Grp94 selective inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-10975030-B2
Application number	US-201716346039-A
Country	US
Kind code	B2
Filing date	Oct 31, 2017
Priority date	Oct 31, 2016
Publication date	Apr 13, 2021
Grant date	Apr 13, 2021

Abstract

The present technology provides compounds according to Formula I or Formula III as well as compositions including such compounds useful for the treatment of metastatic cancer and/or glaucoma.

First claim

What is claimed is:

1. A compound according to Formula I

or a pharmaceutically acceptable salt and/or solvate thereof, wherein
X 1 , X 2 , and X 3 are each independently CH or N;
X 4 is N or C—R 5 ;
X 5 is N or C—R 6 ;
X 6 is N or C—R 7 ;
W 1 is C(R 10 )(R 11 ), O, or S;
R 1 is isopropyl, tert-butyl, cycloalkyl, aryl, heterocyclyl, or X 7 —R 12 ;
R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are each independently H, OH, alkyl, alkoxy, aryloxy, heteroaryloxy, amino, halo, trifluoromethyl, or cyano;
X 7 is O, S, or NH;
R 12 is alkyl, cycloalkyl, aryl, or heterocyclyl;
Z 1 is O, S, or NH; and
n is 0 or 1.

2. The compound of claim 1 , wherein the compound is of Formula Ia

or a pharmaceutically acceptable salt and/or solvate thereof.

3. The compound of claim 1 , wherein
X 4 is C—R 5 ;
X 5 is N; and
X 6 is C—R 7 .

4. The compound of claim 1 , wherein R 1 is isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

where R 13 , R 14 , R 15 , R 16 and R 17 are each independently H, alkyl, alkoxy, amino, halo, trifluoromethyl, or cyano.

5. The compound of claim 1 , wherein R 12 is isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

where
X 8 and X 9 are each independently OH, amino, SH, sulfide, sulfoxide, or sulfone; and
R 18 , R 19 , R 20 , R 21 and R 22 are each independently H, alkyl, alkoxy, amino, halo, trifluoromethyl, or cyano.

6. The compound of claim 1 , wherein
one of R 5 , R 6 , and R 7 is OH, alkyl, alkoxy, aryloxy, heteroaryloxy, amino, halo, trifluoromethyl, or cyano, and the remaining R 5 , R 6 , and R 7 are each H;
R 8 and R 9 are each H.

7. The compound of claim 1 , wherein
one of R 5 , R 6 , and R 7 is OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, amino, halo, trifluoromethyl, or cyano, and the remaining R 5 , R 6 , and R 7 are each H;
R 8 and R 9 are each H.

8. The compound of claim 1 , wherein
one of R 5 , R 6 , and R 7 is OH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, NH 2 , NH-CH 3 , N(CH 3 ) 2 , halo, trifluoromethyl, or cyano, and the remaining R 5 , R 6 , and R 7 are each H;
R 8 and R 9 are each H.

9. The compound of claim 1 , wherein the compound Formula I is of Formula II

or a pharmaceutically acceptable salt and/or solvate thereof.

10. A composition comprising a compound of claim 1 , and a pharmaceutically acceptable carrier.

11. A pharmaceutical composition for treating glaucoma, the composition comprising an effective amount of the compound of claim 1 , and a pharmaceutically acceptable excipient.

12. A method of inhibiting death of a cell exhibiting mutant myocilin, the method comprising contacting the cell with a compound of claim 1 .

13. A method of treating a patient or animal suffering from glaucoma, the method comprising administration of an effective amount of a compound of claim 1 to the patient or animal suffering from the glaucoma.

14. The compound of claim 1 , wherein R 12 is

where X 8 and X 9 are each independently OH, amino, SH, sulfide, sulfoxide, or sulfone.

Assignees

• Univ Kansas
• Univ South Florida

Inventors

• Mishra Sanket Jaiprakash
• Blagg Brian S J
• Dickey Chad Anthony

Classifications

• A61P27/06

  Antiglaucoma agents or miotics · CPC title

• A61K9/0053

  Mouth and digestive tract, i.e. intraoral and peroral administration · CPC title

• A61K31/4025

  not condensed and containing further heterocyclic rings, e.g. cromakalim · CPC title

• A61K9/0048

  Eye, e.g. artificial tears · CPC title

• C07D401/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title