Granted Patent B2

US 12,485,118 · App. 19/072,846 · Granted Dec 2, 2025

Inventors: Christopher T. Jones (Walnut Creek, CA); Jeffrey R. Jasper (Mountain View, CA); Olivia D. Teal (Cardiff, CA); Kevin P. Quinn (San Mateo, CA)

Assignee: Terns Pharmaceuticals, Inc.

A61K31/501A61K31/437A61K31/444A61K38/26A61P3/04

Abstract

Claims (78)

1 . A combination comprising:

(i) a THRβ agonist which is:

or a pharmaceutically acceptable salt thereof; and

(ii) a GLP-1R agonist which is a GLP-1R agonist listed in Tables 1-4, orforglipron, danuglipron, liraglutide, exenatide, dulaglutide, albiglutide, lixisenatide, tirzepatide, semaglutide, mazdutide, efpeglenatide, or a compound of Formula (I-1):

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

X is N or CH;

Y is N or CR 4 ;

n is 0 or 1;

R is hydrogen;

R 1 is -C 1 -C 6 alkylene-R 5 ;

R 2 is hydrogen, oxo, or C 1 -C 6 alkyl;

R 3 is hydrogen, oxo, or C 1 -C 6 alkyl and R 4 is hydrogen, OH, or C 1 -C 6 alkyl;

or R 3 and R 4 are taken together with the carbon atoms to which they are attached to form C 3 -C 6 cycloalkyl optionally substituted by halo or C 1 -C 3 alkyl;

R 5 is 5-membered heterocyclyl or 5-membered heteroaryl, each of which comprises 1, 2, or 3 heteroatoms independently selected from O, N, and S, wherein at least one heteroatom of R 5 is S, and further wherein R 5 is optionally substituted by halo, —O—C 1≢ alkyl, C 1≢ alkyl, C 1≢ alkenyl, or C 1 -C 6 haloalkyl;

Ring A is 5- to 12-membered heterocyclene or 5- to 12-membered heteroarylene, each of which is independently optionally substituted by halo, CN, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkyl optionally substituted by halo or OH;

L is a bond, —O—, C 1 -C 6 alkylene, *—O—C 1 -C 6 alkylene-**, *-C 1 -C 6 alkylene-O—**, or *—NR 6 -C 1 -C 6 alkylene-**, wherein

* represents the point of attachment to ring A and ** represents the point of attachment to ring B;

when L is *—O—C 1 -C 6 alkylene-**, the C 1 -C 6 alkylene of L is optionally substituted by R L , wherein each R L is independently C 1 -C 6 alkyl or halo, or two R L are taken together with the carbon atom or atoms to which they are attached to form C 3 -C 6 cycloalkyl or 3- to 6-membered heterocyclyl; and

when L is C 1 -C 6 alkylene, the C 1 -C 6 alkylene is optionally substituted by R L1 , wherein each R L 1 is independently halo, OH, oxo, or C 1 -C 6 alkyl, or two R L 1 are taken together with the carbon atom or atoms to which they are attached to form C 3 -C 6 cycloalkyl or 3- to 6-membered heterocyclyl;

R 6 is hydrogen or C 1 -C 6 alkyl; and

Ring B is C 5 -C 10 cycloalkyl, C 6 -C 14 aryl, 4- to 12-membered heterocyclyl, or 5- to 12-membered heteroaryl, each of which is independently optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 , and phenyl.

2 . The combination of claim 1 , wherein the THRβ agonist is resmetirom, or a pharmaceutically acceptable salt thereof.

3 . The combination of claim 1 , wherein the THRβ agonist is Compound 9, or a pharmaceutically acceptable salt thereof.

4 . The combination of claim 1 , wherein the GLP-1R agonist is a compound of Formula (1-1),

or a pharmaceutically acceptable salt thereof.

5 . The combination of claim 1 , wherein the GLP-1R agonist is Compound 1-2:

or a pharmaceutically acceptable salt thereof.

6 . The combination of claim 1 , wherein the GLP-1R agonist is selected from those listed in Table 1, Table 2, Table 3, or Table 4, or a pharmaceutically acceptable salt thereof.

7 . The combination of claim 1 , wherein the GLP-1R agonist is orforglipron, danuglipron, liraglutide, exenatide, dulaglutide, albiglutide, lixisenatide, tirzepatide, or semaglutide, or a pharmaceutically acceptable salt thereof.

8 . The combination of claim 7 , wherein the GLP-1R agonist is orforglipron, tirzepatide, or semaglutide, or a pharmaceutically acceptable salt thereof.

9 . The combination of claim 1 , wherein the THRβ agonist is Compound 9, or a pharmaceutically acceptable salt thereof, and the GLP-1R agonist is Compound 1-2:

or a pharmaceutically acceptable salt thereof.

10 . A method of treating obesity or effectuating weight loss in a patient in need thereof, comprising administering to the patient:

(i) a THRβ agonist which is:

or a pharmaceutically acceptable salt thereof; and

(ii) a GLP-1R agonist which is a GLP-1R agonist listed in Tables 1-4, orforglipron, danuglipron, liraglutide, exenatide, dulaglutide, albiglutide, lixisenatide, tirzepatide, semaglutide, mazdutide, efpeglenatide, or a compound of Formula (I-1):

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

X is N or CH;

Y is N or CR 4 ;

n is 0 or 1;

R is hydrogen;

R 1 is-C 1 -C 6 alkylene-R 5 ;

R 2 is hydrogen, oxo, or C 1 -C 6 alkyl;

R 3 is hydrogen, oxo, or C 1 -C 6 alkyl and R 4 is hydrogen, OH, or C 1 -C 6 alkyl;

or R 3 and R 4 are taken together with the carbon atoms to which they are attached to form C 3 -C 6 cycloalkyl optionally substituted by halo or C 1 -C 3 alkyl;

R 5 is 5-membered heterocyclyl or 5-membered heteroaryl, each of which comprises 1, 2, or 3 heteroatoms independently selected from O, N, and S, wherein at least one heteroatom of R 5 is S, and further wherein R 5 is optionally substituted by halo, —O—C 1≢ alkyl, C 1≢ alkyl, C 1≢ alkenyl, or C 1 -C 6 haloalkyl;

Ring A is 5- to 12-membered heterocyclene or 5- to 12-membered heteroarylene, each of which is independently optionally substituted by halo, CN, C 8 -C 6 cycloalkyl, or C 1 -C 6 alkyl optionally substituted by halo or OH;

L is a bond, —O—, C 1 -C 6 alkylene, *—O—C 1 -C 6 alkylene-**, *-C 1 -C 6 alkylene-O—**, or *—NR 6 -C 1 -C 6 alkylene-**, wherein

* represents the point of attachment to ring A and ** represents the point of attachment to ring B;

when L is *—O—C 1 -C 6 alkylene-**, the C 1 -C 6 alkylene of Lis optionally substituted by R L , wherein each R L is independently C 1 -C 6 alkyl or halo, or two R L are taken together with the carbon atom or atoms to which they are attached to form C 5 -C 6 cycloalkyl or 3- to 6-membered heterocyclyl; and

when L is C 1 -C 6 alkylene, the C 1 -C 6 alkylene is optionally substituted by R L 1, wherein each R L 1 is independently halo, OH, oxo, or C 1 -C 6 alkyl, or two R L 1 are taken together with the carbon atom or atoms to which they are attached to form C 3 -C 6 cycloalkyl or 3- to 6-membered heterocyclyl;

R 6 is hydrogen or C 1 -C 6 alkyl; and

Ring B is C 3 -C 10 cycloalkyl, C 6 -C 14 aryl, 4- to 12-membered heterocyclyl, or 5- to 12-membered heteroaryl, each of which is independently optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -COCH 3 , -CONH 2 , —S(O) 2CH 3 , and phenyl.

11 . The method of claim 10 , wherein the patient has a Body Mass Index (BMI) of 25 kg/m 2 to 30 kg/m 2 .

12 . The method of claim 10 , wherein the administration of the THRβ agonist and the GLP-1R agonist:

(i) allows for administration of a reduced dose of the GLP-1R agonist while maintaining equivalent weight loss;

(ii) increases weight loss compared to administration of the GLP-1R agonist at an equivalent dose;

increases fat loss associated with administering the GLP-1R agonist; and/or

(iv) increases fat loss associated with administering the GLP-1R agonist while maintaining lean mass.

13 . The method of claim 10 , wherein the GLP-1R agonist is selected from orforglipron, danuglipron, liraglutide, exenatide, dulaglutide, albiglutide, lixisenatide, tirzepatide, semaglutide, mazdutide, or efpeglenatide, or a pharmaceutically acceptable salt thereof.

14 . The method of claim 10 , wherein the THRβ agonist is Compound 9, or a pharmaceutically acceptable salt thereof.

15 . The method of claim 10 , wherein the THRβ agonist is resmetirom, or a pharmaceutically acceptable salt thereof.

16 . The method of claim 10 , wherein the THRβ agonist is Compound 9, or a pharmaceutically acceptable salt thereof, and the GLP-1R agonist is orforglipron, tirzepatide, or semaglutide, or a pharmaceutically acceptable salt thereof.

17 . The method of claim 10 , wherein the THRβ agonist and the GLP-1R agonist are formulated in separate pharmaceutically acceptable compositions.

18 . The method of claim 10 , wherein the THRβ agonist and the GLP-1R agonist are formulated in a single pharmaceutically acceptable composition.

19 . The method of claim 10 , wherein the proportion of lean body mass relative to total body mass in the patient increases compared to administration of the GLP-1R agonist alone.

20 . The method of claim 10 , wherein the THRβ agonist is administered once daily or twice daily.

21 . The method of claim 10 , wherein the THRβ agonist is administered orally.

22 . The method of claim 10 , wherein the GLP-1R agonist is orforglipron, or a pharmaceutically acceptable salt thereof.

23 . The method of claim 10 , wherein the patient has a Body Mass Index (BMI) of 30 kg/m 2 or greater.

24 . The method of claim 10 , wherein the GLP-1R agonist is semaglutide, or a pharmaceutically acceptable salt thereof.

25 . The method of claim 10 , wherein the GLP-1R agonist is Compound 1-2:

or a pharmaceutically acceptable salt thereof.

26 . The method of claim 10 , wherein the patient is administered each of the THRβ agonist and the GLP-1R agonist over a period of at least 8 weeks.

27 . The method of claim 15 , wherein the GLP-1R agonist is semaglutide or orforglipron, or a pharmaceutically acceptable salt thereof.

28 . The method of claim 10 , wherein the GLP-1R agonist is selected from orforglipron, danuglipron, liraglutide, exenatide, dulaglutide, albiglutide, lixisenatide, tirzepatide, semaglutide, mazdutide, or efpeglenatide, or a pharmaceutically acceptable salt thereof, and wherein the patient is administered each of the THRβ agonist and the GLP-1R agonist over a period of at least 8 weeks, and wherein the proportion of lean body mass relative to total body mass in the patient increases compared to administration of the GLP-1R agonist alone.

29 . The method of claim 10 , wherein the patient is not in need of treatment for a liver disorder.

30 . The method of claim 10 , wherein the patient is not in need of treatment for non-alcoholic steatohepatitis.

Assignments (2)

Continuity (5)

References Cited (400)