US 10,239,882 B2 · Substituted 5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine compounds as PDE2 inhibitors

Abstract

The invention provides a chemical entity of Formula (I): (I), wherein R1, R2, R3, and R4, have any of the values described herein, and compositions comprising such chemical entities; methods of making them; and their use in a wide range of methods, including metabolic and reaction kinetic studies; detection and imaging techniques; radioactive treatments; modulating and treating disorders mediated by PDE2 activity; treating neurological disorders, CNS disorders, dementia, neurodegenerative diseases, and trauma-dependent losses of function; treating stroke, including cognitive and motor deficits during stroke rehabilitation; facilitating neuroprotection and neurorecovery; enhancing the efficiency of cognitive and motor training; and treating peripheral disorders, including hematological, cardiovascular, gastroenterological, and dermatological disorders.

Claims20

Dependent claims

A compound of Formula (I):

or pharmaceutically acceptable salts thereof,
wherein,
R1 is —C3-6cycloalkyl unsubstituted or substituted with one or more members selected from halo and —C1-4alkyl;
or R1 is carbon-linked heterocycloalkyl selected from oxolan-2-yl, oxolan-3-yl, oxan-3-yl, oxan-4-yl, 3,6-dihydro-2H-pyran-4-yl, and piperidin-4-yl, each optionally substituted with halo, —C1-4alkyl, or —C(═O)CH3;
R2 is —C1-6alkyl, —C1-6haloalkyl, or —C3-6cycloalkyl;
each R3 is independently —H, or —C1-4alkyl;
and
R4 is selected from the group consisting of:
(a) phenyl unsubstituted or substituted with one or more Ra, wherein each Ra is independently selected from the group consisting of:
—C1-6alkyl, —C1-6haloalkyl, —OC1-6alkyl, —CN, and -halo, or optionally two Ra come together to form a cyclopentyl, furan, dioxane, or 2,2-difluorodioxolane;
and
(b) heteroaryl unsubstituted or substituted with one or more members, each independently selected from the group consisting of:
halo, —C1-6alkyl, —C1-6haloalkyl, -cycloalkyl, phenyl, 2-methylphenyl and 3-methoxyphenyl.

10 more elements

A compound selected from the group consisting of:

N-[(4-Methoxyphenyl)methyl]-5-methyl-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
7-Cyclopropyl-N-(2,3-dihydro-1-benzofuran-5-ylmethyl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
7-Cyclopropyl-N-(2,3-dihydro-1-benzofuran-6-ylmethyl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
7-Cyclopropyl-N-[(4-methoxyphenyl)methyl]-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
7-Cyclopentyl-N-(2,3-dihydro-1H-inden-5-ylmethyl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-(2,3-Dihydro-1H-inden-5-ylmethyl)-5-methyl-7-(propan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-[(3-Chlorophenyl)methyl]-5-methyl-7-(propan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-Benzyl-5-methyl-7-(propan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
7-tert-Butyl-N-[(3-chlorophenyl)methyl]-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-[(4-Methoxyphenyl)methyl]-5-methyl-7-(propan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
7-(Butan-2-yl)-N-[(4-methoxyphenyl)methyl]-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-[(4-Methoxyphenyl)methyl]-5-methyl-7-(oxolan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-[(5-Chloro-2-fluorophenyl)methyl]-5-methyl-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-[(3,5-Difluorophenyl)methyl]-5-methyl-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-[(2-Fluoro-4-methoxyphenyl)methyl]-5-methyl-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-(2,3-Dihydro-1,4-benzodioxin-6-ylmethyl)-5-methyl-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
5-Methyl-7-(oxan-4-yl)-N-[(1-phenyl-1H-pyrazol-4-yl)methyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
1-[4-(2-{[(4-Methoxyphenyl)methyl]amino}-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperidin-1-yl]ethan-1-one;
1-{4-[2-({[3-(Difluoromethyl)-4-methoxyphenyl]methyl}amino)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl]piperidin-1-yl}ethan-1-one;
1-{4-[2-({[3-(Difluoromethyl)phenyl]methyl}amino)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl]piperidin-1-yl}ethan-1-one;
N-[(3-Chloro-4-methoxyphenyl)methyl]-5-methyl-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
7-(4,4-Difluorocyclohexyl)-N-[(4-methoxyphenyl)methyl]-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-{[3-(Difluoromethyl)phenyl]methyl}-5-methyl-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-[(3-Methoxyphenyl)methyl]-5-methyl-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-{[3-(Difluoromethyl)-4-methoxyphenyl]methyl}-5-methyl-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-[(2-Fluorophenyl)methyl]-5-methyl-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-[(2-Fluoro-5-methylphenyl)methyl]-5-methyl-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
5-Methyl-N-[(3-methylphenyl)methyl]-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
5-(Difluoromethyl)-N-[(4-methoxyphenyl)methyl]-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
5-(Fluoromethyl)-N-[(4-methoxyphenyl)methyl]-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-{[1-(3-Methoxyphenyl)-1H-pyrazol-4-yl]methyl}-5-methyl-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-[(2-Fluoro-5-methoxyphenyl)methyl]-5-methyl-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-Benzyl-5-methyl-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-[(4-Methoxyphenyl)methyl]-5-methyl-7-(4-methyloxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
5-Methyl-N-[(2-methylpyridin-4-yl)methyl]-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
5-Methyl-N-{[1-(2-methylphenyl)-1H-pyrazol-4-yl]methyl}-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
5-Methyl-7-(oxan-4-yl)-N-[(3-phenyl-1,2-oxazol-5-yl)methyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-[(4-Methoxyphenyl)methyl]-5-methyl-7-(oxan-3-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-[(3-Bromophenyl)methyl]-5-methyl-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-[(3-Chlorophenyl)methyl]-5-methyl-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
5-Methyl-7-(oxan-4-yl)-N-{[3-(trifluoromethyl)phenyl]methyl}-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-(2,3-Dihydro-1-benzofuran-5-ylmethyl)-5-methyl-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
5-Methyl-7-(4-methyloxan-4-yl)-N-[(2-methylpyridin-4-yl)methyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-[(4-Methoxyphenyl)methyl]-5-methyl-7-(oxolan-3-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-[(2,2-Difluoro-2H-1,3-benzodioxol-5-yl)methyl]-5-methyl-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
5-Methyl-N-[(3-methyl-1-phenyl-1H-pyrazol-4-yl)methyl]-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
5-Methyl-N-[(2-methylphenyl)methyl]-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-[(2-Chlorophenyl)methyl]-5-methyl-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-[(2,5-Difluorophenyl)methyl]-5-methyl-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-[(2,6-Difluoro-4-methoxyphenyl)methyl]-5-methyl-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-[(2,6-Difluorophenyl)methyl]-5-methyl-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-{[2-(Difluoromethyl)pyridin-4-yl]methyl}-5-methyl-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-[(2,6-Dimethylpyridin-4-yl)methyl]-5-methyl-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
5-Methyl-N-[(5-methylpyridin-3-yl)methyl]-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
7-(4-Fluorooxan-4-yl)-N-[(4-methoxyphenyl)methyl]-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-[(3,4-Difluorophenyl)methyl]-5-methyl-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-[(4-Fluorophenyl)methyl]-5-methyl-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-[(3-Fluorophenyl)methyl]-5-methyl-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
5-Methyl-7-(oxan-4-yl)-N-{[2-(trifluoromethyl)pyridin-4-yl]methyl}-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
5-Methyl-7-(oxan-4-yl)-N-(quinolin-4-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
5-Methyl-N-[(3-methyl-1-phenyl-1H-pyrazol-4-yl)methyl]-7-(4-methyloxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
5-Methyl-7-(4-methyloxan-4-yl)-N-[(1-phenyl-1H-pyrazol-4-yl)methyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
7-Cyclopropyl-5-methyl-N-[(3-methyl-1-phenyl-1H-pyrazol-4-yl)methyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-[(1R)-1-(4-Methoxyphenyl)ethyl]-5-methyl-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-{[1-(2,2-Difluoroethyl)-3-methyl-1H-pyrazol-4-yl]methyl}-5-methyl-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
5-Methyl-N-{[3-methyl-1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-[(1-Cyclopentyl-3-methyl-1H-pyrazol-4-yl)methyl]-5-methyl-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-[(2,4-Difluorophenyl)methyl]-5-methyl-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-[(1 S)-1-(4-Methoxyphenyl)ethyl]-5-methyl-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-[(3,5-Difluoropyridin-4-yl)methyl]-5-methyl-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
7-Cyclobutyl-5-methyl-N-[(3-methyl-1-phenyl-1H-pyrazol-4-yl)methyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
5-Methyl-N-[(3-methyl-1-phenyl-1H-pyrazol-4-yl)methyl]-7-(oxolan-3-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
4-Fluoro-3-({[5-methyl-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]amino}methyl)benzonitrile
5-Methyl-N-[(3-methyl-1-phenyl-1H-pyrazol-4-yl)methyl]-7-(propan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-[(4-Methoxyphenyl)methyl]-5-methyl-7-(1-methylcyclopropyl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
5-Methyl-N-[(3-methyl-1-phenyl-1H-pyrazol-4-yl)methyl]-7-(1-methylcyclopropyl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-[(4-Methoxyphenyl)methyl]-7-(2-methoxypropan-2-yl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-[(3-Chloro-2,4-difluorophenyl)methyl]-5-methyl-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
5-Methyl-N-[(4-methyl-2-phenyl-1,3-oxazol-5-yl)methyl]-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-[(5-Chloro-2,4-difluorophenyl)methyl]-5-methyl-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-[(3-Bromo-5-fluorophenyl)methyl]-5-methyl-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
5-Methyl-N-[(1-methyl-3-phenyl-1H-pyrazol-5-yl)methyl]-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-[(3-Bromo-2-fluorophenyl)methyl]-5-methyl-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
N-[(3-Chloro-5-fluorophenyl)methyl]-5-methyl-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
5-Methyl-N-{[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]methyl}-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine;
3-({[5-Methyl-7-(oxan-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]amino}methyl)benzonitrile;
and pharmaceutically acceptable salts thereof.

84 more elements

Dependencies are inferred from the claim text.

Substituted 5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine compounds as PDE2 inhibitors

Life of this patent

Substituted 5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine compounds as PDE2 inhibitors

Life of this patent

Abstract

Claims20