O-GlcNAc transferase inhibitors and uses thereof
AssigneesPresident and Fellows of Harvard College, The United States of America, as represented by the Secretary, Department of Health and Human Services
InventorsSuzanne Walker Kahne, Sara Evelyn Schwanger Martin, Craig Joseph Thomas, Damien Yves Duveau
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Abstract
Provided herein are O-GlcNAc transferase (OGT) inhibitor compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and compositions thereof. Also provided are methods and kits involving the inventive compounds or compositions for treating and/or preventing diseases (e.g., diabetes and complications thereof, neurodegenerative diseases, proliferative diseases such as cancers, autoimmune diseases, and inflammatory diseases) in a subject. Provided are methods of inhibiting OGT in a subject or biological sample.
Claims12
A compound of Formula (I-A):
- or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein
- X is —SO2—, —SO—, or —C(═O)—;
- Ring Y is 5-membered heterocyclyl or 5-membered heteroaryl with 1-2 heteroatoms selected from the group consisting of N and S;
- R1 is chloro;
- R2 is unsubstituted methyl;
- R3 is halogen, —CN, —SCN, —NO2, —N3, optionally substituted alkyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted sulfonyl, —ORa, —N(Rb)2, or —SRa;
- each instance of Ra is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom;
- each instance of Rb is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;
- or optionally two Rb are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl;
- R4 is hydrogen, optionally substituted alkyl, or a nitrogen protecting group;
- R5 is hydrogen, optionally substituted alkyl, or a nitrogen protecting group;
- R6 is hydrogen, optionally substituted alkyl, or a nitrogen protecting group;
- and
- n is 0, 1, 2, 3, 4, or 5.
Dependencies are inferred from the claim text.