US 2016/0096804 A1Published application

Novel histone deacetylase inhibitors

AssigneeKarus Therapeutics Limited

InventorsStephen J. Shuttleworth, Cyrille D. Tomassi, Alexander R. Cecil, Somhairle MacCormick, William J. Nodes, Franck A. Silva

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Abstract

The present invention is a compound of the formula or a pharmaceutically acceptable salt thereof. The compounds are useful as HDAC inhibitors.

Claims23

Dependent claims

A compound of the formula

or a pharmaceutically acceptable salt thereof, wherein:
each R/ is independently selected from H and QR1;
each Q is independently selected from the group consisting of:
a bond, CO, CO2, NH, S, SO, SO2 and O;
each R1 is independently selected from the group consisting of:
H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, C1-C10 cycloalkyl, halogen, C1-C10 alkylaryl, C1-C10 alkyl heteroaryl and C1-C10 heterocycloalkyl;
each L is independently selected from a 5 to 10-membered nitrogen-containing heteroaryl;
W is a zinc-binding group;
each R2 is independently hydrogen or C1 to C6 alkyl;
and
R3 is an aryl or heteroaryl;
each aryl or heteroaryl may be substituted by up to three substituents selected from C1-C6 alkyl, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, amino, C1-C3 mono alkylamino, C1-C3 bis alkylamino, C1-C3 acylamino, C1-C3 aminoalkyl, mono (C1-C3 alkyl) amino C1-C3 alkyl, bis(C1-C3 alkyl) amino C1-C3 alkyl, C1-C3-acylamino, C1-C3 alkyl sulfonylamino, halo, nitro, cyano, trifluoromethyl, carboxy, C1-C3 alkoxycarbonyl, aminocarbonyl, mono C1-C3 alkyl aminocarbonyl, bis C1-C3 alkyl aminocarbonyl, —SO3H, C1-C3 alkylsulfonyl, aminosulfonyl, mono C1-C3 alkyl aminosulfonyl and bis C1-C3-alkyl aminosulfonyl;
and
each alkyl, alkenyl or alkynyl may be substituted with halogen, NH2, NO2 or hydroxyl.

11 more elements

A compound selected from the group consisting of:

4-{[Bis(pyridin-2-yl)amino]methyl}-N-hydroxybenzamide;
4-{[Bis(3-methyl-1,2,4-thiadiazol-5-yl)amino]methyl}-2-fluoro-N-hydroxybenzamide;
2-Fluoro-N-hydroxy-4-{[(3-methyl-1,2,4-oxadiazol-5-yl)(3-methyl-1,2,4-thiadiazol-5-yl)amino]methyl}benzamide;
N-Hydroxy-4-(((3-methyl-1,2,4-oxadiazol-5-yl)(pyridin-2-yl)amino)methyl)benzamide;
N-Hydroxy-4-(((1-methyl-1H-pyrazol-3-yl)(pyridin-2-yl)amino)methyl)benzamide;
N-Hydroxy-4-((pyridin-2-yl(1,3,4-thiadiazol-2-yl)amino)methyl)benzamide;
N-Hydroxy-4-((pyrazin-2-yl(pyridin-2-yl)amino)methyl)benzamide;
N-Hydroxy-4-(((5-methyl-1,3,4-thiadiazol-2-yl)(pyridin-2-yl)amino)methyl)benzamide;
4-((Benzo[d]oxazol-2-yl(pyridin-2-yl)amino)methyl)-N-hydroxybenzamide;
N-Hydroxy-4-(((1-methyl-1H-benzo[d]imidazol-2-yl)(pyridin-2-yl)amino)methyl)benzamide;
N-Hydroxy-4-((pyridin-2-yl(1,2,4-thiadiazol-5-yl)amino)methyl)benzamide;
4-(((5-Fluoropyridin-2-yl)(pyrazin-2-yl)amino)methyl)-N-hydroxybenzamide;
4-(((5-Fluoropyridin-2-yl)(3-methyl-1,2,4-oxadiazol-5-yl)amino)methyl)-N-hydroxybenzamide;
4-(((5-Fluoropyridin-2-yl)(1-methyl-1H-benzo[d]imidazol-2-yl)amino)methyl)-N-hydroxybenzamide;
4-(((5-Fluoropyridin-2-yl)(1-methyl-1H-pyrazol-3-yl)amino)methyl)-N-hydroxybenzamide 4-((Benzo[d]oxazol-2-yl(5-fluoropyridin-2-yl)amino)methyl)-N-hydroxybenzamide;
4-(((4-(4-Fluorophenyl)pyridin-2-yl)(1-methyl-1H-pyrazol-3-yl)amino)methyl)-N-hydroxybenzamide;
4-(((5-Fluoropyridin-2-yl)(3-methyl-1,2,4-thiadiazol-5-yl)amino)methyl)-N-hydroxybenzamide;
4-(((4-(4-Fluorophenyl)pyridin-2-yl)(3-methyl-1,2,4-thiadiazol-5-yl)amino)methyl)-N-hydroxybenzamide;
4-(((5-Fluoropyridin-2-yl)(3-(trifluoromethyl)-1,2,4-thiadiazol-5-yl)amino)methyl)-N-hydroxybenzamide;
4-(((4-(4-Fluorophenyl)pyridin-2-yl)(pyrazin-2-yl)amino)methyl)-N-hydroxybenzamide;
4-((Benzo[d]thiazol-2-yl(pyridin-2-yl)amino)methyl)-N-hydroxybenzamide;
N-Hydroxy-4-((pyridin-2-yl(3-(trifluoromethyl)-1,2,4-thiadiazol-5-yl)amino)methyl)benzamide;
N-Hydroxy-4-(((3-methoxypyridin-2-yl)-(5-methylpyridin-2-yl)amino)methyl)benzamide;
N-Hydroxy-4-(((5-methoxypyridin-2-yl)(5-methylpyridin-2-yl)amino)methyl)benzamide;
N-Hydroxy-4-(((3-methoxypyridin-2-yl)(5-morpholinopyridin-2-yl)amino)methyl)benzamide;
N-Hydroxy-4-(((5-methoxypyridin-2-yl)(5-morpholinopyridin-2-yl)amino)methyl)benzamide;
N-Hydroxy-4-((pyridin-2-yl(thieno[3,2-c]pyridin-4-yl)amino)methyl)benzamide;
N-Hydroxy-4-(((6-methylpyridin-2-yl)(5-morpholinopyridin-2-yl)amino)methyl)benzamide;
N-Hydroxy-4-{[(pyrazin-2-yl)(pyrimidin-4-yl)amino]methyl}benzamide;
N-Hydroxy-4-{[(pyrazin-2-yl)(pyrimidin-4-yl)amino]methyl}benzamide;
N-Hydroxy-6-{[(pyrazin-2-yl)(pyrimidin-4-yl)amino]methyl}pyridine-3-carboxamide;
4-{[Bis(pyrazin-2-yl)amino]methyl}-N-hydroxybenzamide;
4-{[Bis(pyrazin-2-yl)amino]methyl}-3-fluoro-N-hydroxybenzamide;
6-{[Bis(pyrazin-2-yl)amino]methyl}-N-hydroxypyridine-3-carboxamide;
N-Hydroxy-4-{[(3-methoxypyridin-2-yl)(pyrazin-2-yl)amino]methyl}benzamide;
3-Fluoro-N-hydroxy-4-{[(3-methoxypyridin-2-yl)(pyrazin-2-yl)amino]methyl}benzamide;
N-Hydroxy-6-{[(3-methoxypyridin-2-yl)(pyrazin-2-yl)amino]methyl}pyridine-3-carboxamide;
N-Hydroxy-4-{[(pyrazin-2-yl)(pyridazin-3-yl)amino]methyl}benzamide;
3-Fluoro-N-hydroxy-4-{[(pyrazin-2-yl)(pyridazin-3-yl)amino]methyl}benzamide;
N-Hydroxy-4-{[(3-methyl-1,2,4-thiadiazol-5-yl)(pyrazin-2-yl)amino]methyl}benzamide;
N-Hydroxy-4-{[(4-methoxypyridin-2-yl)(pyrazin-2-yl)amino]methyl}benzamide;
N-Hydroxy-4-{[(pyrazin-2-yl)[6-(trifluoromethyl)pyrazin-2-yl]amino]methyl}benzamide;
4-({[5-(6-Aminopyridin-3-yl)pyridin-2-yl](pyrazin-2-yl)amino}methyl)-N-hydroxybenzamide;
4-({[5-(2-Aminopyridin-4-yl)pyridin-2-yl](pyrazin-2-yl)amino}methyl)-N-hydroxybenzamide;
N-hydroxy-4-[({5-[2-(methylamino)pyridin-4-yl]pyridin-2-yl}(pyrazin-2-yl)amino)methyl]benzamide;
N-hydroxy-4-{[(pyrazin-2-yl)[5-(pyridin-4-yl)pyridin-2-yl]amino]methyl}benzamide;
and pharmaceutically acceptable salts thereof.

44 more elements

Dependencies are inferred from the claim text.

Facts

Application: 14/890,331Filed 12 May 2014
Priority: GB 1308409.010 May 2013
Published: 7 Apr 2016
Term ends: Not estimatedThe source records don’t support an estimate.

Classification51 codes

C07D 213/72
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…
A61K 31/433
Having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole: thidiazoles
A61K 31/4365
Ortho- or peri-condensed with heterocyclic ring systems: the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
A61K 31/4439
Containing further heterocyclic ring systems: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole

Family

US 9,862,685 B2Related patent
US 2016/0096804 A1This patent

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

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Abstract

The present invention is a compound of the formula or a pharmaceutically acceptable salt thereof. The compounds are useful as HDAC inhibitors.

Facts

Application

14/890,331Filed 12 May 2014

Priority

GB 1308409.010 May 2013

Published

7 Apr 2016

Term ends

Not estimatedThe source records don’t support an estimate.

Classification51 codes

C07D 213/72
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…
A61K 31/433
Having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole: thidiazoles
A61K 31/4365
Ortho- or peri-condensed with heterocyclic ring systems: the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
A61K 31/4439
Containing further heterocyclic ring systems: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole