Gsk-3 inhibitors

Patent metadata

Field	Value
Publication number	US-2019315714-A1
Application number	US-201716463467-A
Country	US
Kind code	A1
Filing date	Nov 27, 2017
Priority date	Nov 28, 2016
Publication date	Oct 17, 2019
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 to treat disorders associated with GSK-3.

First claim

We claim:

1 . A compound of formula I

where:
R 1 is hydrogen, alkyl, (cycloalkyl)alkyl, alkoxyalkyl, (Ar 2 )alkyl, ((Ar 2 )cycloalkyl)alkyl, cycloalkyl, (alkyl)cycloalkyl, Ar 2 , or Ar 3 ;
or R 1 is (adamantyl)alkyl, (oxetanyl)alkyl, (tetrahydropyranyl)alkyl, (benzodioxolanyl)alkyl, oxetanyl, (alkyl)piperidinyl, (pentaalkyl)piperidinyl, alkoxytetrahydrofuranyl, tetrahydropyranyl, dialkyltetrahydropyranyl, (dihalophenyl)pyrazolyl, acetamidopyridinyl, (dialkylamino)alkoxypyridinyl, pyridazinyl, (imidizolyl)phenyl, tetrahydroisoquinolinyl, isoquinolinyl, quinolinyl, or naphthyl;
R 2 is N(R 3 )(R 4 ), dioxolanyl, (alkyl)dioxolanyl, or tetrahydropyranyl;
R 3 is hydrogen, alkyl, (cycloalkyl)alkyl, cycloalkyl, or is Ar 2 is phenyl substituted with 0-3 substituents selected from the group consisting of halo, alkyl, haloalkyl, alkoxy, haloalkoxy;
R 4 is hydrogen or alkyl;
or N(R 3 )(R 4 ) taken together is azetdinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, and is substituted with 0-4 substituents selected from alkyl and halo;
Ar 1 is 3-pyridinyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyrimidinyl, or 2-pyrazinyl, and is substituted with 0-3 substituents selected from the group consisting of cyano, halo, alkyl, haloalkyl, (R 2 )alkyl, alkoxy, haloalkoxy, R 2 , and Ar 2 ;
Ar 2 is phenyl or pyridinyl and is substituted with 0-3 substituents selected from the group consisting of cyano, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylsulfinyl, alkylsulfonyl, and phenyl that is in turn substituted with 0-3 substituents selected from the group consisting of halo, alkyl, haloalkyl, and alkoxy; and
Ar 3 is pyrazolyl, isothiazolyl, imidazolyl, thiadiazolyl, or triazolyl, and is substituted with 0-3 substituents selected from the group consisting of cyano, halo, alkyl, cycloalkyl, haloalkyl, alkoxy, and haloalkoxy;
or a pharmaceutically acceptable salt thereof.

2 . A compound of claim 1 where R 1 is Ar 2 .

3 . A compound of claim 1 where Ar 1 is 3-pyridinyl or 5-pyrimidinyl and is substituted with 0-3 substituents selected from the group consisting of cyano, halo, alkyl, haloalkyl, (R 2 )alkyl, alkoxy, haloalkoxy, R 2 , and Ar 2 .

4 . A compound of claim 1 where Ar 1 is 3-pyridinyl substituted with 0-3 substituents selected from the group consisting of cyano, halo, alkyl, haloalkyl, (R 2 )alkyl, alkoxy, haloalkoxy, R 2 , and Ar 2 .

5 . A compound of claim 1 where Ar 1 is 5-pyrimidinyl substituted with 0-3 substituents selected from the group consisting of cyano, halo, alkyl, haloalkyl, (R 2 )alkyl, alkoxy, haloalkoxy, R 2 , and Ar 2 .

6 . A compound of claim 1 where Ar 2 is phenyl substituted with 0-3 substituents selected from the group consisting of cyano, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylsulfinyl, and alkylsulfonyl.

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

8 . A method for the treatment of a disease, disorder, or condition selected from the group consisting of neurodegenerative disorders, psychiatric disorders, cancer, metabolic disorders, and inflammatory disorders which comprises administering to a patient a therapeutically affective amount of a compound of claim 1 .

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

• Hartz Richard A
• Ahuja Vijay T
• Luo Guanglin
• Chen Ling
• Sivaprakasam Prasanna
• Dubowchik Gene M
• Jacutin-Porte Swannee E
• Macor John E

Classifications

• C07D401/12 Primary

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

• A61P25/00 Primary

  Drugs for disorders of the nervous system · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title