Malic enzyme inhibitors

Patent metadata

Field	Value
Publication number	US-11225480-B2
Application number	US-202017073017-A
Country	US
Kind code	B2
Filing date	Oct 16, 2020
Priority date	Oct 17, 2019
Publication date	Jan 18, 2022
Grant date	Jan 18, 2022

Abstract

The present invention relates to novel compounds useful as malic enzyme (ME) inhibitors, processes for their preparation and use of these compounds for the therapeutic treatment of disorders mediated by ME such as cancers (e.g. pancreatic ductal adenocarcinoma (PDAC)) in humans. The novel compounds have a structure according to Formula Ior a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein X, R1, R2 and Y are as described herein.

First claim

What is claimed is:

1. A compound of Formula I

or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein
X is nitrogen;
R 1 is selected from hydrogen, —CH 3 , —COOH, fluoro and —CN;
R 2 is selected from hydrogen, —CH 3 , —COOH, fluoro and —CN; and
Y is selected from:

2. A compound of Formula I

or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein
X is nitrogen;
R 1 is selected from hydrogen, —CH 3 , —COOH, fluoro and —CN;
R 2 is selected from hydrogen, —CH 3 , —COOH, fluoro and —CN; and
Y is selected from:

3. The compound of claim 2 , wherein R 1 and R 2 are hydrogen.

4. The compound of claim 1 , wherein
R 1 and R 2 both are hydrogen, and
Y is selected from:

5. The compound of claim 2 , wherein
R 1 and R 2 both are hydrogen; and
Y is selected from:

6. The compound of claim 2 , wherein
R 1 and R 2 both are hydrogen, and
Y is selected from:

7. The compound of claim 1 wherein
R 1 and R 2 both are hydrogen, and
Y is selected from:

8. A compound selected from
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-2-phenylethanone,
[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-(1H-indol-3-yl)-methanone,
Acridin-9-yl-[4-(5-hydroxy-pyridin-2-yl)-piperazin-1-yl]-methanone,
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-phenyl-propan-1-one,
1-[4-(5-Hydroxy-2-pyridyl)piperazin-1-yl]-2,2-diphenyl-ethanone,
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-(1H-indol-3-yl)-propan-1-one,
3-[4-(5-Hydroxy-2-pyridyl)piperazine-1-carbonyl]-1H-quinolin-4-one,
2-(1-Adamantyl)-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]ethanone,
2-(3-Hydroxy-1-adamantyl)-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]ethanone,
2-(1-Adamantylmethylamino)-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]ethanone,
2,2-Bis(4-chlorophenyl)-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]ethanone,
1-(Cyclopropylmethyl)-3-[4-(5-hydroxy-2-pyridyl)piperazine-1-carbonyl]quinolin-4-one,
2-Fluoren-9-ylidene-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]ethanone,
2-(9H-Fluoren-9-yl)-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]ethanone,
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-2-(1H-indol-3-yl)-ethanone,
[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone,
Anthracen-9-yl-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-methanone,
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-4-phenylbutan-1-one,
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-pyridin-4-yl-propan-1-one,
[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-indan-2-yl-methanone,
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-5-phenylpentan-1-one,
3-[4-(5-Hydroxy-2-pyridyl)piperazine-1-carbonyl]-1-methylquinolin-4-one,
5-[4-(5-Hydroxy-2-pyridyl)piperazin-1-yl]-5-oxo-pentanoic acid,
[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-(1-methyl-1H-indol-3-yl)-methanone,
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-(3-trifluoromethyl-phenyl)-propan-1-one,
3-[4-(5-Hydroxy-2-pyridyl)piperazine-1-carbonyl]chromen-2-one,
1-[4-(5-Hydroxy-2-pyridyl)piperazin-1-yl]-3,3-diphenyl-prop-2-en-1-one,
1-[4-(5-Hydroxy-2-pyridyl)piperazin-1-yl]-3,3-diphenyl-propan-1-one,
(5-Chlorothiophen-2-yl)-[4-(5-hydroxy-pyridin-2-yl)-piperazin-1-yl]-methanone,
(E)-1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-(4-nitrophenyl)-propenone,
(E)-3-(4-Chlorophenyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-propenone,
3-(3,4-Dichlorophenyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-propan-1-one,
(2-Chloro-6-methylphenyl)-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-methanone,
[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-[3-(4-methylimidazol-1-yl)-5-trifluoromethylphenyl]-methanone,
3-(4-Chlorophenyl)-1-[4-(5-hydroxy-pyridin-2-yl)-piperazin-1-yl]-propan-1-one,
2-(1-Adamantylamino)-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]ethanone,
1-[4-(5-Hydroxy-2-pyridyl)piperazin-1-yl]-3,3-bis(4-methoxyphenyl)prop-2-en-1-one,
[[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)phenyl]-methanone,
(1H-Benzoimidazol-2-yl)-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-methanone,
(5-Bromothiophen-2-yl)-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-methanone,
[(5-Fluoro-1H-indol-2-yl)-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-methanone,
Quinoline-8-sulfonic acid {2-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-2-oxo-ethyl}-methylamide,
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-3-(4-isobutylphenyl)-propan-1-one,
2-(2,4-Difluorophenyl)-1-[4-(5-hydroxypyridine-2-yl)-piperazin-1-yl]-ethanone,
3-(3-Fluorophenyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-propan-1-one,
1-[4-(5-Hydroxy-2-pyridyl)piperazin-1-yl]-3,3-bis(4-methoxyphenyl)propan-1-one,
1-[4-(5-Hydroxy-2-pyridyl)piperazin-1-yl]-4,4-diphenyl-but-3-en-1-one,
2-Cyclohexyl-2-hydroxy-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]-2-phenyl-ethanone,
2-[1-Adamantylmethyl(methyl)amino]-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]ethanone,
1-[4-(5-Hydroxypyridin-2-yl)-piperazin-1-yl]-2-(5-nitropyridin-2-ylsulfanyl)-ethanone,
3-(1-Adamantyl)-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]propan-1-one,
2-Cyclohexyl-1-[4-(5-hydroxy-2-pyridyl)piperazin-1-yl]-2-phenyl-ethanone,
3-(4-Hydroxyphenyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-propan-1-one,
3-(4-Methoxyphenyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-propan-1-one,
3-(2-Bromophenyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-propan-1-one,
3-(4-Bromophenyl)-1-[4-(5-hydroxypyridin-2-yl)-piperazin-1-yl]-propan-1-one,
3-[4-(5-Hydroxypyridin-2-yl)-piperazine-1-carbonyl]-7-oxa-bicyclo[2.2.1]heptane-2-carboxylic acid methyl est

Assignees

• Sun Pharma Advanced Res Co Ltd

Inventors

• Sheth Gaurav Sanjivkumar
• Chimanwala Sabbirhusen Yusufbhai
• Jarag Tushar Mukund
• Hampiholi Aishwarya
• Maity Saikat
• Sengupta Prabal
• Qureshi Gulamnizami Abdulsattar
• Chaudhari Umesh Vishnu
• Venkat Raj Gopal
• Kadiyala V S N Murty
• Kalapatapu Sairam V V M
• Jain Vaibhav
• Chitturi Trinadha Rao

Classifications

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• C07D295/182

  Radicals derived from carboxylic acids · CPC title

• A61K31/495

  having six-membered rings with two {or more} nitrogen atoms as the only ring heteroatoms, e.g. piperazine {or tetrazines}(A61K31/48 takes precedence {; with three nitrogen atoms A61K31/53}) · CPC title