Quinoline-based kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9932320-B2
Application number	US-201515112294-A
Country	US
Kind code	B2
Filing date	Jan 23, 2015
Priority date	Jan 31, 2014
Publication date	Apr 3, 2018
Grant date	Apr 3, 2018

Abstract

The present disclosure is generally directed to compounds of formula (I) which can inhibit AAKI (adaptor associated kinase 1), compositions comprising such compounds, and methods for inhibiting AAKI.

First claim

The invention claimed is:

1. A compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from imidazopyridazine, isoquinolinyl, oxazolyl, pyridinyl, pyrimidinyl, pyrrolopyridinyl, and quinolinyl, wherein each ring is optionally substituted with one group selected from C 1 -C 3 acylamino, C 1 -C 3 alkyl, amino, C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylamino, C 1 -C 3 dialkylamino, —NHCO 2 (C 1 -C 3 )alkyl, and phenylcarbonylamino optionally substituted with a halo or haloalkyl group;
R 2 is selected from hydrogen, C 1 -C 3 alkoxy, and C 1 -C 3 alkyl;
R 3 is selected from hydrogen, C 1 -C 3 alkoxy, C 1 -C 3 alkyl, cyano, and halo;
R 4 is selected from C 3 -C 6 alkyl optionally substituted with one group selected from amino, haloalkyloxy, hydroxy and oxo; and C 3 -C 6 cycloalkylC 1 -C 3 alkyl optionally substituted with amino;
R 5 is selected from hydrogen, C 1 -C 6 alkyl, amido, cyano, and halo;
when is a double bond, R 6 is selected from hydrogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, amido, cyano, C 1 -C 6 dialkylamino, halo, hydroxy, and a five-membered heteroaromatic ring; and
when is a single bond, R 6 is ═S.

2. A compound of claim 1 wherein R 3 is halo.

3. A compound of claim 1 wherein R 3 is hydrogen.

4. A compound of claim 3 wherein R 2 is C 1 -C 3 alkoxy.

5. A compound of claim 3 wherein R 2 is hydrogen.

6. A compound of claim 5 wherein R 5 is selected from C 1 -C 6 alkyl, amido, cyano, and halo.

7. A compound of claim 5 wherein R 5 is hydrogen.

8. A compound selected from
2-Isopentyl-6-(pyridin-4-yl)quinolin-4-ol;
2-Isopentyl-4-methoxy-6-(pyridin-4-yl)quinoline;
4-Bromo-2-isopentyl-6-(pyridin-4-yl)quinoline;
2-Isopentyl-6-(pyridin-4-yl)quinoline;
2-Isopentyl-N,N-dimethyl-6-(pyridin-4-yl)quinolin-4-amine;
2-Isopentyl-6-(pyridin-4-yl)quinoline-4-carbonitrile;
(−)-(R)-2-(1-Amino-3-methylbutyl)-6-(pyridin-4-yl)quinoline-4-carbonitrile;
(+)-(S)-2-(1-Amino-3-methylbutyl)-6-(pyridin-4-yl)quinoline-4-carbonitrile;
2-Isopentyl-7-methoxy-6-(oxazol-5-yl)quinolin-4-ol;
5-(4-Bromo-2-isopentyl-7-methoxyquinolin-6-yl)oxazole;
2-Isopentyl-7-methoxy-6-(oxazol-5-yl)quinoline-4-carbonitrile;
2-(1-Amino-3-methylbutyl)-7-methoxy-6-(oxazol-5-yl)quinoline-4-carbonitrile;
(+)-2-(1-Amino-3-methylbutyl)-7-methoxy-6-(oxazol-5-yl)quinoline-4-carbonitrile;
3-Isobutyl-2-methyl-6-(pyridin-4-yl)quinolin-4-ol;
3-Isobutyl-6-(pyridin-4-yl)quinolin-4-ol;
3-Bromo-2-isopentyl-6-(pyridin-4-yl)quinolin-4-ol;
2-Isopentyl-6-(pyridin-4-yl)quinoline-3-carboxamide;
2-Isopentyl-6-(pyridin-4-yl)quinoline-3-carbonitrile;
3-Methyl-1-(6-(pyridin-4-yl)quinolin-2-yl)butan-1-one;
(−)-3-Methyl-1-(6-(pyridin-4-yl)quinolin-2-yl)butan-1-amine;
(+)-3-Methyl-1-(6-(pyridin-4-yl)quinolin-2-yl)butan-1-amine;
(+)-1-(6-(3-methoxypyridin-4-yl)quinolin-2-yl)-3-methylbutan-1-amine;
(−)-1-(6-(3-methoxypyridin-4-yl)quinolin-2-yl)-3-methylbutan-1-amine;
1-(6-(3-methoxypyridin-4-yl)quinolin-2-yl)-3-methylbutan-1-amine;
1-(6-(1H-pyrrolo[2,3-b]pyridin-4-yl)quinolin-2-yl)-3-methylbutan-1-amine;
1-([4,6′-biquinolin]-2′-yl)-3-methylbutan-1-amine;
1(6-(isoquinolin-6-yl)quinolin-2-yl)-3-methylbutan-1-amine;
4-(2-(1-amino-3-methylbutyl)quinolin-6-yl)-N,N-dimethylpyrimidin-2-amine;
4-(2-(1-amino-3-methylbutyl)quinolin-6-yl)pyridin-2-amine;
N-(4-(2-(3-methylbutanoyl)quinolin-6-yl)pyridin-2-yl)acetamide;
2-isopentyl-6-(pyridin-4-yl)quinoline-4(1H)-thione;
2-(3-methyl-1-(2,2,2-trifluoroethoxy)butyl)-6-(pyridin-4-yl)quinoline;
N-(4-(2-(1-amino-3-methylbutyl)quinolin-6-yl)pyridin-2-yl)acetamide;
N-(4-(2-(1-amino-3-methylbutyl)quinolin-6-yl)pyridin-2-yl)-3-fluorobenzamide;
4-(2-(amino(cyclohexyl)methyl)quinolin-6-yl)-N-(prop-1-en-2-yl)pyridin-2-amine;
3-methyl-1-(6-(pyridin-4-yl)-4-(1H-tetrazol-5-yl)quinolin-2-yl)butan-1-amine;
4-(2-(1-amino-3-methylbutyl)quinolin-6-yl)-N-cyclopropylpyridin-2-amine;
2-(amino(cyclohexyl)methyl)-6-(pyridin-4-yl)quinoline-4-carboxamide;
2-(amino(cyclohexyl)methyl)-6-(pyridin-4-yl)quinoline-4-carboxamide;
2-(amino(cyclohexyl)methyl)-6-(pyridin-4-yl)quinoline-4-carbonitrile;
N-(4-(2-(1-amino-3-methylbutyl)quinolin-6-yl)pyridin-2-yl)-4-(trifluoromethyl)benzamide;
1-(4-ethyl-6-(pyridin-4-yl)quinolin-2-yl)-3-methylbutan-1-amine;
2-(1-amino-3-methylbutyl)-8-fluoro-6-(pyridin-4-yl)quinoline-4-carbonitrile;
N-(4-(2-(1-hydroxy-3-methylbutyl)quinolin-6-yl)pyridin-2-yl)acetamide;
N-(2′-(1-amino-3-methylbutyl)-4,6′-biquinolin-2-yl)acetamide;
2′-(1-amino-3-methylbutyl)-4,6′-biquinolin-2-amine;
2′-(1-amino-3-methylbutyl)-4,6′-biquinolin-2-amine; and
1-(6-(2-cyclopropylpyridin-4-yl)quinolin-2-yl)-3-methylbutan-1-amine;

or a pharmaceutically acceptable salt thereof.

9. A composition comprising a pharmaceutically acceptable amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

10. A method of inhibiting adaptor associated kinase 1 (AAK1) activity, comprising contacting AAK1 with a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

Assignees

• Bristol Myers Squibb Co

Inventors

• Hartz Richard A
• Ahuja Vijay T
• Macor John E
• Bronson Joanne J
• Dasgupta Bireshwar
• Dzierba Carolyn Diane
• Nara Susheel Jethanand
• Karatholuvhu Maheswaran Sivasamban

Classifications

• A61P43/00

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

• A61P29/02

  without antiinflammatory effect · 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

• A61P25/24

  Antidepressants · CPC title

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title