COMBINATIONS OF GLP-1R AND THRß AGONISTS AND METHODS OF USE THEREOF

1 . A combination comprising a THRβ agonist, or a pharmaceutically acceptable salt thereof, and a GLP-1R agonist, or a pharmaceutically acceptable salt thereof,

wherein the THRβ agonist is a compound of Formula (II-1)

wherein:

R 1 is selected from the group consisting of hydrogen, cyano, substituted or unsubstituted C 1-6 alkyl, and substituted or unsubstituted C 3-6 cycloalkyl, the substituent being selected from the group consisting of halogen atoms, hydroxy, and C 1-6 alkoxy;

R 2 and R 3 are each independently selected from the group consisting of halogen atoms and substituted or unsubstituted C 1-6 alkyl, the substituent being selected from the group consisting of halogen atoms, hydroxy, and C 1-6 alkoxy;

ring A is a substituted or unsubstituted saturated or unsaturated C 5-10 aliphatic ring, or a substituted or unsubstituted C 5-10 aromatic ring, the substituent being one or more substances selected from the group consisting of hydrogen, halogen atoms, hydroxy, —OCF 3 , —NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 , —CONH 2 , —CONHC 1-4 alkyl, —CON(C 1-4 alkyl) 2 , —NHCOC 1-4 alkyl, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl, and when two substituents are contained, the two substituents can form a ring structure together with the carbon connected thereto; and the halogen atoms are selected from the group consisting of F, Cl and Br;

or a pharmaceutically acceptable salt thereof.

2 . (canceled)

3 . The combination of claim 1 , wherein the THRβ agonist is a compound of Formula (II-1a)

wherein:

R 1 to R 3 are defined as detailed herein for Formula (II-1);

R 4 is selected from the group consisting of hydrogen, halogen atoms, hydroxy, —OCF 3 , —NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 , —CONH 2 , —CONHC 1-4 alkyl, —CON(C 1-4 alkyl) 2 , —NHCOC 1-4 alkyl, C 1-6 alkyl, C 1-6 alkoxy and C 3-6 cycloalkyl;

m is an integer from the range 1 to 4; and

the halogen atoms are selected from the group consisting of F, Cl and Br.

or a pharmaceutically acceptable salt thereof.

4 . The combination of a claim 1 , wherein the THRβ agonist is Compound 9:

or a pharmaceutically acceptable salt thereof.

5 . The combination of claim 1 , wherein the THRβ agonist is a potassium salt of Compound 9.

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

or a pharmaceutically acceptable salt thereof, 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 1-6 alkyl, C 1-6 alkyl, C 1-6 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 L1 is independently halo, OH, oxo, or C 1 -C 6 alkyl, or two R L1 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) 2 CH 3 , and phenyl.

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

or a pharmaceutically acceptable salt thereof wherein R 7 is hydrogen, chloro, bromo, fluoro, methyl, or vinyl; and

R 8 is

8 . The combination of claim 1 , wherein the GLP-1R agonist is a compound of Formula (II**):

or a pharmaceutically acceptable salt thereof; wherein

R f4 and R f5 are each independently selected from C 1-6 alkyl, H and D

nf1 is 0, 1, 2, 3, or 4;

nf3 is 0, 1, 2, 3, 4, or 5;

each R f1 is halogen;

R 3 and R 3′ independently are H or D;

X 1 * is N or CR f1 ;

X 2 * and X 3 * independently are CH or CF;

each R f3 is independently selected from halogen, —CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or —C(O)N(R 3′ ) 2 ,

each R f3′ is independently selected from H or C 1-6 alkyl; and

R 1 ** is H or C 1-2 alkyl optionally substituted with one or more deuterium or halogen.

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

or a pharmaceutically acceptable salt thereof.

10 . The combination of claim 1 , wherein the GLP-1R agonist is a meglumine salt of Compound 1-2.

11 . The combination of claim 1 , wherein the THRβ agonist is selected from those listed in Table 6, or a pharmaceutically acceptable salt thereof.

12 . The combination of claim 1 , wherein the GLP-1R agonist is selected from those listed in Tables 1-5 or 5A, or a pharmaceutically acceptable salt thereof.

13 . (canceled)

14 . The combination of claim 1 , wherein the THRβ agonist is compound 9

or a pharmaceutically acceptable salt thereof and the GLP-1R agonist is orforglipron, danuglipron, liraglutide, exenatide, dulaglutide, albiglutide, lixisenatide, tirzepatide, or semaglutide, or a pharmaceutically acceptable salt thereof.

15 . The combination of claim 1 , wherein the THRβ agonist is compound 9

or a pharmaceutically acceptable salt thereof and the GLP-1R agonist is orforglipron, danuglipron, or semaglutide, or a pharmaceutically acceptable salt thereof.

16 . (canceled)

17 . 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.

18 - 31 . (canceled)

32 . A method of effectuating weight loss in a patient in need thereof, comprising administering to the patient a combination according to claim 1 .

33 . The method of claim 32 , wherein the patient has a Body Mass Index (BMI) of 27 kg/m 2 or greater.

34 . The method of claim 32 , wherein the patient has a BMI of 30 kg/m 2 or greater.

35 - 39 . (canceled)

40 . A method of treating obesity or effectuating weight loss in a patient in need thereof, the method comprising

(i) administering to the patient compound 9

or a pharmaceutically acceptable salt thereof, and

(ii) administering to the patient a GLP-1R agonist, or a pharmaceutically acceptable salt thereof;

wherein administering to the patient compound 9, or a pharmaceutically acceptable salt thereof, improves the patient's response to the GLP-1R agonist or a pharmaceutically acceptable salt thereof.

41 - 43 . (canceled)

44 . The method of claim 40 , wherein the GLP-1R agonist comprises compound 1-2, orforglipron, semaglutide, tirzepatide, or danuglipron.

45 - 48 . (canceled)

49 . 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.

50 . The combination of claim 3 , wherein the GLP-1R agonist is orforglipron, danuglipron, liraglutide, exenatide, dulaglutide, albiglutide, lixisenatide, tirzepatide, or semaglutide, or a pharmaceutically acceptable salt thereof.