US 2012/0258982 A1 · ADAMANTYL COMPOUNDS

Abstract

The invention relates to JNK inhibitors and corresponding methods, formulations, and compositions for inhibiting JNK and treating JNK-mediated disorders. The application discloses JNK inhibitors, as described below in Formula I: wherein the variables are as defined herein. The compounds and compositions disclosed herein are useful to modulate the activity of JNK and treat diseases associated with JNK activity. Disclosed are methods and formulations for inhibiting JNK and treating JNK-mediated disorders, and the like, with the compounds, and processes for making said compounds, and corresponding compositions, disclosed herein.

Claims28

Dependent claims

A compound of formula I

wherein:
R is phenyl, or pyridonyl, optionally substituted with one or more R′;
R′ is halo or methoxy;
X is CH or N;
X1 is H or C(═O)OCH3 or 2-oxazole;
Y is CH or N;
Y1 is OH, OC(═O)Y1′, N(Y1′)2, NHS(═O)2Y1′, NHC(═O)Y1′, NHC(═O)C(CH3)2OH, NHCH2C(CH3)2OH, or NHC(═O)C(CH3)2OC(═O)Y1′;
each Y1 is independently H, lower alkyl, lower hydroxyalkyl, or cycloalkyl;
Y2 is H, halo, or haloalkyl;
or a pharmaceutically acceptable salt thereof.

7 more elements

A compound selected from the group consisting of:

rel-3-[4-((1S,2S,3R,5S,7S)-5-Hydroxy-adamantan-2-ylcarbamoyl)-benzyl]-4-oxo-1-phenyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester;
rel-3-[4-((1S,2R,3R,5S,7S)-5-Hydroxy-adamantan-2-ylcarbamoyl)-benzyl]-4-oxo-1-phenyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester;
rel-7-Chloro-3-[4-((1S,2S,3R,5S,7S)-5-hydroxy-adamantan-2-ylcarbamoyl)-benzyl]-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester;
rel-7-Chloro-3-[4-((1S,2R,3R,5S,7S)-5-hydroxy-adamantan-2-ylcarbamoyl)-benzyl]-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester;
rel-4-(7-Chloro-4-oxo-1-pyridin-2-yl-1,4-dihydro-quinolin-3-ylmethyl)-N-((1S,2S,3R,5S,7S)-5-hydroxy-adamantan-2-yl)-benzamide;
rel-3-[4-((1S,2S,3R,5S,7S)-5-Acetoxy-adamantan-2-ylcarbamoyl)-benzyl]-7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester;
rel-3-[4-((1S,2S,3R,5S,7S)-5-amino-adamantan-2-ylcarbamoyl)-benzyl]-4-oxo-1-phenyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester;
rel-3-[4-((1S,2R,3R,5S,7S)-5-amino-adamantan-2-ylcarbamoyl)-benzyl]-4-oxo-1-phenyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester;
rel-3-[4-((1S,2S,3R,5S,7S)-5-Amino-adamantan-2-ylcarbamoyl)-benzyl]-7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester;
rel-3-[4-((1S,2S,3R,5S,7S)-5-Acetylamino-adamantan-2-ylcarbamoyl)-benzyl]-7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester;
rel-7-Chloro-3-{4-[(1S,2S,3R,5S,7S)-5-(2,2-dimethyl-propionylamino)-adamantan-2-ylcarbamoyl]-benzyl}-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester;
rel-3-{4-[(1S,2S,3R,5S,7S)-5-(2-Acetoxy-2-methyl-propionylamino)-adamantan-2-ylcarbamoyl]-benzyl}-7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester;
rel-7-Chloro-3-{4-[(1S,2S,3R,5S,7S)-5-(2-hydroxy-2-methyl-propionylamino)-adamantan-2-ylcarbamoyl]-benzyl}-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester;
rel-7-Chloro-3-[4-((1S,2S,3R,5S,7S)-5-cyclopropanesulfonylamino-adamantan-2-ylcarbamoyl)-benzyl]-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester;
rel-7-Chloro-3-[4-((1S,2S,3R,5S,7S)-5-methanesulfonylamino-adamantan-2-ylcarbamoyl)-benzyl]-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester;
rel-7-Chloro-3-{4-[(1S,2S,3R,5S,7S)-5-(2-hydroxy-2-methyl-propylamino)-adamantan-2-ylcarbamoyl]-benzyl}-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester;
rel-3-[4-((1S,2S,3R,5S,7S)-5-Acetylamino-adamantan-2-ylcarbamoyl)-benzyl]-4-oxo-1-phenyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester;
rel-3-[4-((1S,2S,3R,5S,7S)-5-Cyclopropanesulfonylamino-adamantan-2-ylcarbamoyl)-benzyl]-4-oxo-1-phenyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester;
rel-3-[4-((1S,2S,3R,5S,7S)-5-Methanesulfonylamino-adamantan-2-ylcarbamoyl)-benzyl]-4-oxo-1-phenyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester;
rel-3-{4-[(1S,2S,3R,5S,7S)-5-(2,2-Dimethyl-propionylamino)-adamantan-2-ylcarbamoyl]-benzyl}-4-oxo-1-phenyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester;
rel-3-{4-[(1S,2S,3R,5S,7S)-5-(2-Acetoxy-2-methyl-propionylamino)-adamantan-2-ylcarbamoyl]-benzyl}-4-oxo-1-phenyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester;
rel-3-{4-[(1S,2S,3R,5S,7S)-5-(2-Hydroxy-2-methyl-propionylamino)-adamantan-2-ylcarbamoyl]-benzyl}-4-oxo-1-phenyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl;
rel-3-[4-((1S,2S,3R,5S,7S)-5-Hydroxy-adamantan-2-ylcarbamoyl)-2-methoxy-benzyl]-4-oxo-1-phenyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester;
rel-3-[2-Fluoro-4-((1S,2S,3R,5S,7S)-5-hydroxy-adamantan-2-ylcarbamoyl)-benzyl]-4-oxo-1-phenyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester;
rel-3-[4-((1S,2S,3R,5S,7S)-5-Hydroxy-adamantan-2-ylcarbamoyl)-benzyl]-4-oxo-1-phenyl-7-trifluoromethyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester;
rel-7-Chloro-3-[4-((1S,2S,3R,5S,7S)-5-hydroxy-adamantan-2-ylcarbamoyl)-2-oxo-2H-pyridin-1-ylmethyl]-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester;
and
Rel-4-(7-Chloro-2-oxazol-2-yl-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-N-((1S,2S,3R,5S,7S)-5-hydroxy-adamantan-2-yl)-benzamide.

25 more elements

Dependencies are inferred from the claim text.

Facts

Application

13/437,984Filed 3 Apr 2012

Priority

6 Apr 2011

Published

11 Oct 2012

Term ends

Not estimatedThe source records don’t support an estimate.

Classification20 codes

C07D 215/233
Attached in position 2 or 4: only one oxygen atom which is attached in position 4
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…
A61P 9/12
Drugs for disorders of the cardiovascular system: antihypertensives

Adamantyl compounds

Life of this patent

Adamantyl compounds

Life of this patent

Abstract

Claims28