Biaryl kinase inhibitors

Patent metadata

Field	Value
Publication number	US-10246469-B2
Application number	US-201615763281-A
Country	US
Kind code	B2
Filing date	Sep 29, 2016
Priority date	Oct 1, 2015
Publication date	Apr 2, 2019
Grant date	Apr 2, 2019

Abstract

The present disclosure is directed to biaryl compounds of formula (I) which can inhibit AAK1 (adaptor associated kinase 1), compositions comprising such compounds and their use for treating e.g. pain, Alzheimer's disease, Parkinson's disease and schizophrenia.

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 R 5 and “**” indicates the point of attachment to ring A;
R 1 is selected from hydrogen, amino, —CO 2 H, cyclopropyl, difluoromethyl, ethyl, halo, hydroxymethyl, methoxy, methoxymethyl, methyl, —NHC(O)CH 3 , —NHCO 2 CH 3 , trifluoromethoxy, trifluoromethyl,

wherein R a is selected from hydrogen, halo and methyl;
R 2 is selected from hydrogen, cyano, —CH 2 OH, halo, and methyl;
R 3 is selected from hydrogen, cyano, cyclopropyl, difluoromethyl, fluoromethyl, 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;

provided that when A is

then B is

R 1 is selected from
cyclopropyl, methoxymethyl,

R 5 is selected from

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

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

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

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

6. A compound selected from
(S)-1-(4-(3,5-dimethyl-1H-pyrazol-4-yl)-2-fluorophenoxy)-2,4-dimethylpentan-2-amine;
(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(2,3-dimethylpyrido[2,3-b]pyrazin-8-yl)benzonitrile;
(S)-1-(2-fluoro-4-(pyrido[2,3-b]pyrazin-8-yl)phenoxy)-2,4-dimethylpentan-2-amine
(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(2-amino-3H-imidazo [4,5-b]pyridin-7-yl)benzonitrile;
(S)-7-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)-3H-imidazo[4,5-b]pyridin-2-amine;
(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)thiazol-2-amine;
(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-chlorophenyl)pyridin-2-yl)thiazol-2-amine;
(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)thiazole-2-carboxamide;
(S)-7-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-methylphenyl)-3H-imidazo [4,5-b]pyridin-2-amine;
(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-chlorophenyl)pyridin-2-yl)thiazole-2-carboxamide;
(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-cyanophenyl)pyridin-2-yl)thiazole-2-carboxamide;
(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-chlorophenyl)pyridin-2-yl)-4-methylthiazol-2-amine;
(R)-2,4-dimethyl-1-((3-methyl-5-(pyrazolo[1,5-a]pyrimidin-7-yl)pyridin-2-yl)oxy)pentan-2-amine;
(R)-1-((3-chloro-5-(pyrazolo[1,5-a]pyrimidin-7-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine;
(R)-1-((5-(2-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)-3-methylpyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine;
(S)-2,4-dimethyl-1-((7-(2-methylpyridin-4-yl)benzo[d]thiazol-4-yl)oxy)pentan-2-amine;
(S)-methyl (4-(4-((2-amino-2,4-dimethylpentyl)oxy)benzo [d]thiazol-7-yl)pyridin-2-yl)carbamate;
(S)-2,4-dimethyl-1-(4-(2-methylthiazolo [5,4-d]pyrimidin-7-yl)-2-(trifluoromethyl)phenoxy)pentan-2-amine;
(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(2-methylthiazolo[5,4-d]pyrimidin-7-yl)benzonitrile;
(S)-1-((3-chloro-5-(pyrazolo[1,5-a]pyrimidin-7-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine;
(S)-2,4-dimethyl-1-((3-methyl-5-(pyrazolo[1,5-a]pyrimidin-7-yl)pyridin-2-yl)oxy)pentan-2-amine;
(S)-1-((2-(fluoromethyl)-6-(pyrazolo[1,5-a]pyrimidin-7-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine
2-amino-2-(((2′,4-bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)methyl)-4-methylpentan-1-ol;
(S)-1-(4-(imidazo[1,2-b]pyridazin-8-yl)phenoxy)-2,4-dimethylpentan-2-amine;
(S)-1-(2-chloro-4-(2-methyl-3H-imidazo[4,5-b]pyridin-7-yl)phenoxy)-2,4-dimethylpentan-2-amine;
(S)-1-(4-(imidazo[1,2-b]pyridazin-8-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine;
(S)-1-(2-chloro-4-(1H-pyrazolo[3,4-b]pyridin-4-yl)phenoxy)-2,4-dimethylpentan-2-amine;
(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(6-chloroimidazo[1,2-b]pyridazin-8-yl)benzonitrile;
(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(imidazo[1,2-b]pyridazin-8-yl)benzonitrile;
(S)-1-(2-fluoro-4-(1H-pyrazolo[3,4-b]pyridin-4-yl)phenoxy)-2,4-dimethylpentan-2-amine;
(S)-1-(2-fluoro-4-(1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)phenoxy)-2,4-dimethylpentan-2-amine
2,4-dimethyl-1-(4-(2-methyl-3H-imidazo[4,5-b]pyridin-7-yl)-2-(trifluoromethyl)phenoxy)pentan-2-amine;
(S)-1-(4-(1H-pyrazolo[3,4-b]pyridin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine;
(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(2-methyl-3H-imidazo [4,5-b]pyridin-7-yl)benzonitrile;
(S)-2,4-dimethyl-1-(2-methyl-4-(2-methyl-3H-imidazo[4,5-b]pyridin-7-yl)phenoxy)pentan-2-amine;
(S)-1-(4-(2-(methoxymethyl)-3H-imidazo [4,5-b]pyridin-7-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine;
(S)-1-(4-(2-(methoxymethyl)-3H-imidazo[4,5-b]pyridin-7-yl)-2-methylphenoxy)-2,4-dimethylpentan-2-amine;
(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(2-oxo-2,3-dihydro-1H-pyrrolo [2,3-b]pyridin-4-yl)benzonitrile;
(S)-4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-2(3H)-one
2-methyl-1-((2-methyl-6-(2-methylpyrimidin-4-yl)pyridin-3-yl)oxy)propan-2-amine;
(S)-1-((2-(difluoromethyl)-6-(pyrazolo[1,5-a]pyrimidin-7-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine;
(S)-1-(2-chloro-4-(pyrazolo [,5-a]pyridin-3-yl)phenoxy)-2,4-dimethylpentan-2-amine (S)-2,4-dimethyl-1-(2-methyl-4-(pyrazolo[1,5-a]pyridin-3-yl)phenoxy)pentan-2-amine 4-(4-(((S)-2-amino-2,4-dimethylpentyl)oxy)-3-chlorophenyl)-N-(3-fluorocyclopentyl)pyridin-2-amine;
(S)-1-(2-fluoro-4-(2-(trifluoromethyl) pyrazolo[1,5-a]pyrimidin-7-yl)phenoxy)-2,4-dimethylpentan-2-amine;
(S)-1-(2-chloro-4-(2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-7-yl)phenoxy)-2,4-dimethylpentan-2-amine
4-

Assignees

• Bristol Myers Squibb Co
• Syngene International Ltd

Inventors

• Bronson Joanne J
• Chen Ling
• Ditta Jonathan L
• Dzierba Carolyn Diane
• Jalagam Prasada Rao
• Luo Guanglin
• Macor John E
• Maishal Tarun Kumar
• Nara Susheel Jethanand
• Rajamani Ramkumar
• Sistla Ramesh Kumar
• Thangavel Soodamani

Classifications

• C07D237/08

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

• C07D409/12

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

• C07D239/36

  as doubly bound oxygen atom or as unsubstituted hydroxy radical · CPC title

• C07D239/72

  Quinazolines; Hydrogenated quinazolines · CPC title

• A61K31/50

  Pyridazines; Hydrogenated pyridazines · CPC title