Granted Patent B2

US 12,398,127 · App. 17/642,629 · Granted Aug 26, 2025

Inventors: Thorsten A. Kirschberg (San Carlos, CA); Randall Halcomb (Foster City, CA); Yingzi Xu (Palo Alto, CA); F. Anthony Romero (Redwood City, CA)

Assignee: Terns Pharmaceuticals, Inc.

C07D413/12A61P5/14

Abstract

Claims (43)

1. A compound of formula (I):

or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

R 1 is H or —CH 3 ;

X 1 X 2 X 3 , and X 4 are each independently CR 2 or N, wherein at least two of X 1 , X 2 , X 3 , and X 4 are CR 2 ;

each R 2 is independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 alkyl-CN, C 1 -C 6 alkyl-OH, C 1 -C 6 haloalkyl, —CN, hydroxyl, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —O(C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, 5- to 6-membered heteroaryl, 5- to 7-membered heterocyclyl, or C 6 aryl,

wherein each C 1 -C 6 alkyl, —O(C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, 5- to 6-membered heteroaryl, 5- to 7-membered heterocyclyl, or C 6 aryl is optionally substituted by 1-5 R 3 groups;

or two R 2 groups are taken together with the carbon atoms to which they are attached to form a 5- to 6-membered heteroaryl, 5- to 7-membered heterocyclyl, C 5 -C 7 cycloalkyl, or C 6 aryl, each of which is optionally substituted by 1-5 R 3 groups; and

each R 3 is independently C 1 -C 6 alkyl, —O(C 1 -C 6 alkyl), halo, —CN, hydroxyl, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , or CO 2 H.

2. The compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

R 1 is H.

3. The compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

R 1 is —CH 3 .

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

X 1 , X 2 , X 3 , and X 4 are each independently CR 2 .

5. The compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

one of X 1 , X 2 , X 3 , and X 4 is N.

6. The compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

two of X 1 , X 2 , X 3 , and X 4 are N.

7. The compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

each R 2 is independently H, halo, C 1 -C 3 alkyl, C 1 -C 3 alkyl-CN, C 1 -C 3 alkyl-OH, C 1 -C 3 haloalkyl, —CN, hydroxyl, —NH 2 , —NH(C 1 -C 3 alkyl), —N(C 1 -C 3 alkyl) 2 , —O(C 1 -C 3 alkyl), C 3 -C 6 cycloalkyl, 5- to 6-membered heteroaryl, 5- to 6-membered heterocyclyl, or C 6 aryl,

wherein each C 1 -C 3 alkyl, —O(C 1 -C 3 alkyl), C 3 -C 6 cycloalkyl, 5- to 6-membered heteroaryl, 5- to 6-membered heterocyclyl, or C 6 aryl is optionally substituted by 1-5 R 3 groups.

8. The compound of claim 7 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

each R 2 is independently H, halo, or C 1 -C 3 alkyl optionally substituted by 1-2 R 3 groups.

9. The compound of claim 8 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

each R 2 is independently H, F, Cl, or —CH 3 .

10. The compound of claim 9 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

each R 2 is H.

11. The compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

one or two of R 2 are independently selected from the group consisting of halo, C 1 -C 3 alkyl, C 1 -C 3 alkyl-CN, C 1 -C 3 alkyl-OH, C 1 -C 6 haloalkyl, —CN, hydroxyl, —NH 2 , —NH(C 1 -C 3 alkyl), —N(C 1 -C 3 alkyl) 2 , —O(C 1 -C 3 alkyl), C 3 -C 6 cycloalkyl, 5- to 6-membered heteroaryl, 5- to 6-membered heterocyclyl, and C 6 aryl,

wherein each C 1 -C 3 alkyl, —O(C 1 -C 3 alkyl), C 3 -C 6 cycloalkyl, 5- to 6-membered heteroaryl, 5- to 6-membered heterocyclyl, and C 6 aryl,

wherein each C 1 -C 3 alkyl, —O(C 1 -C 3 alkyl), C 3 -C 6 cycloalkyl, 5- to 6-membered heteroaryl, 5- to 6-membered heterocyclyl, or C 6 aryl is optionally substituted by 1-5 R 3 groups.

12. The compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

two R 2 groups are taken together with the carbon atoms to which they are attached to form a 5- to 6-membered heteroaryl, 5- to 6-membered heterocyclyl, C 5 -C 6 cycloalkyl, or C 6 aryl, each of which is optionally substituted by 1-5 R 3 groups.

13. The compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

each R 3 , if present, is independently C 1 -C 3 alkyl, —O(C 1 -C 3 alkyl), halo, —CN, hydroxyl, —NH 2 , —NH(C 1 -C 3 alkyl), —N(C 1 -C 3 alkyl) 2 , or CO 2 H.

14. The compound of claim 13 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

each R 3 is independently CH 3 , —OCH 3 , F, Cl, —CN, hydroxyl, —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , or CO 2 H.

15. The compound of claim 1 , which is:

or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

16. A pharmaceutical composition comprising the compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and at least one pharmaceutically acceptable excipient.

17. A method of agonizing thyroid hormone receptor beta (THR beta) comprising contacting either an effective amount of the compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

18. A method of treating a disorder which is mediated by THR beta in a patient in need thereof, comprising administering to the patient a effective amount of the compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

19. The method of claim 18 , wherein the disorder is non-alcoholic steatohepatitis (NASH).

Assignments (3)

Continuity (2)

References Cited (236)