Claims for Patent: 7,608,723

Summary for Patent: 7,608,723

Title:	Indole and benzimidazole derivatives
Abstract:	The present invention relates to new indole and benzimidazole compounds and pharmaceutically acceptable salts, esters or prodrugs thereof, compositions of the new compounds together with pharmaceutically acceptable carriers, and uses of the new compounds. The compounds of the invention have the following general formula: ##STR00001##
Inventor(s):	Boyce; Rustum S. (Singapore, CN), Xia; Yi (Palo Alto, CA), Guo; Hongyan (Foster City, CA), Mendenhull; Kris G. (Concord, CA), Walter; Annette O. (Mill Valley, CA), Wang; Weibo (Moraga, CA)
Assignee:	Novartis Vaccines and Diagnostics, Inc. (Emeryville, CA)
Application Number:	11/251,440
Patent Claims:	1. A compound of formula IC: ##STR00095## wherein W is .dbd.CH-- or .dbd.N--; p is equal to 0, 1, 2 or 3; R.sup.9 is alkyl or substituted alkyl; R.sup.11 is --X.sup.1-A.sup.2, wherein X.sup.1 is --C(O)-- and A.sup.2 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; R.sup.12 is selected from the group consisting of -alkylene-amino, -alkylene-substituted amino, -alkylene-aryl, -alkylene-substituted aryl, -alkylene-nitrogen containing heterocyclic, -alkylene-heteroaryl, and -alkylene-substituted heteroaryl wherein the alkylene is optionally substituted; or R.sup.9 and R.sup.12 together with the carbon atom attached to R.sup.9 and the nitrogen atom attached to R.sup.12 form a group selected from the group consisting of heterocyclic, substituted heterocyclic, heteroaryl, and substituted heteroaryl; R.sup.13 is -L.sup.1-A.sup.3, wherein L.sup.1 is --S(O).sub.r-- where r is 1 or 2 or C.sub.1 to C.sub.2 straight chain alkylene, and A.sup.3 is selected from the group consisting of aryl optionally substituted with 1-2 groups independently selected from the group consisting of hydroxy, alkyl, halo, and acylamino, heteroaryl, and substituted heteroaryl; each R.sup.14 is independently selected from the group consisting of halo, C.sub.2 to C.sub.3 alkynyl, C.sub.2 to C.sub.3 alkenyl, C.sub.1 to C.sub.5 alkyl optionally substituted with halo, C.sub.1 to C.sub.3 alkoxy, and phenyl; or a pharmaceutically acceptable salt or ester thereof. 2. The compound of claim 1, wherein R.sup.9 is selected from the group consisting of ethyl, isopropyl, and t-butyl. 3. The compound of claim 1, wherein A.sup.2 is aryl or heteroaryl optionally substituted with a substituent selected from the group consisting of halo, alkyl, acylamino, nitro, and hydroxy. 4. The compound of claim 1, wherein R.sup.11 is selected from the group consisting of (2-chloro-6-methylpyridin-4-yl)carbonyl; (5-methylimidazol-4-yl)carbonyl; (dimethylamino)methyl carbonyl; (naphth-2-yl)carbonyl; (pyridin-3-yl)carbonyl; (pyridin-4-yl)carbonyl; 1,5-dimethylpyrazol-3-ylcarbonyl; 1-methyl-5-trifluoromethylpyrazol-4-ylcarbonyl; 1-methyl-5-chloropyrazol-4-ylcarbonyl; 2-(2-aminoethylamido)-4-methylbenzoyl; 2,4-difluorobenzoyl; 2,4-dimethylthiazol-5-ylcarbonyl; 2,6-difluorobenzoyl; 2-aminoethylcarbonyl; 2-aminothiazol-4-ylcarbonyl; 2-chlorobenzoyl; 2-chloropyridin-5-ylcarbonyl; 2-fluorobenzoyl; 2methoxybenzoyl; 2-methylpyridin-5-ylcarbonyl; 3 ,4-dichlorobenzoyl; 3 ,4-dimethylbenzoyl; 3-chlorobenzoyl; 3-fluoro-4-methylbenzoyl; 3-hydroxypyridin-4-ylcarbonyl; 4-aminopyridin-3-ylcarbonyl; 4-bromobenzoyl; 4-chlorobenzoyl; 4-chloropyridin-3-ylcarbonyl; 4-dimethylaminobenzoyl; 4-hydroxybenzoyl; 4-hydroxypyridin-3-ylcarbonyl; 4-methoxybenzoyl; 4-methyl-2-(aminoethylcarbonylamino)benzoyl; 4-methylbenzoyl; 4-methylisoxazol-3-ylcarbonyl; 4-methylpyridin-3-ylcarbonyl; 4-morpholino-N-ylpyridin-3-ylcarbonyl; 4-nitrobenzoyl; 4-t-butylbenzoyl; 4-trifluoromethylbenzoyl; 4-trifluoromethylpyridin-3-ylcarbonyl; 5-chloropyridin-3-ylcarbonyl; 5-methylpyrazol-3-ylcarbonyl; 6-chloropyridin-3-ylcarbonyl; benzoyl; cyclohexylcarbonyl; furan-3-ylcarbonyl; isoxazol-3-ylcarbonyl; piperidin-4-ylcarbonyl; pyrazin-2-ylcarbonyl; pyridazin-3-ylcarbonyl; pyridazin-4-ylcarbonyl; tetrahydrofuran-2-ylcarbonyl; tetrahydrofuran-3-ylcarbonyl; and thiazol-4-ylcarbonyl. 5. The compound of claim 1, wherein R.sup.11 is selected from the group consisting of: ##STR00096## ##STR00097## ##STR00098## 6. The compound of claim 4, wherein R.sup.11 is selected from the group consisting of 2-aminoethylcarbonyl; 4-methyl-2-(aminoethylcarbonylamino)benzoyl; (naphth-2-yl)carbonyl; (pyridin-3-yl)carbonyl; (pyridin-4-yl)carbonyl; 2-(2-aminoethylamido)-4-methylbenzoyl; 2,4-difluorobenzoyl; 2,6-difluorobenzoyl; 2-fluorobenzoyl; 3,4-dimethylbenzoyl; 3-fluoro-4-methylbenzoyl; 4-bromobenzoyl; 4-chlorobenzoyl; 4-hydroxybenzoyl; 4-methylbenzoyl; 4-nitrobenzoyl; and benzoyl. 7. The compound of claim 1, wherein R.sup.9 and R.sup.12, together with the carbon atom attached to R.sup.9 and the nitrogen atom attached to R.sup.12 form a heterocyclic or substituted heterocyclic group. 8. The compound of claim 7, wherein the substituted heterocyclic group is 3-hydroxy-pyrrolidinyl. 9. The compound of claim 1, wherein R.sup.12 is selected from the group consisting of (aminomethylcarbonyl)aminoethyl; 2,2-dimethyl-3-(4-methylpiperazin-1-yl)propyl; 2,2-dimethyl-3-dimethylaminopropyl; 2-aminoethyl; 2-hydroxyethyl-3-aminopropyl; 2-hydroxypyridin-4-ylmethyl; 2-hydroxypyridin-5-ylmethyl; 3-(1-cyanourea)propyl; 3-(benzylamino)propyl; 3-(cyclobutylamino)propyl; 3-(cyclohexylmethylamino)propyl; 3-(diethylamino)propyl; 3-(isopropylamino)propyl; 3-[(3-trifluoromethylpyridin-6-yl)amino]propyl; 3-[(5-pyridin-3-yloxyindazol-3-yl)methylamino]propyl; 3-[(6-fluoroindazol-3-yl)methylamino]propyl; 3-[(aminomethyl-carbonyl)amino]propyl; 3-[5-cyanopyridin-2-yl]propyl; 3-[[5-(pyridin-3-yloxy)indazol-3-yl]methylamino]propyl; 3-amino-3-(aminopropyl-methyl)propyl; 3-aminopropyl; 3-methylsulfonylaminopropyl; 3-ureapropyl; 5-methoxyindazol-3-ylmethyl; piperidin-3-ylmethyl; and pyrrolidin-2-ylmethyl. 10. The compound of claim 1, wherein R.sup.12 is selected from the group consisting of: ##STR00099## ##STR00100## 11. The compound of claim 1, wherein R.sup.12 is selected from the group consisting of 3-(1-cyanourea)propyl; 3-(benzylamino)propyl; 3-(cyclobutylamino)propyl; 3-(cyclohexylmethylamino)propyl; 3-(diethylamino)propyl; 3-(isopropylamino)propyl; 3-aminopropyl; 3-ureapropyl; 4-methylbenzyl; and imidazol-4-ylmethyl. 12. The compound of claim 1, wherein L.sup.1 is --SO.sub.2-- or --CH.sub.2-- and A.sup.3 is optionally substituted aryl. 13. The compound of claim 1, wherein R.sup.13 is selected from the group consisting of 2,4-difluorobenzyl; 2-methylbenzyl; 3-(methylamido)benzyl; 3,5-difluorobenzyl; 3-chlorobenzyl; 3-fluorobenzyl; 3-hydroxybenzyl; 3-methylbenzyl; 4-chlorobenzyl; 4-methylbenzyl; benzyl; and thiazol-4-ylmethyl. 14. The compound of claim 1, wherein R.sup.13 groups are selected from the group consisting of: 3-(methylamido)benzyl; 3,5-difluorobenzyl; 3-chlorobenzyl; 3-fluorobenzyl; 3-hydroxybenzyl; 4-chlorobenzyl; and benzyl. 15. The compound of claim 1, wherein p is 1. 16. The compound of claim 15, wherein R.sup.14 is selected from the group consisting of propargyl; bromo; --CF.sub.3; chloro; ethyl; ethynyl; fluoro; methoxy; methyl; phenyl; and vinyl. 17. The compound of claim 1, wherein R.sup.14 is selected from the group consisting of bromo; chloro; ethyl; methoxy; methyl; propargyl; vinyl; fluoro; and phenyl. 18. The compound of claim 1, wherein p is 0. 19. A compound selected from the group consisting of: N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-1H-benzimidazol-2-yl)-2-methylpropy- l]-4-chlorobenzamide; N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-1H-benzimidazol-2-yl)-2-methylpropy- l]-4-methylbenzamide; N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-5-methyl-1H-benzimidazol-2-yl)-2-me- thylpropyl]-4-methylbenzamide; N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-5-chloro-1H-benzimidazol-2-yl)-2-me- thylpropyl]-4-methylbenzamide; N-(3-aminopropyl)-N-{(1R)-1-[1-(4-chlorobenzyl)-6-fluoro-1H-benzimidazol-- 2-yl]-2-methylpropyl}-4-methylbenzamide; N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-5-chloro-1H-benzimidazol-2-yl)propy- l]-4-methylbenzamide; N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-1H-benzimidazol-2-yl)-2-methylpropy- l]-4-bromobenzamide; N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-5-bromo-1H-benzimidazol-2-yl)-2-met- hylpropyl]-4-methylbenzamide; N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-5-bromo-1H-benzimidazol-2-yl)propyl- ]benzamide; N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-5-bromo-1H-benzimidazol-2-yl)propyl- ]-4-methylbenzamide; N-(3-aminopropyl)-N-{(1R)-1-[1-(3-hydroxybenzyl)-5-methyl-1H-benzimidazol- -2-yl]-2-methylpropyl}-4-methylbenzamide; N-(3-aminopropyl)-N-{(1R)-1-[1-(3-fluorobenzyl)-5-methyl-1H-benzimidazol-- 2-yl]-2-methylpropyl}-4-methylbenzamide; N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-5-ethyl-1H-benzimidazol-2-yl)-2-met- hylpropyl]-4-methylbenzamide; N-(3-aminopropyl)-N-{(1R)-1-[5-ethyl-1-(3-hydroxybenzyl)-1H-benzimidazol-- 2-yl]-2-methylpropyl}-4-methylbenzamide; N-(3-aminopropyl)-N-{(1R)-1-[5-ethyl-1-(3-fluorobenzyl)-1H-benzimidazol-2- -yl]-2-methylpropyl}-4-methylbenzamide; N-1-[(1R)-1-(1-benzyl-5-bromo-1H-benzimidazol-2-yl)-2-methylpropyl]-N-1-(- 4-methylbenzyl)-beta-alaninamide; N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-5-vinyl-1H-benzimidazol-2-yl)-2-met- hylpropyl]-4-methylbenzamide; N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-5-methoxy-1H-benzimidazol-2-yl)-2-m- ethylpropyl]-4-methylbenzamide; N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-5-phenyl-1H-benzimidazol-2-yl)-2-me- thylpropyl]-4-methylbenzamide; 2-(beta-alanylamino)-N-[(1R)-1-(1-benzyl-5-bromo-1H-benzimidazol-2-yl)-2-- methylpropyl]-4-methylbenzamide; (3R,5R)-5-[1-(3-hydroxybenzyl)-5-methyl-1H-benzimidazol-2-yl]-1-(4-methyl- benzoyl)pyrrolidin-3-ol; N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-5-ethynyl-1H-benzimidazol-2-yl)-2-m- ethylpropyl]-4-methylbenzamide; 2-(2-aminoethyl)-3-[(1R)-1-(1-benzyl-5-bromo-1H-benzimidazol-2-yl)-2-meth- ylpropyl]-7-methylquinazolin-4(3H)-one; N-(3-aminopropyl)-3-fluoro-N-{(1R)-1-[1-(3-fluorobenzyl)-5-methyl-1H-benz- imidazol-2-yl]-2-methylpropyl}-4-methylbenzamide; N-(3-aminopropyl)-N-{(1R)-1-[1-(3-fluorobenzyl)-5-methyl-1H-benzimidazol-- 2-yl]-2-methylpropyl}benzamide; N-(3-aminopropyl)-2,4-difluoro-N-{(1R)-1-[1-(3-fluorobenzyl)-5-methyl-1H-- benzimidazol-2-yl]-2-methylpropyl}benzamide; N-(3-aminopropyl)-N-{(1R)-1-[1-(3-fluorobenzyl)-5-methyl-1H-benzimidazol-- 2-yl]-2-methylpropyl}-3,4-dimethylbenzamide; N-((1R)-1-{1-[3-(acetylamino)benzyl]-5-bromo-1H-benzimidazol-2-yl}-2-meth- ylpropyl)-N-(3-aminopropyl)-4-methylbenzamide; N-(3-aminopropyl)-2,6-difluoro-N-{(1R)-1-[1-(3-fluorobenzyl)-5-methyl-1H-- benzimidazol-2-yl]-2-methylpropyl}benzamide; N-(3-aminopropyl)-2-fluoro-N-{(1R)-1-[1-(3-fluorobenzyl)-5-methyl-1H-benz- imidazol-2-yl]-2-methylpropyl}benzamide; N-(3-aminopropyl)-N-{(1R)-1-[5-bromo-1-(3-chlorobenzyl)-1H-benzimidazol-2- -yl]-2-methylpropyl}benzamide; N-(3-aminopropyl)-N-{(1R)-1-[1-(3-fluorobenzyl)-5-methyl-1H-benzimidazol-- 2-yl]-2-methylpropyl}-4-nitrobenzamide; N-(3-aminopropyl)-N-{(1R)-1-[1-(3-fluorobenzyl)-5-methyl-1H-benzimidazol-- 2-yl]-2-methylpropyl}nicotinamide; N-(3-aminopropyl)-N-{(1R)-1-[1-(3-fluorobenzyl)-5-methyl-1H-benzimidazol-- 2-yl]-2-methylpropyl}isonicotinamide; N-(3-aminopropyl)-N-{(1R)-1-[1-(3-fluorobenzyl)-5-methyl-1H-benzimidazol-- 2-yl]-2-methylpropyl}-2-naphthamide; N-(3-aminopropyl)-N-{(1R)-1-[1-(3-fluorobenzyl)-5-methyl-1H-benzimidazol-- 2-yl]-2,2-dimethylpropyl}benzamide; N-(3-aminopropyl)-N-{(1R)-1-[1-(3-fluorobenzyl)-5-methyl-1H-benzimidazol-- 2-yl]-2-methylpropyl}-4-hydroxybenzamide; N-[3-(benzylamino)propyl]-N-[(1R)-1-(1-benzyl-5-chloro-1H-benzimidazol-2-- yl)-2-methylpropyl]-4-methylbenzamide; N-[(1R)-1-(1-benzyl-5-chloro-1H-benzimidazol-2-yl)-2-methylpropyl]-N-{3-[- (cyclohexylmethyl)amino]propyl}-4-methylbenzamide; N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-1H-benzimidazol-2-yl)-2,2-dimethylp- ropyl]benzamide; N-[(1R)-1-(1-benzyl-5-chloro-1H-benzimidazol-2-yl)-2-methylpropyl]-N-[3-(- isopropylamino)propyl]-4-methylbenzamide; N-[(1R)-1-(1-benzyl-5-chloro-1H-benzimidazol-2-yl)-2-methylpropyl]-N-[3-(- diethylamino)propyl]-4-methylbenzamide; N-[(1R)-1-(1-benzyl-5-chloro-1H-benzimidazol-2-yl)-2-methylpropyl]-N-[3-(- cyclobutylamino)propyl]-4-methylbenzamide; N-(3-aminopropyl)-N-{(1R)-1-[5-bromo-1-(3,5-difluorobenzyl)-1H-benzimidaz- ol-2-yl]-2-methylpropyl}benzamide; N-(3-aminopropyl)-N-[1-(1-benzyl-5-chloro-1H-indol-2-yl)-2-methylpropyl]b- enzamide; N-(3-aminopropyl)-N-[1-(1-benzyl-5-chloro-1H-indol-2-yl)-2-methy- lpropyl]-4-methylbenzamide; N-(3-aminopropyl)-N-{1-[5-chloro-1-(phenylsulfonyl)-1H-indol-2-yl]-2-meth- ylpropyl}-4-methylbenzamide; N-{3-[(aminocarbonyl)(cyano)amino]propyl}-N-[(1R)-1-(1-benzyl-5-chloro- 1H-benzimidazol-2-yl)-2-methylpropyl]-4-methylbenzamide; N-{3-[(aminocarbonyl)amino]propyl}-N-[(1R)-1-(1-benzyl-5-chloro-1H-benzim- idazol-2-yl)-2-methylpropyl]-4-methylbenzamide; and N-{(1R)-1-[1-(3-fluorobenzyl)-5-methyl-1H-benzimidazol-2-yl]-2-methylprop- yl}-N-(1H-imidazol-4-ylmethyl)benzamide; or a pharmaceutically acceptable salt or ester thereof. 20. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier. 21. The composition of claim 20 further comprising at least one additional agent for the treatment of cancer. 22. The composition of claim 21, wherein the additional agent for the treatment of cancer is selected from the group consisting of irinotecan, topotecan, gemcitabine, imatinib, trastuzumab, 5-fluorouracil, leucovorin, carboplatin, cisplatin, docetaxel, paclitaxel, tezacitabine, cyclophosphamide, vinca alkaloids, anthracyclines, rituximab, and trastuzumab.

Details for Patent 7,608,723

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2024-10-19
Idec Pharmaceuticals Corp.	RITUXAN	rituximab	Injection	103737	02/19/2002		2024-10-19
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2024-10-19
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2024-10-19
Genentech, Inc.	RITUXAN HYCELA	rituximab and hyaluronidase human	Injection	761064	06/22/2017		2024-10-19
Genentech, Inc.	HERCEPTIN HYLECTA	trastuzumab and hyaluronidase-oysk	Injection	761106	02/28/2019		2024-10-19