# US 11,111,253 B2 · 6-aryl-7-substituted-3-(1H-pyrazol-5-yl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines as inhibitors of the STAT3 pathway with anti-proliferative activity

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- Number: US 11,111,253 B2
- Document ID: US11111253B2
- Status: Granted
- Kind: B2
- Application number: 16/846,089
- Filed: 2020-04-10
- Published: 2020-10-29
- Granted: 2021-09-07
- Earliest claimed: 2015-01-15
- Assignees: University of Pittsburgh—Of the Commonwealth System of Higher Education
- Applicants: University of Pittsburgh—of the Commonwealth System of Higher Education
- Inventors: Donna M. Huryn; Peter Wipf; Jennifer Rubin Grandis; Matthew G. LaPorte; Paul A. Johnston; Mark E. Schurdak; Raffaele Colombo
- Web page: https://patentgrep.com/patent/US11111253B2

## CPC

- C07D 513/04: Ortho-condensed systems
- A61P 35/00: Antineoplastic agents
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Compounds that selectivity inhibit the STAT3 pathway and not the STAT1 pathway and exhibit anti-proliferative activity are disclosed. Also disclosed are methods of treatment of cancers that are characterized by overexpression of STAT3, which are safer that other therapies.

## Claims

### Claim 1

A compound represented by the following formula:
wherein:
R is selected from the group consisting of a C1-C6 alkyl or aryl, optionally substituted by one or more selected from the group consisting of —OR′, —NR′R″,
and an optionally substituted phenyl, wherein:
(1) R′ and R″ are each independently selected from —H, C1-C6 alkyl and C1-C6 alkyl substituted by one or more fluoro groups, and when R′ and R″ are each alkyl they may form a ring, and
(2) Y is selected from C1-C6 alkyl, and —NR′R″, wherein when the optionally substituted phenyl contains a substituent, the substituent is selected from —OR′, —NR′R″, and
R1 is
wherein:
(1) each Z is independently selected from halogen, C1-C6 alkyl, C1-C6 alkyl substituted by one or more fluoro groups, —OR′, —NR′R″,
(2) a is an integer of 0 to 4,
(3) Y′ is selected from C1-C6 alkyl, C1-C6 alkyl substituted by one or more fluoro groups, —OR′, and —NR′R″,
wherein R and R1 may form a 5 or 6 membered ring that is optionally substituted by one or more selected from the group consisting of —OR′, —NR′R″,
and an optionally substituted phenyl,
X is phenyl optionally substituted by one or more halogen, and
R2 is absent or phenyl optionally substituted by one or more halogen or a pharmaceutically acceptable solvate or salt thereof, and
wherein when R and R1 are both unsubstituted phenyl, then R2 cannot be unsubstituted phenyl.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R is a C1-C6 alkyl or a benzyl.

### Claim 3 (depends on 1)

The compound of claim 1, wherein for R1, a is 1 or 2, and Z is independently selected from fluoro, chloro, methyl, methoxy, and trifluoromethyl.

### Claim 4 (depends on 1)

The compound of claim 1, wherein X is phenyl.

### Claim 5 (depends on 1)

The compound of claim 1, wherein the compound is represented by the formula:

### Claim 6 (depends on 1)

A formulation comprising a compound according to claim 1 and a pharmaceutically acceptable excipient.

### Claim 7 (depends on 6)

A method of treating Squamous Cell Carcinoma in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the pharmaceutical formulation according to claim 6.

### Claim 8 (depends on 7)

The method of claim 7, wherein the Squamous Cell Carcinoma is located in the head and/or neck.

### Claim 9 (depends on 6)

A method of treating a cancer with hyper-activated STAT3 in a patent in need thereof, comprising administering to the patient a therapeutically effective amount of the pharmaceutical formulation according to claim 6.

### Claim 10 (depends on 6)

A method of inhibition of STAT3 comprising contacting STAT3 with the pharmaceutical formulation according to claim 6.

### Claim 11 (depends on 6)

A method of selectively inhibiting STAT3 in the presence of STAT1 comprising contacting STAT3 with the pharmaceutical formulation according to claim 6.

### Claim 12 (depends on 6)

A method of treatment of a STAT3-mediated disease comprising the administration of a therapeutically effective amount of the pharmaceutical formulation according to claim 6 to a patient in need thereof.

### Claim 13 (depends on 12)

The method as recited in claim 12 wherein the disease is cancer.

### Claim 14 (depends on 13)

The method as recited in claim 13 wherein the cancer is Squamous Cell Carcinoma.

### Claim 15 (depends on 7)

The method of claim 7, wherein the pharmaceutical formulation is administered orally.