Selective glycosidase inhibitors and uses thereof
AssigneesAlectos Therapeutics Inc., Merck Sharp & Dohme Corp.
InventorsRamesh Kaul, Ernest J. McEachern, David J. Vocadlo, Yuanxi Zhou, Kun Liu, Harold G. Selnick, Zhongyong Wei, Changwei Mu, Yaode Wang, Xiaona Wang
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Abstract
The invention provides compounds of formula (I) with substituents as specified in claim 1 for selectively inhibiting glycosidases, prodrugs of the compounds, and pharmaceuticals compositions including the compounds or prodrugs of the compounds. The invention also provides methods of treating diseases and disorders related to over-expression of O-GlcNAcase or accumulation of O-GlcNac.
Claims16
A compound of Formula (I) or a pharmaceutically acceptable salt thereof:
- wherein
- each R1 is independently H or C1-6 acyl;
- R2 is selected from the group consisting of:
- OCH3, OC(O)NR52, NHR7, O(SO2)N(CH3)2, azetidin-1-yl, 3-hydroxyazetidin-1-yl, and pyrrolidin-2-one-1-yl;
- R3 is H or CH3;
- R4 is CH3, CH2CH3, or (CH2)2CH3;
- each R5 is independently H or an optionally substituted C1-6 alkyl;
- and
- R7 is selected from the group consisting of:
- C1-6 acyl, C1-6 alkyl, C2-6 alkenyl, C3-6 cycloalkyl, tetrahydro-2H-pyran-4-yl, benzyl, and 1H-pyrazol-3-yl, said C1-6 alkyl optionally substituted with 1 to 2 substituents selected from OH, OCH3, CN, CO2H, and CO2CH3.
A method of selectively inhibiting an O-GIcNAcase, or of elevating the level of O-GlcNAc, or of treating a condition that is modulated by an O-GIcNAcase, 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
- each R1 is independently H or C1-6 acyl;
- R2 is selected from the group consisting of:
- OCH3, OCHF2, OC(O)NR52, OCH2R6, N3, NHR7, O(SO2)N(CH3)2, azetidin-1-yl, 3-hydroxyazetidin-1-yl, and pyrrolidin-2-one-1-yl;
- R3 is H or CH3;
- R4 is CH3, CH2CH3, or (CH2)2CH3;
- each R5 is independently H or an optionally substituted C1-6 alkyl;
- R6 is optionally substituted aryl;
- and
- R7 is selected from the group consisting of:
- C1-6 acyl, C1-6 alkyl, C2-6 alkenyl, C3-6 cycloalkyl, tetrahydro-2H-pyran-4-yl, benzyl, and 1H-pyrazol-3-yl, said C1-6 alkyl optionally substituted with 1 to 2 substituents selected from OH, OCH3, CN, CO2H, and CO2CH3.
Dependencies are inferred from the claim text.