# US 11,896,591 B2 · Compositions and methods for preparing and using mitochondrial uncouplers

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- Number: US 11,896,591 B2
- Document ID: US11896591B2
- Status: Granted
- Kind: B2
- Application number: 16/615,567
- Filed: 2018-05-22
- Published: 2020-10-15
- Granted: 2024-02-13
- Earliest claimed: 2017-05-22
- Assignees: University of Virginia Patent Foundation
- Applicants: University of Virginia Patent Foundation; Virginia Tech Intellectual Properties, Inc.; Newsouth Innovations Pty Limited
- Inventors: Kyle Hoehn; Webster L. Santos; Elizabeth S. Childress; Yumin Dai; Jacob Murray; Jose Santiago-Rivera
- Web page: https://patentgrep.com/patent/US11896591B2

## CPC

- A61K 31/4985: Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
- A61K 31/4965: Non-condensed pyrazines
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/08: for glucose homeostasis (pancreatic hormones A61P5/48)
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- C07D 241/20: Nitrogen atoms (nitro radicals C07D241/16)
- C07D 487/04: Ortho-condensed systems
- C07D 498/04: Ortho-condensed systems
- 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

This disclosure provides compounds of Formula I, II, and III and pharmaceutically acceptable salts thereof for use as mitochondrial uncouplers, where the variables, e.g. R1-R9, X1, X2, and Y1 are defined in the specification. The disclosure also provides pharmaceutical compositions comprising a compound or pharmaceutically acceptable salt of Formula I, II, or III, alone or in combination with another active compound. Compounds and compositions of Formula I, II, and III are useful for treating or preventing certain conditions such as obesity, type II diabetes, fatty liver disease, insulin resistance, Parkinson's disease, ischemia reperfusion injury, heart failure, non-alcoholic fatty liver disease (NALFD), and non-alcoholic steatohepatitis (NASH). Compounds of Formula I, II, and III are also useful for regulating glucose homeostatis and insulin action.

## Claims

### Claim 1

A compound or pharmaceutically acceptable salt thereof, wherein the compound is
N5-(2-fluorophenyl)-N6-(pyridin-2-yl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4b);
N5-(2-fluorophenyl)-N6-(3-fluorophenyl)-[1,2,]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4c);
N5-(2,3-difluorophenyl)-N6-(2-fluorophenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4e);
N5-(2,4-difluorophenyl)-N6-(2-fluorophenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4f);
N5-(2-fluorophenyl)-N6-(o-tolyl)[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4g);
N5-(2-fluorophenyl)-N6-(m-tolyl)[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4h);
N5-(2-fluorophenyl)-N6-(3-methoxyphenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4k);
N5-(2-fluorophenyl)-N6-(4-methoxyphenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4l);
N5-(2-ethoxyphenyl)-N6-(2-fluorophenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4m);
N5-(3-ethoxyphenyl)-N6-(2-fluorophenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4n);
N5-(4-ethoxyphenyl)-N6-(2-fluorophenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4o);
3-((6-(2-fluorophenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-yl)amino)phenol (4p);
N5-(2-fluorophenyl)-N6-(2-(trifluoromethoxy)phenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4q);
N5-(2-fluorophenyl)-N6-(3-(trifluoromethoxy)phenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4r);
N5-(2-fluorophenyl)-N6-(4-(trifluoromethoxy)phenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4s);
2,2,2-Trifluoro-N-(4-((6-(2-fluorophenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-yl)amino)phenyl)acetamide (4t);
N5-(2-fluorophenyl)-N6-(2-(trifluoromethyl)phenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4u);
N5-(2-fluorophenyl)-N6-(3-(trifluoromethyl)phenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4v);
N5-(2-fluorophenyl)-N6-(4-(trifluoromethyl)phenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4w);
Methyl 4-((6-((2-fluorophenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-yl)amino)benzoate (4y);
4-Fluoro-3-((6-((2-fluorophenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-yl)amino)phenol (4z);
N5-(3,5-bis(trifluoromethyl)phenyl)-N6-(2-fluorophenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4aa);
N5-(2-fluoro-3-(trifluoromethyl)phenyl)-N6-(2-fluorophenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4bb);
N5-(2-fluorophenyl)-N6-methyl[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (7a);
N5-ethyl-N6-(2-fluorophenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (7b);
N5-(2-fluorophenyl)-N6-propyl[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (7c);
N5-(2-fluorophenyl)-N6-(3,3,3-trifluoropropyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (7d);
N5-(2-fluorophenyl)-N6-(1-methylpiperidin-4-yl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (7e); or
N5-cyclohexyl-N6-(2-fluorophenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (7f).

### Claim 2 (depends on 1)

A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof of claim 1 as a first active agent, a pharmaceutically acceptable carrier, and optionally an additional active agent.

### Claim 3 (depends on 1)

A method of therapeutically treating a condition responsive to mitochondrial uncoupling, comprising administering a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof of claim 1 to a patient in need of such treatment.

### Claim 4 (depends on 3)

The method of claim 3, wherein the condition responsive to mitochondrial uncoupling is obesity, type II diabetes, fatty liver disease, insulin resistance, Parkinson's disease, ischemia reperfusion injury, heart failure, non-alcoholic fatty liver disease (NALFD), or non-alcoholic steatohepatitis (NASH).

### Claim 5 (depends on 1)

A method of regulating glucose homeostasis or insulin action in a patient comprising administering a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof of claim 1 to a patient in need thereof.

### Claim 6

A compound of the formula:
or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 6)

A pharmaceutical composition comprising the compound of claim 6 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 8 (depends on 6)

A method of therapeutically treating a condition responsive to mitochondrial uncoupling, comprising administering a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof of claim 6 to a patient in need of such treatment.

### Claim 9 (depends on 8)

The method of claim 8, wherein the condition responsive to mitochondrial uncoupling is obesity, type II diabetes, fatty liver disease, insulin resistance, Parkinson's disease, ischemia reperfusion injury, heart failure, non-alcoholic fatty liver disease (NALFD), or non-alcoholic steatohepatitis (NASH).

### Claim 10 (depends on 8)

The method of claim 8, wherein the condition responsive to mitochondrial uncoupling is non-alcoholic steatohepatitis (NASH).

### Claim 11 (depends on 6)

A method of regulating glucose homeostasis or insulin action in a patient comprising administering a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof of claim 6 to the patient.