Selective glycosidase inhibitors and uses thereof

A method of selectively inhibiting an O-GlcNAcase or of elevating the level of O-GlcNAc or of treating a condition that is modulated by an O-GlcNAcase in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof:

• wherein
• R1 and R3 are OR5 and R2 and R4 are H, or R2 and R4 are OR5 and R1 and R3 are H, or R2 and R3 are OR5 and R1 and R4 are H;
• each R5 is independently H or C1-6 acyl;
• and
• each R6 is independently selected from the group consisting of:
• H, C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, and C1-6 alkoxy, wherein the C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, or C1-6 alkoxy are optionally substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl, or the two R6 groups are connected together with the nitrogen atom to which they are attached to form a ring, said ring optionally independently substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl.

A method of treating a condition selected from the group consisting of a neurodegenerative disease, a tauopathy, cancer and stress, in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof:

• wherein
• R1 and R3 are OR5 and R2 and R4 are H, or R2 and R4 are OR5 and R1 and R3 are H, or R2 and R3 are OR5 and R1 and R4 are H;
• each R5 is independently H or C1-6 acyl;
• and
• each R6 is independently selected from the group consisting of:
• H, C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, and C1-6 alkoxy, wherein the C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, or C1-6 alkoxy are optionally substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl, or
• the two R6 groups are connected together with the nitrogen atom to which they are attached to form a ring, said ring optionally independently substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl.

A method for screening for a selective inhibitor of an O-GlcNAcase, the method comprising:

• a) contacting a first sample with a test compound;
• b) contacting a second sample with a compound of Formula (I)
• wherein
• R1 and R3 are OR5 and R2 and R4 are H, or R2 and R4 are OR5 and R1 and R3 are H, or R2 and R3 are OR5 and R1 and R4 are H;
• each R5 is independently H or C1-6 acyl;
• and
• each R6 is independently selected from the group consisting of:
• H, C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, and C1-6 alkoxy, wherein the C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, or C1-6 alkoxy are optionally substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl, or
• the two R6 groups are connected together with the nitrogen atom to which they are attached to form a ring, said ring optionally independently substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl;
• c) determining the level of inhibition of the O-GlcNAcase in the first and second samples, wherein the test compound is a selective inhibitor of a O-GlcNAcase if the test compound exhibits the same or greater inhibition of the O-GlcNAcase when compared to the compound of Formula (I).