IP Library › Granted Patent US 9,598,367
Granted Patent B2
US 9,598,367 · App. 14/997,213 · Granted Mar 21, 2017

Heterocyclic compounds as bromodomain inhibitors

Inventors: Shuang Liu (Schenectady, NY); Bryan Cordell Duffy (Glenmont, NY); John Frederick Quinn (Albany, NY); May Xiaowu Jiang (Guilderland, NY); Ruifang Wang (Schenectady, NY); Gregory Scott Martin (Colonie, NY); He Zhao (Madison, CT); Bruce Francis Molino (Slingerlands, NY); Peter Ronald Young (San Francisco, CA)
Assignee: Zenith Epigenetics Ltd.
C07D213/64A61K31/4439A61K31/496A61K31/50A61K31/501A61K45/06C07D213/74C07D237/04C07D237/14C07D237/22C07D237/32C07D401/12C07D413/04C07D413/14C07D417/04
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Quick Facts
Patent No.
US 9,598,367
App. No.
14/997,213
Granted
Mar 21, 2017
Kind
B2
Abstract

The present disclosure relates to compounds, which are useful for inhibition of BET protein function by binding to bromodomains, and their use in therapy.

Claims (101)

1. A compound selected from:

3-amino-5-(3, 5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)pyridin-2(1H)-one;

3-chloro-5-(3, 5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)pyridin-2(1H)-one;

5-(3, 5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-3-(phenylamino)pyridin-2(1H)-one;

3-(azetidin-1-yl)-1-benzyl-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;

1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-((1-methyl-1H-pyrazol-3-yl)amino)pyridin-2(1H)-one;

3-(1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)benzamide;

1-benzyl-5-(3, 5-dimethylisoxazol-4-yl)-3-(ethylamino)pyridin-2(1H)-one;

1-benzyl-5-(3-(methoxymethyl)-5-methylisoxazol-4-yl)pyridin-2(1H)-one;

1-(4-chlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)-3-(phenylamino)pyridin-2(1H)-one;

3-amino-1-benzyl-5-(3-(hydroxymethyl)-5-methylisoxazol-4-yl)pyridin-2(1H)-one;

1-benzyl-5-(3, 5-dimethylisoxazol-4-yl)-3-morpholinopyridin-2(1H)-one;

1-benzyl-3-(benzyloxy)-5-(3, 5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;

1-benzyl-5-(3, 5-dimethylisoxazol-4-yl)-3-(isopropylamino)pyridin-2(1H)-one;

1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(pyridin-2-ylamino)pyridin-2(1H)-one;

1-benzyl-5-(3, 5-dimethylisoxazol-4-yl)-3-(pyridin-3-ylamino)pyridin-2(1H)-one;

1-benzyl-5-(3, 5-dimethylisoxazol-4-yl)-3-(pyridin-4-ylamino)pyridin-2(1H)-one;

1-benzyl-5-(3,5-dimethylisothiazol-4-yl)pyridin-2(1H)-one;

1-benzyl-5-(3, 5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydropyridine-3-carbonitrile;

methyl 4-(1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-methylisoxazole-3-carboxylate;

N-(1-benzyl-5-(3, 5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)methanesulfonamide;

4-(1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-methylisoxazole-3-carboxamide;

3-amino-1-(4-chloro-3-fluorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;

1-benzyl-5-(3, 5-dimethylisoxazol-4-yl)-3-(1H-imidazol-1-yl)pyridin-2(1H)-one;

3-amino-1-(4-chlorobenzyl)-5-(3-(hydroxymethyl)-5-methylisoxazol-4-yl)pyridin-2(1H)-one;

3-amino-1-(4-chloro-2-fluorobenzyl)-5-(3, 5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;

3-amino-1-(2-chloro-4-fluorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;

1-benzyl-3-(cyclopentylamino)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;

1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-hydroxypyridin-2(1H)-one;

1-benzyl-5-(3, 5-dimethylisoxazol-4-yl)-3-methoxypyridin-2(1H)-one;

3-amino-1-(3,4-difluorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;

3-amino-1-(3-chloro-4-fluorobenzyl)-5-(3, 5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;

3-amino-1-(3,4-dichlorobenzyl)-5-(3, 5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;

1-benzyl-5-(5-(hydroxymethyl)-3-methylisoxazol-4-yl)pyridin-2(1H)-one;

3-amino-5-(3, 5-dimethylisoxazol-4-yl)-1-(thiazol-2-ylmethyl)pyridin-2(1H)-one;

4-((3-amino-5-(3, 5-dimethylisoxazol-4-yl)-2-oxopyridin-1 (2H)-yl)methyl)benzonitrile;

1-benzyl-5-(3, 5-dimethylisoxazol-4-yl)-3-((3, 5-dimethylisoxazol-4-yl)amino)pyridin-2(1H)-one;

5-(3,5-dimethylisoxazol-4-yl)-1-(4-vinylbenzyl)pyridin-2(1H)-one;

3-amino-5-(3, 5-dimethylisoxazol-4-yl)-1-(thiophen-3-ylmethyl)pyridin-2(1H)-one;

3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(4-methoxybenzyl)pyridin-2(1H)-one;

1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(pyridazin-3-ylamino)pyridin-2(1H)-one;

3-amino-1-((5-chlorothiophen-2-yl)methyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;

1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-((5-fluoropyridin-3-yl)amino)pyridin-2(1H)-one;

3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-methylpyridin-2(1H)-one;

4-(1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-methylisoxazole-3-carboxylic acid;

3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(4-(trifluoromethoxy)benzyl)pyridin-2(1H)-one;

3-amino-1-(2-chlorobenzyl)-5-(3, 5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;

3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(4-(trifluoromethyl)benzyl)pyridin-2(1H)-one;

1-benzyl-5-(3, 5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid;

1-benzyl-5-(3, 5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide;

1-benzyl-5-(3, 5-dimethylisoxazol-4-yl)-3-((5-methoxypyridin-3-yl)amino)pyridin-2(1H)-one;

5-((1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)picolinonitrile;

1-benzyl-5-(3, 5-dimethylisoxazol-4-yl)-3-((6-methoxypyridin-3-yl)amino)pyridin-2(1H)-one;

1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(pyrazin-2-ylamino)pyridin-2(1H)-one;

1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(pyrimidin-5-ylamino)pyridin-2(1H)-one;

3-amino-1-(4-(azetidin-1-yl)benzyl)-5-(3, 5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;

3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(4-morpholinobenzyl)pyridin-2(1H)-one;

1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(pyrrolidin-3-ylamino)pyridin-2(1H)-one;

3-amino-5-(3, 5-dimethylisoxazol-4-yl)-1-((3-methylisoxazol-5-yl)methyl)pyridin-2(1H)-one;

3-amino-1-(4-bromobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;

3-amino-5-(3, 5-dimethylisoxazol-4-yl)-1-(4-isopropylbenzyl)pyridin-2(1H)-one;

1-(4-chlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)-3-((2,2,2-trifluoroethyl)amino)pyridin-2(1H)-one;

3-amino-5-(3, 5-dimethylisoxazol-4-yl)-1-((6-methylpyridin-2-yl)methyl)pyridin-2(1H)-one;

1-benzyl-5-(3, 5-dimethylisoxazol-4-yl)-3-((6-methylpyridin-3-yl)amino)pyridin-2(1H)-one;

1-benzyl-5-(3, 5-dimethylisoxazol-4-yl)-3-((5-methylpyridin-3-yl)amino)pyridin-2(1H)-one;

1-((1H-indol-4-yl)methyl)-3-amino-5-(3, 5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;

4-(1-benzyl-6-oxo-1,6-dihydropyridin-3-yl)-N-methoxy-N,5-dimethylisoxazole-3-carboxamide;

3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-((2,5-dimethylthiophen-3-yl)methyl)pyridin-2(1H)-one;

3-amino-1-((5-chloropyridin-3-yl)methyl)-5-(3, 5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;

3-amino-1-((3-chloropyridin-4-yl)methyl)-5-(3, 5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;

3-amino-1-((3-chloropyridin-2-yl)methyl)-5-(3, 5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;

3-amino-1-((5-chloropyridin-2-yl)methyl)-5-(3, 5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;

3-amino-1-(benzo[d][1,3]dioxol-5-ylmethyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;

3-amino-1-(benzo[d][1,3]dioxol-4-ylmethyl)-5-(3, 5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;

3-amino-5-(3, 5-dimethylisoxazol-4-yl)-1-((6-methylpyridin-3-yl)methyl)pyridin-2(1H)-one;

methyl 4-(1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)-3-methylisoxazole-5-carboxylate;

4-(1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)-3-methylisoxazole-5-carboxylic acid;

4-((3-amino-5-(3,5-dimethylisoxazol-1-yl)-2-oxopyridin-1(2H)-yl)methyl)-3-fluorobenzonitrile;

4-((3-amino-5-(3,5-dimethylisoxazol-4-yl)-2-oxopyridin-1(2H)-yl)methyl)-2-fluorobenzonitrile;

3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(1-phenylethyl)pyridin-2(1H)-one;

5-((3-amino-5-(3,5-dimethylisoxazol-4-yl)-2-oxopyridin-1(2H)-yl)methyl)thiophene-2-carbonitrile;

4-(1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)-N,3-dimethylisoxazole-5-carboxamide;

3-(aminomethyl)-1-benzyl-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;

3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(4-iodobenzyl)pyridin-2(1H)-one;

1-benzyl-5-(5-oxopyrrolidin-3-yl)pyridin-2(1H)-one;

4-(1-(3-amino-5-(3,5-dimethylisoxazol-4-yl)-2-oxopyridin-1(2H)-yl)ethyl)benzonitrile;

1-((1H-indol-3-yl)methyl)-3-amino-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;

3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-((3-methyl-1H-indol-4-yl)methyl)pyridin-2(1H)-one;

5-((3-amino-5-(3,5-dimethylisoxazol-4-yl)-2-oxopyridin-1 (2H)-yl)methyl)-2-bromobenzonitrile;

4-((3-amino-5-(3, 5-dimethylisoxazol-4-yl)-2-oxopyridin-1 (2H)-yl)methyl)-2-bromobenzonitrile;

3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(quinolin-5-ylmethyl)pyridin-2(1H)-one;

and

stereoisomers, tautomers, pharmaceutical acceptable salts, and hydrates thereof.

2. A pharmaceutical composition comprising a compound according to claim 1 , or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof.

3. A compound selected from:

2-benzyl-6-(((3, 5-dimethylisoxazol-4-yl)methyl)amino)pyridazin-3(2H)-one;

4-amino-2-(4-chlorobenzyl)-6-(3, 5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one;

2-benzyl-6-(3, 5-dimethylisoxazol-4-yl)-4-(pyridin-3-ylamino)pyridazin-3(2H)-one;

4-amino-2-benzyl-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one; and

stereoisomers, tautomers, pharmaceutical acceptable salts, and hydrates thereof.

4. A pharmaceutical composition comprising a compound according to claim 3 , or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof.

Assignments (5)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 23, 2016
From: ZENITH CAPITAL CORP.
To: ZENITH EPIGENETICS LTD.
Reel/Frame 041182/0891 →
CHANGE OF NAME Recorded Dec 21, 2016
From: ZENITH EPIGENETICS CORP.
To: ZENITH CAPITAL CORP.
Reel/Frame 041120/0548 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 24, 2016
From: LIU, SHUANG; DUFFY, BRYAN CORDELL; JIANG, MAY XIAOWU; WANG, RUIFANG; QUINN, JOHN FREDERICK; MARTIN, GREGORY SCOTT; ZHAO, HE; MOLINO, BRUCE FRANCIS; YOUNG, PETER RONALD
To: RESVERLOGIX CORP.
Reel/Frame 040105/0799 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 24, 2016
From: RESVERLOGIX CORP.
To: RVX THERAPEUTICS INC.
Reel/Frame 040105/0813 →
GENERAL CONVEYANCE AND ASSUMPTION AGREEMENT Recorded Oct 24, 2016
From: RVX THERAPEUTICS INC.
To: ZENITH EPIGENETICS CORP.
Reel/Frame 040264/0102 →
Continuity (3)
Continuation 14134793 · Dec 19, 2013
Provisional Application 61745274 · Dec 21, 2012
Related Publication 20160130228A1 · May 12, 2016