Compounds and compositions as inhibitors of MEK

Patent metadata

Field	Value
Publication number	US-9227969-B2
Application number	US-201414451563-A
Country	US
Kind code	B2
Filing date	Aug 5, 2014
Priority date	Aug 14, 2013
Publication date	Jan 5, 2016
Grant date	Jan 5, 2016

Abstract

The present invention relates to compounds of formula I:

in which n, R 1 , R 2 , R 3a , R 4 and R 5 are defined in the Summary of the Invention; capable of inhibiting the activity of MEK. The invention further provides a process for the preparation of compounds of the invention, pharmaceutical preparations comprising such compounds and methods of using such compounds and compositions in the management of hyperproliferative diseases like cancer.

First claim

We claim:

1. A compound of formula I:

wherein
n is selected from 0, 1, 2 and 3;
R 1 is selected from:

R 2 is selected from chloro, methyl, hydrogen, fluoro and methoxy;
R 3a is selected from cyano-methyl, 2-hydroxy-ethyl, 1-hydroxypropan-2-yl, 3-hydroxy-2-(hydroxy-methyl)propanoyl, 2-methoxy-ethyl, 2-fluoropropanoyl, (3-methyloxetan-3-yl)-methyl, methyl-sulfonyl, amino-carbonyl-methyl, cyclopropyl-sulfonyl, isopropyl-sulfonyl, dimethylcarbamoyl, 3-hydroxy-2-(hydroxy-methyl)propyl, 2-hydroxy-propyl, 2-hydroxyacetyl, 2-acetoxyacetyl, 2-methoxyacetyl, (2,2,2-trifluoroethyl)carbamoyl, 2-aminoacetyl, oxetan-3-ylmethyl, (S)-2-hydroxypropanoyl, 2-hydroxypropanoyl, acetyl, 2-amino-2-oxoethyl, carbamoyl, (oxetan-2-yl)-methanoyl, 2-(sulfooxy)acetyl, 2-fluoroethanoyl, 3-hydroxypropanoyl, and N,N-dimethylsulfonamidyl;
each R 4 is independently selected from hydrogen, halo, methyl and hydroxy-methyl; and
optionally two R 4 groups together with the carbon atoms to which they are attached form —(CH 2 ) 2-3 —;
R 5 is selected from hydrogen and methyl;
R 6 is selected from hydrogen, methoxy and halo;
R 7 is selected from hydrogen, fluoro, CF 3 , CH 2 OH, cyclopropyl and methyl; and
R 8 is cyano;
or the pharmaceutically acceptable salts thereof.

2. The compound of claim 1 , wherein:
n is selected from 0 or 1;
R 1 is selected from:

R 2 is selected from chloro, methyl, hydrogen, fluoro and methoxy;
R 3a is selected from cyano-methyl, 3-hydroxy-2-(hydroxy-methyl)propanoyl, 2-methoxy-ethyl, 2-fluoropropanoyl, (3-methyloxetan-3-yl)-methyl, methyl-sulfonyl, amino-carbonyl-methyl, cyclopropyl-sulfonyl, isopropyl-sulfonyl, dimethylcarbamoyl, 2-hydroxyacetyl, 2-acetoxyacetyl, 2-methoxyacetyl, (2,2,2-trifluoroethyl)carbamoyl, 2-aminoacetyl, oxetan-3-ylmethyl, (S)-2-hydroxypropanoyl, 2-hydroxypropanoyl, acetyl, 2-amino-2-oxoethyl, carbamoyl, (oxetan-2-yl)-methanoyl, 2-(sulfooxy)acetyl, 2-fluoroethanoyl, 3-hydroxypropanoyl, and N,N-dimethylsulfonamidyl;
each R 4 is independently selected from halo, methyl and hydroxy-methyl;
R 5 is selected from hydrogen and methyl;
R 6 is selected from hydrogen and halo; and
R 7 is selected from hydrogen, fluoro, CF 3 , CH 2 OH, cyclopropyl and methyl;
or the pharmaceutically acceptable salts thereof.

3. The compound of claim 1 , wherein:
n is selected from 0 or 1;
R 1 is selected from:

R 2 is selected from chloro, methyl, hydrogen, fluoro and methoxy;
R 3a is selected from 3-hydroxy-2-(hydroxy-methyl)propanoyl, 2-fluoropropanoyl, methyl-sulfonyl, cyclopropyl-sulfonyl, isopropyl-sulfonyl, dimethylcarbamoyl, 2-hydroxyacetyl, 2-acetoxyacetyl, 2-methoxyacetyl, (2,2,2-trifluoroethyl)carbamoyl, 2-aminoacetyl, (S)-2-hydroxypropanoyl, 2-hydroxypropanoyl, acetyl, carbamoyl, 2-(sulfooxy)acetyl, 2-fluoroethanoyl, 3-hydroxypropanoyl, and N,N-dimethylsulfonamidyl;
each R 4 is independently selected from halo, methyl and hydroxy-methyl;
R 5 is selected from hydrogen and methyl;
R 6 is selected from hydrogen and halo; and
R 7 is selected from hydrogen, fluoro, CF 3 , CH 2 OH, cyclopropyl and methyl;
or the pharmaceutically acceptable salts thereof.

4. The compound of claim 1 , wherein:
n is selected from 0 or 1;
R 1 is selected from:

R 2 is selected from chloro and methoxy;
R 3a is selected from 3-hydroxy-2-(hydroxy-methyl)propanoyl, 2-fluoropropanoyl, dimethylcarbamoyl, 2-hydroxyacetyl, 2-acetoxyacetyl, 2-methoxyacetyl, (2,2,2-trifluoroethyl)carbamoyl, 2-aminoacetyl, (S)-2-hydroxypropanoyl, 2-hydroxypropanoyl, acetyl, carbamoyl, 2-(sulfooxy)acetyl, 2-fluoroethanoyl and 3-hydroxypropanoyl;
each R 4 is independently selected from halo, methyl and hydroxy-methyl;
R 5 is selected from hydrogen and methyl;
R 6 is hydrogen; and
R 7 is hydrogen;
or the pharmaceutically acceptable salts thereof.

5. The compound of claim 1 of formula 1e:

wherein:
R 1 is selected from:

R 2 is selected from chloro, methyl, fluoro and methoxy;
R 3a is selected from cyano-methyl, 2-hydroxy-ethyl, 1-hydroxypropan-2-yl, 3-hydroxy-2-(hydroxy-methyl)propanoyl, 2-methoxy-ethyl, 2-fluoropropanoyl, (3-methyloxetan-3-yl)-methyl, methyl-sulfonyl, amino-carbonyl-methyl, cyclopropyl-sulfonyl, isopropyl-sulfonyl, dimethylcarbamoyl, 3-hydroxy-2-(hydroxy-methyl)propyl, 2-hydroxy-propyl, 2-hydroxyacetyl, 2-acetoxyacetyl, 2-methoxyacetyl, (2,2,2-trifluoroethyl)carbamoyl, 2-aminoacetyl, oxetan-3-ylmethyl, (S)-2-hydroxypropanoyl, 2-hydroxypropanoyl, acetyl, 2-amino-2-oxoethyl, carbamoyl, (oxetan-2-yl)-methanoyl, 2-(sulfooxy)acetyl, 2-fluoroethanoyl, 3-hydroxypropanoyl, and N,N-dimethylsulfonamidyl;
R 4a is selected from hydrogen and methyl;
R 4b is selected from hydrogen and fluorine;
R 5 is selected from hydrogen and methyl;
R 6 is selected from hydrogen and fluoro;
R 7 is selected from hydrogen, fluoro, CF 3 , CH 2 OH, cyclopropyl and methyl; and
R 8 is cyano;
or the pharmaceutically acceptable salts thereof.

6. The compound of claim 1 of formula Ie:

wherein
R 1 is selected from:

R 2 is selected from chloro, methyl, fluoro and methoxy;
R 3a is selected from cyano-methyl, 3-hydroxy-2-(hydroxy-methyl)propanoyl, 2-methoxy-ethyl, 2-fluoropropanoyl, (3-methyloxetan-3-yl)-methyl, methyl-sulfonyl, amino-carbonyl-methyl, cyclopropyl-sulfonyl, isopropyl-sulfonyl, dimethylcarbamoyl, 2-hydroxyacetyl, 2-acetoxyacetyl, 2-methoxyacetyl, (2,2,2-trifluoroethyl)carbamoyl, 2-aminoacetyl, oxetan-3-ylmethyl, (S)-2-hydroxypropanoyl, 2-hydroxypropanoyl, acetyl, 2-amino-2-oxoethyl, carbamoyl, (oxetan-2-yl)-methanoyl, 2-(sulfooxy)acetyl, 2-fluoroethanoyl, 3-hydroxypropanoyl, and N,N-dimethylsulfonamidyl;
R 4a is hydrogen;
R 4b is fluorine;
R 5 is methyl;
R 6 is hydrogen and fluoro; and
R 7 is selected from hydrogen, CF 3 , CH 2 OH, and methyl;
or the pharmaceutically acceptable salts thereof.

7. The compound of claim 1 of formula Ie:

wherein
R 1 is selected from:

R 2 is selected from chloro, methyl, fluoro and methoxy;
R 3a is selected from cyano-methyl, methyl-sulfonyl, 2-hydroxyacetyl, 2-acetoxyacetyl, 2-methoxyacetyl, (S)-2-hydroxypropanoyl, acetyl, carbamoyl, (oxetan-2-yl)-methanoyl, 2-(sulfooxy)acetyl, 2-fluoroethanoyl and 3-hydroxyp

Assignees

• Bock Mark Gary
• Moebitz Henrik
• Panigrahi Sunil Kumar
• Poddutoori Ramulu
• Samajdar Susanta
• Novartis Ag

Inventors

• Bock Mark Gary
• Moebitz Henrik
• Panigrahi Sunil Kumar
• Poddutoori Ramulu
• Samajdar Susanta

Classifications

• A61P43/00

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/497

  containing further heterocyclic rings · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/53

  having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495}) · CPC title