US 12,486,289 B2 · Tricyclic compounds as glycogen synthase kinase 3 (GSK3) inhibitors and uses thereof

Abstract

The present disclosure provides compounds of Formula (I), and salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof. The provided compounds may be useful for inhibiting kinases, e.g., glycogen synthase kinase 3 (GSK3). The provided compounds may be able to selectively inhibit GSK3a, as compared to GSK3P and/or other kinases. The present disclosure further provides pharmaceutical compositions, kits, and methods of use, each of which involve the compounds. The compounds, pharmaceutical compositions, and kits may be useful for treating diseases associated with aberrant activity of GSK3a (e.g., Fragile X syndrome, attention deficit hyperactivity disorder (ADHD), childhood seizure, intellectual disability, diabetes, acute myeloid leukemia (AML), autism, and psychiatric disorder).

A method of therapeutically treating a disease 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, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled compound thereof, wherein:
the disease is diffuse Lewy body disease, Huntington's disease, spinal muscular atrophy, Wernicke-Korsakoff's related dementia, multiple sclerosis, neuroblastoma, neurofibroma, post-traumatic stress disorder, depression, or stroke;
X is —O— or —S—;
R1 is substituted or unsubstituted C1-12 alkyl, substituted or unsubstituted C2-12 alkenyl, substituted or unsubstituted C2-12 alkynyl, substituted or unsubstituted, 3- to 13-membered, monocyclic or bicyclic carbocyclyl, substituted or unsubstituted, 3- to 13-membered, monocyclic or bicyclic heterocyclyl, substituted or unsubstituted, 6- to 11-membered, monocyclic or bicyclic aryl, or substituted or unsubstituted, 5- to 11-membered, monocyclic or bicyclic heteroaryl;
R2 is substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkonyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl, or substituted or unsubstituted phenyl;
or R1 and R2 are joined to form substituted or unsubstituted, 3- to 13-membered, monocyclic or bicyclic carbocyclyl, or substituted or unsubstituted, 3- to 13-membered, monocyclic or bicyclic heterocyclyl;
each one of R4a and R4b is independently hydrogen, halogen, —CN, —ORA, —SRA, —N(RA)2, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, or substituted or unsubstituted C2-6 alkynyl;
or R4a and R4b are joined to form substituted or unsubstituted C1-6 alkenyl, substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl, or substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl;
each one of R5a and R5b is independently hydrogen, halogen, —CN, —ORA, —SRA, —N(RA)2, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, or substituted or unsubstituted C2-6 alkynyl;
or R5a and R5b are joined to form substituted or unsubstituted C1-6 alkenyl, substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl, or substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl;
each one of R6a and R6b is independently hydrogen, halogen, —CN, —ORA, —SRA, —N(RA)2, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, or substituted or unsubstituted C2-6 alkynyl;
or R6a and R6b are joined to form substituted or unsubstituted C1-6 alkenyl, substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl, or substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl;
R8 is hydrogen, halogen, —CN, —ORA, —SRA, —N(RA)2, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, or substituted or unsubstituted, 3- to 5-membered, monocyclic carbocyclyl;
each RA is independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl, substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom;
or two RA attached to the same nitrogen atom are joined to form substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl, or substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl;
each instance of the heterocyclyl comprises in the heterocyclic ring system one, two, three, or four heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur, as valency permits;
each instance of the heteroaryl comprises in the heteroaryl ring system one, two, three, or four heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur, as valency permits;
and
the effective amount is effective for treating the disease.

16 more elements

Tricyclic compounds as glycogen synthase kinase 3 (GSK3) inhibitors and uses thereof

Life of this patent

Tricyclic compounds as glycogen synthase kinase 3 (GSK3) inhibitors and uses thereof

Life of this patent

Abstract

Claims31