Arylquinazolines

Patent metadata

Field	Value
Publication number	US-9732094-B2
Application number	US-201414890214-A
Country	US
Kind code	B2
Filing date	May 8, 2014
Priority date	May 11, 2013
Publication date	Aug 15, 2017
Grant date	Aug 15, 2017

Abstract

The invention relates to novel compounds of the formula (I) which can be used for the inhibition of serine-threonine protein kinases and for the sensitization of cancer cells to anticancer agents and/or ionizing radiation.

First claim

The invention claimed is:

1. Process for the preparation of a compound of formula (I)

in which
X is CH, CF, S or N,
Y is CH, S or N,
Z is C or N,
---- forms, if Z═C, a double bond together with the single bond,
is absent if Z═N,

n is 1 or 2, where
if n=1, X═S, and if n=2, both X═CH, or the X linked to the pyrimidine ring is CF and the X not linked to the pyrimidine ring is CH, or one X is CH and the other X is N;

m is 1 or 2, where
if m=1, Y═S, and if m=2, both Y═CH, or one Y is CH and the other Y is N;

R 1 , R 2 , R 3 , R 4 , independently of one another, are H, Hal, CN, OH, CONH 2 , CONH(LA) or LA;
R 5 is H, Hal, CN or C≡CH;
Cyc is phenyl, which may be unsubstituted or mono- or disubstituted, independently of one another, by R 6 , or is Het 1 ;
Het 1 is a mono- or bicyclic, 5-10-membered heterocycle, having 1-3 N, O or S atoms, or 1-4 N atoms, which may be unsubstituted or mono-, di- or trisubstituted, independently of one another, by R 6 , or may be monosubstituted by Het 2 ;
R 6 is Hal, LA, oxo, CN, or NH 2 ;
LA is unbranched or branched alkyl having 1-5 C atoms, which may be saturated or partially unsaturated, in which 1-3 H atoms may be replaced by Hal, or one H atom may be replaced by CN or Het 2 , or one or two CH 2 groups may be replaced by O, NH, N(CH 3 ) or CO;
Het 2 is a 3-5-membered aliphatic homo- or heterocycle having 0, 1, 2 or 3 N, O or S atoms, which is unsubstituted; and
Hal is F, Cl, Br or I;

or a physiologically acceptable salt, tautomer or stereoisomer thereof, including mixtures thereof in all ratios, comprising the following steps:
(a) reacting a compound of formula (V)

in which LG is a conventional leaving group
with a compound of formula (IV)

in which A is boronic acid or a boronic acid ester,
giving the compound of formula (I), and optionally
(b) converting a base or acid of the compounds of formula (I) into one of its salts.

2. The process of claim 1 , wherein said compound is of formula (Ib),

or a physiologically acceptable salt, tautomer or stereoisomer thereof,
including mixtures thereof in all ratios.

3. The process of claim 1 , wherein said compound is selected from the following:
[2-Chloro-4-fluoro-5-(7-morpholin-4-yl quinazolin-4-yl)phenyl]-(5-methoxypyridazin-3-yl)-methanol,
[4-Fluoro-3-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(5-methoxypyridazin-3-yl)methanol,
[2,4-Difluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]imidazo[1,2-b]pyridazin-6-yl-methanol,
(3-Chloro-6-methoxypyrazin-2-yl)-[4-fluoro-3-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-methanol,
(R)-(3-Chloropyrazin-2-yl)-[4-fluoro-3-(7-morpholin-4-yl quinazolin-4-yl)phenyl]methanol,
[2-Chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]pyridazin-4-ylmethanol,
[4-Fluoro-3-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(3-methoxypyrazin-2-yl)methanol,
[4-Fluoro-3-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(6-methoxypyridazin-3-yl)methanol,
(3-Difluoromethoxypyridin-2-yl)-[4-fluoro-3-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-methanol,
(R)-[4-Fluoro-3-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(3-methylpyrazin-2-yl)methanol,
[2,4-Difluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(3-methylpyrazin-2-yl)methanol,
[2,4-Difluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]thieno[2,3-d}pyrimidin-4-ylmethanol,
6-{[4-Fluoro-3-(7-morpholin-4-ylquinazolin-4-yl)phenyl]hydroxymethyl}-1-methyl-1H-pyridin-2-one,
3-[[2-Chloro-4-fluoro-5-(7-morpholinoquinazolin-4-yl)phenyl]hydroxymethyl]-1H-pyridazin-6-one,
(S)-[2-Chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(6-methoxypyridazin-3-yl)-methanol,
(R)-[4-Fluoro-3-(7-morpholin-4-ylpyrido[3,2-d}pyrimidin-4-yl)phenyl]-(3-methylpyrazin-2-yl)-methanol,
4-(4-Chloro-2-fluoro-5-imidazo[1,2-b]pyridazin-6-ylmethylphenyl)-7-morpholin-4-yl-quinazoline,
[4-Fluoro-3-(6-morpholin-4-ylthieno[3,2-d}pyrimidin-4-yl)phenyl]-(3-methylpyrazin-2-yl)-methanol,
(R)-[4-Fluoro-3-(5-fluoro-7-morpholin-4-ylquinazolin-4-yl)phenyl]-(3-methylpyrazin-2-yl)-methanol,
[2-Chloro-4-fluoro-5-(5-fluoro-7-morpholin-4-ylquinazolin-4-yl)phenyl]-(3-methoxypyrazin-2-yl)methanol,
[4-Fluoro-3-(5-fluoro-7-morpholin-4-ylquinazolin-4-yl)phenyl]-(3-methoxypyrazin-2-yl)-methanol,
[4-Fluoro-3-(5-fluoro-7-morpholin-4-ylquinazolin-4-yl)phenyl]-(6-methoxypyridazin-3-yl)-methanol,
[4-Fluoro-3-[7-(2,2,3,3,5,5,6,6-octadeuteriomorpholin-4-yl)quinazolin-4-yl]phenyl]-(3-methylpyrazin-2-yl)methanol,
[4-Fluoro-3-(5-fluoro-7-morpholin-4-ylquinazolin-4-yl)phenyl]-(6-methoxypyridazin-3-yl)-methanol,
[2-Chloro-4-fluoro-5-[7-(2,2,3,3,5,5,6,6-octadeuteriomorpholin-4-yl)quinazolin-4-yl]phenyl]-(6-methoxypyridazin-3-yl)methanol,
[2-Chloro-4-fluoro-5-(6-morpholin-4-ylthieno[3,2-d}pyrimidin-4-yl)phenyl]-(3-methylpyrazin-2-yl)methanol,
[4-Fluoro-3-(6-morpholin-4-ylthieno[3,2-d}pyrimidin-4-yl)phenyl]-(3-methylpyrazin-2-yl)-methanol,
[2-Chloro-4-fluoro-5-(5-fluoro-7-morpholin-4-ylquinazolin-4-yl)phenyl]-(3-methoxypyrazin-2-yl)methanol,
[4-Fluoro-3-(5-fluoro-7-morpholin-4-yl-quinazolin-4-y)-phenyl]-(3-methoxypyrazin-2-yl)-methanol,
[4-Fluoro-3-(5-fluoro-7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(3-methylpyrazin-2-yl)-methanol,
[2-Chloro-4-fluoro-5-(5-fluoro-7-morpholin-4-ylquinazolin-4-yl)phenyl]-(6-methoxypyridazin-3-yl)methanol,
[4-Fluoro-3-(7-morpholin-4-ylquinazolin-4-yl)phenyl]furo[2,3-d]pyridazin-7ylmethanol,
[2,4-Difluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]furo[2,3-d}pyridazin-7-ylmethanol,
[2,4-Difluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]thieno[2,3-d}pyridazin-7-ylmethanol,
(3,5-Dimethylpyrazin-2-yl)-[4-fluoro-3-(7-morpholin-4-ylquinazolin-4-yl)phenyl]methanol,
6-{[2-Chloro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]hydroxymethyl}-1-methyl-1H-pyridin-2-one,
6-{[4-Fluoro-3-(7-morpholin-4-ylquinazolin-4-yl)phenyl]hydroxymethyl}-2H-pyridazin-3-one,
6-{[4-Fluoro-3-(7-morpholin-4-ylquinazolin-4-yl)phenyl]hydroxymethyl}-1-methyl-1H-pyridin-2-one,
6-{[2-Chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]hydroxymethyl}-1-methyl-1H-pyridin-2-one,
[4-Fluoro-3-(7-morpholin-4-ylquinazolin-4-yl)phenyl]furo[2,3-d}pyrimidin-4-ylmethanol,
[4-Fluoro-3-(7-morpholin-4-ylquinazolin-4-yl)phenyl]furo[3,2-d}pyrimidin-4-ylmethanol,
[2,4-Difluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(3-methoxypyrazin-2-yl)methanol,
4-Fluoro-3-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(3-methyl-3H-imidazo[4, 5-c]pyridin-4-yl)methanol, or
[4-Fluoro-3-(7-morpholin-4-ylquinazolin-4-yl)phenyl]furo[3,2-d}pyrimidin-4-ylmethanol,
or a physiologically acceptable salt, tautomer or stereoisomer thereof, including mixtures thereof in all ratios.

Assignees

• Merck Patent Gmbh

Inventors

• Fuchss Thomas
• Emde Ulrich
• Buchstaller Hans-Peter
• Mederski Werner

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

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

• A61P35/04

  specific for metastasis · CPC title

• C07D409/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title