Thyroid hormone receptor agonists and uses thereof

1. A compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein:

R 1 is hydrogen, deuterium, halogen, —CN, —OH, —OR a , —SH, —SR a , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR b R c , —NHS(═O) 2 R a , —S(═O) 2 NR b R c , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR b R c , —OC(═O)NR b R c , —NR b C(═O)NR b R c , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OR a , —NR b R c , —C(═O)R a , —C(═O)OR b , —C(═O)NR b R c , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

R 2 is hydrogen, halogen, —CN, —OH, —OR a , —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR b R c , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —C(═O)NR b R c , C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OR a , —NR b R c , —C(═O)R a , —C(═O)OR b , —C(═O)NR b R c , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

each R 3 is independently hydrogen, deuterium, halogen, —CN, —OH, —OR a , —SH, —SR a , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR b R c , —NHS(═O) 2 R a , —S(═O) 2 NR b R c , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR b R c , —OC(═O)NR b R c , —NR b C(═O)NR b R c , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OR a , —NR b R c , —C(═O)R a , —C(═O)OR b , —C(═O)NR b R c , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

R 4 and R 5 are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, or C 1 -C 6 haloalkyl;

R 6 is hydrogen, —CN, —OH, —OR a , —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR b R c , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —C(═O)NR b R c , C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OR a , —NR b R c , —C(═O)R a , —C(═O)OR b , —C(═O)NR b R c , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

n is 0-4;

each R a is independently C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; and

each R b and R c are independently hydrogen, deuterium, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

or R b and R c are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

R 1 is hydrogen or —CN.

3. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

R 2 is hydrogen or C 1 -C 6 alkyl.

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

n is 2-4 and each R 3 is independently hydrogen, deuterium, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

5. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

R 4 and R 5 are taken together to form a cycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, or C 1 -C 6 haloalkyl.

6. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

R 6 is hydrogen or C 1 -C 6 alkyl.

7. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:

8. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

9. A method of treating a metabolic disease in a subject, comprising administering to the subject a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein the metabolic disease is obesity, hyperlipidemia, hypercholesterolemia, diabetes, nonalcoholic steatohepatitis (NASH), atherosclerosis, a cardiovascular disease, hypothyroidism, or thyroid cancer.

10. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

R 4 and R 5 are taken together to form a 5-membered cycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, or C 1 -C 6 haloalkyl.

11. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

R 4 and R 5 are taken together to form a 5-membered cycloalkyl optionally substituted with one or more C 1 -C 6 alkyl or C 1 -C 6 deuteroalkyl.

12. The compound of claim 11 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

R 4 and R 5 are taken together to form a 5-membered cycloalkyl substituted with one C 1 -C 6 alkyl.

13. The compound of claim 11 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

R 4 and R 5 are taken together to form a 5-membered cycloalkyl substituted with one C 1 -C 6 deuteroalkyl.

14. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

R 1 is —CN.

15. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

R 2 is hydrogen.

16. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

each R 3 is independently hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

17. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

each R 3 is independently halogen.

18. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

n is 2.