Phosphodiesterase 3 (pde3) inhibitors

Patent metadata

Field	Value
Publication number	US-2024308973-A1
Application number	US-202418598312-A
Country	US
Kind code	A1
Filing date	Mar 7, 2024
Priority date	Mar 10, 2023
Publication date	Sep 19, 2024
Grant date	—

Abstract

The invention describes novel PDE3 inhibitors for treating a cardiovascular disease including myxomatous mitral valve disease, congestive heart failure and/or asymptomatic heart failure in animals, particularly canines.

First claim

We claim:

1 . A compound selected from the group consisting of:
8-(2-methoxypyridin-4-yl)-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-3,4-dihydroquinolin-2 (1H)-one; 6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-8-(thiazol-2-yl)-3,4-dihydroquinolin-2 (1H)-one; 8-(2-methoxythiazol-5-yl)-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-3,4-dihydroquinolin-2 (1H)-one; 7-chloro-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indolin-2-one; 7-(4-chlorophenyl)-5-(6-oxo-1,6-dihydropyridazin-3-yl)indolin-2-one; 7′-chloro-5′-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)spiro[cyclopropane-1,3′-indolin]-2′-one; 8-(4-chlorophenyl)-6-(6-oxo-1,6-dihydropyridazin-3-yl)-3,4-dihydroquinolin-2 (1H)-one; 8-(3-fluorophenyl)-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-3,4-dihydroquinolin-2 (1H)-one; 6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-8-(pyridin-3-yl)-3,4-dihydroquinolin-2 (1H)-one; 3,3-dimethyl-5-(4-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-7-(thiazol-4-yl)indolin-2-one; 9-(6-methoxypyridin-3-yl)-7-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one; 6-(2-(1-(4-methoxyphenyl)cyclopropyl)-1H-benzo[d]imidazol-6-yl)-5-methyl-4,5-dihydropyridazin-3 (2H)-one; 7-bromo-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indolin-2-one; 7-chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indolin-2-one; 7-chloro-3,3-dimethyl-5-(6-oxo-1,6-dihydropyridazin-3-yl)indolin-2-one; 7-fluoro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indolin-2-one; 7-fluoro-3,3-dimethyl-5-(6-oxo-1,6-dihydropyridazin-3-yl)indolin-2-one; 7′-fluoro-5′-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)spiro[cyclopropane-1,3′-indolin]-2′-one; 7-chloro-3,3-dimethyl-5-(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indolin-2-one; 4-chloro-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)benzo[d]thiazol-2 (3H)-one; 6-(2-amino-4-chlorobenzo[d]thiazol-6-yl)-5-methyl-4,5-dihydropyridazin-3 (2H)-one; 6-(2-amino-4-fluorobenzo[d]thiazol-6-yl)-5-methyl-4,5-dihydropyridazin-3 (2H)-one; 7-bromo-3,3-dimethyl-5-(6-oxo-1,6-dihydropyridazin-3-yl)indolin-2-one; (R)-7-chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indolin-2-one; 6-(4-fluoro-2-(methylamino)benzo[d]thiazol-6-yl)-5-methyl-4,5-dihydropyridazin-3 (2H)-one; 6-(8-chloro-2-hydroxyquinolin-6-yl)-5-methyl-4,5-dihydropyridazin-3 (2H)-one; 7-chloro-6-fluoro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indolin-2-one; 6-(4-fluoro-2-(3-hydroxyazetidin-1-yl)benzo[d]thiazol-6-yl)-5-methyl-4,5-dihydropyridazin-3 (2H)-one; 2-amino-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)benzo[d]thiazole-4-carbonitrile; 7-chloro-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)isoindolin-1-one; 2-hydroxy-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)quinoline-8-carbonitrile; 7-chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)isoindolin-1-one; 4-chloro-1-methyl-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one; 7′-fluoro-5′-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)spiro[cyclobutane-1,3′-indolin]-2′-one; 6-(8-bromo-2-hydroxyquinolin-6-yl)-5-methyl-4,5-dihydropyridazin-3 (2H)-one; 6-(4-fluoro-2-(((1-methyl-1H-pyrazol-4-yl)methyl)amino)benzo[d]thiazol-6-yl)-5-methyl-4,5-dihydropyridazin-3 (2H)-one; 6-(7-chloro-3-methyl-1H-indazol-5-yl)-5-methyl-4,5-dihydropyridazin-3 (2H)-one; 6-(8-cyclopropyl-2-hydroxyquinolin-6-yl)-5-methyl-4,5-dihydropyridazin-3 (2H)-one; 6-(2-(3-methoxyazetidin-1-yl)benzo[d]thiazol-6-yl)-5-methyl-4,5-dihydropyridazin-3 (2H)-one; 7-fluoro-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indolin-2-one; (S)-7-chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)isoindolin-2-one; 4-chloro-6-(6-oxo-1,6-dihydropyridazin-3-yl)benzo[d]thiazol-2 (3H)-one; 5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-2-oxoindoline-7-carbonitrile; 4-methyl-6-(6-methyl-2-oxo-3,6-dihydro-2H-1,3,4-thiadiazin-5-yl)benzo[d]thiazol-2 (3H)-one; 4-chloro-6-(6-methyl-2-oxo-3,6-dihydro-2H-1,3,4-thiadiazin-5-yl)benzo[d]thiazol-2 (3H)-one; 5-(7-fluoro-2-oxoindolin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7′-chloro-2′-oxospiro[cyclopropane-1,3′-indolin]-5′-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-fluoro-3,3-dimethyl-2-oxoindolin-5-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-chloro-3,3-dimethyl-2-oxoindolin-5-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-chloro-2-oxoindolin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 6-methyl-5-(7-(4-(methylsulfonyl)phenyl)-2-oxoindolin-5-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-bromo-3,3-dimethyl-2-oxoindolin-5-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(3,3-dimethyl-2-oxo-7-(thiazol-4-yl)indolin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-(4-chlorophenyl)-2-oxoindolin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 6-methyl-5-(9-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-fluoro-3,3-dimethyl-2-oxoindolin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-chloro-3,3-dimethyl-2-oxoindolin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-bromo-3,3-dimethyl-2-oxoindolin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(6-methyl-2-oxo-3,6-dihydro-2H-1,3,4-thiadiazin-5-yl)-2-oxoindoline-7-carbonitrile; (S)-5-(7-fluoro-2-oxoindolin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-chloro-1-oxoisoindolin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-chloro-3,3-dimethyl-1-oxoisoindolin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(8-chloro-2-hydroxyquinolin-6-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-chloro-2,2-dioxido-1,3-dihydrobenzo[c]isothiazol-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 6-methyl-5-(8-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 4-chloro-6-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)benzo[d]oxazol-2 (3H)-one; 5-(7-chloro-3,3-dimethyl-2-oxoindolin-5-yl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one; 7-chloro-3,3-dimethyl-5-(pyrimidin-5-yl)indolin-2-one; 6-(7-chloro-3,3-dimethyl-2-oxoindolin-5-yl)-3,4-dihydro-1,8-naphthyridin-2 (1H)-one; 4-chloro-6-(5-oxo-4,5-dihydro-1,3,4-thiadiazol-2-yl)benzo[d]thiazol-2 (3H)-one; and 5-(7-chloro-3,3-dimethyl-2-oxoindolin-5-yl)-1,3,4-thiadiazol-2 (3H)-one, stereoisomers thereof, and veterinarily acceptable salts thereof.

2 . The compound of claim 1 selected form the group consisting of:
8-(2-methoxypyridin-4-yl)-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-3,4-dihydroquinolin-2 (1H)-one;
8-(2-methoxythiazol-5-yl)-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-3,4-dihydroquinolin-2 (1H)-one;
7-chloro-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indolin-2-one;
7′-chloro-5′-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)spiro[cyclopropane-1,3′-indolin]-2′-one;
8-(4-chlorophenyl)-6-(6-oxo-1,6-dihydropyridazin-3-yl)-3,4-dihydroquinolin-2 (1H)-one;
8-(3-fluorophenyl)-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-3,4-dihydroquinolin-2 (1H)-one;
6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-8-(pyridin-3-yl)-3,4-dihydroquinolin-2 (1H)-one;
9-(6-methoxypyridin-3-yl)-7-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one;
6-(2-(1-(4-methoxyphenyl)cyclopropyl)-1H-benzo[d]imidazol-6-yl)-5-methyl-4,5-dihydropyridazin-3 (2H)-one;
7-bromo-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indolin-2-one;
7-chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indolin-2-one;
7-chloro-3,3-dimethyl-5-(6-oxo-1,6-dihydropyridaz

Assignees

• Zoetis Services Llc

Inventors

• Ewin Richard A
• Curtis Michael P
• Maddux Todd M
• Kyne Graham M

Classifications

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D417/04

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

• C07D403/04

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