Biaryl kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9902722-B2
Application number	US-201515300618-A
Country	US
Kind code	B2
Filing date	Apr 1, 2015
Priority date	Apr 2, 2014
Publication date	Feb 27, 2018
Grant date	Feb 27, 2018

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:
A is selected from

wherein “ ” denotes the point of attachment to B;
B is selected from

wherein “*” indicates the point of attachment to R5 and “**” indicates the point of attachment to ring A;
R 1 is selected from hydrogen, amino, —CO 2 H, difluoromethyl, ethyl, halo, hydroxymethyl, methoxy, methyl, —NHC(O)CH 3 , —NHCO 2 CH 3 , trifluoromethoxy, and trifluoromethyl;
R 2 is selected from hydrogen, cyano, —CH 2 OH, halo, and methyl;
R 3 is selected from hydrogen, cyano, cyclopropyl, difluoromethyl, halo, hydroxymethyl, methoxy, methyl, methylsulfonyl, trifluoromethoxy, trifluoromethyl, —CH 2 N(CH 3 ) 2 , and a five-membered aromatic ring containing one, two, or three heteroatoms selected from nitrogen, oxygen, and sulfur;
R 4 is selected from hydrogen, halo, and methyl;
R 5 is selected from

R 6 is selected from hydrogen, ethyl, fluoromethyl, difluoromethyl, methyl, and trifluoromethyl; and

R 7 is methyl.

2. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is selected from

3. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein B is selected from

4. A compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein B is

5. A compound of claim 1 wherein R 5 is

6. A compound selected from
(S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-fluorophenyl)pyridin-2-yl)acetamide;
(S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-methoxyphenyl)pyridin-2-yl)acetamide;
(S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-cyanophenyl)pyridin-2-yl)acetamide;
(S)-2-((2-amino-4-methylpentyl)oxy)-5-(2-aminopyridin-4-yl)benzonitrile;
(S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)acetamide;
(S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-(trifluoromethoxy)phenyl)pyridin-2-yl)acetamide;
(S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-methylphenyl)pyridin-2-yl)acetamide;
(S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-chlorophenyl)pyridin-2-yl)acetamide;
(S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3,5-difluorophenyl)pyridin-2-yl)acetamide;
(S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-chloro-5-fluorophenyl)pyridin-2-yl)acetamide;
(S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-fluoro-5-(trifluoromethyl)phenyl)pyridin-2-yl)acetamide;
(S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-2,5-difluorophenyl)pyridin-2-yl)acetamide;
(S)-methyl (4-(4-((2-amino-4-methylpentyl)oxy)-3-fluorophenyl)pyridin-2-yl)carbamate;
(S)-methyl (4-(4-((2-amino-4-methylpentyl)oxy)-3-(isoxazol-5-yl)phenyl)pyridin-2-yl)carbamate;
(S)-2-((2-amino-4-methylpentyl)oxy)-5-(2-methylpyridin-4-yl)benzonitrile;
(S)-2-((2-amino-4-methylpentyl)oxy)-5-(2-methoxypyridin-4-yl)benzonitrile;
(S)-2-((2-amino-4-methylpentyl)oxy)-5-(2-(trifluoromethyl)pyridin-4-yl)benzonitrile;
(S)-1-(2-(isoxazol-5-yl)-4-(2-methylpyridin-4-yl)phenoxy)-4-methylpentan-2-amine;
(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)acetamide;
(S)-methyl (4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)carbamate;
(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-cyanophenyl)pyridin-2-yl)acetamide;
(S)-methyl (4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-cyanophenyl)pyridin-2-yl)carbamate;
(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(difluoromethyl)phenyl)pyridin-2-yl)acetamide;
(S)-methyl (4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(difluoromethyl)phenyl)pyridin-2-yl)carbamate;
(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethoxy)phenyl)pyridin-2-yl)acetamide;
(S)-methyl (4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethoxy)phenyl)pyridin-2-yl)carbamate;
(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-fluorophenyl)pyridin-2-yl)acetamide;
(S)-methyl (4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-fluorophenyl)pyridin-2-yl)carbamate;
methyl (4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-chlorophenyl)pyridin-2-yl)carbamate;
methyl (4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-methylphenyl)pyridin-2-yl)carbamate;
methyl (4-(4-((2-amino-2,4-dimethylpentyl)oxy)-2,3-dimethylphenyl)pyridin-2-yl)carbamate;
(S)-methyl (4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(hydroxymethyl)phenyl)pyridin-2-yl)carbamate;
(S)-methyl (4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-cyclopropylphenyl)pyridin-2-yl)carbamate;
(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)-5-(hydroxymethyl)pyridin-2-yl)acetamide;
(S)-1-(4-(2-(difluoromethyl)pyridin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine;
(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(2-(difluoromethyl)pyridin-4-yl)benzonitrile;
(S)-1-(2-(difluoromethyl)-4-(2-(difluoromethyl)pyridin-4-yl)phenoxy)-2,4-dimethylpentan-2-amine;
(S)-1-(4-(2-(difluoromethyl)pyridin-4-yl)-2-(trifluoromethoxy)phenoxy)-2,4-dimethylpentan-2-amine;
(S)-1-(4-(3-chloro-2-fluoropyridin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine;
(S)-1-(4-(5-chloro-2-fluoropyridin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine;
(S)-1-(4-(2-fluoro-3-methylpyridin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine;
(S)-1-(4-(2,3-difluoropyridin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine;
(S)-2,4-dimethyl-1-(4-(pyridin-4-yl)-2-(trifluoromethyl)phenoxy)pentan-2-amine;
(S)-1-(4-(2-fluoropyridin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine;
(S)-2,4-dimethyl-1-(4-(2-methylpyridin-4-yl)-2-(trifluoromethyl)phenoxy)pentan-2-amine;
(S)-1-(4-(3-methoxypyridin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine;
(S)-1-(4-(3-fluoropyridin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine;
(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(2-methylpyridin-4-yl)benzonitrile;
(S)-1-(2-cyclopropyl-4-(2-methylpyridin-4-yl)phenoxy)-2,4-dimethylpentan-2-amine;
(S)-1-(2-(difluoromethyl)-4-(2-methylpyridin-4-yl)phenoxy)-2,4-dimethylpentan-2-amine;
methyl (6-((2-amino-2,4-dimethylpentyl)oxy)-[3,4′-bipyridin]-2′-yl)carbamate;
(S)-methyl (6-((2-amino-2,4-dimethylpentyl)oxy)-5-methyl-[3,4′-bipyridin]-2′-yl)carbamate;
(S)-methyl (6-((2-amino-2,4-dimethylpentyl)oxy)-5-cyano-[3,4′-bipyridin]-2′-yl)carbamate;
(S)-methyl (6-((2-amino-2,4-dimethylpentyl)oxy)-4-methyl-[3,4′-bipyridin]-2′-yl)carbamate;
(S)-methyl (6-((2-amino-2,4-dimethylpentyl)oxy)-5-chloro-[3,4′-bipyridin]-2′-yl)carbamate;
(S)-methyl (6-((2-amino-2,4-dimethylpentyl)oxy)-5-methoxy-[3,4′-bipyridin]-2′-yl)carbamate;
(S)-1-((2′-chloro-5-methyl-[3,4′-bipyridin]-6-yl)oxy)-2,4-dimethylpentan-2-amine;
(S)-1-((2′-(difluoromethyl)-5-methyl-[3,4′-bipyridin]-6-yl)oxy)-2,4-dimethylpentan-2-amine;
(S)-6-((2-amino-2,4-dimethylpentyl)oxy)-2′-(difluoromethyl)-[3,4′-bipyridine]-5-carbonitrile;
(S)-1-((5-chloro-2′-methyl-[3,4′-bipyridin]-6-yl)oxy)-2,4-dimethylpentan-2-amine;
(S)-1-((2′,5-dimethyl-[3,4′-bipyridin]-6-yl)oxy)-2,4-dimethylpentan-2-amine;
(S)-1-((5-methoxy-2′-methyl-[3,4′-bipyr

Assignees

• Bristol Myers Squibb Co

Inventors

• Luo Guanglin
• Chen Ling
• Dzierba Carolyn Diane
• Ditta Jonathan L
• Macor John E
• Bronson Joanne J

Classifications

• C07D215/14

  Radicals substituted by oxygen atoms · CPC title

• C07D213/64

  attached in position 2 or 6 · CPC title

• C07D213/74 Primary

  Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals · CPC title

• A61K31/50

  Pyridazines; Hydrogenated pyridazines · CPC title

• C07D237/08

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title