Substituted imidazo[4,5-b]pyridines, imidazo[4,5-b]pyrazines, and oxazolo[4,5- b]pyrazines as mitochondrial uncouplers

Patent metadata

Field	Value
Publication number	US-11708376-B2
Application number	US-201917049232-A
Country	US
Kind code	B2
Filing date	Apr 22, 2019
Priority date	Apr 20, 2018
Publication date	Jul 25, 2023
Grant date	Jul 25, 2023

Abstract

The disclosure provides compounds of Formula (I-A) and (I-B) and the pharmaceutically acceptable salts thereof. The variables, R, R2, R3, X1, X2, X3, Y1, Y, and Z are defined herein. Certain compounds of Formula (I-A) and (I-B) act as selective mitochondrial protonophore uncouplers that do not affect plasma membrane potential. These compounds are useful for treating or decreasing the risk of conditions responsive to mitochondrial uncoupling, such as cancer, 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), Because mitochondrial uncouplers decrease the production of reactive oxygen species (ROS), which are known to contribute to age-related cell damage, the compounds are useful for increasing lifespan. Compounds and salts of Formulae (I-A) and (I-B) are also useful for regulating glucose homeostasis or insulin action in a patient.

First claim

What is claimed is:

1. A compound of Formula I-A or Formula I-B:

or a pharmaceutically acceptable salt or tautomer thereof,
wherein:

X 3 is C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, or phenyl, wherein the phenyl is optionally substituted with one or more independently selected halogen substituents;
Y 1 is —NR 1 — or —O—;
R is H or CH 3 ;
R 1 is H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, or C 2 -C 8 alkynyl;
wherein one or more carbon atoms of the C 1 -C 8 alkyl, C 2 -C 8 alkenyl, or C 2 -C 8 alkynyl is optionally replaced by —C(O)—, —C(O)NR 10 —, —C(O)O—, —NR 10 —, —NR 10 C(O)—, —NR 10 C(O)NR 10 —, —NR 10 S(O) n —, —O—, —OC(O)—, —S(O) n —, or —S(O) n NR 10 —; and
wherein the C 1 -C 8 alkyl, C 2 -C 8 alkenyl, or C 2 -C 8 alkynyl is optionally substituted with one or more independently selected R 13 substituents;

R 2 is C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 0 -C 4 alkylene-C 3 -C 7 cycloalkyl, C 0 -C 4 alkylene-bridged C 7 -C 12 cycloalkyl, C 0 -C 4 alkylene-4- to 7-membered heterocycloalkyl, C 0 -C 4 alkylene-aryl, or C 0 -C 4 alkylene-monocyclic or bicyclic heteroaryl;
wherein one or more carbon atoms of the C 0 -C 4 alkylene, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, or C 2 -C 8 alkynyl is optionally replaced by —C(O)—, —C(O)NR 10 —, —C(O)O—, —NR 10 —, —NR 10 C(O)—, —NR 10 C(O)NR 10 —, —NR 10 S(O) n —, —O—, —OC(O)—, —S(O) n —, or —S(O) n NR 10 —;
wherein the C 0 -C 4 alkylene, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, or C 2 -C 8 alkynyl is optionally substituted with one or more independently selected R 13 substituents;
wherein the C 3 -C 7 cycloalkyl, bridged C 7 -C 12 cycloalkyl, 4- to 7-membered heterocycloalkyl, aryl, or monocyclic or bicyclic heteroaryl is optionally substituted with one or more independently selected R 11 substituents; and
wherein the C 3 -C 7 cycloalkyl, bridged C 7 -C 12 cycloalkyl, 4- to 7-membered heterocycloalkyl, aryl, or monocyclic or bicyclic heteroaryl is optionally substituted with one R 12 substituent; or

R 1 and R 2 , taken together with the nitrogen heteroatom to which they are attached, form a 3- to 7-membered heterocyclyl, wherein one carbon atom of the 3- to 7-membered heterocyclyl is optionally replaced by a heteroatom selected from the group consisting of N, O, and S;
R 3 is H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 0 -C 4 alkylene-C 3 -C 7 cycloalkyl, C 0 -C 4 alkylene-aryl, or C 0 -C 4 alkylene-heteroaryl;
wherein one or more carbon atoms of the C 0 -C 4 alkylene, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, or C 2 -C 8 alkynyl is optionally replaced by —C(O)—, —C(O)NR 10 —, —C(O)O—, —NR 10 —, —NR 10 C(O)—, —NR 10 C(O)NR 10 —, —NR 10 S(O) n —, —O—, —OC(O)—, —S(O) n —, or —S(O) n NR 10 —;
wherein the C 0 -C 4 alkylene, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, or C 2 -C 8 alkynyl is optionally substituted with one or more independently selected R 13 substituents; and
wherein the C 3 -C 7 cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more independently selected R u substituents;

each R 10 is independently H, C 1 -C 6 alkyl, or C 0 -C 2 alkylene-C 3 -C 7 cycloalkyl;
each R 11 is independently halogen, CN, NO 2 , C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C(O)H, C(O)OH, NH 2 , OH, ═O, or halosulfanyl;
wherein one or more carbon atoms of each C 1 -C 8 alkyl, C 2 -C 8 alkenyl, and C 2 -C 8 alkynyl is optionally and independently replaced by —C(O)—, —C(O)NR 10 —, —C(O)O—, —NR 10 —, —NR 10 C(O)—, —O—, —OC(O)—, or —S(O) n —; and
wherein each C 1 -C 8 alkyl, C 2 -C 8 alkenyl, or C 2 -C 8 alkynyl is optionally and independently substituted with one or more independently selected R 13 substituents;

R 12 is O—C 0 -C 4 alkylene-C 3 -C 7 cycloalkyl, O—C 0 -C 4 alkylene-5- or 6-membered heterocycloalkyl, O—C 0 -C 4 alkylene-aryl, O—C 0 -C 4 alkylene-5- or 6-membered heteroaryl, C 0 -C 4 alkylene-C 3 -C 7 cycloalkyl, C 0 -C 4 alkylene-5- or 6-membered heterocycloalkyl, C 0 -C 4 alkylene-aryl, or C 0 -C 4 alkylene-5- or 6-membered heteroaryl, wherein the C 3 -C 7 cycloalkyl, 5- or 6-membered heterocycloalkyl, aryl, or 5- or 6-membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO 2 , C 1 -C 6 alkyl, C 1 -C 2 haloalkyl, C 1 -C 4 alkylene-NHC 1 -C 6 alkyl, C 1 -C 4 alkylene-N(C 1 -C 6 alkyl) 2 , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C(O)H, C(O)C 2 -C 6 alkyl, C(O)OH, C(O)OC 1 -C 6 alkyl, NH 2 , NHC 1 -C 6 alkyl, N(C 1 -C 6 alkyl) 2 , OH, OC 1 -C 6 alkyl, OC 1 -C 2 haloalkyl, and ═O;
each R 13 is independently halogen, CN, NO 2 , C(O)H, C(O)OH, NH 2 , OH, ═O, C 3 -C 7 cycloalkyl, or phenyl;
Z is —O— or —S—; and
each n is independently 0, 1, or 2.

2. The compound of claim 1 , wherein the compound is of Formula I-A:

or a pharmaceutically acceptable salt or tautomer thereof,
wherein:

3. The compound of claim 1 , wherein the compound is of Formula I-B:

or a pharmaceutically acceptable salt or tautomer thereof,
wherein:

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
(i)

and
Z is —O—; or

(ii)

and
Z is —O—.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
(i)

and
Z is —O—; or

(ii)

and
Z is —O—.

7. The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein X 3 is CH 3 , CF 3 , CF 2 CF 3 , or phenyl, wherein the phenyl is optionally substituted with one or more F substituents.

8. The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein:
Y 1 is —NR 1 —; and
R 1 is H or unsubstituted C 1 -C 6 alkyl.

9. The compound of claim 8 , or a pharmaceutically acceptable salt or tautomer thereof, wherein R 2 is C 0 -C 4 alkylene-bridged C 7 -C 12 cycloalkyl or C 0 -C 4 alkylene-aryl;
wherein one or more carbon atoms of the C 0 -C 4 alkylene is optionally replaced by —C(O)—, —C(O)NR 10 —, —C(O)O—, —NR 10 —, —NR 10 C(O)—, —O—, —OC(O)—, or —S(O) n —;
wherein the C 0 -C 4 alkylene is optionally substituted with one or more independently selected R 13 substituents;
wherein the bridged C 7 -C 12 cycloalkyl or aryl is optionally substituted with one or more independently selected R 11 substituents; and
wherein the bridged C 7

Assignees

• Virginia Tech Intellectual Properties Inc

Inventors

• Santos Webster L
• Dai Yumin
• Santiago-Rivera Jose A
• Murray Jacob H

Classifications

• C07D498/04 Primary

  Ortho-condensed systems · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• C07D241/20

  Nitrogen atoms (nitro radicals C07D241/16) · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title