US 10,292,968 B2Granted

Substituted heterocycles as bromodomain inhibitors

AssigneeZenith Epigenetics Ltd.

InventorsSamuel David Brown, Craig Alan Coburn, Olesya Kharenko

Life of this patent

Estimating the term…

Abstract

The present application relates to substituted heterocycles compound of Formula I and pharmaceutical compositions thereof useful for the inhibition of BET protein function by binding to bromodomains (Formula I).

Claims30

Dependent claims

A compound of Formula I:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof,
wherein:
X is selected from CH and N;
Y is selected from —NH, —N—R1b and oxygen;
Z is selected from N, and —CH—;
R1a and R1b are independently selected from (C1-C6)alkyl, (C3-C10)carbocycle, and (C2-C10)heterocycle, each of which may be optionally substituted with 1 to 3 groups selected from R4;
R2 is selected from (C5-C10)aryl and (C5-C10)heteroaryl, each of which may be optionally substituted with 1 to 5 groups selected from R5;
R3 is selected from (C3-C10) carbocycle and (C2-C10)heterocycle, each of which may be optionally substituted with 1 to 5 groups selected from R5;
each R4 is independently selected from deuterium, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, amino, —NHC(O)NH—(C1-C6)alkyl, halogen, amide, —CF3, —CN, —N3, ketone, —S(O)—(C1-C4)alkyl, —SO2—(C1-C6)alkyl, thio-(C1-C6)alkyl, —COOH, and ester, each of which may be optionally substituted with F, Cl, Br, —OH, —NH2, —NHMe, —OMe, —SMe, oxo, and/or thio-oxo;
and
each R5 is independently selected from deuterium, (C1-C5)alkyl, (C1-C6)alkoxy, amino, —NHC(O)NH—(C1-C6)alkyl, halogen, amide, —CF3, —CN, —N3, (C1-C6) ketone, —S(O)—(C1-C4)alkyl, —SO2—(C1-C6)alkyl, thio-(C1-C6)alkyl, —COOH, and ester, each of which may be optionally substituted with F, Cl, Br, —OH, —NH2, —NHMe, —OMe, —SMe, oxo, and/or thio-oxo.

8 more elements

A compound selected from:

3-(5-(3-Acetylphenyl)-2-phenyl-1H-imidazol-4-yl)-4-cyclopropyl-1H-1,2,4-triazol-5(4H)-one;
Methyl 3-(4-(4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-phenyl-1H-imidazol-5-yl)-4-methylbenzoate;
3-(4-(4-Cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-phenyl-1H-imidazol-5-yl)-N-methylbenzamide;
3-(4-(4-Cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-phenyl-1H-imidazol-5-yl)benzamide;
4-Cyclopropyl-3-(5-(3-oxo-2,3-dihydro-1H-inden-5-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;
4-Cyclopropyl-3-(2-phenyl-5-(3-propionylphenyl)-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;
4-Cyclopropyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;
3-(5-(3-Acetyl-4-fluorophenyl)-2-phenyl-1H-imidazol-4-yl)-4-cyclopropyl-1H-1,2,4-triazol-5(4H)-one;
3-(5-(3-Acetyl-5-fluorophenyl)-2-phenyl-1H-imidazol-4-yl)-4-cyclopropyl-1H-1,2,4-triazol-5(4H)-one;
4-cyclopropyl-3-(5-(1-methyl-1H-indazol-5-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;
3-(5-(5-acetyl-2-methylphenyl)-2-phenyl-1H-imidazol-4-yl)-4-cyclopropyl-1H-1,2,4-triazol-5(4H)-one;
3-(5-(5-acetylpyridin-3-yl)-2-phenyl-1H-imidazol-4-yl)-4-cyclopropyl-1H-1,2,4-triazol-5(4H)-one formate;
4-cyclopropyl-3-(5-(1,3-dimethyl-1H-indazol-5-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;
4-(Cyclopropylmethyl)-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;
4-Isopropyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;
4-(tert-Butyl)-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;
4-Cyclopentyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;
4-Cyclobutyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;
4-Cyclohexyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;
4-Isobutyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;
3-(5-(1-Methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-4-neopentyl-1H-1,2,4-triazol-5(4H)-one;
4-Cyclopropyl-1-methyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;
4-Cyclopropyl-1-ethyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;
4-Cyclopropyl-1-(cyclopropylmethyl)-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;
4-Cyclopropyl-1-(2-methoxyethyl)-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;
4-Cyclopropyl-3-(5-(3-methylbenzo[d]isoxazol-5-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;
4-Cyclopropyl-3-(5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;
4-Cyclopropyl-3-(5-(3-methyl-1H-indazol-5-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;
4-Cyclopropyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-(pyridin-4-yl)-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;
4-Cyclopropyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-(pyridin-3-yl)-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;
3-(2-(1H-Indol-6-yl)-5-(1-methyl-1H-indazol-6-yl)-1H-imidazol-4-yl)-4-cyclopropyl-1H-1,2,4-triazol-5(4H)-one;
4-Cyclopropyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-(1H-pyrazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;
4-Cyclopropyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one;
and stereoisomers, tautomers, pharmaceutically acceptable salts, and hydrates thereof.

31 more elements

A compound is selected from:

3-(5-(3-acetylphenyl)-2-phenyl-1H-imidazol-4-yl)-4-cyclopropyl-1H-1,2,4-triazol-5(4H)-one hydrochloride;
methyl 3-(4-(4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-phenyl-1H-imidazol-5-yl)-4-methyl benzoate hydrochloride;
3-(4-(4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-phenyl-1H-imidazol-5-yl)-N-methyl benzamide hydrochloride;
3-(4-(4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-2-phenyl-1H-imidazol-5-yl)benzamide hydrochloride;
4-cyclopropyl-3-(5-(3-oxo-2,3-dihydro-1H-inden-5-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one hydrochloride;
4-cyclopropyl-3-(2-phenyl-5-(3-propionylphenyl)-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one hydrochloride;
4-cyclopropyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one hydrochloride;
3-(5-(3-acetyl-4-fluorophenyl)-2-phenyl-1H-imidazol-4-yl)-4-cyclopropyl-1H-1,2,4-triazol-5(4H)-one hydrochloride;
3-(5-(3-acetyl-5-fluorophenyl)-2-phenyl-1H-imidazol-4-yl)-4-cyclopropyl-1H-1,2,4-triazol-5(4H)-one hydrochloride;
4-cyclopropyl-3-(5-(1-methyl-1H-indazol-5-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one hydrochloride;
3-(5-(5-acetyl-2-methylphenyl)-2-phenyl-1H-imidazol-4-yl)-4-cyclopropyl-1H-1,2,4-triazol-5(4H)-one hydrochloride;
4-cyclopropyl-3-(5-(3-methyl-1H-indazol-5-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one hydrochloride;
4-cyclopropyl-3-(5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one hydrochloride;
4-cyclopropyl-3-(5-(1,3-dimethyl-1H-indazol-5-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one hydrochloride;
4-cyclopropyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-(pyridin-4-yl)-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one dihydrochloride;
4-cyclopropyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-(pyridin-3-yl)-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one dihydrochloride;
4-cyclopropyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one hydrochloride;
4-cyclopropyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-(1H-pyrazol-4-yl)-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one 6hydrochloride;
4-cyclopropyl-1-methyl-3-(5-(1-methyl-1H-indazol-6-yl)-2-phenyl-1H-imidazol-4-yl)-1H-1,2,4-triazol-5(4H)-one hydrochloride;
and stereoisomers, tautomers, and hydrates thereof.

17 more elements

Dependencies are inferred from the claim text.

Facts

Application: 15/534,105Filed 11 Dec 2015 · us provisional application
Priority: 11 Dec 2014
Published: US 2017/0360756 A121 Dec 2017
Granted: 21 May 2019
Term ends: Not estimatedThe source records don’t support an estimate.

Classification28 codes

A61K 31/4184
1,3-Diazoles: condensed with carbocyclic rings, e.g. benzimidazoles
A61K 31/4196
Having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole: 1,2,4-Triazoles
A61K 31/42
Having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole: oxazoles
A61K 31/437
Ortho- or peri-condensed with heterocyclic ring systems: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring…

Family

Application62/090,853Us provisional application · filed 11 Dec 2014
US 2017/0360756 A1Pre-grant publication · published 21 Dec 2017
US 10,292,968 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

Facts

Application

15/534,105Filed 11 Dec 2015 · us provisional application

Priority

11 Dec 2014

Published

US 2017/0360756 A121 Dec 2017

Granted

21 May 2019

Term ends

Not estimatedThe source records don’t support an estimate.

Classification28 codes

A61K 31/4184
1,3-Diazoles: condensed with carbocyclic rings, e.g. benzimidazoles
A61K 31/4196
Having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole: 1,2,4-Triazoles
A61K 31/42
Having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole: oxazoles
A61K 31/437
Ortho- or peri-condensed with heterocyclic ring systems: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring…