Triazolone derivatives or salts thereof and pharmaceutical compositions comprising the same

Patent metadata

Field	Value
Publication number	US-11780830-B2
Application number	US-202117208887-A
Country	US
Kind code	B2
Filing date	Mar 22, 2021
Priority date	Mar 21, 2018
Publication date	Oct 10, 2023
Grant date	Oct 10, 2023

Abstract

The present technology provides triazolone derivatives or pharmaceutically acceptable salts thereof, preparation processes thereof, pharmaceutical compositions comprising the same, and the use thereof. The 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 method for treating diabetic nephropathy in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula X:

or an isomer thereof, or a pharmaceutically acceptable salt thereof;
wherein
n is 1 or 2,
A is a heteroaryl group; said heteroaryl group has 1 to 5 heteroatom ring members chosen from O, N, and S, and said heteroaryl group is optionally substituted with a substituent chosen from C 1-3 alkyl, halogen, —R, —CH═CH—R, and —C≡C—R, and
R is benzyl; or a substituted or unsubstituted cyclic ring, optionally containing 1 to 5 heteroatom ring members chosen from O, N, and S, and the cyclic ring is aromatic or non-aromatic.

2. The method of claim 1 , wherein A is selected from thiazole, thiophene, pyrrole, pyrazole, imidazole, triazole, tetrazole, furan, oxazole, isoxazole, oxadiazole, thiadiazole, pyridine, pyrimidine, pyrazine, triazine, indole, azaindole, isoindole, azaisoindole, indazole, azaindazole, benzimidazole, azabenzimidazole, benzothiophene, azabenzothiophene, benzofuran, azabenzofuran, isobenzofuran, benzoisoxazole, benzooxazole, benzothiazole, benzothiadiazole, purine, and pyrazolo[1,5-a]pyrimidine.

3. The method of claim 1 , wherein A is selected from thiophene, thiazole, and benzothiophene.

4. A method for treating diabetic nephropathy in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula Y:

or an isomer thereof, or a pharmaceutically acceptable salt thereof;
wherein
n is 1 or 2,
wherein A is a heteroaryl group selected from the group consisting of thiophene, thiazole, and benzothiophene,
wherein said heteroaryl group is optionally substituted with a substituent selected from the group consisting of C 1-3 alkyl, halogen, —R, —CH═CH—R, and —C≡C—R, and
R is benzyl or a cyclic ring selected from the group consisting of benzene, pyridine, pyridin-2-one, tetrahydropyridine, pyrimidine, pyridazine, thiophene, imidazole, pyrazole, oxadiazol-5-one, 1,1-dioxidothiomorpholin-4-yl-methyl, benzodioxole, benzooxadiazole, benzothiadiazole, benzooxazole, benzooxazolone, benzothiazole, 1,3-dihydrobenzofuran, indazole, thiazolo[5,4-b]pyridine, pyrrolo[2,3-b]pyridine, pyrrolo[2,3-b]pyridin-2-one, triazolone[1,5-a]pyridine, 1,3-dihydroindol-2-one, 2,3-dihydroisoindol-1-one, triazolone, quinoline, isoquinoline, quinolin-2-one, 3,4-dihydroquinolin-2-one, 3,4-dihydroisoquinolin-1-one, 3,4-dihydroquinazolin-2-one, 3,4-dihydronaphthyridin-2-one, 3,4-dihydro-1,4-benzooxazine, 1,4-benzooxazin-3-one, 1,4-dihydro-3,1-benzooxazin-2-one, 1,4-benzothiazin-3-one, 3,4-dihydro-quinoxaline, 3,4-dihydro-2H-chromene, 1,2,3,4-tetrahydroquinoline, 5,6,7,8-tetrahydronaphthyridine, oxazolo[4,5-b]pyridin-2-one, imidazo[4,5-b]pyridine, pyrido[2,3-b][1,4]oxazine, pyrido[2,3-b][1,4]oxazin-2-one, pyrido[2,3-d][1,3]oxazin-2-one, pyrido[2,3-b][1,4]oxazin-3-one, pyrido[3,2-b][1,4]oxazine, and pyrido[3,2-b][1,4]oxazin-3-one, and
wherein said R is optionally substituted with one to three substituents selected from the group consisting of hydroxy, halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, benzyl, trifluoromethyl, hydroxy-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkoxy, difluoromethoxy, trifluoro-C 1-6 alkoxy, 3,5-dimethoxybenzyloxy, (C 3-6 cycloalkyl)methoxy, amino, mono- or di-C 1-6 alkylamino, C 1-6 alkoxy-C 1-6 alkylamino, C 1-6 alkylsulfonylamino, C 1-6 alkylcarbonylamino, C 1-6 alkylthio, mono- or di-C 1-6 alkylaminocarbonyl, mono- or di-C 1-6 alkylaminosulfonyl, mono- or di-C 3-6 cycloalkylaminosulfonyl, pyrrolidinylsulfonyl, morpholinylsulfonyl, C 1-6 alkylcarbonyl, C 1-6 alkyl sulfonyl, C 1-6 alkylsulfonyl-C 1-6 alkyl, C 1-6 alkoxycarbonyl, morpholinylcarbonyl, pyrrolidinyl, 5-oxopyrrolidinyl, piperidinyl, C 1-6 alkyl-piperidinyl, piperazinyl, acetylpiperazinyl, morpholinyl, morpholinyl-C 1-6 alkyl, tetrahydropyranyl, pyrazolyl, triazolyl, isoxazolyl, oxazolyl, oxadiazolyl, 1,2,4-oxadiazol-5(4H)-onyl, cyclopropyl-oxadiazolyl, and C 1-6 alkyl-oxadiazolyl.

5. The method of claim 1 , wherein n is 1.

6. The method of claim 1 , wherein A is thiophene.

7. The method of claim 1 , wherein said heteroaryl group is substituted with —R.

8. The method of claim 1 , wherein said R is a cyclic ring selected from the group consisting of benzene, pyridin-2-one, pyrazole, pyrrolo[2,3-b]pyridin-2-one, 1,3-dihydroindol-2-one, 2,3-dihydroisoindol-1-one, quinolin-2-one, 3,4-dihydroquinolin-2-one, 3,4-dihydroisoquinolin-1-one, 3,4-dihydroquinazolin-2-one, 1,4-benzooxazin-3-one, 1,4-dihydro-3,1-benzooxazin-2-one, 1,4-benzothiazin-3-one, pyrido[2,3-b][1,4]oxazin-2-one, and pyrido[3,2-b][1,4]oxazine.

9. The method of claim 1 , wherein said R is a cyclic ring selected from the group consisting of benzene, pyridin-2-one, pyrazole, 3,4-dihydroquinolin-2-one, 3,4-dihydroquinazolin-2-one, 1,4-benzooxazin-3-one, and 1,4-dihydro-3,1-benzooxazin-2-one.

10. The method of claim 1 , wherein said cyclic ring is substituted with halogen, C 1-6 alkyl or di-C 1-6 alkylaminocarbonyl.

11. The method of claim 1 , wherein:
n is 1,
A is thiophene substituted with a cyclic ring selected from the group consisting of benzene, pyridin-2-one, pyrazole, 3,4-dihydroquinolin-2-one, 3,4-dihydroquinazolin-2-one, 1,4-benzooxazin-3-one, and 1,4-dihydro-3,1-benzooxazin-2-one, and
said cyclic ring is substituted with halogen, C 1-6 alkyl or di-C 1-6 alkylaminocarbonyl.

12. The method of claim 1 , wherein R is benzyl or selected from the group consisting of benzene, pyridine, pyridin-2-one, tetrahydropyridine, pyrimidine, pyridazine, thiophene, imidazole, pyrazole, oxadiazol-5-one, 1,1-dioxidothiomorpholin-4-yl-methyl, benzodioxole, benzooxadiazole, benzothiadiazole, benzooxazole, benzooxazolone, benzothiazole, 1,3-dihydrobenzofuran, indazole, thiazolo[5,4-b]pyridine, pyrrolo[2,3-b]pyridine, pyrrolo[2,3-b]pyridin-2-one, triazolone[1,5-a]pyridine, 1,3-dihydroindol-2-one, 2,3-dihydroisoindol-1-one, triazolone, quinoline, isoquinoline, quinolin-2-one, 3,4-dihydroquinolin-2-one, 3,4-dihydroisoquinolin-1-one, 3,4-dihydroquinazolin-2-one, 3,4-dihydronaphthyridin-2-one, 3,4-dihydro-1,4-benzooxazine, 1,4-benzooxazin-3-one, 1,4-dihydro-3,1-benzooxazin-2-one, 1,4-benzothiazin-3-one, 3,4-dihydro-quinoxaline, 3,4-dihydro-2H-chromene, 1,2,3,4-tetrahydroquinoline, 5,6,7,8-tetrahydronaphthyridine, oxazolo[4,5-b]pyridin-2-one, imidazo[4,5-b]pyridine, pyrido[2,3-b][1,4]oxazine, pyrido[2,3-b][1,4]oxazin-2-one, pyrido[2,3-d][1,3]oxazin-2-one, pyrido[2,3-b][1,4]oxazin-3-one, pyrido[3,2-b][1,4]oxazine, and pyrido[3,2-b][1,4]oxazin-3-one, and
R is optionally substituted with one to three substituents selected from the group consisting of hydroxy, halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, benzyl, trifluoromethyl, hydroxy-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkoxy, difluoromethoxy, trifluoro-C 1-6 alkoxy, 3,5-dimethoxybenzyloxy, (C 3-6 cycloalkyl)methoxy, amino, mono- or di-C 1-6 alkylamino, C 1-6 alkoxy-C 1-6 alkylamino, C 1-6 alkylsulfonylamino, C 1-6 alkylcarbonylamino, C 1-6 alkylthio, mono- or di-C 1-6 alkylaminocarbonyl, mono- or di-C 1-6 alkylaminosulfonyl, mono- or di-C 3-6 cycloalkylaminosulfonyl, pyrrolidinylsulfonyl, morpholinylsulfonyl, C 1-6 alkylcarbonyl, C 1-6 alkyl sulfonyl, C 1-6 alkylsulfonyl-C 1-6 alkyl, C 1-6 alk

Assignees

• Yuhan Corp

Inventors

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

Classifications

• C07D409/04 Primary

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

• C07D405/14 Primary

  containing three or more hetero rings · CPC title

• C07D409/14

  containing three or more hetero rings · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title