Modulators of THR-β and methods of use thereof

Patent metadata

Field	Value
Publication number	US-11840532-B2
Application number	US-202117370623-A
Country	US
Kind code	B2
Filing date	Jul 8, 2021
Priority date	Jul 10, 2020
Publication date	Dec 12, 2023
Grant date	Dec 12, 2023

Abstract

Disclosed herein are compounds of Formula I′:

or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising such compounds, and methods of treating disease by administering or contacting a patient with one or more of the above compounds.

First claim

What is claimed is:

1. A compound of Formula I′:

or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein
Q 1 is CH or N;
R 1 and R 2 are each independently selected from hydrogen, halogen, cyclopropyl, and C 1-3 alkyl optionally substituted with 1 to 5 fluorine;
R 3 is selected from hydrogen, deuterium, halogen, —CN, C 1-10 alkoxy, and C 1-6 alkyl; or
R 2 and R 3 taken together along with the carbon atoms to which they are attached form a 4- to 6-membered carbocyclic ring or a four- to six-membered heterocyclic ring;
X is

R 4 is selected from hydrogen; C 1 -C 5 alkyl; a non-aromatic C 3 -C 12 carbocyclic ring; a C 6 -C 10 aryl group; a (carbocyclic)alkyl group; and an aralkyl group; wherein R 4 is optionally substituted with one to three R k independently selected from halogen, —CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy; and
R 5 is selected from hydrogen; halogen; C 1 -C 6 alkyl optionally substituted with halogen or C 1 -C 6 alkoxy; and C 3 -C 9 cycloalkyl optionally substituted with halogen or C 1 -C 6 alkoxy; or
R 4 and R 5 taken together along with the carbon atoms to which they are attached form a 4- to 6-membered carbocyclic ring;
R 6 is hydrogen or C 1 -C 3 alkyl;
Q 2 is N, and Q 3, and Q 4 are each independently selected from CH or N;
Y is O or CH 2 ;
Z is selected from the group consisting of:

and
R a and R b are each independently selected from hydrogen, methyl, and fluorine.

2. The compound of claim 1 , or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 is C 1 -C 6 alkyl.

3. The compound of claim 1 , or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen.

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

R 4 is selected from hydrogen; C 1 -C 6 alkyl; a non-aromatic C 3 -C 12 carbocyclic ring; a C 6 -C 10 aryl group; a (carbocyclic)alkyl group; and an aralkyl group; wherein R 4 is optionally substituted with one to three R k independently selected from halogen, —CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy; and
R 5 is selected from hydrogen; halogen; C 1 -C 6 alkyl optionally substituted with halogen or C 1 -C 6 alkoxy; and C 3 -C 9 cycloalkyl optionally substituted with halogen or C 1 -C 6 alkoxy.

5. The compound of claim 1 , or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 3 and Q 4 are CH.

6. The compound of claim 1 , or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound has the chemical structure of Formula I′a:

7. The compound of claim 1 , or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each independently selected from halogen, cyclopropyl, and C 1-3 alkyl optionally substituted with 1 to 5 fluorine.

8. The compound of claim 1 , or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y is CH 2 .

9. The compound of claim 1 , or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein Z is selected from the group consisting of:

10. The compound of claim 1 , or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein Z is selected from the group consisting of:

11. A compound selected from the group consisting of:
2-(4-((3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)methyl)-2,3,5-trimethylphenoxy)acetic acid,
2-(4-((3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)methyl)-3,5-dimethylphenoxy)acetic acid;
N-(4-((3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)methyl)-3,5-dimethylphenyl)-5-oxo-4,5- dihydro-1,2,4-oxadiazole-3-carboxamide;
2-((4-((3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)methyl)-3,5-dimethylphenyl)amino)-2-oxoacetic acid;
ethyl 2-((4-((3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)methyl)-3,5-dimethylphenyl)amino)-2-oxoacetate;
[[5-([3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl]methyl)-3,4,6-trimethylpyridin-2-yl]oxy]acetic acid;

4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-2,3,5-trimethylphenol;
2-(4-((3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)methyl)-2,3,5-trimethylphenoxy)propanoic acid;
2-(4-((3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)methyl)-2,3,5-trimethylphenoxy)-2-methylpropanoic acid;
2-fluoro-2-(4-((3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)methyl)-2,3,5-trimethylphenoxy)acetic acid;
5-(4-((2H-tetrazol-5-yl)methoxy)-2,3,6-trimethylbenzyl)-3-isopropyl-1 H-pyrrolo[3,2-b]pyridine; and
3-((4-((3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)methyl)-2,3,5-trimethylphenoxy)methyl)-1 ,2,4-oxadiazol-5(4 H)-one;
or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising the compound of claim 1 , or the stereoisomer or the tautomer thereof, or the pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

Assignees

• Aligos Therapeutics Inc

Inventors

• Mcgowan David Craig
• Raboisson Pierre Jean-Marie Bernard
• Vandyck Koen
• Deval Jerome

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61K45/06

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

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title

• A61P1/18

  for pancreatic disorders, e.g. pancreatic enzymes · CPC title