Substituted Pyridine Derivatives Useful as GSK-3 Inhibitors

Patent metadata

Field	Value
Publication number	US-2016289210-A1
Application number	US-201415033770-A
Country	US
Kind code	A1
Filing date	Nov 3, 2014
Priority date	Nov 6, 2013
Publication date	Oct 6, 2016
Grant date	—

Abstract

The disclosure generally relates to compounds of formula I, including their salts, as well as compositions and methods of using the compounds. The compounds are ligands, antagonists of the NR2B receptor and may be useful for the treatment of various disorders of the central nervous system.

First claim

We claim:

1 . A compound of formula I

where:
R 1 is alkyl, haloalkyl, cycloalkyl, halocycloalkyl alkylcycloalkyl, dialkylcycloalkyl, phenylcycloalkyl, hydroxycycloalkyl, or ketocycloalkyl;
R 2 is hydrogen or alkyl;
R 3 is hydrogen or alkyl;
or N(R 2 )(R 3 ) taken together is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or azabicycloheptane, and is substituted with 0-4 halo or alkyl substituents;
Ar 1 is 4-pyrazolyl, 5-imidazolyl, 4-thiazolyl, 3-pyridinyl, 5-pyrimidinyl, 4-pyrazinyl, 2-benzothiazolyl, 2-azabenzothiazolyl, 3-quinolinyl, 3-isoquinolinyl, or 3-tetrahydroisoquinolinyl, and is substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, hydroxyalkyl, (hydroxyl)haloalkyl, alkoxyalkyl, (N(R 2 )(R 3 ))alkyl, benzyl, alkenyl, cycloalkyl, hydroxy, alkoxy, haloalkoxy, (hydroxyl)alkoxy, (alkoxy)alkoxy, (cycloalkyl)alkoxy, phenoxy, alkylcarbonyl, (haloalkyl)carbonyl, phenylcarbonyl, alkoxycarbonyl, carboxy, aminocarbonyl, acetamido, N(R 2 )(R 3 ) and Ar 2 ; and
Ar 2 is phenyl, naphthalenyl, pyrrolyl, furanyl, thienyl, pyrrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, benzofuranyl, benzothiophenyl, or quinolinyl, and is substituted with 0-3 substituents selected from the group consisting of cyano, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl, and N(R 2 )(R 3 );
or a pharmaceutically acceptable salt thereof.

2 . A compound of claim 1 where R 1 is isopropyl, haloisopropyl, cyclopropyl, halocyclopropyl, methylcyclopropyl, dimethylcyclopropyl, phenylcyclopropyl, cyclobutyl, halocyclobutyl, dimethylcyclobutyl, hydroxycyclobutyl, ketocyclobutyl, cyclopentyl, halocyclopentyl, hydroxycyclopentyl, or ketocyclopentyl.

3 . A compound of claim 1 where R 1 is cyclopropyl.

4 . A compound of claim 1 where Ar 1 is 3-pyridinyl substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, hydroxyalkyl, (hydroxyl)haloalkyl, alkoxyalkyl, (N(R 2 )(R 3 ))alkyl, benzyl, alkenyl, cycloalkyl, hydroxy, alkoxy, haloalkoxy, (hydroxyl)alkoxy, (alkoxy)alkoxy, (cycloalkyl)alkoxy, phenoxy, alkylcarbonyl, (haloalkyl)carbonyl, phenylcarbonyl, alkoxycarbonyl, carboxy, aminocarbonyl, acetamido, N(R 2 )(R 3 ) and Ar 2 .

5 . A compound of claim 1 where is Ar 2 is phenyl, naphthalenyl, pyrrolyl, furanyl, thienyl, pyrrazolyl, imidazolyl, thiazolyl, pyridinyl, pyrimidinyl, indolyl, benzofuranyl, benzothiophenyl, quinolinyl, and is substituted with 0-1 substituents selected from the group consisting of cyano, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl, or N(R 2 )(R 3 ).

6 . A compound of claim 4 where Ar 2 is phenyl, naphthalenyl, pyrrolyl, furanyl, thienyl, pyrrazolyl, imidazolyl, thiazolyl, pyridinyl, pyrimidinyl, indolyl, benzofuranyl, benzothiophenyl, quinolinyl, and is substituted with 0-1 substituents selected from the group consisting of cyano, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl, or N(R 2 )(R 3 ).

7 . A compound of claim 1 selected from the group consisting of

18-2-(cyclopropanecarboxamido)-N-(4-phenylpyridin-3-yl)isonicotinamide

N-(4-(4-chlorophenyl)pyridin-3-yl)-2-(cyclopropanecarboxamido)isonicotinamide

2-(cyclopropanecarboxamido)-N-(4-(4-fluorophenyl)pyridin-3-yl)isonicotinamide

2-(cyclopropanecarboxamido)-N-(4-(4-methoxyphenyl)pyridin-3-yl)isonicotinamide

2-isobutyramido-N-(4-(2,2,2-trifluoroethoxy)pyridin-3-yl)isonicotinamide

N-(4-(2,2-difluoropropoxy)pyridin-3-yl)-2-isobutyramidoisonicotinamide; and

N-(4-(2,2-difluoroethoxy)pyridin-3-yl)-2-isobutyramidoisonicotinamide
or a pharmaceutically acceptable salt thereof.

8 . A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

9 . A method for the treatment of a condition selected from the group consisting of Alzheimer's disease, frontotemporal dementia, progressive supranuclear palsy, argyophilic grain disease, corticobasal degeneration, Pick's disease, Parkinson's disease, amyotrophic lateral sclerosis, stroke, Huntington's disease, peripheral neuropathy, traumatic brain injury, spinal cord trauma, and vascular dementia, which comprises administering to a patient a therapeutically affective amount of a compound of claim 1 .

10 . The method of claim 9 directed to the treatment of Alzheimer's disease.

Assignees

• Bristol Myers Squibb Co

Inventors

• Luo Guanglin
• Chen Ling
• Dubowchik Gene M
• Jacutin-Porte Swanee E
• Sivaprakasam Prasanna
• Macor John E

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P25/14

  for treating abnormal movements, e.g. chorea, dyskinesia · CPC title