkyl. 5. A compound of claim 1, wherein R.sub.1 is benzyl. 6. A compound of claim 1, wherein R.sub.2 is hydrogen and R.sub.3 is CONR.sub.8R.sub.9. 7. A compound of claim 6, wherein R.sub.8 and R.sub.9 are independently selected from hydrogen, methyl, ethyl, or isopropyl. 8. A compound of claim 1, wherein R.sub.4 is L-R.sub.13. 9. A compound of claim 8, wherein L-R.sub.13 is aminoalkyl. 10. A compound of claim 8, wherein L-R.sub.13 is aminopropyl, alkylaminopropyl, or dialkylaminopropyl. 11. A compound of claim 8, wherein L-R.sub.13 is aminopropyl. 12. A compound of claim 1, wherein R.sub.5 is hydrogen, alkyl, aryl, or COR.sub.7. 13. A compound of claim 1, wherein R.sub.5 is COR.sub.7. 14. A compound of claim 13, wherein R.sub.7 is substituted or unsubstituted aryl or heteroaryl. 15. A compound of claim 13, wherein R.sub.7 is alkyl- or halogen-substituted aryl. 16. A compound of claim 13 wherein R.sub.7 is substituted or unsubstituted phenyl, pyridyl, or pyrazinyl. 17. A compound of claim 1, wherein R.sub.6 is hydrogen, alkyl, chloro, or bromo. 18. A compound having the formula: ##STR00029## wherein X is O or S; Y.sub.1 is S and Y.sub.2 is CR.sub.15; or Y.sub.1 is CR.sub.15 and Y.sub.2 is S; wherein, the dashed line represents a double bond to Y.sub.1, when Y.sub.1 is CR.sub.15, and a double bond to Y.sub.2, when Y.sub.2 is CR.sub.15; R.sub.1 is hydrogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, alkylsulfonyl, or arylsulfonyl; R.sub.2 is hydrogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, alkylsulfonyl, arylsulfonyl, alkylcarboxy, aminocarboxy, aminocarbonyl, or alkylsulfonamido; or COR.sub.7, CO.sub.2R.sub.7, CONR.sub.8R.sub.9, S(O).sub.mR.sub.10, or SO.sub.2NR.sub.11R.sub.12; R.sub.3 is cyano, substituted or unsubstituted arylsulfonyl, or CONR.sub.8R.sub.9; R.sub.4 is hydrogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl; or L-R.sub.13, wherein L is a C1-C10 saturated or unsaturated branched or unbranched carbon chain comprising one or more methylene groups, wherein one or more methylene groups are optionally independently replaced by O, N, or S; and wherein L is optionally substituted with one or two oxo groups and one or more C1-C10 branched or unbranched alkyl optionally substituted by one or more halogen atoms; R.sub.5 is hydrogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or heterocyclyl; or COR.sub.7, CO.sub.2R.sub.7, CONR.sub.8R.sub.9, or SO.sub.(m)R.sub.10; R.sub.6 is hydrogen, halogen, hydroxy, nitro, amino, cyano, alkoxy, alkylthio, methylenedioxy, or haloalkoxy; or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylamino, dialkylamino, alkylsulfonyl, arylsulfonyl, alkylcarboxy, carboxyamino, carboxyamido, aminocarboxy, aminocarbonyl, or alkylsulfonamido; R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.11, and R.sub.12 are independently selected from hydrogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl; or R.sub.8 and R.sub.9, or R.sub.11, and R.sub.12 taken together form a 3- to 7-membered carbocyclic or heterocyclic ring; R.sub.13 is amino, alkylamino, or dialkylamino; or substituted or unsubstituted guanidino or heterocyclyl; R.sub.15 are independently selected from hydrogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl; m=0, 1, or 2; or the tautomers, pharmaceutically acceptable salts, or prodrugs thereof. 19. A compound of claim 18, wherein substituted alkyl comprises arylalkyl, heteroarylalkyl, heterocyclyalkyl, aminoalkyl, alkylaminoalkyl, dialkyaminoalkyl, or sulfonamidoalkyl. 20. A compound of claim 18, wherein X is O. 21. A compound of claim 18, wherein R.sub.1 is arylalkyl. 22. A compound of claim 18, wherein R.sub.1 is benzyl. 23. A compound of claim 18, wherein R.sub.2 is hydrogen and R.sub.3 is CONR.sub.8R.sub.9. 24. A compound of claim 23, wherein R.sub.8 and R.sub.9 are independently selected from hydrogen, methyl, ethyl, or isopropyl. 25. A compound of claim 18, wherein R.sub.4 is L-R.sub.13. 26. A compound of claim 25, wherein L-R.sub.13 is aminoalkyl. 27. A compound of claim 25, wherein L-R.sub.13 is aminopropyl, alkylaminopropyl, or dialkylaminopropyl. 28. A compound of claim 25, wherein L-R.sub.13 is aminopropyl. 29. A compound of claim 18, wherein R.sub.5 is hydrogen, alkyl, aryl, or COR.sub.7. 30. A compound of claim 18, wherein R.sub.5 is COR.sub.7. 31. A compound of claim 30, wherein R.sub.7 is substituted or unsubstituted aryl or heteroaryl. 32. A compound of claim 30, wherein R.sub.7 is alkyl- or halogen-substituted aryl. 33. A compound of claim 30, wherein R.sub.7 is substituted or unsubstituted phenyl, pyridyl, or pyrazinyl. 34. A compound of claim 18, wherein R.sub.6 is hydrogen, alkyl, chloro, or bromo. 35. A compound selected from: N-(3-aminopropyl)-N-[1-(3-benzyl-6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]py- rimidin-2-yl)-2-(dimethylamino)-2-oxoethyl]pyrazine-2-carboxamide; N-(3-aminopropyl)-N-[1-(3-benzyl-6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]py- rimidin-2-yl)-2-(dimethylamino)-2-oxoethyl]-5-methylpyrazine-2-carboxamide- ; N-(3-aminopropyl)-N-[1-(3-benzyl-6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]p- yrimidin-2-yl)-2-(dimethylamino)-2-oxoethyl]-4-chlorobenzamide; N-(3-aminopropyl)-N-[1-(3-benzyl-6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]py- rimidin-2-yl)-2-(dimethylamino)-2-oxoethyl]-6-methylnicotinamide; N-(3-aminopropyl)-N-[1-(3-benzyl-6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]py- rimidin-2-yl)-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide; or N-(3-aminopropyl)-N-[1-(3-benzyl-6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]py- rimidin-2-yl)-2-(dimethylamino)-2-oxoethyl]-6-chloronicotinamide. 36. A composition, comprising a pharmaceutically acceptable carrier and an amount of a compound of claims 1, 18, or 35 effective to inhibit KSP (Kinesin Spindle Protien) activity in a human or animal subject when administered thereto. 37. The composition of claim 36 further comprising at least one additional agent for the treatment of cancer. 38. The composition of claim 37, wherein the additional agent for the treatment of cancer is selected from irinotecan, topotecan, gemcitabine, imatinib, trastuzumab, 5-fluorouracil, leucovorin, carboplatin, cisplatin, docetaxel, paclitaxel, tezacitabine, cyclophosphamide, vinca alkaloids, anthracyclines, rituximab, and trastuzumab. 39. A method for inhibiting KSP (Kinesin Spindle Protien) activity in a human or animal subject, comprising administering to the human or animal subject a composition comprising an amount of a compound of claims 1, 18, or 35 effective to inhibit KSP (Kinesin Spindle Protien) activity the human or animal subject. 40. A kit, comprising a compound of claims 1, 18, or 35 and a package insert or other labeling including directions for treating a cellular proliferative disease by administering an KSP (Kinesin Spindle Protien) inhibitory amount of the compound.

Details for Patent 7,345,046

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
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