TRIAZOLOPYRIDIN-3-ONES OR THEIR SALTS AND PHARMACEUTICAL COMPOSITIONS COMPRISING THE SAME

20200223844

16/712673

December 12, 2019

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).

1. A compound of Formula X [chemical expression included] or a stereoisomer thereof or a pharmaceutically acceptable salt thereof; wherein R1 is hydrogen or fluoro; and R2 and R3, each independently, are selected from the group consisting of hydrogen, halogen, C1-6 alkyl, —R, and —C≡C—R; wherein said R is 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 compound or a stereoisomer thereof or a pharmaceutically acceptable salt thereof of claim 1, wherein R is substituted or unsubstituted aryl.

3. The compound or a stereoisomer thereof or a pharmaceutically acceptable salt thereof of claim 1, wherein R is substituted or unsubstituted phenyl.

4. The compound or a stereoisomer thereof or a pharmaceutically acceptable salt thereof of claim 1, wherein R is substituted or unsubstituted heteroaryl.

5. The compound or a stereoisomer thereof or a pharmaceutically acceptable salt thereof of claim 1, wherein R is substituted or unsubstituted non-aromatic heterocyclic.

6. The compound or a stereoisomer thereof or a pharmaceutically acceptable salt thereof of claim 1, wherein the substituted or unsubstituted cyclic ring is selected from the group consisting of substituted or unsubstituted benzene, substituted or unsubstituted pyridine, substituted or unsubstituted tetrahydropyridine, substituted or unsubstituted pyrazole, substituted or unsubstituted benzodioxole, substituted or unsubstituted 2,3-dihydro benzodioxine, substituted or unsubstituted benzothiazole, substituted or unsubstituted benzoxadiazole, substituted or unsubstituted benzotriazole, substituted or unsubstituted indazole, substituted or unsubstituted pyrrolo[2,3-b]pyridine, substituted or unsubstituted 3,4-dihydroquinolin-2-one, substituted or unsubstituted 3,4-dihydro-1,4-benzoxazine, substituted or unsubstituted 1,4-benzoxazin-3-one, substituted or unsubstituted 1,3-dihydro-3,1-benzoxazin-2-one, substituted or unsubstituted 2,3-dihydro-pyrido[2,3-b][1,4]oxazine, substituted or unsubstituted pyrido[2,3-b][1,4]oxazin-2-one, substituted or unsubstituted 3,4-dihydro-pyrido[3,2-b][1,4]oxazine, and substituted or unsubstituted pyrido[3,2-b][1,4]oxazin-3-one.

7. (canceled)

8. The compound or a stereoisomer thereof or a pharmaceutically acceptable salt thereof of claim 1, wherein said R1 is fluoro.

9. The compound or a stereoisomer thereof or a pharmaceutically acceptable salt thereof of claim 1, wherein said R1 is hydrogen.

10. The compound or a stereoisomer thereof or a pharmaceutically acceptable salt thereof of claim 1, wherein said R2 is hydrogen and R3 is halogen, —R, or —C≡C—R.

11.-16. (canceled)

17. The compound or a stereoisomer thereof or a pharmaceutically acceptable salt thereof of claim 1, wherein R1 is fluoro, R2 is hydrogen, R3 is halogen or —R, wherein said R is a cyclic ring selected from the group consisting of benzene and pyrazole, wherein said cyclic ring is substituted with a substituent selected from the group consisting of C1-6 alkyl, C1-6 alkylsulfonyl, and piperazinyl.

18. The compound of claim 1 of Formula 11 [chemical expression included] or a stereoisomer thereof or a pharmaceutically acceptable salt thereof; wherein R3 is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

19. The compound or a stereoisomer thereof or a pharmaceutically acceptable salt thereof of claim 18, wherein R3 is substituted aryl.

20. (canceled)

21. The compound or a stereoisomer thereof or a pharmaceutically acceptable salt thereof of claim 19, wherein R3 is substituted or unsubstituted benzodioxole, substituted or unsubstituted benzoxadiazole, or phenyl, wherein the phenyl is substituted with C1-6 alkylcarbonylamino or oxazolyl.

22. The compound of claim 1 of Formula 12 [chemical expression included] or a stereoisomer thereof or a pharmaceutically acceptable salt thereof; wherein R3 is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

23. The compound or a stereoisomer thereof or a pharmaceutically acceptable salt thereof of claim 22, wherein R3 is substituted or unsubstituted benzodioxole, substituted or unsubstituted 2,3-dihydrobenzodioxine, substituted or unsubstituted 3,4-dihydroquinolin-2-one, substituted or unsubstituted benzothiazole, substituted or unsubstituted benzoxadiazole, substituted benzene, or substituted pyridine.

24. (canceled)

25. The compound of claim 1 of Formula 13 [chemical expression included] or a stereoisomer thereof or a pharmaceutically acceptable salt thereof; wherein R3 is substituted or unsubstituted aryl, or a substituted or unsubstituted cyclic ring.

26. The compound or a stereoisomer thereof or a pharmaceutically acceptable salt thereof of claim 25, wherein R3 is substituted or unsubstituted aryl.

27. The compound or a stereoisomer thereof or a pharmaceutically acceptable salt thereof of claim 26, wherein R3 is substituted or unsubstituted benzoxadiazole, substituted or unsubstituted 3,4-dihydroquinolin-2-one, substituted or unsubstituted benzodioxole, substituted or unsubstituted indazole, substituted or unsubstituted pyrazole, substituted or unsubstituted benzotriazole, substituted or unsubstituted 1,3-dihydro-3,1-benzoxazin-2-one, substituted or unsubstituted 1,4-benzoxazin-3-one, substituted or unsubstituted 3,4-dihydro-1,4-benzoxazine, or substituted phenyl.

28. (canceled)

29. The compound or a stereoisomer thereof or a pharmaceutically acceptable salt thereof of claim 25, wherein R3 is a substituted or unsubstituted heterocyclic group.

30. (canceled)

31. The compound or a stereoisomer thereof or a pharmaceutically acceptable salt thereof of claim 29, wherein R3 is substituted or unsubstituted heteroaryl.

32. (canceled)

33. (canceled)

34. The compound or a stereoisomer thereof or a pharmaceutically acceptable salt thereof of claim 25, wherein R3 is a cyclic ring selected from the group consisting of benzene, pyridine, benzoxadiazole, 3,4-dihydroquinolin-2-one, benzodioxole, indazole, benzotriazole, 1,3-dihydro-3,1-benzoxazin-2-one, 1,4-benzoxazin-3-one, 3,4-dihydro-1,4-benzoxazine, or pyrrolo[2,3-b]pyridine; wherein said cyclic ring is optionally substituted with a substituent selected from the group consisting of C1-6 alkyl, trifluoromethyl, C1-6 alkoxy, mono- or di-C1-6 alkylamino, di-C1-6 alkylaminomethyl, C1-6 alkylsulfonyl, morpholinylcarbonyl, morpholinyl, pyrazolyl, oxazolyl, oxadiazolyl, and cyclopropyl-oxadiazolyl.

35. The compound of claim 1 of Formula 14 [chemical expression included] or a stereoisomer thereof or a pharmaceutically acceptable salt thereof; wherein R3 is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

36. The compound or a stereoisomer thereof or a pharmaceutically acceptable salt thereof of claim 35, wherein R3 is substituted aryl.

37. (canceled)

38. The compound or a stereoisomer thereof or a pharmaceutically acceptable salt thereof of claim 35, wherein R3 is substituted or unsubstituted heteroaryl.

39. The compound or a stereoisomer thereof or a pharmaceutically acceptable salt thereof of claim 38, wherein R3 is substituted pyrazole, substituted pyridine, substituted or unsubstituted 2,3-dihydro-pyrido[2,3-b][1,4]oxazine, or substituted or unsubstituted 3,4-dihydro-pyrido[3,2-b][1,4]oxazine.

40. (canceled)

41. The compound or a stereoisomer thereof or a pharmaceutically acceptable salt thereof of claim 1, which is 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)-one; 2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-6-[4-(1H-1,2,4-triazol-3-yl)phenyl][1,2,4]triazolo[4,3-a]pyridin-3(2H)-one; 2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-6-[3-(1H-1,2,4-triazol-3-yl)phenyl][1,2,4]triazolo[4,3-a]pyridin-3(2H)-one; 2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-6-[4-(1,2-oxazol-3-yl)phenyl][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]pyridin-2-yl]acetamide; 2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-6-[6-(trifluoromethyl)pyridin-3-yl][1,2,4]triazolo[4,3-a]pyridin-3(2H)-one; 2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-6-[6-(morpholin-4-yl)pyridin-3-yl][1,2,4]triazolo[4,3-a]pyridin-3(2H)-one; 2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-6-[6-(morpholin-4-yl)pyridin-3-yl][1,2,4]triazolo[4,3-a]pyridin-3(2H)-one; 2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-6-(1,3-benzodioxol-5-yl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one; 2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-6-(2,3-dihydro-1,4-benzodioxin-6-yl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one; 6-(2-amino-1,3-benzothiazol-5-yl)-2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl][1,2,4]triazolo[4,3-a]pyridin-3(2H)-one; N-[5-[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]-1,3-benzothiazol-2-yl]acetamide; 2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-6-(2,1,3-benzoxadiazol-5-yl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one; 6-[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]-8-methyl-3,4-dihydroquinolin-2(1H)-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-5-yl]phenyl]acetamide; 2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-5-[4-(1,2-oxazol-3-yl)phenyl][1,2,4]triazolo[4,3-a]pyridin-3(2H)-one; 2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-5-(1,3-benzodioxol-5-yl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one; 2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-5-(2,1,3-benzoxadiazol-5-yl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one; 2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-7-[3-(methylsulfonyl)phenyl][1,2,4]triazolo[4,3-a]pyridin-3(2H)-one; 2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-7-2-[(dimethylamino)methyl]phenyl[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one; 2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-7-[4-(morpholin-4-ylcarbonyl)phenyl][1,2,4]triazolo[4,3-a]pyridin-3(2H)-one; 2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-7-[4-(1,2-oxazol-3-yl)phenyl][1,2,4]triazolo[4,3-a]pyridin-3(2H)-one; 2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-7-[3-(1H-pyrazol-3-yl)phenyl][1,2,4]triazolo[4,3-a]pyridin-3(2H)-one; 2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-7-[4-(1,2,5-oxadiazol-3-yl)phenyl][1,2,4]triazolo[4,3-a]pyridin-3(2H)-one; 2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-7-[3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl][1,2,4]triazolo[4,3-a]pyridin-3(2H)-one; 2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-7-[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl][1,2,4]triazolo[4,3-a]pyridin-3(2H)-one; 2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-7-[6-(trifluoromethyl)pyridin-3-yl][1,2,4]triazolo[4,3-a]pyridin-3(2H)-one; 2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-7-(6-methoxypyridin-3-yl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one; 2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-7-[6-(dimethylamino)pyridin-3-yl][1,2,4]triazolo[4,3-a]pyridin-3(2H)-one; 2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-7-[6-(morpholin-4-yl)pyridin-3-yl][1,2,4]triazolo[4,3-a]pyridin-3(2H)-one; 2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-7-(1,2,3,6-tetrahydropyridin-4-yl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one; 2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-7-(1H-pyrrolo[2,3-b]pyridin-3-yl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one; 2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-7-(1,3-benzodioxol-5-yl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one; 2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-7-(1H-indazol-6-yl)[1,2,4]triazolo[4,3a]pyridin-3(2H)-one; 2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-7-(2,1,3-benzoxadiazol-5-yl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one; 2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-7-(1H-benzotriazol-6-yl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one; 2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-7-(1H-pyrrolo[2,3-b]pyridin-4-yl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one; 7-[2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-3-oxo-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-7-yl]-1,4-dihydro-2H-3,1-benzoxazin-2-one; 6-[2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-3-oxo-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-7-yl]-2H-1,4-benzoxazine-3(4H)-one; 6-[2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-3-oxo-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-7-yl]-8-methyl-3,4-dihydroquinolin-2(1H)-one; 2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-7-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one; 2-[2-(aminomethyl)-3,3-difluoro-allyl]-5-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-one; 2-[2-(aminomethyl)-3,3-difluoro-allyl]-6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-one; 2-[2-(aminomethyl)-3,3-difluoro-allyl]-7-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-one; 2-[2-(aminomethyl)-3,3-difluoro-allyl]-7-(4-methylsulfonylphenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-one; 2-[2-(aminomethyl)-3,3-difluoro-allyl]-7-(4-piperazin-1-ylphenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-one; 2-[2-(aminomethyl)-3,3-difluoro-allyl]-7-[6-(trifluoromethyl)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridin-3-one; 2-[2-(aminomethyl)-3,3-difluoro-allyl]-7-[6-(dimethylamino)-3-pyridyl]-[1,2,4]triazolo[4,3-a]pyridin-3-one; 2-[2-(aminomethyl)-3,3-difluoro-allyl]-7-(1,3-benzodioxol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-one; 6-[2-[2-(aminomethyl)-3,3-difluoro-allyl]-3-oxo-[1,2,4]triazolo[4,3-a]pyridin-7-yl]-8-methyl-3,4-dihydro-1H-quinolin-2-one; 6-[2-[2-(aminomethyl)-3,3-difluoro-allyl]-3-oxo-[1,2,4]triazolo[4,3-a]pyridin-7-yl]-1-methyl-3,4-dihydroquinolin-2-one; 2-[2-(aminomethyl)-3,3-difluoro-allyl]-7-(1-ethylpyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-one; 2-[2-(aminomethyl)-3,3-difluoro-allyl]-7-[2-(1-methylpyrazol-4-yl)ethynyl]-[1,2,4]triazolo[4,3-a]pyridin-3-one; 2-[2-(aminomethyl)-3,3-difluoro-allyl]-7-[2-[6-(dimethylamino)-3-pyridyl]ethynyl]-[1,2,4]triazolo[4,3-a]pyridin-3-one; 2-[2-(aminomethyl)-3,3-difluoro-allyl]-7-[2-(6-morpholino-3-pyridyl)ethynyl]-[1,2,4]triazolo[4,3-a]pyridin-3-one; 2-[2-(aminomethyl)-3,3-difluoro-allyl]-7-[2-(3,4-dihydro-2H-1,4-benzoxazin-6-yl)ethynyl]-[1,2,4]triazolo[4,3-a]pyridin-3-one; 2-[2-(aminomethyl)-3,3-difluoro-allyl]-7-[2-(2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)ethynyl]-[1,2,4]triazolo[4,3-a]pyridin-3-one; 2-[2-(aminomethyl)-3,3-difluoro-allyl]-7-[2-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)ethynyl]-[1,2,4]triazolo[4,3-a]pyridin-3-one; 6-[2-[2-[2-(aminomethyl)-3,3-difluoro-allyl]-3-oxo-[1,2,4]triazolo[4,3-a]pyridin-7-yl]ethynyl]-3,4-dihydro-1H-quinolin-2-one; and 2-[2-(aminomethyl)-3,3-difluoro-allyl]-7-[2-(4-methyl-2,3-dihydro-1,4-benzoxazin-7-yl)ethynyl]-[1,2,4]triazolo[4,3-a]pyridin-3-one; or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

42. A pharmaceutical composition comprising the compound according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

43. A method of inhibiting vascular adhesion protein (VAP-1), comprising administering to a mammal a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof according to claim 1.

44. A method of treating NASH in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

45.-49. (canceled)

50. A method of treating a disease mediated by VAP-1 in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

51. The method of claim 50, wherein the disease mediated by VAP-1 is selected from the group consisting of lipid and lipoprotein disorders, conditions and diseases which result from chronic fatty and fibrotic degeneration of organs due to accumulated lipid and specifically triglyceride accumulation and subsequent activation of profibrotic pathways, Type I or Type II Diabetes and clinical complications of Type I and Type II Diabetes, chronic intrahepatic or some forms of extrahepatic cholestatic conditions, liver fibrosis, acute intraheptic cholestatic conditions, obstructive or chronic inflammatory disorders that arise out of improper bile composition, gastrointestinal conditions with a reduced uptake of dietary fat and fat-soluble dietary vitamins, inflammatory bowel diseases, obesity and metabolic syndrome (combined conditions of dyslipidemia, diabetes and abnormally high body-mass index), persistent infections by intracellular bacteria or parasitic protozoae, non-malignant hyperproliferative disorders, malignant hyperproliferative disorders, colon adenocarcinoma and hepatocellular carcinoma in particular, liver steatosis and associated syndromes, Hepatitis B infection, Hepatitis C infection and/or of cholestatic and fibrotic effects that are associated with alcohol-induced cirrhosis or with viral-borne forms of hepatitis, liver failure or liver malfunction as an outcome of chronic liver diseases or of surgical liver resection, acute myocardial infarction, acute stroke, thrombosis which occurs as an endpoint of chronic obstructive atherosclerosis, osteoarthritis, rheumatoid arthritis, psoriasis, and cerebral infarction, individually or any combination thereof.

52. A method of preparing a compound of Formula 1a, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, [chemical expression included] the method comprising (a) reacting a compound of Formula 2 with a compound of Formula 3a or a compound of Formula 3b to obtain a compound of Formula 1aa: [chemical expression included] wherein Boc is an amine protecting group; R1 is hydrogen or fluoro; R3 is selected from the group consisting of C1-6 alkyl, —R, and —C≡C—R; R is 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; and Z is is boronic acid (B(OH)2) or boronic acid pinacol ester; and (b) removing Boc from the compound of Formula 1aa under reaction conditions to obtain the compound of Formula 1a, or the stereoisomer thereof, or the pharmaceutically acceptable salt thereof.

53. The method of claim 52, wherein the compound of Formula 2 is obtained by (a) reacting a compound of Formula 4 with hydrazine to obtain a compound of Formula 5: [chemical expression included] wherein X is F or Cl; (b) reacting the compound of Formula 5 under cyclization conditions to obtain a compound of Formula 6: [chemical expression included] and (c) reacting the compound of Formula 6 with a compound of Formula 8 to obtain the compound of Formula 2: [chemical expression included] wherein R1 is hydrogen or fluoro.

54. The method of claim 53, wherein the cyclization conditions comprise reacting the compound of Formula 5 with carbonyldiimidazole (CDI) in a polar solvent at a temperature ranging from room temperature to 90° C.

55. The method of claim 52, wherein R is a cyclic ring selected from the group consisting of benzene, pyridine, tetrahydropyridine, pyrazole, benzodioxole, 2,3-dihydrobenzodioxine, benzothiazole, benzoxadiazole, benzotriazole, indazole, pyrrolo[2,3-b]pyridine, 3,4-dihydroquinolin-2-one, 3,4-dihydro-1,4-benzoxazine, 1,4-benzoxazin-3-one, 1,3-dihydro-3,1-benzoxazin-2-one, 2,3-dihydro-pyrido[2,3-b][1,4]oxazine, pyrido[2,3-b][1,4]oxazin-2-one, 3,4-dihydro-pyrido[3,2-b][1,4]oxazine, and pyrido[3,2-b][1,4]oxazin-3-one, wherein said cyclic ring is optionally substituted with a substituent selected from the group consisting of C1-6 alkyl, trifluoromethyl, C1-6 alkoxy, amino, mono- or di-C1-6 alkylamino, di-C1-6 alkylaminomethyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonyl, morpholinylsulfonyl, morpholinylcarbonyl, piperazinyl, morpholinyl, triazolyl, pyrazolyl, oxazolyl, oxadiazolyl, and cyclopropyl-oxadiazolyl.

56. A method of treating NASH in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition according to claim 42.

57. A method of treating a disease mediated by VAP-1 in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition according to claim 42.

58. The method of claim 57, wherein the disease mediated by VAP-1 is selected from the group consisting of lipid and lipoprotein disorders, conditions and diseases which result from chronic fatty and fibrotic degeneration of organs due to accumulated lipid and specifically triglyceride accumulation and subsequent activation of profibrotic pathways, Type I or Type II Diabetes and clinical complications of Type I and Type II Diabetes, chronic intrahepatic or some forms of extrahepatic cholestatic conditions, liver fibrosis, acute intraheptic cholestatic conditions, obstructive or chronic inflammatory disorders that arise out of improper bile composition, gastrointestinal conditions with a reduced uptake of dietary fat and fat-soluble dietary vitamins, inflammatory bowel diseases, obesity and metabolic syndrome (combined conditions of dyslipidemia, diabetes and abnormally high body-mass index), persistent infections by intracellular bacteria or parasitic protozoae, non-malignant hyperproliferative disorders, malignant hyperproliferative disorders, colon adenocarcinoma and hepatocellular carcinoma in particular, liver steatosis and associated syndromes, Hepatitis B infection, Hepatitis C infection and/or of cholestatic and fibrotic effects that are associated with alcohol-induced cirrhosis or with viral-borne forms of hepatitis, liver failure or liver malfunction as an outcome of chronic liver diseases or of surgical liver resection, acute myocardial infarction, acute stroke, thrombosis which occurs as an endpoint of chronic obstructive atherosclerosis, osteoarthritis, rheumatoid arthritis, psoriasis, and cerebral infarction, individually or any combination thereof.

07; 07

edspap.20200223844