NEW ANALOGUES OF THYROID HORMONES BETA RECEPTORS AND THEIR APPLICATIONS

RU2024126490A3Pending Publication Date: 2026-08-28MADRIGAL PHARMACEUTICALS INC

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Patent Information

Application Number: RU2024126490
Authority / Receiving Office: RU · RU
Patent Type: Applications
Current Assignee / Owner
Filing Date: 2023-02-10
Publication Date: 2026-08-28

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Claims

1. Compound of formula I: or a corresponding pharmaceutically acceptable salt, solvate or stereoisomer, wherein: each R 1 independently represents a halogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 1-6 -alkoxy, C 3-10 -carbocyclyl or C 6-14 -aryl; each R 2 independently represents a halogen, C 1-6 -alkyl, C 2-6 -alkenyl or C 2-6 -alkynyl; R 3 is a halogen, -CN, -NO2, C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-6 -hydroxyalkyl, C 1-6 -aminoalkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 6-14 -aryl, 5-14 membered heteroaryl, C 3-10 -carbocyclyl, 3-10-membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NRc R d , -NR c S(=O)2R a , -NR c S(=O)2R a , -NR c S(=O)2OR b , -NR c S(=O)2NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b or -C(=O)NR c R d , wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more R u ; each of R 4 and R 6 independently represents hydrogen, C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-6 -hydroxyalkyl, C 1-6 -aminoalkyl, C2-6 -alkenyl, C 2-6 -alkynyl, C 6-14 -aryl, 5-14 membered heteroaryl, C 3-10 -carbocyclyl or 3- to 10-membered heterocyclyl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl or heterocyclyl is optionally substituted with one or more R u ; each R 5 independently represents halogen, -CN, -NO2, C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-6 -hydroxyalkyl, C 1-6 -aminoalkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 6-14 -aryl, 5-14 membered heteroaryl, C 3-10 -carbocyclyl, 3-10-membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c R d , -NR c S(=O)2R a , -NR c S(=O)2R a , -NR c S(=O)2OR b , -NR c S(=O)2NR c Rd , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b or -C(=O)NR c R d , wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more R u ; m is an integer chosen from 0 to 4; n is an integer chosen from 0 to 2; X is chosen from -C(R 7 )2-, -O-, -NR 8 - and -S-; each R 7 independently represents hydrogen, halogen, -CN, -NO2, C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-6 -hydroxyalkyl, C1-6 -aminoalkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 6-14 -aryl, 5-14-membered heteroaryl, C 3-10 -carbocyclyl, 3-10-membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c R d , -NR c S(=O)2R a , -NR c S(=O)2R a , -NR c S(=O)2OR b , -NR c S(=O)2NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b or -C(=O)NR c R d, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more R u ; And R 8 is hydrogen, C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-6 -hydroxyalkyl, C 1-6 -aminoalkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 6-14 -aryl, 5-14 membered heteroaryl, C 3-10 -carbocyclyl or 3- to 10-membered heterocyclyl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl or heterocyclyl is optionally substituted with one or more R u ; in this case: each R u independently represents halogen, -CN, -NO2, C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-6 -hydroxyalkyl, C 1-6 -aminoalkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 6-14-aryl, 5-14-membered heteroaryl, C 3-10 -carbocyclyl, 3-10-membered heterocyclyl, -SR b , -S(=O)R a , -S(=O)2R a , -S(=O)2OR b , -S(=O)2NR c R d , -NR c R d , -NR c S(=O)2R a , -NR c S(=O)2R a , -NR c S(=O)2OR b , -NR c S(=O)2NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -OR b , -OS(=O)2R a , -OS(=O)2OR b , -OS(=O)2NR c R d , -OC(=O)R a , -OC(=O)ORb, -OC(=O)NR c R d , -C(=O)R a , -C(=O)OR b or -C(=O)NR c R d, wherein alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more of the following substituents: oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1-6 -alkyl or C 1-6 -haloalkyl; two R's u , taken together, form oxo; or two R's u , together with one or more intermediate atoms, form C 6-14 -aryl, 5-14 membered heteroaryl, C 3-10 -carbocyclyl or 3-10-membered heterocyclyl; each R a independently represents C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-6 -hydroxyalkyl, C 1-6 -aminoalkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-10 -carbocyclyl, 3-10-membered heterocyclyl, C 6-14-aryl or 5-14-membered heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more of the following substituents: oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1-6 -alkyl or C 1-6 -haloalkyl; each R b independently represents hydrogen, C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-6 -hydroxyalkyl, C 1-6 -aminoalkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-10 -carbocyclyl, 3-10-membered heterocyclyl, C 6-14 -aryl or 5-14-membered heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more of the following substituents: oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1-6 -alkyl or C1-6 -haloalkyl; and each of R c and R d independently represents hydrogen, C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-6 -hydroxyalkyl, C 1-6 -aminoalkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-10 -carbocyclyl, 3-10-membered heterocyclyl, C 6-14 -aryl or 5-14-membered heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more of the following substituents: oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1-6 -alkyl or C 1-6 -haloalkyl; or R c and R d , together with the nitrogen atom to which they are attached, form a 3- to 10-membered heterocyclyl, optionally substituted with one or more of the following substituents: oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C 1-6-alkyl or C 1-6 -haloalkyl.

2. The compound according to claim 1, wherein each R1 independently represents halogen, C 1-6 -alkyl, C 1-6 -alkoxy or C 6-14 -aryl.

3. The compound of claim 1 or 2, wherein m is 0, 1, or 2.

4. A compound according to any one of paragraphs 1-3, in which each R 2 independently represents halogen or C 1-6 -alkyl.

5. A compound according to any one of paragraphs 1-4, in which each R 2 is a halogen.

6. A compound according to any one of paragraphs 1-5, in which each R 2 is a chloride.

7. A compound according to any one of paragraphs 1-6, in which R 3 represents -CN, -C(=O)OR b or -C(=O)NR c R d .

8. A compound according to any one of paragraphs 1-7, in which R 3 represents -CN.

9. A compound according to any one of paragraphs 1-7, in which each of R c and R drepresents H.

10. A compound according to any one of paragraphs 1-7, in which R 3 is -C(=O)NH2.

11. A compound according to any one of paragraphs 1-7, in which R b represents H.

12. A compound according to any one of paragraphs 1-7, in which R 3 represents -C(=O)OH.

13. A compound according to any one of paragraphs 1-12, in which R 4 is hydrogen.

14. A compound according to any one of claims 1 to 13, wherein n is 0.

15. A compound according to any one of paragraphs 1-14, in which R 6 is hydrogen.

16. A compound according to any one of claims 1 to 15, wherein X is O.

17. The compound of claim 1, wherein the compound is selected from the compounds described in Table I and the corresponding pharmaceutically acceptable salts, stereoisomers and solvates.

18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17, or a corresponding pharmaceutically acceptable salt, stereoisomer or solvate, and a pharmaceutically acceptable excipient.

19. A method for activating a thyroid hormone receptor (THR) beta in a patient or in a biological sample, the method comprising contacting the patient or biological sample with a compound according to any one of claims 1-17, or with a corresponding pharmaceutically acceptable salt, stereoisomer or solvate.

20. A method for treating a disease or disorder of liver function, or a disease or disorder of lipid metabolism, the method comprising administering to a patient in need thereof a compound according to any one of claims 1-17, or a corresponding pharmaceutically acceptable salt, stereoisomer or solvate.

21. The method of claim 20, wherein the liver disease or disorder is non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), or fatty liver disease.

22. The method of claim 20, wherein the lipid metabolism disease or disorder is dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low high-density lipoprotein (HDL) or high low-density lipoprotein (LDL).

23. The method of claim 22, wherein the hypercholesterolemia is heterozygous familial hypercholesterolemia (HeFH) or homozygous familial hypercholesterolemia (HoFH).

24. Use of a compound according to any one of claims 1 to 17 or a corresponding pharmaceutically acceptable salt, stereoisomer or solvate in the manufacture of a medicament for the treatment of a disease or disorder of liver function, or a disease or disorder of lipid metabolism.

25. The use according to claim 24, wherein the liver disease or disorder is non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) or fatty liver disease.

26. The use according to claim 24, wherein the lipid metabolism disease or disorder is dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low high-density lipoprotein (HDL) or high low-density lipoprotein (LDL).

27. The use according to claim 26, wherein the hypercholesterolemia is heterozygous familial hypercholesterolemia (HeFH) or homozygous familial hypercholesterolemia (HoFH).

28. A compound according to any one of claims 1 to 17, or a corresponding pharmaceutically acceptable salt, stereoisomer or solvate, or use in the treatment of a disease or disorder of the liver, or a disease or disorder of lipid metabolism.

29. A compound for use according to claim 28, wherein the liver disease or disorder is non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) or fatty liver disease.

30. A compound for use according to claim 28, wherein the lipid metabolism disease or disorder is dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low high-density lipoprotein (HDL) or high low-density lipoprotein (LDL).

31. A compound for use according to claim 30, wherein the hypercholesterolemia is heterozygous familial hypercholesterolemia (HeFH) or homozygous familial hypercholesterolemia (HoFH).