# US 2021/0276979 A1 · Therapeutic compounds

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- Number: US 2021/0276979 A1
- Document ID: US20210276979A1
- Status: Published application
- Kind: A1
- Application number: 16/327,287
- Filed: 2017-08-18
- Published: 2021-09-09
- Earliest claimed: 2016-08-25
- Assignees: Arizona Board of Regents on behalf of Arizona State University
- Applicants: Arizona Board of Regents On Behalf of Arizona State University
- Inventors: Sidney HECHT; Omar KHDOUR; Arnaud CHEVALIER
- Web page: https://patentgrep.com/patent/US20210276979A1

## CPC

- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07F 9/65616: {containing the ring system [IMAGE cpc-sch-C07F-1006.gif] having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs}
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61P 39/06: Free radical scavengers or antioxidants
- C07D 239/60: Three or more oxygen or sulfur atoms
- C07D 403/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- 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

## Abstract

The invention provides compounds having the general formula I: and pharmaceutically acceptable salts thereof, wherein the variables R1, R2, R3 and R4 have the meaning as described herein, and compositions containing such compounds and methods for using such compounds and compositions.

## Claims

### Claim 1

A compound of formula I:
wherein R1 is hydrogen or C1-6 alkyl;
R2 is C1-20 alkyl, C2-20 alkenyl or C2-20 alkynyl, and wherein the C1-20 alkyl, C2-20 alkenyl and C2-20 alkynyl are optionally substituted with one or more groups independently selected from —F, —Cl, —Br, —I, —ORa, —SRa, —N(Ra)2, oxo, —NO2 and —CN;
R3 is —OR5 or —NR6R7;
R4 is —OR8 or —NR9R10;
R5 is C3-10 cycloalkyl or C1-8 alkyl; wherein C3-10 cycloalkyl and C1-8 alkyl are optionally substituted with one or more groups independently selected from C1-4 alkyl, C1-4 haloalkyl, —F, —Cl, —Br, —I, —ORb, —SRb, —N(Rb)2, oxo, —NO2 and —CN;
R6 is C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, and wherein the C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are optionally substituted with one or more groups independently selected from —F, —Cl, —Br, —I, —ORc, —SRc, —N(Rc)2, oxo, —NO2 and —CN; R7 is C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, and wherein the C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are optionally substituted with one or more groups independently selected from —F, —Cl, —Br, —I, —ORd, —SRd, —N(Rd)2, oxo, —NO2 and —CN; or R6 and R7 taken together with the nitrogen to which they are attached form a 3-10 membered heterocycle that is optionally substituted with one or more groups independently selected from C1-4 alkyl, C1-4 haloalkyl, —F, —Cl, —Br, —I, —ORe, —SRe, —N(Re)2, oxo, —NO2 and —CN;
R8 is C3-10 cycloalkyl or C1-8 alkyl; wherein C3-10 cycloalkyl and C1-8 alkyl are optionally substituted with one or more groups independently selected from C1-4 alkyl, C1-4 haloalkyl, —F, —Cl, —Br, —I, —ORf, —SRf, —N(Rf)2, oxo, —NO2 and —CN;
R9 is C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, and wherein the C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are optionally substituted with one or more groups independently selected from —F, —Cl, —Br, —I, —ORg, —SRg, —N(Rg)2, oxo, —NO2 and —CN; R10 is C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, and wherein the C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are optionally substituted with one or more groups independently selected from —F, —Cl, —Br, —I, —ORh, —SRh, —N(Rh)2, oxo, —NO2 and —CN; or R9 and R10 taken together with the nitrogen to which they are attached form a 3-10 membered heterocycle that is optionally substituted with one or more groups independently selected from C1-4 alkyl, C1-4 haloalkyl, —F, —Cl, —Br, —I, —ORi, —SRi, —N(Ri)2, oxo, —NO2 and —CN;
each Ra is independently hydrogen or C1-4 alkyl; or two Ra taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
each Rb is independently hydrogen or C1-4 alkyl; or two Rb taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
each Rc is independently hydrogen or C1-4 alkyl; or two Rc taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
each Rd is independently hydrogen or C1-4 alkyl; or two Rd taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
each Re is independently hydrogen or C1-4 alkyl; or two Re taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
each Rf is independently hydrogen or C1-4 alkyl; or two Rf taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
each Rg is independently hydrogen or C1-4 alkyl; or two Rg taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
each Rh is independently hydrogen or C1-4 alkyl; or two Rh taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; and
each Ri is independently hydrogen or C1-4 alkyl; or two Ri taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
or a pharmaceutically acceptable salt thereof.

### Claim at position 2

2-3. (canceled)

### Claim 4 (depends on 1)

The compound of claim 1, wherein R2 is C10-20 alkyl.

### Claim 5 (depends on 1)

The compound of claim 1, wherein R2 is methyl, tetradecyl or hexadecyl.

### Claim 6 (depends on 1)

The compound of claim 1, wherein R5 is cyclobutyl.

### Claim 7 (depends on 1)

The compound of claim 1, wherein R6 and R7 taken together with the nitrogen to which they are attached form a 3-10 membered heterocycle that is optionally substituted with one or more groups independently selected from C1-4 alkyl, C1-4haloalkyl, —F, —Cl, —Br, —I, —ORe, —SRe, —N(Re)2, oxo, —NO2 and —CN.

### Claim 8 (depends on 7)

The compound of claim 7 wherein R6 and R7 taken together with the nitrogen to which they are attached form

### Claim 9 (depends on 1)

The compound of claim 1, wherein R9 and R10 taken together with the nitrogen to which they are attached form a 3-10 membered heterocycle that is optionally substituted with one or more groups independently selected from C1-4 alkyl, C1-4haloalkyl, —F, —Cl, —Br, —I, —ORi, —SRi, —N(Ri)2, oxo, —NO2 and —CN.

### Claim 10 (depends on 9)

The compound of claim 9 wherein R9 and R10 taken together with the nitrogen to which they are attached form

### Claim 11 (depends on 1)

The compound of claim 1, wherein R3 is —OR5 and R4 is —NR9R10; or R3 is —NR6R7 and R4 is —OR8.

### Claim 12 (depends on 1)

The compound of claim 1 which is a compound of formula Ia:
or a pharmaceutically acceptable salt thereof.

### Claim 13 (depends on 12)

The compound of claim 12 wherein R2 is C10-20 alkyl.

### Claim 14 (depends on 12)

The compound of claim 12 wherein R9 and R10 taken together with the nitrogen to which they are attached form a 3-10 membered heterocycle that is optionally substituted with one or more groups independently selected from C1-4 alkyl, C1-4 haloalkyl, —F, —Cl, —Br, —I, —ORi, —SRi, oxo, —NO2 and —CN.

### Claim 15 (depends on 1)

The compound of claim 1 which is a compound of formula Ib:
or a pharmaceutically acceptable salt thereof.

### Claim 16

(canceled)

### Claim 17 (depends on 15)

The compound of claim 15 wherein R2 is C10-20 alkyl; and R6 and R7 taken together with the nitrogen to which they are attached form a 3-10 membered heterocycle that is optionally substituted with one or more groups independently selected from C1-4 alkyl, C1-4 haloalkyl, —F, —Cl, —Br, —I, —ORi, —SRi, —N(Ri)2, oxo, —NO2 and —CN.

### Claim 18 (depends on 1)

The compound of claim 1 wherein R3 is

### Claim 19 (depends on 1)

The compound of claim 1 wherein R4 is

### Claim 20 (depends on 1)

The compound of claim 1 that is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.

### Claim 21 (depends on 1)

A pharmaceutical composition comprising a compound of formula I as described in claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 22 (depends on 1)

A method of treating mitochondrial disease, neurodegenerative disease, cardiovascular disease, cancer or diabetes in an animal comprising administering to the animal an effective amount of compound of formula (I) or a pharmaceutically acceptable salt thereof as described in claim 1.

### Claim at position 22

23-24. (canceled)

### Claim 25 (depends on 1)

A method of quenching lipid peroxidation and/or suppress reactive oxygen species (ROS) and/or preserving mitochondrial membrane potential and/or augmenting ATP production in a cell in vitro comprising contacting the cell with an effective amount of compound of formula (I) or a pharmaceutically acceptable salt thereof as described in claim 1.

### Claim at position 24

26-30. (canceled)