# US 11,028,041 B2 · Second generation GRP94-selective inhibitors

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- Number: US 11,028,041 B2
- Document ID: US11028041B2
- Status: Granted
- Kind: B2
- Application number: 16/640,897
- Filed: 2018-08-23
- Published: 2020-06-18
- Granted: 2021-06-08
- Earliest claimed: 2017-08-25
- Assignees: University of Kansas
- Applicants: University of Kansas
- Inventors: Brian S. J. Blagg; Vincent Matthew Crowley
- Web page: https://patentgrep.com/patent/US11028041B2

## CPC

- C07C 69/94: of polycyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of six-membered aromatic rings
- A61K 31/216: of acids having aromatic rings, e.g. benactizyne, clofibrate
- A61K 31/44: Non condensed pyridines; Hydrogenated derivatives thereof
- A61P 27/02: Ophthalmic agents
- A61P 35/04: specific for metastasis
- C07C 69/76: Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
- C07C 69/78: Benzoic acid esters
- C07C 219/34: having amino groups and esterified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
- C07C 229/52: having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
- C07D 213/55: Acids; Esters
- C07D 213/643: 2-Phenoxypyridines; Derivatives thereof
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present technology provides compounds selective for the Grp94 isoform, as well as compositions including such compounds, that are useful for treatment of multiple myeloma, melanoma, lung cancer, hepatocellular carcinoma, breast cancer, prostate cancer, and/or glaucoma. Methods using the compounds are also provided.

## Claims

### Claim 1

A compound of Formula I
or a pharmaceutically acceptable salt thereof, wherein
X1 is Cl or F;
X2 is CH2, O, S, or NH;
R1, R2, R4, R5, and R6 are each independently H, alkoxy, hydroxyl, thiol, or halo; and
R3 is H, alkoxy, amino, hydroxyl, thiol, or halo.

### Claim 2 (depends on 1)

The compound of claim 1, wherein when X2 is 0 and R4, R5, and R6 are each independently H, then R1 and R2 are each independently H, alkoxy, or halo and R3 is H, alkoxy, amino, or halo.

### Claim 3 (depends on 1)

The compound of claim 1, wherein at least two of R1, R2, and R3 are each independently H.

### Claim 4 (depends on 1)

The compound of claim 1, wherein at least two of R4, R5, and R6 are each independently H.

### Claim 5 (depends on 1)

The compound of claim 1, wherein when at least one of R1, R2, and R3 is hydroxyl, then at least one of R4, R5, and R6 is not H.

### Claim 6 (depends on 1)

The compound of claim 1, wherein when one of R1, R2, and R3 is hydroxyl and the remaining R1, R2, and R3 each independently H, then at least one of R4, R5, and R6 is not H.

### Claim 7 (depends on 1)

The compound of claim 1, wherein R1, R2, and R3 are each independently H.

### Claim 8 (depends on 1)

The compound of claim 1, wherein the compound is of Formula II:
or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 8)

The compound of claim 8, wherein when X2 is O and R4, R5, and R6 are each independently H, then R1 and R2 are each independently H, alkoxy, or halo and R3 is H, alkoxy, amino, or halo.

### Claim 10 (depends on 8)

The compound of claim 8, wherein when at least one of R1, R2, and R3 is hydroxyl, then at least one of R4, R5, and R6 is not H.

### Claim 11 (depends on 8)

The compound of claim 8, wherein when one of R1, R2, and R3 is hydroxyl and the remaining R1, R2, and R3 each independently H, then at least one of R4, R5, and R6 is not H.

### Claim 12

A compound of Formula III
or a pharmaceutically acceptable salt thereof, wherein
X3 is Cl or F;
X4 is CH2, O, S, or NH; and
R7 is alkoxy, hydroxyl, thiol, or halo.

### Claim 13 (depends on 1)

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

### Claim 14 (depends on 1)

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

### Claim 15 (depends on 1)

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

### Claim 16 (depends on 1)

A method of treating a patient or animal suffering from metastatic cancer, the method comprising administration of an effective amount of a compound of claim 1 to the patient or animal suffering from the metastatic cancer, wherein the metastatic cancer is selected from multiple myeloma, melanoma, lung cancer, hepatocellular carcinoma, breast cancer, or prostate cancer.

### Claim 17 (depends on 1)

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

### Claim 18 (depends on 1)

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

### Claim 19 (depends on 1)

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.

### Claim 20 (depends on 19)

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