Claims for Patent: 8,258,316

Summary for Patent: 8,258,316

Title:	Alkanoylamino benzamide aniline HDAC inhibitor compounds
Abstract:	The present invention provides a compound of general Formula (I) having histone deacetylase (HDAC) inhibitory activity, a pharmaceutical composition comprising the compound, and a method useful to treat diseases using the compound. ##STR00001##
Inventor(s):	Graupe; Michael (Pacifica, CA), Venkataramani; Chandrasekar (Redwood City, CA)
Assignee:	Gilead Sciences, Inc. (Foster City, CA)
Application Number:	12/795,554
Patent Claims:	1. A compound of Formula (I): ##STR00251## wherein Cy is heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, and piperazinyl; m is 0, 1 or 2; R.sup.1 is independently selected from the group consisting of hydrogen, cyano, oxo, halo, nitro, hydroxy, alkoxy, amino, alkyl, aryl, cycloalkyl, heterocyclyl and heteroaralkyl; wherein the alkyl, aryl, cycloalkyl, heterocyclyl and heteroaralkyl moities are optionally substituted by alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and haloalkoxy of 1-6 carbon atoms; R.sup.2 and R.sup.3 are independently selected from the group consisting of hydrogen, alkyl, and phenyl; R.sup.4 is selected from the group consisting of hydrogen, alkyl, and cycloalkyl; R.sup.5 is independently selected from the group consisting of hydrogen, halo, and C.sub.1-4alkyl; n is 0, 1, or 2; R.sup.6 is independently selected from the group consisting of hydrogen, halo, haloalkyl, aryl, C.sub.2-C.sub.3alkynylaryl, C.sub.2-C.sub.3alkynyl-C.sub.3-C.sub.5cycloalkyl, and heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more substituents selected from amino, halo, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; o is 0, 1, or 2; R.sup.7 is OH or NHZ, where Z is hydrogen, --CH.sub.2-alkoxy of 2-4 carbon atoms or --CH.sub.2-acetylene of 2-4 carbon atoms; or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1, wherein R.sup.2 and R.sup.3 are independently hydrogen, alkyl of 1-4 carbon atoms, or phenyl. 3. The compound of claim 2, wherein R.sup.7 is --NHZ, wherein Z is hydrogen, --CH.sub.2-alkoxy or --CH.sub.2-acetylene. 4. The compound of claim 3, wherein R.sup.6 is hydrogen, halo, optionally substituted phenyl, optionally substituted heteroaryl, cyclopropylalkynyl, phenylalkynyl, and o is 1 or 2. 5. The compound of claim 4, wherein R.sup.4 is hydrogen or methyl, R.sup.5 is hydrogen or halo, and n is 0 or 1. 6. The compound of claim 5, wherein Cy is pyrrolidinyl. 7. The compound of claim 6, chosen from: N-(2-aminophenyl)-4-(2-(pyrrolidin-1-yl)propanamido)benzamide; N-(4-amino-4'-fluorobiphenyl-3-yl)-4-(2-(pyrrolidin-1-yl)propanamido)benz- amide; and N-(2-amino-5-(thiophen-2-yl)phenyl)-4-(2-(pyrrolidin-1-yl)propa- namido)benzamide. 8. The compound of claim 5, wherein Cy is oxopyrrolidinyl. 9. The compound of claim 8, chosen from: N-(2-aminophenyl)-4-(2-(2-oxopyrrolidin-1-yl)propanamido)benzamide; N-(2-amino-5-(thiophen-2-yl)phenyl)-4-(2-(2-oxopyrrolidin-1-yl)propanamid- o)benzamide; N-(4-amino-4'-fluorobiphenyl-3-yl)-4-(2-(2-oxopyrrolidin-1-yl)propanamido- )benzamide; N-(2-amino-5-(thiophen-2-yl)phenyl)-3-fluoro-4-(2-(2-oxopyrrolidin-1-yl)p- ropanamido)benzamide; N-(2-amino-5-(5-chlorothiophen-2-yl)phenyl)-4-(2-(2-oxopyrrolidin-1-yl)pr- opanamido)benzamide; N-(4-amino-4'-fluorobiphenyl-3-yl)-3-fluoro-4-(2-(2-oxopyrrolidin-1-yl)pr- opanamido)benzamide; N-(4-amino-4',6-difluorobiphenyl-3-yl)-4-(2-(2-oxopyrrolidin-1-yl)propana- mido)benzamide; N-(2-amino-5-fluorophenyl)-4-(2-(2-oxopyrrolidin-1-yl)propanamido)benzami- de; N-(2-amino-4,6-difluorophenyl)-4-(2-(2-oxopyrrolidin-1 -yl)propanamido)benzamide; N-(4-amino-4'-fluorobiphenyl-3-yl)-4-(2-(2-oxopyrrolidin-1-yl)acetamido)b- enzamide; N-(4-amino-4'-fluorobiphenyl-3-yl)-4-(2-methyl-2-(2-oxopyrrolidi- n-1-yl)propanamido)benzamide; N-(2-amino-5-(cyclopropylethynyl)phenyl)-4-(2-(2-oxopyrrolidin-1-yl)propa- namido)benzamide; N-(2-amino-5-(phenylethynyl)phenyl)-4-(2-(2-oxopyrrolidin-1-yl)propanamid- o)benzamide; (S)-N-(2-aminophenyl)-4-(3,3-dimethyl-2-(2-oxopyrrolidin-1-yl)butanamido)- benzamide; (S)-N-(4-amino-4'-fluorobiphenyl-3-yl)-4-(3,3-dimethyl-2-(2-oxo- pyrrolidin-1-yl)butanamido)benzamide; N-(4'-fluoro-4-(prop-2-ynylamino)biphenyl-3-yl)-4-(2-(2-oxopyrrolidin-1-y- l)propanamido)benzamide; N-(4'-fluoro-4-(2-methoxyethylamino)biphenyl-3-yl)-4-(2-(2-oxopyrrolidin-- 1-yl)propanamido)benzamide; N-(4-amino-4'-fluorobiphenyl-3 -yl)-3-(2-(2-oxopyrrolidin-1-yl)propanamido)benzamide; N-(4-amino-4'-fluorobiphenyl-3-yl)-4-(N-methyl-2-(2-oxopyrrolidin-1-yl)pr- opanamido)benzamide; (R)-N-(4-amino-4'-fluorobiphenyl-3-yl)-4-(2-(2-oxopyrrolidin-1-yl)propana- mido)benzamide; (S)-N-(4-amino-4'-fluorobiphenyl-3-yl)-4-(2-(2-oxopyrrolidin-1-yl)propana- mido)benzamide; and N-(3-amino-6-phenylpyridin-2-yl)-4-(2-(2-oxopyrrolidin-1-yl)propanamido)b- enzamide. 10. The compound of claim 5, wherein Cy is morpholinyl. 11. The compound of claim 10, chosen from: N-(2-aminophenyl)-4-(2-morpholino-2-phenylacetamido)benzamide; N-(2-amino-5 -(thiophen-2-yl)phenyl)-4-(2-morpholinopropanamido)benzamide N-(4-amino-4'-fluorobiphenyl-3 -yl)-4-(2-morpholinopropanamido)benzamide; N-(4-amino-4'-fluorobiphenyl-3-yl)-4-(2-methyl-2-morpholinopropanamido)be- nzamide; and N-(4-amino-4'-fluorobiphenyl-3-yl)-4-(2-morpholinoacetamido)benzamide. 12. The compound of claim 5, wherein Cy is piperazinyl. 13. The compound of claim 12, chosen from: N-(2-aminophenyl)-4-(2-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl- )propanamido)benzamide; N-(4-amino-4'-fluorobiphenyl-3-yl)-4-(2-methyl-2-(piperazin-1-yl)propanam- ido)benzamide; N-(4-amino-4'-fluorobiphenyl-3-yl)-4-(2-(4-(5-(trifluoromethyppyridin-2-y- l)piperazin-1-yl)propanamido)benzamide; N-(2-aminophenyl)-4-(2-methyl-2-(4-(5-(trifluoromethyl)pyridin-2-yl)piper- azin-1-yl)propanamido)benzamide; N-(4-amino-4'-fluorobiphenyl-3-yl)-4-(2-(4-cyclopropylpiperazin-1-yl)-2-m- ethylpropanamido)benzamide; and N-(4-amino-4'-fluorobiphenyl-3-yl)-4-(2-(4-ethylpiperazin-1-yl)acetamido)- benzamide. 14. The compound of claim 5, wherein Cy is oxopiperidinyl, namely N-(4-amino-4'-fluorobiphenyl-3-yl)-4-(2-(2-oxopiperidin-1-yl)acetamido)be- nzamide. 15. A pharmaceutical composition comprising a pharmaceutically effective amount of one or more compounds according to claim 1 and a pharmaceutically-acceptable carrier. 16. The pharmaceutical composition according to claim 15, further comprising one or more anti-cancer agents. 17. The pharmaceutical composition according to claim 16, wherein the one or more anti-cancer agents are selected from the group consisting of cyclophosphamide, dacarbazine, cisplatin, methotrexate, mercaptopurine, thioguanine, fluorouracil, cytarabine, vinblastine, paclitaxel, doxorubicin, bleomycin, mitomycin, prednisone, tamoxifen, flutamide, asparaginase, rituximab, trastuzumab, imatinib, retinoic acid, colony-stimulating factor, amifostine, lenalidomide, HDAC inhibitor, CDK inhibitor, camptothecin and topotecan.

Details for Patent 8,258,316

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Recordati Rare Diseases, Inc.	ELSPAR	asparaginase	For Injection	101063	01/10/1978		2029-06-08
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2029-06-08
Idec Pharmaceuticals Corp.	RITUXAN	rituximab	Injection	103737	02/19/2002		2029-06-08
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2029-06-08
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2029-06-08
Genentech, Inc.	RITUXAN HYCELA	rituximab and hyaluronidase human	Injection	761064	06/22/2017		2029-06-08
Genentech, Inc.	HERCEPTIN HYLECTA	trastuzumab and hyaluronidase-oysk	Injection	761106	02/28/2019		2029-06-08