GRP94 selective inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-11939291-B2
Application number	US-202117226359-A
Country	US
Kind code	B2
Filing date	Apr 9, 2021
Priority date	Oct 31, 2016
Publication date	Mar 26, 2024
Grant date	Mar 26, 2024

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 III

or a pharmaceutically acceptable salt and/or solvate thereof, wherein
X 21 is N or C—R 35 ;
X 22 is N or C—R 36 ;
X 23 is N or C—R 37 ;
W 2 is C(R 40 )(R 41 ), O, or S;
R 31 is alkyl, cycloalkyl, aryl, heterocyclyl, or X 24 —R 42 ;
R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , and R 41 are each independently H, OH, alkyl, alkoxy, aryloxy, heteroaryloxy, amino, halo, trifluoromethyl, or cyano;
X 24 is O, S, or NH;
R 42 is alkyl, cycloalkyl, aryl, or heterocyclyl;
Z 2 is O, S, or NH; and
m is 0 or 1.

2. The compound of claim 1 , wherein R 42 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, a substituted or unsubstituted phenyl, or C 2 -C 5 heterocyclyl.

3. The compound of claim 1 , wherein R 42 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, substituted or unsubstituted phenyl, or non-aromatic C 2 -C 5 heterocyclyl.

4. The compound of claim 1 , wherein R 31 is isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

where R 43 , R 44 , R 45 , R 46 and R 47 are each independently H, alkyl, alkoxy, amino, halo, trifluoromethyl, or cyano.

5. The compound of claim 1 , wherein R 42 is isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

where
X 25 and X 26 are each independently OH, amino, SH, sulfide, sulfoxide, or sulfone; and
R 48 , R 49 , R 50 , R 51 and R 52 are each independently H, alkyl, alkoxy, amino, halo, trifluoromethyl, or cyano.

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

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

8. The pharmaceutical composition of claim 7 , wherein the cancer is multiple myeloma, breast cancer, or prostate cancer.

9. The pharmaceutical composition of claim 7 , wherein the pharmaceutical composition is for treating glaucoma.

10. The pharmaceutical composition of claim 9 , wherein the glaucoma is myocilin glaucoma.

11. A method for inhibiting cell motility of a cancer cell, the method comprising contacting the cancer cell with a compound of claim 1 .

12. The method of claim 11 , wherein the cancer cell is a multiple myeloma cancer cell, a breast cancer cell, or prostate cancer cell.

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

14. The method of claim 13 , wherein the method comprises contacting the cell with an effective amount of the compound.

15. The method of claim 13 , wherein the contacting inhibits the death of the cell in comparison to a cell exhibiting mutant myocilin that is not contacted with the compound.

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

17. The method of claim 16 , wherein administration of the effective amount of the compound to the patient or animal treats the patient or animal suffering from the cancer or the glaucoma.

18. The method of claim 16 , wherein the cancer is multiple myeloma, breast cancer, or prostate cancer.

19. The method of claim 16 , wherein the glaucoma is myocilin glaucoma.

20. The method of claim 16 , wherein the administration comprises oral administration, parenteral administration, or nasal administration.

Assignees

• Univ Kansas
• Univ South Florida

Inventors

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

Classifications

• C07D207/325 Primary

  with substituted hydrocarbon radicals directly attached to the ring nitrogen atom · CPC title

• A61P27/06

  Antiglaucoma agents or miotics · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07C13/18

  with a cyclohexane ring · CPC title

• C07D213/62

  Oxygen or sulfur atoms · CPC title