Gsk-3 inhibitors

Patent metadata

Field	Value
Publication number	US-2016272621-A1
Application number	US-201415033813-A
Country	US
Kind code	A1
Filing date	Nov 3, 2014
Priority date	Nov 6, 2013
Publication date	Sep 22, 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 to treat disorders associated with GSK-3.

First claim

We claim:

1 . A compound of formula I

where:
R 1 is hydrogen, cyano, halo, alkyl, haloalkyl, alkoxy, or haloalkoxy;
R 2 is hydrogen, cyano, halo, alkyl, cyanoalkyl, haloalkyl, cycloalkyl, cyanocycloalkyl, (alkoxycarbonyl)alkenyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, cycloalkylthio, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylsulfinyl, cycloalkylsulfinyl, phenylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, alkylcarbonylamino, morpholinyl, SO 2 N(R 4 )(R 5 );
R 3 is hydrogen, cyano, halo, alkyl, haloalkyl, alkoxy, or haloalkoxy;
or R 2 and R 3 taken together is —CH═CH—CH═CH—;
R 4 is hydrogen or alkyl;
R 5 is hydrogen or alkyl;
or N(R 4 )(R 5 ) taken together is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and is substituted with 0-4 halo or alkyl substituents;
Ar 1 is 3-pyridinyl, 2-pyrazinyl, 4-pyridazinyl, 4-pyrimidinyl, 4-pyrazolyl, 4-isothiazolyl, or 3-imidazopyridazinyl, and is substituted with 1 substituent selected from hydrogen, cyano, halo, alkyl, haloalkyl, hydroxyalkyl, (cycloalkyl)hydroxyalkyl, (dicycloalkyl)hydroxyalkyl, (hydroxy)haloalkyl, alkoxyalkyl, (N(R 4 )(R 5 ))alkyl, cycloalkyl, hydroxycycloalkyl, cycloalkenyl, alkoxy, haloalkoxy, (cycloalkyl)alkoxy, ((alkyl)cycloalkyl)alkoxy, alkylcarbonyl, cycloalkylcarbonyl, tetrahydrofuranyl, (alkyl)tetrahydrofuranyl, dioxolanyl, (alkyl)dioxolanyl, (cycloalkyl)dioxolanyl, (phenyl)dioxolanyl, (dialkyl)dioxolanyl, (haloalkyl)(alkyl)dioxolanyl, (trialkyl)dioxolanyl, dihydropyranyl, tetrahydropyranyl, hydroxytetrahydropyranyl, N(R 4 )(R 5 ), and Ar 2 ; and is also substituted with 0-1 substituent selected from hydrogen, cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy;
Ar 2 is phenyl, pyridinyl, or pyrazolyl, and is substituted with 0-3 substituents selected from the group consisting of cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy;
or a pharmaceutically acceptable salt thereof.

2 . A compound of claim 1 where R 1 is hydrogen or halo.

3 . A compound of claim 1 where R 2 is haloalkyl.

4 . A compound of claim 1 where Ar 1 is 3-pyridinyl substituted with 1 substituent selected from hydrogen, cyano, halo, alkyl, haloalkyl, hydroxyalkyl, (cycloalkyl)hydroxyalkyl, (dicycloalkyl)hydroxyalkyl, (hydroxy)haloalkyl, alkoxyalkyl, (N(R 4 )(R 5 ))alkyl, cycloalkyl, hydroxycycloalkyl, cycloalkenyl, alkoxy, haloalkoxy, (cycloalkyl)alkoxy, ((alkyl)cycloalkyl)alkoxy, alkylcarbonyl, cycloalkylcarbonyl, tetrahydrofuranyl, (alkyl)tetrahydrofuranyl, dioxolanyl, (alkyl)dioxolanyl, (cycloalkyl)dioxolanyl, (phenyl)dioxolanyl, (dialkyl)dioxolanyl, (haloalkyl)(alkyl)dioxolanyl, (trialkyl)dioxolanyl, dihydropyranyl, tetrahydropyranyl, hydroxytetrahydropyranyl, N(R 4 )(R 5 ), and Ar 2 ; and is also substituted with 0-1 substituent selected from hydrogen, cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy.

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

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

7 . 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 .

8 . The method of claim 7 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
• Vrudhula Vivekananda M
• Pan Senliang
• Sivaprakasam Prasanna
• Macor John E

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title

• A61P25/14

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

• A61P25/00

  Drugs for disorders of the nervous system · CPC title