US 9,000,182 B2 · 2H-imidazol-4-amine compounds and their use as BACE inhibitors

Abstract

2H-imidazol-4-amine compounds, therapeutically acceptable salts thereof, processes for preparation thereof, therapeutic uses of such compounds for treating Aβ-related pathologies such as Down's syndrome, β-amyloid angiopathy, Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration. methods of therapy, and pharmaceutical compositions containing such compounds.

A compound selected from the group consisting of:

(1r,4r)-4″-Amino-5″-methyl-6′-(2-methylpropoxy)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4-ol;
(1r,1′R,4R)-4″-Amino-5″-methyl-6′-(2-methylpropoxy)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4-ol;
(1r,1′S,4S)-4″-Amino-5″-methyl-6′-(2-methylpropoxy)-3′H-dispiro[cyclohexane-1,2″-indene-1′,2″-imidazol]-4ol;
(1r,4r)-6″-(2,2-Difluoropropoxy)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;
(1r,4r)-4″-Amino-6′-bromo-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4-ol;
(1r,1′R,4R)-4″-Amino-6′-bromo-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4-ol;
(1r,1′S,4S)-4″-Amino-6′-bromo-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]4-ol;
(1r,1′R,4R)-6′-(Cyclobutylethynyl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′indene-1′,2″-imidazol]-4″-amine;
(1r,1′S,4S)-6′-(Cyclobutylethynyl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;
(1r,1′R,4R)-4-Methoxy-5″-methyl-6′-(3-methylbut-1-yn-1-yl)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;
(1r,1′S,4S)-4-Methoxy-5″-methyl-6′-(3-methylbut-1-yn-1-yl)-3′H-dispiro[cyclohexane-1,2′indene-1′,2″-imidazol]-4″-amine;
(1r,1′R,4R)-4-Methoxy-5″-methyl-6′-(3,3,3-trifluoropropoxy)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;
(1r,1′S,4S)-4-Methoxy-5″-methyl-6′-(3,3,3-trifluoropropoxy)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;
(1r,4r)-4-(Difluoromethoxy)-6′3-fluoropropoxy)-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;
(1r,1′R,4R)-4-(Difluoromethoxy)-6′-(3-fluoropropoxy)-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;
(1r,1′S,4S)-4-(Difluoromethoxy)-6′(3-fluoropropoxy)-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;
(1r,4r)-6′-(2-Fluoropropoxy)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;
3-[(1r,1′R,4R)-4″-Amino-4-hydroxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]-5-chlorobenzonitrile;
3-[(1r,1′S,4S)-4″-Amino-4-hydroxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]-5-chlorobenzonitrile;
(1r,4r)-6′-Bromo-5″-methyl-4-(propan-2-yloxy)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;
(1r,4r)-6′-(3-Fluoropropoxy)-5″-methyl-4-(propan-2-yloxy)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;
(1r,4r)-6′-[(2S)-Butan-2-yloxy]-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1 ,2′-indene-1′,2″-imidazol]-4″-amine;
(1r,1′R,4R)-4″-Amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-ol;
and
(1r,1′S,4S)-4″-Amino-5″-methyl-6′-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4-ol,
or a pharmaceutically acceptable salt of any foregoing compound.

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2H-imidazol-4-amine compounds and their use as BACE inhibitors

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2H-imidazol-4-amine compounds and their use as BACE inhibitors

Life of this patent

Abstract

Claims7