Aryl amide-based kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9708337-B2
Application number	US-201414767952-A
Country	US
Kind code	B2
Filing date	Feb 6, 2014
Priority date	Feb 22, 2013
Publication date	Jul 18, 2017
Grant date	Jul 18, 2017

Abstract

The present disclosure is generally directed to compounds which can inhibit AAK1 (adaptor associated kinase 1), compositions comprising such compounds, and methods for inhibiting AAK1.

First claim

The invention claimed is:

1. A compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein:
R 1 and R 2 are independently selected from hydrogen, and C 1 -C 3 alkyl wherein the C 1 -C 3 alkyl is optionally substituted with one, two, or three groups independently selected from C 1 -C 3 alkoxy, C 1 -C 3 alkylamino, amino, cyano, C 1 -C 3 dialkylamino, halo, and hydroxy; or
R 1 and R 2 together are oxo;
R 3 is selected from C 1 -C 6 alkoxy, C 2 -C 6 alkynyl, amino, C 3 -C 6 cycloalkyl optionally substituted with C 1 -C 3 alkyl or cyano, C 3 -C 6 cycloalkylamino, piperidinyl optionally substituted with C 1 -C 6 alkyl, C 1 -C 3 alkyl-Y, and C 1 -C 8 alkyl, wherein the C 1 -C 8 alkyl is optionally substituted with one, two, or three groups independently selected from C 1 -C 3 alkoxy, C 1 -C 3 alkylamino, C 1 -C 3 alkoxyC 2 -C 3 alkylamino, C 1 -C 3 alkoxycarbonyl, amino, aminosulfonyl, aryl, cyano, C 1 -C 3 dialkylamino, halo, C 1 -C 3 haloalkylamino, C 1 -C 3 haloalkylcarbonylamino, hydroxy, —NR x R y , and C 3 -C 8 cycloalkyl, wherein the cycloalkyl is further optionally substituted with one, two, or three groups independently selected from C 1 -C 3 alkoxy, C 1 -C 3 alkyl, C 1 -C 3 alkylamino, C 1 -C 3 alkoxyC 2 -C 3 alkylamino, amino, aryl, arylC 1 -C 3 alkyl, halo, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkylamino and hydroxy;
R 4 is selected from hydrogen, C 1 -C 3 alkyl, and C 1 -C 3 alkylcarbonylamino;
R 5 is selected from hydrogen and C 1 -C 3 alkyl;
R x and R y , together with the nitrogen atom to which they are attached, form a three- to six-member ring optionally substituted with oxo; and
Y is selected from

wherein R 6 is selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and C 1 -C 6 alkylcarbonyl;
n is 0, 1, 2, or 3;
each R 7 is independently selected from hydrogen, C 1 -C 6 alkyl, aryl, arylC 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, halo, and C 1 -C 3 haloalkyl;
each R 8 is independently selected from hydrogen, C 1 -C 3 alkoxy and hydroxy; and
R 9 and R 10 are each hydrogen or together form an oxo group.

2. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 9 and R 10 together form an oxo group.

3. A compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen.

4. A compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from hydrogen and C 1 -C 3 alkylcarbonylamino.

5. A compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen.

6. A compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from C 1 -C 6 alkoxy, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl optionally substituted with cyano, C 3 -C 6 cycloalkylamino, piperidinyl optionally substituted with C 1 -C 6 alkyl, and C 1 -C 8 alkyl, wherein the C 1 -C 8 alkyl is optionally substituted with one, group selected from C 1 -C 3 alkoxy, C 1 -C 3 alkoxycarbonyl, amino, aminosulfonyl, cyano, C 1 -C 3 dialkylamino, hydroxy, and —NR x R y ; wherein R x and R y , together with the nitrogen atom to which they are attached, form a five-membered ring optionally substituted with oxo.

7. A compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 and R 2 are independently selected from hydrogen and C 1 -C 3 alkyl, or, R 1 and R 2 together are oxo;
R 3 is selected from C 1 -C 6 alkoxy, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl optionally substituted with cyano, C 3 -C 6 cycloalkylamino, piperidinyl optionally substituted with C 1 -C 6 alkyl, and C 1 -C 8 alkyl, wherein the C 1 -C 8 alkyl is optionally substituted with one, group selected from C 1 -C 3 alkoxy, C 1 -C 3 alkoxycarbonyl, amino, aminosulfonyl, cyano, C 1 -C 3 dialkylamino, hydroxy, and —NR x R y ; wherein R x and R y , together with the nitrogen atom to which they are attached, form a five-membered ring optionally substituted with oxo;
R 4 is selected from hydrogen and C 1 -C 3 alkylcarbonylamino; and
R 5 is hydrogen.

8. A compound selected from
(R)-2-amino-N-(5H-chromeno[3,4-c]pyridin-8-yl)-4-methylpentanamide;
(S)-2-amino-N-(5H-chromeno[3,4-c]pyridin-8-yl)-4-methylpentanamide;
(S)-2-amino-4-methyl-N—((R)-5-methyl-5H-chromeno[3,4-c]pyridin-8-yl)pentanamide;
(S)-2-amino-4-methyl-N—((S)-5-methyl-5H-chromeno[3,4-c]pyridin-8-yl)pentanamide;
(2R)-2-amino-4-methyl-N-(5-methyl-5H-chromeno[3,4-c]pyridin-8-yl)pentanamide;
(R)-2-amino-4-methyl-N—((R)-5-methyl-5H-chromeno[3,4-c]pyridin-8-yl)pentanamide;
(R)-2-amino-4-methyl-N—((S)-5-methyl-5H-chromeno[3,4-c]pyridin-8-yl)pentanamide;
(R)-2-amino-N-(5,5-dimethyl-5H-chromeno[3,4-c]pyridin-8-yl)-4-methylpentanamide;
(S)-2-amino-N-(5,5-dimethyl-5H-chromeno[3,4-c]pyridin-8-yl)-4-methylpentanamide;
N-(5H-chromeno[3,4-c]pyridin-8-yl)-3-isopropylpiperidine-2-carboxamide;
(S)-2-amino-4-methyl-N-(5-oxo-5H-chromeno[3,4-c]pyridin-8-yl)pentanamide;
neopentyl 5H-chromeno[3,4-c]pyridin-8-ylcarbamate;
1-(5H-chromeno[3,4-c]pyridin-8-yl)-3-cyclohexylurea;
N-(5H-chromeno[3,4-c]pyridin-8-yl)pent-4-ynamide;
N-(5H-chromeno[3,4-c]pyridin-8-yl)pentanamide;
N-(5H-chromeno[3,4-c]pyridin-8-yl)-3-cyanopropanamide;
N-(5H-chromeno[3,4-c]pyridin-8-yl)acetamide;
N-(5H-chromeno[3,4-c]pyridin-8-yl)-3-methoxypropanamide;
N-(5H-chromeno[3,4-c]pyridin-8-yl)-3-hydroxypropanamide;
N-(5H-chromeno[3,4-c]pyridin-8-yl)-1-cyanocyclopropanecarboxamide;
N-(5H-chromeno[3,4-c]pyridin-8-yl)-4-sulfamoylbutanamide;
N-(5H-chromeno[3,4-c]pyridin-8-yl)-3-(2-oxopyrrolidin-1-yl)propanamide;
N-(5H-chromeno[3,4-c]pyridin-8-yl)cyclohexanecarboxamide;
N-(5H-chromeno[3,4-c]pyridin-8-yl)isobutyramide;
N-(5H-chromeno[3,4-c]pyridin-8-yl)-2-cyanoacetamide;
N-(5H-chromeno[3,4-c]pyridin-8-yl)-3,3-dimethylbutanamide;
N-(5H-chromeno[3,4-c]pyridin-8-yl)-3-methylbutanamide;
N-(5H-chromeno[3,4-c]pyridin-8-yl)propionamide;
methyl 4-((5H-chromeno[3,4-c]pyridin-8-yl)amino)-4-oxobutanoate;
N-(5H-chromeno[3,4-c]pyridin-8-yl)-4-methylpentanamide;
N-(5H-chromeno[3,4-c]pyridin-8-yl)butyramide;
N-(5H-chromeno[3,4-c]pyridin-8-yl)pivalamide;
N-(5H-chromeno[3,4-c]pyridin-8-yl)-2-(dimethylamino)acetamide;
N-(9-bromo-5H-chromeno[3,4-c]pyridin-8-yl)pentanamide;
(R)—N-(2-acetamido-5H-chromeno[3,4-c]pyridin-8-yl)-2-amino-4-methylpentanamide;
(S)-2-amino-N-(5H-chromeno[3,4-c]pyridin-8-yl)-2-phenylacetamide; and
(S)—N 1 -(5H-chromeno[3,4-c]pyridin-8-yl)-2-phenylethane-1,2-diamine;

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 activity, comprising contacting AAK1 with a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

Assignees

• Bristol Myers Squibb Co

Inventors

• Vrudhula Vivekananda M
• Dzierba Carolyn Diane
• Bronson Joanne J
• Macor John E
• Nara Susheel Jethanand
• Rajamani Ramkumar
• Karatholuvhu Maheswaran Sivasamban

Classifications

• A61P43/00

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

• A61P25/20

  Hypnotics; Sedatives · CPC title

• A61P25/18

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

• A61P25/16

  Anti-Parkinson drugs · CPC title