Triazolopyridin-3-ones or their salts and pharmaceutical compositions comprising the same

Patent metadata

Field	Value
Publication number	US-11820769-B2
Application number	US-202117368712-A
Country	US
Kind code	B2
Filing date	Jul 6, 2021
Priority date	Dec 14, 2018
Publication date	Nov 21, 2023
Grant date	Nov 21, 2023

Abstract

The present technology provides triazolopyridin-3-ones or pharmaceutically acceptable salts thereof, preparation processes thereof, pharmaceutical compositions comprising the same, and uses thereof. The triazolopyridin-3-ones or their pharmaceutically acceptable salts exhibit inhibitory activity on VAP-1 and therefore can be usefully applied, e.g., for the treatment and prophylaxis of nonalcoholic hepatosteatosis (NASH).

First claim

The invention claimed is:

1. A method for treating diabetic kidney disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula X

or a stereoisomer thereof or a pharmaceutically acceptable salt thereof;
wherein
R 1 is hydrogen or fluoro; and
R 2 and R 3 , each independently, are selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, —R, and —C≡C—R;
wherein said R is a substituted or unsubstituted cyclic ring, optionally containing 1 to 5 heteroatom ring members chosen from O, N, or S, and the cyclic ring is aromatic or non-aromatic.

2. The method of claim 1 , wherein R is substituted or unsubstituted aryl.

3. The method of claim 1 , wherein R is substituted or unsubstituted phenyl.

4. The method of claim 1 , wherein R is substituted or unsubstituted heteroaryl.

5. The method of claim 1 , wherein R is substituted or unsubstituted non-aromatic heterocyclic ring.

6. The method of claim 1 , wherein the substituted or unsubstituted cyclic ring is selected from the group consisting of substituted or unsubstituted phenyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted tetrahydropyridinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted benzodioxolyl, substituted or unsubstituted 2,3-dihydro-benzodioxinyl, substituted or unsubstituted benzothiazolyl, substituted or unsubstituted benzoxadiazolyl, substituted or unsubstituted benzotriazolyl, substituted or unsubstituted indazolyl, substituted or unsubstituted pyrrolo[2,3-b]pyridinyl, substituted or unsubstituted 3,4-dihydroquinolin-2-onyl, substituted or unsubstituted 3,4-dihydro-1,4-benzoxazinyl, substituted or unsubstituted 1,4-benzoxazin-3-onyl, substituted or unsubstituted 1,3-dihydro-3,1-benzoxazin-2-onyl, substituted or unsubstituted 2,3-dihydro-pyrido[2,3-b][1,4]oxazinyl, substituted or unsubstituted pyrido[2,3-b][1,4]oxazin-2-onyl, substituted or unsubstituted 3,4-dihydro-pyrido[3,2-b][1,4]oxazinyl, and substituted or unsubstituted pyrido[3,2-b][1,4]oxazin-3-onyl.

7. The method of claim 1 , wherein said R 1 is fluoro.

8. The method of claim 1 , wherein said R 1 is hydrogen.

9. The method of claim 1 , wherein said R 2 is hydrogen and R 3 is halogen, —R, or —C≡C—R.

10. The method of claim 1 , wherein
R 1 is fluoro,
R 2 is hydrogen,
R 3 is halogen or —R,
wherein said R is selected from the group consisting of phenyl and pyrazolyl, and
wherein R is substituted with a substituent selected from the group consisting of C 1-6 alkyl, C 1-6 alkylsulfonyl, and piperazinyl.

11. The method of claim 1 , wherein the compound is of Formula 11

or a stereoisomer thereof or a pharmaceutically acceptable salt thereof;
wherein
R 3 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted benzodioxolyl.

12. The method of claim 11 , wherein R 3 is substituted aryl.

13. The method of claim 11 , wherein R 3 is substituted or unsubstituted benzodioxolyl, substituted or unsubstituted benzoxadiazolyl, or phenyl, wherein the phenyl is substituted with C 1-6 alkylcarbonylamino or oxazolyl.

14. The method of claim 1 , wherein the compound is of Formula 12

or a stereoisomer thereof or a pharmaceutically acceptable salt thereof;
wherein
R 3 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic ring.

15. The method of claim 14 , wherein R 3 is substituted or unsubstituted benzodioxolyl, substituted or unsubstituted 2,3-dihydrobenzodioxinyl, substituted or unsubstituted 3,4-dihydroquinolin-2-onyl, substituted or unsubstituted benzothiazolyl, substituted or unsubstituted benzoxadiazolyl, substituted phenyl, or substituted pyridinyl.

16. The method of claim 1 , wherein the compound is of Formula 13

or a stereoisomer thereof or a pharmaceutically acceptable salt thereof;
wherein
R 3 is substituted or unsubstituted aryl or a substituted or unsubstituted cyclic ring.

17. The method of claim 16 , wherein R 3 is substituted or unsubstituted aryl.

18. The method of claim 16 , wherein R 3 is substituted or unsubstituted benzoxadiazolyl, substituted or unsubstituted 3,4-dihydroquinolin-2-onyl, substituted or unsubstituted benzodioxolyl, substituted or unsubstituted indazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted benzotriazolyl, substituted or unsubstituted 1,3-dihydro-3,1-benzoxazin-2-onyl, substituted or unsubstituted 1,4-benzoxazin-3-onyl, substituted or unsubstituted 3,4-dihydro-1,4-benzoxazinyl, or substituted phenyl.

19. The method of claim 16 , wherein R 3 is a substituted or unsubstituted heterocyclic group.

20. The method of claim 16 , wherein R 3 is substituted or unsubstituted heteroaryl.

21. The method of claim 16 , wherein R 3 is selected from the group consisting of phenyl, pyridinyl, benzoxadiazolyl, 3,4-dihydroquinolin-2-onyl, benzodioxolyl, indazolyl, benzotriazolyl, 1,3-dihydro-3,1-benzoxazin-2-onyl, 1,4-benzoxazin-3-onyl, 3,4-dihydro-1,4-benzoxazinyl, and pyrrolo[2,3-b]pyridinyl;
wherein R 3 is optionally substituted with a substituent selected from the group consisting of C 1-6 alkyl, trifluoromethyl, C 1-6 alkoxy, mono- or di-C 1-6 alkylamino, alkylaminomethyl, C 1-6 alkyl sulfonyl, morpholinylcarbonyl, morpholinyl, pyrazolyl, oxazolyl, oxadiazolyl, and cyclopropyl-oxadiazolyl.

22. The method of claim 1 , wherein the compound is of Formula 14

or a stereoisomer thereof or a pharmaceutically acceptable salt thereof;
wherein
R is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic ring.

23. The method of claim 22 , wherein R is substituted aryl.

24. The method of claim 22 , wherein R is substituted or unsubstituted heteroaryl.

25. The method of claim 22 , wherein R is substituted pyrazoyl, substituted pyridinyl, substituted or unsubstituted 2,3-dihydro-pyrido[2,3-b][1,4]oxazinyl, or substituted or unsubstituted 3,4-dihydro-pyrido[3,2-b][1,4]oxazinyl.

26. A method for treating diabetic kidney disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound selected from the group consisting of:
2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-6-bromo[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;
N-[4-[2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-3-oxo-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl]phenyl]acetamide;
2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-6-[4-(methylsulfonyl)phenyl][1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;
2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-6-[4-(morpholin-4-ylsulfonyl)phenyl][1,2,4]triazolo[4,3-a]pyridin-3(2H

Assignees

• Yuhan Corp

Inventors

• Han Tae Dong
• Tak Hee Jae
• Kim Eun Kyung
• Kim Dong Hoon
• Choi Su Bin
• Park Sol
• Choi Hyun Ho
• Kim Tae Wang
• Ju Mi Kyeong
• Ha Na Ry

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D519/00 Primary

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title

• A61K31/4709

  Non-condensed quinolines and containing further heterocyclic rings · CPC title