U.S. patent application number 17/303403 was filed with the patent office on 2022-04-21 for arylquinazolines.
The applicant listed for this patent is Merck Patent GmbH. Invention is credited to Hans-Peter BUCHSTALLER, Ulrich EMDE, Thomas FUCHSS, Werner MEDERSKI.
Application Number | 20220117970 17/303403 |
Document ID | / |
Family ID | 1000006062613 |
Filed Date | 2022-04-21 |
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United States Patent
Application |
20220117970 |
Kind Code |
A1 |
FUCHSS; Thomas ; et
al. |
April 21, 2022 |
ARYLQUINAZOLINES
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 sensitisation of cancer cells to anticancer
agents and/or ionising radiation.
Inventors: |
FUCHSS; Thomas;
(Bensheim-Auerbach, DE) ; EMDE; Ulrich;
(Darmstadt, DE) ; BUCHSTALLER; Hans-Peter;
(Griesheim, DE) ; MEDERSKI; Werner; (Zwingenberg,
DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Merck Patent GmbH |
Darmstadt |
|
DE |
|
|
Family ID: |
1000006062613 |
Appl. No.: |
17/303403 |
Filed: |
May 28, 2021 |
Related U.S. Patent Documents
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Application
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Filing Date |
Patent Number |
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16452604 |
Jun 26, 2019 |
11065253 |
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17303403 |
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16189113 |
Nov 13, 2018 |
10383874 |
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16452604 |
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15633064 |
Jun 26, 2017 |
10172859 |
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16189113 |
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14890214 |
Nov 10, 2015 |
9732094 |
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PCT/EP2014/001236 |
May 8, 2014 |
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15633064 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 265/30 20130101;
C07D 498/08 20130101; C07D 487/04 20130101; C07D 403/10 20130101;
C07D 405/14 20130101; C07D 239/72 20130101; C07D 417/10 20130101;
C07D 513/04 20130101; C07D 495/04 20130101; C07D 239/74 20130101;
C07D 285/01 20130101; C07D 473/00 20130101; C07D 401/10 20130101;
C07D 417/14 20130101; C07C 25/02 20130101; A61K 31/5377 20130101;
A61K 31/5386 20130101; C07D 237/14 20130101; A61K 31/519 20130101;
C07D 405/04 20130101; C07D 471/04 20130101; C07D 403/14 20130101;
C07D 491/048 20130101; A61K 45/06 20130101 |
International
Class: |
A61K 31/519 20060101
A61K031/519; C07D 405/14 20060101 C07D405/14; C07D 401/10 20060101
C07D401/10; C07D 403/10 20060101 C07D403/10; C07D 405/04 20060101
C07D405/04; C07D 417/10 20060101 C07D417/10; C07D 417/14 20060101
C07D417/14; C07D 471/04 20060101 C07D471/04; C07D 487/04 20060101
C07D487/04; C07D 491/048 20060101 C07D491/048; C07D 495/04 20060101
C07D495/04; C07D 498/08 20060101 C07D498/08; C07D 513/04 20060101
C07D513/04; A61K 31/5377 20060101 A61K031/5377; A61K 31/5386
20060101 A61K031/5386; A61K 45/06 20060101 A61K045/06; C07D 239/74
20060101 C07D239/74; C07D 403/14 20060101 C07D403/14; C07D 473/00
20060101 C07D473/00; C07C 25/02 20060101 C07C025/02; C07D 237/14
20060101 C07D237/14; C07D 239/72 20060101 C07D239/72; C07D 265/30
20060101 C07D265/30; C07D 285/01 20060101 C07D285/01 |
Foreign Application Data
Date |
Code |
Application Number |
May 11, 2013 |
DE |
102013008118.1 |
Claims
1-20. (canceled)
21. A compound selected from the following:
(3,5-Difluoro-pyridin-4-yl)-[4-fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl-
)-phenyl]methanol;
(4-Chloro-5-fluoro-pyridin-3-yl)-[4-fluoro-3-(7-morpholin-4-ylquinazolin--
4-yl)-phenyl]-methanol;
[2-Chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-(4-methoxy-
-pyridazin-3-yl)methanol;
[2-Chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-(6-chloro--
5-methoxypyridazin-3-yl)-methanol;
(3-Chloro-6-methoxy-pyridazin-4-yl)-[4-fluoro-3-(7-morpholin-4-yl-quinazo-
lin-4-yl)-phenyl]-methanol;
[2-Chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-(6-chloro--
4-methoxypyridazin-3-yl)-methanol;
(6-Chloro-4-methoxy-pyridazin-3-yl)-[4-fluoro-3-(7-morpholin-4-ylquinazol-
in-4-yl)-phenyl]-methanol;
[4-Fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(3-pyrrolidin-1-yl-
-pyrazin-2-yl)methanol;
[4-Fluoro-3-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-(3-methoxy-pyrazin--
2-yl)methanol;
(3,5-Dichloro-pyridin-4-yl)-[4-Fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl-
)-phenyl]methanol;
[4-Fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(4-methoxy-pyridaz-
in-3-yl)-methanol;
(3-Chloro-pyrazin-2-yl)-[4-fluoro-3-(6-morpholin-4-yl-thieno
[3,2-d]pyrimidin-4-yl)-phenyl]-methanol;
(S)-(3-Chloro-pyrazin-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--
3-yl-methanol;
(3-Chloro-5-methoxy-pyridin-2-yl)-[4-fluoro-3-(7-morpholin-4-yl-quinazoli-
n-4-yl)-phenyl]-methanol;
[4-fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-[3-(oxetan-3-yloxy-
)-pyrazin-2-yl]-methanol;
[2-Chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-pyrazin-2-
-yl-methanol;
(3,6-Dichloro-pyrazin-2-yl)-[4-fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl-
)-phenyl]-methanol;
(3-Chloro-pyrazin-2-yl)-[4-fluoro-3-(6-morpholin-4-ylthieno-[3,2-d]-pyrim-
idin-4-yl)-phenyl]-methanol;
[2-Chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-pyrazolo[-
methanol;
[2-Chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]--
(4-methoxypyrido[3,4-d] pyridazin-1-yl)-methanol;
[2-Chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-chloro-
-pyridazin-3-yl)methanol;
(3-Chloro-pyridin-2-yl)-[4-fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl)-ph-
enyl]-methanol;
6-{[2-Chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-hydrox-
y-methyl}-pyridazine-3-carboxylic acid methylamide;
6-{[2-Chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-hydrox-
ymethyl}-2-methyl-2H-pyridazin-3-one;
[2-Chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(5-methyl-
pyridazin-3-yl)methanol;
2-Chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-pyridazin--
3-yl-methanol;
[2,4-Difluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-pyridazin-3-yl-
-methanol;
(6-Chloro-pyridazin-3-yl)-[2,4-difluoro-5-(7-morpholin-4-yl-qui-
nazolin-4-yl)-phenyl]methanol;
6-{[2-Chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-hydrox-
y-methyl}-pyridazine-3-carboxylic acid dimethylamide;
[2,4-Difluoro-5-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-imidazo[1,2-b]p-
yridazin-6-ylmethanol;
[4-Fluoro-3-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-(5-methoxy-pyrazin--
2-yl)methanol;
(3-Chloro-pyrazin-2-yl)-[4-fluoro-3-(7-morpholin-4-ylquinazolin-4-yl)-phe-
nyl]-methanol;
6-{[2-Chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-hydrox-
y-methyl}-pyridazine-3-carboxylic acid;
[2-Chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-imidazo[1-
,2-b]pyridazin-6-ylmethanol;
6-{[2-Chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-hydrox-
y-methyl}-pyridazine-3-carboxylic acid methyl ester;
6-{[2-Chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]hydroxy-
methyl}-2-methyl-2H-pyridazin-3-one;
6-{[2-Chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-hydrox-
ymethyl}-pyridazine-3-carboxylic acid amide;
[2-Chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(3-chloro-
-pyrazin-2-yl)methanol;
[4-Fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-pyridazin-3-yl-met-
hanol;
[4-Fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(5-methoxy-p-
yrimidin-2-yl)methanol;
(6-Dimethylamino-pyridazin-3-yl)-[4-fluoro-3-(7-morpholin-4-yl-quinazolin-
-4-yl)-phenyl]-methanol;
[4-Fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methyl-pyridazi-
n-3-yl)methanol;
(R)-[4-Fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxy-pyr-
idazin-3-yl)methanol;
(S)-[4-Fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxy-pyr-
idazin-3-yl)methanol;
4-{2-Fluoro-5-[methoxy-(6-methoxy-pyridazin-3-yl)-methyl]-phenyl}-7-morph-
olin-4-ylquinazoline;
6-{[4-Fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-hydroxymethyl}--
2H-pyridazin-3-one;
(3-Chloro-5-fluoro-pyridin-4-yl)-[4-fluoro-3-(7-morpholin-4-yl-quinazolin-
-4-yl)-phenyl]-methanol;
[4-Fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(3-methyl-pyrazin--
2-yl)-methanol;
[4-Fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(3-trifluoromethyl-
-pyridin-2-yl)methanol;
(S)-[4-Fluoro-3-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-(3-methyl-pyraz-
in-2-yl)methanol;
[4-Fluoro-3-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-(5-methoxy-pyrimidi-
n-4-yl)methanol;
[2,4-Difluoro-5-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-(3,6-dimethyl-p-
yrazin-2-yl)methanol;
[2-Chloro-5-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-thieno[3,2-d]pyrimi-
din-4-ylmethanol;
6-{[2-Chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-hydroxy-
methyl}-2-ethyl-2H-pyridazin-3-one;
2-(2-Amino-ethyl)-6-{[2-chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-y-
l)-phenyl]-hydroxymethyl}-2H-pyridazin-3-one;
6-{[2-Chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-hydroxy-
methyl}-2-cyclopropyl-2H-pyridazin-3-one;
2-(3-{[2-Chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-hydr-
oxymethyl}-6-oxo-6H-pyridazin-1-yl)acetamide;
6-{[2-Chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-hydroxy-
methyl}-2-(2-hydroxy-ethyl)-2H-pyridazin-3-one;
[2-Chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-[6-(oxetan-
-3-yloxy)pyridazin-3-yl]methanol;
2-(6-{[2-Chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-hydr-
oxymethyl}-pyridazin-3-yloxy)-propionitrile;
2-(3-{[4-fluoro-3-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-hydroxymethyl-
}-pyrazin-2-yloxy)ethanol;
2-(3-{[4-fluoro-3-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]hydroxymethyl}-
-pyrazin-2-ylamino)-ethanol;
3-(6-{[2-Chloro-4-fluoro-5-(7-morpholin-4-yl)
quinazolin-4-yl)-phenyl]-hydroxy-methyl}-pyridazin-3-yl-oxy)-propionitril-
e;
[2-Chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-(6-methy-
lsulfanylpyridazin-3-yl)methanol;
[2-Chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-(6-methoxy-
-5-methylpyridazin-3-yl)methanol;
2-(6-{[2-Chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-hydr-
oxymethyl}-pyridazin-3-yloxy)-acetamide;
[2-Chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-[6-(2-meth-
oxyethoxy)pyridazin-3-yl]-methanol;
(6-{[2-Chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-hydrox-
ymethyl}pyridazin-3-yloxy)-acetic acid;
(6-{[2-Chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-hydrox-
ymethyl}pyridazin-3-yloxy)-acetic acid methyl ester;
[2-Chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-[6-(2,2,2--
trifluoroethoxy)-pyridazin-3-yl]-methanol;
2-(6{[2-Chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-hydro-
xymethyl}-pyridazin-3-yloxy)-ethanol;
(3-Amino-pyrazin-2-yl)-[2-chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-
-yl)-phenyl]-methanol;
6-{[2-Chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-hydroxy-
methyl}pyridazine-3-carbonitrile;
(6-{[2-Chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-hydrox-
ymethyl}pyridazin-3-yloxy)-acetonitrile;
(6-Difluoromethoxy-pyridazin-3-yl)-[4-fluoro-3-(7-morpholin-4-ylquinazoli-
n-4-yl)-phenyl]-methanol;
1-[2-Chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-1-(6-met-
hoxy-pyridazin-3-yl)-prop-2-yn-1-ol;
1-[2-Chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-2,2-difl-
uoro-1-(6-methoxypyridazin-3-yl)-ethanol;
1-[2-Chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-1-(6-met-
hoxy-pyridazin-3-yl)-ethanol;
[2-Chloro-4-fluoro-5-(6-morpholin-4-yl-thieno[3,2-d]pyrimidin-4-yl)-pheny-
l]-(6-methoxypyridazin-3-yl)-methanol;
[2-Chloro-5-(2-chloro-7-morpholin-4-ylquinazolin-4-yl)-4-fluorophenyl]-(6-
-methoxy-pyridazin-3-yl)-methanol;
[6-(2-Dimethylamino-ethoxy)pyridazin-3-yl]-[4-fluoro-3-(7-morpholin-4-ylq-
uinazolin-4-yl)phenyl]-methanol;
(6-Ethoxy-pyridazin-3-yl)-[4-fluoro-3-(7-morpholin-4-ylquinazolin-4-yl)-p-
henyl]methanol; and
(R)-[2-Chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-(6-met-
hoxy-pyridazin-3-yl)methanol; or a physiologically acceptable salt,
tautomer and/or stereoisomer thereof, including mixtures thereof in
all ratios.
22. A compound selected from the following:
[2-Chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-(6-methoxy-
-pyridazin-3-yl)methanol;
{3-[7-(3,6-Dihydro-2H-pyran-4-yl)-quinazolin-4-yl]-4-fluoro-phenyl}-thiaz-
ol-2-ylmethanol;
[2-Chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-(4-methyla-
minomethyl-thiazol-2-yl)-methanol;
[4-Fluoro-3-(6-morpholin-4-yl-thieno[3,2-d]pyrimidin-4-yl)-phenyl]-thiazo-
l-2-ylmethanol;
[3-(7-Morpholin-4-ylquinazolin-4-yl)-phenyl]-thiazol-2-ylmethanol;
1-[5-(7-Morpholin-4-ylquinazolin-4-yl)pyridin-3-yl]-1-thiazol-2-ylethanol-
;
1-[4-Fluoro-3-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-1-thiazol-2-ylet-
hanol;
[3-Fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-thiazol-2-ylm-
ethanol;
[2-Fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-thiazol-2-y-
lmethanol;
[3,4-Difluoro-5-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-thiaz-
ol-2-ylmethanol;
7-Morpholin-4-yl-4-piperidin-1-yl-thieno[3,2-d]pyrimidine;
[5-(7-Morpholin-4-ylquinazolin-4-yl)pyridin-3-yl]-thiazol-2-ylmethanol;
4-[2-Fluoro-5-(methoxy-thiazol-2-ylmethyl)-phenyl]-7-morpholin-4-ylquinaz-
oline;
[6-Fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)pyridin-3-yl]-thiazol--
2-ylmethanol;
[3-(6-Morpholin-4-yl-thieno[3,2-d]pyrimidin-4-yl)-phenyl]-thiazol-2-ylmet-
hanol;
(S)-[2-Chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]--
(4-hydroxymethyl-thiazol-2-yl)methanol;
[2-Chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-(4-ethylam-
inomethyl-thiazol-2-yl)-methanol;
(4-Aminomethyl-thiazol-2-yl)-[2-chloro-4-fluoro-5-(7-morpholin-4-yl-quina-
zolin-4-yl)-phenyl]-methanol;
[4-Fluoro-3-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-(1-methyl-1H-pyrazo-
l-4-yl)methanol;
(4,5-Dimethyl-thiazol-2-yl)-[2-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)-
pyridin-3-yl]-methanol;
(4,5-Dimethyl-thiazol-2-yl)-[6-fluoro-5-(7-morpholin-4-yl-pyrido[4,3-d]py-
rimidin-4-yl)pyridin-3-yl]-methanol;
(1-tert-Butyl-1H-pyrazol-4-yl)-[2-fluoro-5-(7-morpholin-4-ylquinazolin-4--
yl)-pyridin-3-yl]-methanol;
[4-Fluoro-3-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-(5-hydroxymethyl-4--
methyl-thiazol-2-yl)-methanol;
1-(2-{[2-Chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-hydr-
oxymethyl}thiazol-4-yl)-ethanol;
[2-Chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-(1-ethyl-1-
H-pyrazol-4-yl)-methanol;
[4-Fluoro-2-methyl-5-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-thiazol-2--
yl-methanol;
[3-(2-Ethynyl-7-morpholin-4-ylquinazolin-4-yl)-4-fluoro-phenyl]-thiazol-2-
-yl-methanol;
[4-Fluoro-3-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-thiazol-2-yl-methan-
ol;
[3-(2-Chloro-7-morpholin-4-ylquinazolin-4-yl)-4-fluoro-phenyl]-(2-meth-
yl-2H-pyrazol-3-yl)-methanol;
[2,4-Difluoro-5-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-pyridin-3-yl-me-
thanol;
[2,4-Difluoro-5-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-pyridin--
2-yl-methanol;
6-{[2,4-Difluoro-5-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-hydroxymethy-
l}-2-methyl-2H-pyridazin-3-one;
[2,4-Difluoro-5-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-(6-methoxy-pyri-
din-3-yl)methanol;
[2,4-Difluoro-5-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-[1,2,4]triazolo-
[1,5-a]pyridin-6-yl-methanol;
[2,4-Difluoro-5-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-imidazo[1,2-a]p-
yrazin-6-ylmethanol;
[2,4-Difluoro-5-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-(5-methoxy-pyri-
din-2-yl)methanol;
[2-Chloro-5-(5,6-dideuterio-7-morpholino-quinazolin-4-yl)-4-fluoro-phenyl-
]-(6-methoxypyridazin-3-yl)-methanol;
3-(5,6-Dideuterio-7-morpholinoquinazolin-4-yl)-4-fluorophenyl]-(3-methylp-
yrazin-2-yl)methanol;
[2-Chloro-4-fluoro-5-(7-morpholin-4-ylpyrido[3,2-d]pyrimidin-4-yl)-phenyl-
]-(6-methoxypyridazin-3-yl)methanol;
2-[2-Chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-2-(3-met-
hoxy-pyrazin-2-yl)N-methyl-acetamide;
2-(3-Chloro-pyridin-2-yl)-2-[4-fluoro-3-(7-morpholin-4-ylquinazolin-4-yl)-
-phenyl]-N-methylacetamide;
[2-Chloro-4-fluoro-5-(7-morpholin-4-yl-pyrido[3,2-d]pyrimidin-4-yl)-pheny-
l]-(3-methoxypyrazin-2-yl)-methanol;
(S)-[4-Fluoro-3-(7-morpholin-4-yl-pyrido[3,2-d]pyrimidin-4-yl)-phenyl]-(3-
-methyl-pyrazin-2-yl)methanol;
2-[2-Chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-2-imidaz-
o[1,2-b]pyridazin-6-yl-N-methyl-acetamide;
[4-Fluoro-3-(7-morpholin-4-yl-pyrido[3,2-d]pyrimidin-4-yl)-phenyl]-(3-met-
hyl-pyrazin-2-yl)methanol;
(R)-[4-Fluoro-3-[7-(2,2,3,3,5,5,6,6-octadeuteriomorpholin-4-yl)-quinazoli-
n-4-yl]-phenyl]-(3-methyl-pyrazin-2-yl)-methanol;
[2-Chloro-4-fluoro-5-(7-morpholin-4-yl-pyrido[3,2-d]pyrimidin-4-yl)-pheny-
l]-(3-methylpyrazin-2-yl)-methanol;
[2-Chloro-4-fluoro-5-[7-(2,2,3,3,5,5,6,6-octadeuteriomorpholin-4-yl)-quin-
azolin-4-yl]-phenyl]-(3-methoxypyrazin-2-yl)-methanol;
(S)-[4-Fluoro-3-[7-(2,2,3,3,5,5,6,6-octadeuteriomorpholin-4-yl)-quinazoli-
n-4-yl]-phenyl]-(3-methylpyrazin-2-yl)-methanol;
[2-Chloro-4-fluoro-5-(7-morpholin-4-yl-pyrido[3,2-d]pyrimidin-4-yl)-pheny-
l]-(3-methoxypyrazin-2-yl)-methanol;
(S)-[4-fluoro-3-(5-fluoro-7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(3-me-
thyl-pyrazin-2-yl)methanol;
2-[2-Chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-N-methy-
l-2-(3-methylpyrazin-2-yl)-acetamide;
[2-Chloro-4-fluoro-5-(7-morpholin-4-yl-pyrido[3,2-d]-pyrimidin-4-yl)-phen-
yl]-(6-methoxypyridazin-3-yl)-methanol;
[2-Chloro-4-fluoro-5-[7-(2,2,3,3,5,5,6,6-octadeuterio-morpholin-4-yl)-qui-
nazolin-4-yl-]-phenyl]-(3-methoxy-pyrazin-2-yl)-methanol; and
2-[2-Chloro-4-fluoro-5-(5-fluoro-7-morpholin-4-yl-quinazolin-4-yl)-phenyl-
]-2-(3-methoxypyrazin-2-yl)-acetamide; or a physiologically
acceptable salt, tautomer and/or stereoisomer thereof, including
mixtures thereof in all ratios.
23. A compound selected from the following:
2-[2-Chloro-4-fluoro-5-(6-morpholin-4-yl-thieno[3,2-d]-pyrimidin-4-yl)-ph-
enyl]-2-(3-methylpyrazin-2-yl)-acetamide;
2-[4-Fluoro-3-(6-morpholin-4-yl-thieno[3,2-d]-pyrimidin-4-yl)-phenyl]-2-(-
3-methyl-pyrazin-2-yl)-acetamide;
2-[2-Chloro-4-fluoro-5-(6-morpholin-4-yl-thieno[3,2-d]-pyrimidin-4-yl)-ph-
enyl]-2-(6-methoxypyridazin-3-yl)-acetamide;
[4-Fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-[1,2,4]-triazolo[1-
,5-a]-pyrazin-8-ylmethanol;
2-[4-Fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-2-[1,2,4]-triazo-
lo[1,5-a]-pyrazin-8-ylacetamide;
2-[4-Fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-2-thieno-[2,3
d]-pyridazin-7-ylacetamide;
2-[4-Fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-2-thieno-[2,3
d]-pyridazin-4-ylacetamide;
(6-Chloro-3-methoxy-pyridazin-4-yl)-[4-fluoro-3-(7-morpholin-4-yl-quinazo-
lin-4-yl)-phenyl]-methanol;
6-{[2-Chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-hydrox-
y-methyl}-2-methyl-4,5-dihydro-2H-pyridazin-3-one;
2-[2-Chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-2-(3-ch-
loro-pyridin-2-yl)acetamide;
6-{Carbamoyl-[4-fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-methy-
l}-pyrazine-2-carboxylic acid amide;
2-[2-Chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-2-pyrid-
in-3-yl-acetamide;
2-[2,4-Difluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-2-pyridin-3--
ylacetamide;
2-[4-Fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-2-pyridin-3-ylac-
etamide;
[4-Fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methyl--
pyrazin-2-yl)-methanol;
2-(5-Chloro-pyridin-3-yl)-2-[4-fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl-
)-phenyl]-acetamide;
2-[2-Chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-2-[1,2,-
4]triazolo[4,3-a]pyridin-5-ylacetamide;
2-[2-Chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-2-pyrid-
azin-3-ylacetamide;
2-[2-Chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-2-(3,5--
dimethyl-pyrazin-2-yl)-acetamide;
(6-Amino-pyrazin-2-yl)-[4-fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl)-phe-
nyl]-methanol;
2-[2-Chloro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-2-(3-methyl-pyra-
zin-2-yl)-acetamide;
2-[2-Chloro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-2-(3-methoxy-pyr-
azin-2-yl)acetamide;
2-[4-Fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-2-(3-methoxy-pyr-
azin-2-yl)acetamide;
2-[2,4-Difluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-2-(6-methoxy-
-pyridazin-3-yl)acetamide;
2-[2-Chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-2-(3-me-
thoxy-pyridazin-4-yl)-acetamide;
2-[4-Fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-2-(6-methoxy-pyr-
idazin-3-yl)acetamide;
2-(3-Chloro-pyridin-2-yl)-2-[4-fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl-
)-phenyl]-acetamide;
(5,6-Dimethyl-pyrazin-2-yl)-[4-fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl-
)-phenyl]-methanol;
2-(3,5-Dimethyl-pyrazin-2-yl)-2-[4-fluoro-3-(7-morpholin-4-yl-quinazolin--
4-yl)-phenyl]-acetamide;
2-[2,4-Difluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-2-(3-methoxy-
-pyrazin-2-yl)acetamide;
2-[2-Chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-2-(3-me-
thoxy-pyrazin-2-yl)acetamide;
2-(3,5-Difluoro-pyridin-4-yl)-2-[4-fluoro-3-(7-morpholin-4-yl-quinazolin--
4-yl)-phenyl]-acetamide;
2-(4-Chloro-5-fluoro-pyridin-3-yl)-2-[4-fluoro-3-(7-morpholin-4-yl-quinaz-
olin-4-yl)-phenyl]-acetamide;
2-[2-Chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-2-imida-
zo[1,2-b]pyridazin-6-yl-acetamide;
2-[2-Chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-2-(3-me-
thyl-pyrazin-2-yl)acetamide;
6-{[4-Fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-hydroxy-methyl}-
-2-methyl-2H-pyridazin-3-one;
2-[4-Fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-2-(3-methyl-pyra-
zin-2-yl)-acetamide;
2-[2,4-Difluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-2-(3-methyl--
pyrazin-2-yl)acetamide;
5-Chloro-6-{[2-chloro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-hydrox-
y-methyl}-pyrimidin-4-ol;
(3-methyl-pyrazin-2-yl)-[3-(7-morpholin-4-yl-quinazolin-4-yl)-4-oxocycloh-
exa-2,5-dien-(E)ylidene]-acetic acid;
[4-Fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-thieno[2,3-d]pyrid-
azin-7-yl-methanol;
[4-Fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-thieno[2,3-d]pyrid-
azin-4-yl-methanol;
7-[[4-Fluoro-3-(7-morpholino-quinazolin-4-yl)-phenyl]-hydroxy-methyl]-5H--
thieno-[2,3-d]pyridazin-4-one;
4-[[4-Fluoro-3-(7-morpholino-quinazolin-4-yl)-phenyl]-hydroxy-methyl]-6H--
thieno[2,3-d]pyridazin-7-one;
6-{[2-Chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-hydrox-
ymethyl}-1,4-dimethyl-1H-pyridin-2-one;
6-{[4-Fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-hydroxymethyl}--
1,4-dimethyl-1H-pyridin-2-one;
[2,4-Difluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-thieno[2,3-d]p-
yridazin-4-yl-methanol;
[4-Fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-[1,2,4]triazolo[4,-
3-a]pyridin-3-ylmethanol;
[2,4-Difluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(9-methyl-9H-p-
urin-6-yl)-methanol;
2-[2,4-Difluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-2-pyrrolo[1,-
2a]pyrazin-1-ylacetamide;
4-[2-Fluoro-5-(3-methyl-pyrazin-2-ylmethyl)-phenyl]-7-morpholin-4-yl-quin-
azoline;
[2,4-Difluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-[1,2,4-
]triazolo[4,3-a]pyridin-5-ylmethanol;
[4-Fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-[1,2,4]-triazolo[4-
,3-a]pyrazin-8-ylmethanol;
4-{2-Fluoro-5-[methoxy-(3-methyl-pyrazin-2-yl)-methyl]-phenyl}-7-morpholi-
n-4-ylquinazoline;
[2,4-Difluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(3,5-dimethyl--
pyrazin-2-yl)methanol;
[2-Fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxy-pyridaz-
in-3-yl)-methanol;
[2,4-Difluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-pyrrolo[1,2-a]-
pyrazin-1-yl-methanol;
2-{[4-Fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-hydroxy-methyl}-
-3-methyl-3H-pyrimidin-4-one;
6-{[2-Fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-hydroxy-methyl}-
-1-methyl-1H-pyridin-2-one;
2-{[2-Chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-hydrox-
y-methyl}-3-methyl-3H-pyrimidin-4-one;
[2-Chloro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-imidazo[1,2
a]pyrazin-8-yl-methanol;
[2-Fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(9-methyl-9H-purin-
-6-yl)-methanol;
[2-Chloro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(9-methyl-9H-purin-
-6-yl)-methanol;
[2-Fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-imidazo[1,2
a]pyrazin-8-yl-methanol;
[2-Fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-[1,2,4]triazolo[4,-
3-a]pyridin-5-ylmethanol;
[2-Fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-furo[3,2-d]pyrimid-
in-4-yl-methanol;
2-[2-Chloro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-2-(5-methyl-pyri-
midin-4-yl)acetamide;
[2,4-Difluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-[1,2,4]triazol-
o[4,3-a]pyridin-3-ylmethanol;
6-{[2,4-Difluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-hydroxy-met-
hyl}-1-methyl-1H-pyridin-2-one;
6-{[2-Chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)-phenyl]-hydroxy-
-methyl}-1-methyl-1H-pyridin-2-one;
(R)-[2,4-Difluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(7-methyl--
7H-purin-6-yl)methanol;
[2-Chloro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(1-methyl-1H-pyraz-
olo[3,4-d]pyrimidin-4-yl)-methanol;
(S)-[2,4-Difluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(7-methyl--
7H-purin-6-yl)methanol;
[2,4-Difluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(5,6,7,8-tetra-
hydropyrido[3,4-d]pyrimidin-4-yl)-methanol;
[4-Fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(5,6,7,8-tetrahydr-
opyrido[3,4-d]pyrimidin-4-yl)-methanol;
[2-Chloro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(5-fluoro-pyrimidi-
n-4-yl)-methanol;
[2-Fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(1-methyl-1H-pyraz-
olo[3,4-d]pyrimidin-4-yl)-methanol;
[2-Fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(5-methyl-pyrimidi-
n-4-yl)-methanol;
[2-Fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(3-methyl-pyrazin--
2-yl)-methanol;
[2-Chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-imidazo[1-
,2 a]pyrazin-8-ylmethanol;
1-Ethyl-6-{[4-fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-hydroxy-
-methyl}-1H-pyridin-2-one;
[2-Chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(1-methyl-
-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-methanol;
[2,4-Difluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(1-methyl-1H-p-
yrazolo[3,4-d]pyrimidin-4-yl)-methanol;
[4-Fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(1-methyl-1H-pyraz-
olo[3,4-d]pyrimidin-4-yl)-methanol;
[2-Fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-thieno[2,3-d]pyrim-
idin-4-yl-methanol;
[2-Chloro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(5-methoxy-pyrimid-
in-4-yl)-methanol;
[2-Chloro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(3-methoxy-pyrazin-
-2-yl)-methanol;
[2-Chloro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-furo[2,3-d]pyrimid-
in-4-yl-methanol;
[2-Chloro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(5-methyl-pyrimidi-
n-4-yl)-methanol;
[4-Fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(9-methyl-9H-purin-
-6-yl)-methanol;
[2-Chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(7-methyl-
-7H-purin-6-yl)methanol;
[2-Chloro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(3-methyl-pyrazin--
2-yl)-methanol;
[2-Chloro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-thieno[2,3-d]pyrim-
idin-4-yl-methanol;
[2,4-Difluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(7-methyl-7H-p-
urin-6-yl)-methanol;
[2-Chloro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-furo[3,2-d]pyrimid-
in-4-yl-methanol;
[4-Fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(7-methyl-7H-purin-
-6-yl)-methanol;
[4-Fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-thieno[2,3-d]pyrim-
idin-4-yl-methanol;
[4-Fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-thieno[3,2-d]pyrim-
idin-4-yl-methanol;
[2,4-Difluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-thieno[3,2-d]p-
yrimidin-4-ylmethanol;
[2-Chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-furo[3,2--
d]pyrimidin-4-ylmethanol;
[2,4-Difluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-furo[3,2-d]pyr-
imidin-4-yl-methanol;
[2-Chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(5-methox-
y-pyrimidin-4-yl)methanol;
[2,4-Difluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(5-methoxy-pyr-
imidin-4-yl)methanol;
(3-Difluoromethoxy-pyrazin-2-yl)-[2,4-difluoro-5-(7-morpholin-4-yl-quinaz-
olin-4-yl)-phenyl]-methanol;
(R)-[2-Chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(3-me-
thoxy-pyrazin-2-yl)methanol;
(S)-[2-Chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(3-me-
thoxy-pyrazin-2-yl)methanol;
[2-Chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(3-methyl-
-pyrazin-2-yl)methanol;
[2-Chloro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxy-pyridaz-
in-3-yl)-methanol;
[4-Fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(3-iodo-pyrazin-2--
yl)-methanol;
(3-Ethoxy-pyridin-2-yl)-[4-fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl)-ph-
enyl]-methanol;
(3-Difluoromethoxy-pyrazin-2-yl)-[4-fluoro-3-(7-morpholin-4-yl-quinazolin-
-4-yl)-phenyl]-methanol;
[2-Chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(3-methox-
y-pyrazin-2-yl)methanol;
[2-Chloro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-pyridazin-3-yl-met-
hanol;
[4-Fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(3-methyl-py-
ridin-2-yl)-methanol;
(3-Bromo-5-methoxy-pyridin-2-yl)-[4-fluoro-3-(7-morpholin-4-yl-quinazolin-
-4-yl)-phenyl]-methanol;
[4-Fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(3-trifluoro-metho-
xypyridin-2-yl)methanol;
[4-Fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(3-trifluoro-methy-
lpyrazin-2-yl)methanol; and
(3-Bromo-pyridin-2-yl)-[4-fluoro-3-(7-morpholin-4-yl-quinazolin-4-yl)-phe-
nyl]-methanol; or a physiologically acceptable salt, tautomer
and/or stereoisomer thereof, including mixtures thereof in all
ratios.
24. A pharmaceutical composition comprising a compound according to
claim 21, or a physiologically acceptable salt, tautomer, and/or
stereoisomer thereof, including mixtures thereof in all ratios; and
a pharmaceutically tolerated adjuvant.
25. A pharmaceutical composition comprising a compound according to
claim 22, or a physiologically acceptable salt, tautomer, and/or
stereoisomer thereof, including mixtures thereof in all ratios; and
a pharmaceutically tolerated adjuvant.
26. A pharmaceutical composition comprising a compound according to
claim 23, or a physiologically acceptable salt, tautomer, and/or
stereoisomer thereof, including mixtures thereof in all ratios; and
a pharmaceutically tolerated adjuvant.
Description
[0001] The invention relates to compounds of the formula (I)
##STR00001## [0002] in which [0003] X is CH, CF, S or N, [0004] Y
is CH, S or N, [0005] Z is C or N, [0006] forms, if Z.dbd.C, a
double bond together with the single bond, is absent if Z.dbd.N,
[0007] n is 1 or 2, where [0008] if n=1, X.dbd.S, [0009] and if
n=2, both X.dbd.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; [0010] m is 1 or 2, where [0011] if m=1,
Y.dbd.S, [0012] and if m=2, both Y.dbd.CH, or one Y is CH and the
other Y is N; [0013] R.sup.1, R.sup.2, R.sup.3, R.sup.4,
independently of one another, are H, Hal, CN, OH, CONH.sub.2,
CONH(LA) or LA; [0014] R.sup.5 is H, Hal, CN or C.ident.CH; [0015]
Cyc is phenyl, which may be unsubstituted or mono- or
disubstituted, independently of one another, by R.sup.6, or is
Het.sup.1; [0016] Het.sup.1 is a mono- or bicyclic, 5-10-membered
heterocycle, having 1-3 N, O and/or S atoms, or 1-4 N atoms, which
may be unsubstituted or mono-, di- or trisubstituted, independently
of one another, by R.sup.6, or may be monosubstituted by Het.sup.2;
[0017] R.sup.6 is Hal, LA, oxo, CN, or NH.sub.2; [0018] LA is
unbranched or branched alkyl having 1-5 C atoms, which may be
saturated or partially unsaturated, in which 1-3H atoms may be
replaced by Hal, and/or one H atom may be replaced by CN or
Het.sup.2, and/or one or two CH.sub.2 groups may be replaced by O,
NH, NH.sub.2, N(CH.sub.3) or CO; [0019] Het.sup.2 is a 3-5-membered
aliphatic homo- or heterocycle having 0, 1, 2 or 3 N, O and/or S
atoms, which is unsubstituted; [0020] Hal is F, Cl, Br or I; and/or
physiologically acceptable salts, tautomers and/or stereoisomers
thereof, including mixtures thereof in all ratios.
[0021] The compounds of the formula (I) can be used for the
inhibition of serine/threonine protein kinases and for the
sensitisation of cancer cells to anticancer agents and/or ionising
radiation. The invention also relates to the use of the compounds
of the formula (I) in the prophylaxis, therapy or progress control
of cancer, tumours or metastases, in combination with radiotherapy
and/or an anticancer agent. The invention furthermore relates to a
process for the preparation of the compounds of the formula (I) by
reaction of compounds of the formulae (IV) and (V) and optionally
conversion of a base or acid of the compounds of the formula (I)
into a salt thereof.
[0022] DNA-dependent protein kinase (DNA-PK) is a serine/threonine
protein kinase which is activated in conjunction with DNA.
Biochemical and genetic data show that DNA-PK consists (a) of a
catalytic sub-unit, which is called DNA-PKcs, and (b) two
regulatory components (Ku70 and Ku80). In functional terms, DNA-PK
is a crucial constituent on the one hand of the repair of DNA
double-strand breaks (DSBs) and on the other hand of somatic or
V(D)J recombination. In addition, DNA-PK and its components are
connected with a multiplicity of further physiological processes,
including modulation of the chromatin structure and telomeric
maintenance (Smith & Jackson (1999) Genes and Dev 13: 916;
Goytisolo et al. (2001) Mol. Cell. Biol. 21: 3642; Williams et al.
(2009) Cancer Res. 69: 2100).
[0023] Human genetic material in the form of DNA is constantly
subjected to attack by reactive oxygen species (ROSs), which are
formed principally as by-products of oxidative metabolism. ROSs are
capable of causing DNA damage in the form of single-strand breaks.
Double-strand breaks can arise if prior single-strand breaks occur
in close proximity. In addition, single- and double-strand breaks
may be caused if the DNA replication fork encounters damaged base
patterns. Furthermore, exogenous influences, such as ionising
radiation (for example gamma or particle radiation), and certain
anticancer medicaments (for example bleomycin) are capable of
causing DNA double-strand breaks. DSBs may furthermore occur as
intermediates of somatic recombination, a process which is
important for the formation of a functional immune system of all
vertebrates. If DNA double-strand breaks are not repaired or are
repaired incorrectly, mutations and/or chromosome aberrations may
occur, which may consequently result in cell death. In order to
counter the severe dangers resulting from DNA double-strand breaks,
eukaryotic cells have developed a number of mechanisms to repair
them. Higher eukaryotes use predominantly so-called non-homologous
end-joining, in which the DNA-dependent protein kinase adopts the
key role. Biochemical investigations have shown that DNA-PK is
activated most effectively by the occurrence of DNA-DSBs. Cell
lines whose DNA-PK components have mutated and are non-functional
prove to be radiation-sensitive (Smith and Jackson, 1999).
[0024] Owing to its catalytic domain, which is in the C-terminal
catalytic sub-unit (DNA-PKcs), which numbers about 500 amino acids,
DNA-PK belongs to the family of
phosphatidylinositol-3-kinase-related kinases (PIKKs), where DNA-PK
is not a lipid kinase (Hartley et al. (1995) Cell 82: 849; Smith
& Jackson (1999) Genes and Dev 13: 916; Lempiainen &
Halazonetis (2009) EMBO J. 28: 3067).
[0025] It has been described by Izzard et al. (1999) Cancer Res.
59: 2581, that the PI3 kinase inhibitor LY294002 inhibits the
function of DNA-PK in in-vitro experiments. The IC.sub.50 value
(concentration at which 50% of the enzyme activity is inhibited) is
at a relatively ineffective 1.25 .mu.M (5.0 mM ATP). Although the
evidence that the inhibitor LY294002 allows mammal cells to become
more radiation-sensitive, i.e. the cytotoxicity of ionising
radiation is increased, in principle implies use in the irradiation
therapy of, for example, solid cancer tumours, only a weak increase
in sensitivity to ionising irradiation has been demonstrated for
LY294002 in cellular terms (Rosenzweig et al. (1999) Clin. Cancer
Res. 3: 1149). KuDOS Pharmaceuticals Ltd. have optimised the lead
structure LY294002 and presented various DNA-PK inhibitors. The
introduction of a dibenzothiophenyl group led to the inhibitor
NU-7441, an ATP-competitive compound having an IC.sub.50 value of
20.0 nM (Hardcastle et al. (2005) J. Med. Chem. 48: 7829).
KU-0060648 combines inhibitory properties with respect to DNA-PK
with an improved solubility profile in aqueous medium, but the
kinases of the PI3K isoenzyme family are likewise potently
inhibited by KU-0060648. The long-existing need for a potent and
selective DNA-PK inhibitor has consequently not been satisfied to
date.
[0026] The invention is based on the object of overcoming the
disadvantages indicated in the prior art and of developing
effective inhibitors of DNA-PK which are selective with respect to
the related kinases of the PIKK family and are of low molecular
size and, in particular, enable effective application in cancer
therapy as radio- and chemosensitisers--with the aim of improving
the therapeutic efficacy with a simultaneous reduction in side
effects.
[0027] The object of the invention is achieved in accordance with
the independent claims. The subclaims contain preferred
embodiments. In accordance with the invention, compounds of the
formula (I) are provided.
[0028] Surprisingly, it has been found that the compounds according
to the invention are provided with inhibiting properties for
serine/threonine protein kinases. The compounds of the formula (I)
are designed in such a way that potent and selective inhibition of
DNA-PK occurs. The compounds according to the invention thus open
up entirely new possibilities with respect to the anticarcinogenic
action of anticancer agents. The compounds of the formula (I) play
a therapeutic role here as radio- and chemosensitisers through
specific inhibition of the repair of DNA double-strand breaks
(non-homologous end-joining) in the treatment of cancer.
[0029] To date, it is known from WO 1992/07844 that
2,4-diaminoquinazoline derivatives are enhancers of
chemotherapeutic agents in the treatment of cancer. The derivatives
address the multiple resistance of tumour cells as a consequence of
overexpression of the mdr1 gene, whose gene product of an efflux P
glycoprotein pump keeps the intracellular active-compound
concentration low. Neither are physicochemical or pharmacological
data disclosed, nor is a marketed medicament is known. Other
quinazoline derivatives as DNA-PK inhibitors are disclosed in WO
2011/113512.
[0030] The present invention provides a new generation of DNA-PK
inhibitors which are not only capable of specific inhibition, which
arises, in particular, in the case of cellular assays. In addition,
they are also distinguished by the absence of the frequently
observed, undesired inhibition of cardiac ion channels, in
particular of Kv1.11 hERG, the blockade of which may result in
life-threatening arrhythmia.
[0031] The compounds according to the invention and salts thereof
consequently have valuable pharmacological properties while at the
same time being well tolerated.
[0032] For the purposes of the invention, the compounds of the
formula (I) are defined in such a way that they are also taken to
mean pharmaceutically usable derivatives, salts, solvates, solvates
of salts, precursors of the compounds, tautomers and optically
active forms (such as, for example, stereoisomers, diastereomers,
enantiomers, racemates). Solvates of the compounds are taken to
mean adductions of inert solvent molecules onto the compounds,
which form owing to their mutual attractive force. Solvates are,
for example, mono- or dihydrates or alcoholates. Pharmaceutically
usable derivatives are taken to mean, for example, the salts of the
compounds according to the invention and so-called precursors of
the compounds. Precursors are taken to mean, for example, compounds
of the formula (I) modified by means of alkyl or acyl groups,
sugars or oligopeptides, which are rapidly cleaved in the organism
to give the effective compounds according to the invention. These
also include biodegradable polymer derivatives of the compounds
according to the invention, as described, for example, in Int. J.
Pharm. 115, 61-67 (1995). Any compound which can be converted in
vivo into a bioactive agent, i.e. compounds of the formula (I), is
a precursor in the sense of this invention. Any biologically active
compound which results from the in-vivo metabolisation of a
compound according to the invention is a metabolite in the sense of
the present invention. The compounds of the formula (I) can have
one or more chiral centres and therefore occur in various
stereoisomeric forms. The formula (I) encompasses all these
forms.
[0033] The invention also relates to the use of mixtures of the
compounds of the formula (I), for example mixtures of two
diastereomers, for example in the ratio 1:1, 1:2, 1:3, 1:4, 1:5,
1:10, 1:100 or 1:1000. Particular preference is given here to
mixtures of stereoisomeric compounds.
[0034] Above and below, the radicals X, Y, R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6, LA, Cyc, Het.sup.1, Het.sup.2
and Hal as well as m and n have the meanings indicated for the
formula (I), unless expressly indicated otherwise. If individual
radicals occur a number of times within a compound or radical, the
radicals adopt, independently of one another, the meanings
indicated, unless expressly indicated otherwise. The terms used
here for the definition of the compounds are generally based on the
rules of the IUPAC organisation for chemical compounds and in
particular organic compounds. The terms for explanation of the
above-mentioned compounds of the invention always have the
following meanings, unless indicated otherwise in the description
or claims.
[0035] "LA" in the sense of the invention denotes a saturated or
partially unsaturated hydrocarbon radical which is unbranched
(linear) or branched and has 1, 2, 3, 4 or 5 C atoms. Examples of
LA are methyl, ethyl, propyl, isopropyl, 1,1-, 1,2- or
2,2-dimethylpropyl, 1-ethylpropyl, butyl, isobutyl, sec-butyl,
tert-butyl. However, the hydrocarbon radical may also be
substituted in such a way that 1-3H atoms may be replaced by Hal,
and/or one H atom may be replaced by CN or Het.sup.2, and/or one or
two CH.sub.2 groups may be replaced by O, NH, N(CH.sub.3) or CO.
Examples thereof are methoxy, methylsulfanyl, ethoxy, cyanomethoxy,
2-propionitriloxy, oxetan-3-yloxy, N-methylaminocarbonyl,
carboxamido, 2-methoxyethoxy, 2,2,2-trifluoroethoxy, or
2-hydroxyethoxy.
[0036] "Het.sup.1" in the sense of the invention denotes a mono- or
bicyclic aliphatic or aromatic hydrocarbon heterocycle having 3, 4,
5, 6, 7, 8, 9 or 10 C atoms and 0, 1, 2 or 3 N, O and/or S atoms,
which may be substituted. Examples of suitable "Cyc" are phenyl,
pyridine, pyrazine, pyridazine, pyrazolo[1,5-a]pyrimidinyl, or
imidazo[1,2-b]pyridazinyl.
[0037] "Het.sup.2" in the sense of the invention denotes a
3-5-membered aliphatic homo- or heterocycle having 0, 1, 2 or 3 N,
O or S atoms. Examples of Het.sup.2 are oxetane, pyrrolidine or
cyclopropyl.
[0038] In a preferred embodiment of the present invention,
arylquinazoline derivatives of the formula (Ia) are provided
##STR00002## [0039] in which [0040] X,Y, independently of one
another, are CH, S or N, [0041] Z is C or N, [0042] forms, if
Z.dbd.C, a double bond together with the single bond, is absent if
Z.dbd.N, [0043] n is 1 or 2, where [0044] if n=1, X.dbd.S, [0045]
and if n=2, both X.dbd.CH, or the X linked to the pyrimidine ring
is CH and the X not linked to the pyrimidine ring is N; [0046] m is
1 or 2, where [0047] if m=1, Y.dbd.S, [0048] and if m=2, both
Y.dbd.CH, or one Y is CH and the other Y is N; [0049] R.sup.1,
R.sup.2, R.sup.3, R.sup.4, independently of one another, are H,
Hal, CN, OH, CONH.sub.2 or LA; [0050] R.sup.5 is H, Hal, CN or
C.ident.CH; [0051] Cyc is phenyl, which may be unsubstituted or
mono- or disubstituted, independently of one another, by R.sup.6,
or Het.sup.1; [0052] Het.sup.1 is a mono- or bicyclic,
5-10-membered heterocycle, having 1-3 N, O and/or S atoms, which
may be unsubstituted or mono- or disubstituted, independently of
one another, by R.sup.6; [0053] R.sup.6 is Hal, LA, oxo, CN,
NH.sub.2 or Het.sup.2; [0054] LA is unbranched or branched alkyl
having 1-5 C atoms, which may be saturated or partially
unsaturated, in which 1-3H atoms may be replaced by Hal, and/or one
H atom may be replaced by CN or Het.sup.2, and/or one or two
CH.sub.2 groups may be replaced by O, NH, NH.sub.2, N(CH.sub.3) or
CO; [0055] Het.sup.2 is a 3-5-membered aliphatic homo- or
heterocycle having 0, 1, 2 or 3 N, O and/or S atoms, which is
unsubstituted; [0056] Hal is F, Cl, Br or I;
[0057] Furthermore preferred arylquinazoline derivatives conform to
the formula (Ib)
##STR00003##
in which all substituents have the meaning indicated for the
formulae (I) or (Ia), and/or physiologically acceptable salts,
tautomers and/or stereoisomers thereof, including mixtures thereof
in all ratios.
[0058] In a furthermore preferred embodiment of the present
invention, arylquinazoline derivatives of the formula (II) are
provided
##STR00004##
in which R.sup.3 is Hal, CN, OH, CONH.sub.2, CONH(LA) or LA;
R.sup.6', R.sup.6'', independently of one another, are H, Hal, LA,
oxo, CN, NH.sub.2 or Het.sup.2; Q.sup.1, Q.sup.2, independently of
one another, are CH, N or NH and are in each case unsubstituted;
denotes the presence or absence of double bonds in Cyc; and the
other substituents have the meaning indicated for the formula (I),
and/or physiologically acceptable salts, tautomers and/or
stereoisomers thereof, including mixtures thereof in all
ratios.
[0059] It has namely been found that the activity of the compounds
according to the invention is particularly high if R.sup.3 has the
configuration depicted in the formula (II) and Q carries no
substituent.
[0060] In a furthermore preferred embodiment of the present
invention, arylquinazoline derivatives of the formula (III) are
provided
##STR00005##
in which R.sup.3 is Hal, CN, OH, CONH.sub.2, CONH(LA) or LA;
R.sup.6 is Hal, LA, oxo, CN, NH.sub.2 or Het.sup.2; R.sup.6' is H,
Hal, LA, oxo, CN, NH.sub.2 or Het.sup.2; denotes the presence or
absence of double bonds in Cyc; and the other substituents have the
meaning indicated for the formula (I), and/or physiologically
acceptable salts, tautomers and/or stereoisomers thereof, including
mixtures thereof in all ratios.
[0061] It has namely been found that the activity of the compounds
according to the invention is particularly high if R.sup.3 has the
configuration depicted in the formula (III) and Cyc is substituted
in the ortho-position by R.sup.6.
[0062] Very particular preference is given to the sub-formulae
(IIa), (IIb), (IIIa) and (IIIb) of the formulae (II) and (III):
##STR00006##
in which R.sup.2, R.sup.3, independently of one another, are Hal,
CN, OH, CONH.sub.2, CON(LA) or LA; R.sup.6', R.sup.6'',
independently of one another, are H, Hal, LA, oxo, CN, NH.sub.2 or
Het.sup.2; Q.sup.1, Q.sup.2, independently of one another, are CH,
N or NH and are in each case unsubstituted;
X.sup.1 is CH, CF or N;
X.sup.2 is CH or N,
[0063] where X.sup.1, X.sup.2 are not simultaneously N;
Y is CH or N;
[0064] denotes the presence or absence of double bonds in Cyc; and
the other substituents have the meaning indicated for the formula
(I), and/or physiologically acceptable salts, tautomers and/or
stereoisomers thereof, including mixtures thereof in all
ratios;
##STR00007##
in which R.sup.2, R.sup.3, independently of one another, are Hal,
CN, OH, CONH.sub.2, CON(LA) or LA; R.sup.6', R.sup.6'',
independently of one another, are H, Hal, LA, oxo, CN, NH.sub.2 or
Het.sup.2; Q.sup.1, Q.sup.2 independently of one another, are CH, N
or NH and are in each case unsubstituted;
Y is CH or N,
[0065] denotes the presence or absence of double bonds in Cyc; and
all other substituents have the meaning indicated for the formula
(I), and/or physiologically acceptable salts, tautomers and/or
stereoisomers thereof, including mixtures thereof in all
ratios;
##STR00008##
in which R.sup.3 is Hal, CN, OH, CONH.sub.2, CON(LA) or LA; R.sup.6
is Hal, LA, oxo, CN, NH.sub.2 or Het.sup.2; R.sup.6'' is H, Hal,
LA, oxo, CN, NH.sub.2 or Het.sup.2;
X.sup.1 is CH, CF or N;
X.sup.2 is CH or N,
[0066] where X.sup.1, X.sup.2 are not simultaneously N;
Y is CH or N;
[0067] denotes the presence or absence of double bonds in Cyc; and
the other substituents have the meaning indicated for the formula
(I), and/or physiologically acceptable salts, tautomers and/or
stereoisomers thereof, including mixtures thereof in all
ratios;
##STR00009##
in which R.sup.3 is Hal, CN, OH, CONH.sub.2, CON(LA) or LA; R.sup.6
is Hal, LA, oxo, CN, NH.sub.2 or Het.sup.2; R.sup.6 is H, Hal, LA,
oxo, CN, NH.sub.2 or Het.sup.2;
Y is CH or N,
[0068] denotes the presence or absence of double bonds in Cyc; and
all other substituents have the meaning indicated for the formula
(I), and/or physiologically acceptable salts, tautomers and/or
stereoisomers thereof, including mixtures thereof in all
ratios.
[0069] Furthermore preferred sub-groups of compounds of the formula
(IIa) can be expressed by the following sub-formulae (IIa-A) to
(IIa-O), which conform to the formula (IIa), but in which
in the case of the sub-formula (IIa-A) [0070] X.sup.1 is CH, [0071]
R.sup.1 is F or Cl, [0072] R.sup.2 is F or Cl, in the case of the
sub-formula (IIa-B) [0073] R.sup.1 is F, [0074] R.sup.2 is F or Cl,
in the case of the sub-formula (IIa-C) [0075] X.sup.1, X.sup.2 is
CH, in the case of the sub-formula (IIa-D) [0076] X.sup.1 is CH,
[0077] R.sup.5 is H, in the case of the sub-formula (IIa-E) [0078]
R.sup.3 is H, OH, in the case of the sub-formula (IIa-F) [0079]
X.sup.1 is CH, [0080] R.sup.3 is OH, in the case of the sub-formula
(IIa-G) [0081] X.sup.1 is CH, [0082] Y is CH, in the case of the
sub-formula (IIa-H) [0083] X.sup.1 is CH, [0084] Cyc is pyridine,
pyrazine or pyridazine, or pyrazolo[1,5-a]pyrimidinyl or
imidazo[1,2-b]pyridazinyl, in the case of the sub-formula (IIa-J)
[0085] Cyc is pyridine, pyrazine, pyridazine,
pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl,
furo[2,3-c]pyridinyl, furo[2,3-d}pyridazinyl,
thieno[2,3-d}pyridazinyl, thieno[2,3-d}-pyrimidinyl or
imidazo[4,5-c]pyridinyl, each of which may be unsubstituted, or may
be mono- or disubstituted by methoxy, methyl, oxo, Cl or
CHF.sub.2O, in the case of the sub-formula (IIa-K) [0086] R.sup.1
is F or Cl, [0087] R.sup.2 is F or Cl, [0088] R.sup.3 is OH, [0089]
R.sup.5 is H, [0090] X.sup.1, X.sup.2 is CH, in the case of the
sub-formula (IIa-L) [0091] R.sup.1 is F, [0092] R.sup.2 is F or Cl,
[0093] R.sup.3 is H or OH, [0094] R.sup.5 is H, in the case of the
sub-formula (IIa-M) [0095] R.sup.1 is F or Cl, [0096] R.sup.2 is F
or Cl, [0097] R.sup.3 is OH, [0098] R.sup.5 is H, [0099] X.sup.1,
X.sup.2 is CH, [0100] Cyc is pyridine, pyrazine or pyridazine, or
pyrazolo[1,5-a]pyrimidinyl or imidazo[1,2-b]pyridazinyl, in the
case of the sub-formula (IIa-N) [0101] R.sup.1 is F, [0102] R.sup.2
is F or Cl, [0103] R.sup.3 is H or OH, [0104] R.sup.5 is H, [0105]
Cyc is pyridine, pyrazine, pyridazine, pyrazolo[1,5-a]pyrimidinyl,
imidazo[1,2-b]pyridazinyl, furo[2,3-c]pyridinyl,
furo[2,3-d}pyridazinyl, thieno[2,3-d}pyridazinyl,
thieno[2,3-d}-pyrimidinyl or imidazo[4,5-c]pyridinyl, each of which
may be unsubstituted, or may be mono- or disubstituted by methoxy,
methyl, oxo, Cl or CHF.sub.2O, in the case of the sub-formula
(IIa-O) [0106] R.sup.1 is F, [0107] R.sup.2 is F or Cl, [0108]
R.sup.3 is H or OH, [0109] R.sup.5 is H, [0110] Cyc is
5-methoxypyridazin-3-yl, imidazo[1,2-b]pyridazin-6-yl,
3-chloro-6-methoxypyrazin-2-yl, 3-chloropyrazin-2-yl,
pyridazin-4-yl, 3-methoxypyrazin-2-yl, 6-methoxypyridazin-3-yl,
3-difluoromethoxypyridin-2-yl, 3-methylpyrazin-2-yl,
thieno[2,3-d}pyrimidin-4-yl, 1-methyl-1H-pyridin-2-one-6-yl,
1H-pyridazin-6-one-3-yl, furo[2,3-d}pyridazin-7-yl,
thieno[2,3-d}pyridazin-7-yl, 3,5-dimethylpyrazin-2-yl,
furo[2,3-d}pyrimidin-4-yl, 3-methyl-3H-imidazo[4,5-c]pyridin-4-yl,
and/or physiologically acceptable salts, tautomers and/or
stereoisomers thereof, including mixtures thereof in all
ratios.
[0111] Furthermore preferred sub-groups of compounds of the formula
(IIIa) can be expressed by the following sub-formulae (IIIa-B) to
(IIIa-O), which conform to the formula (IIIa), but in which
in the case of the sub-formula (IIIa-B) [0112] R.sup.1 is F, in the
case of the sub-formula (IIIa-C) [0113] X.sup.1, X.sup.2 is CH, in
the case of the sub-formula (IIIa-D) [0114] X.sup.1 is CH, [0115]
R.sup.5 is H, in the case of the sub-formula IIIa-(E) [0116]
R.sup.3 is H, OH, in the case of the sub-formula (IIIa-F) [0117]
X.sup.1 is CH, [0118] R.sup.3 is OH, in the case of the sub-formula
(IIIa-G) [0119] X.sup.1 is CH, [0120] Y is CH, in the case of the
sub-formula (IIIa-H) [0121] X.sup.1 is CH, [0122] Cyc is pyridine,
pyrazine or pyridazine, or pyrazolo[1,5-a]pyrimidinyl or
imidazo[1,2-b]-pyridazinyl, in the case of the sub-formula (IIIa-J)
[0123] Cyc is pyridine, pyrazine, pyridazine,
pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl,
furo[2,3-c]pyridinyl, furo[2,3-d}pyridazinyl,
thieno[2,3-d}pyridazinyl, thieno[2,3-d}-pyrimidinyl or
imidazo[4,5-c]pyridinyl, each of which may be unsubstituted, or may
be mono- or disubstituted by methoxy, methyl, oxo, Cl or
CHF.sub.2O, in the case of the sub-formula (IIIa-K) [0124] R.sup.1
is F or Cl, [0125] R.sup.3 is OH, [0126] R.sup.5 is H, [0127]
X.sup.1, X.sup.2 is CH, in the case of the sub-formula (IIIa-L)
[0128] R.sup.1 is F, [0129] R.sup.3 is H or OH, [0130] R.sup.5 is
H, in the case of the sub-formula (IIIa-M) [0131] R.sup.1 is F or
Cl, [0132] R.sup.3 is OH, [0133] R.sup.5 is H, [0134] X.sup.1,
X.sup.2 is CH, [0135] Cyc is pyridine, pyrazine or pyridazine, or
pyrazolo[1,5-a]pyrimidinyl or imidazo[1,2-b]-pyridazinyl, in the
case of the sub-formula (IIIa-N) [0136] R.sup.1 is F, [0137]
R.sup.3 is H or OH, [0138] R.sup.5 is H, [0139] Cyc is pyridine,
pyrazine, pyridazine, pyrazolo[1,5-a]pyrimidinyl,
imidazo[1,2-b]pyridazinyl, furo[2,3-c]pyridinyl,
furo[2,3-d}pyridazinyl, thieno[2,3-d}pyridazinyl,
thieno[2,3-d}-pyrimidinyl or imidazo[4,5-c]pyridinyl, each of which
may be unsubstituted, or may be mono- or disubstituted by methoxy,
methyl, oxo, Cl or CHF.sub.2O, in the case of the sub-formula
(IIIa-O) [0140] R.sup.1 is F, [0141] R.sup.3 is H or OH, [0142]
R.sup.5 is H, [0143] Cyc is 5-methoxypyridazin-3-yl,
imidazo[1,2-b]pyridazin-6-yl, 3-chloro-6-methoxypyrazin-2-yl,
3-chloropyrazin-2-yl, pyridazin-4-yl, 3-methoxypyrazin-2-yl,
6-methoxypyridazin-3-yl, 3-difluoromethoxypyridin-2-yl,
3-methylpyrazin-2-yl, thieno[2,3-d}pyrimidin-4-yl,
1-methyl-1H-pyridin-2-one-6-yl, 1H-pyridazin-6-one-3-yl,
furo[2,3-d}pyridazin-7-yl, thieno[2,3-d}pyridazin-7-yl,
3,5-dimethylpyrazin-2-yl, furo[2,3-d}pyrimidin-4-yl,
3-methyl-3H-imidazo[4,5-c]pyridin-4-yl, and/or physiologically
acceptable salts, tautomers and/or stereoisomers thereof, including
mixtures thereof in all ratios.
[0144] Furthermore preferred sub-groups of compounds of the formula
(IIb) can be expressed by the following sub-formulae (IIb-Q) to
(IIb-U), which conform to the formula (IIb), but in which
in the case of the sub-formula (IIb-Q) [0145] R.sup.1 is F or Cl,
[0146] R.sup.2 is F or Cl, [0147] R.sup.3 is OH, [0148] R.sup.5 is
H, [0149] Y is CH, in the case of the sub-formula (IIb-R) [0150]
R.sup.1 is F, [0151] R.sup.2 is F or Cl, [0152] R.sup.3 is OH,
[0153] R.sup.5 is H, [0154] Y is CH, in the case of the sub-formula
(IIb-S) [0155] Cyc is pyridine, pyrazine or pyridazine, in the case
of the sub-formula (IIb-T) [0156] R.sup.1 is F or Cl, [0157]
R.sup.2 is F or Cl, [0158] R.sup.3 is OH, [0159] R.sup.5 is H,
[0160] Cyc is pyridine, pyrazine or pyridazine, in the case of the
sub-formula (IIb-U) [0161] R.sup.1 is F, [0162] R.sup.2 is F or Cl,
[0163] R.sup.3 is OH, [0164] R.sup.5 is H, [0165] Cyc is pyridine,
pyrazine, pyridazine or 3-methylpyrazin-2-yl, and/or
physiologically acceptable salts, tautomers and/or stereoisomers
thereof, including mixtures thereof in all ratios.
[0166] Furthermore preferred sub-groups of compounds of the formula
(IIIb) can be expressed by the following sub-formulae (IIIb-Q) to
(IIIb-U), which conform to the formula (IIIb), but in which
in the case of the sub-formula (IIIb-Q) [0167] R.sup.1 is F or Cl,
[0168] R.sup.3 is OH, [0169] R.sup.5 is H, [0170] Y is CH, in the
case of the sub-formula (IIIb-R) [0171] R.sup.1 is F, [0172]
R.sup.3 is OH, [0173] R.sup.5 is H, [0174] Y is CH, in the case of
the sub-formula (IIIb-S) [0175] Cyc is pyridine, pyrazine or
pyridazine, in the case of the sub-formula (IIIb-T) [0176] R.sup.1
is F or Cl, [0177] R.sup.3 is OH, [0178] R.sup.5 is H, [0179] Cyc
is pyridine, pyrazine or pyridazine, in the case of the sub-formula
(IIIb-U) [0180] R.sup.1 is F, [0181] R.sup.3 is OH, [0182] R.sup.5
is H, [0183] Cyc is pyridine, pyrazine, pyridazine or
3-methylpyrazin-2-yl, and/or physiologically acceptable salts,
tautomers and/or stereoisomers thereof, including mixtures thereof
in all ratios.
[0184] Very particular preference is given to those compounds of
the formulae (I) and sub-formulae thereof, and/or physiologically
acceptable salts, tautomers and/or stereoisomers thereof, including
mixtures thereof in all ratios, that are compiled in Tables
1-8.
[0185] The compounds of the formula (I) and also the starting
materials for their preparation are prepared by methods known per
se, as are described in the literature (for example in standard
works, such as Houben-Weyl, Methoden der organischen Chemie
[Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart)
and/or are known person skilled in the art, and under reaction
conditions which are known and suitable for the said reactions. Use
can also be made here of variants known per se which are not
mentioned here in greater detail. Depending on the conditions used,
the reaction time is between a few min and 14 days, the reaction
temperature is between -70.degree. C. and 150.degree. C., normally
between -50.degree. C. and 100.degree. C., particularly preferably
between -10.degree. C. and 70.degree. C.
[0186] The reaction is carried out in an inert solvent and
generally in the presence of an acid-binding agent, preferably an
organic base, such as DIPEA, triethylamine, dimethylaniline,
pyridine, quinoline, piperidine or diethanolamine. The addition of
an alkali-metal or alkaline-earth metal hydroxide, carbonate or
bicarbonate or another salt of a weak acid of the alkali or
alkaline-earth metals, preferably of potassium, sodium, calcium or
caesium, may also be favourable. Suitable bases are metal oxides,
such as, for example, aluminium oxide, alkali-metal hydroxides
(including potassium hydroxide, sodium hydroxide and lithium
hydroxide), alkaline-earth metal hydroxides (for example barium
hydroxide and calcium hydroxide) and alkali-metal alkoxides (for
example potassium ethoxide and sodium propoxide).
[0187] Suitable inert solvents are, inter alia, hydrocarbons, such
as cyclohexane, toluene or xylene; chlorinated hydrocarbons, such
as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride,
chloroform or dichloromethane; alcohols, such as methanol, ethanol,
isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as
diethyl ether, diisopropyl ether, methyl tert-butyl ether,
tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene
glycol monomethyl or monoethyl ether, ethylene glycol dimethyl
ether (diglyme); ketones, such as acetone or butanone; amides, such
as acetamide, dimethylacetamide or dimethylformamide (DMF);
nitriles, such as acetonitrile; sulfoxides, such as dimethyl
sulfoxide (DMSO); carbon disulfide; carboxylic acids, such as
formic acid or acetic acid; nitro compounds, such as nitromethane
or nitrobenzene; esters, such as ethyl acetate, or mixtures of the
said solvents. Particular preference is given to DMF, methanol,
dichloromethane, THF, acetic acid and acetonitrile.
[0188] The process and the subsequent work-up of the reaction
mixture can basically be carried out as a batch reaction or in a
continuous reaction procedure. The continuous reaction procedure
comprises, for example, reaction in a continuous stirred-kettle
reactor, a stirred-kettle cascade, a loop or cross-flow reactor, a
flow tube or in a microreactor. The reaction mixtures are
optionally worked up, as needed, by filtration via solid phases,
chromatography, separation between immiscible phases (for example
extraction), adsorption onto solid supports, removal of solvents
and/or azeotropic mixtures by distillation, selective distillation,
sublimation, crystallisation, co-crystallisation or by
nanofiltration on membranes.
[0189] The compounds of the formula (I) can preferably be obtained
by reacting compounds of the formulae (V) and (VI). The present
invention thus also relates to a process for the preparation of
compounds of the formula (I), sub-formulae thereof and/or
physiologically acceptable salts, tautomers and/or stereoisomers
thereof, including mixtures thereof in all ratios, having the
following steps:
(a) reaction of a compound of the formula (V)
##STR00010##
in which LG is a conventional leaving group, such as Hal, with a
compound of the formula (IV)
##STR00011##
in which A is boronic acid or a boronic acid ester, to give the
compounds of the formula (I) and optionally (b) conversion of a
base or acid of the compounds of the formula (I) into one of their
salts.
[0190] The starting compounds are generally known. If they are
novel, they can be prepared by methods known per se. The compounds
of the formulae (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa),
(IIIb), (IV) and (V) can be prepared by known methods. If desired,
the starting materials can be formed in situ, so that they are not
isolated from the reaction mixture, but instead are immediately
converted further into the compounds according to the invention. It
is likewise possible to carry out the reaction stepwise.
[0191] The said compounds according to the invention can be used in
their final non-salt form. On the other hand, the present invention
also encompasses the use of these compounds in the form of their
pharmaceutically acceptable salts, which can be derived from
various organic and inorganic acids and bases by procedures known
in the art. Pharmaceutically acceptable salt forms of the compounds
of the formula (I) and sub-formulae thereof are for the most part
prepared by conventional methods. If the compounds contain a
carboxyl group, one of its suitable salts can be formed by reacting
the compound with a suitable base to give the corresponding
base-addition salt. Such bases are, for example, alkali-metal
hydroxides (for example potassium hydroxide, sodium hydroxide and
lithium hydroxide), alkaline-earth metal hydroxides (for example
barium hydroxide and calcium hydroxide), alkali-metal alkoxides
(for example potassium ethoxide and sodium propoxide) and various
organic bases, such as piperidine, diethanolamine and
N-methylglutamine. A base of the formula (I) and sub-formulae
thereof can be converted into the associated acid-addition salt
using an acid, for example by reaction of equivalent amounts of the
base and the acid in an inert solvent, such as, for example,
ethanol, with subsequent evaporation. Suitable acids for this
reaction are, in particular, those which give physiologically
acceptable salts, such as, for example, hydrogen halides (for
example hydrogen chloride, hydrogen bromide or hydrogen iodide),
other mineral acids and corresponding salts thereof (for example
sulfate, nitrate or phosphate and the like), alkyl- and
monoarylsulfonates (for example ethanesulfonate, toluenesulfonate
and benzenesulfonate) and other organic acids and corresponding
salts thereof (for example acetate, trifluoroacetate, tartrate,
maleate, succinate, citrate, benzoate, salicylate, ascorbate and
the like. Salts with physiologically unacceptable acids, for
example picrates, can be used for the isolation and/or purification
of the compounds of the formula (I).
[0192] With regard to that stated above, it can be seen that the
expression "pharmaceutically acceptable salt" in the present
connection is taken to mean an active compound which comprises a
compound of the formula (I) in the form of one of its salts, in
particular if this salt form imparts improved pharmacokinetic
properties on the active compound compared with the free form of
the active compound. The pharmaceutically acceptable salt form of
the active compound can also provide this active compound for the
first time with a desired pharmacokinetic property and can even
have a positive influence on the pharmacodynamics of this active
compound with respect to its therapeutic efficacy in the body.
[0193] Compounds according to the invention may be chiral owing to
their molecular structure and may accordingly occur in various
enantiomeric forms. They may therefore be in racemic or optically
active form. Since the pharmaceutical efficacy of the racemates or
stereoisomers of the compounds of the formula (I) may differ, it
may be desirable to use the enantiomers. In these cases, the end
product, or even the intermediate, may be separated into
enantiomeric compounds by chemical or physical measures known to
the person skilled in the art or already employed as such in the
synthesis.
[0194] It is generally known that atoms can have atomic masses or
mass numbers which can differ from the atomic masses or mass
numbers usually occurring naturally. Examples of isotopes which are
commercially available and which can be incorporated into a
compound according to the invention by known methods are isotopes
of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and
chlorine, for example .sup.2H, .sup.3H, .sup.13C, .sup.14C,
.sup.15N, .sup.18O, .sup.17O, .sup.31P, .sup.32P, .sup.35S,
.sup.18F and .sup.36Cl. The incorporation of heavier isotopes, in
particular deuterium (.sup.2H) into a compound according to the
invention has therapeutic advantages due to the higher metabolic
stability of this isotope-labelled compound. Higher metabolic
stability results directly in an increased in vivo half life, which
enables a lower dosage.
[0195] The definitions of the atoms H, C, N, etc., as used in the
compounds according to the invention, generally also relate to the
heavier isotopes of these atoms.
[0196] Particular preference is given in accordance with the
invention to the use of D (deuterium, .sup.2H) instead of hydrogen
(1H).
[0197] It has been found that the compounds according to the
invention cause specific inhibition of serine/threonine protein
kinases. The invention therefore furthermore relates to the use of
compounds of the formula (I) or sub-formulae thereof and/or
physiologically acceptable salts, tautomers and/or stereoisomers
thereof, including mixtures thereof in all ratios, for the
inhibition of serine/threonine protein kinases, preferably PIKK,
particularly preferably DNA-PK. Especial preference is given to the
inhibition of the above-mentioned serine/threonine protein kinases
ex vivo or in vitro. The term "inhibition" relates to any reduction
in the activity which is based on the action of the specific
compounds according to the invention in that the latter are capable
of interacting with the target molecule in such a way that
recognition, binding and blocking is made possible. The compounds
are distinguished by high affinity to at least one serine/threonine
protein kinases, ensuring reliable binding and preferably complete
blocking of the kinase activity. The compounds are particularly
preferably monospecific in order to guarantee exclusive and direct
recognition of the selected kinase. The term "recognition" relates
here to any type of interaction between the compound and the said
target molecules, in particular covalent or non-covalent bonds,
such as, for example, a covalent bond, hydrophobic/hydrophilic
interactions, van der Waals forces, ion attraction, hydrogen bonds,
ligand/receptor interactions, base pairs of nucleotides or
interactions between epitope and antibody binding site.
[0198] The compounds according to the invention exhibit an
advantageous biological activity which can be demonstrated in the
tests described herein, such as, for example, enzyme-based assays.
Measurement of the kinase activity is a technique which is well
known to the person skilled in the art. Generic test systems for
the determination of the kinase activity using substrates, for
example histone (Alessi et al. (1996) FEBS Lett. 399(3): 333) or
the basic myelin protein, are described in the literature
(Campos-Gonzalez & Glenney (1992) JBC 267: 14535). Various
assay systems are available for the identification of kinase
inhibitors. In the scintillation proximity assay (Sorg et al.
(2002) J Biomolecular Screening 7: 11) and the flash-plate assay,
the radioactive phosphorylation of a protein or peptide as
substrate are measured using ATP. In the presence of an inhibitory
compound, a decreased radioactive signal, or none at all, is
detectable. Furthermore, homogeneous time-resolved fluorescence
resonance energy transfer (HTR-FRET) and fluorescence polarisation
(FP) technologies are useful as assay methods (Sills et al. (2002)
J Biomolecular Screening 191). Other non-radioactive ELISA methods
use specific phospho-antibodies (phospho-ABs). The phospho-AB binds
only the phosphorylated substrate. This binding can be detected by
chemiluminescence using a second peroxidase-conjugated anti-sheep
antibody.
[0199] The above-mentioned use of the compounds can take place in
in-vitro or in-vivo models. The susceptibility of a particular cell
to treatment with the compounds according to the invention can be
determined by testing in vitro. Typically, a culture of the cell is
incubated with a compound according to the invention at various
concentrations for a period of time which is sufficient to enable
the active agents to induce cell death or to inhibit cell
proliferation, cell vitality or migration, usually between about
one hour and up to 9 days. For testing in vitro, cultivated cells
from a biopsy sample can be used. The amount of cells remaining
after the treatment is then determined. The use in vitro takes
place, in particular, on samples of mammal species which are
suffering from cancer, tumours or metastases. The host or patient
can belong to any mammal species, for example a primate species, in
particular humans, but also rodents (including mice, rats and
hamsters), rabbits, horses, cows, dogs, cats, etc. Animal models
are of interest for experimental investigations, providing a model
for the treatment of a human disease.
[0200] The testing of a plurality of specific compounds enables the
selection of the active compound which appears the most suitable
for the treatment of the patient. The in-vivo dose of the selected
compound is advantageously matched to the susceptibility of the
kinase and/or severity of the disease of the patient taking into
account the in-vitro data, as a result of which the therapeutic
efficacy is noticeably increased. The dose varies depending on the
specific compound used, the specific disease, the patient status,
etc. A therapeutic dose is typically sufficient considerably to
reduce the undesired cell population in the target tissue, while
the viability of the patient is maintained. The following teaching
of the invention and embodiments thereof relating to the use of
compounds of the formula (I) for the preparation of a medicament
for the prophylaxis, therapy and/or progress control is valid and
can be applied without restrictions to the use of the compounds for
the inhibition of the kinase activity, if it appears
appropriate.
[0201] The treatment is generally continued until a considerable
reduction has occurred, for example at least about 50% reduction of
the cell load, and can be continued until essentially no more
undesired cells are detected in the body. In tests of this type,
the compounds according to the invention exhibit and cause an
inhibiting effect, which is usually documented by IC.sub.50 values
in a suitable range, preferably in the micromolar range and more
preferably in the nanomolar to picomolar range. The kinase is
inhibited, in particular, to the extent of 50% if the concentration
of the compounds is less than 1 .mu.M, preferably equal to or less
than 0.5 .mu.M, particularly preferably less than 0.1 .mu.M. This
concentration is called the IC.sub.50 value.
[0202] The invention also relates to a medicament comprising at
least one compound of the formula (I) or sub-formulae thereof
and/or physiologically acceptable salts, tautomers and/or
stereoisomers thereof, including mixtures thereof in all ratios.
The invention also relates to a pharmaceutical composition
comprising, as active compound, an effective amount of at least one
compound of the formula (I) or sub-formulae thereof and/or
physiologically acceptable salts, tautomers and/or stereoisomers
thereof, including mixtures thereof in all ratios, together with
pharmaceutically tolerated assistants.
[0203] A "medicament", "drug" and a "pharmaceutical composition" or
"pharmaceutical formulation" here is any composition which can be
employed in the prophylaxis, therapy, progress control or
aftertreatment of patients who, at least temporarily, exhibit a
pathogenic modification of the overall condition or the condition
of individual parts of the patient organism, preferably as a
consequence of cancer, tumours, or metastases.
[0204] In order to increase the protective or therapeutic action of
the compounds according to the invention, pharmaceutically
tolerated adjuvants can be added. For the purposes of the
invention, any substance which facilitates, enhances or modifies an
effect with the compounds in accordance with the invention is an
"adjuvant". Known adjuvants are, for example, aluminium compounds,
such as, for example, aluminium hydroxide or aluminium phosphate,
saponins, such as, for example, QS 21, muramyl dipeptide or muramyl
tripeptide, proteins, such as, for example, gamma-interferon or
TNF, MF 59, phosphatdibylcholine, squalene or polyols. The
co-application of egg albumin in complete Freund's adjuvant can
likewise cause increased cell-mediated immunity and thus support
the action of neutralising antibodies formed. Furthermore, DNA,
which has an immunostimulatory property, or which encodes a protein
with an adjuvant effect, such as, for example, a cytokine, can be
applied in parallel or in a construct.
[0205] The introduction of the pharmaceutical composition into a
cell or organism can be carried out in accordance with the
invention in any manner which enables the kinases to be brought
into contact with the compounds present in the composition, as a
consequence of which a response is induced. The pharmaceutical
composition of the present invention can be administered orally,
transdermally, transmucosally, transurethrally, vaginally,
rectally, pulmonarily, enterally and/or parenterally. The type of
administration selected depends on the indication, the dose to be
administered, individual-specific parameters, etc. In particular,
the various types of administration facilitate site-specific
therapy, which minimises side effects and reduces the
active-compound dose. Very particularly preferred injections are
intradermal, subcutaneous, intramuscular or intravenous injection.
The administration can be carried out, for example, with the aid of
so-called vaccination guns or by means of syringes. It is also
possible to prepare the substance as an aerosol, which is inhaled
by the organism, preferably a human patient.
[0206] The administration forms of the pharmaceutical composition
are prepared corresponding to the desired type of administration in
a suitable dosage and in a manner known per se using the
conventional solid or liquid vehicles and/or diluents and the
assistants usually employed. Thus, pharmaceutically acceptable
excipients known to the person skilled in the art can basically
form part of the pharmaceutical composition according to the
invention, where the amount of excipient material which is combined
with the active compound in order to prepare a single dose varies
depending on the individual to be treated and the type of
administration. These pharmaceutically tolerated additives include
salts, buffers, fillers, stabilisers, complexing agents,
antioxidants, solvents, binders, lubricants, tablet coatings,
flavours, dyes, preservatives, adjusters and the like. Examples of
excipients of this type are water, vegetable oils, benzyl alcohols,
alkylene glycol, polyethylene glycol, Kolliphor, glycerol
triacetate, gelatine, hydroxypropylmethylcellulose (HPMC),
carbohydrates, such as, for example, lactose or starch, magnesium
stearate, talc and Vaseline.
[0207] The pharmaceutical formulation can be in the form of a
tablet, film tablet, dragee, lozenge, capsule, pill, powder,
granules, syrup, juice, drops, solution, dispersion, suspension,
suppository, emulsion, extrudate, implant, cream, gel, ointment,
paste, lotion, serum, oil, spray, aerosol, adhesive, plaster or
bandage. Oral administration forms which are prepared are
preferably tablets, film tablets, dragees, lozenges, capsules,
pills, powders, granules, syrups, juices, drops, solutions,
dispersions or suspensions--including as depot form. Furthermore,
parenteral medicament forms, such as, for example, suppositories,
suspensions, emulsions, implants or solutions, should be
considered, preferably oily or aqueous solutions. For topical
application, the medicament active compound is formulated in a
conventional manner with at least one pharmaceutically acceptable
vehicle, such as, for example, microcrystalline cellulose, and
optionally further assistants, such as, for example, moisturisers,
to give solid formulations which can be applied to the skin, such
as, for example, creams, gels, ointments, pastes, powders or
emulsions, or to give liquid formulations which can be applied to
the skin, such as, for example, solutions, suspensions, lotions,
sera, oils, sprays or aerosols. The pharmaceutical composition is
preferably in the form of an injection solution. For the
preparation of the injection solution, aqueous media, such as, for
example, distilled water or physiological salt solutions, can be
used, where the latter include acidic and basic addition salts. The
pharmaceutical composition may also be in the form of a solid
composition, for example in the lyophilised state, and can then be
prepared before use by addition of a dissolving agent, such as, for
example, distilled water. The person skilled in the art is familiar
with the basic principles of the preparation of lyophilisates.
[0208] The concentration of the active compound in the formulation
can be 0.1 to 100 percent by weight. It is crucial that the
pharmaceutical composition comprises, as active compound, an
effective amount of the compound together with the pharmaceutically
tolerated assistants. The terms "effective amount" or "effective
dose" are used interchangeably herein and denote an amount of the
pharmaceutical active compound which has a prophylactically or
therapeutically relevant action on a disease or pathological change
in cell, tissue, organ or mammal. A "prophylactic action" prevents
the outbreak of a disease or even infection with a pathogen after
ingress of individual representatives in such a way that subsequent
spread thereof is greatly reduced or they are even completely
deactivated. A "prophylactic action" also includes an increase in
normal physiological function. Prophylaxis is advisable, in
particular, if an individual has predispositions for the onset of
the above-mentioned diseases, such as, for example, a family
history, a gene defect or a recently survived disease. A
"therapeutically relevant action" frees in part or full from one,
more than one or all disease symptoms or results in the partial or
complete reversal of one, more than one or all physiological or
biochemical parameters which are associated with or causally
involved in the disease or pathological change into the normal
state. Progress control is also taken to be a type of therapeutic
treatment if the compounds are administered at certain time
intervals, for example in order completely to eliminate the
symptoms of a disease. The respective dose or dose range for the
administration of the compounds according to the invention is
sufficiently large to achieve the desired prophylactic or
therapeutic effect of induction of a biological or medical
response. In general, the dose will vary with the age, constitution
and gender of the patient, and the severity of the disease will be
taken into account. It goes without saying that the specific dose,
frequency and duration of administration are, in addition,
dependent on a multiplicity of factors, such as, for example, the
targeting and binding ability of the compounds, feeding habits of
the individual to be treated, type of administration, excretion
rate and combination with other drugs. The individual dose can be
adjusted both with respect to the primary disease and also with
respect to the occurrence of any complications. The precise dose
can be established by a person skilled in the art using known means
and methods. This teaching of the invention is valid and can be
applied without restrictions to the pharmaceutical composition
comprising the compounds of the formula (I), if it appears
appropriate.
[0209] In an embodiment of the invention, the compounds are
administered in a dose of 0.01 mg to 1 g per dosage unit,
preferably between 1 to 700 mg, particularly preferably 5 to 200
mg. The daily dose is in particular between 0.02 and 100 mg/kg of
body weight.
[0210] In order to support the medical effect, the pharmaceutical
composition may, in an embodiment of the invention, also comprise
one or more further active compounds, where simultaneous or
successive administration is conceivable. The therapeutic effect of
the pharmaceutical composition according to the invention can
consist, for example, in certain anticancer agents having a better
action through the inhibition of DNA-PK as a desired side effect or
in the number of side effects of these medicaments being reduced by
the reduction in the dose.
[0211] In a preferred embodiment of the invention, the
pharmaceutical composition according to the invention is combined
with an anticancer agent. As used here, the term "anticancer agent"
relates to any agent which is administered to a patient with
cancer, tumours or metastases for the purpose of treatment of the
cancer. Anticancer agents which are preferred in accordance with
the invention are those which damage the DNA of tumour cells and
thus engage in DNA replication, DNA transcription or gene
expression. The following, in particular, are suitable for this
purpose: [0212] alkylating agents, such as altretamine,
bendamustine, busulfan, carmustine, chloroambucil, chloromethine,
cyclophosphamide, dacarbazine, ifosfamide, improsulfan tosylate,
lomustine, melphalan, mitobronitol, mitolactol, nimustine,
ranimustine, temozolomide, thiotepa, treosulfan, mechloroetamine,
carboquone, apaziquone, fotemustine, glufosfamide, palifosfamide,
pipobroman, trofosfamide, uramustine; [0213] platinum compounds,
such as carboplatin, cisplatin, eptaplatin, miriplatin hydrate,
oxaliplatin, lobaplatin, nedaplatin, picoplatin, satraplatin;
[0214] topoisomerase inhibitors, such as etoposide, irinotecan,
razoxane, sobuzoxane, [0215] DNA-modifying agents, such as
amrubicin, bisantrene, decitabine, mitoxantrone, procarbazine,
trabectedine, clofarabine, amsacrine, brostallicin, pixantrone,
laromustine; [0216] anticancer antibiotics, such as bleomycin,
dactinomycin, doxorubicin, epirubicin, idarubicin, levamisol,
miltefosine, mitomycin C, romidepsin, streptozocin, valrubicin,
zinostatin, zorubicin, daunurobicin, plicamycin, aclarubicin,
peplomycin, pirarubicin; [0217] alpha emitters, such as alpharadin
(.sup.223Ra dichloride, Xofgio), .sup.211At, .sup.213Bi;
.sup.225Ac, .sup.227Th; particular preference is given to bleomycin
and alpharadin.
[0218] The invention can also be practised as a kit which comprises
the compounds according to the invention. The kit consists of
separate packs of (a) an effective amount of a compound of the
formula (I) and/or physiologically acceptable salts, tautomers
and/or stereoisomers thereof, including mixtures thereof in all
ratios, and (b) an effective amount of an anticancer agent. The kit
comprises suitable containers, such as, for example, boxes or
cartons, individual bottles, bags or ampoules. The kit may, for
example, comprise separate ampoules, each containing an effective
amount of a compound of the formula (I) and/or pharmaceutically
usable salts, tautomers and/or stereoisomers thereof, including
mixtures thereof in all ratios, and an effective amount of an
anticancer agent in dissolved or lyophilised form. The kit of the
invention may also contain an article which contains written
instructions or points the user towards written instructions which
explain the handling of the compounds of the invention.
[0219] In accordance with the invention, the compounds of the
formula (I) or sub-formulae thereof and/or physiologically
acceptable salts, tautomers and/or stereoisomers thereof, including
mixtures thereof in all ratios, are used for the prophylaxis,
therapy and/or progress control of diseases which are caused,
promoted and/or spread by the activity of serine/threonine protein
kinases. The present invention therefore also relates to the use of
compounds of the formula (I) or sub-formulae thereof and/or
physiologically acceptable salts, tautomers and/or stereoisomers
thereof, including mixtures thereof in all ratios, for the
preparation of a medicament for the prophylaxis, therapy and/or
progress control of diseases which are caused, promoted and/or
spread by the activity of serine/threonine protein kinases. In
accordance with the invention, compounds of the formula (I) or
sub-formulae thereof and/or physiologically acceptable salts,
tautomers and/or stereoisomers thereof, including mixtures thereof
in all ratios, are suitable for use in the prophylaxis, therapy
and/or progress control of diseases which are caused, promoted
and/or spread by activity of serine/threonine protein kinases. For
the identification of a corresponding signalling pathway and in
order to detect interactions between various signalling pathways,
suitable models or model systems have been developed, for example
cell culture models (Khwaja et al. (1997) EMBO 16: 2783) and models
of transgenic animals (White et al. (2001) Oncogene 20: 7064). In
order to determine certain stages in the signalling cascade,
interacting compounds can be used in order to modulate the signal
(Stephens et al. (2000) Biochemical J 351: 95). In addition, the
compounds according to the invention can also be used as reagents
for testing kinase-dependent signalling pathways in animals and/or
cell culture models or in the clinical diseases mentioned in this
application. As discussed herein, these signalling pathways are
relevant for various diseases. Accordingly, the compounds according
to the invention are useful in the prophylaxis, therapy and/or
progress control of diseases which are dependent on signalling
pathways with participation by serine/threonine protein
kinases.
[0220] In accordance with the invention, the compounds of the
formula (I) or sub-formulae thereof and/or physiologically
acceptable salts, tautomers and/or stereoisomers thereof, including
mixtures thereof in all ratios, are suitable for use in the
prophylaxis, therapy and/or progress control of cancer, tumours
and/or metastases.
[0221] The tumour is selected, in particular, from the group of
malignant diseases of bladder, stomach, kidneys, head, neck,
oesophagus, cervix, thyroid, intestine, liver, brain, prostate,
urogenital tract, lymphatic system, larynx, lung, skin, blood,
bones and immune system, and/or the cancer is selected from the
group of monocytic leukaemia, non-small-cell lung carcinoma,
small-cell lung carcinoma, pancreatic cancer, glioblastoma,
colorectal carcinoma, breast carcinoma, acute myeloid leukaemia,
chronic myeloid leukaemia, acute lymphatic leukaemia, chronic
lymphatic leukaemia, Hodgkin's lymphoma and non-Hodgkin's
lymphoma.
[0222] A further embodiment of the present invention relates to the
compounds according to the invention in combination with
radiotherapy and/or with at least one further active compound,
preferably in combination with radiotherapy and/or an anticancer
agent. Industrial irradiation methods which are used clinically
preferably include photon irradiation (classical, electromagnetic
X-ray/gamma radiation), proton irradiation, heavy-ion irradiation
(ionised carbon) and neutron irradiation, without being restricted
thereto. In addition, brachytherapy is used clinically with the aid
of a suitable radiation source (for example alpha emitters) in the
form of surface application and intracavitary and interstitial
administration. These radiotherapies and other suitable irradiation
therapies in the sense of the invention are known to the person
skilled in the art, such as, for example, from Herrmann et al.
(2006) Klinische Strahlenbiologie [Clinical Radiation Biology],
Elsevier Munich, 4th Edition, 67-68; Bhide & Nutting (2010) BMC
Medicine 8: 25; Choi & Hung (2010) Current Urology Reports
11(3): 172. As the most frequent application, photon irradiation
has been refined technically by the IMRT (intensitymodulated
radiotherapy) method and by imaging methods (three-dimensional
conformal radiotherapy) in irradiation planning and performance for
the most precise focusing possible. The compounds according to the
invention achieve synergistic effects in existing cancer
chemotherapies and irradiations and/or restore the efficacy of
existing cancer therapies and irradiations.
[0223] Still a further embodiment of the invention relates to the
use of at least one compound of the formula (I) and/or
physiologically acceptable salts, tautomers and/or stereoisomers
thereof, including mixtures thereof in all ratios, for the
sensitisation of cancer cells to an anticancer agent and/or
ionising radiation, with the proviso that the sensitisation does
not take place in vivo on the human or animal body. The
sensitisation preferably takes place ex vivo or in vitro by
administering the compounds to cells, cell cultures, tissues or
organs which comprise serine/threonine protein kinases. The ex-vivo
use is used, in particular, in the case of animal cells which
originate from an animal organism which is affected by a disease
which is selected from the group of cancer, tumours or metastases.
The cells treated ex vivo can either continue to be kept in culture
for subsequent investigations or transferred into an animal, which
can be the host animal or another animal. The ex-vivo sensitisation
according to the invention is particularly advantageous for testing
the specific action of the compounds, so that the in-vivo dose can
be pre-adjusted correspondingly with evaluation of these ex-vivo
data. As a result thereof, the therapeutic effect is increased
significantly. Alternatively, the invention is also designed for
use in vivo and relates to at least one compound of the formula (I)
and/or physiologically acceptable salts, tautomers and/or
stereoisomers thereof, including mixtures thereof in all ratios,
for use for the sensitisation of cancer cells to an anticancer
agent and/or ionising radiation.
[0224] The invention furthermore teaches a method for the
prophylaxis, therapy and/or progress control of cancer, tumours or
metastases in which an effective amount of at least one compound
according to the invention and/or physiologically acceptable salts,
tautomers and/or stereoisomers thereof, including mixtures thereof
in all ratios, is administered to a subject to be treated.
Preferred subjects in the sense of the invention are humans or
animals, particularly preferably humans. It is known to the person
skilled in the art here that he can administer the compounds
according to the invention, which can of course also be used as the
pharmaceutical composition according to the invention, in various
doses to an organism, in particular a human patient. The effective
amount and the type of administration can be determined by the
person skilled in the art by routine experiments. The previous
teaching of the invention and embodiments thereof are valid and can
be applied without restrictions to the treatment method, if it
appears appropriate.
[0225] All said and further constituents or components are familiar
to the person skilled in the art and can experience a specific
embodiment for the teaching according to the invention in routine
experiments. All documents cited in the description are hereby
intended to be incorporated in their entirety into the disclosure
of the present invention as reference.
[0226] As part of the invention presented here, novel
arylquinazoline compounds of the formula (I) were provided for the
first time. The compounds according to the invention control
serine/threonine protein kinases, in particular DNA-PK,
affinitively and/or selectively. The compounds from formula (I) and
derivatives thereof are distinguished by high specificity and
stability, low preparation costs and easy handling. These
properties form the basis for a reproducible mode of action, and
reliable and safe interaction with the corresponding target
structures. The invention also includes the use of the present
arylquinazoline derivatives for the inhibition, regulation and/or
modulation of the signalling cascade of serine/threonine protein
kinases, in particular DNA-PK, and thus offers novel tools for
research and/or diagnostics.
[0227] Medicaments and pharmaceutical compositions which comprise
the said compounds and the use of these compounds for the treatment
of kinase-promoted disorders are, in addition, a highly promising
approach for a broad spectrum of therapies, enabling direct and
immediate alleviation of symptoms to be achieved in humans and
animals. This is particularly advantageous for effective combating
of severe diseases, such as cancer, either as monotherapy or in
combination with other antineoplastic therapies. The key
participation by DNA-PK in DNA repair processes and the evidence
that the DNA-PK inhibitors allows mammal cells to become more
radiation-sensitive enable therapeutic use of the DNA-PK-specific
inhibitors as part of the treatment of, for example, solid cancer
tumours by radiotherapy and/or chemotherapy aimed at DNA-DSBs.
[0228] The compounds of the formula (I), salts, isomers, tautomers,
enantiomers, diastereomers, racemates, derivatives, prodrugs and/or
metabolites thereof are effective not only in the case of the said
clinical disease pictures, but likewise in the diagnosis and
therapy of all diseases in connection with the DNA-PK signalling
cascade, in particular with respect to the inhibition of cell
proliferation and migration. In addition, the inhibitors according
to the invention can be used in the treatment of retroviral
diseases by suppression of retroviral integration (R. Daniel (1999)
Science 284: 644). Finally, the inhibitors according to the
invention can be employed as immunomodulators and modulators of
telomeric maintenance. The low-molecular-weight inhibitors are used
individually and/or in combination with other treatment measures,
such as, for example, surgical interventions, immunotherapy,
radiotherapy and/or chemotherapy. The latter relate to targeted
therapy with any desired NME (i.e. NCE and/or NBE) as monotherapy
and/or on-target/off-target combination therapy.
[0229] Owing to their surprisingly strong and/or selective
inhibition of enzymes which regulate cellular processes via the
repair of dsDNA, the compounds of the invention can be administered
in advantageously low dose, while they achieve a similar or even
superior biological efficacy compared with the less-potent or
less-selective inhibitors of the prior art. The reduced dose is
also accompanied by reduced or no medical side effects. In
addition, the highly selective inhibition by the compounds
according to the invention is also accompanied by a reduction in
undesired side effects, which is independent of the dose. In
particular, the compounds according to the invention have no
physiologically relevant inhibitions or blockades of the Kv 11.1
hERG potassium ion channel
[0230] It goes without saying that this invention is not restricted
to the specific compounds, pharmaceutical compositions, uses and
methods as described herein, since such things can be varied. It
furthermore goes without saying that the terminology used here
serves exclusively the purpose of description of particular
embodiments and is not intended to restrict the scope of protection
of the invention. As used here in the specification, including the
appended claims, word forms in the singular, such as, for example,
"a" or "the", include the equivalent in the plural, so long as the
context does not specifically indicate otherwise. For example, the
reference to "a compound" includes a single compound or a plurality
of compounds, which may in turn be identical or different, or the
reference to "a method" includes equivalent steps and methods which
are known to the person skilled in the art.
[0231] The invention is explained in greater detail below with
reference to non-limiting examples of specific embodiments. The
examples should, in particular, be interpreted as not being
restricted to the feature combinations specifically illustrated,
but instead the illustrative features can in turn be freely
combined so long as the object of the invention is achieved.
EXAMPLES
[0232] An overview of the working examples is given by Tables
1-7.
[0233] The following ranges apply to the biological data reproduced
therein:
DNA-PK (enzymatic):
A: IC.sub.50<3 nM
[0234] B: 3 nM.ltoreq.IC.sub.50<7 nM C: 7
nM.ltoreq.IC.sub.50<30 nM D: 30 nM.ltoreq.IC.sub.50 pDNA-PK
(cellular):
A: IC.sub.50<0.5 .mu.M
B: 0.5 .mu.M.ltoreq.IC.sub.50<5 .mu.M
C: 5 .mu.M.ltoreq.IC.sub.50<10 .mu.M
D: 10 .mu.M.ltoreq.IC.sub.50<30 .mu.M
[0235] Kv11.1 hERG:
A: K.sub.i>25 .mu.M
B: 25 .mu.M.gtoreq.K.sub.i>15 .mu.M
C: 15 .mu.M.gtoreq.K.sub.i>10 .mu.M
D: 10 .mu.M.gtoreq.K.sub.i
Analysis
[0236] NMR (.sup.1H) was carried out with the following
parameters.
Instruments: Bruker Avance DRX 500, Bruker Avance 400, Bruker DPX
300 Reference: TMS
[0237] TD (time domaine=number of data points or digital
resolution): 65536 Solvent: DMSO-d6 NS (number of scans=frequency
of scanning): 32 SF (spectrometer frequence=transmission
frequency): 400 or 500 MHz TE (temperature): 303 K, 363 K or 393 K
Coupling constants (J) are indicated in hertz (Hz) HPLC: high
performance chromatography with UV detector LC-MS: high performance
chromatography with UV and MS detector SFC: supercritical fluid
chromatography with UV detector
Identification of Synthesis Intermediates and Synthesis Final
Products by Means of LC-MS:
[0238] LC-MS method A:
[0239] Column: Chromolith SpeedROD RP-18e 50-4.6 mm, flow rate: 2.4
ml/min., wavelength: 220 nm, eluent A: water+0.05% by vol. of
formic acid, eluent B: acetonitrile+0.4% by vol. of formic acid,
gradient: 4% by vol.-100% by vol. of eluent B in 2.8 min, then 100%
of eluent B for a period of 0.5 min.
LC-MS method B:
[0240] Column: Chromolith SpeedROD RP-18e 50-4.6 mm, flow rate: 2.4
ml/min., wavelength: 220 nm, eluent A: water+0.1% by vol. of
trifluoroacetic acid, eluent B: acetonitrile+0.1% by vol. of
trifluoroacetic acid, gradient: 4% by vol.-100% by vol. of eluent B
in 2.8 min, then 100% by vol. of eluent B for a period of 0.5
min.
Separation of Stereoisomeric Mixtures by Means of HPLC and SFC:
[0241] HPLC: firstly, a column screening is carried out for each
stereoisomeric mixture, with the following columns: Chiralpak AD-H,
Chiralpak AS-H, Chiralpak IA, Chiralpak IB, Chiralpak IC, Chiralcel
OD-H, Chiralcel OJ-H, Lux Cellulose-2, Lux-Amylose-2, all columns:
250-4.6 mm.
[0242] The most suitable column is used for the further
measurements (for example determination of the enantiomeric ratio).
Flow rate: 0.8 ml/min, wavelength: variable, is adapted
corresponding to the extinction maximum and the eluents used.
Eluent: the following solvents or solvent mixtures are used for the
eluents: n-heptane, n-hexane, ethanol, methanol, 2-propanol,
acetonitrile, ethyl acetate, dichloromethane; the following can be
used as eluent additive: 0.01-0.5% by vol. of formic acid,
0.01-0.5% by vol. of diethylamine; gradients or isocratic
measurement conditions are used as required.
[0243] SFC: firstly, a column screening is carried out for each
stereoisomeric mixture, with the following columns: Chiralpak AD-H,
Chiralpak AS-H, Chiralpak IA, Chiralpak IB, Chiralpak IC, Chiralcel
OD-H, Chiralcel OJ-H, Lux Cellulose-2, Lux-Amylose-2, all columns:
250-4.6 mm. The most suitable column is used for the further
measurements (for example determination of the enantiomeric ratio).
Flow rate: 5 ml/min, wavelength: variable, is adapted corresponding
to the extinction maximum and the eluents used. Eluent: liquid
carbon dioxide (>70 bar), co-eluent: the following solvents or
solvent mixtures are used for the co-eluents: ethanol, methanol,
isopropanol, acetonitrile, ethyl acetate, dichloromethane. The
following can be used as eluent additive: 0.01-0.5% by vol. of
formic acid, 0.01-0.5% by vol. of diethylamine. Gradients or
isocratic measurement conditions are used as required.
Biological Testing
A) DNA-Pk Assay (Biochemical)
[0244] The kinase assay was carried out in streptavidin-coated
348-well microtitre flashplates. To this end, 1.5 .mu.g of
DNA-PK/protein complex and 100 ng of biotinylated substrate, such
as, for example, PESQEAFADLWKK-biotin-NH2 ("biotin-DNA-PK
peptide"), were incubated for 90 min at room temperature in a total
volume of 36.5 .mu.l (34.25 mM HEPES/KOH; 7.85 mM Tris HCl; 68.5 mM
KCl; 5 .mu.M ATP; 6.85 mM MgCl.sub.2; 0.5 mM EDTA; 0.14 mM EGTA;
0.69 mM DTT; pH 7.4) with 500 ng of DNA from calf thymus, 0.1
.mu.Ci of 33P-ATP and 1.8% of DMSO per well with and without the
test compound. The reaction was stopped using 50 .mu.l/well of 200
mM EDTA. After incubation for a further 30 min at room temperature,
the liquid was removed. Each well was washed three times with 100
.mu.l of 0.9% saline solution. A nonspecific reaction (blank value)
was determined using 10 .mu.M of an innate kinase inhibitor. The
radioactivity measurement was carried out using a TopCount.
IC.sub.50 values were calculated in RS1.
Literature: Kashishian et al. (2003) Molecular Cancer Therapeutics
1257.
B) DNA-Pk Phosphorylation at Serine 2056 (Cellular)
[0245] HCT116 cells were cultivated at 37.degree. C. and 10% CO2 in
MEM alpha medium with 10% of foetal calf serum and 2 mM glutamine.
The cells were detached from the base of the culture vessels with
the aid of trypsin/EDTA, centrifuged off in centrifuge tubes, taken
up in fresh medium, and the cell density was determined. 100,000
cells were sown in 1 ml of culture medium per cavity of a 24-well
cell culture plate and cultivated overnight. Next day, 10 .mu.M
bleomycin (DNA intercalator and inductor of DNA double-strand
breaks) and test substances in fresh culture medium were added to
the cells, and these were cultivated for a further six hours. Cell
lysis was subsequently carried out, and the cell lysates were added
to a blocked 96-well ELISA plate coated with DNA-PK-specific
antibodies (Sigma-Aldrich WH0005591M2: total DNA-PK; Abcam ab18192
or Epitomics EM09912: phospho-serine 2056 DNA-PK) and incubated at
4.degree. C. overnight. The 96-well ELISA plates were subsequently
treated with a detection antibody (Abcam ab79444: total DNA-PK) and
a streptavidin-HRP conjugate. The development of the enzymatic
reaction was carried out with the aid of a chemiluminescent
reagent, the chemiluminescence was measured with the aid of a
Mithras LB940. The signals with the phospho-DNA-PK-specific
antibody were standardised to the signal with the antibody against
the total protein DNA-PKc. The determination of IC50 values or of
percentage values was carried out by referencing to the signal
level of the bleomycin-treated vehicle controt group (100% of the
control). The DMSO control was used as blank.
C) Kv11.1 (hERG) Ion Channel Activity (Patch Clamp Assay)
[0246] Method for the detection and characterisation of test
substances which interfere with the Kv1 1.1 (hERG) channel: Kv11.1
(hERG, human ether a-go-go related gene) is a potassium channel
which plays a central role for repolarisation of the cells in the
ventricular cardiomyocytes.
[0247] The patch-clamp measurement was carried out at room
temperature in whole-cell configuration on human embryonic kidney
cells (HEK293) which have been transfected in a stable manner with
the hERG gene.
[0248] The whole-cell configurations were carried out using an
automated patch clamp device (Patchliner.TM., Nanion Technologies,
Munich). This is a glass chip-based system with which automated
whole-cell measurements on up to 8 cells simultaneously are
possible. The glass chip has a hole of defined size to which the
cell is transferred into the Gigaseal by application of a reduced
pressure and brought into the whole-cell configuration. Buffer,
cell suspension and test substances were added to microchannels of
the chip using a Teflon-coated pipette.
[0249] The cells were clamped to a holding potential of -80 mV. For
measurement of substance-promoted inhibition of the Kv11.1 channel,
the following voltage protocol was applied at 10-second intervals:
51 ms/-80 mV, 500 ms/+40 mV, 500 ms/-40 mV, 200 ms/-80 mV. The
leakage current is subtracted by means of the P4 method. The cells
were resuspended in extracellular buffer (EC) and applied to the
chip. After the cell had been collected, the seal was improved by
addition of a seal enhancer buffer. As soon as the whole-cell
configuration had been reached, the seal enhancer buffer was washed
out and replaced by extracellular buffer. The measurement started
in EC for 1.5 min. DMSO (vehicle control, 0.1% of DMSO) was then
applied, and the control current was recorded for 3 min. The test
substance was subsequently added twice in the same concentration,
and the potassium current was measured for 3.5 min in each
case.
[0250] If the measurement result of a test substance at an initial
concentration of 10 .mu.M was smaller than (-)50% effect (threshold
value) (for example (-)60% effect), the test substance was, in
order to determine a dose/action relationship, added cumulatively
in increasing concentration, where each concentration was measured
for 5 min.
[0251] The reference substance used was the Kv11.1 (hERG) ion
channel blocker quinidine. The effects of test substances and
quinidine were standardised to the associated vehicle control. The
effect on the Kv11.1 (hERG) channel activity was assessed from the
potassium current at -40 mV. For the calculation, the current was
evaluated for the respective final trace. A test-substance-induced
inhibition of the Kv11.1(hERG) channel was standardised to the
vehicle control (0.1% of DMSO).
[0252] During the measurement, an aliquot of the test substance was
taken for concentration determination. The sample was measured
immediately by HPLC, and the final concentration was determined
from a calibration curve.
[0253] If the measurement result of a test substance at an initial
concentration of 10 .mu.M is greater than or equal to (-)50% effect
(threshold value) (for example (-)30% effect, i.e. 30% inhibition
at 10 .mu.M), the K.sub.i is calculated in accordance with the
following formula: K.sub.i=1.0E-5.times.(100+% effect)/(-% effect),
[M].
[0254] The measurement result of (-)30% effect at a test substance
concentration of 10 .mu.M gives a K.sub.i of 23 .mu.M.
D) Kv11.1 Ion Channel Binding Assay
[0255] Kv11.1 (hERG=human ether a go-go related enzyme) is a
cardiac K.sup.+ channel which should if possible not interact with
the test substances. This interaction is determined quantitatively
with the aid of the Predictor.TM. hERG Fluorescence Polarizations
(FP) Assays from Life Technologies. In the case of this assay
principle, cardiomyocyte cell membranes having a certain proportion
of Kv11.1 channels are isolated. A dye-labelled Kv11.1 binding
partner gives a high fluorescence polarisation signal by
interaction with the Kv11.1. In the case of displacement of the
dye, a reduction in the fluorescence polarisation signal
occurs.
[0256] The assay is carried out automatically as follows: 15 nl of
the test substances (highest concentration: 10 mM, 10
concentrations: dilution factors 1:3.16, DMSO) are transferred into
an empty microtitre plates having 384 wells by means of an acoustic
pipetter. 3 .mu.l of the isolated membranes are subsequently added.
Membranes and test substances are incubated at 22.degree. C. for 15
min (+/-5 min). In the next step, the dye-labelled binding partner
is added, followed by incubation at 22.degree. C. After incubation
for two hours, the measurement of the fluorescence polarisation is
carried out on an Envision multimode Reader. Measured raw data are
standardised with the aid of Genedata Assay Analyzer. The IC50 and
% effect values are calculated in Genedata Condoseo.
[0257] Chemical Synthesis
[0258] Above and below, all temperatures are indicated in .degree.
C.
[0259] The stereochemical configuration assignments of enantiomeric
Examples 27, 72, 82, 83, 135, 136, 185, 234, 251, 455 and 456 were
confirmed by X-ray structural analyses. For Examples 234 and 251,
the identification was carried out by crystallisation and X-ray
structural analysis of a precursor.
[0260] The other compounds denoted as chiral in the tables
(asterisk on the asymmetrical C atom) were obtained by
chromatography on a chiral solid phase. The enantiomer eluted first
under the respective conditions was given the name "Ena1", the
enantiomer eluted second was given the name "Ena2".
Examples 1 and 2
(3,5-Difluoropyridin-4-yl)-[4-fluoro-3-(7-morpholin-4-ylquinazolin-4-yl)ph-
enyl]methanol (1)
(4-Chloro-5-fluoropyridin-3-yl)-[4-fluoro-3-(7-morpholin-4-ylquinazolin-4-
-yl)phenyl]methanol (2)
##STR00012##
[0262] (3-Bromo-4-fluorophenyl)acetonitrile (4.00 g, 18.32 mmol),
bis(pinacolato)diboron (5.22 g, 20.15 mmol), potassium acetate
(55.86 mmol) and bis(triphenylphosphine)palladium(II) chloride
(15.2% of Pd) (393.53 mg, 0.55 mmol) were dissolved in oxygen-free
1,4-dioxane (40 ml, max. 0.005% of water) under argon. The reaction
mixture was subsequently heated at a temperature of 130.degree. C.
for 90 min. When the reaction conversion was complete, the mixture
was filtered through kieselguhr. The filtrate was diluted with
dichloromethane (200 ml) and water (50 ml) and extracted. The
organic phase was dried over sodium sulfate, subsequently filtered
and evaporated to dryness in vacuo, giving
[4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetonitr-
ile as oil (7.59 g, purity 81%, MS: 262.2 [M+H.sup.+]), which was
reacted further without further work-up.
##STR00013##
[0263]
4-Fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acet-
onitrile (7.60 g, 23.53 mmol), 1,4-dioxane (85.6 ml, max. 0.005% of
water), 4-chloro-7-morpholin-4-ylquinazoline (5.00 g, 20.02 mmol),
bis(tricyclohexylphosphine)palladium(II) dichloride (597.24 mg,
0.80 mmol) and sodium carbonate solution (2.0 M, 30 ml, 60.07 mmol)
were initially introduced in a three-necked flask. The suspension
obtained was heated at a temperature of 140.degree. C. under a
nitrogen atmosphere with stirring for a period of 2.5 h. When the
reaction was complete, the mixture was cooled to room temperature
and filtered through kieselguhr. The filtrate was diluted with
ethyl acetate (250 ml) and water (100 ml) and extracted. The
aqueous phase was rinsed twice with ethyl acetate (75 ml in each
case). The combined organic phases were dried over sodium sulfate,
subsequently filtered and evaporated to dryness in vacuo. For
further work-up, the residue was suspended in methyl tertbutyl
ether, filtered off and rinsed twice with further methyl tert-butyl
ether (30 ml in each case). The filter cake was dried overnight in
vacuo, giving
[4-fluoro-3-(7-morpholin-4-ylquinazolin-4-yl)phenyl]acetonitrile
(4.91 g, 13.49 mmol, MS: 349.1 [M+H.sup.+], 67% yield) as yellow
solid.
##STR00014##
[0264]
[4-Fluoro-3-(7-morpholin-4-ylquinazolin-4-yl)phenyl]acetonitrile
(400 mg, 1.12 mmol), 4-chloro-3,5-difluoropyridine (189.9 mg, 1.23
mmol) were dissolved in oxygen-free, degassed tetrahydrofuran (8
ml, max. 0.0075% of water) under a dry argon atmosphere. Potassium
tert-butoxide (263.9 mg, 2.35 mmol) was subsequently added to the
reaction mixture, during which a dark-red solution formed, which
was stirred at room temperature for a further 30 min. When the
reaction was complete, the mixture was diluted with saturated
ammonium chloride solution (20 ml) and water (50 ml). The aqueous
phase was subsequently extracted twice with dichloromethane (60 ml
in each case). The organic phase was dried over sodium sulfate,
filtered off and evaporated to dryness in vacuo in a rotary
evaporator. The residue was purified by flash column chromatography
(gradient: dichloromethane/0-4% by vol. of ethanol), giving a
mixture (420 mg, about 5:3) of the oils
(3,5-difluoropyridin-4-yl)-[4-fluoro-3-(7-morpholin-4-ylquinazolin-4-yl)p-
henyl]acetonitrile (263 mg, 0.57 mmol, MS: 462.1 [M+H.sup.+], 50%
yield) and
(4-chloro-5-fluoropyridin-3-yl)-[4-fluoro-3-(7-morpholin-4-ylquinazol-
in-4-yl)phenyl]acetonitrile (157 mg, 0.33 mmol, MS: 478.1/480.1
[M+H.sup.+], 29% yield).
##STR00015##
[0265] The mixture (420 mg, about 5:3) of
(3,5-difluoropyridin-4-yl)-[4-fluoro-3-(7-morpholin-4-ylquinazolin-4-yl)p-
henyl]acetonitrile and
(4-chloro-5-fluoropyridin-3-yl)-[4-fluoro-3-(7-morpholin-4-ylquinazolin-4-
-yl)phenyl]acetonitrile was dissolved in acetonitrile (12.7 ml).
Potassium tertbutoxide (80.90 mg, 0.72 mmol) was added to the
reaction solution with stirring, during which a dark-red solution
formed. After stirring for 15 min, the mixture was cooled to
0.degree. C., and 30% hydrogen peroxide solution (276 .mu.l, 2.70
mmol) was subsequently added dropwise. The cooling bath was removed
after stirring for 5 min at 0.degree.. The reaction solution was
stirred at room temperature for a further 1 h. When the reaction
conversion was complete, 10% sodium thiosulfate solution (5 ml) was
added, and the mixture was diluted with water (25 ml). The aqueous
solution was extracted twice with dichloromethane (50 ml in each
case). The combined organic phases were dried over sodium sulfate,
filtered off and evaporated to dryness in vacuo. The residue was
purified by flash column chromatography (gradient:
dichloromethane/0-4% by vol. of ethanol), giving a mixture (310 mg,
about 3:1) of the oils
(3,5-difluoropyridin-4-yl)-[4-fluoro-3-(7-morpholin-4-ylquinazolin-4-yl)p-
henyl]methanone (233 mg, 0.50 mmol, MS: 451.1 [M+H.sup.+]) and
(4-chloro-5-fluoropyridin-3-yl)-[4-fluoro-3-(7-morpholin-4-ylquinazolin-4-
-yl)phenyl]methanone (77 mg, 0.16 mmol, MS: 467.1/469.1
[M+H.sup.+]).
##STR00016##
[0266] The mixture (310 mg, about 3:1) of
(3,5-difluoropyridin-4-yl)-[4-fluoro-3-(7-morpholin-4-ylquinazolin-4-yl)p-
henyl]methanone and
(4-chloro-5-fluoropyridin-3-yl)-[4-fluoro-3-(7-morpholin-4-ylquinazolin-4-
-yl)phenyl]methanone was dissolved in methanol (15 ml). Sodium
borohydride (30.4 mg, 0.80 mmol) was subsequently added (evolution
of gas). The reaction solution was stirred at room temperature for
45 min. When the reaction was complete, the mixture was diluted
with saturated ammonium chloride solution (5 ml) and water (15 ml).
The aqueous phase was subsequently extracted three times with
dichloromethane (20 ml in each case). The combined organic phases
were dried over sodium sulfate, filtered off and evaporated to
dryness in vacuo in a rotary evaporator. The residue was dissolved
in dimethyl sulfoxide (4.8 ml) and purified by chromatography by
means of preparative HPLC (gradient: water/1-50% by vol. of
acetonitrile over 21 min, flow rate 50 ml/min). The product
fractions were combined, diluted with saturated sodium
hydrogencarbonate solution (5 ml in each case) and extracted twice
with dichloromethane (40 ml in each case). The organic phases were
evaporated in vacuo, the residues were subsequently taken up in
1,4-dioxane (5 ml) and water (30 ml) and freeze-dried, giving pure
(3,5-difluoropyridin-4-yl)-[4-fluoro-3-(7-morpholin-4-ylquinazolin-4-yl)p-
henyl]methanol (EXAMPLE 1, 42.50 mg, 0.09 mmol, MS: 453.1
[M+H.sup.+]) and
(4-chloro-5-fluoropyridin-3-yl)-[4-fluoro-3-(7-morpholin-4-ylquinazolin-4-
-yl)phenyl]methanol (EXAMPLE 2, 28.40 mg, 0.06 mmol, MS:
469.1/471.1 [M+H.sup.+]) as solids.
Example 37
(3-Chloropyrazin-2-yl)-[4-fluoro-3-(6-morpholin-4-ylthieno[3,2-d}pyrimidin-
-4-yl)phenyl]-methanol (37)
##STR00017##
[0268] Sodium hydride (60% suspension in paraffin oil, 1.41 g, 35.0
mmol) was suspended in dry tetrahydrofuran (25 ml) under argon in a
glass vessel. 4-Methoxyphenylmethanol (4.21 g, 30.0 mmol),
dissolved in dry tetrahydrofuran (5 ml), was subsequently slowly
added dropwise with stirring, and the mixture was stirred at room
temperature for 1 h. A suspension of
4-chlorothieno[3,2-d}pyrimidine (4.00 g, 23.4 mmol) in dry
tetrahydrofuran (20 ml) was then added slowly, and the mixture was
stirred for a further hour. When the reaction conversion was
complete, methanol (15 ml) was carefully added, the mixture was
subsequently evaporated in vacuo and diluted with a mixture of
water (100 ml) and ethyl acetate (150 ml). The aqueous phase was
extracted three times with ethyl acetate (100 ml in each case),
dried over sodium sulfate, filtered off with suction, and the
filtrate was evaporated in vacuo. The solvent-free residue was
taken up in ethanol (40 ml) and carefully stirred at about
5.degree. C. for 16 h. The crystals which precipitated out
overnight were filtered off with suction, rinsed with a little cold
ethanol and dried at room temperature, giving
4-(4-methoxybenzyloxy)thieno-[3,2-d}pyrimidine (4.15 g, 15.24 mmol,
MS: 273.0 [M+H.sup.+]), 65% yield) as crystalline solid.
##STR00018##
[0269] 4-(4-Methoxybenzyloxy)thieno[3,2-d}pyrimidine (2.60 g, 9.55
mmol) was dissolved in dry tetrahydrofuran (35 ml) and cooled to
(-55.degree. C. A freshly prepared lithium diisopropylamide
solution (21 mmol, prepared from diisopropylamine [2.13 g, 21 mmol]
and n-BuLi [15% solution from n-hexane, 13.13 ml, 21 mmol in dry
tetrahydrofuran [35 ml] at [-]10.degree. C.) was added dropwise at
(-)55.degree. C. over 10 min. The suspension obtained was stirred
further. 1,2-dibromoethane (10.76 g, 6.0 mmol) was subsequently
added. After a further 10 min, the mixture was warmed to
(-)20.degree. C. and stirred for 1 h. With the reaction complete,
the reaction solution was added to a 50% aqueous sodium
hydrogencarbonate/sodium thiosulfate solution (volume ratio 1:1,
120 ml). The aqueous phase was extracted three times with ethyl
acetate. The combined organic phases were washed with saturated
sodium chloride solution, subsequently dried over sodium sulfate,
filtered and evaporated to dryness in a rotary evaporator. The
residue was purified by means of flash column chromatography
(gradient cyclohexane/0-18% by vol. of ethyl acetate, CombiFlash Rf
200, 80 g silica column, flow rate=50 ml/min., .lamda..dbd.220 nm),
giving 6-bromo-4-(4-methoxybenzyloxy)thieno[3,2-d}pyrimidine (1.39
g, 3.95 mmol, MS: 351.0/353.0 [M+H.sup.+]), 41% yield) as
solid.
##STR00019##
[0270] 6-Bromo-4-(4-methoxybenzyloxy)thieno[3,2-d}pyrimidine (1.38
g, 3.93 mmol), morpholine (1.03 g, 11.79 mmol), sodium
tert-butoxide (1.13 g, 11.79 mmol),
(S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphtyl (S-BINAP, 122.3
mg, 0.196 mmol) and tris(dibenzylideneacetone)dipalladium (179.9
mg, 0.196 mmol) was dissolved in toluene (20 ml) under nitrogen in
a microwave vessel. The reaction solution was heated at 95.degree.
C. for 4 h. The mixture was subsequently diluted with water (60 ml)
and dichloromethane (60 ml). The aqueous phase was extracted three
times with dichloromethane. The combined organic phases were dried
over sodium sulfate and evaporated in a rotary evaporator. The
residue was purified by means of flash chromatography (gradient
dichloromethane/5-25% by vol. of [dichloromethane/ethanol 9:1],
CombiFlash Rf 200, 80 g silica column, .lamda.=220 nm). The
suitable product fractions were combined, and the solvents were
removed in a rotary evaporator, giving
4-(4-methoxybenzyloxy)-6-morpholin-4-ylthieno[3,2-d}pyrimidine
(756.0 mg, 2.12 mmol, MS: 358.2 [M+H.sup.+]) 54% yield) as
solid.
##STR00020##
[0271]
4-(4-Methoxybenzyloxy)-6-morpholin-4-ylthieno[3,2-d}pyrimidine (923
mg, 2.58 mmol) was dissolved in tetrahydrofuran (5 ml) and methanol
(5 ml). Pd/C (5%, 1.9 g) was added in portions (at the beginning of
the reaction, after a further 7 h and 24 h), and the mixture was
hydrogenated at a maximum hydrogen pressure of 5 bar (H.sub.2,
purity 3.0, 57.9 g) for 36 h. The solution obtained was filtered
through kieselguhr and evaporated in a rotary evaporator. The
residue was purified by means of flash column chromatography
(gradient: dichloromethane/10-20% by vol. of [methanol/ammonia
10:1], CombiFlash Rf 200, 24 g silica column, .lamda.=220 nm). The
suitable product fractions were combined, and the solvents were
removed in a rotary evaporator, giving
6-morpholin-4-yl-3H-thieno[3,2-d}pyrimidin-4-one (361.0 mg, 1.521
mmol, MS: 238.0 [M+H.sup.+], 59% yield) as solid.
##STR00021##
[0272] 6-Morpholin-4-yl-3H-thieno[3,2-d}pyrimidin-4-one (206 mg,
0.87 mmol) was suspended in phosphoryl chloride (1.67 g, 10.89
mmol). N-Ethyldiisopropylamine (56.1 mg, 0.43 mmol) was
subsequently added to the suspension. The reaction mixture was
stirred overnight at room temperature. For work-up, a mixture of
saturated sodium hydrogencarbonate solution (30 ml) and
dichloromethane (20 ml) was added. The resultant solution was
extracted three times with dichloromethane. The combined organic
phases were dried over sodium sulfate, filtered and evaporated to
dryness in vacuo, giving
4-chloro-6-morpholin-4-ylthieno[3,2-d}-pyrimidine (127 mg, 0.497
mmol, MS: 256.0/258.0 [M+H.sup.+], 57% yield) as solid.
##STR00022##
[0273] Starting from
4-chloro-6-morpholin-4-ylthieno[3,2-d}pyrimidine,
(3-chloropyrazin-2-yl)-[4-fluoro-3-(6-morpholin-4-ylthieno[3,2-d}pyrimidi-
n-4-yl)phenyl]methanol (EXAMPLE 37) was prepared analogously to the
synthesis sequence described for Examples 1 and 2.
[0274] Compounds which were prepared in accordance with Examples 1,
2 and 37 can be found in Table 1 below.
TABLE-US-00001 TABLE 1 Compounds of the formula (I) IC.sub.50
IC.sub.50 K.sub.i DNA- pDNA- [Kv1.11 Example Structural formula
Name PK PK hERG] 1 ##STR00023## (3,5-Difluoro-pyridin-4-
yl)-[4-fluoro-3-(7- morpholin-4-yl- quinazolin-4-yl)phenyl]-
methanol B B B MS: 453.1 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6)
ppm = 9.10 (s, 1H), 8.50 (s, 2H), 7.65-7.60 (m, 2H), 7.55-7.48 (m,
2H), 7.45-7.40 (m, 1H), 7.20 (d, J = 2.1, 1H), 6.62 (d, J = 4.6,
1H), 6.23 (d, J = 4.6, 1H), 3.80-3.75 (m, 4H), 3.47-3.42 (m, 4H) 2
##STR00024## (4-Chloro-5-fluoro- pyridin-3-yl)-[4-fluoro-3-
(7-morpholin-4-yl- quinazolin-4-yl)phenyl]- methanol B A C MS:
469.1/471.1 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.10 (s,
1H), (Cl isotopy, rel. peak 8.70 (s, 1H), 8.66 (s, 1H), 7.64-7.59
(m, 2H), 7.55- intensity ratio [%] 100:37) 7.48 (m, 2H), 7.44-7.39
(m, 1H), 7.20 (d, J = 2.2, 1H), 6.56 (d, J = 4.4, 1H), 6.12 (d, J =
4.5, 1H), 3.81- 3.74 (m, 4H), 3.47-3.40 (m, 4H) 3 ##STR00025##
[2-Chloro-4-fluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)phenyl]-
(4-methoxy-pyridazin-3- yl)methanol B B A MS: 504.1/506.1 (M +
Na.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.13 (s, 1H), (Cl
isotopy, rel. peak 8.96 (d, J = 6.0, 1H), 8.04-8.01 (m, 1H), 7.65-
intensity ratio [%] 100:35) 7.60 (m, 2H), 7.56 (dd, J = 9.4, 2.5,
1H), 7.32 (d, J = 6.0, 1H), 7.22 (d, J = 2.5, 1H), 6.46 (d, J =
6.2, 1H), 6.39 (d, J = 6.3, 1H), 3.96 (s, 3H), 3.81-3.75 (m, 4H),
3.50-3.43 (m, 4H) 4 ##STR00026## [2-Chloro-4-fluoro-5-(7-
morpholin-4-yl- quinazolin-4-yl)phenyl]- (5-methoxy-pyridazin-3-
yl)methanol A A A MS: 482.1/484.1 (M + H.sup.+) 1H NMR (500 MHz,
DMSO-d6) ppm = 9.07 (s, 1H), (Cl isotopy, rel. peak 8.88 (d, J =
4.7, 1H), 7.71 (d, J = 9.5, 1H), 7.59 (dd, intensity ratio [%]
100:34) J = 4.7, 0.9, 1H), 7.54 (d, J = 7.6, 1H), 7.52-7.50 (m,
2H), 7.21-7.17 (m, 1H), 6.46 (d, J = 5.1, 1H), 6.15 (d, J = 5.2,
1H), 4.01 (s, 3H), 3.81-3.74 (m, 4H), 3.48-3.41 (m, 4H) 5
##STR00027## 3-{[4-Fluoro-3-(7- morpholin-4-yl-
quinazolin-4-yl)phenyl]- hydroxymethyl}-1H- pyrazin-2-one D D B MS:
434.2 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.09 (s, 1H),
7.69-7.59 (m, 2H), 7.56-7.50 (m, 2H), 7.39- 7.28 (m, 3H), 7.20 (d,
J = 2.1, 1H), 6.00 (s, 1H), 5.87-5.75 (m, 1H), 3.81-3.74 (m, 4H),
3.44 (t, J = 5.0, 4H) 6 ##STR00028## [2-Chloro-4-fluoro-5-(7-
morpholin-4-yl- quinazolin-4-yl)phenyl]- (6-chloro-5-methoxy-
pyridazin-3-yl)methanol A A C MS: 516.1/518.1/520.1 1H NMR (500
MHz, DMSO-d6) ppm = 9.07 (s, 1H), (M + H.sup.+) (Cl.sub.2 isotopy,
rel. 7.75 (d, J = 1.0, 1H), 7.72 (d, J = 9.5, 1H), 7.56 (d, peak
intensity ratio [%] J = 7.6, 1H), 7.51 (dd, J = 9.5, 2.5, 1H), 7.47
(dd, 100:71:14) J = 9.4, 2.9, 1H), 7.19 (d, J = 2.4, 1H), 6.59 (d,
J = 5.0, 1H), 6.13-6.10 (m, 1H), 3.98 (s, 3H), 3.80-3.74 (m, 4H),
3.48-3.41 (m, 4H) 7 ##STR00029## (3-Chloro-6-methoxy-
pyridazin-4-yl)-[4-fluoro- 3-(7-morpholin-4-yl-
quinazolin-4-yl)phenyl]- methanol B A B MS: 482.1/484.1 (M +
H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.09 (s, 1H), (Cl isotopy,
rel. peak 7.62-7.57 (m, 2H), 7.55-7.47 (m, 3H), 7.43- intensity
ratio [%] 100:39) 7.39 (m, 1H), 7.20 (d, J = 2.4, 1H), 6.58 (d, J =
4.5, 1H), 5.88 (d, J = 4.4, 1H), 4.04 (s, 3H), 3.80-3.75 (m, 4H),
3.46-3.42 (m, 4H) 8 ##STR00030## [2-Chloro-4-fluoro-5-(7-
morpholin-4-yl- quinazolin-4-yl)phenyl]- (6-chloro-4-methoxy-
pyridazin-3-yl)methanol C B C MS: 516.1/518.1/520.1 1H NMR (500
MHz, DMSO-d6) ppm = 9.13 (s, 1H), (M + H.sup.+) (Cl.sub.2 isotopy,
rel. 8.01-7.99 (m, 1H), 7.65-7.59 (m, 3H), 7.56 (dd, peak intensity
ratio [%] J = 9.5, 2.5, 1H), 7.22 (d, J = 2.5, 1H), 6.52 (d, J =
6.2, 100:72:16) 1H), 6.39 (d, J = 6.2, 1H), 4.02 (s, 3H), 3.80-3.76
(m, 4H), 3.48-3.44 (m, 4H) 9 ##STR00031## (6-Chloro-5-methoxy-
pyridazin-3-yl)-[4-fluoro- 3-(7-morpholin-4-yl-
quinazolin-4-yl)phenyl]- methanol B A D MS: 482.1/484.1 (M +
H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.10 (s, 1H), (Cl isotopy,
rel. peak 7.88 (d, J = 1.0, 1H), 7.63-7.58 (m, 2H), 7.55- intensity
ratio [%] 100:38) 7.47 (m, 2H), 7.42-7.35 (m, 1H), 7.20 (d, J =
2.3, 1H), 6.46 (d, J = 4.3, 1H), 5.85-5.82 (m, 1H), 4.00 (s, 3H),
3.81-3.74 (m, 4H), 3.48-3.41 (m, 4H) 10 ##STR00032##
(6-Chloro-4-methoxy- pyridazin-3-yl)-[4-fluoro-
3-(7-morpholin-4-yl- quinazolin-4-yl)phenyl]- methanol B A A MS:
482.1/484.1 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.09 (s,
1H), (Cl isotopy, rel. peak 7.64-7.60 (m, 2H), 7.53-7.51 (m, 3H),
7.40- intensity ratio [%] 100:38) 7.35 (m, 1H), 7.21-7.19 (m, 1H),
6.29 (d, J = 5.3, 1H), 6.18 (d, J = 4.3, 1H), 3.93 (s, 3H),
3.80-3.75 (m, 4H), 3.46-3.42 (m, 4H) 11 ##STR00033##
[4-Fluoro-3-(7- morpholin-4-yl- quinazolin-4-yl)phenyl]-
(5-methoxy-pyridazin-3- yl)methanol (Ena 1) B A C MS: 448.2 (M +
H.sup.+); R.sub.t see racemate 6.1 min (SFC, Chiracel OJ- H,
CO.sub.2/15% by vol. of methanol, 0.5% by vol. of diethylamine) 12
##STR00034## [4-Fluoro-3-(7- morpholin-4-yl-
quinazolin-4-yl)phenyl]- (5-methoxy-pyridazin-3- yl)methanol (Ena
2) A B B MS: 448.2 (M + H.sup.+); R.sub.t see racemate 8.72 min
(SFC, Chiracel OJ-H, CO.sub.2/15% by vol. of methanol, 0.5% by vol.
of diethylamine) 13 ##STR00035## (3-tert-Butoxy-pyrazin-
2-yl)-[4-fluoro-3-(7- morpholin-4-yl- quinazolin-4-yl)phenyl]-
methanol D D C MS: 490.2 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6)
ppm = 9.09 (s, 1H), 8.14 (d, J = 2.7, 1H), 8.08 (d, J = 2.7, 1H),
7.63- 7.56 (m, 2H), 7.54-7.47 (m, 2H), 7.40-7.35 (m, 1H), 7.21-7.18
(m, 1H), 5.97 (d, J = 6.0, 1H), 5.91 (d, J = 6.1, 1H), 3.81-3.75
(m, 4H), 3.47-3.41 (m, 4H), 1.47 (s, 9H) 14 ##STR00036##
[4-Fluoro-3-(7- morpholin-4-yl- quinazolin-4-yl)phenyl]-
(3-pyrrolidin-1-yl- pyrazin-2-yl)methanol B B A MS: 487.2 (M +
H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.09 (s, 1H), 7.99 (d, J =
2.4, 1H), 7.80 (d, J = 2.5, 1H), 7.58- 7.52 (m, 4H), 7.38-7.32 (m,
1H), 7.21-7.17 (m, 1H), 6.18-6.13 (m, 1H), 6.09-6.01 (m, 1H), 3.78
(t, J = 4.9, 4H), 3.68-3.56 (m, 4H), 3.44 (t, J = 4.9, 4H),
1.96-1.81 (m, 4H) 15 ##STR00037## [4-Fluoro-3-(7- morpholin-4-yl-
quinazolin-4-yl)phenyl]- (3-methoxy-pyrazin-2- yl)methanol (Ena 2)
A A B MS: 448.2 (M + H.sup.+); R.sub.t see racemate 19.73 min,
(HPLC, Chiracel OJ-H, methanol) 16 ##STR00038## [4-Fluoro-3-(7-
morpholin-4-yl- quinazolin-4-yl)phenyl]- (3-methoxy-pyrazin-2-
yl)methanol (Ena 1) C B A MS: 448.2 (M + H.sup.+); R.sub.t see
racemate 7.55 min, (HPLC, Chiracel OJ-H, methanol) 17 ##STR00039##
(3,5-Dichloro-pyridin-4- yl)-[4-Fluoro-3-(7- morpholin-4-yl-
quinazolin-4-yl)phenyl]- methanol B B C MS: 485.1/487.1/489.1 1H
NMR (500 MHz, DMSO-d6) ppm = 9.09 (s, 1H), (M + H.sup.+) (Cl.sub.2
isotopy, rel. 8.62 (s, 2H), 7.58-7.48 (m, 4H), 7.43-7.37 (m, peak
intensity ratio [%] 1H), 7.19 (d, J = 2.2, 1H), 6.70-6.65 (m, 1H),
6.52 100:64:11) (d, J = 4.7, 1H), 3.81-3.74 (m, 4H), 3.48-3.40 (m,
4H) 18 ##STR00040## [4-Fluoro-3-(7- morpholin-4-yl-
quinazolin-4-yl)phenyl]- (4-methoxy-pyridazin-3- yl)methanol A B B
MS: 448.1 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.11-9.08
(m, 1H), 8.99-8.95 (m, 1H), 7.65-7.59 (m, 2H), 7.55-7.50 (m, 2H),
7.40-7.34 (m, 1H), 7.27 (d, J = 5.9, 1H), 7.22-7.18 (m, 1H),
6.24-6.18 (m, 2H), 3.88 (s, 3H), 3.81-3.74 (m, 4H), 3.48-3.40 (m,
4H) 19 ##STR00041## [4-Fluoro-3-(7- morpholin-4-yl-
quinazolin-4-yl)phenyl]- (5-methoxy-pyridazin-3- yl)methanol A A A
MS: 448.2 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.11-9.08
(m, 1H), 8.94-8.90 (m, 1H), 7.80-7.77 (m, 1H), 7.59-7.55 (m, 2H),
7.51 (qd, J = 9.4, 2.5, 2H), 7.41- 7.35 (m, 1H), 7.20 (d, J = 2.3,
1H), 6.34-6.31 (m, 1H), 5.87 (d, J = 4.2, 1H), 4.01 (s, 3H),
3.82-3.74 (m, 4H), 3.48-3.40 (m, 4H) 20 ##STR00042##
[2,4-Difluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)phenyl]-
imidazo[1,2-b]pyridazin- 6-ylmethanol (Ena 2) C C A MS: 475.2 (M +
H.sup.+); R.sub.t see racemate 15.12 min (HPLC, Chiralpak AD-H,
n-heptane/2-propanol, 1:9 vol./vol.) 21 ##STR00043##
[2,4-Difluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)phenyl]-
imidazo[1,2-b]pyridazin- 6-ylmethanol (Ena 1) A A A MS: 475.2 (M +
H.sup.+); R.sub.t see racemate 8.05 min (HPLC, Chiralpak AD-H,
n-heptane/2-propanol, 1:9 vol./vol.) 22 ##STR00044##
(2-Chloro-5-methoxy- pyridin-3-yl)-[4-fluoro-3- (7-morpholin-4-yl-
quinazolin-4-yl)phenyl]- methanol A A D MS: 481.2/483.2 (M +
H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.09 (s, 1H), (Cl isotopy,
rel. peak 8.28 (d, J = 2.6, 1H), 7.62-7.55 (m, 3H), 7.55- intensity
ratio [%] 100:30) 7.49 (m, 2H), 7.41-7.32 (m, 1H), 7.21-7.18 (m,
1H), 6.16 (d, J = 6.1, 1H), 6.03 (d, J = 6.1, 1H), 3.85 (s, 3H),
3.80-3.75 (m, 4H), 3.47-3.42 (m, 4H) 23 ##STR00045##
(3-Chloro-pyrazin-2-yl)- [4-fluoro-3-(6- morpholin-4-yl-thieno-
[3,2-d}pyrimidin-4-yl)- phenyl]methanol (Ena 1) C C A MS:
458.1/460.1 (M + H.sup.+) identical to enantiomer (24) (Cl isotopy,
rel. peak intensity ratio [%] 100:41); R.sub.t 4.96 min (SFC,
Chiracel OD-H, CO.sub.2/30% by vol. methanol)
24 ##STR00046## (3-Chloro-pyrazin-2-yl)- [4-fluoro-3-(6-
morpholin-4-yl-thieno- [3,2-d}pyrimidin-4-yl)- phenyl]methanol (Ena
2) A A B MS: 458.1/460.1 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6)
ppm = 8.88 (s, 1H), (Cl isotopy, rel. peak 8.68 (d, J = 2.4, 1H),
8.47 (d, J = 2.4, 1H), 7.73 (dd, intensity ratio [%] 100:40); J =
7.0, 2.3, 1H), 7.66-7.61 (m, 1H), 7.39 (dd, R.sub.t 7.13 min (SFC,
Chiracel J = 10.3, 8.6, 1H), 6.52 (s, 1H), 6.39 (d, J = 5.7, 1H),
OD-H, CO.sub.2/30% by vol. 6.21 (d, J = 5.7, 1H), 3.78-3.71 (m,
4H), 3.44- methanol) 3.37 (m, 4H). 25 ##STR00047##
(6-Chloro-3-methoxy- pyrazin-2-yl)-[4-fluoro- 3-(7-morpholin-4-yl-
quinazolin-4-yl)phenyl]- methanol B A D MS: 482.1/484.1 (M +
H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.11 (s, 1H), (Cl isotopy,
rel. peak 8.30 (s, 1H), 7.65-7.60 (m, 2H), 7.57-7.51 (m, intensity
ratio [%] 100:36) 2H), 7.43-7.36 (m, 1H), 7.22-7.19 (m, 1H), 6.18
(s, 1H), 6.06-6.02 (m, 1H), 3.94 (s, 3H), 3.81- 3.75 (m, 4H),
3.47-3.43 (m, 4H) 26 ##STR00048## (3-Chloro-6-methoxy-
pyrazin-2-yl)-[4-fluoro- 3-(7-morpholin-4-yl-
quinazolin-4-yl)phenyl]- methanol A A A MS: 482.1/484.1 (M +
H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.10 (s, 1H), (Cl isotopy,
rel. peak 8.11 (s, 1H), 7.73-7.68 (m, 2H), 7.54-7.50 (m, intensity
ratio [%] 100:35) 2H), 7.44-7.38 (m, 1H), 7.21-7.19 (m, 1H), 6.31
(d, J = 5.7, 1H), 6.11 (d, J = 5.8, 1H, 3.89 (s, 3H), 3.80-3.75 (m,
4H), 3.47-3.41 (m, 4H) 27 ##STR00049## (R)-(3-Chloro-pyrazin-2-
yl)-[4-fluoro-3-(7- morpholin-4-yl- quinazolin-4-yl)phenyl]-
methanol A A A MS: 452.1/454.1 (M + H.sup.+) see racemate (Cl
isotopy, rel. peak intensity ratio [%] 100:40); R.sub.t 67.12 min,
(HPLC, ChiralPak AD-H, ethanol) 28 ##STR00050##
(S)-(3-Chloro-pyrazin-2- yl)-[4-fluoro-3-(7- morpholin-4-yl-
quinazolin-4-yl)phenyl]- methanol C C B MS: 452.1/454.1 (M +
H.sup.+) see racemate (Cl isotopy, rel. peak intensity ratio [%]
100:40); R.sub.t 37.09 min, (HPLC, ChiralPak AD-H, ethanol) 29
##STR00051## [2-Chloro-4-fluoro-5-(7- morpholin-4-yl-
quinazolin-4-yl)phenyl]- pyridazin-3-ylmethanol (Ena 2) C D B MS:
452.1/454.0 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.14 (dd,
(Cl isotopy, rel. peak J = 4.9, 1.7, 1H), 9.11 (s, 1H), 7.88 (d, J
= 7.7, 1H), intensity ratio [%] 100:35); 7.80 (dd, J = 8.6, 1.7,
1H), 7.72-7.66 (m, 2H), 7.58 R.sub.t 5.61 min (SFC, (dd, J = 9.4,
3.3, 1H), 7.53 (dd, J = 9.5, 2.5, 1H), 7.21 ChiralPak IA,
CO.sub.2/40% (d, J = 2.4, 1H), 6.71 (d, J = 5.0, 1H), 6.32 (d, J =
4.9, by vol. of 2-propanol, 1H), 3.80-3.75 (m, 4H), 3.47-3.43 (m,
4H) 0.5% by vol. of diethylamine) 30 ##STR00052##
[2-Chloro-4-fluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)phenyl]-
pyridazin-3-ylmethanol (Ena 1) A A B MS: 474.1/476.1 (M + Na.sup.+)
1H NMR (500 MHz, DMSO-d6) ppm = 9.14 (dd, (Cl isotopy, rel. peak J
= 4.9, 1.7, 1H), 9.11 (s, 1H), 7.88 (d, J = 7.7, 1H), intensity
ratio [%] 100:34); 7.80 (dd, J = 8.6, 1.7, 1H), 7.73-7.66 (m, 2H),
7.58 R.sub.t 2.87 min (SFC, (dd, J = 9.4, 3.3, 1H), 7.53 (dd, J =
9.5, 2.5, 1H), 7.21 ChiralPak IA, CO.sub.2/40% (d, J = 2.4, 1H),
6.71 (d, J = 5.0, 1H), 6.32 (d, J = 4.9, by vol. of 2-propanol,
1H), 3.80-3.75 (m, 4H), 3.48-3.42 (m, 4H) 0.5% by vol. of
diethylamine) 31 ##STR00053## (3-Chloro-5-methoxy-
pyridin-2-yl)-[4-fluoro-3- (7-morpholin-4-yl-
quinazolin-4-yl)phenyl]- methanol A A C MS: 481.1/482.1 (M +
H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.09 (s, 1H), (Cl isotopy,
rel. peak 8.28 (d, J = 2.6, 1H), 7.62-7.55 (m, 3H), 7.55- intensity
ratio [%] 100:30) 7.49 (m, 2H), 7.41-7.32 (m, 1H), 7.21-7.18 (m,
1H), 6.16 (d, J = 6.1, 1H), 6.03 (d, J = 6.1, 1H), 3.85 (s, 3H),
3.80-3.75 (m, 4H), 3.47-3.42 (m, 4H) 32 ##STR00054##
[4-fluoro-3-(7- morpholin-4-yl- quinazolin-4-yl)phenyl]-
[3-(oxetan-3-yloxy)- pyrazin-2-yl]methanol C C B MS: 490.2 (M +
H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.09 (s, 1H), 8.24 (d, J =
2.7, 1H), 8.09 (d, J = 2.8, 1H), 7.71- 7.64 (m, 2H), 7.54-7.51 (m,
2H), 7.42-7.36 (m, 1H), 7.22-7.19 (m, 1H), 6.15-6.11 (m, 2H), 5.63-
5.58 (m, 1H), 4.88-4.83 (m, 2H), 4.58-4.52 (m, 2H), 3.80-3.75 (m,
4H), 3.47-3.41 (m, 4H) 33 ##STR00055## [4-Fluoro-3-(7-
morpholin-4-yl- quinazolin-4-yl)phenyl]- pyrazin-2-ylmethanol C D D
MS: 418.1 (M + H.sup.+) 1H NMR (400 MHz, DMSO-d6) ppm = 9.11 (s,
1H), 8.89 (d, J = 1.5, 1H), 8.59-8.53 (m, 2H), 7.71- 7.65 (m, 2H),
7.57-7.50 (m, 2H), 7.44-7.37 (m, 1H), 7.21-7.19 (m, 1H), 5.94 (s,
1H), 3.81-3.75 (m, 4H), 3.49-3.44 (m, 4H) 34 ##STR00056##
[2-Chloro-4-fluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)phenyl]-
pyrazin-2-ylmethanol C C B MS: 452.1/454.1 (M + H.sup.+) 1H NMR
(500 MHz, DMSO-d6) ppm = 9.11 (s, 1H), (Cl isotopy, rel. peak 8.86
(d, J = 1.3, 1H), 8.58-8.55 (m, 2H), 7.88 (d, intensity ratio [%]
100:36) J = 7.7, 1H), 7.66 (d, J = 9.5, 1H), 7.60-7.52 (m, 2H),
7.21 (d, J = 2.3, 1H), 6.62 (d, J = 4.9, 1H), 6.19 (d, J = 4.8,
1H), 3.80-3.75 (m, 4H), 3.49-3.42 (m, 4H) 35 ##STR00057##
(3,6-Dichloro-pyrazin-2- yl)-[4-fluoro-3-(7- morpholin-4-yl-
quinazolin-4-yl)phenyl]- methanol A A C MS: 486.1/488.1/490.0 1H
NMR (500 MHz, DMSO-d6) ppm = 9.10 (s, 1H), (M + H.sup.+) (Cl.sub.2
isotopy, rel. 8.63 (s, 1H), 7.68-7.64 (m, 2H), 7.55-7.51 (m, peak
intensity ratio [%] 2H), 7.45-7.40 (m, 1H), 7.20 (d, J = 2.1, 1H),
6.51 100:65:15) (d, J = 5.5, 1H), 6.18 (d, J = 5.5, 1H), 3.81-3.75
(m, 4H), 3.48-3.41 (m, 4H) 36 ##STR00058## [2-Chloro-4-fluoro-5-(7-
morpholin-4-yl- quinazolin-4-yl)phenyl]- pyridazin-4-ylmethanol A A
A MS: 452.1/454.1 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm =
9.27-9.25 (Cl isotopy, rel. peak (m, 1H), 9.19 (dd, J = 5.3, 1.2,
1H), 9.11 (s, 1H), intensity ratio [%] 100:33) 7.89 (d, J = 7.6,
1H), 7.72 (d, J = 9.5, 1H), 7.62- 7.56 (m, 2H), 7.53 (dd, J = 9.4,
2.5, 1H), 7.21 (d, J = 2.4, 1H), 6.72 (s, 1H), 6.13 (s, 1H),
3.81-3.75 (m, 4H), 3.48-3.43 (m, 4H) 37 ##STR00059##
(3-Chloro-pyrazin-2-yl)- [4-fluoro-3-(6- morpholin-4-ylthieno-
[3,2-d}pyrimidin-4-yl)- phenyl]methanol A A C MS: 458.1/460.1 (M +
H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 8.88 (s, 1H), (Cl isotopy,
rel. peak 8.68 (d, J = 2.4, 1H), 8.47 (d, J = 2.4, 1H), 7.73 (dd,
intensity ratio [%] 100:39) J = 7.0, 2.3, 1H), 7.66-7.61 (m, 1H),
7.43-7.35 (m, 1H), 6.52 (s, 1H), 6.39 (d, J = 5.7, 1H), 6.21 (d, J
= 5.6, 1H), 3.77-3.71 (m, 4H), 3.44-3.37 (m, 4H) 38 ##STR00060##
[4-Fluoro-3-(7- morpholin-4-yl- quinazolin-4-yl)phenyl]-
(3-methoxy-pyrazin-2- yl)methanol A A A MS: 448.2 (M + H.sup.+) 1H
NMR (500 MHz, DMSO-d6) ppm = 9.09 (s, 1H), 8.19 (d, J = 2.7, 1H),
8.15 (d, J = 2.7, 1H), 7.64- 7.59 (m, 2H), 7.55-7.50 (m, 2H),
7.39-7.34 (m, 1H), 7.21-7.18 (m, 1H), 6.08 (d, J = 5.9, 1H), 6.04
(d, J = 5.9, 1H), 3.93 (s, 3H), 3.80-3.75 (m, 4H), 3.47-3.42 (m,
4H) 39 ##STR00061## [2-Chloro-4-fluoro-5-(7- morpholin-4-yl-
quinazolin-4-yl)phenyl]- pyrazolo[1,5-a]- pyrimidin-5-ylmethanol B
A B MS: 491.1/493.1 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm =
9.11 (s, 1H), (Cl isotopy, rel. peak 9.08 (dd, J = 7.2, 0.9, 1H),
8.19 (d, J = 2.4, 1H), 7.87 intensity ratio [%] 100:38) (d, J =
7.7, 1H), 7.69 (d, J = 9.5, 1H), 7.58 (dd, J = 9.4, 3.2, 1H), 7.52
(dd, J = 9.5, 2.5, 1H), 7.21 (d, J = 2.5, 1H), 7.17 (d, J = 7.3,
1H), 6.71 (d, J = 5.0, 1H), 6.67 (dd, J = 2.3, 0.9, 1H), 6.11 (d, J
= 4.8, 1H), 3.82- 3.74 (m, 4H), 3.49-3.41 (m, 4H) 40 ##STR00062##
[2-Chloro-4-fluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)phenyl]-
(4-methoxypyrido- [3,4-d}pyridazin-1-yl)- methanol C B C MS:
533.2/535.2 (M + H.sup.+) 1H NMR (400 MHz, DMSO-d6) ppm = 9.97 (s,
1H), (Cl isotopy, rel. peak 9.15 (s, 1H), 9.11 (d, J = 5.5, 1H),
8.10-8.02 (m, intensity ratio [%] 100:38) 2H), 7.73-7.62 (m, 2H),
7.57 (dd, J = 9.5, 2.5, 1H), 7.23 (d, J = 2.4, 1H), 6.95-6.87 (m,
2H), 4.18 (s, 3H), 3.84-3.74 (m, 4H), 3.52-3.41 (m, 4H) 41
##STR00063## [2-Chloro-4-fluoro-5-(7- morpholin-4-yl-
quinazolin-4-yl)phenyl]- (6-chloro-pyridazin-3- yl)methanol B A B
MS: 486.0/488.1/490.0 1H NMR (400 MHz, DMSO-d6) ppm = 9.11 (s, 1H),
(M + H.sup.+) (Cl.sub.2 isotopy, rel. 7.92-7.90 (m, 2H), 7.90-7.87
(m, 1H), 7.69 (d, peak intensity ratio [%] J = 9.5, 1H), 7.58 (dd,
J = 9.4, 3.2, 1H), 7.53 (dd, 100:67:17) J = 9.5, 2.4, 1H), 7.20 (d,
J = 2.3, 1H), 6.86 (d, J = 5.0, 1H), 6.32 (d, J = 4.5, 1H),
3.81-3.74 (m, 4H), 3.48- 3.43 (m, 4H) 42 ##STR00064##
(3-Chloro-pyridin-2-yl)- [4-fluoro-3-(7- morpholin-4-yl-
quinazolin-4-yl)phenyl]- methanol A A B MS: 451.1/452.1 (M +
H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.09 (s, 1H), (Cl isotopy,
rel. peak 8.56 (dd, J = 4.6, 1.4, 1H), 7.92 (dd, J = 8.1, 1.4, 1H),
intensity ratio [%] 100:35) 7.64-7.59 (m, 2H), 7.54-7.49 (m, 2H),
7.40- 7.34 (m, 2H), 7.22-7.17 (m, 1H), 6.21 (s, 1H), 6.18-6.09 (m,
1H), 3.81-3.73 (m, 4H), 3.48- 3.40 (m, 4H) 43 ##STR00065##
6-{[2-Chloro-4-fluoro-5- (7-morpholin-4-yl-
quinazolin-4-yl)phenyl]- hydroxymethyl}- pyridazine-3-carboxylic
acid methylamide B B A MS: 531.2/533.2 (M + Na.sup.+) 1H NMR (500
MHz, DMSO-d6) ppm = 9.14 (q, (Cl isotopy, rel. peak J = 4.7, 1H),
9.11 (s, 1H), 8.19 (d, J = 8.7, 1H), 7.99 intensity ratio [%]
100:39) (d, J = 8.7, 1H), 7.87 (d, J = 7.7, 1H), 7.69 (d, J = 9.5,
1H), 7.58-7.51 (m, 2H), 7.22-7.19 (m, 1H), 6.84 (s, 1H), 6.42 (s,
1H), 3.80-3.76 (m, 4H), 3.47- 3.42 (m, 4H), 2.85 (d, J = 4.7, 3H)
44 ##STR00066## 6-{[2-Chloro-4-fluoro-5- (7-morpholin-4-yl-
quinazolin-4-yl)phenyl]- hydroxymethyl}-2- methyl-2H-pyridazin-3-
one (Ena 2) C C B
MS: 482.0/484.1 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.12
(s, 1H), (Cl isotopy, rel. peak 7.93 (d, J = 7.7, 1H), 7.68 (d, J =
9.5, 1H), 7.61- intensity ratio [%] 100:35) 7.52 (m, 2H), 7.48 (d,
J = 9.6, 1H), 7.21 (d, J = 2.4, R.sub.t 5.91 min, (SFC, 1H), 6.93
(d, J = 9.6, 1H), 6.60 (d, J = 4.8, 1H), 5.89 Chiralcel OJ-H,
CO.sub.2/20% (d, J = 4.8, 1H), 3.80-3.75 (m, 4H), 3.59 (s, 3H), by
vol. of methanol, 0.5% 3.48-3.43 (m, 4H) by vol. of diethylamine)
45 ##STR00067## 6-{[2-Chloro-4-fluoro-5- (7-morpholin-4-yl-
quinazolin-4-yl)phenyl]- hydroxymethyl}-2- methyl-2H-pyridazin-3-
one (Ena 1) A A B MS: 482.1/484.1 (M + H.sup.+) 1H NMR (500 MHz,
DMSO-d6) ppm = 9.12 (s, 1H), (Cl isotopy, rel. peak 7.93 (d, J =
7.7, 1H), 7.68 (d, J = 9.5, 1H), 7.60- intensity ratio [%] 100:35)
) 7.52 (m, 2H), 7.48 (d, J = 9.6, 1H), 7.21 (d, J = 2.4, R.sub.t
4.10 min, (SFC, 1H), 6.93 (d, J = 9.6, 1H), 6.60 (d, J = 4.9, 1H),
5.89 Chiralcel OJ-H, CO.sub.2/20% (d, J = 4.8, 1H), 3.81-3.75 (m,
4H), 3.59 (s, 3H), by vol. of methanol, 0.5% 3.48-3.42 (m, 4H) by
vol. of diethylamine) 46 ##STR00068## [2-Chloro-4-fluoro-5-(7-
morpholin-4-yl- quinazolin-4-yl)phenyl]- (5-methylpyridazin-3-
yl)methanol C C B MS: 488.1/490.2 (M + Na.sup.+) 1H NMR (500 MHz,
DMSO-d6) ppm = 9.11 (s, 1H), (Cl isotopy, rel. peak 9.00 (d, J =
2.0, 1H), 7.87 (d, J = 7.7, 1H), 7.67 (d, intensity ratio [%]
100:32) J = 9.5, 1H), 7.63-7.61 (m, 1H), 7.58 (dd, J = 9.4, 3.3,
1H), 7.53 (dd, J = 9.5, 2.5, 1H), 7.21 (d, J = 2.4, 1H), 6.65 (d, J
= 4.9, 1H), 6.28 (d, J = 4.9, 1H), 3.80- 3.75 (m, 4H), 3.48-3.42
(m, 4H), 2.32 (s, 3H) 47 ##STR00069## [2-Chloro-4-fluoro-5-(7-
morpholin-4-yl- quinazolin-4-yl)phenyl]- pyridazin-3-ylmethanol B A
A MS: 452.1/454.1 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm =
9.16-9.12 (Cl isotopy, rel. peak (m, 1H), 9.12-9.09 (m, 1H),
7.91-7.86 (m, 1H), intensity ratio [%] 100:39) 7.81-7.77 (m, 1H),
7.73-7.65 (m, 2H), 7.61- 7.56 (m, 1H), 7.55-7.51 (m, 1H), 7.23-7.19
(m, 1H), 6.72-6.69 (m, 1H), 6.34-6.30 (m, 1H), 3.81- 3.75 (m, 4H),
3.48-3.42 (m, 4H) 48 ##STR00070## [2,4-Difluoro-5-(7-
morpholin-4-yl- quinazolin-4-yl)phenyl]- pyridazin-3-ylmethanol B B
B MS: 436.2 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.14 (dd,
J = 4.9, 1.6, 1H), 9.10 (s, 1H), 7.86 (dd, J = 8.5, 1.6, 1H), 7.81
(t, J = 8.1, 1H), 7.72 (dd, J = 8.5, 4.9, 1H), 7.58-7.51 (m, 2H),
7.46 (t, J = 10.1, 1H), 7.20 (d, J = 2.3, 1H), 6.66 (d, J = 4.9,
1H), 6.26 (d, J = 4.9, 1H), 3.81-3.75 (m, 4H), 3.45 (t, J = 4.9,
4H) 49 ##STR00071## (6-Chloro-pyridazin-3- yl)-[2,4-difluoro-5-(7-
morpholin-4-yl- quinazolin-4-yl)phenyl]- methanol A B A MS:
470.1/471.1 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.10 (s,
1H), (Cl isotopy, rel. peak 7.98-7.91 (m, 2H), 7.82 (t, J = 8.1,
1H), 7.58-7.51 intensity ratio [%] 100:35) (m, 2H), 7.47 (t, J =
10.1, 1H), 7.20 (d, J = 2.3, 1H), 6.78 (d, J = 4.9, 1H), 6.26 (d, J
= 4.6, 1H), 3.82- 3.74 (m, 4H), 3.48-3.41 (m, 4H) 50 ##STR00072##
6-{[2-Chloro-4-fluoro-5- (7-morpholin-4-yl-
quinazolin-4-yl)phenyl]- hydroxymethyl}- pyridazine-3-carboxylic
acid dimethylamide C D A MS: 523.2/525.2 (M + H.sup.+) 1H NMR (500
MHz, chloroform-d) ppm = 9.15 (s, (Cl isotopy, rel. peak 1H), 7.85
(d, J = 8.7, 1H), 7.79 (d, J = 7.4, 1H), 7.65 intensity ratio [%]
100:35) (d, J = 8.7, 1H), 7.56 (dd, J = 9.3, 3.3, 1H), 7.36 (d, J =
9.0, 1H), 7.27 (d, J = 2.5, 1H), 7.22 (d, J = 2.5, 1H), 6.54 (s,
1H), 4.99 (s, 1H), 3.92-3.87 (m, 4H), 3.46-3.42 (m, 4H), 3.22 (s,
3H), 3.19 (s, 3H) 51 ##STR00073## [2,4-Difluoro-5-(7-
morpholin-4-yl- quinazolin-4-yl)phenyl]- imidazo[1,2-b]pyridazin-
6-ylmethanol A A B MS: 475.2 (M + H.sup.+) 1H NMR (500 MHz,
DMSO-d6) ppm = 9.12 (s, 1H), 8.26 (s, 1H), 8.12 (d, J = 9.5, 1H),
7.92 (t, J = 8.1, 1H), 7.77 (s, 1H), 7.61-7.51 (m, 2H), 7.48 (t, J
= 10.1, 1H), 7.35 (d, J = 9.5, 1H), 7.21 (d, J = 2.4, 1H), 6.75 (d,
J = 4.9, 1H), 6.10 (d, J = 4.7, 1H), 3.78 (t, J = 4.9, 4H), 3.45
(t, J = 4.9, 4H) 52 ##STR00074## [4-Fluoro-3-(7- morpholin-4-yl-
quinazolin-4-yl)phenyl]- (5-methoxy-pyrazin-2- yl)methanol (Ena 1)
B C A MS: 448.2 (M + H.sup.+); R.sub.t 1H NMR (500 MHz, DMSO-d6)
ppm = 9.09 (s, 1H), 16.15 min, (HPLC, 2 .times. 8.39-8.38 (m, 1H),
8.23 (d, J = 1.3, 1H), 7.66- Chiralcel OJ-H, methanol) 7.61 (m,
2H), 7.55-7.50 (m, 2H), 7.40-7.35 (m, 1H), 7.21-7.18 (m, 1H), 6.30
(d, J = 4.4, 1H), 5.88 (d, J = 4.4, 1H), 3.89 (s, 3H), 3.80-3.75
(m, 4H), 3.46-3.42 (m, 4H) 53 ##STR00075## [4-Fluoro-3-(7-
morpholin-4-yl- quinazolin-4-yl)phenyl]- (5-methoxy-pyrazin-2-
yl)methanol (Ena 2) B C A MS: 448.2 (M + H.sup.+); R.sub.t 1H NMR
(500 MHz, DMSO-d6) ppm = 9.09 (s, 1H), 19.06 min, (HPLC, 2 .times.
8.39-8.38 (m, 1H), 8.23 (d, J = 1.3, 1H), 7.66- Chiralcel OJ-H,
methanol) 7.61 (m, 2H), 7.55-7.50 (m, 2H), 7.40-7.35 (m, 1H),
7.21-7.18 (m, 1H), 6.30 (d, J = 4.4, 1H), 5.88 (d, J = 4.4, 1H),
3.89 (s, 3H), 3.80-3.75 (m, 4H), 3.46-3.42 (m, 4H) 54 ##STR00076##
(3-Chloro-pyrazin-2-yl)- [4-fluoro-3-(7- morpholin-4-yl-
quinazolin-4-yl)phenyl]- methanol A A B MS: 452.1/453.1 (M +
H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.09 (s, 1H), (Cl isotopy,
rel. peak 8.69 (d, J = 2.4, 1H), 8.46 (d, J = 2.4, 1H), 7.67-
intensity ratio [%] 100:35) 7.63 (m, 2H), 7.54-7.52 (m, 2H),
7.43-7.37 (m, 1H), 7.20-7.19 (m, 1H), 6.39 (d, J = 5.7, 1H), 6.23
(d, J = 5.7, 1H), 3.79-3.76 (m, 4H), 3.46-3.42 (m, 4H) 55
##STR00077## 6-{[2-Chloro-4-fluoro-5- (7-morpholin-4-yl-
quinazolin-4-yl)phenyl]- hydroxymethyl}- pyridazine-3-carboxylic
acid B D A MS: 496.1/498.0 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6)
ppm = 13.30 (s, (Cl isotopy, rel. peak 1H), 9.11 (s, 1H), 8.21 (d,
J = 8.7, 1H), 7.99 (d, intensity ratio [%] 100:36) J = 8.7, 1H),
7.87 (d, J = 7.6, 1H), 7.71 (d, J = 9.5, 1H), 7.55 (qd, J = 9.4,
2.7, 2H), 7.20 (d, J = 2.3, 1H), 7.08-6.66 (m, 1H), 6.42 (s, 1H),
3.80-3.75 (m, 4H), 3.49-3.44 (m, 4H) 56 ##STR00078##
[2-Chloro-4-fluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)phenyl]-
imidazo[1,2-b]pyridazin- 6-ylmethanol (Ena 2) B B C MS: 491.1/493.1
(M + H.sup.+) see racemate (Cl isotopy, rel. peak intensity ratio
[%] 100:34); R.sub.t 13.59 min (SFC, Chiralpak AD-H, CO.sub.2/ 40%
by vol. of methanol, 0.5% by vol. of diethylamine) 57 ##STR00079##
[2-Chloro-4-fluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)phenyl]-
imidazo[1,2-b]pyridazin- 6-ylmethanol (Ena 1) A A C MS: 491.1/493.1
(M + H.sup.+) see racemate (Cl isotopy, rel. peak intensity ratio
[%] 100:36); R.sub.t 3.87 min (SFC, Chiralpak AD-H, CO.sub.2/ 40%
by vol. of methanol, 0.5% by vol. of diethylamine) 58 ##STR00080##
6-{[2-Chloro-4-fluoro-5- (7-morpholin-4-yl-
quinazolin-4-yl)phenyl]- hydroxymethyl}- pyridazine-3-carboxylic
acid methyl ester B C A MS: 510.1/512.1 (M + H.sup.+) 1H NMR (500
MHz, DMSO-d6) ppm = 9.11 (s, 1H), (Cl isotopy, rel. peak 8.23 (d, J
= 8.7, 1H), 8.01 (d, J = 8.7, 1H), 7.86 (d, intensity ratio [%]
100:33) J = 7.6, 1H), 7.70 (d, J = 9.5, 1H), 7.55 (qd, J = 9.4,
2.8, 2H), 7.20 (d, J = 2.4, 1H), 6.94-6.81 (m, 1H), 6.42 (s, 1H),
3.94 (s, 3H), 3.81-3.75 (m, 4H), 3.48-3.42 (m, 4H) 59 ##STR00081##
6-{[2-Chloro-4-fluoro-5- (7-morpholin-4-yl-
quinazolin-4-yl)phenyl]- hydroxymethyl}-2- methyl-2H-pyridazin-3-
one A B B MS: 482.1/484.1 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6)
ppm = 9.12 (s, 1H), (Cl isotopy, rel. peak 7.92 (d, J = 7.7, 1H),
7.68 (d, J = 9.5, 1H), 7.59 (dd, intensity ratio [%] 100:45) J =
9.4, 3.1, 1H), 7.55 (dd, J = 9.4, 2.5, 1H), 7.49 (d, J = 9.6, 1H),
7.21 (d, J = 2.4, 1H), 6.95 (d, J = 9.6, 1H), 6.68 (d, J = 4.8,
1H), 5.90 (d, J = 3.6, 1H), 3.80- 3.77 (m, 4H), 3.61-3.58 (m, 3H),
3.45 (s, 4H) 60 ##STR00082## [4-Fluoro-3-(7- morpholin-4-yl-
quinazolin-4-yl)phenyl]- (5-methoxypyrazin-2- yl)methanol C B B MS:
448.2 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.09 (s, 1H),
8.39-8.38 (m, 1H), 8.23 (d, J = 1.3, 1H), 7.66- 7.61 (m, 2H),
7.55-7.50 (m, 2H), 7.40-7.35 (m, 1H), 7.21-7.18 (m, 1H), 6.30 (d, J
= 4.4, 1H), 5.88 (d, J = 4.4, 1H), 3.89 (s, 3H), 3.80-3.75 (m, 4H),
3.46-3.42 (m, 4H) 61 ##STR00083## [4-methoxy-3-(7- morpholin-4-yl-
quinazolin-4-yl)phenyl]- (5-methoxypyrazin-2- yl)methanol D D A MS:
460.2 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.04 (s, 1H),
8.36-8.35 (m, 1H), 8.20 (d, J = 1.4, 1H), 7.53 (dd, J = 8.6, 2.3,
1H), 7.44 (dd, J = 9.4, 2.5, 1H), 7.38 (d, J = 9.4, 1H), 7.35 (d, J
= 2.2, 1H), 7.17 (d, J = 8.6, 1H), 7.14 (d, J = 2.5, 1H), 6.13 (d,
J = 4.4, 1H), 5.79 (d, J = 4.4, 1H), 3.88 (s, 3H), 3.79-3.75 (m,
4H), 3.66 (s, 3H), 3.43-3.38 (m, 4H) 62 ##STR00084##
6-{[2-Chloro-4-fluoro-5- (7-morpholin-4-yl-
quinazolin-4-yl)phenyl]- hydroxymethyl}- pyridazine-3-carboxylic
acid amide B B A MS: 495.1/497.1 (M + H.sup.+) 1H NMR (500 MHz,
DMSO-d6) ppm = 9.11 (s, 1H), (Cl isotopy, rel. peak 8.49 (s, 1H),
8.20 (d, J = 8.7, 1H), 8.00 (d, J = 8.7, intensity ratio [%]
100:35) 1H), 7.91-7.85 (m, 2H), 7.69 (d, J = 9.5, 1H), 7.59- 7.51
(m, 2H), 7.21 (d, J = 2.2, 1H), 6.84 (d, J = 5.0, 1H), 6.42 (d, J =
5.0, 1H), 3.80-3.75 (m, 4H), 3.48- 3.42 (m, 4H) 63 ##STR00085##
[2-Chloro-4-fluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)phenyl]-
imidazo[1,2-b]pyridazin- 6-ylmethanol A B C
MS: 491.1/493.1 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.13
(s, 1H), (Cl isotopy, rel. peak 8.27-8.25 (m, 1H), 8.11 (dd, J =
9.4, 0.7, 1H), 8.00 intensity ratio [%] 100:38) (d, J = 7.7, 1H),
7.77 (d, J = 1.2, 1H), 7.70 (d, J = 9.5, 1H), 7.61 (dd, J = 9.4,
3.3, 1H), 7.55 (dd, J = 9.4, 2.5, 1H), 7.30 (d, J = 9.5, 1H), 7.22
(d, J = 2.5, 1H), 6.81 (d, J = 4.5, 1H), 6.15 (d, J = 4.2, 1H,
3.81-3.75 (m, 4H), 3.48-3.44 (m, 4H) 64 ##STR00086##
[2-Chloro-4-fluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)phenyl]-
(3-chloropyrazin-2-yl)- methanol B A C MS: 486.1/488.1/490.0 1H NMR
(500 MHz, DMSO-d6) ppm = 9.14 (s, 1H), (M + H.sup.+) (Cl.sub.2
isotopy, rel. 8.61 (d, J = 2.4, 1H), 8.49 (d, J = 2.4, 1H), 8.00
(d, peak intensity ratio [%] J = 7.7, 1H), 7.66 (d, J = 9.5, 1H),
7.64-7.55 (m, 100:63:11) 2H), 7.22 (d, J = 2.4, 1H), 6.70 (d, J =
6.0, 1H), 6.42 (d, J = 6.0, 1H), 3.81-3.76 (m, 4H), 3.49-3.44 (m,
4H) 65 ##STR00087## [4-Fluoro-3-(7- morpholin-4-yl-
quinazolin-4-yl)phenyl]- pyridazin-3-ylmethanol C B A MS: 418.3 (M
+ H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.12 (dd, J = 4.9, 1.7,
1H), 9.09 (s, 1H), 7.83 (dd, J = 8.6, 1.7, 1H), 7.72-7.65 (m, 3H),
7.52-7.49 (m, 2H), 7.42- 7.37 (m, 1H), 7.21-7.18 (m, 1H), 6.56 (d,
J = 4.3, 1H), 6.12-6.09 (m, 1H), 3.80-3.75 (m, 4H), 3.46- 3.41 (m,
4H) 66 ##STR00088## [4-Fluoro-3-(7- morpholin-4-yl-
quinazolin-4-yl)phenyl]- (5-methoxypyrimidin-2- yl)methanol (Ena 2)
C D A MS: 448.1 (M + H.sup.+); R.sub.t 1H NMR (500 MHz, DMSO-d6)
ppm = 9.09 (s, 1H), 53.23 min, (HPLC, 8.53 (s, 2H), 7.70-7.63 (m,
2H), 7.52 (s, 2H), Chiralpak AD-H, ethanol) 7.40-7.32 (m, 1H),
7.22-7.15 (m, 1H), 6.06 (d, J = 5.5, 1H), 5.86 (d, J = 5.5, 1H),
3.89 (s, 3H), 3.79- 3.76 (m, 4H), 3.45-3.43 (m, 4H) 67 ##STR00089##
[4-Fluoro-3-(7- morpholin-4-yl- quinazolin-4-yl)phenyl]-
(5-methoxypyrimidin-2- yl)methanol (Ena 1) C C A MS: 448.1 (M +
H.sup.+); R.sub.t 1H NMR (500 MHz, DMSO-d6) ppm = 9.09 (s, 1H),
45.79 min, (HPLC, 8.53 (s, 2H), 7.70-7.63 (m, 2H), 7.52 (s, 2H),
Chiralpak AD-H, ethanol) 7.40-7.32 (m, 1H), 7.22-7.15 (m, 1H), 6.06
(d, J = 5.5, 1H), 5.86 (d, J = 5.5, 1H), 3.89 (s, 3H), 3.79- 3.76
(m, 4H), 3.45-3.43 (m, 4H) 68 ##STR00090## (6-Dimethylamino-
pyridazin-3-yl)-[4-fluoro- 3-(7-morpholin-4-yl-
quinazolin-4-yl)phenyl]- methanol B C A MS: 461.2 (M + H.sup.+) 1H
NMR (500 MHz, DMSO-d6) ppm = 9.09 (s, 1H), 7.65-7.56 (m, 2H),
7.55-7.48 (m, 2H), 7.43- 7.34 (m, 2H), 7.24-7.17 (m, 1H), 7.07 (d,
J = 9.4, 1H), 6.27 (d, J = 4.4, 1H), 5.93 (d, J = 4.4, 1H), 3.81-
3.75 (m, 4H), 3.47-3.41 (m, 4H), 3.06 (s, 6H) 69 ##STR00091##
[4-Fluoro-3-(7- morpholin-4-yl- quinazolin-4-yl)phenyl]-
(5-methoxypyrimidin-2- yl)methanol B C A MS: 448.1 (M + H.sup.+) 1H
NMR (500 MHz, DMSO-d6) ppm = 9.09 (s, 1H), 8.53 (s, 2H), 7.70-7.63
(m, 2H), 7.52 (s, 2H), 7.40-7.32 (m, 1H), 7.22-7.15 (m, 1H), 6.06
(d, J = 5.5, 1H), 5.86 (d, J = 5.5, 1H), 3.89 (s, 3H), 3.79- 3.76
(m, 4H), 3.45-3.43 (m, 4H) 70 ##STR00092## [4-Fluoro-3-(7-
morpholin-4-yl- quinazolin-4-yl)phenyl]- (6-methylpyridazin-3-
yl)methanol B B A MS: 432.1 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6)
ppm = 9.09 (s, 1H), 7.72-7.61 (m, 3H), 7.58-7.47 (m, 3H), 7.43-
7.33 (m, 1H), 7.22-7.16 (m, 1H), 6.50 (d, J = 4.0, 1H), 6.07 (d, J
= 3.8, 1H), 3.77 (t, J = 5.9, 3.9, 4H), 3.44 (t, J = 4.9, 4H), 2.58
(s, 3H) 71 ##STR00093## (R)-[4-Fluoro-3-(7- morpholin-4-yl-
quinazolin-4-yl)phenyl]- (6-methoxypyridazin-3- yl)methanol A B A
MS: 448.1 (M + H.sup.+); R.sub.t 1H NMR (500 MHz, DMSO-d6) ppm =
9.09 (s, 1H), 24.02 min, (SFC, Chiralcel 7.70 (d, J = 9.2, 1H),
7.66-7.61 (m, 2H), 7.53- OJ-H, CO.sub.2/15% by vol. of 7.50 (m,
2H), 7.42-7.37 (m, 1H), 7.22-7.19 (m, 2-propanol, 0.5% by vol. 2H),
6.48 (d, J = 4.4, 1H), 6.02 (d, J = 4.4, 1H), 4.00 of diethylamine)
(s, 3H), 3.80-3.75 (m, 4H), 3.46-3.41 (m, 4H) 72 ##STR00094##
(S)-[4-Fluoro-3-(7- morpholin-4-yl- quinazolin-4-yl)phenyl]-
(6-methoxypyridazin-3- yl)methanol A B A MS: 448.1 (M + H.sup.+);
R.sub.t 1H NMR (500 MHz, DMSO-d6) ppm = 9.09 (s, 1H), 19.10 min,
(SFC, Chiralcel 7.69 (d, J = 9.2, 1H), 7.66-7.61 (m, 2H), 7.53-
OJ-H, CO.sub.2/15% by vol. of 7.50 (m, 2H), 7.41-7.37 (m, 1H),
7.21-7.19 (m, 2-propanol, 0.5% by vol. 2H), 6.48 (d, J = 4.4, 1H),
6.02 (d, J = 4.4, 1H), 4.00 of diethylamine) (s, 3H), 3.79-3.76 (m,
4H), 3.46-3.42 (m, 4H) 73 ##STR00095## 4-{2-Fluoro-5-[methoxy-
(6-methoxy-pyridazin-3- yl)methyl]phenyl}-7- morpholin-4-yl-
quinazoline B B A MS: 462.1 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6)
ppm = 9.10 (s, 1H), 7.69 (d, J = 9.1, 1H), 7.65-7.61 (m, 2H), 7.54-
7.48 (m, 2H), 7.45-7.40 (m, 1H), 7.23 (d, J = 9.2, 1H), 7.21-7.19
(m, 1H), 5.71 (s, 1H), 4.01 (s, 3H), 3.80-3.75 (m, 4H), 3.47-3.41
(m, 4H), 3.36 (s, 3H) 74 ##STR00096## [4-Fluoro-3-(7-
morpholin-4-yl- quinazolin-4-yl)phenyl]- (6-methoxypyridazin-3-
yl)methanol A A A MS: 448.1 (M + H.sup.+) 1H NMR (400 MHz, DMSO-d6)
ppm = 9.09 (s, 1H), 7.69 (d, J = 9.2, 1H), 7.67-7.61 (m, 2H), 7.54-
7.48 (m, 2H), 7.42-7.36 (m, 1H), 7.22-7.17 (m, 2H), 6.51-6.45 (m,
1H), 6.04-6.00 (m, 1H), 4.00 (s, 3H), 3.80-3.74 (m, 4H), 3.47-3.41
(m, 4H) 75 ##STR00097## 6-({4-Fluoro-3-[7-(3- oxa-8-aza-bicyclo-
[3.2.1]oct-8-yl)- quinazolin-4-yl]phenyl}- hydroxymethyl)-2H-
pyridazin-3-one D A MS: 460.1 (M + H.sup.+) 1H NMR (500 MHz,
DMSO-d6) ppm = 12.88- 12.84 (m, 1H), 9.04 (s, 1H), 7.63-7.57 (m,
2H), 7.50-7.45 (m, 2H), 7.44-7.38 (m, 2H), 7.14 (d, J = 2.4, 1H),
6.87 (dd, J = 9.8, 2.2, 1H), 6.42 (d, J = 4.4, 1H), 5.68-5.64 (m,
1H), 4.55-4.46 (m, 2H), 3.69 (d, J = 10.9, 2H), 3.54 (d, J = 10.4,
2H), 2.09-1.94 (m, 4H) 76 ##STR00098## 6-{[4-Fluoro-3-(7-
morpholin-4-yl- quinazolin-4-yl)phenyl]- hydroxymethyl}-2H-
pyridazin-3-one (Ena 2) A B A MS: 434.1 (M + H.sup.+); R.sub.t 1H
NMR (400 MHz, DMSO-d6) ppm = 12.86 (s, 16.74 min, (SFC, Chiralcel
1H), 9.10 (s, 1H), 7.64-7.58 (m, 2H), 7.55-7.50 OJ-H, CO.sub.2/15%
by vol. of (m, 2H), 7.48 (d, J = 9.8, 1H), 7.45-7.38 (m, 1H),
methanol, 0.5% by vol. of 7.23-7.16 (m, 1H), 6.87 (d, J = 9.8, 1H),
6.44 (d, diethylamin) J = 4.3, 1H), 5.70-5.62 (m, 1H), 3.81-3.74
(m, Ena 1 to this compound: 4H), 3.47-3.41 (m, 4H) Example 367 77
##STR00099## (3-Chloro-5-fluoro- pyridin-4-yl)-[4-fluoro-3-
(7-morpholin-4-yl- quinazolin-4-yl)phenyl]- methanol B A C MS:
469.1/471.1 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.10 (s,
1H), (Cl isotopy, rel. peak 8.58-8.53 (m, 2H), 7.65-7.56 (m, 2H),
7.56- intensity ratio [%] 100:31) 7.47 (m, 2H), 7.46-7.38 (m, 1H),
7.23-7.17 (m, 1H), 6.65 (d, J = 4.7, 1H), 6.33 (d, J = 4.7, 1H),
3.80- 3.75 (m, 4H), 3.47-3.41 (m, 4H) 78 ##STR00100##
[4-Fluoro-3-(7- morpholin-4-yl- quinazolin-4-yl)phenyl]-
(3-methylpyrazin-2-yl)- methanol B A B MS: 432.2 (M + H.sup.+) 1H
NMR (400 MHz, DMSO-d6) ppm = 9.09 (s, 1H), 8.43 (s, 2H), 7.63-7.55
(m, 2H), 7.55-7.50 (m, 2H), 7.42-7.34 (m, 1H), 7.22-7.17 (m, 1H),
6.28 (d, J = 5.5, 1H), 6.08 (d, J = 5.4, 1H, 3.81-3.74 (m, 4H),
3.48-3.40 (m, 4H), 2.58-2.53 (m, 3H) 79 ##STR00101##
(5-Ethoxypyridazin-3- yl)-[4-fluoro-3-(7- morpholin-4-yl-
quinazolin-4-yl)phenyl]- methanol D C B MS: 462.1 (M + H.sup.+) 1H
NMR (500 MHz, DMSO-d6) ppm = 9.09 (s, 1H), 8.84 (d, J = 2.9, 1H),
7.72-7.66 (m, 2H), 7.52-7.49 (m, 2H), 7.41-7.36 (m, 1H), 7.30 (d, J
= 2.9, 1H), 7.21-7.18 (m, 1H), 6.52 (d, J = 4.5, 1H), 6.04 (d, J =
4.5, 1H), 4.26-4.16 (m, 2H), 3.81-3.74 (m, 4H), 3.48-3.40 (m, 4H),
1.34 (t, J = 6.9, 3H). 80 ##STR00102## [4-Fluoro-3-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]-(3-trifluoro-
methylpyridin-2-yl)- methanol B B A MS: 485.2 (M + H.sup.+) 1H NMR
(500 MHz, DMSO-d6) ppm = 9.10 (s, 1H), 8.90-8.85 (m, 1H), 8.20 (dd,
J = 8.1, 1.6, 1H), 7.63 (dd, J = 6.9, 2.3, 1H), 7.60-7.51 (m, 4H),
7.38 (dd, J = 9.9, 8.6, 1H), 7.21-7.18 (m, 1H), 6.32 (d, J = 6.3,
1H), 6.12 (d, J = 6.0, 1H), 3.81-3.74 (m, 4H), 3.47-3.41 (m, 4H).
81 ##STR00103## (3-Difluoromethoxy- pyridin-2-yl)-[4-fluoro-
3-(7-morpholin-4-yl- quinazolin-4-yl)- phenyl]methanol A A A MS:
483.2 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.09 (s, 1H),
8.46 (dd, J = 4.6, 1.3, 1H), 7.67-7.64 (m, 1H), 7.62- 7.57 (m, 2H),
7.54-7.49 (m, 2H), 7.42 (dd, J = 8.3, 4.6, 1H), 7.40-7.10 (m, 3H),
6.14-6.07 (m, 2H), 3.81-3.75 (m, 4H), 3.47-3.41 (m, 4H). 82
##STR00104## (S)-[4-Fluoro-3-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]-(3-methyl- pyrazin-2-yl)methanol C B A MS: 432.2 (M +
H.sup.+); ); R.sub.t 1H NMR (500 MHz, DMSO-d6) ppm = 9.10 (s, 1H),
12.50 min (SFC, ChiralPak 8.44 (s, 2H), 7.64-7.51 (m, 4H),
7.44-7.35 (m, AD-H, CO.sub.2/25% by vol. 1H), 7.20 (s, 1H), 6.31
(d, J = 5.5, 1H), 6.09 (d, of 2-propanol, 0.5% by J = 5.4, 1H),
3.81-3.74 (m, 4H), 3.48-3.40 (m, vol. of diethylamine) 4H), 2.56
(s, 3H). 83 ##STR00105## (R)-[4-Fluoro-3-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]-(3-methyl- pyrazin-2-yl)methanol A A A
MS: 432.1 (M + H.sup.+); R.sub.t 1H NMR (400 MHz, DMSO-d6) ppm =
9.09 (s, 1H), 19.51 min (SFC, ChiralPak 8.43 (s, 2H), 7.63-7.49 (m,
4H), 7.43-7.34 (m, AD-H, CO.sub.2/25% by vol. 1H), 7.19 (s, 1H),
6.28 (d, J = 5.5, 1H), 6.08 (d, of 2-propanol, 0.5% by J = 5.4,
1H), 3.82-3.73 (m, 4H), 3.48-3.40 (m, vol. of diethylamine) 4H),
2.55 (s, 3H). 84 ##STR00106## [2,4-Difluoro-5-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]-(3-methyl- pyrazin-2-yl)methanol B A B
MS: 450.2 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.12 (s,
1H), 8.45 (d, J = 2.5, 1H), 8.39 (dd, J = 2.5, 0.8, 1H), 7.89 (t, J
= 8.2, 1H), 7.61 (dd, J = 9.4, 3.2, 1H), 7.56 (dd, J = 9.4, 2.5,
1H), 7.40 (t, J = 10.1, 1H), 7.21 (d, J = 2.4, 1H), 6.39-6.35 (m,
1H), 6.27 (s, 1H), 3.81- 3.75 (m, 4H), 3.49-3.43 (m, 4H), 2.67 (s,
3H). 85 ##STR00107## [2,4-Difluoro-5-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]-(3-methyl- pyrazin-2-yl)methanol (Ena 1)
A B B MS: 450.2 (M + H.sup.+); R.sub.t see racemate 3.45 min (SFC,
ChiralPak AD-H, CO.sub.2/30% by vol. of methanol, 0.5% by vol. of
diethylamine) 86 ##STR00108## [2,4-Difluoro-5-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]-(3-methyl- pyrazin-2-yl)methanol (Ena 2)
A A A
MS: 450.2 (M + H.sup.+); R.sub.t see racemate 5.60 min (SFC,
ChiralPak AD-H, CO.sub.2/25% by vol. of methanol, 0.5% by vol. of
diethylamine) 87 ##STR00109## [4-Fluoro-3-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]-(5-methoxy- pyrimidin-4-yl)- methanol A A
B MS: 448.1 (M + H.sup.+) 1H NMR (400 MHz, DMSO-d6) ppm = 9.11 (s,
1H), 8.82 (s, 1H), 8.58 (s, 1H), 7.67-7.61 (m, 2H), 7.55-7.52 (m,
2H), 7.41-7.34 (m, 1H), 7.23- 7.19 (m, 1H), 6.13 (d, J = 6.1, 1H),
6.07 (d, J = 6.2, 1H), 3.95 (s, 3H), 3.83-3.76 (m, 4H), 3.49-3.42
(m, 4H). 88 ##STR00110## [2,4-Difluoro-5-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]-(3,6-dimethyl- pyrazin-2-yl)methanol A A
B MS: 464.2 (M + H.sup.+) 1H NMR (400 MHz, DMSO-d6) ppm = 9.13 (s,
1H), 8.35 (s, 1H), 7.88 (t, J = 8.2, 1H), 7.61 (dd, J = 9.4, 3.0,
1H), 7.56 (dd, J = 9.5, 2.5, 1H), 7.42 (t, J = 10.2, 1H), 7.23 (d,
J = 2.4, 1H), 6.31 (d, J = 5.9, 1H), 6.22 (d, J = 5.6, 1H),
3.85-3.75 (m, 4H), 3.51-3.43 (m, 4H), 2.58 (s, 3H), 2.40 (s, 3H).
89 ##STR00111## [2-Chloro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]thieno[3,2-d}- pyrimidin-4-ylmethanol B A C MS: 490.1/492.1
(M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.06 (s, 1H), (Cl
isotopy, rel. peak 9.04 (s, 1H), 8.47 (d, J = 5.6, 1H), 7.89 (d, J
= 2.1, intensity ratio [%] 100:43) 1H), 7.76 (d, J = 9.4, 1H), 7.73
(dd, J = 8.2, 2.2, 1H), 7.69 (d, J = 8.2, 1H), 7.62 (d, J = 5.6,
1H), 7.47 (dd, J = 9.5, 2.6, 1H), 7.20-7.16 (m, 2H), 6.47 (d, J =
4.9, 1H), 3.81-3.74 (m, 4H), 3.47-3.39 (m, 4H). 90 ##STR00112##
[2,4-Difluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]thieno[2,3-d}- pyrimidin-4-ylmethanol A A A MS: 492.2 (M +
H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.07 (s, 1H), 9.05 (s,
1H), 8.47 (d, J = 5.6, 1H), 7.76 (t, J = 8.0, 1H), 7.61 (d, J =
5.6, 1H), 7.55-7.46 (m, 3H), 7.20- 7.17 (m, 2H), 6.32 (d, J = 4.7,
1H), 3.81-3.74 (m, 4H), 3.47-3.41 (m, 4H). 91 ##STR00113##
6-{[4-Fluoro-3-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]hydroxy- methyl}-1-methyl-1H- pyridin-2-one A A A MS: 447.2
(M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.10 (s, 1H),
7.60-7.56 (m, 2H), 7.55-7.51 (m, 2H), 7.48- 7.43 (m, 1H), 7.40 (dd,
J = 9.1, 6.9, 1H), 7.21-7.19 (m, 1H), 6.52 (d, J = 5.3, 1H), 6.36
(dd, J = 9.1, 1.4, 1H), 6.25 (dd, J = 7.0, 1.4, 1H), 5.94 (d, J =
5.1, 1H), 3.80-3.75 (m, 4H), 3.47-3.41 (m, 4H), 3.38 (s, 3H).
Examples 92 and 93
3-[[2-Chloro-4-fluoro-5-(7-morpholinylquinazolin-4-yl)phenyl]hydroxymethyl-
]-1H-pyridazin-6-one (92)
6-{[2-Chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]hydroxymet-
hyl}-2-ethyl-2H-pyridazin-3-one (93)
##STR00114##
[0276]
[2-Chloro-4-fluoro-5-(7-morpholinylquinazolin-4-yl)phenyl]-(6-chlor-
opyridazin-3-yl)methanone, starting from 2,6-dichloropyridazine and
2-[2-chloro-4-fluoro-5-(7-morpholinylquinazolin-4-yl)phenyl]acetonitrile,
and
3-[[2-chloro-4-fluoro-5-(7-morpholinylquinazolin-4-yl)phenyl]-hydroxy-
methyl]-1H-pyridazin-6-one (EXAMPLE 92) were prepared analogously
to the synthetic processes described under EXAMPLES 1 and 2.
Preparation of
3-[2-chloro-4-fluoro-5-(7-morpholinylquinazolin-4-yl)benzoyl]-1H-pyridazi-
n-6-one from
[2-chloro-4-fluoro-5-(7-morpholinylquinazolin-4-yl)phenyl]-(6-chloropyrid-
azin-3-yl)methanone
[0277]
[2-Chloro-4-fluoro-5-(7-morpholinylquinazolin-4-yl)phenyl]-(6-chlor-
opyridazin-3-yl)methanone (2.0 g, 4.13 mmol) was dissolved in
1,4-dioxane (80 ml, max. 0.005% of water) under an argon
atmosphere. 3-Hydroxypropionitrile (570 .mu.l ml, 8.27 mmol) and
sodium hydride (60% dispersion in paraffin oil) (215 mg; 5.37 mmol)
were subsequently added (evolution of gas). The reaction mixture
was stirred at room temperature for 2 h. After termination of the
reaction, the mixture was carefully diluted with water (100 ml) and
neutralised using hydrochloric acid (1.0 M). The aqueous phase was
subsequently extracted twice with ethyl acetate (200 ml in each
case). The combined organic phases were washed with saturated
sodium chloride solution, subsequently dried over sodium sulfate,
filtered and evaporated to dryness in a rotary evaporator. The
residue was purified by means of flash column chromatography
(dichloromethane/0-10% by vol. of ethanol, CombiFlash Rf 200),
giving
3-[2-chloro-4-fluoro-5-(7-morpholinylquinazolin-4-yl)benzoyl]-1H-pyridazi-
n-6-one (695 mg, 1.47 mmol, MS: 466.1/468.1 [M+H.sup.+)), 36%
yield) as solid.
Preparation of
6-{[2-chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]hydroxy-m-
ethyl}-2-ethyl-2H-pyridazin-3-one (EXAMPLE 93) from
3-[[2-chloro-4-fluoro-5-(7-morpholinylquinazolin-4-yl)phenyl]hydroxymethy-
l]-1H-pyridazin-6-one (EXAMPLE 92)
[0278]
3-[[2-Chloro-4-fluoro-5-(7-morpholinylquinazolin-4-yl)phenyl]hydrox-
ymethyl]-1H-pyridazin-6-one (150 mg; 0.316 mmol) was dissolved in
N,N-dimethylformamide (5.0 ml). Iodoethane (52 .mu.l, 0.632 mmol)
and potassium carbonate (132 mg, 0.947 mmol) were subsequently
added. The reaction mixture was stirred at room temperature for 6
h. After termination of the reaction, the mixture was decanted off
onto water (100 ml). The aqueous phase was subsequently extracted
twice with ethyl acetate (100 ml in each case). The combined
organic phases were rinsed with water (40 ml), subsequently dried
over sodium sulfate, filtered us evaporated to dryness in vacuo.
The residue was suspended in acetone and filtered off with suction.
The filter cake was dried at room temperature in a high vacuum,
giving
6-{[2-chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]hydroxyme-
thyl}-2-ethyl-2H-pyridazin-3-one (EXAMPLE 93, 157 mg, 0.31 mmol,
MS: 496.1/498.1 [M+H.sup.+], 97% yield) as solid.
[0279] Compounds which were prepared in accordance with EXAMPLE 93
can be found in Table 2 below.
TABLE-US-00002 TABLE 2 Compounds of the formula (I) IC.sub.50
IC.sub.50 K.sub.i DNA- pDNA- [Kv1.11 No. Structural formula Name PK
PK hERG] 92 ##STR00115## 3-[[2-Chloro-4-fluoro-5- (7-morpholino-
quinazolin-4-yl)phenyl]- hydroxymethyl]-1H- pyridazin-6-one A A A
MS: 468.1/470.0 (M + H.sup.+) 1H NMR (400 MHz, DMSO-d6) ppm = 12.89
(d, (Cl isotopy, rel. peak J = 2.4, 1H), 9.12 (s, 1H), 7.92 (d, J =
7.7, 1H), 7.68 intensity ratio [%] 100:38) (d, J = 9.5, 1H),
7.59-7.55 (m, 2H), 7.53 (d, J = 9.8, 1H), 7.21 (d, J = 2.2, 1H),
6.90 (dd, J = 9.8, 2.3, 1H), 6.61 (d, J = 5.1, 1H), 5.89 (d, J =
5.1, 1H), 3.81-3.76 (m, 4H), 3.48-3.44 (m, 4H) 93 ##STR00116##
6-{[2-Chloro-4-fluoro-5- (7-morpholin-4-yl-
quinazolin-4-yl)phenyl]- hydroxymethyl}-2-ethyl- 2H-pyridazin-3-one
B A C MS: 496.1/498.1 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm =
9.13 (s, 1H), (Cl isotopy, rel. peak 7.94 (d, J = 7.7, 1H), 7.68
(d, J = 9.5, 1H), 7.59-7.52 intensity ratio [%] 100:41) (m, 2H),
7.46 (d, J = 9.6, 1H), 7.22 (d, J = 2.3, 1H), 6.92 (d, J = 9.6,
1H), 6.61 (d, J = 4.8, 1H), 5.90 (d, J = 4.8, 1H), 4.08-3.95 (m,
2H), 3.81-3.74 (m, 4H), 3.49-3.41 (m, 4H), 1.20 (t, J = 7.2, 3H) 94
##STR00117## 2-(2-Amino-ethyl)-6-{[2- Chloro-4-fluoro-5-(7-
morpholin-4-yl- quinazolin-4-yl)phenyl]- hydroxymethyl}-2H-
pyridazin-3-one C D A MS: 511.1/513.2 (M + H.sup.+) 1H NMR (500
MHz, DMSO-d6) ppm = 9.13 (s, 1H), (Cl isotopy, rel. peak 7.94 (d, J
= 7.7, 1H), 7.68 (d, J = 9.5, 1H), 7.60-7.52 intensity ratio [%]
100:38) (m, 2H), 7.48 (d, J = 9.7, 1H), 7.21 (d, J = 2.2, 1H), 6.94
(d, J = 9.6, 1H), 6.72-6.57 (m, 1H), 5.91 (s, 1H), 4.10-3.96 (m,
2H), 3.82-3.73 (m, 4H), 3.48- 3.43 (m, 4H), 2.88 (t, J = 6.6, 2H)
95 ##STR00118## 6-{[2-Chloro-4-fluoro-5- (7-morpholin-4-yl-
quinazolin-4-yl)phenyl]- hydroxymethyl}-2- cyclopropyl-2H-
pyridazin-3-one C B A MS: 508.1/510.1 (M + H.sup.+) 1H NMR (400
MHz, Methylenchlorid-d2) ppm = 9.04 (Cl isotopy, rel. peak (s, 1H),
7.71 (d, J = 7.6, 1H), 7.49 (dd, J = 9.3, 3.5, intensity ratio [%]
100:38) 1H), 7.26-7.20 (m, 2H), 7.18-7.14 (m, 2H), 6.74 (d, J =
9.6, 1H), 5.97 (s, 1H), 4.03-3.94 (m, 1H), 3.82-3.74 (m, 4H),
3.39-3.31 (m, 4H), 0.98-0.82 (m, 4H) 96 ##STR00119##
6-{[2-Chloro-4-fluoro-5- (7-morpholin-4-yl-
quinazolin-4-yl)phenyl]- hydroxymethyl}-2-ethyl- 2H-pyridazin-3-one
(Ena 2) C B A MS: 496.2/498.1 (M + H.sup.+) see racemate (Cl
isotopy, rel. peak intensity ratio [%] 100:34); R.sub.t 4.59 min
(SFC, Chiralcel OJ-H, CO.sub.2/20% by vol. of methanol, 0.5% by
vol. of diethylamine) 97 ##STR00120## 6-{[2-Chloro-4-fluoro-5-
(7-morpholin-4-yl- quinazolin-4-yl)phenyl]- hydroxymethyl}-2-ethyl-
2H-pyridazin-3-one (Ena 1) A B A MS: 496.2/498.1 (M + H.sup.+) see
racemate (Cl isotopy, rel. peak intensity ratio [%] 100:36);
R.sub.t 3.00 min (SFC, Chiralcel OJ-H, CO.sub.2/20% by vol. of
methanol, 0.5% by vol. of diethylamine) 98 ##STR00121##
2-(3-{[2-Chloro-4- fluoro-5-(7-morpholin- 4-ylquinazolin-4-yl)-
phenyl]hydroxymethyl}- 6-oxo-6H-pyridazin-1- yl)acetamide B D A MS:
525.1/527.1 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.12 (s,
1H), (Cl isotopy, rel. peak 7.93 (d, J = 7.7, 1H), 7.67 (d, J =
9.5, 1H), 7.58 (dd, intensity ratio [%] 100:36) J = 9.4, 3.0, 1H),
7.53 (dd, J = 9.5, 2.5, 1H), 7.51- 7.44 (m, 2H), 7.21 (d, J = 2.4,
1H), 7.15 (s, 1H), 6.94 (d, J = 9.6, 1H), 6.62 (d, J = 4.8, 1H),
5.89 (d, J = 4.8, 1H), 4.61-4.51 (m, 2H), 3.81-3.75 (m, 4H),
3.48-3.42 (m, 4H) 99 ##STR00122## 6-{[2-Chloro-4-fluoro-5-
(7-morpholin-4-yl- quinazolin-4-yl)phenyl]- hydroxymethyl}-2-(2-
hydroxy-ethyl)-2H- pyridazin-3-one B B A MS: 512.2/514.2 (M +
H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.13 (s, 1H), (Cl isotopy,
rel. peak 7.94 (d, J = 7.7, 1H), 7.68 (d, J = 9.5, 1H), 7.60-7.52
intensity ratio [%] 100:38) (m, 2H), 7.46 (d, J = 9.6, 1H), 7.22
(d, J = 2.3, 1H), 6.92 (d, J = 9.6, 1H), 6.61 (d, J = 4.8, 1H),
5.90 (d, J = 4.8 Hz, 1H), 4.75 (t, J = 5.8, 1H), 4.11-4.00 (m, 2H),
3.82-3.74 (m, 4H), 3.65 (q, J = 6.2, 2H), 3.49-3.42 (m, 4H)
Example 100
[2-Chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-[6-(oxetan-3-
-yloxy)pyridazin-3-yl]methanol (100)
##STR00123##
[0281]
[2-Chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(6-ch-
loropyridazin-3-yl)methanone (700 mg, 1.30 mmol) and oxetan-3-ol
(112 mg, 1.43 mmol) were initially introduced dissolved in
1,4-dioxane (25 ml, max. 0.005% of water) under an argon
atmosphere. Sodium hydride (60% dispersion in paraffin oil, 62 mg,
1.56 mmol) was subsequently added (evolution of gas). The reaction
mixture was stirred at room temperature for 30 min. After
termination of the reaction, the mixture was carefully diluted with
water (80 ml) and neutralised using hydrochloric acid (1.0 M). The
aqueous phase was subsequently extracted twice with ethyl acetate
(80 ml in each case). The combined organic phases were rinsed with
water (20 ml), subsequently dried over sodium sulfate, filtered and
evaporated to dryness in a rotary evaporator. The residue was
purified by means of flash column chromatography
(dichloromethane/0-10% by vol. of ethanol, CombiFlash Rf 200),
giving
[2-chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-[6-(oxetan--
3-yloxy)pyridazin-3-yl]methanone (264 mg, 0.506 mmol, 522.2
[M+H.sup.+]), 39% yield) as solid.
[0282]
[2-Chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-[6-(o-
xetan-3-yloxy)pyridazin-3-yl]methanol (EXAMPLE 100) was prepared
analogously to the synthetic process described under EXAMPLES 1 and
2 starting from
[2-chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-[6-(oxetan--
3-yloxy)pyridazin-3-yl]methanone.
[0283] Compounds which were prepared in accordance with EXAMPLE 100
can be found in Table 3 below.
TABLE-US-00003 TABLE 3 Compounds of the formula (I) IC.sub.50
IC.sub.50 K.sub.i DNA- pDNA- [Kv1.11 No. Structural formula Name PK
PK hERG] 100 ##STR00124## [2-Chloro-4-fluoro-5- (7-morpholin-4-yl-
quinazolin-4-yl)- phenyl]-6-(oxetan-3- yloxy)pyridazin-3-yl]-
methanol A A C MS: 524.2/526.1 (M + H.sup.+) (Cl 1H NMR (500 MHz,
DMSO-d6) ppm = 9.11 (s, isotopy, rel. peak intensity ratio 1H),
7.91 (d, J = 7.7, 1H), 7.77 (d, J = 9.2, 1H), [%] 100:39) 7.66 (d,
J = 9.4, 1H), 7.61-7.51 (m, 2H), 7.32 (d, J = 9.2, 1H), 7.21 (d, J
= 2.3, 1H), 6.63 (d, J = 4.8, 1H), 6.22 (d, J = 4.8 Hz, 1H), 5.69
(p, J = 5.7, 1H), 4.94-4.87 (m, 2H), 4.62-4.56 (m, 2H), 3.80-3.76
(m, 4H), 3.48-3.43 (m, 4H) 101 ##STR00125## 2-(6-{[2-Chloro-4-
fluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)- phenyl]hydroxy-
methyl}pyridazin-3- yloxy)propionitrile A A C MS: 521.2/523.2 (M +
H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm = 9.12 (d, isotopy, rel.
peak intenisty ratio J = 2.7, 1H), 7.93 (dd, J = 11.2, 7.7, 1H),
7.84 (dd, [%] 100:39) J = 16.3, 9.2, 1H), 7.70-7.65 (m, 1H), 7.63-
7.57 (m, 1H), 7.57-7.51 (m, 1H), 7.38 (dd, J = 9.1, 3.5, 1H), 7.21
(d, J = 2.4, 1H), 6.71 (dd, J = 10.3, 5.0, 1H), 6.28 (dd, J = 9.5,
5.0, 1H), 5.95- 5.87 (m, 1H), 3.81-3.74 (m, 4H), 3.48-3.42 (m, 4H),
1.76-1.70 (m, 3H) 102 ##STR00126## 2-(6-{[2-Chloro-4- fluoro-5-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]hydroxy-
methyl}pyridazin-3- yloxy)propionitrile (eluate 1) A A B MS:
543.0/545.0 (M + Na.sup.+) (Cl see also diastereomer mixure
isotopy, rel. peak intensity ratio [%] 100:35), R.sub.t 4.09 min
(SFC, Chiralpak AS-H, CO.sub.2/20% by vol. of methanol, 0.5% by
vol. of diethylamine) 103 ##STR00127## 2-(6-{[2-Chloro-4-
fluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)- phenyl]hydroxy-
methyl}pyridazin-3- yloxy)propionitrile (eluate 3) D D A MS:
521.1/523.1 (M + H.sup.+) (Cl see also diastereomer mixture
isotopy, rel. peak intensity ratio [%] 100:38); R.sub.t 6.68 min
(SFC, Chiralpak AS-H, CO.sub.2/20% by vol. of methanol, 0.5% by
vol. of diethylamine) 104 ##STR00128## 2-(6-{[2-Chloro-4-
fluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)- phenyl]hydroxy-
methyl}pyridazin-3- yloxy)propionitrile (eluate 2) C B B MS:
521.1/523.1 (M + H.sup.+) (Cl see also diastereomer mixture
isotopy, rel. peak intensity ratio [%] 100:35); R.sub.t 5.12 min
(SFC, Chiralpak AS-H, CO.sub.2/20% by vol. of methanol, 0.5% by
vol. of diethylamine) 105 ##STR00129## 2-(3-{[4-fluoro-3-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]hydroxy-
methyl}pyrazin-2-yl- oxy)ethanol C D A MS: 478.2 (M + H.sup.+) 1H
NMR (500 MHz, DMSO-d6) ppm = 9.09 (s, 1H), 8.91 (d, J = 2.8, 1H),
8.12 (d, J = 2.8, 1H), 7.70-7.64 (m, 2H), 7.54-7.51 (m, 2H), 7.38-
7.33 (m, 1H), 7.21-7.19 (m, 1H), 6.14 (d, J = 5.9, 1H), 6.00 (d, J
= 6.0, 1H), 4.86 (t, J = 5.7, 1H), 4.34-4.30 (m, 2H), 3.80-3.75 (m,
4H), 3.74-3.69 (m, 2H), 3.46-3.42 (m, 4H) 106 ##STR00130##
2-(3-{[4-fluoro-3-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]hydroxy- methyl}pyrazin-2-yl- amino)ethanol C C B MS: 477.1
(M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.09 (s, 1H), 7.91
(d, J = 2.7, 1H), 7.67 (d, J = 2.8, 1H), 7.63-7.58 (m, 2H),
7.55-7.49 (m, 2H), 7.41- 7.35 (m, 1H), 7.20 (d, J = 2.0, 1H),
6.82-6.75 (m, 2H), 5.91 (d, J = 4.2, 1H), 4.74 (t, J = 5.1, 1H),
3.82-3.73 (m, 4H), 3.60-3.45 (m, 8H) 107 ##STR00131##
3-(6-{[2-Chloro-4- fluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]hydroxy- methyl}pyridazin-3-yl- oxy)propionitrile B B A MS:
521.2/523.2 (M + H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm = 9.12
(s, isotopy, rel. peak intensity ratio 1H), 7.95 (d, J = 7.7, 1H),
7.67 (d, J = 9.5, 1H), [%] 100:39) 7.59 (dd, J = 9.4, 3.2, 1H),
7.55-7.49 (m, 2H), 7.21 (d, J = 2.4, 1H), 6.99 (d, J = 9.6, 1H),
6.67 (d, J = 4.9, 1H), 5.92 (d, J = 4.9, 1H), 4.31-4.17 (m, 2H),
3.81-3.75 (m, 4H), 3.49-3.42 (m, 4H), 2.99-2.88 (m, 2H) 108
##STR00132## [2-Chloro-4-fluoro-5- (7-morpholin-4-yl-
quinazolin-4-yl)- phenyl]-6-methyl- sulfanylpyridazin-3-
yl)methanol B A B MS: 498.1/500.1 (M + H.sup.+) (Cl 1H NMR (500
MHz, DMSO-d6) ppm = 9.12 (s, isotopy, rel. peak intensity ratio
1H), 7.90 (d, J = 7.7, 1H), 7.68 (d, J = 9.5, 1H), [%] 100:47)
7.66-7.60 (m, 2H), 7.60-7.56 (m, 1H), 7.54 (dd, J = 9.4, 2.5, 1H),
7.21 (d, J = 2.4, 1H), 6.68 (s, 1H), 6.25 (s, 1H), 3.80-3.76 (m,
4H), 3.47- 3.43 (m, 4H), 2.61 (s, 3H) 109 ##STR00133##
[2-Chloro-4-fluoro-5- (7-morpholin-4-yl- quinazolin-4-yl)-
phenyl]-(6-methoxy- 4-methylpyridazin-3- yl)methanol D C A MS:
518.2/520.2 (M + Na.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm = 9.14
(s, isotopy, rel. peak intensity ratio 1H), 7.99 (d, J = 7.8, 1H),
7.67-7.61 (m, 2H), [%] 100:38) 7.57 (dd, J = 9.4, 2.6, 1H), 7.23
(d, J = 2.5, 1H), 7.10 (d, J = 1.1, 1H), 6.42 (d, J = 6.4, 1H),
6.25 (d, J = 6.3, 1H), 3.96 (s, 3H), 3.82-3.75 (m, 4H), 3.50-3.42
(m, 4H), 2.49-2.46 (m, 3H) 110 ##STR00134## [2-Chloro-4-fluoro-5-
(7-morpholin-4-yl- quinazolin-4-yl)- phenyl]-(6-methoxy-
5-methylpyridazin-3- yl)methanol C B C MS: 496.1/498.1 (M +
H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm = 9.12 (s, isotopy, rel.
peak intensity ratio 1H), 7.91 (d, J = 7.8, 1H), 7.66 (d, J = 9.6,
1H), [%] 100:38) 7.59 (dd, J = 9.4, 3.3, 1H), 7.56-7.52 (m, 2H),
7.21 (d, J = 2.4, 1H), 6.54 (d, J = 4.9, 1H), 6.18 (d, J = 4.9,
1H), 4.02 (s, 3H), 3.80-3.75 (m, 4H), 3.48-3.43 (m, 4H), 2.17 (d, J
= 1.0, 3H) 111 ##STR00135## 2-(6-{[2-Chloro-4- fluoro-5-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]hydroxy-
methyl}pyridazin-3- yloxy)acetamide B C A MS: 525.2/527.2 (M +
H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm = 9.12 (s, isotopy, rel.
peak intensity ratio 1H), 7.92 (d, J = 7.7, 1H), 7.74 (d, J = 9.1,
1H), [%] 100:34) 7.66 (d, J = 9.5, 1H), 7.59 (dd, J = 9.4, 3.3,
1H), 7.57-7.49 (m, 2H), 7.27 (d, J = 9.1, 1H), 7.23- 7.16 (m, 2H),
6.63 (d, J = 5.0, 1H), 6.23 (d, J = 5.0, 1H), 4.81 (s, 2H),
3.81-3.75 (m, 4H), 3.49-3.43 (m, 4H) 112 ##STR00136##
[2-Chloro-4-fluoro-5- (7-morpholin-4-yl- quinazolin-4-yl)-
phenyl]-[6-(2- methoxyethoxy)- pyridazin-3-yl]- methanol A B B MS:
526.2/528.3 (M + H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm = 9.12
(s, isotopy, rel. peak intensity ratio 1H), 7.91 (d, J = 7.7, 1H),
7.69 (d, J = 9.2, 1H), [%] 100:38) 7.67 (d, J = 9.5, 1H), 7.59 (dd,
J = 9.4, 3.3, 1H), 7.54 (dd, J = 9.5, 2.5, 1H), 7.25-7.19 (m, 2H),
6.61 (d, J = 5.0, 1H), 6.23 (d, J = 5.0, 1H), 4.54- 4.50 (m, 2H),
3.80-3.75 (m, 4H), 3.71-3.67 (m, 2H), 3.48-3.43 (m, 4H), 3.29 (s,
3H) 113 ##STR00137## (6-{[2-Chloro-5- fluoro-5-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]hydroxy- methyl}pyridazin-3-yl- oxy)acetic
acid B D A MS: 526.2/528.1 (M + H.sup.+) (Cl 1H NMR (500 MHz,
DMSO-d6) ppm = 12.91 (s, isotopy, rel. peak intensity ratio 1H),
9.12 (s, 1H), 7.92 (d, J = 7.7, 1H), 7.75 (d, [%] 100:39) J = 9.1,
1H), 7.66 (d, J = 9.5, 1H), 7.59 (dd, J = 9.4, 3.3, 1H), 7.54 (dd,
J = 9.5, 2.5, 1H), 7.31 (d, J = 9.1, 1H), 7.21 (d, J = 2.4, 1H),
6.66 (s, 1H), 6.23 (s, 1H), 4.97 (s, 2H), 3.81-3.75 (m, 4H),
3.48-3.43 (m, 4H) 114 ##STR00138## (6-{[2-Chloro-4- fluoro-5-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]hydroxy-
methyl}pyridazin-3-yl- oxy)acetic acid methyl ester B D A MS:
540.2/542.2 (M + H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm = 9.12
(s, isotopy, rel. peak intensity ratio 1H), 7.92 (d, J = 7.7, 1H),
7.77 (d, J = 9.1, 1H), [%] 100:38) 7.67 (d, J = 9.5, 1H), 7.59 (dd,
J = 9.3, 3.2, 1H), 7.57-7.51 (m, 1H), 7.35 (d, J = 9.1, 1H), 7.23-
7.19 (m, 1H), 6.62 (s, 1H), 6.23 (s, 1H), 5.07 (s, 2H), 3.81-3.75
(m, 4H), 3.67 (s, 3H), 3.49- 3.44 (m, 4H) 115 ##STR00139##
[2-Chloro-4-fluoro-5- (7-morpholin-4-yl- quinazolin-4-yl)-
phenyl]-[6-(2,2,2- trifluoroethoxy)- pyridazin-3-yl]- methanol B B
C MS: 550.2/552.1 (M + H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm =
9.11 (s, isotopy, rel. peak intensity ratio 1H), 7.91 (d, J = 7.7,
1H), 7.81 (d, J = 9.2, 1H), [%] 100:40) 7.66 (d, J = 9.5, 1H),
7.60-7.52 (m, 2H), 7.41 (d, J = 9.1, 1H), 7.20 (d, J = 2.3, 1H),
6.72 (d, J = 5.0, 1H), 6.26 (d, J = 4.5, 1H), 5.22-5.08 (m, 2H),
3.80-3.75 (m, 4H), 3.47-3.43 (m, 4H) 116 ##STR00140##
2-(6-{[2-Chloro-4- fluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]hydroxy- methyl}pyridazin-3-yl- oxy)ethanol A B A MS:
512.2/514.1 (M + H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm = 9.12
(s, isotopy, rel. peak intensity ratio 1H), 7.91 (d, J = 7.7, 1H),
7.71-7.64 (m, 2H), [%] 100:38) 7.61-7.51 (m, 2H), 7.23-7.17 (m,
2H), 6.60 (d, J = 5.0, 1H), 6.22 (d, J = 5.0, 1H), 4.84 (t, J =
5.5, 1H), 4.44-4.39 (m, 2H), 3.81-3.76 (m, 4H), 3.74 (q, J = 5.4,
2H), 3.48-3.43 (m, 4H) 117 ##STR00141## (3-Amino-pyrazin-2-
yl)-[2-chloro-4-fluoro- 5-(7-morpholin-4-yl- quinazolin-4-yl)-
phenyl]methanol B B B MS: 467.1/469.1 (M + H.sup.+) (Cl 1H NMR (400
MHz, DMSO-d6) ppm = 9.14 (s, isotopy, rel. peak intensity ratio
1H), 7.91 (d, J = 7.8, 1H), 7.87 (d, J = 2.7, 1H), [%] 100:34)
7.67-7.55 (m, 4H), 7.21 (d, J = 2.5, 1H), 6.41 (s, 3H), 6.09 (s,
1H), 3.81-3.75 (m, 4H), 3.50- 3.45 (m, 4H) 118 ##STR00142##
6-{[2-Chloro-4-fluoro- 5-(7-morpholin-4-yl- quinazolin-4-yl)-
phenyl]hydroxy- methyl}pyridazine-3- carbonitrile B B B MS:
477.0/479.1 (M + H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm = 9.11
(s, isotopy, rel. peak intensity ratio 1H), 8.36 (d, J = 8.7, 1H),
8.13 (d, J = 8.7, 1H), [%] 100:41) 7.86 (d, J = 7.6, 1H), 7.71 (d,
J = 9.5, 1H), 7.55 (qd, J = 9.4, 2.7, 2H), 7.21 (d, J = 2.3, 1H),
6.96 (d, J = 4.9, 1H), 6.43 (d, J = 4.9, 1H), 3.80-3.76 (m, 4H),
3.48-3.43 (m, 4H) 119 ##STR00143## (6-{[2-Chloro-4- fluoro-5-(7-
morpholin-4-yl-
quinazolin-4-yl)- phenyl]hydroxy- methyl}pyridazin-3-yl-
oxy)acetonitrile A A B MS: 507.1/509.1 (M + H.sup.+) (Cl 1H NMR
(400 MHz, DMSO-d6) ppm = 9.12 (s, isotopy, rel. peak intensity
ratio 1H), 7.93 (d, J = 7.7, 1H), 7.85 (d, J = 9.2, 1H), [%]
100:35) 7.67 (d, J = 9.5, 1H), 7.60 (dd, J = 9.4, 3.3, 1H), 7.54
(dd, J = 9.4, 2.5, 1H), 7.40 (d, J = 9.1, 1H), 7.21 (d, J = 2.4,
1H), 6.72 (d, J = 5.0, 1H), 6.28 (d, J = 4.8, 1H), 5.38 (s, 2H),
3.81-3.75 (m, 4H), 3.48-3.42 (m, 4H)
Examples 120, 121 and 122
[2,4-Difluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(4-methoxyphenyl)-
methanol (EXAMPLE 120)
##STR00144##
[0285] 5-Bromo-2,4-difluorobenzaldehyde (280 mg, 1.27 mmol) in dry
tetrahydrofuran (10 ml) was initially introduced in a three-necked
flask with internal thermometer, protective-gas inlet, septum and
stirrer bar which had been dried by heating. 4-Methoxyphenyl
magnesium bromide (1 M in THF, 1.39 ml, 1.39 mmol) was slowly added
dropwise at 5.degree. C., and the reaction solution was stirred at
room temperature for 18 h. With water (20 ml) was subsequently
added to the reaction solution. The phases were separated, and the
aqueous phase was extracted twice with ethyl acetate (20 ml). The
combined organic phases were washed with water, dried over sodium
sulfate, filtered and evaporated to dryness in a rotary evaporator,
giving (5-bromo-2,4-difluorophenyl)-(4-methoxyphenyl)methanol (530
mg, 1.61 mmol, MS: 353 [M+H.sup.+]) as oily crude product, which
was used without further purification for the next synthesis
step.
##STR00145##
[0286] Starting from
(5-bromo-2,4-difluorophenyl)-(4-methoxyphenyl)methanol,
[2,4-difluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(4-methoxyphenyl-
)methanol (EXAMPLE 120) was prepared analogously to the synthetic
processes described under EXAMPLES 1 and 2.
(6-Difluoromethoxypyridazin-3-yl)-[4-fluoro-3-(7-morpholin-4-ylquinazolin--
4-yl)phenyl]-methanol (EXAMPLE 121)
##STR00146##
[0288] 6-Chloro-2H-pyridazin-3-one (944 mg, 7.23 mmol) and
difluoro(fluorosulfonyl)acetic acid (1.42 g, 7.96 mmol) were
dissolved in acetonitrile (19 ml) in a vessel with stirrer bar and
stirred at room temperature for 40 h. The reaction solution was
then diluted with ethyl acetate (150 ml) and washed successively
with water, saturated sodium hydrogencarbonate solution and again
with water. The organic phase was dried using sodium sulfate,
filtered and evaporated to dryness in a rotary evaporator. The
residue was taken up in cyclohexane, re-filtered, and the solvent
was removed in a rotary evaporator. The residue obtained was
purified by means of flash column chromatography (gradient
cyclohexane/0-50% by vol. of ethyl acetate, CombiFlash Rf 200). The
suitable product fractions were combined, and the solvents were
removed in a rotary evaporator, giving
3-chloro-6-(difluoromethoxy)pyridazine (285 mg, 1.58 mmol, MS:
181.0/183.1[M+H.sup.+]), 22% yield) as colourless liquid.
##STR00147##
[0289] Potassium hydroxide powder (603 mg, 10.75 mmol) was
suspended in dry N,N-dimethylformamide (2 ml) in a glass vessel
with stirrer bar and stirred at room temperature for 30 min.
(3-Bromo-4-fluorophenyl)acetonitrile (1.0 g, 4.67 mmol), dissolved
in N,N'-dimethylformamide (1.3 ml), was subsequently added
dropwise. The reaction mixture was stirred at room temperature for
a further 30 min.
(5-Bromo-2,4-difluorophenyl)-(4-methoxyphenyl)methanol (506 mg,
2.80 mmol) was then added in portions to the reaction mixture and
stirred at 50.degree. C. for 2 h under an oxygen-free argon
protective-gas atmosphere. The reaction mixture was added to a
mixture of water (50 ml) and saturated sodium chloride solution (35
ml) and extracted twice with ethyl acetate. The combined organic
phases were dried over sodium sulfate, filtered and evaporated to
dryness in a rotary evaporator. The residue was purified by means
of RP column chromatography (gradient water/acetonitrile with 0.1%
by vol. of formic acid, CombiFlash Rf 200). The suitable product
fractions were combined, and the solvents were removed in a rotary
evaporator, giving
(3-bromo-4-fluorophenyl)-(6-difluoromethoxy-pyridazin-3-yl)acetonitrile
(146 mg, 0.41 mmol, MS: 358.0/360.0[M+H.sup.+], 14% yield) as
liquid.
2-(3-Bromo-4-fluorophenyl)-2-(6-chloropyridazin-3-yl)acetonitrile
is formed as by-product.
##STR00148##
[0290]
(3-Bromo-4-fluorophenyl)-(6-difluoromethoxypyridazin-3-yl)acetonitr-
ile (146 mg, 0.41 mmol) was dissolved in dry acetonitrile (4 ml).
Potassium tert-butoxide (43.6 mg, 0.388 mmol) was subsequently
added, and the reaction mixture was stirred at room temperature for
25 min. The reaction solution was then cooled to 0.degree. C. in an
ice bath, hydrogen peroxide (30% in water, 92 .mu.l, 0.90 mmol) was
added dropwise, and the reaction mixture was stirred firstly at
0.degree. C. for a further 25 min and then at room temperature for
1 h. For work-up, the reaction mixture was added to water (40 ml)
and extracted twice with ethyl acetate. The combined organic phases
were dried over sodium sulfate, filtered and evaporated to dryness
in a rotary evaporator, giving
(3-bromo-4-fluorophenyl)-(6-difluoromethoxypyridazin-3-yl)methanon-
e (113 mg, 0.32 mmol, MS: 346.9/349.0[M+H.sup.+], 79% yield) as
solid.
##STR00149##
[0291]
(3-Bromo-4-fluorophenyl)-(6-difluoromethoxypyridazin-3-yl)methanone
(126 mg, 0.36 mmol) was dissolved in methanol (4 ml). Sodium
borohydride (60.4 mg, 1.60 mmol) was subsequently added in
portions, and the reaction mixture was stirred at room temperature
for 1 h. After termination of the reaction, the mixture was diluted
with saturated ammonium chloride solution (5 ml) and subsequently
extracted twice with ethyl acetate (30 ml). The combined organic
phases were washed with water, dried over sodium sulfate, filtered
and evaporated to dryness in a rotary evaporator, giving
(3-bromo-4-fluorophenyl)-(6-difluoromethoxypyridazin-3-yl)methanol
(127 mg, MS: 349/351[M+H.sup.+]) as crude product in the form of a
solid, which was used without further purification for further
synthesis steps.
[0292]
(6-Difluoromethoxypyridazin-3-yl)-[4-fluoro-3-(7-morpholin-4-ylquin-
azolin-4-yl)phenyl]-methanol (EXAMPLE 121) was obtained analogously
by the synthetic process described for
[2,4-difluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(4-methoxyphenyl-
)methanol (EXAMPLE 120).
1-[2-Chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-1-(6-metho-
xypyridazin-3-yl)prop-2-yn-1-ol (EXAMPLE 122)
##STR00150##
[0294]
([2-Chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(6-m-
ethoxypyridazin-3-yl)methanol (EXAMPLE 137, 898 mg, 1.75 mmol) was
dissolved in diochloromethane (15 ml). Dess-Martin
triacetoxyperiodinane (15% in dichloromethane, 7.23 ml, 3.50 mmol)
was subsequently added. The reaction suspension was stirred at room
temperature for 1 h. For workup, water (60 ml) and a 10%, aqueous
sodium thiosulfate solution was added. The aqueous phase was
extracted twice with ethyl acetate (80 ml in each case). The
combined organic phases were washed with saturated sodium chloride
solution (30 ml), dried over sodium sulfate, filtered, and the
filtrate was evaporated to dryness in vacuo, giving 2.1 g of a
crude product in the form of an oil. The residue was purified by
means of flash column chromatography (gradient:
dichloromethane/0-25% by vol. of dichloromethane/ethanol 9:1,
CombiFlash Rf 200), giving
[2-chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(6-methoxyp-
yridazin-3-yl)methanone (792 mg, 1.65 mmol, MS: 480.1/482.1
[M+H.sup.+], 94% yield) as foam.
[0295] Trimethylsilylacetylene (179 .mu.l, 125 mg, 1.25 mmol)
dissolved in dry tetrahydrofuran (3 ml) was initially introduced in
a glass vessel with stirrer bar and internal thermometer under
argon. The reaction solution was cooled to (-)20.degree. C., and
n-butyllithium (1.6 M in n-hexane, 781 .mu.l, 1.25 mmol) was slowly
added dropwise. The reaction mixture was stirred at (-)20.degree.
C. for a further 30 min. The reaction solution was then cooled to
(-)70.degree. C., and
[2-chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(6-methoxyp-
yridazin-3-yl)methanone (200 mg, 0.417 mmol) dissolved in dry
tetrahydrofuran (6 ml) was subsequently added dropwise. The
temperature of the reaction mixture was increased to (-)40.degree.
C. over a period of 1 h. Water (40 ml) was subsequently added, and
the phases were separated. The organic phase was extracted twice
with dichloromethane. The combined organic phases were dried using
sodium sulfate, filtered and evaporated to dryness in vacuo. The
residue was dissolved in dry tetrahydrofuran (4 ml), and
tetra-n-butylammonium fluoride trihydrate (109 mg, 0.42 mmol) was
added. The mixture was subsequently stirred at room temperature for
18 h. The volatile reaction constituents were then removed in a
rotary evaporator. The residue was pre-purified by means of flash
column chromatography (gradient: dichloromethane/0-34% by vol. of
dichloromethane/ethanol 1:1, CombiFlash Rf 200). The product
fractions were combined, and the solvents were removed in vacuo in
a rotary evaporator. The residue was finally purified by means of
preparative RP chromatography (Chromolith RP-18e 21.2.times.100 mm,
flow rate: 50 ml/min., wavelength: 220 nm). The volatile solvent
constituents of the suitable fractions were removed by means of a
vacuum centrifuge (Genevac HT-12), and the product was freeze-dried
from acetonitrile/water (1:3 parts by volume), giving
1-[2-chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-1-(6-meth-
oxypyridazin-3-yl)prop-2-yn-1-ol (EXAMPLE 122, 102 mg, 0.20 mmol,
MS: 506.1/508.1 [M+H.sup.+], 48% yield) as solid.
[0296] Compounds which were prepared in accordance with EXAMPLES
120, 121 and 122 can be found in Table 4 below.
TABLE-US-00004 TABLE 4 Compounds of the formula (I) IC.sub.50
IC.sub.50 K.sub.i DNA- pDNA- [Kv1.11 No. Structural formula Name PK
PK hERG] 120 ##STR00151## [2,4-Difluoro-5-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]-(4- methoxyphenyl)- methanol C B D MS:
464.2 (M + H.sup.+) 1H NMR (400 MHz, DMSO-d6) ppm = 9.09 (s, 1H),
7.61-7.47 (m, 3H), 7.36-7.30 (m, 2H), 7.27 (t, J = 9.1, 1H), 7.20
(d, J = 2.3, 1H), 6.93- 6.87 (m, 2H), 6.18 (d, J = 4.6, 1H), 6.14
(d, J = 4.6, 1H), 3.81-3.75 (m, 4H), 3.73 (s, 3H), 3.48-3.41 (m,
4H) 121 ##STR00152## (6-Difluoro- methoxy- pyridazin-3-yl)-[4-
fluoro-3-(7- morpholin-4-yl- quinazolin-4-yl)- phenyl]methanol B B
B MS: 484.1 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.10 (s,
1H), 7.96 (d, J = 9.1, 1H), 7.73-7.63 (m, 2H), 7.57-7.47 (m, 3H),
7.46-7.31 (m, 1H), 7.22- 7.16 (m, 1H), 6.63 (d, J = 4.4, 1H), 6.10
(d, J = 4.4, 1H), 3.81-3.75 (m, 4H), 3.47-3.41 (m, 4H) 122
##STR00153## 1-[2-Chloro-4- fluoro-5-(7- morpholin-4-yl-
quinzolin-4-yl)- phenyl]-1-(6- methoxy- pyridazin-3-yl)-
prop-2-yn-1-ol C B C MS: 506.1/508.1 (M + H.sup.+) 1H NMR (500 MHz,
DMSO-d6) ppm = 9.16 (s, (Cl isotopy, rel. peak intensity 1H), 8.28
(d, J = 7.7, 1H), 7.96 (d, J = 9.2, 1H), ratio [%] 100:35)
7.69-7.63 (m, 2H), 7.59 (dd, J = 9.5, 2.5, 1H), 7.50 (s, 1H), 7.30
(d, J = 9.2, 1H), 7.23 (d, J = 2.5, 1H), 4.02 (s, 3H), 3.94 (s,
1H), 3.81- 3.76 (m, 4H), 3.50-3.44 (m, 4H) 123 ##STR00154##
1-[2-Chloro-4- fluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]-2,2- difluoro-1-(6- methoxy- pyridazin-3-yl)- ethanol C D A
MS: 532.1/534.1 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.15
(s, (Cl isotopy, rel. peak intensity 1H), 8.17 (d, J = 7.7, 1H),
7.67-7.61 (m, 3H), ratio [%] 100:40) 7.57 (dd, J = 9.5, 2.5, 1H),
7.32 (s, 1H), 7.26 (d, 1H), 7.25-7.22 (m, 1H), 7.22-6.96 (m, 2H),
4.05 (s, 3H), 3.81-3.75 (m, 4H), 3.50- 3.45 (m, 4H). 124
##STR00155## [2,4-Difluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]-(2-fluoro- 4-methoxy- phenyl)methanol C B D MS: 582.1 (M +
H.sup.+) 1H NMR (400 MHz, DMSO-d6) ppm = 9.09 (s, 1H), 7.70 (t, J =
8.8, 1H), 7.62-7.44 (m, 3H), 7.25 (t, J = 9.2, 1H), 7.20 (d, J =
2.4, 1H), 6.82 (dd, J = 8.6, 2.5, 1H), 6.74 (dd, J = 12.6, 2.5,
1H), 6.34 (d, J = 4.6, 1H), 6.28 (d, J = 4.6, 1H), 3.82-3.71 (m,
7H), 3.49-3.41 (m, 4H) 125 ##STR00156## 1-[2-Chloro-4- fluoro-5-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]-1-(6- methoxy-
pyridazin-3-yl)- ethanol B D B MS: 496.1/498.1 (M + H.sup.+) 1H NMR
(500 MHz, DMSO-d6) ppm = 9.15 (s, (Cl isotopy, rel. peak intensity
1H), 8.20 (d, J = 7.9, 1H), 7.67 (dd, J = 9.4, 3.4, ratio [%]
100:35) 1H), 7.60-7.54 (m, 3H), 7.23 (d, J = 2.5, 1H), 7.18 (d, J =
9.2, 1H), 6.39 (s, 1H), 4.03 (s, 3H), 3.82-3.75 (m, 4H), 3.49-3.45
(m, 4H), 2.02 (s, 3H) 126 ##STR00157## [2-Chloro-4-fluoro-
5-(6-morpholin-4- ylthieno[3,2-d}- pyrimidin-4-yl)- phenyl]-6-
methoxy- pyridazin-3-yl)- methanol (Ena 2) A A C MS: 488.1/490.1 (M
+ H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm = 8.90 (s, isotopy,
rel. peak intensity ratio 1H), 8.00 (d, J = 7.9, 1H), 7.69 (d, J =
9.2, 1H), [%] 100:39); R.sub.t 16.85 min (SFC, 7.66 (d, J = 10.0,
1H), 7.22 (d, J = 9.2, 1H), 6.62 Chiracel OD-H, CO.sub.2/15% by (d,
J = 4.9, 1H), 6.54 (s, 1H), 6.22 (d, J = 4.9, vol. of methanol,
0.5% by vol. of 1H), 3.99 (s, 3H), 3.77-3.72 (m, 4H), 3.45-
diethylamine) 3.39 (m, 4H) 127 ##STR00158## [2-Chloro-4-fluoro-
5-(6-morpholin-4- ylthieno[3,2-d}- pyrimidin-4-yl)- phenyl]-(6-
methoxy- pyridazin-3-yl)- methanol (Ena 1) B C C MS: 488.1/490.1 (M
+ H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm = 8.90 (s, isotopy,
rel. peak intensity ratio 1H), 8.00 (d, J = 7.9, 1H), 7.69 (d, J =
9.2, 1H), [%] 100:40); R.sub.t 14.73 min (SFC, 7.66 (d, J = 10.0,
1H), 7.22 (d, J = 9.1, 1H), 6.61 Chiral OD-H, CO.sub.2/15% by (d, J
= 5.0, 1H), 6.54 (s, 1H), 6.21 (d, J = 4.9, vol. of methanol, 0.5%
by vol. of 1H), 3.99 (s, 3H), 3.77-3.72 (m, 4H), 3.45-
diethylamine) 3.40 (m, 4H) 128 ##STR00159## [2-Chloro-4-fluoro-
5-(6-morpholin-4- ylthieno[3,2-d}- pyrimidin-4-yl)- phenyl]-(6-
methoxy- pyridazin-3-yl)- methanol A B B MS: 488.1/490.1 (M +
H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm = 8.90 (s, isotopy, rel.
peak intensity ratio 1H), 8.00 (d, J = 7.99, 1H), 7.69 (d, J = 9.2,
1H), [%] 100:41) 7.66 (d, J = 10.0, 1H), 7.22 (d, J = 9.1, 1H),
6.61 (d, J = 4.9, 1H), 6.54 (s, 1H), 6.22 (d, J = 4.9, 1H), 3.99
(s, 3H), 3.77-3.73 (m, 4H), 3.44- 3.40 (m, 4H) 129 ##STR00160##
[2,4-Difluoro-5-(7- morpholin-4-yl- quinazoin-4-yl)- phenyl]-6-
methoxy- pyridazin-3-yl)- methanol (Ena 2) C C B MS: 466.2 (M +
H.sup.+); R.sub.t 4.13 min, see racemate (SFC, Chiralpak AS-H,
CO.sub.2/ 18% by vol. of methanol, 0.5% by vol. of diethylamine)
130 ##STR00161## [2,4-Difluoro-5-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]-(6- methoxy- pyridazin-3-yl)- methanol
(Ena 1) A A A MS: 466.2 (M + H.sup.+); R.sub.t 2.79 min, see
racemate (SFC, Chiralpak AS-H, CO.sub.2/ 18% by vol. of methanol,
0.5% by vol. of diethylamine) 131 ##STR00162## [2,4-Difluoro-5-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]-(6- methoxy-
pyridazin-3-yl)- methanol B B B MS: 466.2 (M + H.sup.+) 1H NMR (500
MHz, DMSO-d6) ppm = 9.11 (s, 1H), 7.83 (t, J = 8.1, 1H), 7.75 (d, J
= 9.2, 1H), 7.56 (qd, J = 9.4, 2.8, 2H), 7.45 (t, J = 10.1, 1H),
7.25-7.19 (m, 2H), 6.59-6.57 (m, 1H), 6.20- 6.16 (m, 1H), 4.00 (s,
3H), 3.81-3.75 (m, 4H), 3.48-3.42 (m, 4H) 132 ##STR00163##
[2-Chloro-5-(2- chloro-7- morpholin-4-yl- quinazolin-4-yl)-4-
fluorophenyl]-(6- methoxy- pyridazin-3-yl)- methanol B B A MS:
516.1/518.1/520.0 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm =
7.94 (d, (Cl.sub.2 isotopy, rel. peak intensity J = 7.7, 1H),
7.72-7.65 (m, 2H), 7.63-7.49 ratio [%] 100:69:12) (m, 2H), 7.21 (d,
J = 9.1, 1H), 7.15 (d, J = 2.4, 1H), 6.22 (s, 1H), 4.00 (s, 3H),
3.79-3.73 (m, 4H), 3.53-3.47 (m, 4H) 133 ##STR00164##
[6-(2-Dimethyl- amino-ethoxy)- pyridazin-3-yl]-[4- fluoro-3-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]methanol C C A MS: 505.3
(M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.09 (s, 1H), 7.69
(d, J = 9.2, 1H), 7.67-7.61 (m, 2H), 7.55-7.47 (m, 2H), 7.44-7.36
(m, 1H), 7.24- 7.15 (m, 2H), 6.49 (d, J = 4.0, 1H), 6.04- 5.98 (m,
1H), 4.56-4.41 (m, 2H), 3.80-3.74 (m, 4H), 3.47-3.41 (m, 4H), 2.64
(t, J = 5.8, 2H), 2.19 (s, 6H) 134 ##STR00165## (6-Ethoxy-
pyridazin-3-yl)-[4- fluoro-3-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]methanol C B C MS: 462.1 (M + H.sup.+) 1H NMR (500 MHz,
DMSO-d6) ppm = 9.09 (s, 1H), 7.68 (d, J = 9.2, 1H), 7.66-7.61 (m,
2H), 7.53-7.50 (m, 2H), 7.43-7.35 (m, 1H), 7.21- 7.19 (m, 1H), 7.17
(d, J = 9.1, 1H), 6.47 (d, J = 4.4, 1H), 6.01 (d, J = 4.3, 1H),
4.52-4.38 (m, 2H), 3.82-3.73 (m, 4H), 3.46-3.41 (m, 4H), 1.36 (t, J
= 7.0, 3H) 135 ##STR00166## (R)-[2-Chloro-4- fluoro-5-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]-6- methoxy-
pyridazin-3-yl)- methanol C D A MS: 482.1/484.1 (M + H.sup.+) (Cl
1H NMR (500 MHz, DMSO-d6) ppm = 9.12 (s, isotopy, rel. peak
intensity ratio 1H), 7.91 (d, J = 7.7, 1H), 7.69 (d, J = 9.2, 1H),
[%] 100:36); R.sub.t 5.34 min (SFC, 7.67 (d, J = 9.5, 1H),
7.62-7.51 (m, 2H), 7.24- Chiralpak AD-H, CO.sub.2/40% by 7.18 (m,
2H), 6.61 (d, J = 4.8, 1H), 6.23 (d, vol. of methanol, 0.5% by vol.
of J = 4.8, 1H), 4.00 (s, 3H), 3.81-3.75 (m, 4H), diethylamine)
3.48-3.42 (m, 4H) 136 ##STR00167## (S)-[2-Chloro-4- fluoro-5-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]-(6- methoxy-
pyridazin-3-yl)- methanol A A A MS: 482.1/484.1 (M + H.sup.+) (Cl
1H NMR (500 MHz, DMSO-d6) ppm = 9.12 (s, isotopy, rel. peak
intensity ratio 1H), 7.91 (d, J = 7.7, 1H), 7.69 (d, J = 9.2, 1H),
[%] 100:36); R.sub.t 3.38 min (SFC, 7.66 (d, J = 9.5, 1H),
7.61-7.52 (m, 2H), 7.24- Chiralpak AD-H, CO.sub.2/40% by 7.19 (m,
2H), 6.61 (d, J = 5.0, 1H), 6.23 (d, vol. of methanol, 0.5% by vol.
of J = 4.9, 1H), 4.00 (s, 3H), 3.81-3.75 (m, 4H), diethylamine)
3.48-3.43 (m, 4H) 137 ##STR00168## [2-Chloro-4-fluoro-
5-(7-morpholin-4- ylquinazolin-4-yl)- phenyl]-(6- methoxy-
pyridazin-3-yl)- methanol A B C MS: 482.1/484.1 (M + H.sup.+) (Cl
1H NMR (400 MHz, DMSO-d6) ppm = 9.12 (s, isotopy, rel. peak
intensity ratio 1H), 7.91 (d, J = 7.7, 1H), 7.69 (d, J = 9.1, 1H),
[%] 100:36) 7.66 (d, J = 9.5, 1H), 7.62-7.51 (m, 2H), 7.24- 7.17
(m, 2H), 6.60 (d, J = 4.9, 1H), 6.23 (d, J = 3.5, 1H), 4.00 (s,
3H), 3.82-3.74 (m, 4H), 3.49-3.42 (m, 4H)
Example 138
1-[5-(7-Morpholin-4-ylquinazolin-4-yl)pyridin-3-yl]-1-thiazol-2-ylethanol
(EXAMPLE 138)
##STR00169##
[0298] Thiazole (143 .mu.l, 2.0 mmol) in dry tetrahydrofuran (10
ml) was initially introduced in a three-necked flask which had been
dried by heating. The reaction solution was cooled to (-)78.degree.
C. by means of acetone/dry-ice bath. n-Butyllithium (15% solution
in n-hexane, 1.63 ml, 2.6 mmol) was added dropwise over a period of
10 min at constant temperature. The reaction mixture was stirred
for a further 10 min. The suspension was was subsequently warmed to
(-)30.degree. C. and re-cooled to (-)55.degree. C., and
1-(5-bromopyridin-3-yl)ethanone (380 mg, 1.90 mmol), dissolved in
dry tetrahydrofuran (6 ml), was added dropwise at (-)40.degree. C.
The reaction temperature is allowed to rise to (-)10.degree. C.
over 1.5 h. After termination of the reaction (HPLC check),
saturated ammonium chloride solution was added, and the mixture was
stirred at room temperature for 30 min. The reaction mixture was
added to a two-phase solution of water (60 ml) and ethyl acetate
(80 ml) and extracted three times with ethyl acetate. The combined
organic phases were washed with saturated sodium chloride solution,
dried over sodium sulfate, filtered and evaporated in a rotary
evaporator. The oily crude product was purified by means of flash
column chromatography (solvent: dichloromethane/2.0% by vol. of
methanol, then dichloromethane/3.0% by vol. of methanol+1.0% by
vol. of ammonia, amount of flash silica gel 30 g). The product
fractions were combined, and the solvents were removed in vacuo in
a rotary evaporator, giving
1-(5-bromopyridin-3-yl)-1-thiazol-2-ylethanol (479 mg, 1.68 mmol,
MS: 285.0/287.0 [M+H.sup.+], 84% yield) as oil.
##STR00170##
[0299] 1-(5-Bromopyridin-3-yl)-1-thiazol-2-ylethanol (162 mg, 0.55
mmol), bis(pinacolato)diboron (140 mg, 0.55 mmol),
1,1'-bis(diphenylphosphino)ferrocene (Dppf, 7.1 mg, 0.013 mmol),
1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride
[Pd(dppf)Cl.sub.2, 10.4 mg, 0.013 mmol] and potassium acetate (167
mg, 1.7 mmol) were suspended in dry, oxygen-free 1,4-dioxane in a
glass vessel with stirrer bar. The glass vessel was sealed using a
septum. The reaction solution was stirred and heated at 115.degree.
C. for 2.5 h. The reaction monitoring is carried out by means of
HPLC. 4-Chloro-7-morpholin-4-ylquinazoline (106 mg, 0.43 mmol),
bis(tricyclohexylphosphine)palladium(II) dichloride (9.4 mg, 0.013
mmol) and 2.0 M sodium carbonate solution (531 .mu.l) were added to
the reaction solution. The reaction mixture was subsequently
stirred at a temperature of 125.degree. C. for 1.5 h. The mixture
was decanted into water/dichloromethane (1:1 parts by volume, 40
ml), and the resultant solution was extracted three times with
dichloromethane. The combined organic phases were dried over sodium
sulfate, filtered and evaporated in a rotary evaporator. The
residue was purified by means of flash chromatography [gradient:
dichloromethane/20-58% by vol. of a solvent mixture of
dichloromethane/methanol 9:1 (parts by volume), CombiFlash Rf 200].
The suitable product fractions were combined, and the solvents were
removed in a rotary evaporator, giving
1-[5-(7-morpholin-4-ylquinazolin-4-yl)pyridin-3-yl]-1-thiazol-2-ylethanol
(EXAMPLE 138, 95 mg, 0.23 mmol, MS: 420.2 [M+H.sup.+], 53% yield)
as oil.
Example 139
{3-[7-(3,6-Dihydro-2H-pyran-4-yl)quinazolin-4-yl]-4-fluorophenyl}thiazol-2-
-ylmethanol (139)
##STR00171##
[0301]
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyra-
n (575 mg, 2.74 mmol), methyl 2-amino-4-bromobenzoate (600 mg, 2.61
mmol), bis(tricyclohexylphosphine)palladium(II) dichloride (57.8
mg, 0.078 mmol) and oxygen-free 2.0 M sodium carbonate solution
(3.26 ml, 6.52 mmol) in degassed, oxygen-free 1,4-dioxane (12 ml)
were initially introduced in a microwave glass vessel with stirrer
bar. The substance mixture was heated at 135.degree. C. for a
period of 55 min in a Personal Chemistry Microwave Synthesiser at
100 watts. The reaction solution was subsequently decanted off into
a mixture of water (40 ml) and ethyl acetate (30 ml) mixture. The
resultant solution was extracted three times with ethyl acetate.
The combined organic phases were washed with saturated sodium
chloride solution, dried over sodium sulfate, filtered and
evaporated in vacuo in a rotary evaporator. The residue was
purified by means of flash chromatography [gradient:
dichloromethane/0-10% by vol. of a solvent mixture of
dichloromethane/methanol 10:1 (parts by volume), CombiFlash Rf
200]. The suitable product fractions were combined, and the
solvents were removed in a rotary evaporator, giving methyl
2-amino-4-(3,6-dihydro-2H-pyran-4-yl)benzoate (371.1 mg, 1.59 mmol,
MS: 234.2 [M+H.sup.+], 61% yield) as solid
##STR00172##
[0302] Methyl 2-amino-4-(3,6-dihydro-2H-pyran-4-yl)benzoate (620
mg, 2.66 mmol), trimethyl orthoformate (564.1 mg, 5.32 mmol) and
ammonium acetate (410 mg, 5.32 mmol) dissolved in methanol (20 ml)
was initially introduced in a glass vessel with stirrer bar. The
substance mixture was stirred overnight at 80.degree. C. Water (10
ml) was subsequently added, and the solid which precipitated out
was filtered off with suction, washed with a little water and
subsequently dried in vacuo, giving
7-(3,6-dihydro-2H-pyran-4-yl)-3H-quinazolin-4-one (520 mg, 2.28
mmol, MS: 229.1 [M+H.sup.+], 86% yield) as solid.
##STR00173##
[0303]
{3-[7-(3,6-Dihydro-2H-pyran-4-yl)quinazolin-4-yl]-4-fluorophenyl}th-
iazol-2-ylmethanol (EXAMPLE 139) was obtained analogously to the
synthetic processes for the preparation of
1-[5-(7-morpholin-4-ylquinazolin-4-yl)pyridin-3-yl]-1-thiazol-2-ylethanol
(EXAMPLE 138).
Example 140
[4-Fluoro-3-(7-morpholin-4-ylpyrido[4,3-d}pyrimidin-4-yl)phenyl]thiazol-2--
ylmethanol (140)
##STR00174##
[0305] Ethyl 4-amino-6-chloronicotinate (8.38 g, 39.7 mmol) were
dissolved in morpholine (40 ml). The substance mixture was heated
at 120.degree. C. for 4 h. When the reaction was terminated, the
cooled reaction solution was decanted into water (400 ml). The
aqueous suspension was stirred for 10 min, and the precipitate was
subsequently filtered off. The filter cake was rinsed with a little
water and dried overnight at 60.degree. C. in vacuo, giving pure
ethyl 4-amino-6-morpholin-4-ylnicotinate (8.55 g, 34.03 mmol, MS:
252.2 [M+H.sup.+], 85% yield) as colourless solid.
##STR00175##
[0306] Analogously to the synthetic process described for EXAMPLE
139, ethyl 4-amino-6-morpholin-4-ylnicotinate (3.54 g, 14.1 mmol)
gave 7-morpholin-4-yl-3H-pyrido[4,3-d}pyrimidin-4-one (2.29 g, 9.86
mmol, MS: 233.1 [M+H.sup.+] 70% yield) as solid.
##STR00176##
[0307] 7-Morpholin-4-yl-3H-pyrido[4,3-d}pyrimidin-4-one (600 mg,
2.58 mmol) was suspended in 1,4-dioxane (10 ml). Phosphoryl
chloride (POCl.sub.3, 546 .mu.l, 5.9 mmol) and Hunig's base
(N-ethyldiisopropylamine, 220 .mu.l, 1.29 mmol) were added to the
reaction mixture. The mixture was subsequently stirred at a
temperature of 100.degree. C. for 3 h. After termination of the
reaction, the reaction solution was decanted into a semi-saturated
sodium hydrogencarbonate solution (80 ml). The aqueous phase was
extracted three times with dichloromethane (40 ml in each case).
The combined organic phases were dried over sodium sulfate,
filtered and evaporated in vacuo in a rotary evaporator, giving
4-chloro-7-morpholin-4-ylpyrido[4,3-d}pyrimidine (627 mg, 2.50
mmol, MS: 251.0/253.0 [M+H.sup.+], 96% yield) as solid.
##STR00177##
[0308]
[4-Fluoro-3-(7-morpholin-4-ylpyrido[4,3-d}pyrimidin-4-yl)phenyl]thi-
azol-2-ylmethanol (EXAMPLE 140) was obtained analogously to the
synthetic processes for the preparation of
1-[5-(7-morpholin-4-ylquinazolin-4-yl)pyridin-3-yl]-1-thiazol-2-ylethanol
(EXAMPLE 138).
Example 141
[0309]
[2-Chloro-4-fluoro-5-(7-morpholin-4-ylpyrido[4,3-d}pyrimidin-4-yl)p-
henyl]-(4-hydroxymethyl-thiazol-2-yl)methanol (141)
##STR00178##
[0310] 4-(tert-Butyldimethylsilanyloxymethyl)thiazole (10.15 g,
43.5 mmol) dissolved in dry tetrahydrofuran (78 ml) was initially
introduced in a two-necked flask with stirrer bar, internal
thermometer and septum under argon. The reaction solution was
cooled to (-)75.degree. C. by means of an acetone/dry-ice bath.
n-Butyllithium (15% solution in n-hexane, 29.3 ml, 46.6 mmol) was
subsequently slowly added dropwise to the reaction solution at
constant temperature. The reaction solution was stirred at
(-)75.degree. C. for a further 30 min, subsequently warmed to
0.degree. C. Then re-cooled to (-)50.degree. C. A solution,
pre-cooled to (-)50.degree. C., of
5-bromo-2-chloro-4-fluoro-N-methoxy-N-methylbenzamide (5.58 g, 12.4
mmol), dissolved in dry tetrahydrofuran (21 ml), was slowly added
dropwise to the reaction solution at (-)50.degree. C. over a period
of 1.5 h. The reaction solution was stirred at (-)50.degree. C. for
a further 30 min. When the reaction was complete, water (20 ml) was
added to the reaction solution. The reaction solution was then
allowed to warm to room temperature with stirring. The reaction
solution was diluted with ethyl acetate (400 ml) and saturated
sodium chloride solution (100 ml). The phases were separated, and
the aqueous phase was extracted with ethyl acetate. The combined
organic phases were dried over sodium sulfate, filtered and
evaporated in vacuo in a rotary evaporator. The residue was
purified by means of flash chromatography (gradient:
cyclohexane/0-7% by vol. of ethyl acetate, CombiFlash Rf 200). The
suitable product fractions were combined, and the organic solvents
were removed in a rotary evaporator, giving
(5-bromo-2-chloro-4-fluorophenyl)-[4-(tert-butyldimethylsilanyloxymethyl)-
thiazol-2-yl]methanone (4.94 g, 10.39 mmol, MS: main peak 466
[M+H.sup.+], 84% yield) as oil.
##STR00179##
[0311]
[4-[[tert-Butyl(dimethyl)silyl]oxymethyl]thiazol-2-yl]-[2-chloro-4--
fluoro-5-(7-morpholinopyrido-[4,3-d}pyrimidin-4-yl)phenyl]methanol
was prepared analogously to the synthetic processes of EXAMPLES 1
and 2 and 138 from
(5-bromo-2-chloro-4-fluorophenyl)-[4-(tert-butyldimethylsilanylo-
xymethyl)thiazol-2-yl]methanone and
4-chloro-7-morpholin-4-ylpyrido[4,3-d}-pyrimidine.
##STR00180##
[0312]
[4-(tert-Butyldimethylsilanyloxymethyl)thiazol-2-yl]-[2-chloro-4-fl-
uoro-5-(7-morpholin-4-ylpyrido[4,3-d}pyrimidin-4-yl)phenyl]methanol
(333 mg, 0.55 mmol) was dissolved in 1,4-dioxane (7 ml). 4.0 M HCl
dissolved in 1,4-dioxane (1.38 ml, 5.53 mmol) was added, and the
reaction solution was subsequently stirred at room temperature for
30 min. When the reaction was complete, the reaction solution was
filtered, and solvents were removed in a rotary evaporator. The
residue was purified by means of flash chromatography (gradient:
dichloromethane/0-15% by vol. of ethanol, CombiFlash Rf 200). The
suitable product fractions were combined, and the solvents were
removed in vacuo. The residue was taken up in dichloromethane,
extracted with saturated sodium hydrogencarbonate solution, dried
over sodium sulfate, filtered, and the filtrate was evaporated to
dryness, where
[2-chloro-4-fluoro-5-(7-morpholin-4-ylpyrido[4,3-d}pyrimidin-4-yl)phenyl]-
-(4-hydroxymethylthiazol-2-yl)methanol (EXAMPLE 141, 229 mg, 0.47
mmol, MS: 488.0/490.0 [M+H.sup.+], 85% yield) as solid.
Examples 142 and 143
2-Chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(4-hydroxymet-
hylthiazol-2-yl)methanol (142)
[2-Chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(4-methylami-
nomethylthiazol-2-yl)methanol (143)
##STR00181##
[0314]
[2-Chloro-4-fluoro-5-(7-morpholin-4-ylpyrido[4,3-d}pyrimidin-4-yl)p-
henyl]-(4-hydroxymethylthiazol-2-yl)methanol (46.6 mg, 96 .mu.mol)
was dissolved in dry tetrahydrofuran (3.1 ml) under argon.
N-Ethyldiisopropylamine (98 .mu.l, 57.4 .mu.mol) and
methanesulfonyl chloride (14.8 .mu.l, 191 .mu.mol) were added. The
reaction solution was stirred at room temperature for 30 min.
Methylamine (40% solution in water, 183 .mu.l, 1.91 mol) was
subsequently added, and the mixture was stirred at room temperature
for a further 2 h. After termination of the reaction, ethyl acetate
(15 ml) and saturated sodium chloride solution (10 ml) were added
to the reaction solution. The phases were separated, and the
aqueous phase was extracted with ethyl acetate. The combined
organic phases were dried over sodium sulfate and filtered. The
filtrate was evaporated in a rotary evaporator, and the residue was
purified by means of preparative RP-HPLC (gradient water+0.1% of
trifluoroacetic acid/acetonitrile+0.1% of trifluoroacetic acid,
Sunfire Prep C-18 150-21 mm, flow rate: 50 ml/min., .lamda.=220
nm). The suitable product fractions were combined, and the solvents
were removed in vacuo in a rotary evaporator, and the residue was
freeze-dried from dioxane/water, where
[2-chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(4-me-
thylaminomethylthiazol-2-yl)methanol (EXAMPLE 143, 14.8 mg, 0.030
mmol, MS: 500.1/502.0 [M+H.sup.+], 31% yield) as solid.
Examples 144, 145 and 146
##STR00182##
[0316] Racemic
[4-fluoro-3-(6-morpholin-4-ylthieno[3,2-d}pyrimidin-4-yl)phenyl]thiazol-2-
-ylmethanol (EXAMPLE 144, 35 mg, 0.082 mmol) was separated by
chromatography into its enantiomers on a chiral stationary phase
using preparative SFC: after analytic column screening for
identification of the most suitable chiral phase having the highest
selectivity, the Lux amylose-2 phase from Phenomex was selected.
SFC conditions: apparatus: SFC Berger minigram; column: Lux
amylose-2, 250.times.4.6 mm; eluent: carbon dioxide+20% by vol. of
methanol+0.5% by vol. of diethylamine, flow rate: 5 ml/min,
wavelength: 220 nm. The preparative separation into the enantiomers
was carried out under the same conditions in SFC Berger minigram
Stacked Injection Mode. The suitable fractions were collected, and
the solvents were removed in vacuo in a rotary evaporator, giving
enantiomerically pure
[4-fluoro-3-(6-morpholin-4-ylthieno[3,2-d}pyrimidin-4-yl)phenyl]thiazol-2-
-ylmethanol (EXAMPLE 145, R.sub.t=7.85 min 12 mg, 0.028 mmol,
>99% ee Ena 1) and
[4-fluoro-3-(6-morpholin-4-ylthieno[3,2-d}pyrimidin-4-yl)phenyl]thiazol-2-
-ylmethanol (EXAMPLE 146, R.sub.t=8.82 min, 12.0 mg, 0.028 mmol,
92% ee, Ena 2) as solids.
[0317] Compounds which were prepared analogously to EXAMPLES
138-146 can be found in Table 5 below.
TABLE-US-00005 TABLE 5 Compounds of the formula (I) IC.sub.50
IC.sub.50 K.sub.i DNA- pDNA- [Kv1.11 No. Structural formula Name PK
PK hERG] 138 ##STR00183## 1-[5-(7-Morpholin-4- ylquinazolin-4-yl)-
pyridin-3-yl]-1- thiazol-2-ylethanol D B MS: 420.2 (M + H.sup.+) 1H
NMR (400 MHz, DMSO-d6) ppm = 9.11 (s, 1H), 8.97 (d, J = 2.2, 1H),
8.83 (d, J = 2.1, 1H), 8.30 (t, J = 2.2, 1H), 7.82 (d, J = 9.5,
1H), 7.79 (d, J = 3.2, 1H), 7.65 (d, J = 3.3, 1H), 7.57 (dd, J =
9.5, 2.6, 1H), 7.22 (d, J = 2.5, 1H), 7.09 (s, 1H), 3.82-3.75 (m,
4H), 3.50-3.43 (m, 4H), 2.02 (s, 3H) 139 ##STR00184##
{3-[7-(3,6-Dihydro- 2H-pyran-4-yl)- quinazolin-4-yl]-4-
fluoro-phenyl}- thiazol-2-ylmethanol C D A MS: 420.0 (M + H.sup.+)
1H NMR (500 MHz, DMSO-d6) ppm = 9.36 (s, 1H), 8.02 (d, J = 1.8,
1H), 7.94 (dd, J = 8.9, 1.9, 1H), 7.76-7.69 (m, 4H), 7.65 (d, J =
3.2, 1H), 7.49-7.43 (m, 1H), 7.00-6.96 (m, 1H), 6.71- 6.67 (m, 1H),
6.11-6.08 (m, 1H), 4.33-4.30 (m, 2H), 3.89 (t, J = 5.5 Hz, 2H),
2.65-2.60 (m, 2H) 140 ##STR00185## [4-Fluoro-3-(7- morpholin-4-yl-
pyrido[4,3-d}- pyrimidin-4-yl)- phenyl]thiazol-2-yl- methanol D D B
MS: 424.2 (M + H.sup.+) 1H NMR (400 MHz, DMSO-d6) ppm = 9.16 (s,
1H), 8.80 (d, J = 3.6, 1H), 7.77-7.70 (m, 3H), 7.65 (d, J = 3.2,
1H), 7.48-7.42 (m, 1H), 7.08- 6.94 (m, 2H), 6.10 (s, 1H), 3.78-3.66
(m, 8H) 141 ##STR00186## [2-Chloro-4-fluoro- 5-(7-morpholin-4-yl-
pyrido[4,3-d}- pyrimidin-4-yl)- phenyl]-(4- hydroxymethyl-
thiazol-2-yl)- methanol D D B MS: 488.0/490.0 (M + H.sup.+) 1H NMR
(400 MHz, DMSO-d6) ppm = 9.15 (s, (Cl isotopy, rel. peak 1H), 8.84
(d, J = 3.4, 1H), 7.83 (d, J = 7.6, 1H), intensity ratio [%]
100:38) 7.74 (d, J = 9.7, 1H), 7.39-7.35 (m, 1H), 7.04 (s, 1H),
6.99 (s, 1H), 6.28 (s, 1H), 5.24 (s, 1H), 4.50 (s, 2H), 3.77-3.69
(m, 8H) 142 ##STR00187## [2-Chloro-4-fluoro- 5-(7-morpholin-4-yl-
quinazolin-4-yl)- phenyl]-(4- hydroxymethyl- thiazol-2-yl)-
methanol A B D MS: 487.1/489.0 (M + H.sup.+) 1H NMR (400 MHz,
DMSO-d6) ppm = 9.10 (s, (Cl isotopy, rel. peak 1H), 7.75-7.69 (m,
2H), 7.59-7.49 (m, 2H), intensity ratio [%] 100:41) 7.36 (t, J =
1.1, 1H), 7.23-7.17 (m, 1H), 7.00 (d, J = 5.1, 1H), 6.27 (d, J =
5.0, 1H), 5.24 (t, J = 5.1, 1H), 4.52-4.45 (m, 2H), 3.81-3.74 (m,
4H), 3.49-3.41 (m, 4H) 143 ##STR00188## [2-Chloro-4-fluoro-
5-(7-morpholin-4-yl- quinazolin-4-yl)- phenyl]-(4-
methylaminomethyl- thiazol-2-yl)- methanol C C C MS: 500.1/502.0 (M
+ H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.10 (s, (Cl isotopy,
rel. peak 1H), 8.26 (s, 1H), 7.76-7.69 (m, 2H), 7.58- intensity
ratio [%] 100:34) 7.50 (m, 2H), 7.48-7.43 (m, 1H), 7.24-7.16 (m,
1H), 6.97 (s, 1H), 6.28 (s, 1H), 3.80 (s, 2H), 3.79-3.74 (m, 4H),
3.48-3.42 (m, 4H), 2.33 (s, 3H) 144 ##STR00189## [4-Fluoro-3-(6-
morpholin-4-yl- thieno[3,2-d}- pyrimidin-4-yl)-
phenyl]thiazol-2-yl- methanol A B B MS: 429.0 (M + H.sup.+) 1H NMR
(500 MHz, DMSO-d6) ppm = 8.89 (s, 1H), 7.76 (dd, J = 7.0, 2.3, 1H),
7.73 (d, J = 3.2, 1H), 7.69-7.64 (m, 2H), 7.43-7.38 (m, 1H), 6.96
(d, J = 4.6, 1H), 6.53 (s, 1H), 6.07 (d, J = 4.6, 1H), 3.77-3.71
(m, 4H), 3.44-3.38 (m, 4H) 145 ##STR00190## [4-Fluoro-3-(6-
morpholin-4-yl- thieno[3,2-d}- pyrimidin-4-yl)-
phenyl]thiazol-2-yl- methanol (Ena 1) A B A MS: 429.0 (M +
H.sup.+); R.sub.t 7.85 see racemate min, (SFC, Lux amylose,
CO2/0.5% by vol. of methanol) 146 ##STR00191## [4-Fluoro-3-(6-
morpholin-4-yl- thieno[3,2-d}- pyrimidin-4-yl)-
phenyl]thiazol-2-yl- methanol (Ena 2) A B A MS: 429.0 (M +
H.sup.+); R.sub.t 8.82 see racemate min, (SFC, Lux amylose-2,
CO2/0.5% by vol. of methanol) 147 ##STR00192## [5-(7-Morpholin-4-
ylquinazolin-4-yl)- thiophen-2-yl]- thiazol-2-ylmethanol D C MS:
411.0 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 8.93 (s, 1H),
8.34 (d, J = 9.5, 1H), 7.83 (d, J = 3.9, 1H), 7.79 (d, J = 3.2,
1H), 7.71 (d, J = 3.2, 1H), 7.56 (dd, J = 9.5, 2.7, 1H), 7.32 (d, J
= 4.8, 1H), 7.26- 7.24 (m, 1H), 7.16 (d, J = 2.6, 1H), 6.31-6.29
(m, 1H), 3.81-3.75 (m, 4H), 3.47-3.41 (m, 4H) 148 ##STR00193##
[3-(7-Morpholin-4- ylquinazolin-4-yl)- phenyl]thiazol-2-yl-
methanol C D C MS: 405.2 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6)
ppm = 9.07 (s, 1H), 7.86 (d, J = 9.4, 1H), 7.83-7.81 (m, 1H), 7.74
(d, J = 3.2, 1H), 7.68-7.64 (m, 3H), 7.59- 7.55 (m, 1H), 7.52 (dd,
J = 9.5, 2.6, 1H), 7.20 (d, J = 2.6, 1H), 6.93 (d, J = 4.5, 1H),
6.10 (d, J = 4.0, 1H), 3.80-3.76 (m, 4H), 3.46-3.42 (m, 4H) 149
##STR00194## [3-(7-Morpholin-4- ylquinazolin-4-yl)-
phenyl]thiazol-2-yl- methanol (Ena 1) D A MS: 405.2 (M + H.sup.+);
R.sub.t see racemate 10.57 min, (HPLC, Chiralpak AD-H,
heptane/ethanol (40/60) 150 ##STR00195## [3-(7-Morpholin-4-
ylquinazolin-4-yl)- phenyl]thiazol-2-yl- methanol (Ena 2) C C A MS:
405.2 (M + H.sup.+); R.sub.t 13.55 see racemate min, (HPLC,
Chiralpak AD- H, heptane/ethanol 40/60) 151 ##STR00196##
1-[5-(7-Morpholin- 4-ylquinazolin-4-yl)- pyridin-3-yl]-1-
thiazol-2-ylethanol (Ena 1) D MS: 420.2 (M + H.sup.+); R.sub.t 8.95
see racemate min, (SFC, Chiralpak AS-H, CO2/10% by vol. of
methanol, 0.5% by vol. of diethylamine) 152 ##STR00197##
1-[5-(7-Morpholin- 4-ylquinazolin-4-yl)- pyridin-3-yl]-1-
thiazol-2-ylethanol (Ena 2) C D A MS: 420.2 (M + H.sup.+), R.sub.t
see racemate 10.45 min, (SFC, Chiralpak AS-H, CO2/10% by vol. of
methanol, 0.5% by vol. of diethylamine) 153 ##STR00198##
1-[4-(7-Morpholin- 4-ylquinazolin-4-yl)- pyridin-2-yl]-1-
thiazol-2-ylethanol D MS: 420.2 (M + H.sup.+) 1H NMR (400 MHz,
DMSO-d6) ppm = 9.11 (s, 1H), 8.73 (dd, J = 5.0, 0.8, 1H), 7.99-7.97
(m, 1H), 7.79 (d, J = 9.4, 1H), 7.72 (d, J = 3.2, 1H), 7.64 (dd, J
= 5.0, 1.6, 1H), 7.62 (d, J = 3.2, 1H), 7.56 (dd, J = 9.5, 2.6,
1H), 7.23 (d, J = 2.5, 1H), 6.84 (s, 1H), 3.81-3.75 (m, 4H),
3.49-3.44 (m, 4H), 2.04 (s, 3H) 154 ##STR00199## 1-[3-(7-Morpholin-
4-ylquinazolin-4-yl)- phenyl]-1-thiazol-2- ylethanol D B MS: 419.2
(M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.07 (s, 1H),
7.96-7.93 (m, 1H), 7.83 (d, J = 9.4, 1H), 7.79-7.76 (m, 1H), 7.74
(d, J = 3.2, 1H), 7.63- 7.61 (m, 1H), 7.60 (d, J = 3.3, 1H), 7.55
(d, J = 7.7, 1H), 7.53-7.50 (m, 1H), 7.20 (d, J = 2.6, 3.42 (m,
4H), 1.98 (s, 3H) 155 ##STR00200## 1-[4-methyl-3-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]-1-thiazol-2- ylethanol D
MS: 433.2 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.07 (s,
1H), 7.70 (d, J = 3.2, 1H), 7.61 (dd, J = 8.0, 2.1, 1H), 7.57 (d, J
= 3.2, 1H), 7.48-7.44 (m, 2H), 7.34 (d, J = 8.1, 1H), 7.32 (d, J =
9.3, 1H), 7.19 (d, J = 2.5, 1H), 6.70 (s, 1H), 3.79-3.76 (m, 4H),
3.44-3.41 (m, 4H), 2.03 (s, 3H), 1.92 (s, 3H) 156 ##STR00201##
1-[4-(7-Morpholin- 4-ylquinazolin-4-yl)- thiophen-2-yl]-1-
thiazol-2-ylethanol D MS: 425.0 (M + H.sup.+) 1H NMR (400 MHz,
DMSO-d6) ppm = 8.99 (s, 1H), 8.13 (d, J = 9.5, 1H), 8.04 (d, J =
1.5, 1H), 7.76 (d, J = 3.2, 1H), 7.64 (d, J = 3.2, 1H), 7.54 (dd, J
= 9.5, 2.6, 1H), 7.52 (d, J = 1.5, 1H), 7.20 (s, 1H), 7.16 (d, J =
2.6, 1H), 3.82-3.75 (m, 4H), 3.47-3.40 (m, 4H), 2.04 (s, 3H) 157
##STR00202## 1-[4-(7-Morpholin- ylquinazolin-4-yl)-
pyridin-2-yl]-1- thiazol-2-ylethanol (Ena 1) D MS: 420.2 (M +
H.sup.+); R.sub.t see racemate 22.14 min, (HPLC, Chiralpak AD-H,
heptane/ethanol 70/30, 0.5% by vol. of diethylamine) 158
##STR00203## 1-[4-(7-Morpholin- 4-ylquinazolin-4-yl)-
pyridin-2-yl]-1- thiazol-2-ylethanol (Ena 2) D MS: 420.2 (M +
H.sup.+); R.sub.t see racemate 27.88 min, (HPLC, Chiralpak AD-H,
heptane/ethanol 70/30, 0.5% by vol. of diethylamine) 159
##STR00204## 2,2,2-Trifluoro-1-[3- (7-morpholin-4-yl-
quinazolin-4-yl)- phenyl]-1-thiazol-2- ylethanol C D D MS: 473.0 (M
+ H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.08 (s, 1H), 8.54 (s,
1H), 8.15-8.13 (m, 1H), 7.98- 7.95 (m, 1H), 7.94 (d, J = 3.3, 1H),
7.87 (d, J = 3.2, 1H), 7.83-7.79 (m, 2H), 7.67 (t, J = 7.8, 1H),
7.53 (dd, J = 9.5, 2.6, 1H), 7.21 (d, J = 2.6, 1H), 3.80-3.76 (m,
4H), 3.47-3.43 (m, 4H) 160 ##STR00205## [5-(7-Morpholin-4-
ylquinazolin-4-yl)- thiophen-2-yl]- thiazol-2-yl- methanol (Ena 1)
D MS: 409.0 (M - H.sup.+) see racemate O-TBDPS ether derivative:
R.sub.t 4.78 min (SFC, Chiralpak AD-H, CO.sub.2/30% by vol. of
2-propanol, 0.5% by vol. of diethylamine 161 ##STR00206##
[5-(7-Morpholin-4- ylquinazolin-4-yl)- thiophen-2-yl]-
thiazol-2-yl- methanol (Ena 2) D MS: 409.0 (M - H.sup.+); see
racemate O-TBDPS ether derivative: R.sub.t 7.20 min (SFC, Chiralpak
AD-H, CO.sub.2/30% by vol. of 2-propanol, 0.5% by vol. of
diethylamine 162 ##STR00207## 1-[2-Fluoro-3-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]-1-thiazol-2- ylethanol D MS: 437.2 (M +
H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.07 (s, 1H), 7.94-7.87
(m, 1H), 7.71 (d, J = 3.2, 1H), 7.63 (d, J = 3.3, 1H), 7.55-7.40
(m, 4H), 7.17
(d, J = 2.4, 1H), 6.75 (s, 1H), 3.79-3.74 (m, 4H), 3.46-3.40 (m,
4H), 2.01 (s, 3H) 163 ##STR00208## 1-[4-Fluoro-3-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]-1-thiazol-2- ylethanol C
D C MS: 437.2 (M + H.sup.+) 1H NMR (400 MHz, DMSO-d6) ppm = 9.11
(s, 1H), 7.82-7.75 (m, 2H), 7.73 (d, J = 3.2, 1H), 7.61 (d, J =
3.2, 1H), 7.53-7.50 (m, 2H), 7.41- 7.36 (m, 1H), 7.20 (d, J = 1.9,
1H), 6.90 (s, 1H), 3.80-3.75 (m, 4H), 3.46-3.41 (m, 4H), 1.95 (s,
3H) 164 ##STR00209## [5-(7-Morpholin-4- ylquinazolin-4-yl)-
thiophen-3-yl]- thiazol-2-yl- methanol D MS: 411.0 (M + H.sup.+) 1H
NMR (500 MHz, DMSO-d6) ppm = 8.95 (s, 1H), 8.30 (d, J = 9.5, 1H),
7.93 (d, J = 1.3, 1H), 7.80-7.78 (m, 1H), 7.76 (d, J = 3.2, 1H),
7.67 (d, J = 3.2, 1H), 7.62 (dd, J = 9.5, 2.7, 1H), 7.17 (d, J =
2.6, 1H), 6.93 (d, J = 5.0, 1H), 6.14-6.11 (m, 1H), 3.81-3.76 (m,
4H), 3.48-3.43 (m, 4H) 165 ##STR00210## 1-[4-(7-Morpholin-
4-ylquinazolin-4-yl)- thiophen-2-yl]-1- thiazol-2-ylethanol (Ena 1)
D MS: 425.0 (M + H.sup.+); R.sub.t 1H NMR (500 MHz, DMSO-d6) ppm =
8.99 (s, 5.32 min, (SFC, Chiralcel 1H), 8.13 (d, J = 9.4, 1H), 8.05
(d, J = 1.5, 1H), OJ-H, CO2/25% by vol. of 7.76 (d, J = 3.2, 1H),
7.64 (d, J = 3.2, 1H), 7.54 2-propanol, 0.5% by vol. of (dd, J =
9.5, 2.6, 1H), 7.52 (d, J = 1.5, 1H), 7.20 diethylamine) (s, 1H),
7.16 (d, J = 2.6, 1H), 3.81-3.74 (m, 4H), 3.46-3.39 (m, 4H), 2.04
(s, 3H) 166 ##STR00211## 1-[4-(7-Morpholin- 4-ylquinazolin-4-yl)-
thiophen-2-yl]-1- thiazol-2-ylethanol (Ena 2) D MS: 425.0 (M +
H.sup.+); R.sub.t 1H NMR (500 MHz, DMSO-d6) ppm = 8.99 (s, 7.18
min, (SFC, Chiralcel 1H), 8.13 (d, J = 9.4, 1H), 8.05 (d, J = 1.5,
1H), OJ-H, CO2/25% by vol. of 7.76 (d, J = 3.2, 1H), 7.64 (d, J =
3.2, 1H), 7.54 2-propanol, 0.5% by vol. of (dd, J = 9.5, 2.7, 1H),
7.52 (d, J = 1.5, 1H), 7.20 diethylamine) (s, 1H), 7.16 (d, J =
2.6, 1H), 3.81-3.75 (m, 4H), 3.46-3.40 (m, 4H), 2.03 (s, 3H) 167
##STR00212## [5-(7-Morpholin-4- ylquinazolin-4-yl)- thiophen-3-yl]-
thiazol-2-yl- methanol (Ena 1) D MS: 411.0 (M + H.sup.+); 1H NMR
(500 MHz, DMSO-d6) ppm = 8.95 (s, O-TBDPS-Etherderivat: R.sub.t
1H), 8.30 (d, J = 9.5, 1H), 7.94-7.92 (m, 1H), 13.11 min (SFC,
Chiralpak 7.79-7.78 (m, 1H), 7.76 (d, J = 3.2, 1H), 7.67 IA,
CO.sub.2/20% by vol. of (d, J = 3.2, 1H), 7.62 (dd, J = 9.5, 2.7,
1H), 7.17 2-methanol, 0.5% by vol. of (d, J = 2.6, 1H), 6.93 (d, J
= 5.0, 1H), 6.12 (d, diethylamine J = 4.9, 1H), 3.81-3.77 (m, 4H),
3.47-3.44 (m, 4H) 168 ##STR00213## [5-(7-Morpholin-4-
ylquinazolin-4-yl)- thiophen-3-yl]- thiazol-2-yl- methanol (Ena 2)
D MS: 411.0 (M + H.sup.+); 1H NMR (500 MHz, DMSO-d6) ppm = 8.95 (s,
O-TBDPS ether derivative: 1H), 8.30 (d, J = 9.5, 1H), 7.94-7.92 (m,
1H), R.sub.t 16.81 min (SFC, 7.79-7.78 (m, 1H), 7.76 (d, J = 3.2,
1H), 7.67 Chiralpak IA, CO.sub.2/20% by (d, J = 3.2, 1H), 7.62 (dd,
J = 9.5, 2.7, 1H), 7.17 vol. of 2-methanol, 0.5% by (d, J = 2.6,
1H), 6.93 (s, 1H), 6.12 (s, 1H), 3.82- vol. of diethylamine 3.74
(m, 4H), 3.50-3.42 (m, 4H) 169 ##STR00214## [3-Fluoro-5-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]thiazol-2-yl- methanol C D
MS: 423.0 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.08 (s,
1H), 7.86 (d, J = 9.4, 1H), 7.77 (d, J = 3.2, 1H), 7.68-7.66 (m,
2H), 7.54 (dd, J = 9.4, 2.6, 1H), 7.51-7.46 (m, 2H), 7.21 (d, J =
2.6, 1H), 7.08 (d, J = 4.7, 1H), 6.14 (d, J = 4.7, 1H), 3.80-3.76
(m, 4H), 3.47-3.43 (m, 4H) 170 ##STR00215## [2-Fluoro-5-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]thiazol-2-yl- methanol C C
MS: 423.0 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.04 (s,
1H), 7.85-7.81 (m, 2H), 7.77-7.73 (m, 1H), 7.72 (d, J = 3.2, 1H),
7.66 (d, J = 3.2, 1H), 7.52 (dd, J = 9.5, 2.6, 1H), 7.44-7.39 (m,
1H), 7.18 (d, J = 2.5, 1H), 7.05 (d, J = 4.9, 1H), 6.28 (d, J =
3.8, 1H), 3.79-3.75 (m, 4H), 3.33-3.29 (m, 4H) 171 ##STR00216##
[3,4-Difluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]thiazol-2-yl- methanol A B D MS: 441.0 (M + H.sup.+) 1H NMR
(500 MHz, DMSO-d6) ppm = 9.11 (s, 1H), 7.75 (d, J = 3.2, 1H),
7.72-7.66 (m, 2H), 7.61-7.57 (m, 1H), 7.56-7.49 (m, 2H), 7.21 (d, J
= 2.4, 1H), 7.10 (d, J = 4.8, 1H), 6.10 (d, J = 4.8, 1H), 3.81-3.75
(m, 4H), 3.48-3.43 (m, 4H) 172 ##STR00217## 2,2,2-Trifluoro-1-[3-
(7-morpholin-4-yl- quinazolin-4-yl)- phenyl]-1-thiazol-2- ylethanol
(Ena 1) C D MS: 473.0 (M + H.sup.+); R.sub.t see racemate 12.21
min, (HPLC, Chiralpak AD-H, n-heptane/ethanol, 70:30, vol.:vol) 173
##STR00218## 2,2,2-Trifluoro-1-[3- (7-morpholin-4-yl-
quinazolin-4-yl)- phenyl]-1-thiazol-2- ylethanol (Ena 2) A C D MS:
473.0 (M + H.sup.+); R.sub.t see racemate 16.91 min, (HPLC,
Chiralpak AD-H, n-heptane/ethanol, 70:30, vol.:vol.) 174
##STR00219## 7-Morpholin-4-yl-4- piperidin-1-yl- thieno[3,2-d}-
pyrimidine C D MS: 305.2 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6)
ppm = 9.10 (s, 1H), 8.88-8.85 (m, 2H), 8.19-8.17 (m, 1H), 7.84 (d,
J = 9.4, 1H), 7.78 (d, J = 3.2, 1H), 7.69 (d, J = 3.2, 1H), 7.56
(dd, J = 9.5, 2.6, 1H), 7.22 (d, J = 2.6, 1H), 7.14 (d, J = 4.8,
1H), 6.23 (d, J = 4.8, 1H), 3.81-3.76 (m, 4H), 3.48-3.43 (m, 4H)
175 ##STR00220## 4-[2-Fluoro-5- (methoxy-thiazol-2-
ylmethyl)phenyl]-7- morpholin-4-yl- quinazoline D MS: 337.2 (M +
H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.11 (s, 1H), 7.78 (d, J =
3.2, 1H), 7.73 (d, J = 3.2, 1H), 7.67-7.62 (m, 2H), 7.54-7.52 (m,
2H), 7.49- 7.44 (m, 1H), 7.21-7.19 (m, 1H), 5.84 (s, 1H), 3.80-3.75
(m, 4H), 3.46-3.43 (m, 4H), 3.43 (s, 3H) 176 ##STR00221##
4-[2-Fluoro-5-(- methoxy-thiazol-2- ylmethyl)phenyl]-7-
morpholin-4-yl- quinazoline (Ena 1) C MS: 437.2 (M + H.sup.+);
R.sub.t 8.47 see racemate min, (SFC, Chiralcel OD-H, CO2/20% by
vol. of 2-propanol, 0.5% by vol. of diethylamine) 177 ##STR00222##
4-[2-Fluoro-5-(- methoxythiazol-2- ylmethyl)phenyl]-7-
morpholin-4-yl- quinazoline (Ena 2) B D A MS: 437.2 (M + H.sup.+);
R.sub.t 9.90 see racemate min, (SFC, Chiralcel OD-H, CO2/20% by
vol. of 2-propanol, 0.5% by vol. of diethylamine) 178 ##STR00223##
[3,4-Difluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]thiazol-2-yl- methanol (Ena 1) A B A MS: 441.0 (M +
H.sup.+); R.sub.t 8.34 see racemate min, (SFC, Chiralcel OD-H,
CO2/20% by vol. of 2-propanol, 0.5% by vol. of diethylamine) 179
##STR00224## [3,4-Difluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]thiazol-2-yl- methanol (Ena 2) B B D MS: 441.0 (M +
H.sup.+); R.sub.t 9.68 min, (SFC, Chiralcel OD-H, CO2/20% by vol.
of 2-propanol, 0.5% by vol. of diethylamine) 180 ##STR00225##
[6-Fluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
pyridin-3-yl]thiazol- 2-ylmethanol A C D MS: 424.2 (M + H.sup.+) 1H
NMR (400 MHz, DMSO-d6) ppm = 9.11 (s, 1H), 8.56-8.52 (m, 1H), 8.21
(dd, J = 9.0, 2.3, 1H), 7.77 (d, J = 3.2, 1H), 7.69 (d, J = 3.2,
1H), 7.59-7.52 (m, 2H), 7.23-7.20 (m, 1H), 7.18 (d, J = 4.7, 1H),
6.23 (d, J = 4.5, 1H), 3.82-3.73 (m, 4H), 3.50-3.42 (m, 4H) 181
##STR00226## [2-Chloro-4-fluoro- 5-(7-morpholin-4-yl-
quinazolin-4-yl)- phenyl]-(4-methyl- thiazol-2-yl)- methanol A B D
MS: 471.1/473.1 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.10
(s, (Cl isotopy, rel. peak 1H), 7.73 (dd, J = 10.5, 8.6, 2H),
7.57-7.51 (m, intensity ratio [%] 100:42) 2H), 7.22-7.18 (m, 2H),
6.97 (s, 1H), 6.26 (s, 1H), 3.80-3.74 (m, 4H), 3.49-3.41 (m, 4H),
2.30 (d, J = 1.0, 3H) 182 ##STR00227## [3-(6-Morpholin-4-
ylthieno[3,2-d}- pyrimidin-4-yl)- phenyl]thiazol-2-yl- methanol C C
MS: 411.0 (M + H.sup.+) 1H NMR (400 MHz, DMSO-d6) ppm = 8.90 (s,
1H), 8.14 (t, J = 1.8, 1H), 7.97-7.93 (m, 1H), 7.73 (d, J = 3.2,
1H), 7.68-7.64 (m, 2H), 7.61- 7.54 (m, 1H), 6.93 (d, J = 4.4, 1H),
6.54 (s, 1H), 6.09 (d, J = 4.4, 1H), 3.81-3.74 (m, 4H), 3.47- 3.41
(m, 4H) 183 ##STR00228## [5-(7-Morpholin-4- ylquinazolin-4-yl)-
pyridin-3-yl]thiazol- 2-ylmethanol (Ena 1) C MS: 406.0 (M +
H.sup.+); R.sub.t see racemate 20.67 min, (HPLC, Chiralcel OD-H,
2-propanol) 184 ##STR00229## [5-(7-Morpholin-4- ylquinazolin-4-yl)-
pyridin-3-yl]thiazol- 2-ylmethanol (Ena 2) C MS: 406.0 (M +
H.sup.+); R.sub.t see racemate 24.19 min, (HPLC, Chiralcel OD-H,
2-propanol) 185 ##STR00230## (S)-[2-Chloro-4- fluoro-5-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]-(4- hydroxymethyl-
thiazol-2-yl)- methanol A B A MS: 487.1/489.1 (M + H.sup.+) 1H NMR
(500 MHz, DMSO-d6) ppm = 9.10 (s, (Cl isotopy, rel. peak 1H), 7.73
(dd, J = 8.6, 4.8, 2H), 7.58-7.50 (m, intensity ratio [%] 100:41);
2H), 7.39-7.34 (m, 1H), 7.22-7.18 (m, 1H), R.sub.t 2.83 min (SFC,
Chiralpak 7.02 (d, J = 5.0 1H), 6.27 (d, J = 5.0, 1H), 5.27 AD-H,
CO.sub.2/40% by vol. of (t, J = 5.7, 1H), 4.51-4.47 (m, 2H),
3.80-3.74 methanol, 0.5% by vol. of (m, 4H), 3.48-3.40 (m, 4H)
diethylamine) 186 ##STR00231## (R)-[2-Chloro-4- fluoro-5-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]-(4- hydroxymethyl-
thiazol-2-yl)- methanol C C D MS: 487.1/489.1 (M + H.sup.+) 1H NMR
(500 MHz, DMSO-d6) ppm = 9.10 (s, (Cl is isotopy, rel. peak 1H),
7.73 (dd, J = 8.6, 4.5, 2H), 7.57-7.52 (m, intensity ratio [%]
100:41); 2H), 7.38-7.35 (m, 1H), 7.22-7.19 (m, 1H), R.sub.t 5.77
min (SFC, Chiralpak 7.03 (d, J = 5.0, 1H), 6.27 (d, J = 5.0,
1H), 5.27 AD-H, CO.sub.2/40% by vol. of (t, J = 5.7, 1H), 4.50-4.46
(m, 2H), 3.80-3.74 methanol, 0.5% by vol. of (m, 4H), 3.48-3.42 (m,
4H) diethylamine) 187 ##STR00232## {2-Chloro-4-fluoro-
5-[7-(3-oxa-8-aza- bicyclo[3.2.1]oct-8- yl)quinazolin-4-yl]-
phenyl}-(4-hydroxy- methylthiazol-2-yl)- methanol D D B MS:
513.1/515.0 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.03 (s,
(Cl isotopy, rel. peak 1H), 7.71 (t, J = 8.5, 2H), 7.50 (dd, J =
9.3, 3.2, intensity ratio [%] 100:41) 1H), 7.40 (dd, J = 9.4, 2.5,
1H), 7.37-7.35 (m, 1H), 7.13 (d, J = 2.4, 1H), 7.01 (d, J = 5.1,
1H), 6.27 (d, J = 5.0, 1H), 5.26 (t, J = 5.7, 1H), 4.52- 4.50 (m,
2H), 4.50-4.47 (m, 2H), 3.69 (d, J = 10.9, 2H), 3.57-3.50 (m, 2H),
2.09-1.94 (m, 4H) 188 ##STR00233## [6-Fluoro-5-(7- morpholin-4-yl-
quinazolin-4-yl)- pyridin-3-yl]thiazol- 2-ylmethanol (Ena 1) A C A
MS: 424.0 (M + H.sup.+); R.sub.t 44.51 see racemate min, (HPLC,
Chiralcel OD- H, hexane/2-propanol 80/20) 189 ##STR00234##
[6-Fluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
pyridin-3-yl]thiazol- 2-ylmethanol (Ena 2) B B B MS: 424.0 (M +
H.sup.+); R.sub.t 49.66 see racemate min, (HPLC, Chiralcel OD- H,
hexane/2-propanol 80/20) 190 ##STR00235## [2-Chloro-4-fluoro-
5-(7-morpholin-4-yl- quinazolin-4-yl)- phenyl]-(4-ethyl-
aminomethyl- thiazol-2-yl)- methanol C B B MS: 514.2/516.1 (M +
H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.09 (s, (Cl isotopy, rel.
peak 1H), 8.25 (s, 1H), 7.73 (d, J = 1.6, 1H), 7.71 (s, intensity
ratio [%] 100:41) 1H), 7.58-7.49 (m, 2H), 7.44-7.40 (m, 1H),
7.23-7.18 (m, 1H), 7.05 (s, 1H), 6.27 (s, 1H), 3.80-3.76 (m, 6H),
3.48-3.40 (m, 4H), 2.60 (q, J = 7.1, 2H), 1.01 (t, J = 7.1, 3H) 190
##STR00236## (4-Aminomethyl- thiazol-2-yl)-[2- chloro-4-fluoro-5-
(7-morpholin-4-yl- quinazolin-4-yl)- phenyl]methanol C B B MS:
486.0/488.1 (M + H.sup.+) 1H NMR (400 MHz, DMSO-d6) ppm = 9.09 (s,
(Cl isotopy, rel. peak 1H), 8.30 (s, 1H), 7.76-7.69 (m, 2H), 7.57-
intensity ratio [%] 100:38) 7.50 (m, 2H), 7.48-7.43 (m, 1H),
7.23-7.17 (m, 1H), 6.28 (s, 1H), 3.86 (s, 2H), 3.81-3.74 (m, 4H),
3.47-3.44 (m, 4H) 191 ##STR00237## [4-Fluoro-3-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]-(1-methyl- 1H-pyrazol-4-yl)- methanol A D
A MS: 420.1 (M + H.sup.+) 1H NMR (400 MHz, DMSO-d6) ppm = 9.10 (s,
1H), 7.68-7.33 (m, 6H), 7.31-7.15 (m, 2H), 5.76 (s, 2H), 3.90-3.64
(m, 7H), 3.51-3.39 (m, 4H) 192 ##STR00238## (4,5-Dimethyl-
thiazol-2-yl)-[2- fluoro-5-(7- morpholin-4-yl- pyrido[4,3-d}-
pyrimidin-4-yl)- pyridin-3-yl]- methanol D C MS: 453.0 (M +
H.sup.+) 1H NMR (400 MHz, DMSO-d6) ppm = 9.14 (s, 1H), 9.09 (s,
1H), 8.67-8.65 (m, 1H), 8.46 (dd, J = 9.0, 2.4, 1H), 7.03-6.99 (m,
2H), 6.11 (d, J = 5.2, 1H), 3.77-3.68 (m, 8H), 2.31 (s, 3H), 2.19
(s, 3H) 194 ##STR00239## (4,5-Dimethyl- thiazol-2-yl)-[2-
fluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)- pyridin-3-yl]-
methanol C A MS: 452.2 (M + H.sup.+) 1H NMR (400 MHz, DMSO-d6) ppm
= 9.10 (s, 1H), 8.58-8.56 (m, 1H), 8.37 (dd, J = 9.0, 2.4, 1H),
7.87 (d, J = 9.4, 1H), 7.57 (dd, J = 9.4, 2.6, 1H), 7.22 (d, J =
2.5, 1H), 6.99 (d, J = 5.1, 1H), 6.11 (d, J = 5.1, 1H), 3.80-3.76
(m, 4H), 3.49- 3.43 (m, 4H), 2.30 (s, 3H), 2.19 (s, 3H) 195
##STR00240## [6-Fluoro-5-(7- morpholin-4-yl- pyrido[4,3-d}-
pyrimidin-4-yl)- pyridin-3-yl]-(4- methyl-thiazol-2-yl)- methanol D
B MS: 439.0 (M + H.sup.+) 1H NMR (400 MHz, DMSO-d6) ppm = 9.17 (s,
1H), 8.90 (d, J = 2.5, 1H), 8.57-8.53 (m, 1H), 8.29 (dd, J = 9.1,
2.4, 1H), 7.24-7.21 (m, 1H), 7.10 (d, J = 4.9, 1H), 7.00 (s, 1H),
6.16 (d, J = 4.9, 1H), 3.79-3.67 (m, 8H), 2.33 (d, J = 1.0, 3H) 196
##STR00241## (4,5-Dimethyl- thiazol-2-yl)-[6- fluoro-5-(7-
morpholin-4-yl- pyrido[4,3-d}- pyrimidin-4-yl)- pyridin-3-yl]-
methanol C D A MS: 407.2 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6)
ppm = 9.16 (s, 1H), 8.90 (d, J = 2.4, 1H), 8.53 (d, J = 2.3, 1H),
8.27 (dd, J = 9.1, 2.4, 1H), 7.06 (d, J = 4.9, 1H), 6.99 (s, 1H),
6.08 (d, J = 4.9, 1H), 3.76-3.69 (m, 8H), 2.30 (s, 3H), 2.21 (s,
3H) 197 ##STR00242## [4-Fluoro-3-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]-(1- isopropyl-1H- pyrazol-4-yl)- methanol
B C D MS: 448.2 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.10
(s, 1H), 7.64-7.60 (m, 1H), 7.60-7.57 (m, 2H), 7.56-7.50 (m, 2H),
7.41-7.35 (m, 1H), 7.28 (s, 1H), 7.20 (d, J = 2.2, 1H), 5.76 (s,
2H), 4.42 (h, J = 6.6, 1H), 3.80-3.76 (m, 4H), 3.46-3.42 (m, 4H),
1.36 (d, J = 6.7, 6H) 198 ##STR00243## (1-tert-Butyl-1H-
pyrazol-4-yl)-[2- fluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
pyridin-3-yl]- methanol C A MS: 463.2 (M + H.sup.+) 1H NMR (500
MHz, DMSO-d6) ppm = 9.10 (s, 1H), 8.54-8.49 (m, 1H), 8.46 (dd, J =
9.4, 2.6, 1H), 7.89 (d, J = 9.4, 1H), 7.73 (s, 1H), 7.57 (dd, J =
9.5, 2.6, 1H), 7.36 (s, 1H), 7.23 (d, J = 2.5, 1H), 6.02 (d, J =
4.8, 1H), 5.95 (d, J = 4.6, 1H), 3.82-3.75 (m, 4H), 3.50-3.42 (m,
4H), 1.48 (s, 9H) 199 ##STR00244## 4-[5-(Difluoro-
methoxy-thiazol-2- ylmethyl)-2-fluoro- phenyl]-7- morpholin-4-yl-
quinazoline B D D MS: 473.0 (M + H.sup.+) 1H NMR (400 MHz, DMSO-d6)
ppm = 9.11 (s, 1H), 7.85 (d, J = 3.2, 1H), 7.81 (d, J = 3.2, 1H),
7.73-7.71 (m, 2H), 7.55-7.52 (m, 2H), 7.52- 7.48 (m, 1H), 7.22-6.82
(m, 3H), 3.80-3.75 (m, 4H), 3.48-3.42 (m, 4H) 200 ##STR00245##
[4-Fluoro-3-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]-(5-hydroxy- methyl-4-methyl- thiazol-2-yl)- methanol B C A
MS: 467.2 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.11 (s,
1H), 7.70-7.63 (m, 2H), 7.55-7.50 (m, 2H), 7.44-7.39 (m, 1H),
7.22-7.19 (m, 1H), 6.81 (d, J = 4.5, 1H), 5.95 (d, J = 4.3, 1H),
5.35 (t, J = 5.6, 1H), 4.54 (d, J = 5.4, 2H), 3.80-3.75 (m, 4H),
3.47-3.42 (m, 4H), 2.22 (s, 3H) 201 ##STR00246## 1-(2-{[2-Chloro-4-
fluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)- phenyl]hydroxy-
methyl}thiazol-4- yl)-ethanol B B B MS: 501.0/503.0 (M + H.sup.+)
1H NMR (500 MHz, DMSO-d6) ppm = 9.11- (Cl isotopy, rel. peak 9.09
(m, 1H), 7.75-7.70 (m, 2H), 7.55-7.52 intensity ratio [%] 100:39)
(m, 2H), 7.34-7.32 (m, 1H), 7.21-7.19 (m, 1H), 7.00-6.96 (m, 1H),
6.28-6.25 (m, 1H), 5.26-5.18 (m, 1H), 4.77-4.70 (m, 1H), 3.79- 3.75
(m, 4H), 3.47-3.43 (m, 4H), 1.36-1.30 (m, 3H) 202 ##STR00247##
[2-Chloro-4-fluoro- 5-(7-morpholin-4- ylquinazolin-4-yl)-
phenyl]-(1-ethyl- 1H-pyrazol-4-yl)- methanol C B B MS: 468.0/470.0
(M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.12 (s, (Cl isotopy,
rel. peak 1H), 7.91-7.88 (m, 1H), 7.64 (d, J = 9.6, 1H), intensity
ratio [%] 100:35) 7.59 (dd, J = 9.4, 3.2, 1H), 7.57-7.52 (m, 2H),
7.29 (s, 1H), 7.22-7.20 (m, 1H), 5.98 (d, J = 4.8, 1H), 5.93 (d, J
= 4.8, 1H), 4.08-4.02 (m, 2H), 3.80-3.76 (m, 4H), 3.48-3.43 (m,
4H), 1.34-1.28 (m, 3H) 203 ##STR00248## (4,5-Dimethyl-
thiazol-2-yl)-[6- fluoro-5-(7- morpholin-4-yl- pyrido[4,3-d}-
pyrimidin-4-yl)- pyridin-3-yl]- methanol (Ena 2) D D A MS: 453.2 (M
+ H.sup.+); R.sub.t see racemate 73.58 min, (HPLC, Chiralcel OD-H,
hexane/2-propanol 90/10) 204 ##STR00249## (R)-(4,5-Dimethyl-
thiazol-2-yl)-[6- fluoro-5-(7- morpholin-4-yl- pyrido[4,3-d}-
pyrimidin-4-yl)- pyridin-3-yl]- methanol (Ena 1) D D C MS: 453.2 (M
+ H.sup.+); R.sub.t see racemate 68.00 min, (HPLC, Chiralcel OD-H,
hexane/2-propanol 90/10) 205 ##STR00250## (4,5-Dimethyl-
thiazol-2-yl)-[2- fluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
pyridin-3-yl]- methanol (Ena 1) C D C MS: 452.2 (M + H.sup.+);
R.sub.t see racemate 24.50 min, (HPLC, Chiralpak AD-H, ethanol) 206
##STR00251## (4,5-Dimethyl- thiazol-2-yl)-[2- fluoro-5-(7-
morpholin-4-yl- quinazolin-4-yl)- pyridin-3-yl]- methanol (Ena 2) D
B MS: 452.2 (M + H.sup.+); Rt see racemate 27.44 min, (HPLC,
Chiralpak AD-H, ethanol)
Example 207
[4-Fluoro-2-methyl-5-(7-morpholinylquinazolin-4-yl)phenyl]thiazol-2-ylmeth-
anol (EXAMPLE 207)
##STR00252##
[0319] Methyl
4-fluoro-2-methyl-5-(7-morpholinylquinazolin-4-yl)benzoate was
prepared analogously to the synthetic processes described under
EXAMPLES 1 and 2 starting from 4-chloro-7-morpholin-4-ylquinazoline
and methyl
4-fluoro-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)b-
enzoate.
##STR00253##
[0320]
[4-Fluoro-2-methyl-5-(7-morpholinylquinazolin-4-yl)phenyl]thiazol-2-
-ylmethanone was prepared analogously to the synthetic processes
described under EXAMPLE 138 starting from thiazole and methyl
4-fluoro-2-methyl-5-(7-morpholinylquinazolin-4-yl)benzoate.
##STR00254##
[0321]
[4-Fluoro-2-methyl-5-(7-morpholinylquinazolin-4-yl)phenyl]thiazol-2-
-ylmethanol (EXAMPLE 207) was prepared analogously to the synthetic
processes described under EXAMPLES 1 and 2 starting from
[4-fluoro-2-methyl-5-(7-morpholinylquinazolin-4-yl)phenyl]thiazol-2-ylmet-
hanone.
Example 208
[3-(2-Ethynyl-7-morpholinylquinazolin-4-yl)-4-fluorophenyl]thiazol-2-ylmet-
hanol (EXAMPLE 208)
##STR00255##
[0323]
[3-(2-Chloro-7-morpholinylquinazolin-4-yl)-4-fluorophenyl]thiazol-2-
-ylmethanol was prepared analogously to the synthetic processes
described under EXAMPLE 138 starting from
(3-bromo-4-fluorophenyl)thiazol-2-ylmethanol and
4-(2,4-dichloroquinazolin-7-yl)morpholine.
##STR00256##
[0324]
[3-(2-Chloro-7-morpholinylquinazolin-4-yl)-4-fluorophenyl]thiazol-2-
-ylmethanol (102 mg, 0.225 mmol) was dissolved in oxygen-free
N,N-dimethylformamide (4 ml) in an argon atmosphere. CuI (17 mg, 90
.mu.mop, (Ph.sub.3P).sub.2PdCl.sub.2 (63 mg, 90 .mu.mol),
2-diphenylphosphanylpyridine (95 mg, 0.359 mmol), DIPEA (765 .mu.l,
4.49 mmol) and triethylethynylsilane (275 .mu.l, 1.48 mmol) were
subsequently added. The reaction mixture was then heated at a
temperature of 140.degree. C. for 1 h. For work-up, ethyl acetate
(50 ml), water (10 ml) and saturated sodium chloride solution (15
ml) were added. The aqueous phase was separated off and extracted
with ethyl acetate (20 ml). The combined organic phases were dried
over sodium sulfate, filtered, and the filtrate was evaporated to
dryness in vacuo. The residue was dissolved in dimethyl sulfoxide
(2 ml) purified by means of RP chromatography (solvent:
acetonitrile/water/0.1% by vol. of HCOOH, CombiFlash Rf 200). The
suitable product fractions were combined, and the solvents were
removed in a rotary evaporator, giving
[4-fluoro-3-[7-morpholinyl-2-(2-triethylsilylethynyl)quinazolin-4-yl]phen-
yl]thiazol-2-ylmethanol (64 mg, 0.114 mmol, MS: 561.2 [M+H.sup.+],
50% yield) as wax-like solid.
##STR00257##
[0325]
[4-Fluoro-3-[7-morpholinyl-2-(2-triethylsilylethynyl)quinazolin-4-y-
l]phenyl]thiazol-2-ylmethanol (552 mg, 0.985 mmol) was dissolved in
methanol (102 ml). Potassium hydroxide solution (1.0 M, 15 ml, 15
mmol) was subsequently added, and the mixture was stirred at room
temperature for 90 min. When the reaction was complete, the mixture
was carefully neutralised using hydrochloric acid (1.0 M, 15 ml, 15
mmol). Ethyl acetate (500 ml), water (100 ml) and saturated sodium
chloride solution (150 ml) were subsequently added. The phases were
separated, and the aqueous phase was extracted with ethyl acetate
(100 ml). The combined organic phases were dried over sodium
sulfate, filtered, and the filtrate was evaporated to dryness in
vacuo. The residue, dissolved in dimethyl sulfoxide (8 ml), was
purified by means of flash column chromatography (gradient:
dichloromethane/0-5% by vol. of ethanol, CombiFlash Rf 200). The
suitable product fractions were combined, and the solvents were
removed in a rotary evaporator, giving
[3-(2-ethynyl-7-morpholinylquinazolin-4-yl)-4-fluorophenyl]-thiazol-2-ylm-
ethanol (EXAMPLE 208, 221 mg, 0.495 mmol, MS: 447.1 [M+H.sup.+],
50% yield) as solid.
[0326] Compounds which were prepared analogously to EXAMPLES 207
and 208 can be found in Table 6 below.
TABLE-US-00006 TABLE 6 Compounds of the formula (I) IC.sub.50
IC.sub.50 K.sub.i DNA- pDNA- [Kv1.11 No. Structural formula Name PK
PK hERG] 207 ##STR00258## [4-Fluoro-2- methyl-5-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]thiazol-2- ylmethanol A B B MS: 437.1 (M +
H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.09 (s, 1H), 7.71 (d, J =
3.2, 1H), 7.64 (d, J = 3.2, 1H), 7.62 (d, J = 7.5, 1H), 7.58-7.51
(m, 2H), 7.28 (d, J = 10.9, 1H), 7.19 (d, J = 2.1, 1H), 6.84 (s,
1H), 6.20 (s, 1H), 3.80-3.75 (m, 4H), 3.48- 3.43 (m, 4H), 2.49 (s,
3H) 208 ##STR00259## [3-(2-Ethynyl-7- morpholin-4-yl-
quinazolin-4-yl)- 4-fluoro-phenyl]- thiazol-2-yl- methanol B B D
MS: 447.0 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 7.81- 7.47
(m, 6H), 7.46-7.36 (m, 1H), 7.18 (d, J = 2.4, 1H), 6.99 (d, J =
4.6, 1H), 6.08 (d, J = 4.3, 1H), 4.30 (s, 1H), 3.80-3.74 (m, 4H),
3.49- 3.41 (m, 4H) 209 ##STR00260## [4-Fluoro-2- methyl-5-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]thiazol-2- ylmethanol (Ena
1) D D A MS: 437.1 (M + H.sup.+); R.sub.t 1H NMR (400 MHz, DMSO-d6)
ppm = 9.09 (s, 4.77 min (SFC, Chiracel OJ- 1H), 7.72 (d, J = 3.3,
1H), 7.68-7.59 (m, 2H), H, CO.sub.2/15% by vol. of 7.60-7.47 (m,
2H), 7.28 (d, J = 10.9, 1H), 7.19 methanol, 0.5% by vol. of (s,
1H), 6.99-6.71 (m, 1H), 6.20 (s, 1H), 3.82- diethylamine) 3.73 (m,
4H), 3.48-3.42 (m, 4H), 2.58-2.50 (m, 3H) 210 ##STR00261##
[4-Fluoro-2- methyl-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]thiazol-2- ylmethanol (Ena 2) B B A MS: 437.1 (M + H.sup.+);
R.sub.t 1H NMR (400 MHz, DMSO-d6) ppm = 9.09 (s, 6.01 min (SFC,
Chiracel OJ- 1H), 7.72 (d, J = 3.3, 1H), 7.68-7.59 (m, 2H), H,
CO.sub.2/15% by vol. of 7.60-7.47 (m, 2H), 7.28 (d, J = 10.9, 1H),
7.19 methanol, 0.5% by vol. of (s, 1H), 6.99-6.71 (m, 1H), 6.20 (s,
1H), 3.82- diethylamine) 3.73 (m, 4H), 3.48-3.42 (m, 4H), 2.58-2.50
(m, 3H) 211 ##STR00262## [4-Fluoro-3-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]thiazol-2- ylmethanol B B A MS: 423.1 (M +
H.sup.+) 1H NMR (400 MHz, DMSO-d6) ppm = 9.10 (s, 1H), 7.78-7.61
(m, 4H), 7.57-7.49 (m, 2H), 7.46-7.37 (m, 1H), 7.23-7.17 (m, 1H),
6.95 (s, 1H), 6.08 (s, 1H), 3.81-3.74 (m, 4H), 3.48- 3.41 (m, 4H)
212 ##STR00263## [4-Fluoro-3-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]thiazol-2- ylmethanol (Ena 1) A D A MS: 423.1 (M + H.sup.+);
R.sub.t 1H NMR (400 MHz, DMSO-d6) ppm = 9.10 (s, 15.65 min (SFC,
Chiracel 1H), 7.73 (d, J = 3.2, 1H), 7.71-7.63 (m, 3H), OJ-H,
CO.sub.2/10% by vol. of 7.55-7.49 (m, 2H), 7.44-7.38 (m, 1H), 7.22-
methanol, 0.5% by vol. of 7.18 (m, 1H), 6.95 (d, J = 4.6, 1H), 6.08
(d, diethylamine) J = 4.5, 1H), 3.81-3.75 (m, 4H), 3.47-3.42 (m,
4H) 213 ##STR00264## [4-Fluoro-3-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]thiazol-2- ylmethanol (Ena 2) A C A MS:
423.1 (M + H.sup.+); R.sub.t 1H NMR (400 MHz, DMSO-d6) ppm = 9.10
(s, 18.36 min (SFC, Chiracel 1H), 7.73 (d, J = 3.2, 1H), 7.72-7.65
(m, 2H), OJ-H, CO.sub.2/10% by vol. of 7.65-7.64 (m, 1H), 7.54-7.52
(m, 2H), 7.44- methanol, 0.5% by vol. of 7.39 (m, 1H), 7.21-7.19
(m, 1H), 6.96 (d, diethylamine) J = 4.6, 1H), 6.08 (d, J = 4.6,
1H), 3.80-3.75 (m, 4H), 3.46-3.42 (m, 4H) 214 ##STR00265##
[3-(2-Chloro-7- morpholin-4-yl- quinazolin-4-yl)- 4-fluoro-phenyl]
(2-methyl-2H- pyrazol-3-yl)- methanol B D B MS: 454.1/456.1 (M +
H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 7.71- (Cl isotopy, rel.
peak 7.59 (m, 3H), 7.58-7.51 (m, 2H), 7.50-7.41 intensity ratio [%]
100:35) (m, 1H), 7.31-7.26 (m, 1H), 7.18-7.12 (m, 1H), 5.99 (s,
1H), 5.95-5.90 (m, 1H), 3.78 (s, 3H), 3.78-3.73 (m, 4H), 3.52-3.45
(m, 4H) 215 ##STR00266## [3-(2-Ethynyl-7- morpholin-4-yl-
quinazolin-4-yl)- 4-fluorophenyl]- thiazol-2-yl- methanol (Ena 1) A
C D MS: 447.1 (M + H.sup.+); R.sub.t 1H NMR (500 MHz, DMSO-d6) ppm
= 7.73 (d, 10.67 min (HPLC, Chiralpak J = 3.2, 1H), 7.72-7.65 (m,
2H), 7.65 (d, J = 3.2, AD-H, n-heptane/40% by 1H), 7.53 (qd, J =
9.4, 2.7, 2H), 7.46-7.38 (m, vol. of 2-propanol 1H), 7.18 (d, J =
2.3, 1H), 6.97 (d, J = 4.6, 1H), 6.09 (d, J = 4.6, 1H), 4.30 (s,
1H), 3.80-3.74 (m, 4H), 3.49-3.43 (m, 4H) 216 ##STR00267##
[3-(2-Ethynyl-7- morpholin-4-yl- quinazolin-4-yl)- 4-fluorophenyl]-
thiazol-2-yl- methanol (Ena 2) A D C MS: 447.1 (M + H.sup.+);
R.sub.t 1H NMR (500 MHz, DMSO-d6) ppm = 7.73 (d, 13.14 min (HPLC,
Chiralpak J = 3.2, 1H), 7.72-7.65 (m, 2H), 7.65 (d, J = 3.2, AD-H,
n-heptane/40% by 1H), 7.53 (qd, J = 9.4, 2.7, 2H), 7.46-7.38 (m,
vol. of 2-propanol 1H), 7.18 (d, J = 2.3, 1H), 6.97 (d, J = 4.6,
1H), 6.09 (d, J = 4.6, 1H), 4.30 (s, 1H), 3.80-3.74 (m, 4H),
3.49-3.43 (m, 4H)
Example 217
[2,4-Difluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]pyridin-3-ylmethan-
ol (217)
##STR00268##
[0328] 1,5-Dibromo-2,4-difluorobenzene (500 mg, 1.78 mmol) was
dissolved in dry diethyl ether (10 ml) under argon. The reaction
solution was cooled to (-)65.degree. C. by means of an
acetone/dry-ice bath. n-Butyllithium (15% solution in n-hexane,
1.23 ml, 1.96 mmol) was added dropwise over the course of 15 min at
a constant temperature of (-)65.degree. C., and the reaction
solution was stirred at (-)65.degree. C. for a further 30 min. A
pre-prepared solution of nicotinaldehyde (201 .mu.l, 2.14 mmol) in
dry diethyl ether (5 ml) was subsequently added dropwise over a
period of 15 min at (-)65.degree. C., and the reaction mixture was
stirred for a further 10 min and then warmed slowly to 0.degree. C.
over a period of one hour. After termination of the reaction,
saturated ammonium chloride solution (5 ml) and water (30 ml) were
added to the reaction solution. The aqueous phase was extracted
three times with t-butyl methyl ether. The combined organic phases
were washed with saturated sodium chloride solution, dried over
sodium sulfate, filtered and evaporated in a rotary evaporator. The
crude product (oil) was purified by means of preparative RP column
chromatography (solvent gradient water/acetonitrile/0.1% by vol. of
trifluoroacetic acid [5.5 min], CombiFlash Rf 200). The suitable
product fractions were combined and evaporated in vacuo. The
aqueous residue was neutralised using saturated sodium
hydrogencarbonate solution and extracted three times with ethyl
acetate. The combined organic phases were washed with saturated
sodium chloride solution, dried over sodium sulfate, filtered and
evaporated to dryness in vacuo in a rotary evaporator, giving
(5-bromo-2,4-difluorophenyl)-(3-pyridyl)methanol (215 mg, 0.717
mmol, MS: 300.0/302.0 [M+H.sup.+], 40% yield) as colourless
oil.
##STR00269##
[0329]
[2,4-Difluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]pyridin-3-y-
lmethanol (EXAMPLE 217) was obtained analogously to the synthetic
processes for the preparation of
1-[5-(7-morpholin-4-ylquinazolin-4-yl)pyridin-3-yl]-1-thiazol-2-ylethanol
(EXAMPLE 138) starting from
(5-bromo-2,4-difluorophenyl)-(3-pyridyl)methanol.
[0330] Compounds which were prepared analogously to EXAMPLE 217 can
be found in Table 7 below.
TABLE-US-00007 TABLE 7 Compounds of the formula (I) IC.sub.50
IC.sub.50 K.sub.i DNA- pDNA- [Kv1.11 No. Structural formula Name PK
PK hERG] 217 ##STR00270## [2,4-Difluoro-5-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]pyridin-3-yl- methanol B A A MS: 435.2 (M
+ H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.11 (s, 1H), 8.62-8.59
(m, 1H), 8.47 (dd, J = 4.8, 1.6, 1H), 7.84 (t, J = 8.2, 1H),
7.77-7.72 (m, 1H), 7.55 (qd, J = 9.4, 2.8, 2H), 7.46 (t, J = 10.1,
1H), 7.39-7.34 (m, 1H), 7.21 (d, J = 2.4, 1H), 6.36 (d, J = 4.5,
1H), 6.06 (d, J = 4.5, 1H), 3.81-3.74 (m, 4H), 3.48-3.42 (m, 4H)
218 ##STR00271## [2,4-Difluoro-5-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]pyridin-2-yl- methanol B A B MS: 435.2 (M
+ H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.09 (s, 1H), 8.50-8.46
(m, 1H), 7.82 (td, J = 7.7, 1.8, 1H), 7.68 (t, J = 8.1, 1H),
7.64-7.59 (m, 1H), 7.57-7.50 (m, 2H), 7.43 (t, J = 10.1, 1H), 7.29-
7.24 (m, 1H), 7.21-7.17 (m, 1H), 6.34 (d, J = 5.0, 1H), 6.02 (d, J
= 5.0, 1H), 3.82-3.72 (m, 4H), 3.48-3.41 (m, 4H). 219 ##STR00272##
6-{[2,4-Difluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]hydroxy- methyl}-2-methyl-2H- pyridazin-3-one B B B MS:
466.2 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.11 (s, 1H),
7.85 (t, J = 8.1, 1H), 7.61-7.51 (m, 3H), 7.47 (t, J = 10.1, 1H),
7.21 (d, J = 2.3, 1H), 6.94 (d, J = 9.6, 1H), 6.56 (d, J = 4.8,
1H), 5.85 (d, J = 4.8, 1H), 3.81-3.75 (m, 4H), 3.60 (s, 3H),
3.48-3.42 (m, 4H) 220 ##STR00273## 6-{[2,4-Difluoro-3-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]hydroxy-
methyl}-2-methyl-2H- pyridazin-3-one D C A MS: 466.2 (M + H.sup.+)
1H NMR (500 MHz, DMSO-d6) ppm = 9.10 (s, 1H), 7.75 (d, J = 9.6,
1H), 7.67-7.61 (m, 1H), 7.51 (qd, J = 9.4, 2.6, 2H), 7.32 (t, J =
8.8, 1H), 7.20 (d, J = 2.3, 1H), 6.99 (d, J = 9.7, 1H), 6.64 (d, J
= 5.1, 1H), 6.02 (d, J = 5.1, 1H), 3.78 (t, J = 4.9, 4H), 3.57 (s,
3H), 3.45 (t, J = 4.9, 4H) 221 ##STR00274## [2,4-Difluoro-5-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]-(6-methoxy-
pyridin-3-yl)methanol B B B MS: 465.2 (M + H.sup.+) 1H NMR (500
MHz, DMSO-d6) ppm = 9.11 (s, 1H), 8.17 (d, J = 2.4, 1H), 7.84 (t, J
= 8.2, 1H), 7.63 (dd, J = 8.6, 2.5, 1H), 7.60-7.52 (m, 2H), 7.44
(t, J = 10.2, 1H), 7.21 (d, J = 2.3, 1H), 6.79 (d, J = 8.6, 1H),
6.22 (d, J = 4.0, 1H), 5.99 (d, J = 3.7, 1H), 3.83 (s, 3H),
3.80-3.76 (m, 4H), 3.47-3.43 (m, 4H) 222 ##STR00275##
[2,4-Difluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]-[1,2,4]- triazolo[1,5-a]pyridin- 6-ylmethanol B B A MS:
475.2 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.10 (s, 1H),
8.98-8.95 (m, 1H), 8.49 (s, 1H), 7.88 (t, J = 8.1, 1H), 7.83-7.80
(m, 1H), 7.62-7.56 (m, 2H), 7.53 (dd, J = 9.5, 2.5, 1H), 7.48 (t, J
= 10.1, 1H), 7.20 (d, J = 2.4, 1H), 6.52 (s, 1H), 6.17 (s, 1H),
3.82-3.74 (m, 4H), 3.49-3.41 (m, 4H) 223 ##STR00276##
[2,4-Difluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]imidazo- [1,2-a]pyrazin-6-yl- methanol C B A MS: 475.2 (M +
H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.13 (s, 1H), 9.06-9.02
(m, 1H), 8.83 (t, J = 1.3, 1H), 8.25-8.22 (m, 1H), 7.86 (d, J =
1.0, 1H), 7.76 (t, J = 8.1, 1H), 7.63-7.56 (m, 2H), 7.52 (t, J =
10.1, 1H), 7.24 (d, J = 2.1, 1H), 6.53 (d, J = 4.7, 1H), 6.16 (d, J
= 4.5, 1H), 3.87-3.80 (m, 4H), 3.54- 3.46 (m, 4H) 224 ##STR00277##
[2,4-Difluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]-(5-methoxy- pyridin-2-yl)methanol B B B MS: 465.2 (M +
H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.09 (s, 1H), 8.20-8.17
(m, 1H), 7.68 (t, J = 8.1, 1H), 7.55-7.51 (m, 3H), 7.43-7.37 (m,
2H), 7.21- 7.18 (m, 1H), 6.23 (d, J = 4.9, 1H), 5.98 (d, J = 4.6,
1H), 3.80 (s, 3H), 3.80-3.74 (m, 4H), 3.48-3.41 (m, 4H)
Example 225
[2-Chloro-5-(5,6-dideuterio-7-morpholinylquinazolin-4-yl)-4-fluorophenyl]--
(6-methoxypyridazin-3-yl)methanol (225)
##STR00278##
[0332] Reaction of
5,6,8-trideuterio-7-morpholinyl-3H-quinazolin-4-one with phosphorus
oxychloride gave
4-chloro-5,6-dideuterio-7-N-morpholinylquinazoline.
Example 237
[4-Fluoro-3-(7-morpholin-4-ylpyrido[3,2-d}pyrimidin-4-yl)phenyl]-(3-methyl-
pyrazin-2-yl)methanol (237)
##STR00279##
[0333] Example 258
[0334]
[2-Chloro-4-fluoro-5-[7-(2,2,3,3,5,5,6,6-octadeuteriomorpholin-4-yl-
)quinazolin-4-yl]phenyl]-(3-methoxypyrazin-2-yl)methanol (258)
##STR00280##
Examples 268 and 278
[4-Fluoro-3-(5-fluoro-7-morpholin-4-ylquinazolin-4-yl)phenyl]-(3-methylpyr-
azin-2-yl)methanol (268),
[2-chloro-4-fluoro-5-(5-fluoro-7-morpholin-4-ylquinazolin-4-yl)phenyl]-(6-
-methoxypyridazin-3-yl)methanol (278)
##STR00281##
[0335] Example 319
2-[2,4-Difluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-2-(3-methoxypyr-
azin-2-yl)acetamide (319)
##STR00282##
[0337]
[2,4-Difluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]acetonitril-
e (300 mg, 0.82 mmol) and 2-chloro-3-methoxypyrazine (297 mg, 1.97
mmol) were dissolved in tetrahydrofuran. Nitrogen was subsequently
passed into the solution for a period of 10 min. Potassium
tert-butoxide (193 mg, 1.72 mmol) was then added to the reaction
solution, and the mixture was stirred at room temperature under an
argon atmosphere for a period of 30 min. When the reaction was
complete, the reaction mixture was neutralised using saturated
NH.sub.4Cl solution, diluted with distilled water (30 ml) and
extracted three times with dichloromethane (30 ml in each case).
The organic phase was dried over NaSO.sub.4, filtered off with
suction and evaporated to dryness in vacuo. The residue was
purified by means of flash column chromatography (gradient:
dichloromethane/0-5% by vol. of ethanol, CombiFlash Rf 200, 40 g
silica column, .lamda..dbd.220 nm). The suitable product fractions
were combined, and solvents were removed in a rotary evaporator,
giving
[2,4-difluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(3-methoxypyrazi-
n-2-yl)acetonitrile (218 mg, 0.46 mmol; MS: 475.2 [M+H.sup.+], 56%
yield) as solid.
[2,4-Difluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(3-met-
hoxypyrazin-2-yl)acetonitrile (218 mg, 0.46 mmol) was initially
introduced in the reaction flask and subsequently dissolved with
H.sub.2SO.sub.4 (95-98%, 3.53 ml, 64 mmol). The reaction solution
was stirred at room temperature for 2.5 h. When the reaction was
complete, ice (80 g) was added to the reaction solution. The
mixture was subsequently carefully neutralised using NaOH solution
(32%, 10.6 ml). The suspension obtained was diluted with distilled
water (50 ml) and extracted three times with dichloromethane (100
ml in each case). The organic phase was dried over over a SO.sub.4,
filtered off with suction and evaporated to dryness in vacuo. The
residue was purified by means of flash column chromatography
(gradient: dichloromethane/0-12% by vol. of ethanol, CombiFlash Rf
200, 40 g silica column, .lamda..dbd.220 nm). The suitable product
fractions were combined, and solvents were removed in a rotary
evaporator, giving
2-[2,4-difluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-2-(3-methoxypy-
razin-2-yl)acetamide (182 mg, 0.37 mmol, MS: 493.4 [M+H.sup.+], 81%
yield) as solid.
[0338] Compounds which were prepared corresponding to EXAMPLES 225,
237, 258, 268, 278 and 319 and analogously to the synthesis
sequences of EXAMPLES 1, 2, 37, 137, 121, 217 can be found in Table
8 below:
TABLE-US-00008 IC.sub.50 IC.sub.50 K.sub.i DNA- pDNA- [Kv1.11 No.
Structural formula Name PK PK hERG] 225 ##STR00283##
[2-Chloro-5-(5,6- dideuterio-7- morpholino- quinazolin-4-yl)-4-
fluorophenyl]-(6- methoxypyridazin-3- yl)methanol B A A MS:
484.3/486.3 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.12 (s,
(Cl isotopy, rel. peak 1H), 7.91 (d, J = 7.8, 1H), 7.72-7.64 (m,
2H), 7.27- intensity ratio [%] 100:37) 7.17 (m, 2H), 6.61 (d, J =
5.0, 1H), 6.23 (d, J = 5.0, 1H), 4.00 (s, 3H), 3.81-3.72 (m, 4H),
3.49-3.36 (m, 4H). 226 ##STR00284## [3-(5,6-Dideuterio-7-
morpholino- quinazolin-4-yl)-4- fluorophenyl]-(3-
methylpyrazin-2-yl)- methanol B A A MS: 434.4/436.4 (M + H.sup.+)
(Cl 1H NMR (500 MHz, DMSO-d6) ppm = 9.09 (s, isotopy, rel. peak
intensity 1H), 8.43 (s, 2H), 7.64-7.55 (m, 2H), 7.42-7.34 ratio [%]
100:40) (m, 1H), 7.19 (s, 1H), 6.34-6.20 (m, 1H), 6.08 (s, 1H),
3.86-3.68 (m, 4H), 3.50-3.36 (m, 4H), 2.55 (s, 3H). 227
##STR00285## [2-Chloro-4-fluoro-5- (7-morpholin-4-yl-
pyrido[3,2-d}- pyrimidin-4-yl)- phenyl]-(6-methoxy-
pyridazin-3-yl)- methanol (Ena 1) B B A MS: 483.2/485.1 (M +
H.sup.+) (Cl see racemate isotopy, rel. peak intensity ratio [%]
100:33); R.sub.t 8.37 min (HPLC, Chiralpak AD-H, n-heptane/90% by
vol. of 2-propanol) 228 ##STR00286## [2-Chloro-4-fluoro-5-
(7-morpholin-4-yl- pyrido[3,2-d}- pyrimidin-4-yl)-
phenyl]-(6-methoxy- pyridazin-3-yl)- methanol (Ena 2) D D A MS:
483.2/485.1 (M + H.sup.+) (Cl see racemate isotopy, rel. peak
intensity ratio [%] 100:33); R.sub.t 12.45 min (HPLC, Chiralpak
AD-H, n-heptane/90% by vol. of 2-propanol) 229 ##STR00287##
2-[2-Chloro-4-fluoro- 5-(7-morpholin-4-yl- quinazolin-4-yl)-
phenyl]-2-(3- methoxypyrazin-2- yl)-N-methyl- acetamide C B A MS:
523.3/525.2 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.09 (s,
(Cl isotopy, rel. peak 1H), 8.26 (q, J = 4.5, 1H), 8.13 (d, J =
2.8, 1H), 8.11 intensity ratio [%] 100:40) (d, J = 2.8, 1H), 7.73
(d, J = 9.6, 1H), 7.59 (dd, J = 9.4, 2.6, 1H), 7.56 (dd, J = 9.5,
2.3, 1H), 7.47 (d, J = 7.7, 1H), 7.20 (d, J = 2.2, 1H), 5.66 (s,
1H), 3.94 (s, 3H), 3.80-3.71 (m, 4H), 3.48-3.42 (m, 4H), 2.61 (d, J
= 4.6, 3H). 230 ##STR00288## 2-(3-Chloro-pyridin-
2-yl)-2-[4-fluoro-3-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]-N-methyl- acetamide C C B* MS: 492.3/494.2 (M + H.sup.+)
(Cl 1H NMR (500 MHz, DMSO-d6) ppm = 9.09 (s, isotopy, rel. peak
intensity 1H), 8.51 (dd, J = 4.7, 1.4, 1H), 8.03 (q, J = 4.4, 1H),
ratio [%] 100:40) 7.92 (dd, J = 8.1, 1.5, 1H), 7.63 (dd, J = 9.4,
2.7, 1H), 7.58-7.54 (m, 3H), 7.41-7.33 (m, 2H), 7.20 (d, J = 2.4,
1H), 5.52 (s, 1H), 3.85-3.71 (m, 4H), 3.51- 3.40 (m, 4H), 2.60 (d,
J = 4.6, 3H). 231 ##STR00289## [2-Chloro-4-fluoro-5-
(7-morpholin-4-yl- pyrido[3,2-d}- pyrimidin-4-yl)-
phenyl]-(3-methoxy- pyrazin-2-yl)- methanol (Ena 2) C B A MS:
483.1/485.1 (M + H.sup.+) (Cl see racemate isotopy, rel. peak
intensity ratio [%] 100:38); R.sub.t 8.72 min (SFC, Chiralpak AD-H,
CO.sub.2/40% by vol. of methanol) 232 ##STR00290##
[2-Chloro-4-fluoro-5- (7-morpholin-4-yl- pyrido[3,2-d}-
pyrimidin-4-yl)- phenyl]-(3-methoxy- pyrazin-2-yl)- methanol (Ena
1) C D A MS: 483.1/485.1 (M + H.sup.+) (Cl see racemate isotopy,
rel. peak intensity ratio [%] 100:38); R.sub.t 7.27 min (SFC,
Chiralpak AD-H, CO.sub.2/40% by vol. of methanol) 233 ##STR00291##
(S)-[4-Fluoro-3-(7- morpholin-4-yl- pyrido[3,2-d}- pyrimidin-4-yl)-
phenyl]-(3-methyl- pyrazin-2-yl)- methanol C D A MS: 433.1 (M +
H.sup.+); R.sub.t see racemate 4.40 min (SFC, Chiralcel OD-H,
CO.sub.2/40% by vol. of 2-propanol, 0.5% by vol. of diethylamine)
234 ##STR00292## (R)-[4-Fluoro-3-(7- morpholin-4-yl- pyrido[3,2-d}-
pyrimidin-4-yl)- phenyl]-(3-methyl- pyrazin-2-yl)- methanol A A A
MS: 433.1 (M + H.sup.+); R.sub.t see racemate 3.01 min (SFC,
Chiralcel OD-H, CO.sub.2/40% by vol. of 2-propanol, 0.5% by vol. of
diethylamine) 235 ##STR00293## 4-(4-Chloro-2-fluoro-
5-imidazo[1,2-b]- pyridazin-6-ylmethyl- phenyl)-7-morpholin-
4-ylquinazoline A A A* MS: 475.1/477.1 (M + H.sup.+) (Cl 1H NMR
(500 MHz, DMSO-d6) ppm = 9.10 (s, isotopy, rel. peak intensity 1H),
8.22 (s, 1H), 8.07 (d, J = 9.4, 1H), 7.78-7.74 ratio [%] 100:35)
(m, 2H), 7.74-7.71 (m, 1H), 7.60 (dd, J = 9.4, 3.1, 1H), 7.54 (dd,
J = 9.4, 2.5, 1H), 7.20 (d, J = 2.5, 1H), 7.16 (d, J = 9.4, 1H),
4.42 (s, 2H), 3.80-3.75 (m, 4H), 3.47-3.43 (m, 4H). 236
##STR00294## 2-[2-Chloro-4-fluoro- 5-(7-morpholin-4-yl-
quinazolin-4-yl)- phenyl]-2-imidazo- [1,2-b]pyridazin-6-yl-
N-methylacetamide D C A* MS: 532.2/534.2 (M + H.sup.+) (Cl 1H NMR
(500 MHz, DMSO-d6) ppm = 9.11 (s, isotopy, rel. peak intensity 1H),
8.56 (q, J = 4.5, 1H), 8.26 (s, 1H), 8.10 (d, ratio [%] 100:35) J =
9.5, 1H), 7.81 (d, J = 9.5, 1H), 7.77 (d, J = 1.2, 1H), 7.74 (d, J
= 7.6, 1H), 7.60 (dd, J = 9.4, 3.0, 1H), 7.55 (dd, J = 9.4, 2.5,
1H), 7.21 (d, J = 2.4, 1H), 7.12 (d, J = 9.5, 1H), 5.62 (s, 1H),
3.81-3.75 (m, 4H), 3.48-3.40 (m, 4H), 2.65 (d, J = 4.6, 3H). 237
##STR00295## [4-Fluoro-3-(7- morpholin-4-yl- pyrido[3,2-d}-
pyrimidin-4-yl)- phenyl]-(3-methyl- pyrazin-2-yl)- methanol A A C
MS: 433.3 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.18 (s,
1H), 9.02 (d, J = 2.9, 1H), 8.47-8.39 (m, 2H), 7.64 (dd, J = 6.7,
2.2, 1H), 7.59-7.50 (m, 1H), 7.45 (d, J = 2.9, 1H), 7.31 (dd, J =
9.7, 8.6, 1H), 6.28 (d, J = 5.4, 1H), 6.06 (d, J = 5.4, 1H),
3.81-3.76 (m, 4H), 3.56-3.50 (m, 4H), 2.55 (s, 3H). 238
##STR00296## [4-Fluoro-3-[7- (2,2,3,3,5,5,6,6-
octadeuteriomorpholin- 4-yl)quinazolin-4- yl]phenyl]-(3-methyl-
pyrazin-2-yl)- methanol (Ena 2) A A B MS: 440.4 (M + H.sup.+);
R.sub.t S. Racemat 10.58 min (SFC, Chiralpak AD-H, CO.sub.2/30% by
vol. of 2-propanol, 0.5% by vol. of diethylamine) 239 ##STR00297##
[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
(Ena 2) C D B MS: 490.3/492.2 (M + H.sup.+) (Cl see racemate
isotopy, rel. peak intensity ratio [%] 100:38); R.sub.t 5.20 min
(SFC, Chiralpak AD-H, CO.sub.2/40% by vol. of methanol, 0.5% by
vol. of diethylamine) 240 ##STR00298## [2-Chloro-4-fluoro-5-
(7-morpholin-4-yl- pyrido[3,2-d}- pyrimidin-4-yl)-
phenyl]-(3-methyl- pyrazin-2-yl)- methanol C B A MS: 467.3/469.2 (M
+ H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm = 9.23 (s, isotopy,
rel. peak intensity 1H), 9.06 (d, J = 2.9, 1H), 8.43 (d, J = 2.5,
1H), 8.33 ratio [%] 100:38) (d, J = 2.5, 1H), 8.05 (d, J = 7.5,
1H), 7.54 (d, J = 9.2, 1H), 7.48 (d, J = 2.9, 1H), 6.65-6.27 (m,
1H), 6.25- 6.22 (m, 1H), 3.82-3.77 (m, 4H), 3.58-3.52 (m, 4H), 2.74
(s, 3H). 241 ##STR00299## [2-Chloro-4-fluoro-5-
[7-(2,2,3,3,5,5,6,6- octadeuteriomorpholin- 4-yl)quinazolin-4-
yl]phenyl]-(3- methoxypyrazin-2- yl)methanol (Ena 2) A A C MS:
490.2/492.2 (M + H.sup.+) (Cl see racemate isotopy, rel. peak
intensity ratio [%] 100:38); R.sub.t 6.47 min (SFC, Chiralpak AD-H,
CO.sub.2/40% by vol. of methanol, 0.5% by vol. of diethylamine) 242
##STR00300## [2-Chloro-4-fluoro-5- [7-(2,2,3,3,5,5,6,6-
octadeuteriomorpholin- 4-yl)quinazolin-4- yl]phenyl]-(3-
methoxypyrazin-2- yl)methanol (Ena 1) A A B MS: 490.2/492.2 (M +
H.sup.+) (Cl see racemate isotopy, rel. peak intensity ratio [%]
100:35); R.sub.t 2.91 min (SFC, Chiralpak AD-H, CO.sub.2/40% by
vol. of methanol, 0.5% by vol. of diethylamine) 243 ##STR00301##
(S)-[4-Fluoro-3-[7- (2,2,3,3,5,5,6,6- octadeuteriomorpholin-
4-yl)quinazolin-4- yl]phenyl]-(3- methylpyrazin-2- yl)methanol (Ena
1) C B B MS: 440.4 (M + H.sup.+); R.sub.t see racemate 8.16 min
(SFC, Chiralpak AD-H, CO.sub.2/30% by vol. of 2-propanol, 0.5% by
vol. of diethylamine) 244 ##STR00302## [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 (Ena 1) A A B MS:
490.1/492.1 (M + H.sup.+) (Cl see racemate isotopy, rel. peak
intensity ratio [%] 100:33); R.sub.t 3.39 min (SFC, Chiralpak AD-H,
CO.sub.2/40% by vol. of methanol, 0.5% by vol. of diethylamine) 245
##STR00303## [4-Fluoro-3-(6- morpholin-4-yl- thieno[3,2-d}-
pyrimidin-4-yl)- phenyl]-(3-methyl- pyrazin-2-yl)- methanol (Ena 1)
A A A* MS: 438.1 (M + H.sup.+); R.sub.t see racemate 4.70 min (SFC,
Chiralcel OD-H, CO.sub.2/30% by vol. of 2-propanol, 0.5% by vol. of
diethylamine) 246 ##STR00304## [4-Fluoro-3-(6- morpholin-4-yl-
thieno[3,2-d}- pyrimidin-4-yl)- phenyl]-(3-methyl- pyrazin-2-yl)-
methanol (Ena 2) B B A* MS: 438.1 (M + H.sup.+); R.sub.t see
racemate 7.04 min (SFC, Chiralcel
OD-H, CO.sub.2/30% by vol. of 2-propanol, 0.5% by vol. of
diethylamine) 247 ##STR00305## [2-Chloro-4-fluoro-5-
(7-morpholin-4-yl- pyrido[3,2-d}- pyrimidin-4-yl)-
phenyl]-(3-methoxy- pyrazin-2-yl)- methanol C C B MS: 483.1/485.1
(M + H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm = 9.22 (s, isotopy,
rel. peak intensity 1H), 9.04 (d, J = 2.9, 1H), 8.16 (d, J = 2.7,
1H), 8.08 ratio [%] 100:35) (d, J = 2.7, 1H), 8.02 (d, J = 7.6,
1H), 7.51 (d, J = 9.3, 1H), 7.47 (d, J = 2.8, 1H), 6.32-6.28 (m,
2H), 4.00 (s, 3H), 3.82-3.77 (m, 4H), 3.57-3.52 (m, 4H). 248
##STR00306## (R)-[4-Fluoro-3-(5- fluoro-7-morpholin-4-
ylquinazolin-4-yl)- phenyl]-(3-methyl- pyrazin-2-yl)- methanol A A
A MS: 450.1 (M + H.sup.+); R.sub.t see racemate 7.18 min (SFC,
Chiralcel OD-H, CO.sub.2/25% by vol. of 2-propanol, 0.5% by vol. of
diethylamine) 249 ##STR00307## [2-Chloro-4-fluoro-5- (5-fluoro-7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]-(3-methoxy-
pyrazin-2-yl)- methanol (Ena 2) A A A* MS: 500.2/502.1 (M +
H.sup.+) (Cl see racemate isotopy, rel. peak intensity ratio [%]
100:35); R.sub.t 7.94 min (SFC, Chiralpak AD-H, CO.sub.2/40% by
vol. of methanol) 250 ##STR00308## [2-Chloro-4-fluoro-5-
(5-fluoro-7- morpholin-4-yl- quinazolin-4-yl)- phenyl]-(3-methoxy-
pyrazin-2-yl)- methanol (Ena 1) A A A* MS: 500.2/502.1 (M +
H.sup.+) (Cl see racemate isotopy, rel. peak intensity ratio [%]
100:35); R.sub.t 3.46 min (SFC, Chiralpak AD-H, CO.sub.2/40% by
vol. of methanol) 251 ##STR00309## (S)-[4-fluoro-3-(5-
fluoro-7-morpholin-4- ylquinazolin-4-yl)- phenyl]-(3-methyl-
pyrazin-2-yl)- methanol B B A* MS: 450.1 (M + H.sup.+); R.sub.t see
racemate 8.84 min (SFC, Chiralcel OD-H, CO.sub.2/25% by vol. of
2-propanol, 0.5% by vol. of diethylamine) 252 ##STR00310##
[4-Fluoro-3-(5-fluoro- 7-morpholin-4-yl- quinazolin-4-yl)-
phenyl]-(3-methoxy- pyrazin-2-yl)- methanol (Ena 2) A A A* MS:
466.2 (M + H.sup.+); R.sub.t see racemate 10.46 min (SFC, Chiralcel
OD-H, CO.sub.2/25% by vol. of 2-propanol, 0.5% by vol. of
diethylamine) 253 ##STR00311## [4-Fluoro-3-(5-fluoro-
7-morpholin-4-yl- quinazolin-4-yl)- phenyl]-(3-methoxy-
pyrazin-2-yl)- methanol (Ena 1) C C A* MS: 466.2 (M + H.sup.+);
R.sub.t see racemate 7.37 min (SFC, Chiralcel OD-H, CO.sub.2/25% by
vol. of 2-propanol, 0.5% by vol. of diethylamine) 254 ##STR00312##
2-[2-Chloro-4-fluoro- 5-(7-morpholin-4-yl- quinazolin-4-yl)-
phenyl]-N-methyl-2- (3-methyl-pyrazin-2- yl)acetamide C D A* MS:
507.2/509.2 (M + H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm = 9.08
(s, isotopy, rel. peak intensity 1H), 8.41 (d, J = 2.6, 1H), 8.39
(d, J = 2.5, 1H), 8.30 ratio [%] 100:35) (q, J = 4.5, 1H), 7.74 (d,
J = 9.5, 1H), 7.59 (dd, J = 9.4, 2.6, 1H), 7.55 (dd, J = 9.5, 2.4,
1H), 7.47 (d, J = 7.7, 1H), 7.20 (d, J = 2.3, 1H), 5.66 (s, 1H),
3.78 (t, J = 5.8, 3.9, 4H), 3.46 (t, J = 4.9, 4H), 2.63 (d, J =
4.5, 3H), 2.52 (s, 3H). 255 ##STR00313## [4-Fluoro-3-(5-fluoro-
7-morpholin-4-yl- quinazolin-4-yl)- phenyl]-(6-methoxy-
pyridazin-3-yl)- methanol (Ena 2) C A A* MS: 466.2 (M + H.sup.+);
R.sub.t see racemate 10.43 min (SFC, Chiralpak AS-H, CO.sub.2/15%
by vol. of methanol, 0.5% by vol. of diethylamine) 256 ##STR00314##
[4-Fluoro-3-(5-fluoro- 7-morpholin-4-yl- quinazolin-4-yl)-
phenyl]-(6-methoxy- pyridazin-3-yl)- methanol (Ena 1) A A A* MS:
466.2 (M + H.sup.+); R.sub.t see racemate 7.26 min (SFC, Chiralpak
AS-H, CO.sub.2/15% by vol. of methanol, 0.5% by vol. of
diethylamine) 257 ##STR00315## [2-Chloro-4-fluoro-5-
(7-morpholin-4-yl- pyrido[3,2-d}- pyrimidin-4-yl)-
phenyl]-(6-methoxy- pyridazin-3-yl)- methanol B B A MS: 483.2/485.1
(M + H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm = 9.21 (s, isotopy,
rel. peak intensity 1H), 9.04 (d, J = 2.9, 1H), 7.96 (d, J = 7.5,
1H), 7.68 ratio [%] 100:33) (d, J = 9.2, 1H), 7.58 (d, J = 9.3,
1H), 7.46 (d, J = 2.9, 1H), 7.22 (d, J = 9.1, 1H), 6.60 (d, J =
4.9, 1H), 6.23 (d, J = 4.9, 1H), 4.00 (s, 3H), 3.84-3.76 (m, 4H),
3.57-3.51 (m, 4H). 258 ##STR00316## [2-Chloro-4-fluoro-5-
[7-(2,2,3,3,5,5,6,6- octadeuterio- morpholin-4-yl)-
quinazolin-4-yl-] phenyl]-(3-methoxy- pyrazin-2-yl)- methanol B A
A* MS: 490.1/492.3 (M + H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm
= 9.13 (s, isotopy, rel. peak intensity 1H), 8.17 (d, J = 2.7, 1H),
8.11 (d, J = 2.7, 1H), 7.97 ratio [%] 100:36) (d, J = 7.8, 1H),
7.67-7.58 (m, 2H), 7.56 (dd, J = 9.4, 2.6, 1H), 7.21 (d, J = 2.5,
1H), 6.34 (d, J = 5.9, 1H), 6.31 (d, J = 5.9, 1H), 4.00 (s, 3H).
259 ##STR00317## [4-Fluoro-3-[7- (2,2,3,3,5,5,6,6-
octadeuteriomorpholin- 4-yl)quinazolin-4- yl]phenyl]-(3-methyl-
pyrazin-2-yl)- methanol A A A* MS: 440.4 (M + H.sup.+) 1H NMR (500
MHz, DMSO-d6) ppm = 9.09 (s, 1H), 8.44 (s, 2H), 7.63-7.55 (m, 2H),
7.53 (s, 2H), 7.42-7.34 (m, 1H), 7.19 (s, 1H), 6.30 (d, J = 5.3,
1H), 6.08 (d, J = 4.6, 1H), 2.55 (s, 3H). 260 ##STR00318##
[4-Fluoro-3-(5-fluoro- 7-morpholin-4-yl- quinazolin-4-yl)-
phenyl]-(6-methoxy- pyridazin-3-yl)- methanol A A A MS: 466.2 (M +
H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.09 (d, J = 6.1, 1H),
7.69 (d, J = 9.2, 1H), 7.66-7.48 (m, 2H), 7.37 (dt, J = 15.3, 2.7,
1H), 7.29 (ddd, J = 9.8, 8.5, 3.1, 1H), 7.21 (t, J = 9.2, 1H), 7.08
(d, J = 2.4, 1H), 6.57-6.43 (m, 1H), 6.00 (d, J = 4.4, 1H), 4.00
(d, J = 2.9, 3H), 3.81-3.69 (m, 4H), 3.53-3.40 (m, 4H). 261
##STR00319## 2-[2-Chloro-4-fluoro- 5-(5-fluoro-7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]-2-(3- methoxy-pyrazin-2- yl)acetamide C B
B MS: 527.2/529.2 (M + H.sup.+) (Cl 1H NMR (400 MHz, DMSO-d6) ppm =
9.07 (s, isotopy, rel. peak intensity 1H), 8.10 (d, J = 2.8, 1H),
8.07 (d, J = 2.8, 1H), 7.56 ratio [%] 100:35) (d, J = 7.7, 1H),
7.51 (d, J = 9.7, 1H), 7.41-6.85 (m, 5H), 3.96 (s, 3H), 3.82-3.74
(m, 4H), 3.52-3.45 (m, 4H). 262 ##STR00320## [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 A A A* MS:
490.2/492.2 (M + H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm = 9.12
(s, isotopy, rel. peak intensity 1H), 7.91 (d, J = 7.8, 1H),
7.71-7.64 (m, 2H), 7.59 ratio [%] 100:36) (dd, J = 9.4, 3.4, 1H),
7.54 (dd, J = 9.4, 2.6, 1H), 7.23-7.19 (m, 2H), 6.63 (d, J = 5.0,
1H), 6.23 (d, J = 5.0, 1H), 4.00 (s, 3H). 263 ##STR00321##
[2-Chloro-4-fluoro-5- (5-fluoro-7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]-(6-methoxy- pyridazin-3-yl)- methanol
(Ena 2) C D A* MS: 500.1/502.1 (M + H.sup.+) (Cl see racemate
isotopy, rel. peak intensity ratio [%] 100:30); R.sub.t 6.17 min
(SFC, Chiralpak AD-H, CO.sub.2/40% by vol. of methanol, 0.5% by
vol. of diethylamine) 264 ##STR00322## [2-Chloro-4-fluoro-5-
(6-morpholin-4-yl- thieno[3,2-d}- pyrimidin-4-yl)-
phenyl]-(3-methyl- pyrazin-2-yl)- methanol A A A* MS: 472.1/474.0
(M + H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm = 8.93 (s, isotopy,
rel. peak intensity 1H), 8.43 (d, J = 2.5, 1H), 8.33 (d, J = 2.4,
1H), 8.11 ratio [%] 100:40) (d, J = 7.9, 1H), 7.63 (d, J = 9.9,
1H), 6.56 (s, 1H), 6.47 (d, J = 6.0, 1H), 6.23 (d, J = 4.6, 1H),
3.79- 3.71 (m, 4H), 3.48-3.39 (m, 4H), 2.73 (s, 3H). 265
##STR00323## [4-Fluoro-3-(6- morpholin-4-yl- thieno[3,2-d}-
pyrimidin-4-yl)- phenyl]-(3-methyl- pyrazin-2-yl)- methanol A A A*
MS: 438.1 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 8.88 (s,
1H), 8.46-8.42 (m, 2H), 7.67 (dd, J = 7.0, 2.3, 1H), 7.60-7.55 (m,
1H), 7.38 (dd, J = 10.3, 8.6, 1H), 6.52 (s, 1H), 6.32 (d, J = 5.4,
1H), 6.08-6.05 (m, 1H), 3.79-3.70 (m, 4H), 3.44-3.37 (m, 4H), 2.54
(s, 3H). 266 ##STR00324## [2-Chloro-4-fluoro-5- (5-fluoro-7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]-(3-methoxy-
pyrazin-2-yl)- methanol A A A* MS: 500.2/502.1 (M + H.sup.+) (Cl 1H
NMR (400 MHz, 90.degree. C., DMSO-d6) ppm = 9.08 isotopy, rel. peak
intensity (s, 1H), 8.11 (d, J = 2.7, 1H), 8.07 (d, J = 2.7, 1H),
ratio [%] 100:35) 7.90 (d, J = 8.0, 1H), 7.39 (d, J = 9.7, 1H),
7.29 (dd, J = 15.2, 2.3, 1H), 7.07 (d, J = 2.3, 1H), 6.30 (s, 1H),
3.96 (s, 3H), 3.80-3.72 (m, 4H), 3.51-3.44 (m, 4H). 267
##STR00325## [4-Fluoro-3-(5-fluoro 7-morpholin-4-yl-
quinazolin-4-yl)- phenyl]-(3-methoxy- pyrazin-2-yl)- methanol A A
A* MS: 466.2 (M + H.sup.+) 1H NMR (400 MHz, 90.degree. C., DMSO-d6)
ppm = 9.05 (s, 1H), 8.15 (d, J = 2.5, 1H), 8.11 (d, J = 2.5, 1H),
7.62-7.44 (m, 2H), 7.30-7.12 (m, 2H), 7.05 (d, J = 2.2, 1H),
6.09-5.95 (m, 2H), 3.91 (s, 3H), 3.81- 3.70 (m, 4H), 3.52-3.41 (m,
4H). 268 ##STR00326## [4-Fluoro-3-(5-fluoro- 7-morpholin-4-yl-
quinazolin-4-yl)- phenyl]-(3-methyl- pyrazin-2-yl)- methanol A A A*
MS: 450.1 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.08 (s,
1H), 8.45 (s, 2H), 7.63-7.56 (m, 1H), 7.56-7.46 (m, 1H), 7.46-7.34
(m, 1H), 7.34-7.22 (m, 1H), 7.08 (s, 1H), 6.36-6.27 (m, 1H), 6.06
(d, J = 5.4, 1H), 3.81-3.73 (m, 4H), 3.53-3.43 (m, 4H), 2.53 (s,
3H). 269 ##STR00327## 2-[2-Chloro-4-fluoro- 5-(6-morpholin-4-yl-
thieno[3,2-d}- pyrimidin-4-yl)- phenyl]-2-(3-methyl- pyrazin-2-yl)-
acetamide B B A* MS: 499.1/501.1 (M + H.sup.+) (Cl 1H NMR (500 MHz,
DMSO-d6) ppm = 8.87 (s, isotopy, rel. peak intensity 1H), 8.43 (d,
J = 2.6, 1H), 8.40 (d, J =
2.7, 1H), 7.82- ratio [%] 100:39) 7.78 (m, 1H), 7.74 (d, J = 10.0,
1H), 7.55 (d, J = 7.8, 1H), 7.41-7.36 (m, 1H), 6.53 (s, 1H), 5.63
(s, 1H), 3.79-3.73 (m, 4H), 3.43-3.38 (m, 4H), 2.51 (s, 3H). 270
##STR00328## 2-[4-Fluoro-3-(6- morpholin-4-yl- thieno[3,2-d}-
pyrimidin-4-yl)- phenyl]-2-(3-methyl- pyrazin-2-yl)- acetamide B C
A* MS: 465.1 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 8.88 (s,
1H), 8.42-8.37 (m, 2H), 7.67 (dd, J = 7.1, 2.3, 1H), 7.61-7.55 (m,
2H), 7.41-7.34 (m, 1H), 7.25- 7.19 (m, 1H), 6.53 (s, 1H), 5.40 (s,
1H), 3.79- 3.71 (m, 4H), 3.44-3.39 (m, 4H), 2.53 (s, 3H). 271
##STR00329## [2-Chloro-4-fluoro-5- (5-fluoro-7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]-(6-methoxy- pyridazin-3-yl)- methanol
(Ena 1) A A A MS: 500.1/502.1 (M + H.sup.+) (Cl 1H NMR (400 MHz,
DMSO-d6/DMSO, 120.degree. C.) isotopy, rel. peak intensity ppm =
9.05 (s, 1H), 7.84 (d, J = 7.7 Hz, 1H), 7.60 ratio [%] 100:32);
R.sub.t (d, J = 9.0 Hz, 1H), 7.40 (d, J = 9.5 Hz, 1H), 4.25 min
(SFC, Chiralpak 7.23 (d, J = 14.5 Hz, 1H), 7.11 (d, J = 9.1 Hz,
1H), AD-H, CO.sub.2/40% by vol. of 7.06 (s, 1H), 6.24 (d, J = 4.7
Hz, 1H), 6.16 (d, J = methanol, 0.5% by vol. of 4.7 Hz, 1H), 4.02
(s, 3H), 3.80-3.72 (m, 4H), diethylamine) 3.51-3.43 (m, 4H). 272
##STR00330## 2-[2-Chloro-4-fluoro- 5-(6-morpholin-4-yl-
thieno[3,2-d}- pyrimidin-4-yl)- phenyl]-2-(6- methoxy-pyridazin-3-
yl)acetamide B B A* MS: 515.2/517.2 (M + H.sup.+) (Cl 1H NMR (400
MHz, DMSO-d6) ppm = 8.89 (s, isotopy, rel. peak intensity 1H), 7.94
(s, 1H), 7.81 (d, J = 7.7, 1H), 7.74 (d, ratio [%] 100:41) J =
10.0, 1H), 7.47 (d, J = 9.2, 1H), 7.40 (s, 1H), 7.19 (d, J = 9.2,
1H), 6.53 (s, 1H), 5.65 (s, 1H), 4.00 (s, 3H), 3.79-3.71 (m, 4H),
3.45-3.39 (m, 4H). 278 ##STR00331## [2-Chloro-4-fluoro-5-
(5-fluoro-7- morpholin-4-yl- quinazolin-4-yl)- phenyl]-(6-methoxy-
pyridazin-3-yl)- methanol A A A* MS: 500.2/502.2 (M + H.sup.+) (Cl
1H NMR (400 MHz, 120.degree. C., DMSO-d6) ppm = isotopy, rel. peak
intensity 9.05 (s, 1H), 7.84 (d, J = 7.8, 1H), 7.60 (d, J = ratio
[%] 100:35) 9.1, 1H), 7.40 (d, J = 9.6, 1H), 7.23 (dd, J = 15.2,
2.5, 1H), 7.11 (d, J = 9.1, 1H), 7.06 (d, J = 2.5, 1H), 6.25 (d, J
= 5.1, 1H), 6.16 (d, J = 5.1, 1H), 4.03 (s, 3H), 3.80-3.73 (m, 4H),
3.49-3.43 (m, 4H). 279 ##STR00332## [4-Fluoro-3-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]-[1,2,4]- triazolo[1,5-a]- pyrazin-8-
ylmethanol B C A* MS: 458.2 (M + H.sup.+) 1H NMR (400 MHz, DMSO-d6)
ppm = 9.10 (s, 1H), 9.03 (d, J = 4.5, 1H), 8.76 (s, 1H), 8.25 (d, J
= 4.5, 1H), 7.84-7.76 (m, 2H), 7.59-7.51 (m, 2H), 7.39 (dd, J =
9.9, 8.5, 1H), 7.20 (d, J = 2.1, 1H), 6.48 (s, 1H), 3.82-3.75 (m,
4H), 3.51-3.43 (m, 4H). 280 ##STR00333## 2-[4-Fluoro-3-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]-2-[1,2,4]-
triazolo[1,5-a]- pyrazin-8-yl- acetamide C D A* MS: 485.2 (M +
H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.10 (s, 1H), 9.02 (d, J =
4.5, 1H), 8.74 (s, 1H), 8.21 (d, J = 4.5, 1H), 7.79-7.75 (m, 1H),
7.74-7.69 (m, 2H), 7.64 (dd, J = 9.4, 2.9, 1H), 7.56 (dd, J = 9.5,
2.5, 1H), 7.45-7.40 (m, 1H), 7.31-7.27 (m, 1H), 7.20 (d, J = 2.4,
1H), 5.89 (s, 1H), 3.81-3.74 (m, 4H), 3.49-3.41 (m, 4H). 282
##STR00334## [4-Fluoro-3-(6-fluoro- 7-morpholin-4-yl-
quinazolin-4-yl)- phenyl]-(6-methoxy- pyridazin-3-yl)- methanol D D
A* MS: 466.2 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.24 (s,
DELETE 1H), 7.74-7.63 (m, 3H), 7.48-7.39 (m, 2H), 7.34 (dd, J =
13.6, 3.1, 1H), 7.21 (d, J = 9.2, 1H), 6.53 (d, J = 4.3, 1H), 6.03
(d, J = 4.4, 1H), 4.00 (s, 3H), 3.83-3.77 (m, 4H), 3.36-3.27 (m,
4H). 283 ##STR00335## [4-Fluoro-3-(6-fluoro- 7-morpholin-4-yl-
quinazolin-4-yl)- phenyl]-(3-methyl- pyrazin-2-yl)- methanol C D A
MS: 450.2 (M + H.sup.+) 1H NMR (400 MHz, DMSO-d6) ppm = 9.23 (s,
DELETE 1H), 8.46-8.41 (m, 2H), 7.66-7.58 (m, 2H), 7.49-7.31 (m,
3H), 6.32 (d, J = 5.5, 1H), 6.10 (d, J = 5.5, 1H), 3.84-3.78 (m,
4H), 3.36-3.27 (m, 4H), 2.57 (s, 3H). 284 ##STR00336##
2-[4-Fluoro-3-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]-2-thieno- [2,3-d}pyridazin-7-yl- acetamide B D A* MS: 501.1
(M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.59 (s, 1H), 9.09
(s, 1H), 8.24 (d, J = 5.3, 1H), 7.92 (s, 1H), 7.73-7.65 (m, 3H),
7.57 (dd, J = 9.4, 3.1, 1H), 7.50 (dd, J = 9.5, 2.5, 1H), 7.47-7.36
(m, 2H), 7.19 (d, J = 2.5, 1H), 5.72 (s, 1H), 3.84-3.73 (m, 4H),
3.46-3.41 (m, 4H), 9.09-9.09 (m, 0H). 285 ##STR00337##
2-[4-Fluoro-3-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]-2-thieno- [2,3-d}pyridazin-4-yl- acetamide B D B MS: 501.1
(M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.83-9.79 (m, 1H),
9.08 (s, 1H), 8.30 (d, J = 5.4, 1H), 7.81- 7.75 (m, 2H), 7.75-7.68
(m, 2H), 7.56 (dd, J = 9.4, 3.1, 1H), 7.49 (dd, J = 9.4, 2.6, 1H),
7.40 (dd, J = 9.8, 8.4, 1H), 7.32 (s, 1H), 7.19 (d, J = 2.5, 1H),
5.90 (s, 1H), 3.81-3.74 (m, 4H), 3.47-3.40 (m, 4H). 286
##STR00338## (6-Chloro-3-methoxy- pyridazin-4-yl)-[4- fluoro-3-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]methanol (Ena 1) C C A*
MS: 482.1/484.2 (M + H.sup.+) (Cl see racemate isotopy, rel. peak
intensity ratio [%] 100:36); R.sub.t 5.83 min (SFC, Chiralpak AS-H,
CO.sub.2/20% by vol. of methanol, 0.5% by vol. of diethylamine) 288
##STR00339## 6-{[2-Chloro-4-fluoro- 5-(7-morpholin-4-yl-
quinazolin-4-yl)- phenyl]hydroxy- methyl}-2-methyl-4,5- dihydro-2H-
pyridazin-3-one C C A* MS: 484.2/486.2 (M + H.sup.+) (Cl 1H NMR
(500 MHz, DMSO-d6) ppm = 9.12 (s, isotopy, rel. peak intensity 1H),
7.84 (d, J = 7.8, 1H), 7.68 (d, J = 9.5, 1H), 7.57 ratio [%]
100:35) (dd, J = 9.4, 2.8, 1H), 7.54 (dd, J = 9.5, 2.4, 1H), 7.21
(d, J = 2.3, 1H), 6.42 (s, 1H), 5.57 (s, 1H), 3.81-3.75 (m, 4H),
3.47-3.43 (m, 4H), 3.16 (s, 3H), 2.61-2.51 (m, 1H), 2.43-2.28 (m,
3H). 289 ##STR00340## 2-[2-Chloro-4-fluoro- 5-(7-morpholin-4-yl-
quinazolin-4-yl)- phenyl]-2-(3-chloro- pyridin-2-yl)- acetamide A B
B MS: 512.2/514.2/516.2 1H NMR (500 MHz, DMSO-d6) ppm = 9.08 (s, (M
+ H.sup.+) (Cl.sub.2 isotopy, rel. 1H), 8.44 (dd, J = 4.7, 1.5,
1H), 7.95 (dd, J = 8.1, peak intensity ratio [%] 1.5, 1H), 7.76 (s,
1H), 7.72 (d, J = 9.6, 1H), 7.58 100:71:21) (dd, J = 9.4, 2.9, 1H),
7.54 (dd, J = 9.5, 2.5, 1H), 7.41 (d, J = 7.6, 1H), 7.35 (dd, J =
8.1, 4.7, 1H), 7.28 (s, 1H), 7.19 (d, J = 2.4, 1H), 5.81 (s, 1H),
3.80- 3.75 (m, 4H), 3.48-3.42 (m, 4H). 290 ##STR00341##
2-(4-Chlorothieno- [2,3-d}pyridazin-7-yl)- 2-[4-fluoro-3-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]acetamide B C D MS:
535.3/537.2 (M + H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm = 9.09
(s, isotopy, rel. peak intensity 1H), 8.41 (d, J = 5.4, 1H), 7.94
(s, 1H), 7.71-7.65 ratio [%] 100:41) (m, 3H), 7.56 (dd, J = 9.4,
3.1, 1H), 7.51 (dd, J = 9.4, 2.5, 1H), 7.48-7.40 (m, 2H), 7.20 (d,
J = 2.4, 1H), 5.75 (s, 1H), 3.82-3.73 (m, 4H), 3.48-3.40 (m, 4H).
291 ##STR00342## 2-(7-Chlorothieno- [2,3-d}pyridazin-4-yl)-
2-[4-fluoro-3-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]acetamide B C D MS: 535.2/537.2 (M + H.sup.+) (Cl 1H NMR
(500 MHz, DMSO-d6) ppm = 9.09 (s, isotopy, rel. peak intensity 1H),
8.43 (d, J = 5.4, 1H), 7.86 (d, J = 5.4, 1H), 7.77 ratio [%]
100:41) (s, 1H), 7.74-7.67 (m, 2H), 7.56 (dd, J = 9.4, 3.1, 1H),
7.50 (dd, J = 9.5, 2.5, 1H), 7.44-7.35 (m, 2H), 7.19 (d, J = 2.4,
1H), 5.92 (s, 1H), 3.81-3.74 (m, 4H), 3.47-3.40 (m, 4H). 292
##STR00343## 6-{Carbamoyl-[4- fluoro-3-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]methyl}- pyrazine-2-carboxylic acid amide
C D A MS: 488.2 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.12
(s, 1H), 9.06 (s, 1H), 8.90 (s, 1H), 8.08-8.01 (m, 1H), 7.99-7.93
(m, 1H), 7.85-7.77 (m, 2H), 7.77-7.71 (m, 1H), 7.59 (dd, J = 9.4,
3.6, 1H), 7.52 (dd, J = 9.5, 2.5, 1H), 7.46-7.39 (m, 1H), 7.38-7.32
(m, 1H), 7.20 (d, J = 2.5, 1H), 5.39 (s, 1H), 3.80-3.75 (m, 4H),
3.47-3.42 (m, 4H). 293 ##STR00344## 2-[2-Chloro-4-fluoro-
5-(7-morpholin-4-yl- quinazolin-4-yl)- phenyl]-2-pyridin-3-
ylacetamide B C A MS: 478.2/480.2 (M + H.sup.+) (Cl 1H NMR (500
MHz, DMSO-d6) ppm = 9.09 (s, isotopy, rel. peak intensity 1H), 8.49
(s, 1H), 8.46 (d, J = 3.9, 1H), 7.94 (s, ratio [%] 100:30) 1H),
7.74 (d, J = 9.5, 1H), 7.67 (d, J = 7.7, 1H), 7.66- 7.63 (m, 1H),
7.56 (dd, J = 9.4, 3.2, 1H), 7.53 (dd, J = 9.5, 2.4, 1H), 7.37 (dd,
J = 7.9, 4.8, 1H), 7.33 (s, 1H), 7.20 (d, J = 2.3, 1H), 5.41 (s,
1H), 3.81-3.74 (m, 4H), 3.49-3.42 (m, 4H). 294 ##STR00345##
2-[2,4-Difluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]-2-pyridin-3- ylacetamide B D A MS: 462.3 (M + H.sup.+) 1H
NMR (500 MHz, DMSO-d6) ppm = 9.08 (s, 1H), 8.53 (d, J = 2.3, 1H),
8.48 (dd, J = 4.8, 1.6, 1H), 7.89 (s, 1H), 7.72 (dt, J = 8.0, 2.0,
1H), 7.61 (t, J = 8.2, 1H), 7.59-7.48 (m, 3H), 7.38 (dd, J = 7.9,
4.7, 1H), 7.32 (s, 1H), 7.19 (d, J = 2.3, 1H), 5.31 (s, 1H),
3.82-3.73 (m, 4H), 3.47-3.42 (m, 4H). 295 ##STR00346##
[4-Fluoro-3-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]-(6-methyl- pyrazin-2-yl)- methanol C D A MS: 444.2 (M +
H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.09 (s, 1H), 8.55 (s,
1H), 8.47 (s, 1H), 7.82 (s, 1H), 7.79 (d, J = 8.0, 1H), 7.62-7.56
(m, 2H), 7.56-7.49 (m, 2H), 7.45-7.35 (m, 2H), 7.25 (s, 1H), 7.20
(d, J = 2.0, 1H), 5.12 (s, 1H), 3.80-3.74 (m, 4H), 3.47-3.41 (m,
4H). 296 ##STR00347## [4-Fluoro-3-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]-(6-methyl- pyrazin-2-yl)- methanol C C A
MS: 432.2 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.10 (s,
1H), 8.66 (s, 1H), 8.43 (s, 1H), 7.68-7.63 (m, 2H), 7.54-7.49 (m,
2H), 7.42-7.35 (m, 1H), 7.21-7.18 (m, 1H), 6.40 (d, J = 4.3, 1H),
5.87 (d, J = 4.3, 1H), 3.81-3.74 (m, 4H), 3.47-3.41 (m, 4H), 2.46
(s, 3H). 297 ##STR00348## 2-(5-Chloro-pyridin-
3-yl)-2-[4-fluoro-3-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]acetamide C D C MS: 478.3/480.2 (M + H.sup.+) (Cl 1H NMR
(500 MHz, DMSO-d6) ppm = 9.10 (s, isotopy, rel. peak intensity 1H),
8.54 (d, J = 2.4, 1H), 8.52 (d, J = 1.9, 1H), 7.90- ratio [%]
100:38) 7.87 (m, 1H), 7.85 (s, 1H), 7.61 (tt, J = 6.9, 2.3, 2H),
7.53 (qd, J = 9.4, 2.8, 2H), 7.47-7.39 (m, 1H), 7.33 (s, 1H), 7.20
(d, J = 2.3, 1H), 5.16 (s, 1H), 3.82-3.73 (m, 4H), 3.48-3.40 (m,
4H). 298 ##STR00349## 2-[2-Chloro-4-fluoro- 5-(7-morpholin-4-yl-
quinazolin-4-yl)- phenyl]-2-[1,2,4]- triazolo[4,3-a]pyridin-
5-ylacetamide C D A
MS: 518.2/520.2 (M + H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm =
9.21 (d, isotopy, rel. peak intensity J = 0.8, 1H), 9.08 (s, 1H),
8.13 (s, 1H), 7.88 (d, ratio [%] 100:35) J = 9.5, 1H), 7.79 (d, J =
9.2, 1H), 7.73 (s, 1H), 7.57-7.48 (m, 3H), 7.38 (dd, J = 9.2, 6.9,
1H), 7.19 (d, J = 2.3, 1H), 6.57 (d, J = 6.9, 1H), 5.84 (s, 1H),
3.80-3.75 (m, 4H), 3.48-3.42 (m, 4H). 299 ##STR00350##
2-[4-Fluoro-3-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]-2-pyrrolo- [2,1-f][1,2,4]triazin-4- ylacetamide C D D MS:
484.2 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 13.68 (d, J =
4.0, 1H), 9.09 (s, 1H), 7.84-7.74 (m, 2H), 7.57- 7.46 (m, 3H),
7.46-7.39 (m, 1H), 7.31-7.25 (m, 1H), 7.24-7.16 (m, 1H), 7.02 (s,
1H), 6.21 (dd, J = 4.4, 2.7, 1H), 6.08 (s, 1H), 4.81 (dd, J = 4.3,
1.7, 1H), 3.90-3.70 (m, 4H), 3.53-3.38 (m, 4H). 300 ##STR00351##
2-[2-Chloro-4-fluoro- 5-(7-morpholin-4-yl- quinazolin-4-yl)-
phenyl]-2-pyridazin- 3-ylacetamide C D A MS: 479.2/481.2 (M +
H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm = 9.14 (dd, isotopy,
rel. peak intensity J = 4.9, 1.6, 1H), 9.10 (s, 1H), 8.03 (s, 1H),
7.76 ratio [%] 100:33) (d, J = 9.6, 1H), 7.71 (d, J = 7.6, 1H),
7.65 (dd, J = 8.5, 4.9, 1H), 7.60 (dd, J = 9.4, 3.4, 1H), 7.53 (dd,
J = 5.6, 2.1, 1H), 7.52 (dd, J = 4.7, 2.0, 1H), 7.43 (s, 1H), 7.20
(d, J = 2.5, 1H), 5.78 (s, 1H), 3.78 (dd, J = 5.8, 4.0, 4H), 3.46
(dd, J = 6.0, 3.9, 4H). 301 ##STR00352## 2-[2-Chloro-4-fluoro-
5-(7-morpholin-4-yl- quinazolin-4-yl)- phenyl]-2-(3,5-
dimethyl-pyrazin-2- yl)acetamide C B A MS: 507.2/509.2 (M +
H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm = 9.08 (s, isotopy, rel.
peak intensity 1H), 8.25 (s, 1H), 7.75-7.69 (m, 2H), 7.58 (dd,
ratio [%] 100:35) J = 9.4, 3.0, 1H), 7.54 (dd, J = 9.5, 2.5, 1H),
7.47 (d, J = 7.7, 1H), 7.28 (s, 1H), 7.19 (d, J = 2.4, 1H), 5.60
(s, 1H), 3.81-3.74 (m, 4H), 3.49-3.42 (m, 4H), 2.49 (s, 3H), 2.41
(s, 3H). 302 ##STR00353## (6-Amino-pyrazin-2- yl)-[4-fluoro-3-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]methanol B C A MS: 433.1
(M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.09 (s, 1H), 7.91
(s, 1H), 7.74 (s, 1H), 7.63-7.56 (m, 2H), 7.54-7.51 (m, 2H),
7.39-7.34 (m, 1H), 7.21-7.19 (m, 1H), 6.36 (s, 2H), 6.10 (d, J =
4.3, 1H), 5.60 (d, J = 4.3, 1H), 3.81-3.74 (m, 4H), 3.47- 3.41 (m,
4H). 303 ##STR00354## 2-[2-Chloro-5-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]-2-(3-methyl- pyrazin-2-yl)- acetamide C C
B MS: 475.2/477.2 (M + H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm =
9.05 (s, isotopy, rel. peak intensity 1H), 8.43-8.37 (m, 2H), 7.87
(d, J = 9.4, 1H), 7.80 ratio [%] 100:38) (s, 1H), 7.75-7.65 (m,
3H), 7.51 (dd, J = 9.5, 2.6, 1H), 7.33 (s, 1H), 7.19 (d, J = 2.5,
1H), 5.71 (s, 1H), 3.85-3.74 (m, 4H), 3.52-3.39 (m, 4H), 2.55 (s,
3H). 304 ##STR00355## 2-[2-Chloro-5-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]-2-(3- methoxy-pyrazin-2- yl)acetamide C C
A MS: 491.3/493.2 (M + H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm =
9.06 (s, isotopy, rel. peak intensity 1H), 8.12 (d, J = 2.8, 1H),
8.10 (d, J = 2.8, 1H), 7.89 ratio [%] 100:38) (d, J = 9.4, 1H),
7.79-7.75 (m, 1H), 7.73-7.69 (m, 2H), 7.67 (d, J = 8.1, 1H), 7.52
(dd, J = 9.5, 2.6, 1H), 7.27-7.23 (m, 1H), 7.20 (d, J = 2.6, 1H),
5.71 (s, 1H), 3.95 (s, 3H), 3.81-3.75 (m, 4H), 3.49-3.41 (m, 4H).
305 ##STR00356## 2-[4-Fluoro-3-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]-2-(3- methoxy-pyrazin-2- yl)acetamide C C
A MS: 475.3 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.09 (s,
1H), 8.13 (d, J = 2.8, 1H), 8.10 (d, J = 2.8, 1H), 7.63 (dd, J =
9.4, 2.8, 1H), 7.61-7.52 (m, 4H), 7.41- 7.35 (m, 1H), 7.20 (d, J =
2.4, 1H), 7.11 (s, 1H), 5.34 (s, 1H), 3.93 (s, 3H), 3.82-3.74 (m,
4H), 3.48-3.41 (m, 4H). 306 ##STR00357## 2-[2,4-Difluoro-5-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]-2-(6-
methoxy-pyridazin-3- yl)acetamide C D A MS: 493.3 (M + H.sup.+) 1H
NMR (500 MHz, DMSO-d6) ppm = 9.10 (s, 1H), 7.90 (s, 1H), 7.71 (t, J
= 8.2, 1H), 7.61-7.49 (m, 4H), 7.37 (s, 1H), 7.20 (d, J = 2.4, 1H),
7.18 (d, J = 9.2, 1H), 5.57 (s, 1H), 4.00 (s, 3H), 3.81-3.74 (m,
4H), 3.49-3.41 (m, 4H). 307 ##STR00358## 2-[2-Chloro-4-fluoro-
5-(7-morpholin-4-yl- quinazolin-4-yl)- phenyl]-2-(3-
methoxypyridazin-4- yl)acetamide B C A MS: 509.2/511.1 (M +
H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm = 9.09 (s, isotopy, rel.
peak intensity 1H), 8.80 (d, J = 4.7, 1H), 8.02 (s, 1H), 7.80 (d,
ratio [%] 100:39) J = 9.5, 1H), 7.59 (dd, J = 9.4, 3.3, 1H), 7.53
(dd, J = 9.5, 2.5, 1H), 7.46 (d, J = 7.5, 1H), 7.42 (s, 1H), 7.20
(d, J = 2.4, 1H), 7.08 (dd, J = 4.7, 0.5, 1H), 5.46 (s, 1H), 4.07
(s, 3H), 3.80-3.76 (m, 4H), 3.49- 3.43 (m, 4H). 308 ##STR00359##
2-[4-Fluoro-3-(7- morpholin-4-yl- quinazolin-4-yl)- phenyl]-2-(6-
methoxypyridazin-3- yl)acetamide C D A MS: 475.3 (M + H.sup.+) 1H
NMR (500 MHz, DMSO-d6) ppm = 9.10 (s, 1H), 7.87 (s, 1H), 7.67 (d, J
= 9.2, 1H), 7.64-7.57 (m, 2H), 7.57-7.49 (m, 2H), 7.46-7.38 (m,
1H), 7.31 (s, 1H), 7.20 (d, J = 2.2, 1H), 7.18 (d, J = 9.2, 1H),
5.40 (s, 1H), 4.00 (s, 3H), 3.78 (dd, J = 5.8, 3.9, 4H), 3.44 (dd,
J = 5.8, 4.1, 4H). 309 ##STR00360## 2-[2-Chloro-4-fluoro-
5-(7-morpholin-4-yl- quinazolin-4-yl)- phenyl]-2-[3H-
pyrrolo[2,1-f][1,2,4]- triazin-(4E)-ylidene]- acetamide D D D MS:
518.2/520.2 (M + H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm = 13.76
(d, isotopy, rel. peak intensity J = 3.9, 1H), 9.07 (s, 1H), 7.86
(d, J = 9.7, 1H), 7.84- ratio [%] 100:37) 7.76 (m, 2H), 7.56 (d, J
= 7.8, 1H), 7.51 (dd, J = 9.5, 2.5, 1H), 7.32 (dd, J = 2.7, 1.7,
1H), 7.18 (d, J = 2.4, 1H), 6.99 (s, 1H), 6.37 (s, 1H), 6.26 (dd, J
= 4.4, 2.7, 1H), 4.87 (dd, J = 4.4, 1.7, 1H), 3.81- 3.74 (m, 4H),
3.49-3.42 (m, 4H). 310 ##STR00361## 2-[2-Chloro-5-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]-2-(6-
methoxy-pyridazin-3- yl)acetamide D D B MS: 491.2/493.2 (M +
H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm = 9.07 (s, isotopy, rel.
peak intensity 1H), 7.97 (s, 1H), 7.89-7.85 (m, 2H), 7.73 (dd,
ratio [%] 100:35) J = 8.2, 2.1, 1H), 7.70 (d, J = 8.2, 1H), 7.52
(dd, J = 9.5, 2.6, 1H), 7.46 (d, J = 9.2, 1H), 7.39 (s, 1H), 7.21
(d, J = 2.5, 1H), 7.18 (d, J = 9.2, 1H), 5.72 (s, 1H), 4.01 (s,
3H), 3.82-3.75 (m, 4H), 3.48-3.42 (m, 4H). 311 ##STR00362##
2-[2-Chloro-4-fluoro- 5-(7-morpholin-4-yl- quinazolin-4-yl)-
phenyl]-2-(1-methyl- 6-oxo-1,6-dihydro- pyridazin-3-yl)- acetamide
D D A MS: 509.3/511.3 (M + H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6)
ppm = 9.11 (s, isotopy, rel. peak intensity 1H), 7.92 (s, 1H), 7.76
(d, J = 9.5, 1H), 7.68 (d, ratio [%] 100:38) J = 7.5, 1H), 7.58
(dd, J = 9.4, 3.1, 1H), 7.54 (dd, J = 9.5, 2.5, 1H), 7.41 (s, 1H),
7.33 (d, J = 9.6, 1H), 7.21 (d, J = 2.4, 1H), 6.90 (d, J = 9.6,
1H), 5.33 (s, 1H), 3.81-3.75 (m, 4H), 3.59 (s, 3H), 3.49-3.42 (m,
4H). 312 ##STR00363## 2-[2-Chloro-4-fluoro- 5-(7-morpholin-4-yl-
quinazolin-4-yl)- phenyl]-2-(1-methyl- 6-oxo-1,6-dihydro-
pyridin-2-yl)- acetamide D D A MS: 508.3/510.2 (M + H.sup.+) (Cl 1H
NMR (500 MHz, DMSO-d6) ppm = 9.09 (s, isotopy, rel. peak intensity
1H), 8.04 (s, 1H), 7.83 (d, J = 9.4, 1H), 7.62-7.44 ratio [%]
100:38) (m, 3H), 7.42-7.27 (m, 2H), 7.19 (d, J = 2.4, 1H), 6.36
(dd, J = 9.1, 1.3, 1H), 5.90 (dd, J = 7.1, 1.3, 1H), 5.48 (s, 1H),
3.77 (dd, J = 5.8, 4.0, 4H), 3.52-3.42 (m, 4H), 3.40 (s, 3H). 313
##STR00364## 2-(3-Chloro-pyridin- 2-yl)-2-[4-fluoro-3-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]acetamide C C B MS:
478.2/480.2 (M + H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm = 9.10
(s, isotopy, rel. peak intensity 1H), 8.51 (dd, J = 4.7, 1.5, 1H),
7.93 (dd, J = 8.1, ratio [%] 100:36) 1.5, 1H), 7.64 (dd, J = 9.4,
2.9, 1H), 7.61-7.53 (m, 4H), 7.39 (dd, J = 9.9, 8.7, 1H), 7.36 (dd,
J = 8.1, 4.7, 1H), 7.21 (d, J = 2.5, 1H), 7.17 (s, 1H), 5.53 (s,
1H), 3.84-3.73 (m, 4H), 3.50-3.41 (m, 4H). 314 ##STR00365##
(5,6-Dimethyl- pyrazin-2-yl)-[4- fluoro-3-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]methanol C B B MS: 446.2 (M + H.sup.+) 1H
NMR (500 MHz, DMSO-d6) ppm = 9.09 (s, 1H), 8.51 (s, 1H), 7.66-7.61
(m, 2H), 7.54-7.49 (m, 2H), 7.40-7.35 (m, 1H), 7.21-7.19 (m, 1H),
6.32 (d, J = 4.2, 1H), 5.84 (d, J = 4.0, 1H), 3.80- 3.75 (m, 4H),
3.46-3.42 (m, 4H), 2.45 (s, 3H), 2.44 (s, 3H). 315 ##STR00366##
2-[2-Chloro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]-2-(3-chloro- pyrazin-2-yl)- acetamide D D C MS:
495.0/497.1/499.1 1H NMR (500 MHz, DMSO-d6) ppm = 9.07 (s, (M +
H.sup.+) (Cl.sub.2 isotopy, rel. 1H), 8.60 (d, J = 2.5, 1H), 8.45
(d, J = 2.5, 1H), 7.97- peak intensity ratio [%] 7.91 (m, 1H), 7.88
(d, J = 9.5, 1H), 7.75 (dd, 100:75:20) J = 8.3, 2.1, 1H), 7.71 (d,
J = 8.2, 1H), 7.66 (d, J = 2.1, 1H), 7.53 (dd, J = 9.5, 2.6, 1H),
7.47-7.42 (m, 1H), 7.22-7.19 (m, 1H), 5.87 (s, 1H), 3.81- 3.76 (m,
4H), 3.47-3.42 (m, 4H). 316 ##STR00367## 2-[2-Fluoro-5-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]-2-(3- methoxy-pyrazin-2-
yl)acetamide D C B MS: 475.4 (M + H.sup.+) 1H NMR (500 MHz,
DMSO-d6) ppm = 9.05 (s, 1H), 8.13 (d, J = 2.9, 2H), 7.94 (d, J =
9.4, 1H), 7.78- 7.70 (m, 3H), 7.53 (dd, J = 9.5, 2.6, 1H), 7.41
(dd, J = 9.6, 8.6, 1H), 7.23 (s, 1H), 7.19 (d, J = 2.5, 1H), 5.59
(s, 1H), 3.95 (s, 3H), 3.82-3.74 (m, 4H), 3.48-3.40 (m, 4H). 317
##STR00368## 2-[4-Fluoro-3-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]-2-(1-methyl- 6-oxo-1,6-dihydro- pyridazin-3-yl)- acetamide
D D B MS: 475.3 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.10
(s, 1H), 7.86 (s, 1H), 7.64-7.50 (m, 4H), 7.47 (d, J = 9.6, 1H),
7.44 (dd, J = 9.8, 8.5, 1H), 7.34 (s, 1H), 7.20 (d, J = 2.2, 1H),
6.90 (d, J = 9.6, 1H), 5.05 (s, 1H), 3.83-3.73 (m, 4H), 3.61 (s,
3H), 3.44 (t, J = 4.9, 4H). 318 ##STR00369## 2-(3,5-Dimethyl-
pyrazin-2-yl)-2-[4- fluoro-3-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]acetamide C D A MS: 473.4 (M + H.sup.+) 1H NMR (500 MHz,
DMSO-d6) ppm = 9.09 (s, 1H), 8.29 (s, 1H), 7.60 (dd, J = 9.5, 2.9,
1H), 7.59- 7.55 (m, 2H), 7.54 (dd, J = 9.5, 2.5, 1H), 7.50 (s, 1H),
7.42-7.33 (m, 1H), 7.20 (d, J = 2.5, 1H), 7.15 (s, 1H), 5.35 (s,
1H), 3.78 (dd, J = 5.8, 4.0, 4H), 3.44 (dd, J = 6.0, 3.9, 4H), 2.49
(s, 3H), 2.41 (s, 3H). 319 ##STR00370## 2-[2,4-Difluoro-5-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]-2-(3- methoxy-pyrazin-2-
yl)acetamide C C A MS: 493.4 (M + H.sup.+) 1H NMR (500 MHz,
DMSO-d6) ppm = 9.08 (s, 1H), 8.13 (d, J = 2.8, 1H), 8.11 (d, J =
2.8, 1H), 7.73 (s, 1H), 7.61 (dd, J = 9.4, 3.2, 1H), 7.58-7.46 (m,
3H), 7.24 (s, 1H), 7.20 (d, J = 2.4, 1H), 5.53 (s, 1H), 3.95 (s,
3H), 3.78 (dd, J = 5.8, 4.0, 4H), 3.45
(dd, J = 6.0, 3.9, 4H). 320 ##STR00371## 2-[2-Chloro-4-fluoro-
5-(7-morpholin-4-yl- quinazolin-4-yl)- phenyl]-2-(3-
methoxy-pyrazin-2- yl)acetamide C B A MS: 509.3/511.3 (M + H.sup.+)
(Cl 1H NMR (500 MHz, DMSO-d6) ppm = 9.09 (s, isotopy, rel. peak
intensity 1H), 8.12 (d, J = 2.8, 1H), 8.09 (d, J = 2.8, 1H), 7.78
ratio [%] 100:38) (s, 1H), 7.72 (d, J = 9.6, 1H), 7.60 (dd, J =
9.4, 3.1, 1H), 7.55 (dd, J = 9.5, 2.5, 1H), 7.51 (d, J = 7.6, 1H),
7.26 (s, 1H), 7.20 (d, J = 2.4, 1H), 5.65 (s, 1H), 3.95 (s, 3H),
3.86-3.66 (m, 4H), 3.56-3.37 (m, 4H). 321 ##STR00372##
2-(3,5-Difluoro- pyridin-4-yl)-2-[4- fluoro-3-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]acetamide C B B MS: 480.2 (M + H.sup.+) 1H
NMR (500 MHz, DMSO-d6) ppm = 9.09 (s, 1H), 8.50 (s, 2H), 7.59 (s,
1H), 7.58-7.49 (m, 4H), 7.46-7.37 (m, 2H), 7.20 (d, J = 2.2, 1H),
5.42 (s, 1H), 3.87-3.64 (m, 4H), 3.59-3.40 (m, 4H). 322
##STR00373## 2-(4-Chloro-5-fluoro- pyridin-3-yl)-2-[4- fluoro-3-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]acetamide B B C MS:
496.2/498.1 (M + H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm = 9.09
(d, isotopy, rel. peak intensity J = 2.3, 1H), 8.65 (s, 1H), 8.33
(s, 1H), 7.94 (s, ratio [%] 100:37) 1H), 7.61-7.50 (m, 4H), 7.44
(dt, J = 20.5, 9.0, 2H), 7.20 (d, J = 2.1, 1H), 5.44 (s, 1H),
3.80-3.75 (m, 4H), 3.47-3.42 (m, 4H). 323 ##STR00374##
2-[2-Chloro-4-fluoro- 5-(7-morpholin-4-yl- quinazolin-4-yl)-
phenyl]-2-imidazo- [1,2-b]pyridazin-6-yl- acetamide B B B MS:
518.2/520.2 (M + H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm = 9.10
(d, isotopy, rel. peak intensity J = 10.0, 1H), 8.24 (s, 1H), 8.08
(d, J = 9.5, 1H), ratio [%] 100:35) 8.02 (s, 1H), 7.79 (d, J = 9.5,
1H), 7.76 (d, J = 1.2, 1H), 7.72 (d, J = 7.6, 1H), 7.60 (dd, J =
9.5, 3.2, 1H), 7.53 (dd, J = 9.5, 2.5, 1H), 7.47 (s, 1H), 7.22 (d,
J = 2.5, 1H), 7.11 (d, J = 9.5, 1H), 5.61 (s, 1H), 3.81- 3.74 (m,
4H), 3.49-3.42 (m, 4H). 324 ##STR00375## 2-[2-Chloro-4-fluoro-
5-(7-morpholin-4-yl- quinazolin-4-yl)- phenyl]-2-(3-methyl-
pyrazin-2-yl)- acetamide B B A MS: 493.3/495.3 (M + H.sup.+) (Cl 1H
NMR (500 MHz, DMSO-d6) ppm = 9.08 (s, isotopy, rel. peak intensity
1H), 8.40 (d, J = 2.5, 1H), 8.38 (d, J = 2.5, 1H), 7.80 ratio [%]
100:38) (s, 1H), 7.73 (d, J = 9.5, 1H), 7.59 (dd, J = 9.4, 3.0,
1H), 7.54 (dd, J = 9.5, 2.5, 1H), 7.48 (d, J = 7.6, 1H), 7.34 (s,
1H), 7.19 (d, J = 2.4, 1H), 5.66 (s, 1H), 3.78 (dd, J = 5.8, 4.0,
4H), 3.45 (dd, J = 5.9, 3.9, 4H), 2.55 (s, 3H). 325 ##STR00376##
2-[2-Chloro-4-fluoro- 5-(7-morpholin-4-yl- quinazolin-4-yl)-
phenyl]-2-(6- methoxypyridazin-3- yl)acetamide D D B MS:
509.2/511.1 (M + H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm = 9.11
(s, isotopy, rel. peak intensity 1H), 7.96 (s, 1H), 7.75 (d, J =
9.5, 1H), 7.71 (d, ratio [%] 100:37) J = 7.6, 1H), 7.63-7.51 (m,
2H), 7.47 (d, J = 9.2, 1H), 7.39 (s, 1H), 7.21 (d, J = 2.4, 1H),
7.17 (d, J = 9.2, 1H), 5.67 (s, 1H), 4.00 (s, 3H), 3.82-3.74 (m,
4H), 3.50-3.42 (m, 4H). 326 ##STR00377## 6-{[4-Fluoro-3-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]hydroxy-
methyl}-2-methyl-2H- pyridazin-3-one C B A MS: 448.2 (M + H.sup.+)
1H NMR (500 MHz, DMSO-d6) ppm = 9.10 (s, 1H), 7.66-7.60 (m, 2H),
7.55-7.49 (m, 2H), 7.47 (d, J = 9.6, 1H), 7.44-7.39 (m, 1H), 7.21-
7.19 (m, 1H), 6.93 (d, J = 9.6, 1H), 6.46 (d, J = 4.3, 1H), 5.66
(d, J = 4.3, 1H), 3.80-3.75 (m, 4H), 3.62 (s, 3H), 3.46-3.42 (m,
4H). 327 ##STR00378## 2-[4-Fluoro-3-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]-2-(3-methyl- pyrazin-2-yl)- acetamide C D
A MS: 459.3 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.09 (s,
1H), 8.41 (d, J = 2.4, 1H), 8.38 (d, J = 2.6, 1H), 7.64- 7.51 (m,
5H), 7.38 (dd, J = 10.6, 8.5, 1H), 7.21- 7.16 (m, 2H), 5.41 (s,
1H), 3.83-3.74 (m, 4H), 3.46-3.40 (m, 4H), 2.54 (s, 3H). 328
##STR00379## [4-Fluoro-3-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]furo[2,3-c]- pyridin-7-ylmethanol A A D MS: 457.2 (M +
H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.08 (s, 1H), 8.32 (d, J =
5.2, 1H), 8.21 (d, J = 2.2, 1H), 7.74- 7.67 (m, 2H), 7.64 (d, J =
5.2, 1H), 7.52-7.49 (m, 2H), 7.36 (dd, J = 9.9, 8.4, 1H), 7.22-7.16
(m, 1H), 7.06 (d, J = 2.2, 1H), 6.32 (d, J = 5.0, 1H), 6.25 (d, J =
5.0, 1H), 3.80-3.75 (m, 4H), 3.46-3.41 (m, 4H). 329 ##STR00380##
2-[2,4-Difluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]-2-(3-methyl- pyrazin-2-yl)- acetamide C C A MS: 477.2 (M +
H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.08 (s, 1H), 8.41 (d, J =
2.6, 1H), 8.39 (d, J = 2.7, 1H), 7.77- 7.68 (m, 1H), 7.61 (dd, J =
9.4, 3.1, 1H), 7.59- 7.47 (m, 3H), 7.32 (s, 1H), 7.19 (d, J = 2.5,
1H), 5.57 (s, 1H), 3.84-3.74 (m, 4H), 3.48-3.41 (m, 4H), 2.55 (s,
3H). 330 ##STR00381## 5-Chloro-6-{[2- chloro-5-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]hydroxy- methyl}pyrimidin- 4-ol C D A MS:
484.1/486.1/488.1 1H NMR (500 MHz, DMSO-d6) ppm = 13.06 (s, (M +
H.sup.+) (Cl.sub.2 isotopy, rel. 1H), 9.09 (s, 1H), 8.22-8.14 (m,
2H), 7.97 (d, peak intensity ratio [%] J = 9.4, 1H), 7.71 (dd, J =
8.2, 2.2, 1H), 7.62-7.56 100:70:18) (m, 2H), 7.22 (d, J = 2.6, 1H),
6.46 (d, J = 5.5, 1H), 6.31 (d, J = 5.5, 1H), 3.83-3.77 (m, 4H),
3.48- 3.43 (m, 4H). 331 ##STR00382## (3-methyl-pyrazin-2-
yl)-[3-(7-morpholin-4- ylquinazolin-4-yl)-4- oxocyclohexa-2,5-
dien-(E)-ylidene]- acetic acid C C A MS: 456.2 (M + H.sup.+) 1H NMR
(500 MHz, DMSO-d6) ppm = 9.06 (s, 1H), 8.70 (d, J = 2.5, 1H), 8.56
(d, J = 2.6, 1H), 8.01 (dd, J = 8.8, 2.3, 1H), 7.84 (d, J = 2.3,
1H), 7.48 (d, J = 1.4, 2H), 7.38 (d, J = 8.8, 1H), 7.17-7.14 (m,
1H), 3.81-3.74 (m, 4H), 3.45-3.39 (m, 4H), 2.55 (s, 3H). 332
##STR00383## [4-Fluoro-3-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]thieno[2,3-d}- pyridazin-7-yl- methanol A A B MS: 474.1 (M +
H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.56 (s, 1H), 9.08 (s,
1H), 8.26 (d, J = 5.4, 1H), 7.79-7.72 (m, 2H), 7.70 (d, J = 5.4,
1H), 7.51-7.44 (m, 2H), 7.43-7.35 (m, 1H), 7.21-7.16 (m, 1H), 7.10
(d, J = 3.8, 1H), 6.38 (d, J = 3.9, 1H), 3.82-3.74 (m, 4H),
3.47-3.40 (m, 4H). 333 ##STR00384## [4-Fluoro-3-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]thieno[2,3-d}- pyridazin-4-yl- methanol A
A B MS: 474.2 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.84
(d, J = 0.6, 1H), 9.08 (s, 1H), 8.28 (d, J = 5.3, 1H), 7.89 (dd, J
= 5.4, 0.7, 1H), 7.75-7.67 (m, 2H), 7.49 (dd, J = 9.4, 2.4, 1H),
7.45 (dd, J = 9.4, 2.9, 1H), 7.42- 7.34 (m, 1H), 7.19 (d, J = 2.3,
1H), 6.82 (s, 1H), 6.42 (s, 1H), 3.81-3.75 (m, 4H), 3.47-3.41 (m,
4H). 334 ##STR00385## 2-[2-Chloro-4-fluoro- 5-(7-morpholin-4-yl-
quinazolin-4-yl)- phenyl]-2-(1,4- dimethyl-6-oxo-1,6-
dihydropyridin-2-yl)- acetamide D D A MS: 522.1/524.1 (M + H.sup.+)
(Cl 1H NMR (500 MHz, DMSO-d6) ppm = 9.10 (s, isotopy, rel. peak
intensity 1H), 8.10-7.99 (m, 1H), 7.85 (d, J = 9.4, 1H), 7.58-
ratio [%] 100:35) 7.49 (m, 3H), 7.34 (d, J = 7.4, 1H), 7.24-7.17
(m, 1H), 6.22-6.15 (m, 1H), 5.79-5.77 (m, 1H), 5.47 (s, 1H),
3.82-3.75 (m, 4H), 3.46 (t, J = 5.0, 4H), 3.36 (s, 3H), 2.05 (s,
3H). 335 ##STR00386## [4-Fluoro-3-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]furo[2,3-d}- pyridazin-7-yl- methanol A A
A MS: 458.2 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.59 (s,
1H), 9.09 (s, 1H), 8.37 (d, J = 2.1, 1H), 7.82-7.70 (m, 2H),
7.54-7.47 (m, 2H), 7.40 (dd, J = 9.8, 8.6, 1H), 7.23-7.16 (m, 2H),
6.69 (d, J = 4.6, 1H), 6.40 (d, J = 4.6, 1H), 3.81-3.75 (m, 4H),
3.47-3.41 (m, 4H). 336 ##STR00387## [2,4-Difluoro-5-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]furo[2,3-d}-
pyridazin-7-yl- methanol A A A MS: 475.7 (M + H.sup.+) 1H NMR (500
MHz, DMSO-d6) ppm = 9.63 (s, 1H), 9.14 (s, 1H), 8.41 (d, J = 2.1,
1H), 8.10 (t, J = 8.1, 1H), 7.63 (dd, J = 9.4, 3.0, 1H), 7.58 (dd,
J = 9.4, 2.5, 1H), 7.45 (t, J = 10.1, 1H), 7.27-7.19 (m, 2H), 6.82
(d, J = 5.3, 1H), 6.63 (d, J = 5.3, 1H), 3.83-3.77 (m, 4H),
3.50-3.45 (m, 4H). 337 ##STR00388## 7-[[4-Fluoro-3-(7- morpholino-
quinazolin-4-yl)- phenyl]hydroxy- methyl]-5H-thieno-
[2,3-d}pyridazin-4- one A B B MS: 490.1 (M + H.sup.+) 1H NMR (500
MHz, DMSO-d6) ppm = 12.73 (s, 1H), 9.10 (s, 1H), 8.04 (d, J = 5.3,
1H), 7.74-7.63 (m, 2H), 7.59 (d, J = 5.2, 1H), 7.53-7.45 (m, 2H),
7.44-7.37 (m, 1H), 7.23-7.13 (m, 1H), 6.88 (s, 1H), 5.94 (s, 1H),
3.82-3.71 (m, 4H), 3.46-3.41 (m, 4H). 338 ##STR00389##
4-[[4-Fluoro-3-(7- morpholino- quinazolin-4-yl)- phenyl]hydroxy-
methyl]-6H- thieno[2,3-d}- pyridazin-7-one A B A MS: 490.1 (M +
H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 12.82 (s, 1H), 9.09 (s,
1H), 8.18 (d, J = 5.2, 1H), 7.70-7.64 (m, 2H), 7.62 (d, J = 5.2,
1H), 7.50 (dd, J = 9.4, 2.4, 1H), 7.47 (dd, J = 9.4, 2.8, 1H),
7.44-7.36 (m, 1H), 7.19 (d, J = 2.3, 1H), 6.62 (s, 1H), 6.01 (s,
1H), 3.81-3.73 (m, 4H), 3.48-3.40 (m, 4H). 339 ##STR00390##
6-{[2-Chloro-4-fluoro- 5-(7-morpholin-4-yl- quinazolin-4-yl)-
phenyl]hydroxy- methyl}-1,4-dimethyl- 1H-pyridin-2-one C B A MS:
494.7/496.7 (M + H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm = 9.13
(s, isotopy, rel. peak intensity 1H), 7.79 (d, J = 9.5, 1H), 7.71
(d, J = 7.6, 1H), 7.60 ratio [%] 100:37) (dd, J = 9.4, 3.2, 1H),
7.54 (dd, J = 9.4, 2.5, 1H), 7.22 (d, J = 2.4, 1H), 6.60 (d, J =
6.2, 1H), 6.27- 6.15 (m, 1H), 6.05 (d, J = 6.2, 1H), 5.84-5.68 (m,
1H), 3.81-3.75 (m, 4H), 3.52-3.43 (m, 7H), 2.05 (s, 3H). 340
##STR00391## 6-{[4-Fluoro-3-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]hydroxy- methyl}-1,4-dimethyl- 1H-pyridin-2-one A B A MS:
461.2 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.10 (s, 1H),
7.62-7.54 (m, 2H), 7.54-7.49 (m, 2H), 7.49-7.41 (m, 1H), 7.22-7.18
(m, 1H), 6.50 (d, J = 5.1, 1H), 6.21-6.15 (m, 2H), 5.90 (d, J =
5.1, 1H), 3.81-3.74 (m, 4H), 3.48-3.41 (m, 4H), 3.30 (s, 3H), 2.12
(s, 3H). 341 ##STR00392## [2,4-Difluoro-5-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]thieno[2,3-d}- pyridazin-4-yl- methanol A
A B MS: 492.2 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.85
(d, J = 0.8, 1H), 9.12 (s, 1H), 8.33 (d, J = 5.3, 1H), 8.01 (t, J =
8.1, 1H), 7.91 (dd, J = 5.4, 0.8, 1H), 7.66- 7.50 (m, 2H), 7.43 (t,
J = 10.1, 1H), 7.21 (d, J = 2.4, 1H), 6.84 (s, 1H), 6.63 (s, 1H),
3.86-3.70 (m, 4H), 3.54-3.40 (m, 4H). 342 ##STR00393##
[2,4-Difluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]thieno[2,3-d}- pyridazin-7-yl- methanol A A A MS: 492.2 (M +
H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.57 (s, 1H), 9.09 (s,
1H), 8.27 (d, J = 5.4, 1H), 7.86 (t,
J = 8.0, 1H), 7.71 (d, J = 5.4, 1H), 7.61-7.42 (m, 3H), 7.19 (d, J
= 2.4, 1H), 7.16 (d, J = 4.8, 1H), 6.54 (d, J = 4.8, 1H), 3.85-3.69
(m, 4H), 3.50-3.38 (m, 4H). 343 ##STR00394## [4-Fluoro-3-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]-[1,2,4]-
triazolo[4,3-a]pyridin- 3-ylmethanol (Ena 2) A B B MS: 457.2 (M +
H.sup.+); R.sub.t see racemate 11.36 min (SFC, Chiralpak AS-H,
CO.sub.2/20% by vol. of methanol, 0.5% by vol. of diethylamine) 344
##STR00395## [4-Fluoro-3-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]-[1,2,4]- triazolo[4,3-a]pyridin- 3-ylmethanol (Ena 1) A C A
MS: 457.2 (M + H.sup.+); R.sub.t see racemate 8.65 min (SFC,
Chiralpak AS-H, CO.sub.2/20% by vol. of methanol, 0.5% by vol. of
diethylamine) 345 ##STR00396## [4-Fluoro-3-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]pyrrolo[2,1-f]- [1,2,4]triazin-4-yl-
methanol A A D MS: 457.2 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6)
ppm = 9.09 (s, 1H), 8.49 (s, 1H), 8.08 (dd, J = 2.6, 1.4, 1H),
7.84- 7.76 (m, 2H), 7.53-7.45 (m, 2H), 7.42-7.36 (m, 1H), 7.29 (dd,
J = 4.6, 1.4, 1H), 7.19 (d, J = 2.0, 1H), 7.02 (dd, J = 4.6, 2.6,
1H), 6.62 (s, 1H), 6.07 (s, 1H), 3.80-3.74 (m, 4H), 3.46-3.41 (m,
4H). 346 ##STR00397## [2,4-Difluoro-5-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]-(9-methyl- 9H-purin-6-yl)- methanol (Ena
2) C D B MS: 490.2 (M + H.sup.+); R.sub.t see racemate 7.65 min
(SFC, Chiralpak AD-H, CO.sub.2/40% by vol. of methanol, 0.5% by
vol. of diethylamine) 347 ##STR00398## [2,4-Difluoro-5-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]-(9-methyl-
9H-purin-6-yl)- methanol (Ena 1) B B A MS: 490.2 (M + H.sup.+);
R.sub.t see racemate 4.59 min (SFC, Chiralpak AD-H, CO.sub.2/40% by
vol. of methanol, 0.5% by vol. of diethylamine) 348 ##STR00399##
2-[2,4-Difluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]-2-pyrrolo- [1,2-a]pyrazin-1-yl- acetamide A B C MS: 501.3
(M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.10 (s, 1H),
8.23-8.19 (m, 1H), 7.93 (s, 1H), 7.80 (t, J = 8.2, 1H), 7.77 (dd, J
= 2.4, 1.4, 1H), 7.63 (dd, J = 9.4, 3.1, 1H), 7.55 (dd, J = 12.3,
2.8, 1H), 7.50 (d, J = 10.0, 1H), 7.44 (d, J = 4.8, 1H), 7.33 (s,
1H), 7.21 (d, J = 2.5, 1H), 6.94-6.89 (m, 2H), 5.75 (s, 1H),
3.82-3.77 (m, 4H), 3.49-3.45 (m, 4H). 349 ##STR00400##
4-[2-Fluoro-5-(3- methyl-pyrazin-2- ylmethyl)phenyl]-7-
morpholin-4-yl- quinazoline B A A MS: 416.3 (M + H.sup.+) 1H NMR
(500 MHz, DMSO-d6) ppm = 9.09 (s, 1H), 8.43-8.36 (m, 2H), 7.56-7.49
(m, 2H), 7.46 (dd, J = 7.8, 5.5, 2H), 7.39-7.33 (m, 1H), 7.22-7.16
(m, 1H), 4.28 (s, 2H), 3.81-3.75 (m, 4H), 3.46-3.41 (m, 4H), 2.53
(s, 3H). 350 ##STR00401## [2,4-Difluoro-5-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]-[1,2,4]- triazolo[4,3-a]pyridin-
5-ylmethanol B C A MS: 475.2 (M + H.sup.+) 1H NMR (500 MHz,
DMSO-d6) ppm = 9.33 (s, 1H), 9.13 (s, 1H), 7.94 (t, J = 8.1, 1H),
7.80 (d, J = 9.2, 1H), 7.61-7.50 (m, 3H), 7.42 (dd, J = 9.2, 6.8,
1H), 7.22 (d, J = 2.4, 1H), 6.93 (d, J = 5.7, 1H), 6.87 (d, J =
6.8, 1H), 6.49 (d, J = 5.6, 1H), 3.83- 3.75 (m, 4H), 3.49-3.43 (m,
4H). 351 ##STR00402## [4-Fluoro-3-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]-[1,2,4]- triazolo[4,3-a]-
pyrazin-8-ylmethanol C D A MS: 458.1 (M + H.sup.+) 1H NMR (500 MHz,
DMSO-d6) ppm = 9.44 (s, 1H), 9.09 (s, 1H), 8.52 (d, J = 4.7, 1H),
7.91 (d, J = 4.7, 1H), 7.85-7.78 (m, 2H), 7.53 (dd, J = 9.4, 2.9,
1H), 7.50 (dd, J = 9.4, 2.4, 1H), 7.41-7.35 (m, 1H), 7.20 (d, J =
2.3, 1H), 6.51 (s, 1H), 6.43 (s, 1H), 3.82-3.74 (m, 4H), 3.47-3.41
(m, 4H). 352 ##STR00403## 4-{2-Fluoro-5- [methoxy-(3-methyl-
pyrazin-2-yl)methyl]- phenyl}-7-morpholin- 4-ylquinazoline (Ena 1)
D A* MS: 446.2 (M + H.sup.+); R.sub.t 1H NMR (500 MHz, DMSO-d6) ppm
= 9.11 (s, 3.08 min (SFC, Chiralcel 1H), 8.53-8.42 (m, 2H),
7.69-7.58 (m, 2H), OJ-H, CO.sub.2/20% by vol. of 7.58-7.48 (m, 2H),
7.48-7.38 (m, 1H), 7.21 (d, 2-propanol, 0.5% by vol. of J = 1.9,
1H), 5.80 (s, 1H), 3.81-3.70 (m, 4H), 3.48- diethylamine) 3.39 (m,
4H), 3.36 (s, 3H), 2.59 (s, 3H). 353 ##STR00404## 4-{2-Fluoro-5-
[methoxy-(3-methyl- pyrazin-2-yl)methyl]- phenyl}-7-morpholin-
4-ylquinazoline (Ena 2) C D A MS: 446.2 (M + H.sup.+); R.sub.t 1H
NMR (500 MHz, DMSO-d6) ppm = 9.11 (s, 3.78 min (SFC, Chiralcel 1H),
8.52-8.43 (m, 2H), 7.69-7.58 (m, 2H), OJ-H, CO.sub.2/20% by vol. of
7.58-7.51 (m, 2H), 7.49-7.39 (m, 1H), 7.28- 2-propanol, 0.5% by
vol. of 7.15 (m, 1H), 5.81 (s, 1H), 3.84-3.74 (m, 4H),
diethylamine) 3.49-3.42 (m, 4H), 3.36 (s, 3H), 2.59 (s, 3H). 354
##STR00405## (3,5-Dimethyl- pyrazin-2-yl)-[4- fluoro-3-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]methanol A A A MS: 446.2
(M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.09 (s, 1H), 8.30
(s, 1H), 7.60-7.50 (m, 4H), 7.41-7.33 (m, 1H), 7.23-7.17 (m, 1H),
6.20 (d, J = 5.4, 1H), 6.04 (d, J = 5.2, 1H), 3.81-3.76 (m, 4H),
3.47- 3.42 (m, 4H), 2.50 (s, 3H), 2.43 (s, 3H). 355 ##STR00406##
[2,4-Difluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)- phenyl]-(3,5-
dimethyl-pyrazin-2- yl)methanol B B B MS: 464.3 (M + H.sup.+) 1H
NMR (500 MHz, DMSO-d6) ppm = 9.12 (s, 1H), 8.26 (s, 1H), 7.89 (t, J
= 8.2, 1H), 7.61 (dd, J = 9.4, 3.2, 1H), 7.56 (dd, J = 9.4, 2.5,
1H), 7.39 (t, J = 10.1, 1H), 7.21 (d, J = 2.4, 1H), 6.28 (d, J =
6.0, 1H), 6.23 (d, J = 6.0, 1H), 3.82-3.75 (m, 4H), 3.49- 3.41 (m,
4H), 2.62 (s, 3H), 2.43 (s, 3H). 356 ##STR00407## [4-Fluoro-3-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]pyrrolo[1,2-a]-
pyrazin-1-ylmethanol A A D MS: 456.2 (M + H.sup.+) 1H NMR (500 MHz,
DMSO-d6) ppm = 9.10 (s, 1H), 8.20 (dd, J = 4.8, 1.0, 1H), 7.79-7.72
(m, 3H), 7.53-7.45 (m, 3H), 7.40-7.34 (m, 1H), 7.20 (d, J = 2.1,
1H), 7.02 (dt, J = 4.1, 1.2, 1H), 6.87 (dd, J = 4.1, 2.5, 1H), 6.33
(d, J = 4.9, 1H), 6.06 (d, J = 4.8, 1H), 3.82-3.76 (m, 4H),
3.48-3.42 (m, 4H). 357 ##STR00408## [2-Fluoro-5-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]-(6-methoxy- pyridazin-3-yl)- methanol B B
A MS: 448.2 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.08 (s,
1H), 8.00 (dd, J = 7.1, 2.3, 1H), 7.89 (d, J = 9.4, 1H), 7.80-7.71
(m, 2H), 7.55 (dd, J = 9.5, 2.6, 1H), 7.38 (dd, J = 10.0, 8.4, 1H),
7.27-7.18 (m, 2H), 6.57 (d, J = 4.8, 1H), 6.24 (d, J = 4.8, 1H),
4.01 (s, 3H), 3.85-3.71 (m, 4H), 3.51-3.40 (m, 4H). 358
##STR00409## [2,4-Difluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]pyrrolo[1,2-a]- pyrazin-1-ylmethanol A A C MS: 474.2 (M +
H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.12 (s, 1H), 8.25-8.19
(m, 1H), 7.94 (t, J = 8.2, 1H), 7.78 (dd, J = 2.5, 1.3, 1H), 7.58
(dd, J = 9.3, 3.0, 1H), 7.55 (dd, J = 9.4, 2.4, 1H), 7.47-7.39 (m,
2H), 7.22 (d, J = 2.3, 1H), 6.97-6.93 (m, 1H), 6.91 (dd, J = 4.1,
2.5, 1H), 6.43 (d, J = 5.9, 1H), 6.30 (d, J = 5.9, 1H), 3.82-3.76
(m, 4H), 3.49-3.44 (m, 4H). 359 ##STR00410## [2-Chloro-4-fluoro-5-
(7-morpholin-4-yl- quinazolin-4-yl)- phenyl]pyrrolo[1,2-a]-
pyrazin-1-ylmethanol A A D MS: 490.2/492.2 (M + H.sup.+) (Cl 1H NMR
(500 MHz, DMSO-d6) ppm = 9.12 (s, isotopy, rel. peak intensity 1H),
8.20 (dd, J = 4.7, 1.0, 1H), 7.97 (d, J = 7.8, 1H), ratio [%]
100:31) 7.76 (dd, J = 2.5, 1.3, 1H), 7.63 (d, J = 9.5, 1H), 7.60
(dd, J = 9.4, 3.2, 1H), 7.55 (dd, J = 9.4, 2.6, 1H), 7.40 (d, J =
4.8, 1H), 7.21 (d, J = 2.5, 1H), 7.00- 6.95 (m, 1H), 6.91 (dd, J =
4.1, 2.5, 1H), 6.48 (d, J = 6.2, 1H), 6.36 (d, J = 6.1, 1H),
3.81-3.75 (m, 4H), 3.48-3.43 (m, 4H). 360 ##STR00411##
2-{[4-Fluoro-3-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]hydroxy- methyl}-3-methyl-3H- pyrimidin-4-one B B A MS:
448.3 (M + H.sup.+) 1H NMR (400 MHz, DMSO-d6) ppm = 9.10 (s, 1H),
7.91 (d, J = 6.5, 1H), 7.67-7.60 (m, 2H), 7.60- 7.50 (m, 2H), 7.44
(t, J = 9.5, 1H), 7.20 (d, J = 1.7, 1H), 6.72 (s, 1H), 6.38 (d, J =
6.5, 1H), 6.00 (s, 1H), 3.82-3.73 (m, 4H), 3.48 (s, 3H), 3.47-3.42
(m, 4H). 361 ##STR00412## [2-Chloro-5-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]pyrrolo[1,2-a]- pyrazin-1-ylmethanol B B D
MS: 472.2/474.2 (M + H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm =
9.08 (s, isotopy, rel. peak intensity 1H), 8.22-8.19 (m, 1H), 8.14
(d, J = 2.2, 1H), 7.89 ratio [%] 100:33) (d, J = 9.4, 1H), 7.76
(dd, J = 2.5, 1.3, 1H), 7.70 (dd, J = 8.2, 2.2, 1H), 7.61 (d, J =
8.2, 1H), 7.53 (dd, J = 9.5, 2.6, 1H), 7.43 (d, J = 4.8, 1H), 7.21
(d, J = 2.6, 1H), 7.00-6.97 (m, 1H), 6.93-6.90 (m, 1H), 6.45-6.40
(m, 2H), 3.81-3.76 (m, 4H), 3.48-3.42 (m, 4H). 362 ##STR00413##
[2-Chloro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]pyrrolo[2,1-f]- [1,2,4]triazin-4-yl- methanol B B D MS:
473.2/475.2 (M + H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm = 9.08
(s, isotopy, rel. peak intensity 1H), 8.49 (s, 1H), 8.16 (d, J =
2.2, 1H), 8.12 (dd, ratio [%] 100:38) J = 2.6, 1.4, 1H), 7.88 (d, J
= 9.4, 1H), 7.74 (dd, J = 8.2, 2.2, 1H), 7.64 (d, J = 8.2, 1H),
7.54 (dd, J = 9.5, 2.6, 1H), 7.23-7.19 (m, 2H), 7.06 (dd, J = 4.6,
2.6, 1H), 6.80 (d, J = 5.7, 1H), 6.44 (d, J = 5.7, 1H), 3.81-3.76
(m, 4H), 3.48-3.43 (m, 4H). 363 ##STR00414## 6-{[2-Chloro-5-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]hydroxy-
methyl}-1-methyl-1H- pyridin-2-one (Ena 2) C C B MS: 463.2/465.1 (M
+ H.sup.+) (Cl see racemate isotopy, rel. peak intensity ratio [%]
100:42); R.sub.t 4.63 min (SFC, Chiralcel OJ-H, CO.sub.2/20% by
vol. of methanol, 0.5% by vol. of diethylamine) 364 ##STR00415##
6-{[2-Chloro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]hydroxy- methyl}-1-methyl-1H- pyridin-2-one (Ena 1) A A A
MS: 463.2/465.2 (M + H.sup.+) (Cl see racemate isotopy, rel. peak
intensity ratio [%] 100:41); R.sub.t 2.74 min (SFC, Chiralcel OJ-H,
CO.sub.2/20% by vol. of methanol, 0.5% by vol. of diethylamine) 365
##STR00416## 6-{[2-Fluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]hydroxy- methyl}-1-methyl-1H- pyridin-2-one (Ena 2) B B A
MS: 447.2 (M + H.sup.+); R.sub.t see racemate 7.64 min (SFC,
Chiralpak AS-H, CO.sub.2/25% by vol. of methanol)
366 ##STR00417## 6-{[2-Fluoro-5-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]hydroxy- methyl}-1-methyl-1H-
pyridin-2-one (Ena 1) C C A MS: 447.2 (M + H.sup.+); R.sub.t see
racemate 4.61 min (SFC, Chiralpak AS-H, CO.sub.2/25% by vol. of
methanol) 367 ##STR00418## 6-{[4-Fluoro-3-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]hydroxy- methyl}-2H- pyridazin-3-one (Ena
1) A B A MS: 434.1 (M + H.sup.+); R.sub.t 13.79 see enantiomer min,
(SFC, Chiralcel OJ-H, CO.sub.2/15% by vol. of methanol, 0.5% by
vol. of diethylamine) Ena 2 to this compound: Example 76 368
##STR00419## 2-{[2-Chloro-4-fluoro- 5-(7-morpholin-4-yl-
quinazolin-4-yl)- phenyl]hydroxy- methyl}-3-methyl-3H-
pyrimidin-4-one C C A MS: 482.2/484.2 (M + H.sup.+) (Cl 1H NMR (500
MHz, DMSO-d6) ppm = 9.14 (s, isotopy, rel. peak intensity 1H), 7.88
(d, J = 7.7, 1H), 7.83 (d, J = 6.5, 1H), 7.70 ratio [%] 100:41) (d,
J = 9.4, 1H), 7.63 (dd, J = 9.4, 3.2, 1H), 7.57 (dd, J = 9.5, 2.5,
1H), 7.23 (d, J = 2.4, 1H), 6.91 (d, J = 7.0, 1H), 6.39 (d, J =
6.5, 1H), 6.15 (d, J = 7.0, 1H), 3.83-3.76 (m, 4H), 3.72 (s, 3H),
3.50-3.44 (m, 4H). 369 ##STR00420## [2-Chloro-5-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]imidazo- [1,2-a]pyrazin-8-yl- methanol C C
B MS: 473.1/475.2 (M + H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm =
9.11 (s, isotopy, rel. peak intensity 1H), 8.57 (d, J = 4.5, 1H),
8.27 (d, J = 2.2, 1H), 8.18 ratio [%] 100:25) (d, J = 1.1, 1H),
8.04 (d, J = 9.4, 1H), 7.88 (d, J = 1.1, 1H), 7.83 (d, J = 4.5,
1H), 7.72 (dd, J = 8.2, 2.3, 1H), 7.62-7.55 (m, 2H), 7.23 (d, J =
2.6, 1H), 6.87 (d, J = 5.8, 1H), 6.50 (d, J = 5.9, 1H), 3.83-3.78
(m, 4H), 3.50-3.45 (m, 4H). 370 ##STR00421## [2-Fluoro-5-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]-(9-methyl-
9H-purin-6-yl)- methanol C B A MS: 472.2 (M + H.sup.+) 1H NMR (500
MHz, DMSO-d6) ppm = 9.07 (s, 1H), 8.91 (s, 1H), 8.58 (s, 1H), 8.28
(dd, J = 7.0, 2.3, 1H), 8.05 (d, J = 9.4, 1H), 7.72 (ddd, J = 8.3,
5.0, 2.4, 1H), 7.58 (dd, J = 9.5, 2.6, 1H), 7.30 (dd, J = 10.0,
8.5, 1H), 7.21 (d, J = 2.5, 1H), 6.66 (d, J = 5.5, 1H), 6.44 (d, J
= 5.6, 1H), 3.85 (s, 3H), 3.82- 3.78 (m, 4H), 3.49-3.45 (m, 4H).
371 ##STR00422## [2-Chloro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]-(9-methyl- 9H-purin-6-yl)- methanol C B C MS: 488.2/490.2
(M + H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm = 9.10 (s, isotopy,
rel. peak intensity 1H), 8.90 (s, 1H), 8.59 (s, 1H), 8.38 (d, J =
2.2, ratio [%] 100:33) 1H), 8.12 (d, J = 9.4, 1H), 7.70 (dd, J =
8.2, 2.3, 1H), 7.60 (dd, J = 9.5, 2.6, 1H), 7.56 (d, J = 8.2, 1H),
7.23 (d, J = 2.6, 1H), 6.71 (d, J = 5.4, 1H), 6.53 (d, J = 5.4,
1H), 3.86 (s, 3H), 3.82-3.77 (m, 4H), 3.49-3.45 (m, 4H). 372
##STR00423## [2-Fluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]imidazo- [1,2-a]pyrazin-8-yl- methanol C B A MS: 457.2 (M +
H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.08 (s, 1H), 8.58 (d, J =
4.5, 1H), 8.24-8.16 (m, 2H), 8.00 (d, J = 9.4, 1H), 7.91-7.83 (m,
2H), 7.74 (ddd, J = 8.1, 5.0, 2.4, 1H), 7.57 (dd, J = 9.5, 2.6,
1H), 7.33 (dd, J = 10.0, 8.5, 1H), 7.22 (d, J = 2.5, 1H), 6.80 (d,
J = 5.9, 1H), 6.39 (d, J = 6.0, 1H), 3.86- 3.75 (m, 4H), 3.52-3.43
(m, 4H). 373 ##STR00424## [2-Fluoro-5-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]-[1,2,4]- triazolo[4,3-a]pyridin-
5-ylmethanol B B B MS: 457.2 (M + H.sup.+) 1H NMR (500 MHz,
DMSO-d6) ppm = 9.36-9.30 (m, 1H), 9.07 (s, 1H), 8.03 (dd, J = 7.2,
2.3, 1H), 7.86-7.76 (m, 3H), 7.52-7.38 (m, 3H), 7.21 (d, J = 2.6,
1H), 6.91 (d, J = 5.6, 1H), 6.87-6.80 (m, 1H), 6.53 (d, J = 5.6,
1H), 3.83-3.74 (m, 4H), 3.48- 3.40 (m, 4H). 374 ##STR00425##
[2-Fluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]furo[3,2-d}- pyrimidin-4-yl- methanol A B B MS: 458.2 (M +
H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.08 (s, 1H), 9.02 (s,
1H), 8.59 (d, J = 2.2, 1H), 8.20 (dd, J = 7.0, 2.3, 1H), 7.92 (d, J
= 9.4, 1H), 7.77 (ddd, J = 8.4, 5.0, 2.4, 1H), 7.57 (dd, J = 9.5,
2.6, 1H), 7.37 (dd, J = 10.0, 8.5, 1H), 7.27 (d, J = 2.3, 1H), 7.22
(d, J = 2.5, 1H), 6.73 (d, J = 5.2, 1H), 6.48 (d, J = 5.1, 1H),
3.82-3.76 (m, 4H), 3.49-3.44 (m, 4H). 375 ##STR00426##
6-{[4-Fluoro-3-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]hydroxy- methyl}-1-methyl-1H- pyridin-2-one (Ena 2) A B A
MS: 447.3 (M + H.sup.+); R.sub.t see racemate 4.15 min (SFC,
Chiralcel OJ-H, CO.sub.2/20% by vol. of methanol, 0.5% by vol. of
diethylamine) 376 ##STR00427## 6-{[4-Fluoro-3-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]hydroxy- methyl}-1-methyl-1H-
pyridin-2-one (Ena 1) A A A MS: 447.3 (M + H.sup.+); R.sub.t see
racemate 3.23 min (SFC, Chiralcel OJ-H, CO.sub.2/20% by vol. of
methanol, 0.5% by vol. of diethylamine) 377 ##STR00428##
2-[2-Chloro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]-2-(5-methyl- pyrimidin-4-yl)- acetamide (Ena 2) B B B MS:
475.1/477.1 (M + H.sup.+) (Cl see racemate isotopy, rel. peak
intensity ratio [%] 100:34); R.sub.t 6.14 min (SFC, Chiralpak AD-H,
CO.sub.2/40% by vol. of methanol, 0.5% by vol. of diethylamine) 378
##STR00429## B B A MS: 475.1/477.1 (M + H.sup.+) (Cl see racemate
isotopy, rel. peak intensity ratio [%] 100:34); R.sub.t 3.81 min
(SFC, Chiralpak AD-H, CO.sub.2/40% by vol. of methanol, 0.5% by
vol. of diethylamine) 379 ##STR00430## [2,4-Difluoro-5-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]-[1,2,4]-
triazolo[4,3-a]pyridin- 3-ylmethanol B B A MS: 475.2 (M + H.sup.+)
1H NMR (500 MHz, DMSO-d6) ppm = 9.14 (s, 1H), 8.63 (dt, J = 7.1,
1.2, 1H), 8.02 (t, J = 8.1, 1H), 7.81 (dt, J = 9.3, 1.1, 1H), 7.64
(dd, J = 9.4, 3.3, 1H), 7.60-7.50 (m, 2H), 7.44 (ddd, J = 9.3, 6.6,
1.1, 1H), 7.23 (d, J = 2.5, 1H), 7.06 (td, J = 6.8, 1.0, 1H), 6.87
(d, J = 6.0, 1H), 6.69 (d, J = 6.0, 1H), 3.82- 3.77 (m, 4H),
3.49-3.45 (m, 4H). 380 ##STR00431## 6-{[2,4-Difluoro-5-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]hydroxy-
methyl}-1-methyl-1H- pyridin-2-one (Ena 2) B B A MS: 465.2 (M +
H.sup.+); R.sub.t see racemate 10.95 min (SFC, Chiralpak AD-H,
CO.sub.2/20% by vol. of methanol, 0.5% by vol. of diethylamine) 381
##STR00432## 6-{[2,4-Difluoro-5-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]hydroxy- methyl}-1-methyl-1H-
pyridin-2-one (Ena 1) A B A MS: 465.2 (M + H.sup.+); R.sub.t see
racemate 7.49 min (SFC, Chiralpak AD-H, CO.sub.2/20% by vol. of
methanol, 0.5% by vol. of diethylamine) 382 ##STR00433##
6-{[2-Chloro-4-fluoro- 5-(7-morpholin-4-yl- quinazolin-4-yl)-
phenyl]hydroxy- methyl}-1-methyl-1H- pyridin-2-one (Ena 2) C B B
MS: 481.1/483.1 (M + H.sup.+) (Cl see racemate isotopy, rel. peak
intensity ratio [%] 100:35); R.sub.t 4.55 min (SFC, Chiralpak AD-H,
CO.sub.2/40% by vol. of methanol, 0.5% by vol. of diethylamine) 383
##STR00434## 6-{[2-Chloro-4-fluoro- 5-(7-morpholin-4-yl-
quinazolin-4-yl)- phenyl]hydroxy- methyl}-1-methyl-1H-
pyridin-2-one (Ena 1) A A A MS: 481.1/483.1 (M + H.sup.+) (Cl see
racemate isotopy, rel. peak intensity ratio [%] 100:35); R.sub.t
2.24 min (SFC, Chiralpak AD-H, CO.sub.2/40% by vol. of methanol,
0.5% by vol. of diethylamine) 384 ##STR00435## (R)-[2,4-Difluoro-5-
(7-morpholin-4-yl- quinazolin-4-yl)- phenyl]-(7-methyl-
7H-purin-6-yl)- methanol (Ena 2) C D A MS: 490.2 (M + H.sup.+);
R.sub.t see racemate 5.77 min (SFC, Chiralpak AD-H, CO.sub.2/40% by
vol. of methanol, 0.5% by vol. of diethylamine) 385 ##STR00436##
[2-Chloro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]-(1-methyl- 1H-pyrazolo[3,4-d}- pyrimidin-4-yl)- methanol C
B A MS: 488.2/490.2 (M + H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm
= 9.05 (s, isotopy, rel. peak intensity 1H), 8.92 (s, 1H), 8.44 (s,
1H), 7.95 (d, J = 2.2, ratio [%] 100:31) 1H), 7.80 (d, J = 9.4,
1H), 7.72 (dd, J = 8.2, 2.2, 1H), 7.66 (d, J = 8.2, 1H), 7.50 (dd,
J = 9.5, 2.6, 1H), 7.19 (d, J = 2.5, 1H), 6.90 (d, J = 4.9, 1H),
6.49 (d, J = 4.9, 1H), 4.05 (s, 3H), 3.82-3.76 (m, 4H), 3.47-3.41
(m, 4H). 386 ##STR00437## [2,4-Difluoro-5-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]-(7-methyl- 7H-purin-6-yl)- methanol (Ena
1) B C A MS: 490.2 (M + H.sup.+); R.sub.t see racemate 3.50 min
(SFC, Chiralpak AD-H, CO.sub.2/40% by vol. of methanol, 0.5% by
vol. of diethylamine) 387 ##STR00438## [2,4-Difluoro-5-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]-(5,6,7,8-
tetrahydropyrido- [3,4-d}pyrimidin-4-yl)- methanol C B B MS: 491.2
(M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.11 (s, 1H), 8.83
(s, 1H), 7.87 (t, J = 8.2, 1H), 7.60 (dd, J = 9.4, 3.0, 1H), 7.56
(dd, J = 9.4, 2.5, 1H), 7.42 (t, J = 10.1, 1H), 7.21 (d, J = 2.4,
1H), 6.33 (d, J = 6.3, 1H), 6.16 (d, J = 6.3, 1H), 3.86 (s, 2H),
3.82-3.75 (m, 4H), 3.49-3.42 (m, 4H), 3.09-2.94 (m, 2H), 2.94-2.72
(m, 2H). 388 ##STR00439## [4-Fluoro-3-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]-(5,6,7,8- tetrahydropyrido-
[3,4-d}pyrimidin-4-yl)- methanol C B C MS: 473.2 (M + H.sup.+) 1H
NMR (500 MHz, DMSO-d6) ppm = 9.09 (s, 1H), 8.88 (s, 1H), 7.64-7.56
(m, 2H), 7.55-7.50
(m, 2H), 7.38 (dd, J = 10.5, 8.1, 1H), 7.23-7.16 (m, 1H), 6.20 (d,
J = 5.8, 1H), 5.96 (d, J = 5.8, 1H), 3.83 (s, 2H), 3.81-3.72 (m,
4H), 3.49-3.39 (m, 4H), 3.05-2.84 (m, 2H), 2.77-2.72 (m, 2H). 389
##STR00440## [2-Chloro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]-(5-fluoro- pyrimidin-4-yl)- methanol (Ena 2) C C C MS:
452.1/454.1 (M + H.sup.+) (Cl see racemate isotopy, rel. peak
intensity ratio [%] 100:34); R.sub.t 3.98 min (SFC, Chiralpak AD-H,
CO.sub.2/40% by vol. of 2-propanol, 0.5% by vol. of diethylamine)
390 ##STR00441## [2-Chloro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]-(5-fluoro- pyrimidin-4-yl)- methanol (Ena 1) B B B MS:
452.1/454.1 (M + H.sup.+) (Cl see racemate isotopy, rel. peak
intensity ratio [%] 100:34); R.sub.t 2.20 min (SFC, Chiralpak AD-H,
CO.sub.2/40% by vol. of 2-propanol, 0.5% by vol. of diethylamine)
391 ##STR00442## [2-Fluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]-(1-methyl- 1H-pyrazolo[3,4-d}- pyrimidin-4-yl)- methanol C
B B MS: 472.2 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.05
(s, 1H), 8.90 (s, 1H), 8.49 (s, 1H), 7.93 (dd, J = 6.9, 2.3, 1H),
7.81 (d, J = 9.4, 1H), 7.74 (ddd, J = 8.4, 4.9, 2.3, 1H), 7.52 (dd,
J = 9.5, 2.6, 1H), 7.40 (dd, J = 9.9, 8.5, 1H), 7.19 (d, J = 2.6,
1H), 6.88 (s, 1H), 6.37 (s, 1H), 4.05 (s, 3H), 3.81-3.75 (m, 4H),
3.51-3.42 (m, 4H). 392 ##STR00443## [2-Fluoro-5-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]-(5-methyl- pyrimidin-4-yl)- methanol B B
B MS: 432.2 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.08 (s,
1H), 8.98 (s, 1H), 8.64 (s, 1H), 8.07 (dd, J = 7.1, 2.3, 1H), 7.93
(d, J = 9.4, 1H), 7.74 (ddd, J = 8.3, 5.0, 2.3, 1H), 7.57 (dd, J =
9.5, 2.6, 1H), 7.35 (dd, J = 10.1, 8.4, 1H), 7.21 (d, J = 2.6, 1H),
6.38 (d, J = 6.0, 1H), 6.25 (d, J = 6.0, 1H), 3.82-3.76 (m, 4H),
3.51-3.43 (m, 4H), 2.41 (s, 3H). 393 ##STR00444## [2-Fluoro-5-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]-(3-methyl- pyrazin-2-yl)-
methanol B C B MS: 432.2 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6)
ppm = 9.08 (s, 1H), 8.45 (d, J = 2.5, 1H), 8.41 (d, J = 2.5, 1H),
8.09 (dd, J = 7.1, 2.3, 1H), 7.94 (d, J = 9.4, 1H), 7.74 (ddd, J =
7.9, 5.0, 2.3, 1H), 7.56 (dd, J = 9.5, 2.6, 1H), 7.33 (dd, J =
10.1, 8.4, 1H), 7.21 (d, J = 2.5, 1H), 6.35 (d, J = 5.8, 1H), 6.32
(d, J = 5.9, 1H), 3.83- 3.76 (m, 4H), 3.45 (t, J = 4.9, 4H), 2.68
(s, 3H). 394 ##STR00445## [2-Fluoro-5-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]-(3-methoxy- pyrazin-2-yl)- methanol B B D
MS: 448.2 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.08 (s,
1H), 8.19 (d, J = 2.7, 1H), 8.17 (d, J = 2.7, 1H), 8.07 (dd, J =
7.1, 2.3, 1H), 7.93 (d, J = 9.4, 1H), 7.73 (ddd, J = 8.3, 5.0, 2.4,
1H), 7.57 (dd, J = 9.5, 2.6, 1H), 7.33 (dd, J = 10.1, 8.4, 1H),
7.22 (d, J = 2.5, 1H), 6.35 (d, J = 6.0, 1H), 6.21 (d, J = 6.0,
1H), 3.98 (s, 3H), 3.82-3.76 (m, 4H), 3.46 (dd, J = 5.9, 3.9, 4H).
395 ##STR00446## [2-Chloro-4-fluoro-5- (7-morpholin-4-yl-
quinazolin-4-yl)- phenyl]imidazo- [1,2-a]pyrazin-8-yl- methanol
(Ena 2) C C B MS: 491.2/493.2 (M + H.sup.+) (Cl see racemate
isotopy, rel. peak intensity ratio [%] 100:37); R.sub.t 14.57 min
(SFC, Chiralpak AD-H, CO.sub.2/40% by vol. of methanol, 0.5% by
vol. of diethylamine) 396 ##STR00447## (S)-[2-Chloro-4-
fluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)- phenyl]imidazo-
[1,2-a]pyrazin-8-yl- methanol (Ena 1) B A A MS: 491.2/493.1 (M +
H.sup.+) (Cl see racemate isotopy, rel. peak intensity ratio [%]
100:35); R.sub.t 4.27 min (SFC, Chiralpak AD-H, CO.sub.2/40% by
vol. of methanol, 0.5% by vol. of diethylamine) 397 ##STR00448##
[2-Chloro-4-fluoro-5- (7-morpholin-4-yl- quinazolin-4-yl)-
phenyl]imidazo- [1,2-a]pyrazin-8-yl- methanol B A A MS: 491.2/493.1
(M + H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm = 9.13 (s, isotopy,
rel. peak intensity 1H), 8.55 (d, J = 4.5, 1H), 8.17 (d, J = 1.1,
1H), 8.06 ratio [%] 100:35) (d, J = 7.8, 1H), 7.85 (d, J = 1.1,
1H), 7.80 (d, J = 4.5, 1H), 7.67 (dd, J = 9.4, 3.1, 1H), 7.61 (d, J
= 9.5, 1H), 7.57 (dd, J = 9.5, 2.6, 1H), 7.22 (d, J = 2.5, 1H),
6.81 (d, J = 5.3, 1H), 6.52 (d, J = 6.1, 1H), 3.81-3.77 (m, 4H),
3.49-3.45 (m, 4H). 398 ##STR00449## 1-Ethyl-6-{[4-fluoro-
3-(7-morpholin-4-yl- quinazolin-4-yl)- phenyl]hydroxy-
methyl}-1H-pyridin-2- one B B A MS: 461.2 (M + H.sup.+) 1H NMR (500
MHz, DMSO-d6) ppm = 9.10 (s, 1H), 7.63-7.56 (m, 2H), 7.54 (dd, J =
9.4, 2.5, 1H), 7.52-7.43 (m, 2H), 7.41 (dd, J = 9.1, 6.9, 1H), 7.20
(d, J = 2.4, 1H), 6.58 (d, J = 5.0, 1H), 6.35 (dd, J = 9.1, 1.4,
1H), 6.31 (dd, J = 7.0, 1.4, 1H), 5.91 (d, J = 5.0, 1H), 4.05-3.88
(m, 2H), 3.81-3.74 (m, 4H), 3.48-3.39 (m, 4H), 0.95 (t, J = 6.9,
3H). 399 ##STR00450## [4-Fluoro-3-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]-[1,2,4]- triazolo[4,3-a]pyridin-
3-ylmethanol A B A MS: 457.2 (M + H.sup.+) 1H NMR (500 MHz,
DMSO-d6) ppm = 9.10 (s, 1H), 8.51-8.39 (m, 1H), 7.83-7.74 (m, 1H),
7.74-7.64 (m, 2H), 7.55 (dd, J = 9.4, 3.0, 1H), 7.51 (dd, J = 9.4,
2.4, 1H), 7.48-7.42 (m, 1H), 7.42-7.35 (m, 1H), 7.20 (d, J = 2.3,
1H), 7.04- 6.94 (m, 1H), 6.83 (d, J = 5.2, 1H), 6.52 (d, J = 4.8,
1H), 3.88-3.72 (m, 4H), 3.49-3.37 (m, 4H). 400 ##STR00451##
6-{[2-Chloro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]hydroxy- methyl}-1-methyl-1H- pyridin-2-one A A B MS:
463.1/465.1 (M + H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm = 9.08
(s, isotopy, rel. peak intensity 1H), 7.90 (d, J = 2.1, 1H), 7.84
(d, J = 9.4, 1H), 7.79 ratio [%] 100:37) (dd, J = 8.2, 2.2, 1H),
7.72 (d, J = 8.2, 1H), 7.51 (dd, J = 9.5, 2.6, 1H), 7.33 (dd, J =
9.1, 7.0, 1H), 7.21 (d, J = 2.5, 1H), 6.60 (d, J = 6.2, 1H), 6.38
(dd, J = 9.1, 1.3, 1H), 6.10 (d, J = 6.1, 1H), 5.88 (dd, J = 7.0,
1.4, 1H), 3.84-3.74 (m, 4H), 3.56 (s, 3H), 3.48-3.40 (m, 4H). 401
##STR00452## 6-{[2-Fluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]hydroxy- methyl}-1-methyl-1H- pyridin-2-one B B C MS: 447.2
(M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.06 (s, 1H),
7.85-7.75 (m, 3H), 7.51 (dd, J = 9.5, 2.6, 1H), 7.46 (dd, J = 10.1,
8.4, 1H), 7.38 (dd, J = 9.1, 7.0, 1H), 7.20 (d, J = 2.5, 1H), 6.59
(d, J = 5.9, 1H), 6.38 (dd, J = 9.1, 1.1, 1H), 6.21-6.15 (m, 1H),
6.14 (d, J = 5.8, 1H), 3.81-3.74 (m, 4H), 3.46 (s, 3H), 3.45-3.41
(m, 4H). 402 ##STR00453## [2-Chloro-4-fluoro-5- (7-morpholin-4-yl-
quinazolin-4-yl)- phenyl]-(1-methyl- 1H-pyrazolo[3,4-d}-
pyrimidin-4-yl)- methanol B B B MS: 506.2/508.1 (M + H.sup.+) (Cl
1H NMR (500 MHz, DMSO-d6) ppm = 9.08 (s, isotopy, rel. peak
intensity 1H), 8.90 (s, 1H), 8.44 (s, 1H), 7.81 (d, J = 7.6, ratio
[%] 100:38) 1H), 7.69 (d, J = 9.5, 1H), 7.56-7.48 (m, 2H), 7.22-
7.16 (m, 1H), 6.92 (d, J = 5.0, 1H), 6.43 (d, J = 5.0, 1H), 4.04
(s, 3H), 3.81-3.74 (m, 4H), 3.48-3.40 (m, 4H). 403 ##STR00454##
[2,4-Difluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]-(1-methyl- 1H-pyrazolo[3,4-d}- pyrimidin-4-yl)- methanol B
B B MS: 490.2 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.07
(s, 1H), 8.89 (s, 1H), 8.49 (s, 1H), 7.79 (t, J = 8.0, 1H),
7.56-7.50 (m, 2H), 7.47 (t, J = 10.0, 1H), 7.19 (s, 1H), 6.88 (s,
1H), 6.32 (s, 1H), 4.04 (s, 3H), 3.81-3.74 (m, 4H), 3.48-3.40 (m,
4H). 404 ##STR00455## [4-Fluoro-3-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]-(1-methyl- 1H-pyrazolo[3,4-d}-
pyrimidin-4-yl)- methanol B A A MS: 472.2 (M + H.sup.+) 1H NMR (500
MHz, DMSO-d6) ppm = 9.09 (s, 1H), 8.91 (s, 1H), 8.53 (s, 1H),
7.79-7.72 (m, 2H), 7.54-7.44 (m, 2H), 7.38 (dd, J = 9.8, 8.4, 1H),
7.19 (d, J = 2.1, 1H), 6.79 (d, J = 4.0, 1H), 6.10 (d, J = 3.3,
1H), 4.03 (s, 3H), 3.80-3.75 (m, 4H), 3.46-3.41 (m, 4H). 405
##STR00456## [2-Fluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]thieno[3,2-d}- pyrimidin-4-yl- methanol A A D MS: 474.2 (M +
H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.07 (s, 1H), 9.04 (s,
1H), 8.49 (d, J = 5.5, 1H), 7.91 (dd, J = 6.9, 2.3, 1H), 7.80 (d, J
= 9.4, 1H), 7.79-7.74 (m, 1H), 7.63 (d, J = 5.5, 1H), 7.49 (dd, J =
9.5, 2.6, 1H), 7.43 (dd, J = 9.9, 8.5, 1H), 7.21-7.15 (m, 2H), 6.38
(d, J = 2.1, 1H), 3.83-3.76 (m, 4H), 3.47- 3.42 (m, 4H). 406
##STR00457## [2-Fluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]thieno[2,3-d}- pyrimidin-4-yl- methanol A A C MS: 474.1 (M +
H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.06 (s, 1H), 9.03 (s,
1H), 8.48 (d, J = 5.6, 1H), 7.90 (dd, J = 6.9, 2.3, 1H), 7.79 (d, J
= 9.4, 1H), 7.78-7.73 (m, 1H), 7.62 (d, J = 5.6, 1H), 7.48 (dd, J =
9.5, 2.6, 1H), 7.41 (dd, J = 9.9, 8.5, 1H), 7.18 (d, J = 2.6, 1H),
7.16 (d, J = 4.7, 1H), 6.36 (d, J = 4.5, 1H), 3.82- 3.74 (m, 4H),
3.48-3.40 (m, 4H). 407 ##STR00458## 2-[2-Chloro-5-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]-2-(5-methyl-
pyrimidin-4-yl)- acetamide A B B MS: 475.2/477.2 (M + H.sup.+) (Cl
1H NMR (400 MHz, DMSO-d6) ppm = 9.06 (s, isotopy, rel. peak
intensity 1H), 8.95 (s, 1H), 8.64-8.60 (m, 1H), 7.89 (d, ratio [%]
100:36) J = 9.5, 1H), 7.85-7.79 (m, 1H), 7.76-7.67 (m, 3H), 7.54
(dd, J = 9.4, 2.6, 1H), 7.42-7.34 (m, 1H), 7.20 (d, J = 2.5, 1H),
5.67 (s, 1H), 3.84-3.74 (m, 4H), 3.50-3.42 (m, 4H), 2.31 (s, 3H).
408 ##STR00459## [2-Chloro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]-(5-methoxy- pyrimidin-4-yl)- methanol (Ena 2) B B C MS:
464.2/466.2 (M + H.sup.+) (Cl see racemate isotopy, rel. peak
intensity ratio [%] 100:36); R.sub.t 5.41 min (SFC, Chiralpak AD-H,
CO.sub.2/40% by vol. of 2-propanol, 0.5% by vol. of diethylamine)
409 ##STR00460## [2-Chloro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]-(5-methoxy- pyrimidin-4-yl)- methanol (Ena 1) B B A MS:
464.1/466.1 (M + H.sup.+) (Cl see racemate isotopy, rel. peak
intensity ratio [%] 100:35); R.sub.t 3.05 min (SFC, Chiralpak AD-H,
CO.sub.2/40% by vol. of 2-propanol, 0.5% by vol. of diethylamine)
410 ##STR00461## [2-Chloro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]-(3-methoxy- pyrazin-2-yl)- methanol (Ena 2) A A D MS:
464.2/466.2 (M + H.sup.+) (Cl see racemate isotopy, rel. peak
intensity
ratio [%] 100:35); R.sub.t 5.47 min (SFC, Chiralpak AD-H,
CO.sub.2/40% by vol. of 2-propanol, 0.5% by vol. of diethylamine)
411 ##STR00462## (S)-[2-Chloro-5-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]-(3-methoxy- pyrazin-2-yl)- methanol (Ena
1) B B C MS: 464.1/466.1 (M + H.sup.+) (Cl see racemate isotopy,
rel. peak intensity ratio [%] 100:35); R.sub.t 2.84 min (SFC,
Chiralpak AD-H, CO.sub.2/40% by vol. of 2-propanol, 0.5% by vol. of
diethylamine) 412 ##STR00463## [2-Chloro-5-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]-(5-fluoro- pyrimidin-4-yl)- methanol C C
B MS: 452.1/454.1 (M + H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm =
9.10 (s, isotopy, rel. peak intensity 1H), 9.03 (d, J = 2.9, 1H),
8.93 (d, J = 2.1, 1H), 8.24 ratio [%] 100:35) (d, J = 2.2, 1H),
7.96 (d, J = 9.4, 1H), 7.74 (dd, J = 8.2, 2.3, 1H), 7.62 (d, J =
8.2, 1H), 7.59 (dd, J = 9.5, 2.6, 1H), 7.23 (d, J = 2.5, 1H), 6.77
(d, J = 5.5, 1H), 6.38 (d, J = 5.5, 1H), 3.82-3.76 (m, 4H),
3.49-3.44 (m, 4H). 413 ##STR00464## [2-Chloro-5-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]-(5-methoxy- pyrimidin-4-yl)- methanol B B
B MS: 464.2/466.2 (M + H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm =
9.09 (s, isotopy, rel. peak intensity 1H), 8.74 (s, 1H), 8.64 (s,
1H), 8.15 (d, J = 2.2, ratio [%] 100:36) 1H), 7.95 (d, J = 9.4,
1H), 7.69 (dd, J = 8.2, 2.3, 1H), 7.57 (dd, J = 8.9, 2.8, 2H), 7.22
(d, J = 2.5, 1H), 6.43 (d, J = 6.0, 1H), 6.31 (d, J = 6.0, 1H),
4.01 (s, 3H), 3.83-3.74 (m, 4H), 3.50-3.41 (m, 4H). 414
##STR00465## [2-Chloro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]furo[3,2-d}- pyrimidin-4-yl- methanol (Ena 2) C A C MS:
474.1/476.1 (M + H.sup.+) (Cl see racemate isotopy, rel. peak
intensity ratio [%] 100:34); R.sub.t 6.16 min (SFC, Chiralpak AD-H,
CO.sub.2/40% by vol. of 2-propanol, 0.5% by vol. of diethylamine)
415 ##STR00466## [2-Chloro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]furo[3,2-d}- pyrimidin-4-yl- methanol (Ena 1) B A C MS:
474.1/476.1 (M + H.sup.+) (Cl see racemate isotopy, rel. peak
intensity ratio [%] 100:35); R.sub.t 3.19 min (SFC, Chiralpak AD-H,
CO.sub.2/40% by vol. of 2-propanol, 0.5% by vol. of diethylamine)
416 ##STR00467## [2-Chloro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]furo[2,3-d}- pyrimidin-4-yl- methanol B B C MS: 474.1/476.1
(M + H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm = 9.07 (s, isotopy,
rel. peak intensity 1H), 8.88 (s, 1H), 8.20 (d, J = 2.5, 1H), 8.03
(d, ratio [%] 100:34) J = 2.2, 1H), 7.84 (d, J = 9.4, 1H), 7.72
(dd, J = 8.2, 2.2, 1H), 7.65 (d, J = 8.3, 1H), 7.52 (dd, J = 9.4,
2.6, 1H), 7.26 (d, J = 2.5, 1H), 7.20 (d, J = 2.5, 1H), 6.88- 6.72
(m, 1H), 6.46 (s, 1H), 3.82-3.76 (m, 4H), 3.48-3.42 (m, 4H). 417
##STR00468## [2-Chloro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]-(5-methyl- pyrimidin-4-yl)- methanol (Ena 2) C B B MS:
448.1/450.1 (M + H.sup.+) (Cl see racemate isotopy, rel. peak
intensity ratio [%] 100:36); R.sub.t 6.39 min (SFC, Chiralpak AD-H,
CO.sub.2/40% by vol. of methanol, 0.5% by vol. of diethylamine) 418
##STR00469## [2-Chloro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]-(5-methyl- pyrimidin-4-yl)- methanol (Ena 1) C B A MS:
448.1/450.1 (M + H.sup.+) (Cl see racemate isotopy, rel. peak
intensity ratio [%] 100:36); R.sub.t 4.95 min (SFC, Chiralpak AD-H,
CO.sub.2/40% by vol. of methanol, 0.5% by vol. of diethylamine) 419
##STR00470## [4-Fluoro-3-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]-(9-methyl- 9H-purin-6-yl)- methanol C B B MS: 448.1/450.1
(M + H.sup.+) (Cl 1H NMR (400 MHz, DMSO-d6) ppm = 9.10 (s, isotopy,
rel. peak intensity 1H), 8.94 (s, 1H), 8.67 (s, 1H), 8.16 (d, J =
2.2, ratio [%] 100:37 1H), 7.98 (d, J = 9.4, 1H), 7.72 (dd, J =
8.2, 2.2, 1H), 7.64-7.53 (m, 2H), 7.22 (d, J = 2.5, 1H), 6.47 (d, J
= 6.0, 1H), 6.25 (d, J = 6.0, 1H), 3.84-3.73 (m, 4H), 3.51-3.42 (m,
4H), 2.49 (s, 3H). 420 ##STR00471## [4-Fluoro-3-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]-(9-methyl- 9H-purin-6-yl)- methanol C C A
MS: 472.3 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.08 (s,
1H), 8.91 (s, 1H), 8.55 (s, 1H), 7.82-7.73 (m, 2H), 7.56-7.47 (m,
2H), 7.40-7.31 (m, 1H), 7.19 (d, J = 1.3, 1H), 6.43 (d, J = 3.0,
1H), 6.30 (d, J = 5.2, 1H), 3.83 (s, 3H), 3.81-3.75 (m, 4H),
3.47-3.40 (m, 4H). 421 ##STR00472## [2,4-Difluoro-5-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]-(9-methyl-
9H-purin-6-yl)- methanol C B A MS: 490.3 (M + H.sup.+) 1H NMR (500
MHz, DMSO-d6) ppm = 9.11 (s, 1H), 8.90 (s, 1H), 8.56 (s, 1H), 8.07
(t, J = 8.2, 1H), 7.66 (dd, J = 9.4, 2.9, 1H), 7.56 (dd, J = 9.4,
2.5, 1H), 7.38 (t, J = 10.1, 1H), 7.21 (d, J = 2.4, 1H), 6.61 (d, J
= 4.8, 1H), 6.48 (d, J = 5.6, 1H), 3.85 (s, 3H), 3.82-3.75 (m, 4H),
3.52-3.43 (m, 4H). 422 ##STR00473## [2-Chloro-5-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]-(3-methoxy- pyrazin-2-yl)- methanol B B C
MS: 464.1/466.1 (M + H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm =
9.09 (s, isotopy, rel. peak intensity 1H), 8.19-8.14 (m, 2H), 8.11
(d, J = 2.7, 1H), 7.95 ratio [%] 100:37) (d, J = 9.4, 1H), 7.69
(dd, J = 8.2, 2.3, 1H), 7.60- 7.53 (m, 2H), 7.22 (d, J = 2.6, 1H),
6.38 (d, J = 5.8, 1H), 6.27 (d, J = 5.8, 1H), 4.00 (s, 3H),
3.82-3.75 (m, 4H), 3.49-3.42 (m, 4H). 423 ##STR00474##
[2-Chloro-4-fluoro-5- (7-morpholin-4-yl- quinazolin-4-yl)-
phenyl]-(7-methyl- 7H-purin-6-yl)- methanol C C A MS: 506.2/4508.3
(M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.14 (s, (Cl isotopy,
rel. peak 1H), 8.83 (s, 1H), 8.69 (s, 1H), 8.01 (d, J = 7.8,
intensity ratio [%] 100:40) 1H), 7.71-7.63 (m, 2H), 7.59 (dd, J =
9.4, 2.5, 1H), 7.22 (d, J = 2.4, 1H), 6.87 (d, J = 6.3, 1H), 6.66
(d, J = 6.3, 1H), 4.25 (s, 3H), 3.84-3.73 (m, 4H), 3.52-3.42 (m,
4H). 424 ##STR00475## 1-(3-{[4-Fluoro-3-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]hydroxy- methyl}pyrazin-2-yl)- 3-methyl-
imidazolidin-2-one D D A MS: 516.4 (M + H.sup.+) 1H NMR (500 MHz,
DMSO-d6) ppm = 9.09 (s, 1H), 8.50 (d, J = 2.4, 1H), 8.43 (d, J =
2.4, 1H), 7.69- 7.59 (m, 2H), 7.59-7.49 (m, 2H), 7.35 (t, J = 9.2,
1H), 7.19 (d, J = 1.9, 1H), 6.23 (d, J = 4.4, 1H), 5.95 (d, J =
5.3, 1H), 3.85 (t, J = 7.8, 2H), 3.82-3.73 (m, 4H), 3.52-3.40 (m,
6H), 2.78 (s, 3H). 425 ##STR00476## 1-(3-{[4-Fluoro-3-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]hydroxy-
methyl}pyrazin-2-yl)- pyrrolidin-2-one D D A MS: 501.4 (M +
H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.09 (s, 1H), 8.61 (d, J =
2.4, 1H), 8.52 (d, J = 2.4, 1H), 7.65- 7.56 (m, 2H), 7.56-7.49 (m,
2H), 7.36 (t, J = 9.5, 1H), 7.19 (s, 1H), 6.02 (s, 2H), 3.89-3.82
(m, 1H), 3.81-3.74 (m, 4H), 3.74-3.64 (m, 1H), 3.50-3.39 (m, 4H),
2.57-2.41 (m, 2H), 2.17- 2.08 (m, 1H), 2.07-1.98 (m, 1H). 426
##STR00477## [2-Chloro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]-(3-methyl- pyrazin-2-yl)- methanol (Ena 2) C B A MS:
448.1/450.1 (M + H.sup.+) (Cl see racemate isotopy, rel. peak
intensity ratio [%] 100:36); R.sub.t 5.95 min (SFC, Chiralpak AD-H,
CO.sub.2/40% by vol. of methanol, 0.5% by vol. of diethylamine) 427
##STR00478## [2-Chloro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]-(3-methyl- pyrazin-2-yl)- methanol (Ena 1) C B B MS:
448.1/450.2 (M + H.sup.+) (Cl see racemate isotopy, rel. peak
intensity ratio [%] 100:31); R.sub.t 3.91 min (SFC, Chiralpak AD-H,
CO.sub.2/40% by vol. of methanol, 0.5% by vol. of diethylamine) 428
##STR00479## [2-Chloro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]-(3-methyl- pyrazin-2-yl)- methanol C A C MS: 448.2/450.2 (M
+ H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm = 9.10 (s, isotopy,
rel. peak intensity 1H), 8.43 (d, J = 2.5, 1H), 8.36 (d, J = 2.5,
1H), 8.18 ratio [%] 100:36) (d, J = 2.2, 1H), 7.97 (d, J = 9.4,
1H), 7.71 (dd, J = 8.2, 2.3, 1H), 7.61-7.54 (m, 2H), 7.22 (d, J =
2.6, 1H), 6.41 (d, J = 5.8, 1H), 6.30 (d, J = 5.8, 1H), 3.81-3.75
(m, 4H), 3.49-3.42 (m, 4H), 2.76 (s, 3H). 429 ##STR00480##
[2-Chloro-4-fluoro-5- (7-morpholin-4-yl- quinazolin-4-yl)-
phenyl]thieno[2,3-d}- pyrimidin-4-yl- methanol A A D MS:
508.1/510.1 (M + H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm = 9.07
(s, isotopy, rel. peak intensity 1H), 9.05 (s, 1H), 8.46 (d, J =
5.6, 1H), 7.75 (d, ratio [%] 100:40) J = 7.6, 1H), 7.72 (d, J =
9.6, 1H), 7.61 (d, J = 5.6, 1H), 7.55-7.49 (m, 2H), 7.20 (d, J =
5.0, 1H), 7.19- 7.17 (m, 1H), 6.42 (d, J = 5.1, 1H), 3.80-3.75 (m,
4H), 3.46-3.42 (m, 4H). 430 ##STR00481## [2-Chloro-5-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]thieno[2,3-d}-
pyrimidin-4-yl- methanol B A A MS: 490.2/492.1 (M + H.sup.+) (Cl 1H
NMR (500 MHz, DMSO-d6) ppm = 9.06 (s, isotopy, rel. peak intensity
1H), 9.04 (s, 1H), 8.47 (d, J = 5.6, 1H), 7.89 (d, ratio [%]
100:40) J = 2.1, 1H), 7.76 (d, J = 9.4, 1H), 7.73 (dd, J = 8.2,
2.2, 1H), 7.69 (d, J = 8.3, 1H), 7.62 (d, J = 5.5, 1H), 7.47 (dd, J
= 9.5, 2.6, 1H), 7.20-7.16 (m, 2H), 6.47 (d, J = 4.9, 1H),
3.80-3.75 (m, 4H), 3.46- 3.41 (m, 4H). 431 ##STR00482##
[2,4-Difluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]-(7-methyl- 7H-purin-6-yl)- methanol C B A MS: 490.2 (M +
H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.12 (s, 1H), 8.85 (s,
1H), 8.67 (s, 1H), 7.91 (t, J = 8.1, 1H), 7.64 (dd, J = 9.4, 3.2,
1H), 7.58 (dd, J = 9.4, 2.5, 1H), 7.46 (t, J = 10.1, 1H), 7.21 (d,
J = 2.5, 1H), 6.82 (d, J = 6.5, 1H), 6.65 (d, J = 6.5, 1H), 4.19
(s, 3H), 3.81-3.76 (m, 4H), 3.49-3.44 (m, 4H). 432 ##STR00483##
[2-Chloro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]furo[3,2-d}- pyrimidin-4-yl- methanol C B C MS: 474.1/476.1
(M + H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm = 9.10 (s, isotopy,
rel. peak intensity 1H), 9.02 (s, 1H), 8.59 (d, J = 2.3, 1H), 8.30
(d, ratio [%] 100:34) J = 2.2, 1H), 7.96 (d, J = 9.4, 1H), 7.74
(dd, J = 8.2, 2.3, 1H), 7.62 (d, J = 8.2, 1H), 7.59 (dd, J = 9.5,
2.6, 1H), 7.28 (d, J = 2.3, 1H), 7.23 (d, J = 2.6, 1H), 6.79 (d, J
= 5.2, 1H), 6.54 (d, J = 5.2, 1H), 3.83-3.75 (m, 4H), 3.50-3.42 (m,
4H). 433 ##STR00484## [4-Fluoro-3-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]-(7-methyl- 7H-purin-6-yl)- methanol C B A
MS: 472.2 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.08 (s,
1H), 8.90 (s, 1H), 8.60 (s, 1H), 7.68-7.60 (m, 2H), 7.56 (dd, J =
9.4, 2.8, 1H), 7.52 (dd, J = 9.4, 2.4, 1H), 7.44-7.38 (m, 1H), 7.19
(d, J = 2.3, 1H), 6.84 (d, J = 5.5, 1H), 6.37 (d, J = 5.4, 1H),
4.04 (s, 3H), 3.81-3.75 (m, 4H), 3.47-3.41 (m, 4H). 434
##STR00485## [4-Fluoro-3-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]furo[2,3-d}- pyrimidin-4-yl- methanol A A A MS: 458.2 (M +
H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.10 (s, 1H), 8.89 (s,
1H), 8.18 (d, J = 2.5, 1H), 7.77-7.72 (m, 2H), 7.54-7.47 (m, 2H),
7.40 (t, J = 9.5, 1H), 7.36 (d, J = 2.5, 1H), 7.20 (d, J = 2.2,
1H), 6.71 (d, J = 4.2, 1H), 6.13 (d, J = 4.2, 1H), 3.81-3.76 (m,
4H), 3.47-3.42 (m, 4H). 435 ##STR00486## 6-{[2-Chloro-4-fluoro-
5-(7-morpholin-4-yl- quinazolin-4-yl)- phenyl]hydroxy-
methyl}-1-methyl-1H- pyridin-2-one B A A MS: 481.2/483.2 (M +
H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm = 9.09 (s, isotopy, rel.
peak intensity 1H), 7.63 (t, J = 8.1, 1H), 7.59-7.51 (m, 3H), 7.38
ratio [%] 100:38) (dd, J = 9.1, 7.0, 1H), 7.20 (d, J = 2.3, 1H),
6.60 (d, J = 5.9, 1H), 6.39-6.35 (m, 1H), 6.20-6.16 (m, 1H), 6.09
(d, J = 5.9, 1H), 3.81-3.75 (m, 4H), 3.49-3.40 (m, 7H). 436
##STR00487## 6-{[2,4-Difluoro-5-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]hydroxy- methyl}-1-methyl-1H-
pyridin-2-one B B A MS: 465.3 (M + H.sup.+) 1H NMR (500 MHz,
DMSO-d6) ppm = 9.09 (s, 1H), 7.63 (t, J = 8.1, 1H), 7.59-7.51 (m,
3H), 7.38 (dd, J = 9.1, 7.0, 1H), 7.20 (d, J = 2.3, 1H), 6.60 (d, J
= 5.9, 1H), 6.39-6.35 (m, 1H), 6.20-6.16 (m, 1H), 6.09 (d, J = 5.9,
1H), 3.81-3.75 (m, 4H), 3.49-3.40 (m, 7H). 437 ##STR00488##
[4-Fluoro-3-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]thieno[2,3-d}- pyrimidin-4-yl- methanol A A C MS: 474.1 (M +
H.sup.+) 1H NMR (400 MHz, DMSO-d6) ppm = 9.09 (s, 1H), 9.08 (s,
1H), 8.47 (d, J = 5.6, 1H), 7.78-7.73 (m, 2H), 7.61 (d, J = 5.6,
1H), 7.54-7.46 (m, 2H), 7.43-7.36 (m, 1H), 7.21-7.18 (m, 1H), 7.13
(d, J = 3.9, 1H), 6.12 (d, J = 3.9, 1H), 3.82-3.73 (m, 4H),
3.48-3.40 (m, 4H). 438 ##STR00489## [4-Fluoro-3-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]thieno[3,2-d}- pyrimidin-4-yl- methanol A
A C MS: 474.2 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.09
(s, 1H), 9.07 (s, 1H), 8.46 (s, 1H), 8.45 (s, 1H), 7.78- 7.73 (m,
2H), 7.60 (d, J = 5.5, 1H), 7.52-7.46 (m, 2H), 7.41-7.36 (m, 1H),
7.20-7.18 (m, 1H), 7.11 (d, J = 3.9, 1H), 6.12 (d, J = 3.9, 1H),
3.80- 3.75 (m, 4H), 3.46-3.41 (m, 4H). 439 ##STR00490##
[2,4-Difluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]thieno[3,2-d}- pyrimidin-4-yl- methanol A A C MS: 492.2 (M +
H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.07 (s, 1H), 9.05 (s,
1H), 8.47 (d, J = 5.6, 1H), 7.76 (t, J = 8.0, 1H), 7.61 (d, J =
5.6, 1H), 7.54-7.46 (m, 3H), 7.21-7.16 (m, 2H), 6.32 (d, J = 4.8,
1H), 3.80-3.74 (m, 4H), 3.46-3.41 (m, 4H). 440 ##STR00491##
[2-Chloro-4-fluoro-5- (7-morpholin-4-yl- quinazolin-4-yl)-
phenyl]furo[3,2-d}- pyrimidin-4-yl- methanol (Ena 2) A A B MS:
492.1/494.1 (M + H.sup.+) (Cl see racemate isotopy, rel. peak
intensity ratio [%] 100:38); R.sub.t 8.33 min (SFC, Chiralpak AD-H,
CO.sub.2/40% by vol. of methanol, 0.5% by vol. of diethylamine) 441
##STR00492## [2-Chloro-4-fluoro-5- (7-morpholin-4-yl-
quinazolin-4-yl)- phenyl]furo[3,2-d}- pyrimidin-4-yl- methanol (Ena
1) A A C MS: 492.1/494.1 (M + H.sup.+) (Cl see racemate isotopy,
rel. peak intensity ratio [%] 100:38); R.sub.t 3.83 min (SFC,
Chiralpak AD-H, CO.sub.2/40% by vol. of methanol, 0.5% by vol. of
diethylamine) 442 ##STR00493## [4-Fluoro-3-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]furo[3,2-d}- pyrimidin-4-yl- methanol (Ena
2) A A A MS: 458.2 (M + H.sup.+); R.sub.t see racemate 7.52 min
(SFC, Chiralpak AD-H, CO.sub.2/40% by vol. of 2-propanol, 0.5% by
vol. of diethylamine) 443 ##STR00494## [4-fluoro-3-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]furo[3,2-d}-
pyrimidin-4-yl- methanol (Ena 1) B B A* MS: 458.1 (M + H.sup.+);
R.sub.t see racemate 3.43 min (SFC, Chiralpak AD-H, CO.sub.2/40% by
vol. of 2-propanol, 0.5% by vol. of diethylamine) 444 ##STR00495##
[2,4-Difluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]furo[3,2-d}- pyrimidin-4-yl- methanol (Ena 2) A B A MS:
476.2 (M + H.sup.+); R.sub.t see racemate 9.29 min (SFC, Chiralpak
AD-H, CO.sub.2/30% by vol. of methanol, 0.5% by vol. of
diethylamine) 445 ##STR00496## [2,4-Difluoro-5-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]furo[3,2-d}- pyrimidin-4-yl- methanol (Ena
1) B A A MS: 476.1 (M + H.sup.+); R.sub.t see racemate 5.74 min
(SFC, Chiralpak AD-H, CO.sub.2/30% by vol. of methanol, 0.5% by
vol. of diethylamine) 446 ##STR00497## [2,4-Difluoro-5-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]furo[3,2-d}-
pyrimidin-4-yl- methanol A B A MS: 476.2 (M + H.sup.+) 1H NMR (500
MHz, DMSO-d6) ppm = 9.12 (s, 1H), 9.00 (s, 1H), 8.57 (d, J = 2.3,
1H), 8.00 (t, J = 8.1, 1H), 7.59 (dd, J = 9.4, 2.8, 1H), 7.56 (dd,
J = 9.4, 2.4, 1H), 7.45 (t, J = 10.1, 1H), 7.27 (d, J = 2.3, 1H),
7.21 (d, J = 2.3, 1H), 6.75 (d, J = 5.4, 1H), 6.43 (d, J = 5.3,
1H), 3.81-3.76 (m, 4H), 3.49-3.42 (m, 4H). 447 ##STR00498##
[2-Chloro-4-fluoro-5- (7-morpholin-4-yl- quinazolin-4-yl)-
phenyl]-(5-methoxy- pyrimidin-4-yl)- methanol A B C MS: 482.2/484.1
(M + H.sup.+) (Cl 1H NMR (400 MHz, DMSO-d6) ppm = 9.14 (s, isotopy,
rel. peak intensity 1H), 8.74 (s, 1H), 8.65 (s, 1H), 7.97 (d, J =
7.9, ratio [%] 100:40) 1H), 7.69-7.52 (m, 3H), 7.23 (d, J = 2.4,
1H), 6.43-6.32 (m, 2H), 4.01 (s, 3H), 3.80 (dd, J = 5.9, 3.9, 4H),
3.47 (t, J = 4.9, 4H). 448 ##STR00499## [2,4-Difluoro-5-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]-(5-methoxy-
pyrimidin-4-yl)- methanol A B C MS: 466.2 (M + H.sup.+) 1H NMR (400
MHz, DMSO-d6) ppm = 9.11 (s, 1H), 8.77 (s, 1H), 8.62 (s, 1H), 7.86
(t, J = 8.2, 1H), 7.66-7.50 (m, 2H), 7.41 (t, J = 10.1, 1H), 7.21
(d, J = 2.1, 1H), 6.32 (d, J = 6.2, 1H), 6.25 (d, J = 6.3, 1H),
3.97 (s, 3H), 3.78 (t, J = 4.9, 4H), 3.45 (t, J = 4.9, 4H). 449
##STR00500## (3-Difluoromethoxy- pyrazin-2-yl)-[2,4- difluoro-5-(7-
morpholin-4-yl- qurnazolin-4-yl)- phenyl]methanol (Ena 2) A B A MS:
502.2 (M + H.sup.+); R.sub.t see racemate 3.40 min (SFC, Chiralpak
AD-H, CO.sub.2/40% by vol. of methanol, 0.5% by vol. of
diethylamine) 450 ##STR00501## (3-Difluoromethoxy-
pyrazin-2-yl)-[2,4- difluoro-5-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]methanol C C B MS: 502.2 (M + H.sup.+);
R.sub.t see racemate 2.00 min (SFC, Chiralpak AD-H, CO.sub.2/40% by
vol. of methanol, 0.5% by vol. of diethylamine) 451 ##STR00502##
(3-Difluoromethoxy- pyrazin-2-yl)-[2,4- difluoro-5-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]methanol B B B MS: 502.2
(M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.12 (s, 1H), 8.49
(d, J = 2.6, 1H), 8.32 (d, J = 2.6, 1H), 7.91 (t, J = 8.2, 1H),
7.77 (t, J = 71.7, 1H), 7.61-7.51 (m, 2H), 7.43 (t, J = 10.1, 1H),
7.21 (d, J = 2.4, 1H), 6.48 (d, J = 5.9, 1H), 6.29 (d, J = 4.7,
1H), 3.81- 3.75 (m, 4H), 3.48-3.42 (m, 4H). 452 ##STR00503##
[2-Chloro-4-fluoro-5- (7-morpholin-4-yl- quinazolin-4-yl)-
phenyl]furo[3,2-d}- pyrimidin-4-yl- methanol A A C MS: 492.1/494.1
(M + H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm = 9.15 (s, isotopy,
rel. peak intensity 1H), 9.01 (s, 1H), 8.59 (d, J = 2.3, 1H), 8.11
(d, ratio [%] 100:41) J = 7.7, 1H), 7.67 (d, J = 9.4, 1H), 7.64
(dd, J = 9.4, 2.9, 1H), 7.59 (dd, J = 9.4, 2.5, 1H), 7.29 (d, J =
2.3, 1H), 7.24 (d, J = 2.4, 1H), 6.85 (d, J = 5.4, 1H), 6.50 (d, J
= 5.3, 1H), 3.83-3.77 (m, 4H), 3.51-3.44 (m, 4H). 453 ##STR00504##
[2,4-Difluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]-(3-methoxy- pyrazin-2-yl)- methanol (Ena 1) B A C MS: 466.1
(M + H.sup.+); R.sub.t see racemate 2.76 min (SFC, Chiralpak AD-H,
CO.sub.2/40% by vol. of methanol, 0.5% by vol. of diethylamine) 454
##STR00505## [2,4-Difluoro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]-(3-methoxy- pyrazin-2-yl)- methanol (Ena 2) A A A MS: 466.2
(M + H.sup.+); R.sub.t see racemate 4.60 min (SFC, Chiralpak AD-H,
CO.sub.2/40% by vol. of methanol, 0.5% by vol. of diethylamine) 455
##STR00506## (R)-[2-Chloro-4- fluoro-5-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]-(3-methoxy- pyrazin-2-yl)- methanol A A B
MS: 482.1/484.1 (M + H.sup.+) (Cl see racemate isotopy, rel. peak
intensity ratio [%] 100:36); R.sub.t 5.48 min (SFC, Chiralpak AD-H,
CO.sub.2/40% by vol. of methanol, 0.5% by vol. of diethylamine) 456
##STR00507## (S)-[2-Chloro-4- fluoro-5-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]-(3-methoxy- pyrazin-2-yl)- methanol A A C
MS: 482.1/484.1 (M + H.sup.+) (Cl see racemate isotopy, rel. peak
intensity ratio [%] 100:35); R.sub.t 2.58 min (SFC, Chiralpak AD-H,
CO.sub.2/40% by vol. of methanol, 0.5% by vol. of diethylamine) 457
##STR00508## [2-Chloro-4-fluoro-5- (7-morpholin-4-yl-
quinazolin-4-yl)- phenyl]-(3-methyl- pyrazin-2-yl)- methanol B A A
MS: 466.1/468.1 (M + H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm =
9.13 (s, isotopy, rel. peak intensity 1H), 8.43 (d, J = 2.5, 1H),
8.36 (d, J = 2.5, 1H), 7.99 ratio [%] 100:36) (d, J = 7.8, 1H),
7.67-7.60 (m, 2H), 7.57 (dd, J = 9.4, 2.5, 1H), 7.22 (d, J = 2.4,
1H), 6.44 (d, J = 5.9, 1H), 6.25 (d, J = 5.6, 1H), 3.86-3.72 (m,
4H), 3.52-3.42 (m, 4H), 2.74 (s, 3H). 458 ##STR00509##
[2-Chloro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]-(6-methoxy- pyridazin-3-yl)- methanol (Ena 1) A A C MS:
464.1/466.1 (M + H.sup.+) (Cl 1H NMR (400 MHz, DMSO-d6) ppm = 9.08
(s, isotopy, rel. peak intensity 1H), 8.07 (d, J = 2.2, 1H), 7.89
(d, J = 9.5, 1H), 7.73- ratio [%] 100:36); R.sub.t 7.67 (m, 2H),
7.63 (d, J = 8.2, 1H), 7.54 (dd, 11.22 min (SFC, Chiralcel J = 9.5,
2.6, 1H), 7.24-7.19 (m, 2H), 6.59 (d, OJ-H, CO.sub.2/15% by vol. of
J = 4.8, 1H), 6.28 (d, J = 4.8, 1H), 4.00 (s, 3H), 2-propanol, 0.5%
by vol. of 3.82-3.75 (m, 4H), 3.48-3.41 (m, 4H). diethylamine) 459
##STR00510## [2-Chloro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]-(6-methoxy- pyridazin-3-yl)- methanol (Ena 2) B B A* MS:
464.1/466.1 (M + H.sup.+) (Cl see racemate isotopy, rel. peak
intensity ratio [%] 100:36); R.sub.t 14.88 min (SFC, Chiralcel
OJ-H, CO.sub.2/15% by vol. of 2-propanol, 0.5% by vol. of
diethylamine) 460 ##STR00511## [2-Chloro-5-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]-(6-methoxy- pyridazin-3-yl)- methanol B A
A* MS: 464.1/466.1 (M + H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm
= 9.09 (s, isotopy, rel. peak intensity 1H), 8.08 (d, J = 2.2, 1H),
7.89 (d, J = 9.5, 1H), ratio [%] 100:36) 7.73-7.67 (m, 2H), 7.63
(d, J = 8.2, 1H), 7.54 (dd, J = 9.4, 2.7, 1H), 7.23-7.19 (m, 2H),
6.59 (d, J = 4.9, 1H), 6.28 (d, J = 4.8, 1H), 4.00 (s, 3H),
3.81-3.75 (m, 4H), 3.48-3.42 (m, 4H). 461 ##STR00512##
[4-Fluoro-3-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]-(3-methyl- 3H-imidazo[4,5-c]- pyridin-4-yl)methanol A A A*
MS: 471.2 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.08 (s,
1H), 8.33 (s, 1H), 8.25 (d, J = 5.5, 1H), 7.62 (d, J = 5.5, 1H),
7.61-7.50 (m, 4H), 7.42-7.37 (m, 1H), 7.19 (d, J = 2.3, 1H), 6.61
(d, J = 5.5, 1H), 6.43 (d, J = 5.4, 1H), 4.01 (s, 3H), 3.80-3.74
(m, 4H), 3.46-3.41 (m, 4H). 462 ##STR00513## [4-Fluoro-3-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]-(3-iodo- pyrazin-2-yl)-
methanol A A B MS: 544.1 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6)
ppm = 9.09 (s, 1H), 8.62 (d, J = 2.4, 1H), 8.37 (d, J = 2.4, 1H),
7.69- 7.61 (m, 2H), 7.58-7.49 (m, 2H), 7.44-7.36 (m, 1H), 7.22-7.17
(m, 1H), 6.33 (d, J = 5.7, 1H), 6.17 (d, J = 5.7, 1H), 3.81-3.75
(m, 4H), 3.47-3.41 (m, 4H). 463 ##STR00514## (3-Ethoxy-pyridin-2-
yl)-[4-fluoro-3-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]methanol B A B MS: 461.2 (M + H.sup.+) 1H NMR (500 MHz,
DMSO-d6) ppm = 9.09 (s, 1H), 8.14 (dd, J = 4.7, 1.2, 1H), 7.63-7.55
(m, 2H), 7.55-7.47 (m, 2H), 7.41 (dd, J = 8.3, 1.3, 1H), 7.38-7.31
(m, 1H), 7.29 (dd, J = 8.3, 4.7, 1H), 7.21-7.17 (m, 1H), 6.07 (d, J
= 6.3, 1H), 5.79 (d, J = 6.6, 1H), 4.06 (q, J = 7.0, 2H), 3.81-3.75
(m, 4H), 3.47-3.41 (m, 4H), 1.28 (t, J = 6.9, 3H). 464 ##STR00515##
(3-Difluoromethoxy- pyrazin-2-yl)-[4- fluoro-3-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]methanol B B B MS: 484.2 (M + H.sup.+) 1H
NMR (500 MHz, DMSO-d6) ppm = 9.09 (s, 1H), 8.51 (d, J = 2.6, 1H),
8.28 (d, J = 2.6, 1H), 7.86- 7.55 (m, 3H), 7.54-7.49 (m, 2H),
7.43-7.36 (m, 1H), 7.22-7.17 (m, 1H), 6.30 (d, J = 5.6, 1H), 6.10
(d, J = 4.9, 1H), 3.83-3.73 (m, 4H), 3.48-3.40 (m, 4H). 465
##STR00516## (3-Chloro-pyridin-2- yl)-[4-fluoro-3-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]methanol (Ena 2) A A B MS:
451.1/453.1 (M + H.sup.+) (Cl see racemate isotopy, rel. peak
intensity ratio [%] 100:35); R.sub.t 6.63 min (SFC, Chiralpak AD-H,
CO.sub.2/40% by vol. of 2-propanol, 0.5% by vol. of diethylamine)
466 ##STR00517## (3-Chloro-pyridin-2- yl)-[4-fluoro-3-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]methanol (Ena 1) C B B MS:
451.1/453.1 (M + H.sup.+) (Cl see racemate isotopy, rel. peak
intensity ratio [%] 100:35); R.sub.t 3.98 min (SFC, Chiralpak AD-H,
CO.sub.2/40% by vol. of 2-propanol, 0.5% by vol. of diethylamine)
467 ##STR00518## [2,4-Difluoro-5-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]-(3-methoxy- pyrazin-2-yl)- methanol B A A
MS: 466.2 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.11 (s,
1H), 8.16 (dd, J = 16.4, 2.7, 2H), 7.87 (t, J = 8.2, 1H), 7.59 (dd,
J = 9.4, 3.0, 1H), 7.56 (dd, J = 9.4, 2.4, 1H), 7.40 (t, J = 10.1,
1H), 7.21 (d, J = 2.5, 1H), 6.28 (s, 1H), 6.23 (s, 1H), 3.96 (s,
3H), 3.81- 3.75 (m, 4H), 3.49-3.43 (m, 4H). 468 ##STR00519##
[2-Chloro-4-fluoro-5- (7-morpholin-4-yl- quinazolin-4-yl)-
phenyl]-(3-methoxy- pyrazin-2-yl)- methanol A A B MS: 482.1/484.1
(M + H.sup.+) (Cl 1H NMR (500 MHz, DMSO-d6) ppm = 9.13 (s, isotopy,
rel. peak intensity 1H), 8.17 (d, J = 2.7, 1H), 8.11 (d, J = 2.7,
1H), 7.97 ratio [%] 100:37) (d, J = 7.8, 1H), 7.65-7.58 (m, 2H),
7.56 (dd, J = 9.4, 2.5, 1H), 7.22 (d, J = 2.4, 1H), 6.31 (s, 2H),
4.00 (s, 3H), 3.81-3.76 (m, 4H), 3.48-3.43 (m, 4H). 469
##STR00520## [2-Chloro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]pyridazin-3-yl- methanol (Ena 2) D D C MS: 434.1/436.1 (M +
H.sup.+) (Cl see racemate isotopy, rel. peak intensity ratio [%]
100:38); R.sub.t 4.70 min (SFC, Chiralcel OJ-H, CO.sub.2/20% by
vol. of methanol, 0.5% by vol. of diethylamine) 470 ##STR00521##
[2-Chloro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]pyridazin-3-yl- methanol (Ena 1) B A A MS: 434.1/436.1 (M +
H.sup.+) (Cl see racemate isotopy, rel. peak intensity ratio [%]
100:38); R.sub.t 2.52 min (SFC, Chiralcel OJ-H, CO.sub.2/20% by
vol. of methanol, 0.5% by vol. of diethylamine) 471 ##STR00522##
[4-Fluoro-3-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]furo[3,2-d}- pyrimidin-4-yl- methanol A A A* MS: 458.1 (M +
H.sup.+) 1H NMR (500 MHz, DMSO-d6) ppm = 9.10 (s, 1H), 9.01 (s,
1H), 8.55 (d, J = 2.3, 1H), 7.79-7.73 (m, 2H), 7.54-7.49 (m, 2H),
7.44-7.38 (m, 1H), 7.24 (d, J = 2.2, 1H), 7.22-7.18 (m, 1H), 6.62
(d, J = 4.6, 1H), 6.20 (d, J = 4.6, 1H), 3.80-3.75 (m, 4H),
3.47-3.42 (m, 4H). 472 ##STR00523## [4-Fluoro-3-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]-(3-methyl- pyridin-2-yl)methanol B A A
MS: 431.2 (M + H.sup.+) 1H NMR (400 MHz, DMSO-d6) ppm = 9.08 (s,
1H), 8.43-8.39 (m, 1H), 7.63-7.57 (m, 1H), 7.56-7.49 (m, 4H),
7.39-7.32 (m, 1H), 7.28- 7.23 (m, 1H), 7.21-7.17 (m, 1H), 6.09 (s,
1H), 6.01 (s, 1H), 3.82-3.73 (m, 4H), 3.48-3.40 (m, 4H), 2.28 (s,
3H). 473 ##STR00524## (3-bromo-5-methoxy- pyridin-2-yl)-[4-
fluoro-3-(7- morpholin-4-yl- quinazolin-4-yl)- phenyl]methanol B A
B MS: 525.1/527.1 (M + H.sup.+) 1H NMR (400 MHz, DMSO-d6) ppm =
9.09 (s, (Br isotopy, rel. peak 1H), 8.31 (d, J = 2.6, 1H), 7.70
(d, J = 2.6, 1H), 7.62- intensity ratio [%] 100:97) 7.56 (m, 2H),
7.54-7.50 (m, 2H), 7.39-7.33 (m, 1H), 7.21-7.18 (m, 1H), 6.16 (d, J
= 6.1, 1H), 6.01 (d, J = 6.1, 1H), 3.84 (s, 3H), 3.80-3.75 (m, 4H),
3.46-3.41 (m, 4H). 474 ##STR00525## [2,4-Difluoro-5-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]imidazo-
[2,1-b]thiazol-6-yl- methanol D D C MS: 480.1 (M + H.sup.+) 1H NMR
(400 MHz, DMSO-d6) ppm = 9.09 (s, 1H), 7.85 (d, J = 4.5, 1H),
7.71-7.68 (m, 1H), 7.62- 7.55 (m, 1H), 7.54-7.51 (m, 2H), 7.26 (t,
J = 9.1, 1H), 7.21-7.17 (m, 2H), 6.18-6.13 (m, 2H), 3.80-3.75 (m,
4H), 3.47-3.41 (m, 4H). 475 ##STR00526## [4-Fluoro-3-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]-(3-trifluoro-
methoxypyridin-2-yl)- methanol A A B MS: 501.2 (M + H.sup.+) 1H NMR
(400 MHz, DMSO-d6) ppm = 9.11 (s, 1H), 8.61 (dd, J = 4.6, 1.3, 1H),
7.87 (dp, J = 8.4, 1.6, 1H), 7.69-7.57 (m, 2H), 7.57-7.46 (m, 3H),
7.40 (dd, J = 9.9, 8.4, 1H), 7.21 (d, J = 1.9, 1H), 6.26 (d, J =
5.9, 1H), 6.13 (d, J = 5.9, 1H), 3.89-3.65 (m, 4H), 3.54-3.38 (m,
4H). 476 ##STR00527## [4-Fluoro-3-(7- morpholin-4-yl-
quinazolin-4-yl)- phenyl]-(3-trifluoro- methylpyrazin-2-yl)-
methanol B A A MS: 486.2 (M + H.sup.+) 1H NMR (500 MHz, DMSO-d6)
ppm = 9.10 (s, 1H), 9.00 (d, J = 2.3, 1H), 8.77 (d, J = 2.3, 1H),
7.66 (dd, J = 6.9, 2.3, 1H), 7.63-7.59 (m, 1H), 7.56- 7.50 (m, 2H),
7.43-7.37 (m, 1H), 7.21-7.18 (m, 1H), 6.54 (d, J = 5.7, 1H), 6.21
(d, J = 4.3, 1H), 3.81-3.74 (m, 4H), 3.48-3.40 (m, 4H). 478
##STR00528## (3-bromo-pyridin-2- yl)-[4-fluoro-3-(7-
morpholin-4-yl- quinazolin-4-yl)- phenyl]methanol A A D MS:
495.1/497.1 (M + H.sup.+) 1H NMR (400 MHz, DMSO-d6) ppm = 9.09 (s,
(Br isotopy, rel. peak 1H), 8.60 (dd, J = 4.6, 1.4, 1H), 8.08 (dd,
J = 8.1, intensity ratio [%] 100:96) 1.5, 1H), 7.65-7.59 (m, 2H),
7.54-7.50 (m, 2H), 7.41-7.34 (m, 1H), 7.29 (dd, J = 8.1, 4.6, 1H),
7.21-7.18 (m, 1H), 6.20 (d, J = 6.3, 1H), 6.12 (d, J = 6.3, 1H),
3.82-3.74 (m, 4H), 3.49-3.40 (m, 4H). 479 ##STR00529##
[2-Chloro-5-(7- morpholin-4-yl- quinazolin-4-yl)-
phenyl]pyridazin-3-yl- methanol B A B MS: 434.1/436.1 (M + H.sup.+)
(Cl 1H NMR (500 MHz, DMSO-d6) ppm = 9.15 (dd, isotopy, rel. peak
intensity J = 4.9, 1.7, 1H), 9.08 (s, 1H), 8.04 (d, J = 2.2, 1H),
ratio [%] 100:37) 7.87 (d, J = 9.4, 1H), 7.80 (dd, J = 8.5, 1.7,
1H), 7.74- 7.69 (m, 2H), 7.64 (d, J = 8.2, 1H), 7.52 (dd,
J = 9.5, 2.6, 1H), 7.21 (d, J = 2.5, 1H), 6.69 (d, J = 4.9, 1H),
6.38 (d, J = 4.9, 1H), 3.83-3.72 (m, 4H), 3.49-3.40 (m, 4H). (*) In
the second column: enantiomer isolated by chromatography which
represents either the pure R or S configuration of the molecule (*)
In the final column: potassium channel activity measured using hERG
binding assay instead of hERG patch clamp assay Example numbers
273-277, 281-283, 287 and 477 have intentionally been omitted.
* * * * *