Pyrazolyl quinoxaline kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9850228-B2
Application number	US-201615141061-A
Country	US
Kind code	B2
Filing date	Apr 28, 2016
Priority date	Apr 30, 2010
Publication date	Dec 26, 2017
Grant date	Dec 26, 2017

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 process for the preparation of a compound selected from the group consisting of a compound of formula (I)

a tautomeric form, stereochemically isomeric form and isotopic form thereof, or an N-oxide, a pharmaceutically acceptable salt, or a solvate of the compound, said process comprising:
(i) deprotecting a compound of formula (XXX) wherein P represents a suitable protective group, in the presence of a suitable acid,

 or
(ii) the reaction of a compound of the formula (IX) or (IX′):

or a protected form thereof, with an appropriately substituted amine or a reactive derivative thereof, in the presence of a suitable base, and/or in the presence or absence of a solvent; or
(iii) the reaction of a compound of the formula (VI):

or a protected form thereof, with a compound of formula W 6 —C 1-6 alkyl-NR 10 P wherein P represents a suitable protective group and W 6 represents a suitable leaving group, in the presence of a suitable base, and a suitable solvent, followed by removing P and optionally removing any further protecting group present; or
(iv) the reaction of a compound of the formula (VI):

or a protected form thereof, with a compound of formula W 6 —C 1-6 alkyl-NHR 10 wherein W 6 represents a suitable leaving group, in the presence of a suitable base, and a suitable solvent;
(v) the reaction of a compound of formula (XXXVI)

with hydrazine in the presence of a suitable solvent; or
(vi) the reaction of a compound of formula (IX-1) wherein R u represents —O—S(═O) 2 —CH 3 ,

with an intermediate of formula (X) in the presence of a suitable solvent; or
(vii) the reaction of a compound of formula (VI)

with an intermediate of formula W 11 -R 3b wherein R 3b represents optionally substituted C 2-6 alkynyl and W 11 represents a suitable leaving group, in the presence of a suitable base and a suitable solvent; or
(viii) the reaction of a compound of formula (VIII′) wherein R x and R y represent C 1 1-4 alkyl, and R z represents C 1-4 alkyl or phenyl,

with a suitable acid, in the presence of a suitable solvent; or
(viii) deprotecting a compound of formula (XXXXII)

in the presence of a suitable base and a suitable solvent; or
(ix) the reaction of a compound of formula (VI)

with di(C 1-6 alkyl)vinylphosphonate in the presence of a suitable catalyst and a suitable solvent; or
(x) deprotecting a compound of formula (XXXXI) wherein P represents a suitable protective group

in the presence of a suitable base and a suitable solvent; or
(xi) the reaction of a compound of formula (XIX) wherein R 3a represents optionally substituted C 1-6 alkyl, with a compound of formula (III)

in the presence of a suitable catalyst, a suitable ligand, a suitable base, and a suitable solvent; or
(xii) the reaction of a compound of formula (XX) wherein R 3a represents optionally substituted C 1-6 alkyl, with a compound of formula (XIV) wherein W 5 represents a suitable leaving group

in the presence of a suitable catalyst, a suitable ligand, a suitable base, and a suitable solvent; or
(xiii) the reaction of a compound of formula (XXXI)

with W 8 -CN, wherein W 8 represents a suitable leaving group, in the presence of a suitable base and a suitable solvent; or
(xiv) the reaction of a compound of formula (XXXV)

with a suitable base in the presence of a suitable solvent; or
(xv) deprotecting a compound of formula (XXVI) wherein P represents a suitable protective group,

in the presence of a suitable acid, or a suitable de-silylating agent, and a suitable solvent; or
(xvi) the reaction of a compound of formula (XXIX) with a compound of formula (XXI)

in the presence of suitable peptide coupling reagents; or
(xvii) the reaction of a compound of formula (XXIX)

with NHR 4 R 5 in the presence of suitable peptide coupling reagents and a suitable base, and a suitable solvent; or
(xviii) reacting the below compound

with NHR 7 R 8 in the presence of a suitable base and a suitable solvent; or
(xviii) deprotecting the below compound

in the presence of hydrazine monohydrate and a suitable solvent;
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 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 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 alke

Assignees

• Astex Therapeutics Ltd

Inventors

• Saxty Gordon
• Murray Christopher William
• Berdini Valerio
• Besong Gilbert Ebai
• Hamlett Christopher Charles Frederick
• Johnson Christopher Norbert
• Woodhead Steven John
• Reader Michael
• Rees David Charles
• Mevellec Laurence Anne
• Angibaud Patrick René
• Freyne Eddy Jean Edgard
• Govaerts Tom Cornelis Hortense
• Weerts Johan Erwin Edmond
• Perera Timothy Pietro Suren
• Gilissen Ronaldus Arnodus Hendrika Joseph
• Wroblowski Berthold
• Lacrampe Jean Fernand Armand
• Papanikos Alexandra
• Querolle Olivier Alexis Georges
• Pasquier Elisabeth Thérèse Jeanne
• Pilatte Isabelle Noëlle Constance
• Bonnet Pascal Ghislain André
• Embrechts Werner Constant Johan
• Akkari Rhalid
• Meerpoel Lieven

Classifications

• 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

• A61P35/04

  specific for metastasis · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P43/00

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