Pyrazolyl quinoxaline kinase inhibitors

Patent metadata

Field	Value
Publication number	US-10519137-B2
Application number	US-201715810521-A
Country	US
Kind code	B2
Filing date	Nov 13, 2017
Priority date	Apr 30, 2010
Publication date	Dec 31, 2019
Grant date	Dec 31, 2019

Abstract

The invention relates to new quinoxaline 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 (VI):

a tautomeric form, stereochemically isomeric form and isotopic form thereof, wherein
n is an integer equal to 0, 1, 2, 3 or 4;
R 1 is
hydrogen,
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 is optionally substituted with one or two hydroxyl groups,
C 1-6 alkyl substituted with —NR 4 R 6 ,
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 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 ;

each R 1a is independently selected from
hydrogen,
C 1-4 alkyl,
hydroxyC 1-4 alkyl,
C 1-4 alkyl substituted with amino or mono- or di(C 1-4 alkyl)amino or —NH(C 3-8 cycloalkyl),
cyanoC 1-4 alkyl,
C 1-4 alkoxyC 1-4 alkyl, and
C 1-4 alkyl substituted with one or more fluoro atoms;

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 is optionally 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 are optionally 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 is hydrogen or fluorine, p is 1 or 2 and X is O or S;
R 4 and R 5 are each independently
hydrogen,
C 1-6 alkyl,
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 is optionally 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 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 is C 3-8 cycloalkyl, C 3-8 cycloalkenyl, phenyl, 4 to 7-membered monocyclic heterocyclyl containing at least one heteroatom selected from N, O and S; said C 3-8 cycloalkyl, C 3-8 cycloalkenyl, phenyl, 4 to 7-membered monocyclic heterocyclyl, each optionally and each independently substituted by 1, 2, 3, 4 or 5 substituents, each substituent independently selected from cyano, C 1-6 alkyl, cyanoC 1-6 alkyl, hydroxyl, carboxyl, hydroxyC 1-6 alkyl, halogen, haloC 1-6 alkyl, hydroxyhaloC 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, C 1-6 alkyl-O—C(═O)—, —NR 14 R 15 , —C(═O)—NR 14 R 15 , C 1-6 alkyl substituted with —NR 14 R 15 , C 1-6 alkyl substituted with —C(═O)—NR 14 R 15 , —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 or C 1-6 alkyl substituted with —NH—S(═O) 2 —NR 14 R 15 ;
R 7 and R 8 each independently represent hydrogen, C 1-6 alkyl, hydroxyC 1-6 alkyl, haloC 1-6 alkyl, hydroxyhaloC 1-6 alkyl or C 1-6 alkoxyC 1-6 alkyl;
R 12 is hydrogen or C 1-4 alkyl optionally substituted with C 1-4 alkoxy;
R 13 is C 3-8 cycloalkyl or a saturated 4 to 6-membered monocyclic heterocyclyl containing at least one heteroatom selected from N, O or S, wherein said C 3-8 cycloalkyl or monocyclic heterocyclyl is optionally substituted with 1, 2 or 3 substituents each independently selected from halogen, hydroxyl, C 1-6 alkyl, —C(═O)—C 1-6 alkyl, C 1-6 alkoxy, and —NR 14 R 15 ; and
R 14 and R 15 are each independently
hydrogen, or
haloC 1-4 alkyl, or
C 1-4 alkyl optionally substituted with a substituent selected from hydroxyl, C 1-4 alkoxy, amino and mono- or di(C 1-4 alkyl)amino;
or an N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

2. The compound according to claim 1 wherein
R 1 is
hydrogen,
C 1-6 alkyl,
hydroxyC 1-6 alkyl,
haloC 1-6 alkyl,
C 1-6 alkoxyC 1-6 alkyl wherein each C 1-6 alkyl is optionally substituted with one or two hydroxyl groups,
C 1-6 alkyl substituted with —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 —NR 14 R 15 ,
C 1-6 alkyl substituted with —S(═O) 2 —C 1-6 alkyl,
C 1-6 alkyl substituted with —NH—S(═O) 2 —C 1-6 alkyl,
R 6 ,
C 1-6 alkyl substituted with R 6 ,
C 1-6 alkyl substituted with —C(═O)—R 6 ,
hydroxyC 1-6 alkyl substituted with R 6 , or
C 1-6 alkyl substituted with —Si(CH 3 ) 3 ;
wherein each R 1a is hydrogen;

or an N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

3. The compound according to claim 1 wherein each R 1a is hydrogen; or an N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

4. The compound according to claim 1 wherein R 1 is C 1-6 alkyl; or an N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

5. The compound according to claim 1 wherein R 1 is CH 3 - or CD 3 -; or an N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

6. The compound according claim 1 wherein R 2 is independently selected from halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 1-4 alkoxy, hydroxyC 1-4 alkyl, hydroxyC 1-4 alkoxy, haloC 1-4 alkoxy, C 1-4 alkoxyC 1-4 alkyl, R 13 , C 1-4 alkoxy substituted with R 13 , —C(═O)—R 13 , C 1-4 alkyl substituted with NR 7 R 8 , C 1-4 alkoxy substituted with NR 7 R 8 , —NR 7 R 8 and —C(═O)—NR 7 R 8 ; or an N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

7. The compound according to claim 6 wherein R 2 represents C 1-4 alkoxy; or an N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

8. The compound according to claim 6 wherein R 2 represents CH 3 O— or CD 3 O—; or an N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

9. The compound according to claim 1 wherein R 1 is C 1-6 a

Assignees

• Astex Therapeutics Ltd

Inventors

• Saxty Gordon
• Murray Christopher William
• Berdini Valerio
• Besong Gilbert Ebai
• Woodhead Steven John
• Reader Michael
• Mevellec Laurence Anne
• Angibaud Patrick René
• Freyne Eddy Jean Edgard
• Perera Timothy Pietro Suren
• Wroblowski Berthold
• Papanikos Alexandra
• Querolle Olivier Alexis Georges
• Pilatte Isabelle Noëlle Constance
• Bonnet Pascal Ghislain André
• Embrechts Werner Constant Johan
• Akkari Rhalid
• Meerpoel Lieven

Classifications

• A61P43/00

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

• A61P35/04

  specific for metastasis · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/06

  Antiarrhythmics · CPC title

• A61P7/06

  Antianaemics · CPC title