Proteostasis regulators
The present invention is directed to compounds having the Formulae (Ia-Ie), (II), (IIIa-IIId), (IVa-IVc), (Va-Vb), (VIa-VIe), (VII), (VIIIa-VIIIc), and (IX), pharmaceutically acceptable salts, prodrugs and solvates thereof, compositions of any of thereof and methods for the treatment of a condition associated with a dysfunction in proteostasis comprising an effective amount of these compounds.
1. A compound having the Formula (VII):
or a pharmaceutically acceptable salt thereof; wherein:
Ring T is a ring selected from the group consisting of:
A 6 is phenyl substituted with halogen;
each R d is independently hydrogen or methyl;
R 16 and R 17 are hydrogen;
Z 6 is selected from the group consisting of optionally substituted C 3 -C 12 cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl and NR c R c ;
each R c is independently selected from the group consisting of optionally substituted C 1 -C 10 alkyl, and optionally substituted C 3 -C 12 cycloalkyl; alternatively, two R c groups are taken together with the nitrogen atom which they are attached to form a optionally substituted 3- to 8-membered heterocycle; and
n is 0, 1 or 2.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z 6 is NR c R c , and the two R c groups are taken together with the nitrogen atom to which they are attached to form a 5- to 6-membered heterocycle.
3. The compound of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
4. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of claim 1 , or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 , wherein Ring T is
or a pharmaceutically acceptable salt thereof.
6. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
7. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein:
A 6 is phenyl substituted with halogen;
each R d is independently hydrogen or methyl;
R 16 and R 17 are each hydrogen;
Z 6 is NR c R c ; and
each R c is independently selected from the group consisting of optionally substituted C 1 -C 10 alkyl, and optionally substituted C 3 -C 12 cycloalkyl; alternatively, two R c groups are taken together with the nitrogen atom to which they are attached to form an optionally substituted 3- to 8-membered heterocycle.
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
Ring T is
A 6 is phenyl substituted with halogen;
each R d is independently hydrogen or methyl;
R 16 and R 17 are each hydrogen;
Z 6 is NR c R c , and the two R c groups are taken together with the nitrogen atom to which they are attached to form a 5- to 6-membered heterocycle.
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring T is
10. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein:
A 6 is phenyl substituted with halogen;
each R d is independently hydrogen or methyl;
R 16 and R 17 are each hydrogen;
Z 6 is NR c R c ; and
each R c is independently selected from the group consisting of optionally substituted C 1 -C 10 alkyl and optionally substituted C 3 -C 12 cycloalkyl; alternatively, two R c groups are taken together with the nitrogen atom to which they are attached to form an optionally substituted 3- to 8-membered heterocycle.