Aryl or heteroaryl triazolone derivatives or salts thereof, or pharmaceutical compositions comprising the same

Patent metadata

Field	Value
Publication number	US-10562865-B2
Application number	US-201916359984-A
Country	US
Kind code	B2
Filing date	Mar 20, 2019
Priority date	Mar 21, 2018
Publication date	Feb 18, 2020
Grant date	Feb 18, 2020

Abstract

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

First claim

What is claimed is:

1. A compound of Formula X, or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof:

wherein
A is an aryl or heteroaryl group, said heteroaryl group has 1 to 5 heteroatom ring members chosen from O, N, or S, and said aryl or heteroaryl group is optionally substituted with one to three substituents chosen from C 1-3 alkyl, C 1-3 alkoxy, halogen, benzyloxy, —R, —CH 2 —R, —CH═CH—R, and —C≡C—R; and
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 or a tautomer thereof, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein A is selected from phenyl, naphthalene, pyridine, pyrimidine, pyrazine, triazine, thiazole, thiophene, pyrrole, pyrazole, imidazole, triazole, tetrazole, furan, oxazole, isoxazole, oxadiazole, and thiadiazole.

3. The compound, or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein A is selected from phenyl, pyridine, pyrazine, and thiazole.

4. A compound of Formula 1 below

or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof;
wherein
A is an aryl or heteroaryl group selected from the group consisting of phenyl, pyridine, pyrazine, and thiazole,
wherein said aryl or heteroaryl group is optionally substituted with one to three substituents selected from the group consisting of C 1-3 alkyl, C 1-3 alkoxy, halogen, benzyloxy, —R, —CH 2 —R, —CH═CH—R, and —C≡C—R,
wherein said R is a cyclic ring selected from the group consisting of benzene, phenylbenzene, pyridine, tetrahydropyridine, pyridin-2-one, pyrimidine, thiophene, thiazole, imidazole, pyrazole, piperazine, morpholine, benzodioxole, benzoxadiazole, benzothiophene, benzothiazole, 2,3-dihydro-benzodioxine, indazole, indole, 1,3-dihydroindol-2-one, 1,2-dihydroindol-3-one, quinoline, isoquinoline, quinolin-2-one, 3,4-dihydroquinolin-2-one, 3,4-dihydro-1,4-benzoxazine, 1,4-benzoxazin-3-one, 3,1-benzoxazin-2-one, 2,3-dihydro-imidazo[4,5-b]pyridine, oxazolo[4,5-b]pyridin-2-one, 2,3-dihydro-pyrido[2,3-b][1,4]oxazine, 3,4-dihydro-pyrido[3,2-b][1,4]oxazine, pyrido[2,3-b][1,4]oxazin-2-one, pyrido[3,2-b][1,4]oxazin-3-one, and dibenzo[b,d]furan,
wherein said cyclic ring is optionally substituted with one or two substituents selected from the group consisting of hydroxy, halogen, C 1-6 alkyl, trifluoromethyl, C 1-6 alkoxy, trifluoromethoxy, amino, mono- or di-C 1-6 alkylamino, C 1-6 alkylcarbonylamino, C 1-6 alkylthio, mono- or di-C 1-6 alkylaminosulfonyl, C 1-6 alkylsulfonyl, C 1-6 alkylcarbonyl, morpholinylcarbonyl, benzodioxolyl, pyrrolidinyl, piperazinyl, acetylpiperazinyl, morpholinyl, tetrahydropyranyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, cyclopropyl-oxadiazolyl, C 1-6 alkyl-oxadiazolyl, and oxadiazol-5-onyl.

5. The compound, or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein A is pyridine.

6. The compound, or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein said aryl or heteroaryl group is substituted with one or two substituents selected from the group consisting of C 1-3 alkyl, halogen, —R, and —C≡C—R.

7. The compound, or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein said R is a cyclic ring selected from the group consisting of benzene, pyridine, and pyrazole.

8. The compound, or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, of claim 7 , wherein said cyclic ring is unsubstituted; or substituted with a substituent selected from the group consisting of C 1-6 alkyl, trifluoromethyl, and oxazolyl.

9. The compound, or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein
A is pyridine,
wherein said pyridine is substituted with one or two substituents selected from the group consisting of C 1-3 alkyl, halogen, —R, and —C≡C—R,
wherein said R is a cyclic ring selected from the group consisting of benzene, pyridine, and pyrazole,
wherein said cyclic ring is unsubstituted; or substituted with a substituent selected from the group consisting of C 1-6 alkyl, trifluoromethyl, and oxazolyl.

10. The compound of claim 1 , which is selected from the group consisting of the compounds below:
2-[(2Z)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-4-(4-bromophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;
2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-4-(4-bromophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;
2-[(2Z)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-4-(3-bromophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one hydrochloride;
2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-4-(3-bromophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one hydrochloride;
2-[(2Z)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-4-(4-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;
2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-4-(4-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one hydrochloride;
2-[(2Z)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-4-[4-(benzyloxy)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;
2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-4-[4-(benzyloxy)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one hydrochloride;
2-[(2Z)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-4-(3,4-difluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;
2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-4-(3,4-difluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one hydrochloride;
2-[(2Z)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-4-(4-bromo-2-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one hydrochloride;
2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-4-(4-bromo-2-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one hydrochloride;
2-[(2Z)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-4-(4-bromo-3-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;
2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-4-(4-bromo-3-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one hydrochloride;
2-[(2Z)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-4-(4-bromo-3-methylphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;
2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-4-(4-bromo-3-methylphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one hydrochloride;
2-[(2Z)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-4-(4-bromo-3-methoxyphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;
2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-4-(4-bromo-3-methoxyphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one hydrochloride;
2-[(2Z)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-4-(4-bromo-3,5-difluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;
2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-4-(4-bromo-3,5-difluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one hydrochloride;
2-[(2Z)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-4-(4-bromo-2,6-difluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one hydrochloride;
2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-4-(4-bromo-2,6-difluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one hydrochloride;
2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-4-(4-bromo-2,5-difluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one hydrochloride;
2-[(2Z)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-4-(6-bromopyridin-3-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one;
2-[(2E)-2-(aminomethyl)-3-fluoroprop-2-en-1-yl]-4-(6-bromopyridin-3-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one h

Assignees

• Yuhan Corp

Inventors

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

Classifications

• C07D403/14

  containing three or more hetero rings · CPC title

• C07D403/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D401/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D407/14

  containing three or more hetero rings · CPC title

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title