Compounds

Patent metadata

Field	Value
Publication number	US-9303030-B2
Application number	US-201314404188-A
Country	US
Kind code	B2
Filing date	May 30, 2013
Priority date	May 30, 2012
Publication date	Apr 5, 2016
Grant date	Apr 5, 2016

Abstract

The invention relates to new pyridopyrazine and naphthyridine derivative compounds, to pharmaceutical compositions comprising said compounds, to processes for the preparation of said compounds and to the use of said compounds in the treatment of diseases, e.g. cancer.

First claim

The invention claimed is:

1. A compound selected from the group consisting of a compound of formula (I-A) or (I-B)

a tautomeric form, stereochemically isomeric form and isotropic form thereof, wherein
for (I-A)
X 1 is N, X 2 is N and X 3 is CH; or
X 1 is CR 3d , X 2 is N and X 3 is CH; or
X 1 is CR 3d , X 2 is CR 3d and X 3 is N;
for (I-B)
X 1 is N or CR 3d ;
each R 2 is independently selected from hydroxyl, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, hydroxyC 1-4 alkyl, hydroxyC 1-4 alkoxy, haloC 1-4 alkyl, haloC 1-4 alkoxy, hydroxyhaloC 1-4 alkyl, hydroxyhaloC 1-4 alkoxy, C 1-4 alkoxyC 1-4 alkyl, haloC 1-4 alkoxyC 1-4 alkyl, C 1-4 alkoxyC 1-4 alkyl wherein each C 1-4 alkyl may optionally be substituted with one or two hydroxyl groups, hydroxyhaloC 1-4 alkoxyC 1-4 alkyl, R 13 , C 1-4 alkyl substituted with R 13 , C 1-4 alkyl substituted with —C(═O)—R 13 , C 1-4 alkoxy substituted with R 13 , C 1-4 alkoxy substituted with —C(═O)—R 13 , —C(═O)—R 13 , C 1-4 alkyl substituted with —NR 7 R 8 , C 1-4 alkyl substituted with —C(═O)—NR 7 R 8 , C 1-4 alkoxy substituted with —NR 7 R 8 , C 1-4 alkoxy substituted with —C(═O)—NR 7 R 8 , —NR 7 R 8 and —C(═O)—NR 7 R 8 ; or when two R 2 groups are attached to adjacent carbon atoms they may be taken together to form a radical of formula:
—O—(C(R 17 ) 2 ) p —O—;
—X—CH═CH—; or
—X—CH═N—; wherein R 17 represents hydrogen or fluorine, p represents 1 or 2 and
X represents O or S;

D represents a 3 to 12 ring membered monocyclic or bicyclic carbocyclyl or a 3 to 12 ring membered monocyclic or bicyclic heterocyclyl containing at least one heteroatom selected from N, O or S, wherein said carbocyclyl and heterocyclyl may each be optionally substituted by one or more R 1 groups;
R 1 represents hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, —C(═O)—O—C 1-6 alkyl, C 2-4 alkenyl, hydroxyC 1-6 alkyl, haloC 1-6 alkyl, hydroxyhaloC 1-6 alkyl, cyanoC 1-4 alkyl, C 1-6 alkoxyC 1-6 alkyl wherein each C 1-6 alkyl may optionally be substituted with one or two hydroxyl groups, —NR 4 R 5 , C 1-6 alkyl substituted with —O—C(═O)—C 1-6 alkyl, C 1-6 alkyl substituted with —NR 4 R 5 , —C(═O)—NR 4 R 5 , —C(═O)—C 1-6 alkyl-NR 4 R 5 , C 1-6 alkyl substituted with —C(═O)—NR 4 R 5 , —S(═O) 2 —C 1-6 alkyl, —S(═O) 2 -haloC 1-6 alkyl, —S(═O) 2 —NR 14 R 15 , C 1-6 alkyl substituted with —S(═O) 2 —C 1-6 alkyl, C 1-6 alkyl substituted with —S(═O) 2 -haloC 1-6 alkyl, C 1-6 alkyl substituted with —S(═O) 2 —NR 14 R 15 , C 1-6 alkyl substituted with —NH—S(═O) 2 —C 1-6 alkyl, C 1-6 alkyl substituted with —NH—S(═O) 2 -haloC 1-6 alkyl, C 1-6 alkyl substituted with —NR 12 —S(═O) 2 —NR 14 R 15 , R 6 , C 1-6 alkyl substituted with R 6 , —C(═O)—R 6 , C 1-6 alkyl substituted with —C(═O)—R 6 , hydroxyC 1-6 alkyl substituted with R 6 , C 1-6 alkyl substituted with —Si(CH 3 ) 3 , C 1-6 alkyl substituted with —P(═O)(OH) 2 or C 1-6 alkyl substituted with —P(═O)(OC 1-6 alkyl) 2 ;
R 3a represents —NR 10 R 11 , hydroxyl, C 1-6 alkoxy, hydroxyC 1-6 alkoxy, C 1-6 alkoxy substituted with —NR 10 R 11 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, haloC 1-6 alkyl optionally substituted with —O—C(═O)—C 1-6 alkyl, hydroxyC 1-6 alkyl optionally substituted with —O—C(═O)—C 1-6 alkyl, hydroxyC 2-6 alkenyl, hydroxyC 2-6 alkynyl, hydroxyhaloC 1-6 alkyl, cyanoC 1-6 alkyl, C 1-6 alkyl substituted with carboxyl, C 1-6 alkyl substituted with —C(═O)—C 1-6 alkyl, C 1-6 alkyl substituted with —C(═O)—O—C 1-6 alkyl, C 1-6 alkyl substituted with C 1-6 alkoxyC 1-6 alkyl-O—C(═O)—, C 1-6 alkyl substituted with C 1-6 alkoxyC 1-6 alkyl-C(═O)—, C 1-6 alkyl substituted with —O—C(═O)—C 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl wherein each C 1-6 alkyl may optionally be substituted with one or two hydroxyl groups or with —O—C(═O)—C 1-6 alkyl, C 2-6 alkenyl substituted with C 1-6 alkoxy, C 2-6 alkynyl substituted with C 1-6 alkoxy, C 1-6 alkyl substituted with R 9 and optionally substituted with —O—C(═O)—C 1-6 alkyl, C 1-6 alkyl substituted with —C(═O)—R 9 , C 1-6 alkyl substituted with hydroxyl and R 9 , C 2-6 alkenyl substituted with R 9 , C 2-6 alkynyl substituted with R 9 , C 1-6 alkyl substituted with —NR 10 R 11 , C 2-6 alkenyl substituted with —NR 10 R 11 , C 2-6 alkynyl substituted with —NR 10 R 11 , C 1-6 alkyl substituted with hydroxyl and —NR 10 R 11 , C 1-6 alkyl substituted with one or two halogens and —NR 10 R 11 , —C 1-6 alkyl-C(R 12 )═N—O—R 12 , C 1-6 alkyl substituted with —C(═O)—NR 10 R 11 , C 1-6 alkyl substituted with —O—C(═O)—NR 10 R 11 , S(═O) 2 —C 1-6 alkyl, —S(═O) 2 -haloC 1-6 alkyl, —S(═O) 2 —NR 14 R 15 , C 1-6 alkyl substituted with —S(═O) 2 —C 1-6 alkyl, C 1-6 alkyl substituted with —S(═O) 2 -haloC 1-6 alkyl, C 1-6 alkyl substituted with —S(═O) 2 —NR 14 R 15 , C 1-6 alkyl substituted with —NR 12 —S(═O) 2 —C 1-6 alkyl, C 1-6 alkyl substituted with —NH—S(═O) 2 -haloC 1-6 alkyl, C 1-6 alkyl substituted with —NR 12 —S(═O) 2 —NR 14 R 15 , R 13 , C 1-6 alkyl substituted with —P(═O)(OH) 2 or C 1-6 alkyl substituted with —P(═O)(OC 1-6 alkyl) 2 ; provided that for a compound of formula (I-B), R 3a may not represent —NR 10 R 11 ;
R 3b represents hydrogen or hydroxyl; provided that if R 3a represents —NR 10 R 11 , then R 3 ″ represents hydrogen; or
for a compound of formula (I-A), R 3a and R 3b may also be taken together to form ═O, to form ═NR 10 , to form cyclopropyl together with the carbon atom to which they are attached, to form ═CH—C 0-4 alkyl substituted with R 3c , or to form

wherein ring A is a monocyclic 5 to 7 membered saturated heterocycle containing one heteroatom selected from N, O or S, said heteroatom not being positioned in alpha position of the double bond, wherein ring A is optionally being substituted with cyano, C 1-4 alkyl, hydroxyC 1-4 alkyl, H 2 N—C 1-4 alkyl, (C 1-4 alkyl)NH—C 1-4 alkyl, (C 1-4 alkyl) 2 N—C 1-4 alkyl, haloC 1-4 alkyl)NH—C 1-4 alkyl, C 1-4 alkoxyC 1-4 alkyl, —C(═O)—NH 2 , —C(═O)—NH(C 1-4 alkyl), —C(═O)—N(C 1-4 alkyl) 2 ;
R 3c represents hydrogen, hydroxyl, C 1-6 alkoxy, R 9 , —NR 10 R 11 , —C(═O)—NR 14 R 15 , cyano, —C(═O)—C 1-6 alkyl or —CH(OH)—C 1-6 alkyl;
R 3d represents hydrogen, chlorine, hydroxyl, or C 1-6 alkoxy;
R 4 and R 5 each independently represent hydrogen, C 1-6 alkyl, C 1-6 alkyl substituted with —NR 14 R 15 , hydroxyC 1-6 alkyl, haloC 1-6 alkyl, hydroxyhaloC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl wherein each C 1-6 alkyl may optionally be substituted with one or two hydroxyl groups, —S(═O) 2 —C 1-6 alkyl, —S(═O) 2 -haloC 1-6 alkyl, —S(═O) 2 —NR 14 R 15 , —C(═O)—NR 14 R 15 , —C(═O)—O—C 1-6 alkyl, —C(═O)—R 13 , C 1-6 alkyl substituted with —S(═O) 2 —C 1-6 alkyl, C 1-6 alkyl substituted with —S(═O) 2 -haloC 1-6 alkyl, C 1-6 alkyl substituted with —S(═O) 2 —NR 14 R 15 , C 1-6 alkyl substituted with —NH—S(═O) 2 —C 1-6 alkyl, C 1-6 alkyl substituted with —NH—S(═O) 2 -haloC 1-6 alkyl, C 1-6 alkyl substituted with —NH—S(═O) 2 —NR 14 R 15 , R 13 or C 1-6 alkyl substituted with R 13 ;
R 6 represents C 3-8 cycloalkyl, C 3-8 cycloalkenyl, phenyl, 4 to 7-membered monocyclic heterocyclyl containing at least one heteroatom selected from N, O or S; said C 3-8 cycloalkyl, C 3-8 cycloalkenyl, phenyl, 4 to 7-membered monocyclic heterocyclyl, optionally and each independently being substituted by 1, 2, 3, 4 or 5 substituents, each substituent independently being selected from cyano, C 1-6 alkyl, cyanoC 1-6 alkyl, hydroxyl, carboxyl, hydroxyC 1-6 al

Assignees

• Astex Therapeutics Ltd

Inventors

• Angibaud Patrick René
• Pilatte Isabelle Noëlle Constance
• Querolle Olivier Alexis Georges

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P43/00

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

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title