Claims for Patent: 7,939,539

Summary for Patent: 7,939,539

Title:	Quinazolinone compounds as anticancer agents
Abstract:	Quinazolinone compounds, pharmaceutically acceptable salts, and prodrugs thereof; compositions that include a pharmaceutically acceptable carrier and one or more of the quinazolinone compounds, either alone or in combination with at least one additional therapeutic agent. Methods of using the quinazolinone 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 M. (Berkeley, CA), Constantine; Ryan N. (Oakland, CA), Desai; Manoj C. (Pleasant Hill, CA)
Assignee:	Novartis Vaccines and Diagnostics, Inc. (Emeryville, CA)
Application Number:	10/996,814
Patent Claims:	1. A compound having the formula: ##STR00071## or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is O or S; R.sub.1 is substituted alkyl; R.sub.2 is selected from the group consisting of (1) hydrogen, (2) substituted or unsubstituted alkyl, (3) substituted or unsubstituted alkenyl, and (4) substituted or unsubstituted alkynyl; R.sub.3 is selected from the group consisting of: (1) CO.sub.2R.sub.10, and (2) CONR.sub.11R.sub.12; R.sub.4 is selected from the group consisting of: (1) hydrogen, (2) substituted or unsubstituted alkyl, (3) substituted or unsubstituted alkenyl, (4) substituted or unsubstituted alkynyl, (5) substituted or unsubstituted aryl, (6) substituted or unsubstituted heteroaryl, and (7) substituted or unsubstituted heterocyclyl; R.sub.5 is selected from the group consisting of: (1) hydrogen, (2) substituted or unsubstituted alkyl, (3) substituted or unsubstituted alkoxy, (4) substituted or unsubstituted aryl, (5) substituted or unsubstituted heteroaryl, (6) substituted or unsubstituted heterocyclyl, (7) COR.sub.17, (8) CO.sub.2R.sub.18, (9) CONR.sub.19R.sub.20, and (10) SO.sub.2R.sub.21; R.sub.6, R.sub.7, R.sub.8, and R.sub.9 are independently selected from the group consisting of: (1) hydrogen, (2) halogen, (3) hydroxy, (4) nitro, (5) amino, (6) cyano, (7) alkoxy, (8) alkylthio, (9) methylenedioxy, (10) haloalkoxy, (11) CO.sub.2R.sub.10, (12) COR.sub.10, (13) OR.sub.10, (14) CONR.sub.11R.sub.12, (15) substituted or unsubstituted alkyl, (16) substituted or unsubstituted aryl, (17) substituted or unsubstituted heteroaryl, (18) substituted or unsubstituted alkylamino, (19) substituted or unsubstituted dialkylamino, (20) substituted or unsubstituted alkylsulfonyl, (21) substituted or unsubstituted arylsulfonyl, (22) substituted or unsubstituted alkylcarboxy, (23) substituted or unsubstituted carboxamido, (24) substituted or unsubstituted carboxyamino, (25) substituted or unsubstituted aminocarboxy, (26) substituted or unsubstituted aminocarbonyl, and (27) substituted or unsubstituted alkylsulfonamido; R.sub.10, R.sub.11, R.sub.12, R.sub.17, R.sub.18, R.sub.19, R.sub.20, and R.sub.21 are independently selected from the group consisting of: (1) hydrogen, (2) substituted or unsubstituted alkyl, (3) substituted or unsubstituted alkenyl, (4) substituted or unsubstituted alkynyl, (5) substituted or unsubstituted aryl, (6) substituted or unsubstituted heteroaryl, and (7) substituted or unsubstituted heterocyclyl; or R.sub.11 and R.sub.12, or R.sub.19 and R.sub.20 taken together form a 3- to 7-membered carbocyclic or heterocyclic ring; and m=0, 1, or 2. 2. A compound of claim 1, wherein R.sub.1 is benzyl. 3. A compound of claim 1, wherein R.sub.1 is substituted benzyl. 4. A compound of claim 3, wherein R.sub.1 is a halo-substituted benzyl. 5. A compound of claim 4, wherein R.sub.1 is 3-chlorobenzyl. 6. A compound of claim 4, wherein R.sub.1 is 3-fluorobenzyl. 7. A compound of claim 4, wherein R.sub.1 is 3-methoxybenzyl. 8. A compound of claim 4, wherein R.sub.1 is 3-trifluoromethylbenzyl. 9. A compound of claim 4, wherein R.sub.1 is 3-trifluoromethoxybenzyl. 10. A compound of claim 3, wherein R.sub.1 is 3,5-dimethylbenzyl. 11. A compound of claim 1, wherein R.sub.1 is 2-naphthylmethyl. 12. A compound having the formula: ##STR00072## or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is O or S; R.sub.1 is selected from the group consisting of: (1) hydrogen, (2) substituted or unsubstituted alkyl, (3) substituted or unsubstituted alkenyl, (4) substituted or unsubstituted alkynyl, (5) substituted or unsubstituted aryl, (6) substituted or unsubstituted heteroaryl, (7) substituted or unsubstituted heterocyclyl, (8) substituted or unsubstituted alkylsulfonyl, and (9) substituted or unsubstituted arylsulfonyl; R.sub.2 is hydrogen; R.sub.3 is CO.sub.2R.sub.10; R.sub.4 is selected from the group consisting of: (1) hydrogen, (2) substituted or unsubstituted alkyl, (3) substituted or unsubstituted alkenyl, (4) substituted or unsubstituted alkynyl, (5) substituted or unsubstituted aryl, (6) substituted or unsubstituted heteroaryl, and (7) substituted or unsubstituted heterocyclyl; R.sub.5 is selected from the group consisting of: (1) hydrogen, (2) substituted or unsubstituted alkyl, (3) substituted or unsubstituted alkoxy, (4) substituted or unsubstituted aryl, (5) substituted or unsubstituted heteroaryl, (6) substituted or unsubstituted heterocyclyl, (7) COR.sub.17, (8) CO.sub.2R.sub.18, (9) CONR.sub.19R.sub.20, and (10) SO.sub.2R.sub.21; R.sub.6, R.sub.7, R.sub.8, and R.sub.9 are independently selected from the group consisting of: (1) hydrogen, (2) halogen, (3) hydroxy, (4) nitro, (5) amino, (6) cyano, (7) alkoxy, (8) alkylthio, (9) methylenedioxy, (10) haloalkoxy, (11) CO.sub.2R.sub.10, (12) COR.sub.10, (13) OR.sub.10, (14) CONR.sub.11R.sub.12, (15) substituted or unsubstituted alkyl, (16) substituted or unsubstituted aryl, (17) substituted or unsubstituted heteroaryl, (18) substituted or unsubstituted alkylamino, (19) substituted or unsubstituted dialkylamino, (20) substituted or unsubstituted alkylsulfonyl, (21) substituted or unsubstituted arylsulfonyl, (22) substituted or unsubstituted alkylcarboxy, (23) substituted or unsubstituted carboxamido, (24) substituted or unsubstituted carboxyamino, (25) substituted or unsubstituted aminocarboxy, (26) substituted or unsubstituted aminocarbonyl, and (27) substituted or unsubstituted alkylsulfonamido; R.sub.10, R.sub.11, R.sub.12, R.sub.17, R.sub.18, R.sub.19, R.sub.20, and R.sub.21 are independently selected from the group consisting of: (1) hydrogen, (2) substituted or unsubstituted alkyl, (3) substituted or unsubstituted alkenyl, (4) substituted or unsubstituted alkynyl, (5) substituted or unsubstituted aryl, (6) substituted or unsubstituted heteroaryl, and (7) substituted or unsubstituted heterocyclyl; or R.sub.11 and R.sub.12, or R.sub.19 and R.sub.20 taken together form a 3- to 7-membered carbocyclic or heterocyclic ring; and m=0, 1, or 2. 13. A compound of claim 12, wherein R.sub.10 is alkyl. 14. A compound of claim 1, wherein R.sub.2 is hydrogen, R.sub.3 is CONR.sub.11R.sub.12, and R.sub.11 and R.sub.12 are alkyl. 15. A compound of claim 14, wherein R.sub.11 and R.sub.12 are methyl. 16. A compound of claim 1, wherein R.sub.2 is hydrogen, R.sub.3 is CONR.sub.11R.sub.12, and R.sub.11 and R.sub.12 taken together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclic ring. 17. A compound having the formula: ##STR00073## or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is O or S; R.sub.1 is selected from the group consisting of: (1) hydrogen, (2) substituted or unsubstituted alkyl, (3) substituted or unsubstituted alkenyl, (4) substituted or unsubstituted alkynyl, (5) substituted or unsubstituted aryl, (6) substituted or unsubstituted heteroaryl, (7) substituted or unsubstituted heterocyclyl, (8) substituted or unsubstituted alkylsulfonyl, and (9) substituted or unsubstituted arylsulfonyl; R.sub.2 is selected from the group consisting of: (1) hydrogen, (2) substituted or unsubstituted alkyl, (3) substituted or unsubstituted alkenyl, and (4) substituted or unsubstituted alkynyl; R.sub.3 is selected from the group consisting of: (1) CO.sub.2R.sub.10, and (2) CONR.sub.11R.sub.12; R.sub.4 is amino-substituted alkyl; R.sub.5 is selected from the group consisting of: (1) hydrogen, (2) substituted or unsubstituted alkyl, (3) substituted or unsubstituted alkoxy, (4) substituted or unsubstituted aryl, (5) substituted or unsubstituted heteroaryl, (6) substituted or unsubstituted heterocyclyl, (7) COR.sub.17, (8) CO.sub.2R.sub.18, (9) CONR.sub.19R.sub.20, and (10) SO.sub.2R.sub.21; R.sub.6, R.sub.7, R.sub.8, and R.sub.9 are independently selected from the group consisting of: (1) hydrogen, (2) halogen, (3) hydroxy, (4) nitro, (5) amino, (6) cyano, (7) alkoxy, (8) alkylthio, (9) methylenedioxy, (10) haloalkoxy, (11) CO.sub.2R.sub.10, (12) COR.sub.10, (13) OR.sub.10, (14) CONR.sub.11R.sub.12, (15) substituted or unsubstituted alkyl, (16) substituted or unsubstituted aryl, (17) substituted or unsubstituted heteroaryl, (18) substituted or unsubstituted alkylamino, (19) substituted or unsubstituted dialkylamino, (20) substituted or unsubstituted alkylsulfonyl, (21) substituted or unsubstituted arylsulfonyl, (22) substituted or unsubstituted alkylcarboxy, (23) substituted or unsubstituted carboxamido, (24) substituted or unsubstituted carboxyamino, (25) substituted or unsubstituted aminocarboxy, (26) substituted or unsubstituted aminocarbonyl, and (27) substituted or unsubstituted alkylsulfonamido; R.sub.10, R.sub.11, R.sub.12, R.sub.17, R.sub.18, R.sub.19, R.sub.20, and R.sub.21 are independently selected from the group consisting of: (1) hydrogen, (2) substituted or unsubstituted alkyl, (3) substituted or unsubstituted alkenyl, (4) substituted or unsubstituted alkynyl, (5) substituted or unsubstituted aryl, (6) substituted or unsubstituted heteroaryl, and (7) substituted or unsubstituted heterocyclyl; or R.sub.11 and R.sub.12, or R.sub.19 and R.sub.20 taken together form a 3- to 7-membered carbocyclic or heterocyclic ring; and m=0, 1, or 2. 18. A compound of claim 17, wherein R.sub.4 is 3-aminopropyl. 19. A compound having the formula: ##STR00074## or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is O or S; R.sub.1 is substituted alkyl R.sub.2 is selected from the group consisting of: (1) hydrogen, (2) substituted or unsubstituted alkyl, (3) substituted or unsubstituted alkenyl, and (4) substituted or unsubstituted alkynyl; R.sub.3 is selected from the group consisting of: (1) CO.sub.2R.sub.10, and (2) CONR.sub.11R.sub.12; R.sub.4 is selected from the group consisting of: (1) hydrogen, (2) substituted or unsubstituted alkyl, (3) substituted or unsubstituted alkenyl, (4) substituted or unsubstituted alkynyl, (5) substituted or unsubstituted aryl, (6) substituted or unsubstituted heteroaryl, and (7) substituted or unsubstituted heterocyclyl; R.sub.5 is hydrogen, alkyl, aryl, or COR.sub.17; R.sub.6, R.sub.7, R.sub.8, and R.sub.9 are independently selected from the group consisting of: (1) hydrogen, (2) halogen, (3) hydroxy, (4) nitro, (5) amino, (6) cyano, (7) alkoxy, (8) alkylthio, (9) methylenedioxy, (10) haloalkoxy, (11) CO.sub.2R.sub.10, (12) COR.sub.10, (13) OR.sub.10, (14) CONR.sub.11R.sub.12, (15) substituted or unsubstituted alkyl, (16) substituted or unsubstituted aryl, (17) substituted or unsubstituted heteroaryl, (18) substituted or unsubstituted alkylamino, (19) substituted or unsubstituted dialkylamino, (20) substituted or unsubstituted alkylsulfonyl, (21) substituted or unsubstituted arylsulfonyl, (22) substituted or unsubstituted alkylcarboxy, (23) substituted or unsubstituted carboxamido, (24) substituted or unsubstituted carboxyamino, (25) substituted or unsubstituted aminocarboxy, (26) substituted or unsubstituted aminocarbonyl, and (27) substituted or unsubstituted alkylsulfonamido; R.sub.10, R.sub.11, R.sub.12, R.sub.17, R.sub.18, R.sub.19, R.sub.20, and R.sub.21 are independently selected from the group consisting of: (1) hydrogen, (2) substituted or unsubstituted alkyl, (3) substituted or unsubstituted alkenyl, (4) substituted or unsubstituted alkynyl, (5) substituted or unsubstituted aryl, (6) substituted or unsubstituted heteroaryl, and (7) substituted or unsubstituted heterocyclyl; or R.sub.11 and R.sub.12, or R.sub.19 and R.sub.20 taken together form a 3- to 7-membered carbocyclic or heterocyclic ring; and m=0, 1, or 2. 20. A compound of claim 19, wherein R.sub.5 is COR.sub.17. 21. A compound of claim 20, wherein R.sub.17 is aryl, arylalkyl, alkyl-substituted aryl, or halogen-substituted aryl. 22. A compound of claim 21, wherein aryl is phenyl. 23. A compound having the formula: ##STR00075## or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is O or S; R.sub.1 is substituted alkyl R.sub.2 is selected from the group consisting of: (1) hydrogen, (2) substituted or unsubstituted alkyl, (3) substituted or unsubstituted alkenyl, and (4) substituted or unsubstituted alkynyl; R.sub.3 is selected from the group consisting of: (1) CO.sub.2R.sub.10, and (2) CONR.sub.11R.sub.12; R.sub.4 is selected from the group consisting of: (1) hydrogen, (2) substituted or unsubstituted alkyl, (3) substituted or unsubstituted alkenyl, (4) substituted or unsubstituted alkynyl, (5) substituted or unsubstituted aryl, (6) substituted or unsubstituted heteroaryl, and (7) substituted or unsubstituted heterocyclyl; R.sub.5 is selected from the group consisting of: (1) hydrogen, (2) substituted or unsubstituted alkyl, (3) substituted or unsubstituted alkoxy, (4) substituted or unsubstituted aryl, (5) substituted or unsubstituted heteroaryl, (6) substituted or unsubstituted heterocyclyl, (7) COR.sub.17, (8) CO.sub.2R.sub.18, (9) CONR.sub.19R.sub.20, and (10) SO.sub.2R.sub.21; R.sub.6, R.sub.8, and R.sub.9 are independently selected from the group consisting of: (1) hydrogen, (2) halogen, (3) hydroxy, (4) nitro, (5) amino, (6) cyano, (7) alkoxy, (8) alkylthio, (9) methylenedioxy, (10) haloalkoxy, (11) CO.sub.2R.sub.10, (12) COR.sub.10, (13) OR.sub.10, (14) CONR.sub.11R.sub.12, (15) substituted or unsubstituted alkyl, (16) substituted or unsubstituted aryl, (17) substituted or unsubstituted heteroaryl, (18) substituted or unsubstituted alkylamino, (19) substituted or unsubstituted dialkylamino, (20) substituted or unsubstituted alkylsulfonyl, (21) substituted or unsubstituted arylsulfonyl, (22) substituted or unsubstituted alkylcarboxy, (23) substituted or unsubstituted carboxamido, (24) substituted or unsubstituted carboxyamino, (25) substituted or unsubstituted aminocarboxy, (26) substituted or unsubstituted aminocarbonyl, and (27) substituted or unsubstituted alkylsulfonamido; R.sub.7 is a halogen; R.sub.10, R.sub.11, R.sub.12, R.sub.17, R.sub.18, R.sub.19, R.sub.20, and R.sub.21 are independently selected from the group consisting of: (1) hydrogen, (2) substituted or unsubstituted alkyl, (3) substituted or unsubstituted alkenyl, (4) substituted or unsubstituted alkynyl, (5) substituted or unsubstituted aryl, (6) substituted or unsubstituted heteroaryl, and (7) substituted or unsubstituted heterocyclyl; or R.sub.11 and R.sub.12, or R.sub.19 and R.sub.20 taken together form a 3- to 7-membered carbocyclic or heterocyclic ring; and m=0, 1, or 2. 24. A compound selected from the group consisting of: ethyl (3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl){(4-bromobenzoyl)[3-(- dimethylamino)propyl]amino}acetate; ethyl [(3-aminopropyl)(4-methylbenzoyl)amino](3-benzyl-7-chloro-4-oxo-3,4-dihyd- roquinazolin-2-yl)acetate; isopropyl (3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)[[3-(dimethylamino)pr- opyl](4-methylbenzoyl)amino]acetate; isopropyl [(3-aminopropyl)(4-bromobenzoyl)amino](3-benzyl-7-chloro-4-oxo-3,4-dihydr- oquinazolin-2-yl)acetate; isopropyl [(3-aminopropyl)(4-methylbenzoyl)amino](3-benzyl-7-chloro-4-oxo-3,4-dihyd- roquinazolin-2-yl)acetate; N-(3-aminopropyl)-N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-y- l)-2-(diethylamino)-2-oxoethyl]-4-bromobenzamide; N-(3-aminopropyl)-N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-y- l)-2-(diethylamino)-2-oxoethyl]-4-methylbenzamide; N-(3-aminopropyl)-N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-y- l)-2-oxo-2-pyrrolidin-1-ylethyl]-4-bromobenzamide; N-(3-aminopropyl)-N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-y- l)-2-oxo-2-pyrrolidin-1-ylethyl]-4-chlorobenzamide; N-(3-aminopropyl)-N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-y- l)-2-morpholin-4-yl-2-oxoethyl]-4-bromobenzamide; N-(3-aminopropyl)-N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-y- l)-2-morpholin-4-yl-2-oxoethyl]-4-chlorobenzamide; N-(3-aminopropyl)-N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-y- l)-2-(dimethylamino)-2-oxoethyl]-4-bromobenzamide; N-(3-aminopropyl)-N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-y- l)-2-(dimethylamino)-2-oxoethyl]-4-chlorobenzamide; N-(3-aminopropyl)-N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-y- l)-2-oxo-2-pyrrolidin-1-ylethyl]-4-methylbenzamide; N-(3-aminopropyl)-N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-y- l)-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide; N-(3-aminopropyl)-N-[1-[7-chloro-3-(3-chlorobenzyl)-4-oxo-3,4-dihydroquin- azolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide; N-(3-aminopropyl)-N-[1-[7-chloro-3-(3-fluorobenzyl)-4-oxo-3,4-dihydroquin- azolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide; N-(3-aminopropyl)-N-[1-[7-chloro-3-(3-methylbenzyl)-4-oxo-3,4-dihydroquin- azolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide; N-(3-aminopropyl)-N-[1-{7-chloro-4-oxo-3-[4-(trifluoromethoxy)benzyl]-3,4- -dihydroquinazolin-2-yl}-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide; N-(3-aminopropyl)-N-[1-[7-chloro-3-(4-chlorobenzyl)-4-oxo-3,4-dihydroquin- azolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide; N-(3-aminopropyl)-N-[1-[7-chloro-3-(3-methoxybenzyl)-4-oxo-3,4-dihydroqui- nazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide; N-(3-aminopropyl)-N-[1-[7-chloro-3-(2-naphthylmethyl)-4-oxo-3,4-dihydroqu- inazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide; N-(3-aminopropyl)-N-[1-{7-chloro-4-oxo-3-[3-(trifluoromethyl)benzyl]-3,4-- dihydroquinazolin-2-yl}-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide; N-(3-aminopropyl)-N-[1-{7-chloro-4-oxo-3-[3-(trifluoromethoxy)benzyl]-3,4- -dihydroquinazolin-2-yl}-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide; N-(3-aminopropyl)-N-[1-[7-chloro-3-(3-hydroxybenzyl)-4-oxo-3,4-dihydroqui- nazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide; N-(3-aminopropyl)-N-[1-[7-chloro-3-(3,5-dimethylbenzyl)-4-oxo-3,4-dihydro- quinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide; N-(3-aminopropyl)-N-[1-[3-(1,1'-biphenyl-3-ylmethyl)-7-chloro-4-oxo-3,4-d- ihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide; N-(3-aminopropyl)-N-[1-[7-chloro-3-(3-cyanobenzyl)-4-oxo-3,4-dihydroquina- zolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide; N-(3-aminopropyl)-N-[1-[7-chloro-3-(3-nitrobenzyl)-4-oxo-3,4-dihydroquina- zolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide; N-(3-aminopropyl)-N-[1-[7-chloro-3-(3,4-dichlorobenzyl)-4-oxo-3,4-dihydro- quinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide; N-(3-aminopropyl)-N-{1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-y- l)-2-[ethyl(methyl)amino]-2-oxoethyl}-4-methylbenzamide; N-(3-aminopropyl)-N-{1-[7-chloro-3-(3,5-dimethylbenzyl)-4-oxo-3,4-dihydro- quinazolin-2-yl]-2-[ethyl(methyl)amino]-2-oxoethyl}-4-methylbenzamide; N-(3-aminopropyl)-N-{1-[7-chloro-3-(3,5-dimethylbenzyl)-4-oxo-3,4-dihydro- quinazolin-2-yl]-2-[ethyl(methyl)amino]-2-oxoethyl}-4-methylbenzamide; N-(3-aminopropyl)-N-{1-[7-chloro-3-(3-methoxybenzyl)-4-oxo-3,4-dihydroqui- nazolin-2-yl]-2-[ethyl(methyl)amino]-2-oxoethyl}-4-methylbenzamide; N-(3-aminopropyl)-N-[1-[7-chloro-3-(3,5-difluorobenzyl)-4-oxo-3,4-dihydro- quinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide; N-(3-aminopropyl)-N-[1-{7-chloro-3-[(6-chloropyridin-2-yl)methyl]-4-oxo-3- ,4-dihydroquinazolin-2-yl}-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide- ; N-(3-aminopropyl)-N-[1-{7-chloro-3-[(2-chloropyridin-4-yl)methyl]-4-oxo-- 3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl}-4-methylbenzamid- e; and N-(3-aminopropyl)-N-[1-[7-chloro-4-oxo-3-(quinolin-2-ylmethyl)-3,4-- dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide. 25. A composition, comprising a pharmaceutically acceptable carrier and an amount of a compound effective to inhibit KSP activity in a human or animal subject when administered thereto, wherein the compound has the formula: ##STR00076## or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is O or S; R.sub.1 is selected from the group consisting of: (1) hydrogen, (2) substituted or unsubstituted alkyl, (3) substituted or unsubstituted alkenyl, (4) substituted or unsubstituted alkynyl, (5) substituted or unsubstituted aryl, (6) substituted or unsubstituted heteroaryl, (7) substituted or unsubstituted heterocyclyl, (8) substituted or unsubstituted alkylsulfonyl, and (9) substituted or unsubstituted arylsulfonyl; R.sub.2 is selected from the group consisting of: (1) hydrogen, (2) substituted or unsubstituted alkyl, (3) substituted or unsubstituted alkenyl, and (4) substituted or unsubstituted alkynyl; R.sub.3 is selected from the group consisting of: (1) CO.sub.2R.sub.10, and (2) CONR.sub.11R.sub.12; with the proviso that when R.sub.4 and R.sub.5 are taken together to form a 5- to 12-membered heterocyclic ring, R.sub.3 is CONR.sub.11R.sub.12 or R.sub.2 and R.sub.3 taken together with the carbon atom to which they are attached form a 3- to 7-membered carbocyclic or heterocyclic ring; R.sub.4 is selected from the group consisting of: (1) hydrogen, (2) substituted or unsubstituted alkyl, (3) substituted or unsubstituted alkenyl, (4) substituted or unsubstituted alkynyl, (5) substituted or unsubstituted aryl, (6) substituted or unsubstituted heteroaryl, and (7) substituted or unsubstituted heterocyclyl; R.sub.5 is selected from the group consisting of: (1) hydrogen, (2) substituted or unsubstituted alkyl, (3) substituted or unsubstituted alkoxy, (4) substituted or unsubstituted aryl, (5) substituted or unsubstituted heteroaryl, (6) substituted or unsubstituted heterocyclyl, (7) COR.sub.17, (8) CO.sub.2R.sub.18, (9) CONR.sub.19R.sub.20, and (10) SO.sub.2R.sub.21; or R.sub.4 and R.sub.5 are taken together with the nitrogen atom to which they are attached form a heteroaryl or heterocyclyl ring, wherein the heteroaryl ring contains one or two ring heteroatoms, wherein the heterocyclyl ring contains one or two ring heteroatoms, and wherein the heteroaryl or heterocyclyl ring is optionally substituted with a halogen, alkyl, hydroxy, amino, cyano, alkylamino, dialkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkoxy, aryl, aryloxy, heteroaryl, arylalkyl, heterocycle, aminocarbonyl, carbonylamino, alkylcarbonyl, alkylcarboxy, alkylaminocarbonyl, alkylcarbonylamino, carbocycle, or heteroarylalkyl group; with the proviso that when R.sub.4 and R.sub.5 taken together with the nitrogen atom to which they are attached form a 5-membered heterocyclic ring, the heterocyclic ring is not a 2,4-dioxo-3-oxazolidinyl ring, a 2,5-dioxo-1-imidazolidinyl ring, or a 2,4,5-trioxo-1-imidazolidinyl ring; R.sub.6, R.sub.7, R.sub.8, and R.sub.9 are independently selected from the group consisting of: (1) hydrogen, (2) halogen, (3) hydroxy, (4) nitro, (5) amino, (6) cyano, (7) alkoxy, (8) alkylthio, (9) methylenedioxy, (10) haloalkoxy, (11) CO.sub.2R.sub.10, (12) COR.sub.10, (13) OR.sub.10, (14) CONR.sub.11R.sub.12, (15) substituted or unsubstituted alkyl, (16) substituted or unsubstituted aryl, (17) substituted or unsubstituted heteroaryl, (18) substituted or unsubstituted alkylamino, (19) substituted or unsubstituted dialkylamino, (20) substituted or unsubstituted alkylsulfonyl, (21) substituted or unsubstituted arylsulfonyl, (22) substituted or unsubstituted alkylcarboxy, (23) substituted or unsubstituted carboxamido, (24) substituted or unsubstituted carboxyamino, (25) substituted or unsubstituted aminocarboxy, (26) substituted or unsubstituted aminocarbonyl, and (27) substituted or unsubstituted alkylsulfonamido; R.sub.10, R.sub.11, R.sub.12, R.sub.17, R.sub.18, R.sub.19, R.sub.20, and R.sub.21 are independently selected from the group consisting of: (1) hydrogen, (2) substituted or unsubstituted alkyl, (3) substituted or unsubstituted alkenyl, (4) substituted or unsubstituted alkynyl, (5) substituted or unsubstituted aryl, (6) substituted or unsubstituted heteroaryl, and (7) substituted or unsubstituted heterocyclyl; or R.sub.11 and R.sub.12, or R.sub.19 and R.sub.20 taken together form a 3- to 7-membered carbocyclic or heterocyclic ring; and m=0, 1, or 2. 26. The composition of claim 25 further comprising at least one additional agent for the treatment of cancer. 27. The composition of claim 26, wherein the at least one additional agent for the treatment of cancer is selected from irinotecan, topotecan, gemcitabine, gleevec, herceptin, 5-fluorouracil, leucovorin, carboplatin, cisplatin, taxanes, tezacitabine, cyclophosphamide, vinca alkaloids, imatinib, anthracyclines, rituximab, and trastuzumab. 28. A compound having the formula: ##STR00077## or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is O or S; R.sub.1 is substituted benzyl; R.sub.2 is selected from the group consisting of: (1) hydrogen, (2) substituted or unsubstituted alkyl, (3) substituted or unsubstituted alkenyl, and (4) substituted or unsubstituted alkynyl; R.sub.3 is selected from the group consisting of: (1) CO.sub.2R.sub.10, and (2) CONR.sub.11R.sub.12; with the proviso that when R.sub.4 and R.sub.5 are taken together to form a 5- to 12-membered heterocyclic ring, R.sub.3 is CONR.sub.11R.sub.12 or R.sub.2 and R.sub.3 taken together with the carbon atom to which they are attached form a 3- to 7-membered carbocyclic or heterocyclic ring; R.sub.4 is selected from the group consisting of: (1) hydrogen, (2) substituted or unsubstituted alkyl, (3) substituted or unsubstituted alkenyl, (4) substituted or unsubstituted alkynyl, (5) substituted or unsubstituted aryl, (6) substituted or unsubstituted heteroaryl, and (7) substituted or unsubstituted heterocyclyl; R.sub.5 is selected from the group consisting of: (1) hydrogen, (2) substituted or unsubstituted alkyl, (3) substituted or unsubstituted alkoxy, (4) substituted or unsubstituted aryl, (5) substituted or unsubstituted heteroaryl, (6) substituted or unsubstituted heterocyclyl, (7) COR.sub.17, (8) CO.sub.2R.sub.18, (9) CONR.sub.19R.sub.20, and (10) SO.sub.2R.sub.21; or R.sub.4 and R.sub.5 are taken together with the nitrogen atom to which they are attached form a heteroaryl or heterocyclyl ring, wherein the heteroaryl ring contains one or two ring heteroatoms, wherein the heterocyclyl ring contains one or two ring heteroatoms, and wherein the heteroaryl or heterocyclyl ring is optionally substituted with a halogen, alkyl, hydroxy, amino, cyano, alkylamino, dialkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkoxy, aryl, aryloxy, heteroaryl, arylalkyl, heterocycle, aminocarbonyl, carbonylamino, alkylcarbonyl, alkylcarboxy, alkylaminocarbonyl, alkylcarbonylamino, carbocycle, or heteroarylalkyl group; with the proviso that when R.sub.4 and R.sub.5 taken together with the nitrogen atom to which they are attached form a 5-membered heterocyclic ring, the heterocyclic ring is not a 2,4-dioxo-3-oxazolidinyl ring, a 2,5-dioxo-1-imidazolidinyl ring, or a 2,4,5-trioxo-1-imidazolidinyl ring; R.sub.6, R.sub.7, R.sub.8, and R.sub.9 are independently selected from the group consisting of: (1) hydrogen, (2) halogen, (3) hydroxy, (4) nitro, (5) amino, (6) cyano, (7) alkoxy, (8) alkylthio, (9) methylenedioxy, (10) haloalkoxy, (11) CO.sub.2R.sub.10, (12) COR.sub.10, (13) OR.sub.10, (14) CONR.sub.11R.sub.12, (15) substituted or unsubstituted alkyl, (16) substituted or unsubstituted aryl, (17) substituted or unsubstituted heteroaryl, (18) substituted or unsubstituted alkylamino, (19) substituted or unsubstituted dialkylamino, (20) substituted or unsubstituted alkylsulfonyl, (21) substituted or unsubstituted arylsulfonyl, (22) substituted or unsubstituted alkylcarboxy, (23) substituted or unsubstituted carboxamido, (24) substituted or unsubstituted carboxyamino, (25) substituted or unsubstituted aminocarboxy, (26) substituted or unsubstituted aminocarbonyl, and (27) substituted or unsubstituted alkylsulfonamido; R.sub.10, R.sub.11, R.sub.12, R.sub.17, R.sub.18, R.sub.19, R.sub.20, and R.sub.21 are independently selected from the group consisting of: (1) hydrogen, (2) substituted or unsubstituted alkyl, (3) substituted or unsubstituted alkenyl, (4) substituted or unsubstituted alkynyl, (5) substituted or unsubstituted aryl, (6) substituted or unsubstituted heteroaryl, and (7) substituted or unsubstituted heterocyclyl; or R.sub.11 and R.sub.12, or R.sub.19 and R.sub.20 taken together form a 3- to 7-membered carbocyclic or heterocyclic ring; and m=0, 1, or 2. 29. A compound having the formula: ##STR00078## or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is O or S; R.sub.1 is selected from the group consisting of: (1) hydrogen, (2) substituted or unsubstituted alkyl, (3) substituted or unsubstituted alkenyl, (4) substituted or unsubstituted alkynyl, (5) substituted or unsubstituted aryl, (6) substituted or unsubstituted heteroaryl, (7) substituted or unsubstituted heterocyclyl, (8) substituted or unsubstituted alkylsulfonyl, and (9) substituted or unsubstituted arylsulfonyl; R.sub.2 is hydrogen; R.sub.3 is CO.sub.2R.sub.10; R.sub.4 is selected from the group consisting of: (1) hydrogen, (2) substituted or unsubstituted alkyl, (3) substituted or unsubstituted alkenyl, (4) substituted or unsubstituted alkynyl, (5) substituted or unsubstituted aryl, (6) substituted or unsubstituted heteroaryl, and (7) substituted or unsubstituted heterocyclyl; R.sub.5 is selected from the group consisting of: (1) hydrogen, (2) substituted or unsubstituted alkyl, (3) substituted or unsubstituted alkoxy, (4) substituted or unsubstituted aryl, (5) substituted or unsubstituted heteroaryl, (6) substituted or unsubstituted heterocyclyl, (7) COR.sub.17, (8) CO.sub.2R.sub.18, (9) CONR.sub.19R.sub.20, and (10) SO.sub.2R.sub.21; or R.sub.4 and R.sub.5 are taken together with the nitrogen atom to which they are attached form a heteroaryl or heterocyclyl ring, wherein the heteroaryl ring contains one or two ring heteroatoms, wherein the heterocyclyl ring contains one or two ring heteroatoms, and wherein the heteroaryl or heterocyclyl ring is optionally substituted with a halogen, alkyl, hydroxy, amino, cyano, alkylamino, dialkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkoxy, aryl, aryloxy, heteroaryl, arylalkyl, heterocycle, aminocarbonyl, carbonylamino, alkylcarbonyl, alkylcarboxy, alkylaminocarbonyl, alkylcarbonylamino, carbocycle, or heteroarylalkyl group; with the proviso that when R.sub.4 and R.sub.5 taken together with the nitrogen atom to which they are attached form a 5-membered heterocyclic ring, the heterocyclic ring is not a 2,4-dioxo-3-oxazolidinyl ring, a 2,5-dioxo-1-imidazolidinyl ring, or a 2,4,5-trioxo-1-imidazolidinyl ring; R.sub.6, R.sub.7, R.sub.8, and R.sub.9 are independently selected from the group consisting of: (1) hydrogen, (2) halogen, (3) hydroxy, (4) nitro, (5) amino, (6) cyano, (7) alkoxy, (8) alkylthio, (9) methylenedioxy, (10) haloalkoxy, (11) CO.sub.2R.sub.10, (12) COR.sub.10, (13) OR.sub.10, (14) CONR.sub.11R.sub.12, (15) substituted or unsubstituted alkyl, (16) substituted or unsubstituted aryl, (17) substituted or unsubstituted heteroaryl, (18) substituted or unsubstituted alkylamino, (19) substituted or unsubstituted dialkylamino, (20) substituted or unsubstituted alkylsulfonyl, (21) substituted or unsubstituted arylsulfonyl, (22) substituted or unsubstituted alkylcarboxy, (23) substituted or unsubstituted carboxamido, (24) substituted or unsubstituted carboxyamino, (25) substituted or unsubstituted aminocarboxy, (26) substituted or unsubstituted aminocarbonyl, and (27) substituted or unsubstituted alkylsulfonamido; R.sub.10, R.sub.11, R.sub.12, R.sub.17, R.sub.18, R.sub.19, R.sub.20, and R.sub.21 are independently selected from the group consisting of: (1) hydrogen, (2) substituted or unsubstituted alkyl, (3) substituted or unsubstituted alkenyl, (4) substituted or unsubstituted alkynyl, (5) substituted or unsubstituted aryl, (6) substituted or unsubstituted heteroaryl, and (7) substituted or unsubstituted heterocyclyl; or R.sub.11 and R.sub.12, or R.sub.19 and R.sub.20 taken together form a 3- to 7-membered carbocyclic or heterocyclic ring; and m=0, 1, or 2. 30. A compound having the formula: ##STR00079## or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is O or S; R.sub.1 is selected from the group consisting of: (1) hydrogen, (2) substituted or unsubstituted alkyl, (3) substituted or unsubstituted alkenyi, (4) substituted or unsubstituted alkynyl, (5) substituted or unsubstituted aryl, (6) substituted or unsubstituted heteroaryl, (7) substituted or unsubstituted heterocyclyl, (8) substituted or unsubstituted alkylsulfonyl, and (9) substituted or unsubstituted arylsulfonyl; R.sub.2 is hydrogen; R.sub.3 is CONR.sub.11R.sub.12, wherein R.sub.11 and R.sub.12 are alkyl; R.sub.4 is selected from the group consisting of: (1) hydrogen, (2) substituted or unsubstituted alkyl, (3) substituted or unsubstituted alkenyl, (4) substituted or unsubstituted alkynyl, (5) substituted or unsubstituted aryl, (6) substituted or unsubstituted heteroaryl, and (7) substituted or unsubstituted heterocyclyl; R.sub.5 is selected from the group consisting of: (1) hydrogen, (2) substituted or unsubstituted alkyl, (3) substituted or unsubstituted alkoxy, (4) substituted or unsubstituted aryl, (5) substituted or unsubstituted heteroaryl, (6) substituted or unsubstituted heterocyclyl, (7) COR.sub.17, (8) CO.sub.2R.sub.18, (9) CONR.sub.19R.sub.20, and (10) SO.sub.2R.sub.21; or R.sub.4 and R.sub.5 are taken together with the nitrogen atom to which they are attached form a heteroaryl or heterocyclyl ring, wherein the heteroaryl ring contains one or two ring heteroatoms, wherein the heterocyclyl ring contains one or two ring heteroatoms, and wherein the heteroaryl or heterocyclyl ring is optionally substituted with a halogen, alkyl, hydroxy, amino, cyano, alkylamino, dialkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkoxy, aryl, aryloxy, heteroaryl, arylalkyl, heterocycle, aminocarbonyl, carbonylamino, alkylcarbonyl, alkylcarboxy, alkylaminocarbonyl, alkylcarbonylamino, carbocycle, or heteroarylalkyl group; with the proviso that when R.sub.4 and R.sub.5 taken together with the nitrogen atom to which they are attached form a 5-membered heterocyclic ring, the heterocyclic ring is not a 2,4-dioxo-3-oxazolidinyl ring, a 2,5-dioxo-1-imidazolidinyl ring, or a 2,4,5-trioxo-1-imidazolidinyl ring; R.sub.6, R.sub.7, R.sub.8, and R.sub.9 are independently selected from the group consisting of: (1) hydrogen, (2) halogen, (3) hydroxy, (4) nitro, (5) amino, (6) cyano, (7) alkoxy, (8) alkylthio, (9) methylenedioxy, (10) haloalkoxy, (11) CO.sub.2R.sub.10, (12) COR.sub.10, (13) OR.sub.10, (14) CONR.sub.11R.sub.12, (15) substituted or unsubstituted alkyl, (16) substituted or unsubstituted aryl, (17) substituted or unsubstituted heteroaryl, (18) substituted or unsubstituted alkylamino, (19) substituted or unsubstituted dialkylamino, (20) substituted or unsubstituted alkylsulfonyl, (21) substituted or unsubstituted arylsulfonyl, (22) substituted or unsubstituted alkylcarboxy, (23) substituted or unsubstituted carboxamido, (24) substituted or unsubstituted carboxyamino, (25) substituted or unsubstituted aminocarboxy, (26) substituted or unsubstituted aminocarbonyl, and (27) substituted or unsubstituted alkylsulfonamido; R.sub.10, R.sub.17, R.sub.18, R.sub.19, R.sub.20, and R.sub.21 are independently selected from the group consisting of: (1) hydrogen, (2) substituted or unsubstituted alkyl, (3) substituted or unsubstituted alkenyl, (4) substituted or unsubstituted alkynyl, (5) substituted or unsubstituted aryl, (6) substituted or unsubstituted heteroaryl, and (7) substituted or unsubstituted heterocyclyl; or R.sub.19 and R.sub.20 taken together form a 3- to 7-membered carbocyclic or heterocyclic ring; and m=0, 1, or 2.

Details for Patent 7,939,539

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2023-11-25
Idec Pharmaceuticals Corp.	RITUXAN	rituximab	Injection	103737	02/19/2002		2023-11-25
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2023-11-25
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2023-11-25
Genentech, Inc.	RITUXAN HYCELA	rituximab and hyaluronidase human	Injection	761064	06/22/2017		2023-11-25
Genentech, Inc.	HERCEPTIN HYLECTA	trastuzumab and hyaluronidase-oysk	Injection	761106	02/28/2019		2023-11-25