U.S. patent application number 14/491558 was filed with the patent office on 2015-04-16 for substituted annellated pyrimidines and use thereof.
The applicant listed for this patent is Bayer Intellectual Property GmbH. Invention is credited to Markus FOLLMANN, Nils GRIEBENOW, Walter HUBSCH, Dieter LANG, Niels LINDNER, Gorden REDLICH, Johannes-Peter STASCH, Adrian TERSTEEGEN, Alexandros VAKALOPOULOS, Frank WUNDER.
Application Number | 20150105374 14/491558 |
Document ID | / |
Family ID | 47755368 |
Filed Date | 2015-04-16 |
United States Patent
Application |
20150105374 |
Kind Code |
A1 |
FOLLMANN; Markus ; et
al. |
April 16, 2015 |
Substituted annellated pyrimidines and use thereof
Abstract
The present application relates to novel substituted annellated
pyrimidines, methods for production thereof, use thereof alone or
in combinations for treating and/or preventing diseases and use
thereof for the production of medicinal products for treating
and/or preventing diseases, in particular for treating and/or
preventing cardiovascular diseases.
Inventors: |
FOLLMANN; Markus; (Wulfrath,
DE) ; STASCH; Johannes-Peter; (Solingen, DE) ;
REDLICH; Gorden; (Bochum, DE) ; GRIEBENOW; Nils;
(Dormagen, DE) ; LANG; Dieter; (Velbert, DE)
; WUNDER; Frank; (Wuppertal, DE) ; HUBSCH;
Walter; (Wuppertal, DE) ; LINDNER; Niels;
(Wuppertal, DE) ; VAKALOPOULOS; Alexandros;
(Hilden, DE) ; TERSTEEGEN; Adrian; (Wuppertal,
DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Bayer Intellectual Property GmbH |
Monheim |
|
DE |
|
|
Family ID: |
47755368 |
Appl. No.: |
14/491558 |
Filed: |
September 19, 2014 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
13599975 |
Aug 30, 2012 |
8859569 |
|
|
14491558 |
|
|
|
|
Current U.S.
Class: |
514/210.21 ;
514/228.5; 514/230.5; 514/234.2; 514/252.16; 514/257; 514/259.1;
514/265.1; 544/105; 544/117; 544/230; 544/280; 544/281;
544/58.2 |
Current CPC
Class: |
A61K 31/5383 20130101;
A61K 31/541 20130101; A61K 31/527 20130101; A61K 31/5377 20130101;
C07D 491/20 20130101; A61P 9/00 20180101; A61K 45/06 20130101; A61P
11/00 20180101; C07D 471/04 20130101; C07D 498/08 20130101; A61P
7/02 20180101; A61P 9/04 20180101; A61P 13/12 20180101; A61K 31/519
20130101; A61P 9/10 20180101; A61P 9/12 20180101; A61K 31/5386
20130101; C07D 487/04 20130101; C07D 519/00 20130101 |
Class at
Publication: |
514/210.21 ;
544/280; 514/265.1; 544/117; 514/234.2; 544/281; 514/259.1;
544/105; 514/230.5; 514/252.16; 544/58.2; 514/228.5; 544/230;
514/257 |
International
Class: |
A61K 31/519 20060101
A61K031/519; A61K 45/06 20060101 A61K045/06; A61K 31/527 20060101
A61K031/527; A61K 31/5377 20060101 A61K031/5377; A61K 31/5386
20060101 A61K031/5386; A61K 31/541 20060101 A61K031/541; C07D
519/00 20060101 C07D519/00; C07D 487/04 20060101 C07D487/04 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 2, 2011 |
DE |
102011082041.8 |
Jan 11, 2012 |
DE |
102012200351.7 |
Claims
1. A compound of general formula (I) ##STR00237## in which L stands
for a group
#.sup.1-CR.sup.7AR.sup.7B--(CR.sup.8AR.sup.8B).sub.m-#.sup.2,
wherein #.sup.1 stands for the point of attachment to the carbonyl
group, #.sup.2 stands for the point of attachment to the pyrimidine
ring, m stands for a number 0, 1 or 2, R.sup.7A stands for
hydrogen, fluorine, (C.sub.1-C.sub.4)-alkyl, hydroxyl or amino, in
which (C.sub.1-C.sub.4)-alkyl can be substituted with 1 to 3
substituents selected independently of one another from the group
fluorine, trifluoromethyl, hydroxy, hydroxycarbonyl,
(C.sub.1-C.sub.4)-alkoxycarbonyl and amino, R.sup.7B stands for
hydrogen, fluorine, difluoromethyl, trifluoromethyl,
(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.4)-alkoxycarbonylamino,
cyano, (C.sub.3-C.sub.7)-cycloalkyl, difluoromethoxy,
trifluoromethoxy, phenyl or a group of formula -M-R.sup.13, in
which (C.sub.1-C.sub.6)-alkyl can be substituted with 1 to 3
substituents selected independently of one another from the group
fluorine, cyano, trifluoromethyl, (C.sub.3-C.sub.7)-cycloalkyl,
hydroxy, difluoromethoxy, trifluoromethoxy,
(C.sub.1-C.sub.4)-alkoxy, hydroxycarbonyl,
(C.sub.1-C.sub.4)-alkoxycarbonyl and amino, and in which M stands
for a bond or (C.sub.1-C.sub.4)-alkanediyl, R.sup.13 stands for
--(C.dbd.O).sub.r--OR.sup.14, --(C.dbd.O).sub.r--NR.sup.14R.sup.15,
--C(.dbd.S)--NR.sup.14R.sup.15, --NR.sup.14--(C.dbd.O)--R.sup.17,
--NR.sup.14--(C.dbd.O)--NR.sup.15R.sup.16,
--NR.sup.14--SO.sub.2--NR.sup.15R.sup.16,
--NR.sup.14--SO.sub.2--R.sup.17, --S(O).sub.s--R.sup.17,
--SO.sub.2--NR.sup.14R.sup.15, 4- to 7-membered heterocyclyl,
phenyl or 5- or 6-membered heteroaryl, in which r denotes the
number 0 or 1, s denotes the number 0, 1 or 2, R.sup.14, R.sup.15
and R.sup.16 each stand, independently of one another, for
hydrogen, (C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.8)-cycloalkyl, 4-
to 7-membered heterocyclyl, phenyl or 5- or 6-membered heteroaryl,
or R.sup.14 and R.sup.15 form, together with the respective atom(s)
to which they are bound, a 4- to 7-membered heterocycle, in which
for its part the 4- to 7-membered heterocycle can be substituted
with 1 or 2 substituents selected independently of one another from
the group cyano, trifluoromethyl, (C.sub.1-C.sub.6)-alkyl, hydroxy,
oxo, (C.sub.1-C.sub.6)-alkoxy, trifluoromethoxy,
(C.sub.1-C.sub.6)-alkoxycarbonyl, amino,
mono-(C.sub.1-C.sub.6)-alkylamino and
di(C.sub.1-C.sub.6)-alkylamino, or R.sup.15 and R.sup.16 form,
together with the respective atom(s) to which they are bound, a 4-
to 7-membered heterocycle, in which for its part the 4- to
7-membered heterocycle can be substituted with 1 or 2 from the
group cyano, trifluoromethyl, (C.sub.1-C.sub.6)-alkyl, hydroxy,
oxo, (C.sub.1-C.sub.6)-alkoxy, trifluoromethoxy,
(C.sub.1-C.sub.6)-alkoxycarbonyl, amino,
mono-(C.sub.1-C.sub.6)-alkylamino and
di(C.sub.1-C.sub.6)-alkylamino, R.sup.17 stands for
(C.sub.1-C.sub.6)-alkyl or (C.sub.3-C.sub.7)-cycloalkyl, or
R.sup.14 and R.sup.17 form, together with the respective atom(s) to
which they are bound, a 4- to 7-membered heterocycle, in which for
its part the 4- to 7-membered heterocycle can be substituted with 1
or 2 substituents selected independently of one another from the
group cyano, trifluoromethyl, (C.sub.1-C.sub.6)-alkyl, hydroxy,
oxo, (C.sub.1-C.sub.6)-alkoxy, trifluoromethoxy,
(C.sub.1-C.sub.6)-alkoxycarbonyl, amino,
mono-(C.sub.1-C.sub.6)-alkylamino and
di(C.sub.1-C.sub.6)-alkylamino, and in which for their part the 4-
to 7-membered heterocyclyl, phenyl and 5- or 6-membered heteroaryl
can be substituted with 1 to 3 substituents selected independently
of one another from the group halogen, cyano, difluoromethyl,
trifluoromethyl, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl, hydroxy, oxo, thiooxo and
(C.sub.1-C.sub.4)-alkoxy, and in which the aforementioned
(C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.8)-cycloalkyl, (C.sub.3-C.sub.7)-cycloalkyl and 4-
to 7-membered heterocyclyl groups, unless stated otherwise, can in
each case be further substituted independently of one another with
1 to 3 substituents selected independently of one another from the
group fluorine, difluoromethyl, trifluoromethyl,
(C.sub.1-C.sub.4)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl, hydroxy,
difluoromethoxy, trifluoromethoxy, (C.sub.1-C.sub.4)-alkoxy,
hydroxycarbonyl, (C.sub.1-C.sub.4)-alkoxycarbonyl, amino, phenyl,
4- to 7-membered heterocyclyl and 5- or 6-membered heteroaryl, or
R.sup.7A and R.sup.7B together with the carbon atom to which they
are bound, form a (C.sub.2-C.sub.4)-alkenyl group, an oxo group, a
3- to 6-membered carbocycle or a 4- to 7-membered heterocycle, in
which the 3- to 6-membered carbocycle and the 4- to 7-membered
heterocycle can be substituted with 1 or 2 substituents selected
independently of one another from the group fluorine and
(C.sub.1-C.sub.4)-alkyl, R.sup.8A stands for hydrogen, fluorine,
(C.sub.1-C.sub.4)-alkyl or hydroxy, R.sup.8B stands for hydrogen,
fluorine, (C.sub.1-C.sub.4)-alkyl or trifluoromethyl, the ring Q
stands for 8- or 9-membered heteroaryl, R.sup.3 stands for
--OR.sup.4 or --NR.sup.5R.sup.6, wherein R.sup.4 stands for
hydrogen, (C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl, 4-
to 7-membered heterocyclyl, phenyl or 5- or 6-membered heteroaryl,
in which (C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl, 4-
to 7-membered heterocyclyl, phenyl and 5- or 6-membered heteroaryl
can be substituted with 1 to 3 substituents selected independently
of one another from the group fluorine, difluoromethyl,
trifluoromethyl, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.6)-cycloalkyl, difluoromethoxy, trifluoromethoxy,
Oxo, --(C.dbd.O).sub.POR.sup.9,
--C(.dbd.O).sub.p--NR.sup.9R.sup.10,
--NR.sup.9--(C.dbd.O)--R.sup.10, --NR.sup.9--(C.dbd.O)--OR.sup.10,
--NR.sup.9--(C.dbd.O)--NR.sup.10R.sup.11,
--NR.sup.9--SO.sub.2--R.sup.10, --S(O).sub.q--R.sup.12 and
--SO.sub.2--NR.sup.9R.sup.10, in which p denotes the number 0 or 1,
q denotes the number 0, 1 or 2, R.sup.9, R.sup.10 and R.sup.11 each
stand, independently of one another, for hydrogen,
(C.sub.1-C.sub.6)-alkyl or (C.sub.3-C.sub.8)-cycloalkyl, in which
(C.sub.1-C.sub.6)-alkyl for its part can be substituted with 1 or 2
substituents selected independently of one another from the group
fluorine, difluoromethyl, trifluoromethyl, hydroxy,
(C.sub.1-C.sub.6)-alkoxy, difluoromethoxy, trifluoromethoxy,
(C.sub.1-C.sub.6)-alkoxycarbonyl, amino,
mono-(C.sub.1-C.sub.6)-alkylamino, di(C.sub.1-C.sub.6)-alkylamino
and 4- to 7-membered heterocyclyl, or R.sup.9 and R.sup.10 form,
together with the respective atom(s) to which they are bound, a 4-
to 7-membered heterocycle, in which for its part the 4- to
7-membered heterocycle can be substituted with 1 or 2 substituents
selected independently of one another from the group fluorine,
trifluoromethyl, (C.sub.1-C.sub.6)-alkyl, hydroxy, oxo,
(C.sub.1-C.sub.6)-alkoxy, trifluoromethoxy,
(C.sub.1-C.sub.6)-alkoxycarbonyl, amino,
mono-(C.sub.1-C.sub.6)-alkylamino and
di(C.sub.1-C.sub.6)-alkylamino, or R.sup.10 and R.sup.11 form,
together with the respective atom(s) to which they are bound, a 4-
to 7-membered heterocycle, in which for its part the 4- to
7-membered heterocycle can be substituted with 1 or 2 substituents
selected independently of one another from the group fluorine,
trifluoromethyl, (C.sub.1-C.sub.6)-alkyl, hydroxy, oxo,
(C.sub.1-C.sub.6)-alkoxy, trifluoromethoxy,
(C.sub.1-C.sub.6)-alkoxycarbonyl, amino,
mono-(C.sub.1-C.sub.6)-alkylamino and
di(C.sub.1-C.sub.6)-alkylamino, and in which R.sup.12 stands for
(C.sub.1-C.sub.6)-alkyl or (C.sub.3-C.sub.7)-cycloalkyl, and in
which the aforementioned (C.sub.1-C.sub.4)-alkyl,
(C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.8)-cycloalkyl,
(C.sub.3-C.sub.7)-cycloalkyl and 4- to 7-membered heterocyclyl
groups, unless stated otherwise, can in each case be further
substituted independently of one another with 1 to 3 substituents
selected independently of one another from the group fluorine,
difluoromethyl, trifluoromethyl, (C.sub.1-C.sub.4)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl, hydroxy, difluoromethoxy,
trifluoromethoxy, (C.sub.1-C.sub.4)-alkoxy, hydroxycarbonyl,
(C.sub.1-C.sub.4)-alkoxycarbonyl, amino, phenyl, 4- to 7-membered
heterocyclyl and 5- or 6-membered heteroaryl, R.sup.5 stands for
hydrogen or (C.sub.1-C.sub.4)-alkyl, R.sup.6 stands for
(C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl, 4- to
7-membered heterocyclyl, phenyl or 5- or 6-membered heteroaryl, in
which (C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl, 4- to
7-membered heterocyclyl, phenyl and 5- or 6-membered heteroaryl can
be substituted with 1 to 3 substituents selected independently of
one another from the group fluorine, difluoromethyl,
trifluoromethyl, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl, difluoromethoxy, trifluoromethoxy,
oxo, --(C.dbd.O).sub.p--OR.sup.9,
--(C.dbd.O).sub.p--NR.sup.9R.sup.10,
--NR.sup.9--(C.dbd.O)--R.sup.10, --NR.sup.9--(C.dbd.O)--OR.sup.10,
--NR.sup.9--(C.dbd.O)--NR.sup.10R.sup.11,
--NR.sup.9--SO.sub.2--R.sup.10, --S(O).sub.q--R.sup.12,
--SO.sub.2--NR.sup.9R.sup.10, phenyl, 4- to 7-membered heterocyclyl
and 5- or 6-membered heteroaryl, in which p denotes the number 0 or
1, q denotes the number 0, 1 or 2, R.sup.9, R.sup.10 and R.sup.11
each stand, independently of one another, for hydrogen,
(C.sub.1-C.sub.6)-alkyl or (C.sub.3-C.sub.8)-cycloalkyl, in which
(C.sub.1-C.sub.6)-alkyl for its part can be substituted with 1 to 3
substituents selected independently of one another from the group
fluorine, difluoromethyl, trifluoromethyl,
(C.sub.3-C.sub.7)-cycloalkyl, difluoromethoxy, trifluoromethoxy and
(C.sub.1-C.sub.4)-alkoxy, or R.sup.9 and R.sup.10 form, together
with the respective atom(s) to which they are bound, a 4- to
7-membered heterocycle, in which for its part the 4- to 7-membered
heterocycle can be substituted with 1 or 2 substituents selected
independently of one another from the group fluorine, cyano,
trifluoromethyl, (C.sub.1-C.sub.6)-alkyl, hydroxy, oxo,
(C.sub.1-C.sub.6)-alkoxy, trifluoromethoxy,
(C.sub.1-C.sub.6)-alkoxycarbonyl, amino,
mono-(C.sub.1-C.sub.6)-alkylamino and
di(C.sub.1-C.sub.6)-alkylamino, or R.sup.10 and R.sup.11 form,
together with the respective atom(s) to which they are bound, a 4-
to 7-membered heterocycle, in which for its part the 4- to
7-membered heterocycle can be substituted with 1 or 2 substituents
selected independently of one another from the group cyano,
trifluoromethyl, (C.sub.1-C.sub.6)-alkyl, hydroxy, oxo,
(C.sub.1-C.sub.6)-alkoxy, trifluoromethoxy,
(C.sub.1-C.sub.6)-alkoxycarbonyl, amino,
mono-(C.sub.1-C.sub.6)-alkylamino and
di(C.sub.1-C.sub.6)-alkylamino, in which R.sup.12 stands for
(C.sub.1-C.sub.6)-alkyl or (C.sub.3-C.sub.7)-cycloalkyl, and in
which phenyl, 4- to 7-membered heterocyclyl and 5- or 6-membered
heteroaryl for their part can be substituted with 1 to substituents
selected independently of one another from the group halogen,
cyano, difluoromethyl, trifluoromethyl, (C.sub.1-C.sub.4)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl, hydroxy, oxo, difluoromethoxy,
trifluoromethoxy and (C.sub.1-C.sub.4)-alkoxy, or R.sup.5 and
R.sup.6 form, together with the nitrogen atom to which they are
bound, a 4- to 7-membered heterocycle or a 5- or 6-membered
heteroaryl, in which the 4- to 7-membered heterocycle and the 5- or
6-membered heteroaryl can be substituted with 1 to 3 substituents
selected independently of one another from the group fluorine,
cyano, difluoromethyl, trifluoromethyl, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl, hydroxy, oxo,
(C.sub.1-C.sub.6)-alkoxy, difluoromethoxy, trifluoromethoxy,
(C.sub.1-C.sub.6)-alkoxycarbonyl,
(C.sub.1-C.sub.6)-alkylcarbonylamino, amino,
mono-(C.sub.1-C.sub.6)-alkylamino, di(C.sub.1-C.sub.6)-alkylamino
and 4- to 7-membered heterocyclyl, and in which the aforementioned
(C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.8)-cycloalkyl, (C.sub.3-C.sub.7)-cycloalkyl and 4-
to 7-membered heterocyclyl groups, unless stated otherwise, can in
each case be further substituted independently of one another with
1 to 3 substituents selected independently of one another from the
group fluorine, difluoromethyl, trifluoromethyl,
(C.sub.1-C.sub.4)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl, hydroxy,
difluoromethoxy, trifluoromethoxy, (C.sub.1-C.sub.4)-alkoxy,
hydroxycarbonyl, (C.sub.1-C.sub.4)-alkoxycarbonyl, amino, phenyl,
4- to 7-membered heterocyclyl and 5- or 6-membered heteroaryl,
R.sup.1 stands for fluorine, chlorine, cyano, difluoromethyl,
trifluoromethyl, (C.sub.1-C.sub.4)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl or (C.sub.1-C.sub.4)-alkoxy, n stands
for a number 0, 1 or 2, R.sup.2 stands for trifluoromethyl,
(C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.8)-cycloalkyl, phenyl or 5-
or 6-membered heteroaryl, wherein (C.sub.1-C.sub.6)-alkyl is
substituted with a substituent selected from the group
difluoromethyl and trifluoromethyl, wherein (C.sub.1-C.sub.6)-alkyl
can be substituted with 1 to 3 fluorine substituents, wherein
(C.sub.3-C.sub.8)-cycloalkyl can be substituted with 1 or 2
substituents selected independently of one another from the group
fluorine, methyl and methoxy, wherein phenyl is substituted with 1
to 3 fluorine substituents, wherein phenyl can be substituted with
1 or 2 substituents selected independently of one another from the
group methyl and methoxy, and wherein 5- and 6-membered heteroaryl
can be substituted with 1 or 2 substituents selected independently
of one another from the group fluorine, trifluoromethyl and methyl,
or a salt thereof.
2. The compound of claim 1, in which L stands for a group
#.sup.1-CR.sup.7AR.sup.7B-(CR.sup.8AR.sup.8B).sub.m-#.sup.2,
wherein #.sup.1 stands for the point of attachment to the carbonyl
group, #.sup.2 stands for the point of attachment to the pyrimidine
ring, m stands for a number 0 or 1, R.sup.7A stands for hydrogen,
fluorine, methyl, ethyl, hydroxy or amino, R.sup.7B stands for
hydrogen, fluorine, difluoromethyl, trifluoromethyl,
(C.sub.1-C.sub.4)-alkyl, methoxycarbonylamino, cyano, cyclopropyl,
cyclobutyl, cyclopentyl, phenyl or a group of formula -M-R.sup.13,
in which (C.sub.1-C.sub.4)-alkyl can be substituted with 1 to 3
substituents selected independently of one another from the group
fluorine, cyano, trifluoromethyl, cyclopropyl, cyclobutyl,
cyclopentyl, hydroxy, difluoromethoxy, trifluoromethoxy, methoxy,
ethoxy, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl and amino,
and in which M stands for a bond or methylene, R.sup.13 stands for
--(C.dbd.O).sub.r--NR.sup.14R.sup.15,
--C(.dbd.S)--NR.sup.14R.sup.15, oxadiazolonyl, oxadiazolethionyl,
phenyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, oxadiazolyl,
thiadiazolyl, pyridyl, pyrimidinyl or pyrazinyl, in which r denotes
the number 0 or 1, R.sup.14 and R.sup.15 each stand, independently
of one another, for hydrogen, methyl, ethyl, isopropyl,
cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl,
tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl,
piperazinyl, morpholinyl, phenyl, pyrazolyl or pyridyl, in which
methyl, ethyl and iso-propyl can be further substituted with 1 or 2
substituents selected independently of one another from the group
fluorine, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl,
cyclopentyl, hydroxy, difluoromethoxy, trifluoromethoxy, methoxy,
ethoxy, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl and amino,
and in which oxadiazolonyl, oxadiazolethionyl, phenyl, oxazolyl,
thiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl,
pyridyl, pyrimidinyl and pyrazinyl for their part can be
substituted with 1 or 2 substituents selected independently of one
another from the group fluorine, chlorine, cyano, difluoromethyl,
trifluoromethyl, methyl, ethyl, isopropyl, 2,2,2-trifluoroethyl,
1,1,2,2,2-pentafluoroethyl, cyclopropyl, cyclobutyl,
cyclopropylmethyl, cyclobutylmethyl, hydroxy, methoxy and ethoxy,
or R.sup.7A and R.sup.7B together with the carbon atom to which
they are bound, form a cyclopropyl, cyclobutyl, cyclopentyl,
azetidinyl, tetrahydrofuranyl, pyrrolidinyl or tetrahydropyranyl
ring, in which the cyclopropyl, cyclobutyl, cyclopentyl,
azetidinyl, tetrahydrofuranyl, pyrrolidinyl and tetrahydropyranyl
ring can be substituted with 1 or 2 substituents selected
independently of one another from the group fluorine and methyl,
R.sup.8A stands for hydrogen, fluorine, methyl, ethyl or hydroxy,
R.sup.8B stands for hydrogen, fluorine, methyl, ethyl or
trifluoromethyl, the ring Q stands for a group of formula
##STR00238## ##STR00239## wherein * stands for the point of
attachment to --CH.sub.2--R.sup.2, ** stands for the point of
attachment to the pyrimidine, the ring Q.sub.1 together with the
atoms to which it is bound, forms a 5- to 7-membered saturated or
partially unsaturated carbocycle or a 5- to 7-membered saturated or
partially unsaturated heterocycle, R.sup.1 stands for fluorine,
chlorine or methyl, n stands for a number 0, 1 or 2, A.sup.1,
A.sup.2, A.sup.3 and A.sup.4 independently of one another stand in
each case for N, CH or CR.sup.1, with the proviso that at most two
of the groups A.sup.1, A.sup.2, A.sup.3 and A.sup.4 stand for N,
R.sup.3 stands for --OR.sup.4 or --NR.sup.5R.sup.6, wherein R.sup.4
stands for (C.sub.1-C.sub.6)-alkyl, cyclopropyl, cyclobutyl,
cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl,
tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl,
pyrazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl,
thiadiazolyl, pyridyl or pyrimidinyl, in which
(C.sub.1-C.sub.6)-alkyl can be substituted with 1 to 3 substituents
selected independently of one another from the group fluorine,
difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl,
cyclopentyl, difluoromethoxy, trifluoromethoxy,
--(C.dbd.O).sub.p--OR.sup.9, --(C.dbd.O).sub.p--NR.sup.9R.sup.10,
and --NR.sup.9--(C.dbd.O)--R.sup.10, and in which cyclopropyl,
cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuranyl,
pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl,
morpholinyl, phenyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl,
oxadiazolyl, thiadiazolyl, pyridyl or pyrimidinyl can be
substituted with 1 to 3 substituents selected independently of one
another from the group fluorine, difluoromethyl, trifluoromethyl,
2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, methyl, ethyl,
isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethoxy,
trifluoromethoxy, oxo, --(C.dbd.O).sub.p--OR.sup.9 and
--(C.dbd.O).sub.p--NR.sup.9R.sup.10, in which p denotes the number
0 or 1, R.sup.9 and R.sup.10 each stand, independently of one
another, for hydrogen, methyl, ethyl, isopropyl, trifluoromethyl,
2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, cyclopropyl,
cyclobutyl or cyclopentyl, or R.sup.9 and R.sup.10 form, together
with the respective atom(s) to which they are bound, an azetidinyl,
pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring, in
which the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and
morpholinyl ring for its part can be substituted with 1 or 2
substituents selected independently of one another from the group
fluorine, trifluoromethyl, methyl, ethyl, hydroxy, oxo, methoxy,
ethoxy, amino, methylamino, ethylamino, dimethylamino and
diethylamino, R.sup.5 stands for hydrogen, methyl or ethyl, R.sup.6
stands for (C.sub.1-C.sub.6)-alkyl, cyclopropyl,
(C.sub.3-C.sub.6)-cycloalkyl, oxetanyl, azetidinyl,
tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl,
piperazinyl, morpholinyl, phenyl, pyrazolyl, oxazolyl, thiazolyl,
triazolyl, oxadiazolyl, thiadiazolyl, pyridyl or pyrimidinyl, in
which (C.sub.1-C.sub.6)-alkyl and (C.sub.3-C.sub.6)-cycloalkyl are
substituted with 1 to 3 substituents selected independently of one
another from the group fluorine, difluoromethyl, trifluoromethyl
methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl,
difluoromethoxy, trifluoromethoxy, --(C.dbd.O).sub.p--OR.sup.9,
--(C.dbd.O).sub.p--NR.sup.9R.sup.10,
--NR.sup.9--(C.dbd.O)--R.sup.10, oxetanyl, azetidinyl,
tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl,
piperazinyl, morpholinyl, phenyl, furanyl, pyrazolyl, imidazolyl,
oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl
and pyrimidinyl, in which cyclopropyl, cyclobutyl, cyclopentyl,
oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl,
tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl,
furanyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl,
oxadiazolyl, thiadiazolyl, pyridyl and pyrimidinyl for their part
can be substituted with 1 or 2 substituents selected independently
of one another from the group fluorine, chlorine, cyano,
difluoromethyl, trifluoromethyl, methyl, ethyl, cyclopropyl,
cyclobutyl, cyclopentyl, hydroxy, oxo, difluoromethoxy,
trifluoromethoxy, methoxy and ethoxy, in which oxetanyl,
azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl,
piperidinyl, piperazinyl, morpholinyl, phenyl, pyrazolyl, oxazolyl,
thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl and
pyrimidinyl can be substituted with 1 to 3 substituents selected
independently of one another from the group fluorine,
difluoromethyl, trifluoromethyl, methyl, ethyl, cyclopropyl,
cyclobutyl, cyclopentyl, difluoromethoxy, trifluoromethoxy, oxo,
--(C.dbd.O).sub.p--OR.sup.9 and
--(C.dbd.O).sub.p--NR.sup.9R.sup.10, in which p denotes the number
0 or 1, R.sup.9 and R.sup.10 each stand, independently of one
another, for hydrogen, methyl, ethyl, isopropyl, trifluoromethyl,
2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, cyclopropyl,
cyclobutyl or cyclopentyl, or R.sup.9 and R.sup.10 form, together
with the respective atom(s) to which they are bound, an azetidinyl,
pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring, in
which the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and
morpholinyl ring for its part can be substituted with 1 or 2
substituents selected independently of one another from the group
fluorine, trifluoromethyl, methyl, ethyl, hydroxy, oxo, methoxy,
ethoxy, amino, methylamino, ethylamino, dimethylamino and
diethylamino, or R.sup.5 and R.sup.6 form, together with the
nitrogen atom to which they are bound, an azetidinyl, pyrrolidinyl,
imidazolidinyl, piperidinyl, dihydropiperidinyl, piperazinyl,
morpholinyl, pyrazolyl, imidazolyl or triazolyl ring, in which the
azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl,
dihydropiperidinyl, piperazinyl, morpholinyl, pyrazolyl, imidazolyl
and triazolyl ring can be substituted with 1 or 2 substituents
selected independently of one another from the group fluorine,
cyano, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl,
1,1,2,2,2-pentafluoroethyl, methyl, ethyl, 1-hydroxyethyl,
cyclopropyl, cyclobutyl, cyclopentyl, hydroxy, oxo, methoxy,
ethoxy, difluoromethoxy, trifluoromethoxy, oxetanyl, azetidinyl,
tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl,
piperazinyl and morpholinyl, R.sup.2 stands for trifluoromethyl,
2,2,2-trifluoroethyl, 3,3,3-trifluoroprop-1-yl,
2,2,3,3,3-pentafluoroprop-1-yl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl or
pyridazinyl, wherein phenyl is substituted with 1 to 3 fluorine
substituents, and wherein cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl can be
substituted with 1 or 2 fluorine substituents, or a salt
thereof.
3. The compound of claim 1, in which L stands for a group
#.sup.1-CR.sup.7AR.sup.7B-(CR.sup.8AR.sup.8B).sub.m-#.sup.2,
wherein #.sup.1 stands for the point of attachment to the carbonyl
group, #.sup.2 stands for the point of attachment to the pyrimidine
ring, m stands for a number 0, R.sup.7A stands for hydrogen,
fluorine, methyl or hydroxy, R.sup.7B stands for hydrogen,
fluorine, trifluoromethyl, methyl or 2,2,2-trifluoroethyl, or
R.sup.7A and R.sup.7B together with the carbon atom to which they
are bound, form a tetrahydrofuranyl ring, the ring Q stands for a
group of formula ##STR00240## wherein * stands for the point of
attachment to --CH.sub.2--R.sup.2, ** stands for the point of
attachment to the pyrimidine, R.sup.1a stands for hydrogen or
methyl, R.sup.1b stands for hydrogen or fluorine, R.sup.1c stands
for hydrogen or chlorine, A.sup.1 stands for N or CH, A.sup.3
stands for N, CH or C--F, R.sup.3 stands for --NR.sup.5R.sup.6,
wherein R.sup.5 stands for hydrogen, R.sup.6 stands for
(C.sub.1-C.sub.6)-alkyl, in which (C.sub.1-C.sub.6)-alkyl is
substituted with 1 or 2 substituents selected independently of one
another from the group fluorine, difluoromethyl, trifluoromethyl or
--(C.dbd.O).sub.p--OR.sup.9, in which p denotes the number 0,
R.sup.9 stands for hydrogen, R.sup.2 stands for 2-fluorophenyl,
2,3-difluorophenyl or 3-fluoropyrid-2-yl, and their salts, solvates
and solvates of the salts.
4. Compounds of formula (I) according to claims 1 to 3, in which L
stands for a group
#.sup.1-CR.sup.7AR.sup.7B--(CR.sup.8AR.sup.8B).sub.m-#.sup.2,
wherein #.sup.1 stands for the point of attachment to the carbonyl
group, #.sup.2 stands for the point of attachment to the pyrimidine
ring, m stands for a number 0, R.sup.7A stands for methyl, R.sup.7B
stands for methyl, the ring Q stands for a group of formula
##STR00241## wherein * stands for the point of attachment to
--CH.sub.2--R.sup.2, ** stands for the point of attachment to the
pyrimidine, R.sup.1a stands for hydrogen or methyl, R.sup.1b stands
for hydrogen or fluorine, R.sup.1c stands for hydrogen or chlorine,
A.sup.1 stands for N or CH, A.sup.3 stands for N, CH or C--F,
R.sup.3 stands for --NR.sup.5R.sup.6, wherein R.sup.5 stands for
hydrogen, methyl or ethyl, R.sup.6 stands for
(C.sub.1-C.sub.6)-alkyl, oxetanyl, azetidinyl, tetrahydrofuranyl,
pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl,
morpholinyl, phenyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl,
oxadiazolyl, thiadiazolyl, pyridyl or pyrimidinyl, in which
(C.sub.1-C.sub.6)-alkyl is substituted with 1 or 2 substituents
selected independently of one another from the group fluorine,
difluoromethyl, trifluoromethyl cyclopropyl, cyclobutyl,
cyclopentyl, trifluoromethoxy, --(C.dbd.O).sub.p--OR.sup.9,
--(C.dbd.O).sub.p--NR.sup.9R.sup.10, tetrahydrofuranyl,
pyrrolidinyl, tetrahydropyranyl, phenyl, furanyl, pyrazolyl,
imidazolyl, triazolyl and pyridyl, in which p denotes the number 0
or 1, R.sup.9 and R.sup.10 each stand, independently of one
another, for hydrogen, methyl, ethyl, trifluoromethyl,
2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, cyclopropyl or
cyclobutyl, and in which tetrahydrofuranyl, pyrrolidinyl,
tetrahydropyranyl, phenyl, furanyl, pyrazolyl, imidazolyl,
triazolyl and pyridyl for their part can be substituted with 1 or 2
substituents selected independently of one another from the group
fluorine, chlorine, cyano, difluoromethyl, trifluoromethyl, methyl,
ethyl and oxo, in which oxetanyl, azetidinyl, tetrahydrofuranyl,
pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl,
morpholinyl, phenyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl,
oxadiazolyl, thiadiazolyl, pyridyl and pyrimidinyl can be
substituted with 1 or 2 substituents selected independently of one
another from the group fluorine, difluoromethyl, trifluoromethyl,
methyl, ethyl and oxo, or R.sup.5 and R.sup.6 form, together with
the nitrogen atom to which they are bound, an azetidinyl,
pyrrolidinyl, imidazolidinyl, piperidinyl, dihydropiperidinyl,
piperazinyl, morpholinyl, pyrazolyl or imidazolyl ring, in which
the azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl,
dihydropiperidinyl, piperazinyl, morpholinyl, pyrazolyl and
imidazolyl ring can be substituted with 1 or 2 substituents
selected independently of one another from the group fluorine,
cyano, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl,
1,1,2,2,2-pentafluoroethyl, methyl, ethyl, 1-hydroxyethyl,
cyclopropyl, cyclobutyl, cyclopentyl, hydroxy, oxo, methoxy,
ethoxy, difluoromethoxy and trifluoromethoxy, R.sup.2 stands for
3,3,3-trifluoroeth-1-yl, 2,2,3,3,3-pentafluoroprop-1-yl, phenyl or
pyridyl, wherein phenyl is substituted with 1 to 3 fluorine
substituents, and wherein pyridyl can be substituted with 1
fluorine substituent, or a salt thereof.
5. The compound of claim 1, in which L stands for a group
#.sup.1-CR.sup.7AR.sup.7B--(CR.sup.8AR.sup.8B).sub.m-#.sup.2,
wherein #.sup.1 stands for the point of attachment to the carbonyl
group, #.sup.2 stands for the point of attachment to the pyrimidine
ring, m stands for a number 0, R.sup.7A stands for hydrogen,
fluorine, methyl, hydroxy, R.sup.7B stands for hydrogen, fluorine,
methyl or trifluoromethyl, or R.sup.7A and R.sup.7B together with
the carbon atom to which they are bound, form a tetrahydrofuranyl
ring, the ring Q stands for a group of formula ##STR00242## wherein
* stands for the point of attachment to --CH.sub.2--R.sup.2, **
stands for the point of attachment to the pyrimidine, R.sup.3
stands for --OR.sup.4 or --NR.sup.5R.sup.6, wherein R.sup.4 stands
for (C.sub.1-C.sub.6)-alkyl or pyrazolyl, in which
(C.sub.1-C.sub.6)-alkyl can be substituted with 1 to 3 substituents
selected independently of one another from the group fluorine,
trifluoromethyl, --(C.dbd.O).sub.p--OR.sup.9 and
--(C.dbd.O).sub.p--NR.sup.9R.sup.10, in which p denotes the number
0 or 1, R.sup.9 and R.sup.10 independently of one another stand in
each case for hydrogen or methyl, and in which pyrazolyl can be
substituted with 1 or 2 substituents selected independently of one
another from the group fluorine, difluoromethyl, trifluoromethyl,
2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, methyl,
cyclopropyl, cyclobutyl, cyclopentyl, R.sup.5 stands for hydrogen,
methyl or ethyl, R.sup.6 stands for (C.sub.1-C.sub.6)-alkyl,
oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl,
tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl,
pyrazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl,
thiadiazolyl, pyridyl or pyrimidinyl, in which
(C.sub.1-C.sub.6)-alkyl is substituted with 1 or 2 substituents
selected independently of one another from the group fluorine,
difluoromethyl, trifluoromethyl cyclopropyl, cyclobutyl,
cyclopentyl, trifluoromethoxy, --(C.dbd.O).sub.p--OR.sup.9,
--(C.dbd.O).sub.p--NR.sup.9R.sup.10, tetrahydrofuranyl,
pyrrolidinyl, tetrahydropyranyl, phenyl, furanyl, pyrazolyl,
imidazolyl, triazolyl and pyridyl, in which p denotes the number 0
or 1, R.sup.9 and R.sup.10 each stand, independently of one
another, for hydrogen, methyl, ethyl, trifluoromethyl,
2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, cyclopropyl or
cyclobutyl, and in which cyclopropyl, cyclobutyl, cyclopentyl,
tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, phenyl,
furanyl, pyrazolyl, imidazolyl, triazolyl and pyridyl for their
part can be substituted with 1 or 2 substituents selected
independently of one another from the group fluorine, chlorine,
cyano, difluoromethyl, trifluoromethyl, methyl, ethyl, oxo and
hydroxy, in which oxetanyl, azetidinyl, tetrahydrofuranyl,
pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl,
morpholinyl, phenyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl,
oxadiazolyl, thiadiazolyl, pyridyl and pyrimidinyl can be
substituted with 1 or 2 substituents selected independently of one
another from the group fluorine, difluoromethyl, trifluoromethyl,
methyl, ethyl, oxo, azetidinyl and pyrrolidinyl, or R.sup.5 and
R.sup.6 form, together with the nitrogen atom to which they are
bound, an azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl,
dihydropiperidinyl, piperazinyl, morpholinyl, pyrazolyl or
imidazolyl ring, in which the azetidinyl, pyrrolidinyl,
imidazolidinyl, piperidinyl, dihydropiperidinyl, piperazinyl,
morpholinyl, pyrazolyl and imidazolyl ring can be substituted with
1 or 2 substituents selected independently of one another from the
group fluorine, cyano, difluoromethyl, trifluoromethyl,
2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, methyl, ethyl,
1-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxy, oxo,
methoxy, ethoxy, difluoromethoxy and trifluoromethoxy, R.sup.2
stands for 2-fluorophenyl, 2,3-difluorophenyl or
3-fluoropyrid-2-yl, or a salt thereof.
6. The compound of claim 1, in which L stands for a group
#.sup.1-CR.sup.7AR.sup.7B-(CR.sup.8AR.sup.8B).sub.m-#.sup.2,
wherein #.sup.1 stands for the point of attachment to the carbonyl
group, #.sup.2 stands for the point of attachment to the pyrimidine
ring, m stands for a number 0, R.sup.7A stands for methyl, R.sup.7B
stands for methyl, or R.sup.7A and R.sup.7B together with the
carbon atom to which they are bound, form a tetrahydrofuranyl ring,
the ring Q stands for a group of formula ##STR00243## wherein *
stands for the point of attachment to --CH.sub.2--R.sup.2, **
stands for the point of attachment to the pyrimidine, R.sup.3
stands for --OR.sup.4 or --NR.sup.5R.sup.6, wherein R.sup.4 stands
for (C.sub.1-C.sub.6)-alkyl or pyrazolyl, in which
(C.sub.1-C.sub.6)-alkyl can be substituted with 1 to 3 substituents
selected independently of one another from the group fluorine,
trifluoromethyl, --(C.dbd.O).sub.p--OR.sup.9 and
--(C.dbd.O).sub.p--NR.sup.9R.sup.10, in which p denotes the number
0 or 1, R.sup.9 and R.sup.10 independently of one another stand in
each case for hydrogen or methyl, and in which pyrazolyl can be
substituted with 1 or 2 substituents selected independently of one
another from the group fluorine, difluoromethyl, trifluoromethyl,
2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, methyl,
cyclopropyl, cyclobutyl, cyclopentyl, R.sup.5 stands for hydrogen,
methyl or ethyl, R.sup.6 stands for (C.sub.1-C.sub.6)-alkyl,
oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl,
tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl,
pyrazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl,
thiadiazolyl, pyridyl or pyrimidinyl, in which
(C.sub.1-C.sub.6)-alkyl is substituted with 1 or 2 substituents
selected independently of one another from the group fluorine,
difluoromethyl, trifluoromethyl cyclopropyl, cyclobutyl,
cyclopentyl, trifluoromethoxy, --(C.dbd.O).sub.p--OR.sup.9,
--(C.dbd.O).sub.p--NR.sup.9R.sup.10, tetrahydrofuranyl,
pyrrolidinyl, tetrahydropyranyl, phenyl, furanyl, pyrazolyl,
imidazolyl, triazolyl and pyridyl, in which p denotes the number 0
or 1, R.sup.9 and R.sup.10 each stand, independently of one
another, for hydrogen, methyl, ethyl, trifluoromethyl,
2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, cyclopropyl or
cyclobutyl, and in which cyclopropyl, cyclobutyl, cyclopentyl,
tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, phenyl,
furanyl, pyrazolyl, imidazolyl, triazolyl and pyridyl for their
part can be substituted with 1 or 2 substituents selected
independently of one another from the group fluorine, chlorine,
cyano, difluoromethyl, trifluoromethyl, methyl, ethyl, oxo and
hydroxy, in which oxetanyl, azetidinyl, tetrahydrofuranyl,
pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl,
morpholinyl, phenyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl,
oxadiazolyl, thiadiazolyl, pyridyl and pyrimidinyl can be
substituted with 1 or 2 substituents selected independently of one
another from the group fluorine, difluoromethyl, trifluoromethyl,
methyl, ethyl, oxo, azetidinyl and pyrrolidinyl, or R.sup.5 and
R.sup.6 form, together with the nitrogen atom to which they are
bound, an azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl,
dihydropiperidinyl, piperazinyl, morpholinyl, pyrazolyl or
imidazolyl ring, in which the azetidinyl, pyrrolidinyl,
imidazolidinyl, piperidinyl, dihydropiperidinyl, piperazinyl,
morpholinyl, pyrazolyl and imidazolyl ring can be substituted with
1 or 2 substituents selected independently of one another from the
group fluorine, cyano, difluoromethyl, trifluoromethyl,
2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, methyl, ethyl,
1-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxy, oxo,
methoxy, ethoxy, difluoromethoxy and trifluoromethoxy, R.sup.2
stands for 2-fluorophenyl, 2,3-difluorophenyl or
3-fluoropyrid-2-yl, or a salt thereof.
7. A method of production of compounds of formula (I), as defined
in claim 1, comprising: converting compound of formula (II)
##STR00244## in which n, L, Q, R.sup.1 and R.sup.2 in each case
have the meanings stated in claim 1, in an inert solvent with
isopentyl nitrite and a halogen equivalent into a compound of
formula (III) ##STR00245## in which n, L, Q, R.sup.1 and R.sup.2 in
each case have the meanings given in claim 1 and X.sup.1 stands for
bromine or iodine reacting the compound of formula (III) in an
inert solvent, optionally in the presence of a suitable base, with
a compound of formula (IV) R.sup.3--H (IV), in which R.sup.3 has
the meaning given in claim 1, thereby producing a compound of
formula (I) ##STR00246## in which n, L, Q, R.sup.1, R.sup.2 and
R.sup.3 in each case have the meanings given in claim 1, and
optionally the resultant compounds of formula (I) optionally with
the corresponding (i) solvents and/or (ii) acids or bases are
transformed to their solvates, salts and/or solvates of the
salts.
8. A pharmaceutical composition comprising the compound of claim 1
and an inert, non-toxic, pharmaceutically suitable excipient.
9. The pharmaceutical composition of claim 11, further comprising
an active substance selected from the group consisting of an
organic nitrate, an NO-donor, a cGMP-PDE inhibitor, an
antithrombotic agent, an agent for lowering blood pressure, and an
agent for altering fat metabolism.
10. A method of treating and/or preventing heart failure, angina
pectoris, hypertension, pulmonary hypertension, ischaemias,
vascular diseases, renal insufficiency, thromboembolic diseases,
fibrotic diseases and arteriosclerosis comprising administering an
effective amount of a compound of claim 1 to a human or animal in
need thereof.
11. A method of treating and/or preventing heart failure, angina
pectoris, hypertension, pulmonary hypertension, ischaemias,
vascular diseases, renal insufficiency, thromboembolic diseases,
fibrotic diseases and arteriosclerosis comprising administering an
effective amount of a pharmaceutical composition of claim 11 to a
human or animal in need thereof.
Description
[0001] The present application relates to novel substituted
annellated pyrimidines, methods of production thereof, use thereof
alone or in combinations for treating and/or preventing diseases
and use thereof for the production of medicinal products for
treating and/or preventing diseases, in particular for treating
and/or preventing cardiovascular diseases.
[0002] One of the most important cellular transmission systems in
mammalian cells is cyclic guanosine monophosphate (cGMP). Together
with nitric oxide (NO), which is released from the endothelium and
transmits hormonal and mechanical signals, it forms the NO/cGMP
system. The guanylate cyclases catalyse the biosynthesis of cGMP
from guanosine triphosphate (GTP). The currently known
representatives of this family can be divided, both on the basis of
structural features and according to the type of ligands, into two
groups: the particulate guanylate cyclases that can be stimulated
by natriuretic peptides, and the soluble guanylate cyclases that
can be stimulated by NO. The soluble guanylate cyclases consist of
two subunits and most probably contain one haem per heterodimer,
which is a part of the regulatory centre. This is of central
importance for the activation mechanism NO can bind to the iron
atom of haem and thus greatly increase the activity of the enzyme.
In contrast, haem-free preparations cannot be stimulated by NO.
Carbon monoxide (CO) is also capable of binding to the central iron
atom of haem, but stimulation by CO is far less than by NO.
[0003] Through the formation of cGMP and the resultant regulation
of phosphodiesterases, ion channels and protein kinases, guanylate
cyclase plays a decisive role in various physiological processes,
in particular in the relaxation and proliferation of smooth muscle
cells, in platelet aggregation and adhesion, in neuronal signal
transmission and in diseases that result from disturbance of the
aforementioned processes. In pathophysiological conditions, the
NO/cGMP system can be suppressed, which can lead for example to
high blood pressure, platelet activation, increased cellular
proliferation, endothelial dysfunction, arteriosclerosis, angina
pectoris, heart failure, myocardial infarction, thromboses, stroke
and sexual dysfunction.
[0004] A possible NO-independent treatment for such diseases that
aims to influence the cGMP signalling pathway in organisms is a
promising approach in view of the expected high efficiency with few
side-effects.
[0005] Up till now, compounds such as organic nitrates, whose
action is based on NO, have been used exclusively for therapeutic
stimulation of the soluble guanylate cyclase. The NO is formed by
bioconversion and activates the soluble guanylate cyclase by acting
on the central iron atom of the haem. In addition to the
side-effects, the decisive disadvantages of this method of
treatment include development of tolerance.
[0006] Some years ago, some substances were described that
stimulate soluble guanylate cyclase directly, i.e. without prior
release of NO, such as for example
3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole [YC-1; Wu et al.,
Blood 84 (1994), 4226; Mulsch et al., Brit. J. Pharmacol. 120
(1997), 681]. The newer stimulators of soluble guanylate cyclase
include inter alia BAY 41-2272, BAY 41-8543 and riociguat (BAY
63-2521) (see e.g. Stasch J.-P. et al., Nat. Rev. Drug Disc. 2006;
5: 755-768; Stasch J.-P. et al., ChemMedChem 2009; 4: 853-865.
Stasch J.-P. et al., Circulation 2011; 123: 2263-2273).
Interestingly, some of these sGC stimulators, for example YC-1 or
BAY 41-2272, display PDE5-inhibitory action in addition to direct
guanylate cyclase stimulation. To maximize the cGMP-pathway, it is
pharmacologically desirable to stimulate the synthesis of cGMP and
simultaneously inhibit the degradation via PDE-5. This dual
principle is especially advantageous pharmacologically (cf. Oudout
et al., Eur. Urol. 2011, 60, 1020-1026). The dual principle is
fulfilled, in the sense of the present invention, if the compounds
according to the invention display an action on recombinant
guanylate cyclase reporter cell lines according to the test under
B-2 as minimal effective concentration (MEC) of .ltoreq.3 .mu.m and
inhibition of human phosphodiesterase 5 (PDE5) according to the
test under B-6 as IC50<100 nm.
[0007] Phosphodiesterase-5 (PDE5) is the name for one of the
enzymes that cleave the phosphoric acid ester bond in cGMP, with
formation of 5'-guanosine monophosphate (5'-GMP). In humans,
phosphodiesterase-5 occurs mainly in the smooth muscles of the
cavernous body of the penis (corpus cavernosum penis) and the
pulmonary arteries. Blocking of cGMP degradation through inhibition
of PDE5 (with for example sildenafil, vardenafil or tadalafil)
leads to increased signals of the relaxation signalling pathways
and especially to increased blood supply to the cavernous body of
the penis and lowering of pressure in the blood vessels of the
lung. They are used for treating erectile dysfunction and pulmonary
arterial hypertension. In addition to PDE5, there are other
phosphodiesterases exclusively cleaving cGMP (Stasch J.-P. et al.
Circulation 2011).
[0008] As stimulators of soluble guanylate cyclase, annellated
pyrazole derivatives are disclosed in WO 00/06568 and WO 00/06569
and carbamate-substituted 3-pyrimidinyl-pyrazolopyridines in WO
03/095451. 3-Pyrimidinyl-pyrazolopyridines with phenylamide
substituents are described in E. M. Becker et al., BMC Pharmacology
1 (13), 2001. WO 2004/009590 describes pyrazolopyridines with
substituted 4-aminopyrimidines for treating CNS disorders. WO
2010/065275 and WO 2011/149921 disclose substituted pyrrolo- and
dihydropyridopyrimidines as sGC activators. As sGC stimulators,
annellated aminopyrimidines are described in WO 2012/004259 and
annellated pyrimidines and triazines in WO 2012/004258. WO
2012/28647 discloses pyrazolopyridines with various azaheterocycles
for treating cardiovascular diseases.
[0009] The problem to be solved by the present invention was to
provide novel substances that act as stimulators of soluble
guanylate cyclase and as stimulators of soluble guanylate cyclase
and inhibitors of phosphodiesterase-5 (dual principle) and have an
equal or improved therapeutic profile versus the compounds known
from the prior art, for example with respect to their in-vivo
properties, for example their pharmacokinetic and pharmacodynamic
behaviour and/or their metabolic profile and/or their dose-effect
relation.
[0010] The present invention relates to compounds of general
formula (I)
##STR00001##
in which [0011] L stands for a group
#.sup.1-CR.sup.7AR.sup.7B--(CR.sup.8AR.sup.8B).sub.m-#.sup.2,
[0012] wherein [0013] #.sup.1 stands for the point of attachment to
the carbonyl group, [0014] #.sup.2 stands for the point of
attachment to the pyrimidine ring, [0015] m stands for a number 0,
1 or 2, [0016] R.sup.7A stands for hydrogen, fluorine,
(C.sub.1-C.sub.4)-alkyl, hydroxyl or amino, [0017] in which
(C.sub.1-C.sub.4)-alkyl can be substituted with 1 to 3 substituents
selected independently of one another from the group fluorine,
trifluoromethyl, hydroxy, hydroxycarbonyl,
(C.sub.1-C.sub.4)-alkoxycarbonyl and amino, [0018] R.sup.7B stands
for hydrogen, fluorine, difluoromethyl, trifluoromethyl,
(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.4)-alkoxycarbonylamino,
cyano, (C.sub.3-C.sub.7)-cycloalkyl, difluoromethoxy,
trifluoromethoxy, phenyl or a group of formula -M-R.sup.13, [0019]
in which (C.sub.1-C.sub.6)-alkyl can be substituted with 1 to 3
substituents selected independently of one another from the group
fluorine, cyano, trifluoromethyl, (C.sub.3-C.sub.7)-cycloalkyl,
hydroxy, difluoromethoxy, trifluoromethoxy,
(C.sub.1-C.sub.4)-alkoxy, hydroxycarbonyl,
(C.sub.1-C.sub.4)-alkoxycarbonyl and amino, [0020] and in which
[0021] M stands for a bond or (C.sub.1-C.sub.4)-alkanediyl, [0022]
R.sup.13 stands for --(C.dbd.O).sub.r--OR.sup.14,
--(C.dbd.O).sub.r--NR.sup.14R.sup.15,
--C(.dbd.S)--NR.sup.14R.sup.15, --NR.sup.14--(C.dbd.O)--R.sup.17,
--NR.sup.14--(C.dbd.O)--NR.sup.15R.sup.16,
--NR.sup.14--SO.sub.2--NR.sup.15R.sup.16,
--NR.sup.14--SO.sub.2--R.sup.17, --S(O).sub.s--R.sup.17,
--SO.sub.2--NR.sup.14R.sup.15, 4- to 7-membered heterocyclyl,
phenyl or 5- or 6-membered heteroaryl, [0023] in which [0024] r
denotes the number 0 or 1, [0025] s denotes the number 0, 1 or 2,
[0026] R.sup.14, R.sup.15 and R.sup.16 each stand, independently of
one another, for hydrogen, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.8)-cycloalkyl, 4- to 7-membered heterocyclyl, phenyl
or 5- or 6-membered heteroaryl, [0027] or [0028] R.sup.14 and
R.sup.15 form, together with the respective atom(s) to which they
are bound, a 4- to 7-membered heterocycle, [0029] in which for its
part the 4- to 7-membered heterocycle can be substituted with 1 or
2 substituents selected independently of one another from the group
cyano, trifluoromethyl, (C.sub.1-C.sub.6)-alkyl, hydroxy, oxo,
(C.sub.1-C.sub.6)-alkoxy, trifluoromethoxy,
(C.sub.1-C.sub.6)-alkoxycarbonyl, amino,
mono-(C.sub.1-C.sub.6)-alkylamino and
di(C.sub.1-C.sub.6)-alkylamino, [0030] or [0031] R.sup.15 and
R.sup.16 form, together with the respective atom(s) to which they
are bound, a 4- to 7-membered heterocycle, [0032] in which for its
part the 4- to 7-membered heterocycle can be substituted with 1 or
2 substituents selected independently of one another from the group
cyano, trifluoromethyl, (C.sub.1-C.sub.6)-alkyl, hydroxy, oxo,
(C.sub.1-C.sub.6)-alkoxy, trifluoromethoxy,
(C.sub.1-C.sub.6)-alkoxycarbonyl, amino,
mono-(C.sub.1-C.sub.6)-alkylamino and
di(C.sub.1-C.sub.6)-alkylamino, [0033] R.sup.17 stands for
(C.sub.1-C.sub.6)-alkyl or (C.sub.3-C.sub.7)-cycloalkyl, [0034] or
[0035] R.sup.14 and R.sup.17 form, together with the respective
atom(s) to which they are bound, a 4- to 7-membered heterocycle,
[0036] in which for its part the 4- to 7-membered heterocycle can
be substituted with 1 or 2 substituents selected independently of
one another from the group cyano, trifluoromethyl,
(C.sub.1-C.sub.6)-alkyl, hydroxy, oxo, (C.sub.1-C.sub.6)-alkoxy,
trifluoromethoxy, (C.sub.1-C.sub.6)-alkoxycarbonyl, amino,
mono-(C.sub.1-C.sub.6)-alkylamino and
di(C.sub.1-C.sub.6)-alkylamino, [0037] and [0038] in which for
their part the 4- to 7-membered heterocyclyl, phenyl and 5- or
6-membered heteroaryl can be substituted with 1 to 3 substituents
selected independently of one another from the group halogen,
cyano, difluoromethyl, trifluoromethyl, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl, hydroxy, oxo, thiooxo and
(C.sub.1-C.sub.4)-alkoxy, [0039] and [0040] in which the
aforementioned (C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.8)-cycloalkyl, (C.sub.3-C.sub.7)-cycloalkyl and 4-
to 7-membered heterocyclyl groups, unless stated otherwise, can in
each case be further substituted independently of one another with
1 to 3 substituents selected independently of one another from the
group fluorine, difluoromethyl, trifluoromethyl,
(C.sub.1-C.sub.4)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl, hydroxy,
difluoromethoxy, trifluoromethoxy, (C.sub.1-C.sub.4)-alkoxy,
hydroxycarbonyl, (C.sub.1-C.sub.4)-alkoxycarbonyl, amino, phenyl,
4- to 7-membered heterocyclyl and 5- or 6-membered heteroaryl,
[0041] or [0042] R.sup.7A and R.sup.7B together with the carbon
atom to which they are bound, form a (C.sub.2-C.sub.4)-alkenyl
group, an oxo group, a 3- to 6-membered carbocycle or a 4- to
7-membered heterocycle, [0043] in which the 3- to 6-membered
carbocycle and the 4- to 7-membered heterocycle can be substituted
with 1 or 2 substituents selected independently of one another from
the group fluorine and (C.sub.1-C.sub.4)-alkyl, [0044] R.sup.8A
stands for hydrogen, fluorine, (C.sub.1-C.sub.4)-alkyl or hydroxy,
[0045] R.sup.8B stands for hydrogen, fluorine,
(C.sub.1-C.sub.4)-alkyl or trifluoromethyl, the ring Q stands for
8- or 9-membered heteroaryl, [0046] R.sup.3 stands for --OR.sup.4
or --NR.sup.5R.sup.6, [0047] wherein [0048] R.sup.4 stands for
hydrogen, (C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl, 4-
to 7-membered heterocyclyl, phenyl or 5- or 6-membered heteroaryl,
[0049] in which (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl, 4- to 7-membered heterocyclyl, phenyl
and 5- or 6-membered heteroaryl can be substituted with 1 to 3
substituents selected independently of one another from the group
fluorine, difluoromethyl, trifluoromethyl, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.6)-cycloalkyl, difluoromethoxy, trifluoromethoxy,
oxo, --(C.dbd.O).sub.p--OR.sup.9,
--C(.dbd.O).sub.p--NR.sup.9R.sup.10,
--NR.sup.9--(C.dbd.O)--R.sup.10, --NR.sup.9--(C.dbd.O)--OR.sup.10,
--NR.sup.9--(C.dbd.O)--NR.sup.10R.sup.11,
--NR.sup.9--SO.sub.2--R.sup.10, --S(O).sub.q--R.sup.12 and
--SO.sub.2--NR.sup.9R.sup.10, [0050] in which [0051] p denotes the
number 0 or 1, [0052] q denotes the number 0, 1 or 2, [0053]
R.sup.9, R.sup.10 and R.sup.11 each stand, independently of one
another, for hydrogen, (C.sub.1-C.sub.6)-alkyl or
(C.sub.3-C.sub.8)-cycloalkyl, [0054] in which
(C.sub.1-C.sub.6)-alkyl for its part can be substituted with 1 or 2
substituents selected independently of one another from the group
fluorine, difluoromethyl, trifluoromethyl, hydroxy,
(C.sub.1-C.sub.6)-alkoxy, difluoromethoxy, trifluoromethoxy,
(C.sub.1-C.sub.6)-alkoxycarbonyl, amino,
mono-(C.sub.1-C.sub.6)-alkylamino, di(C.sub.1-C.sub.6)-alkylamino
and 4- to 7-membered heterocyclyl, [0055] or [0056] R.sup.9 and
R.sup.10 form, together with the respective atom(s) to which they
are bound, a 4- to 7-membered heterocycle, [0057] in which for its
part the 4- to 7-membered heterocycle can be substituted with 1 or
2 substituents selected independently of one another from the group
fluorine, trifluoromethyl, hydroxy, oxo, (C.sub.1-C.sub.6)-alkoxy,
trifluoromethoxy, (C.sub.1-C.sub.6)-alkoxycarbonyl, amino,
mono-(C.sub.1-C.sub.6)-alkylamino and
di(C.sub.1-C.sub.6)-alkylamino, [0058] or [0059] R.sup.10 and
R.sup.11 form, together with the respective atom(s) to which they
are bound, a 4- to 7-membered heterocycle, [0060] in which for its
part the 4- to 7-membered heterocycle can be substituted with 1 or
2 substituents selected independently of one another from the group
fluorine, trifluoromethyl, hydroxy, oxo, (C.sub.1-C.sub.6)-alkoxy,
trifluoromethoxy, (C.sub.1-C.sub.6)-alkoxycarbonyl, amino,
mono-(C.sub.1-C.sub.6)-alkylamino and
di(C.sub.1-C.sub.6)-alkylamino, [0061] and in which [0062] R.sup.12
stands for (C.sub.1-C.sub.6)-alkyl or (C.sub.3-C.sub.7)-cycloalkyl,
[0063] and [0064] in which the aforementioned
(C.sub.1-C.sub.4)-alkyl, (C.sub.3-C.sub.8)-cycloalkyl,
(C.sub.3-C.sub.7)-- cycloalkyl and 4- to 7-membered heterocyclyl
groups, unless stated otherwise, can in each case be further
substituted independently of one another with 1 to 3 substituents
selected independently of one another from the group fluorine,
difluoromethyl, trifluoromethyl, (C.sub.1-C.sub.4)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl, hydroxy, difluoromethoxy,
trifluoromethoxy, (C.sub.1-C.sub.4)-alkoxy, hydroxycarbonyl,
(C.sub.1-C.sub.4)-alkoxycarbonyl, amino, phenyl, 4- to 7-membered
heterocyclyl and 5- or 6-membered heteroaryl, [0065] R.sup.5 stands
for hydrogen or (C.sub.1-C.sub.4)-alkyl, [0066] R.sup.6 stands for
(C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl, 4- to
7-membered heterocyclyl, phenyl or 5- or 6-membered heteroaryl,
[0067] in which (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl, 4- to 7-membered heterocyclyl, phenyl
and 5- or 6-membered heteroaryl can be substituted with 1 to 3
substituents selected independently of one another from the group
fluorine, difluoromethyl, trifluoromethyl, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl, difluoromethoxy, trifluoromethoxy,
oxo, --(C.dbd.O).sub.p--OR.sup.9,
--(C.dbd.O).sub.p--NR.sup.9R.sup.10,
--NR.sup.9--(C.dbd.O)--R.sup.10, --NR.sup.9--(C.dbd.O)--OR.sup.10,
--NR.sup.9--(C.dbd.O)--NR.sup.10R.sup.11,
--NR.sup.9--SO.sub.2--R.sup.10, --S(O).sub.q--R.sup.12,
--SO.sub.2--NR.sup.9R.sup.10, phenyl, 4- to 7-membered heterocyclyl
and 5- or 6-membered heteroaryl, [0068] in which [0069] p denotes
the number 0 or 1, [0070] q denotes the number 0, 1 or 2, [0071]
R.sup.9, R.sup.10 and R.sup.11 each stand, independently of one
another, for hydrogen, (C.sub.1-C.sub.6)-alkyl or
(C.sub.3-C.sub.8)-cycloalkyl, [0072] in which
(C.sub.1-C.sub.6)-alkyl for its part can be substituted with 1 to 3
substituents selected independently of one another from the group
fluorine, difluoromethyl, trifluoromethyl,
(C.sub.3-C.sub.7)-cycloalkyl, difluoromethoxy, trifluoromethoxy and
(C.sub.1-C.sub.4)-alkoxy, [0073] or [0074] R.sup.9 and R.sup.10
form, together with the respective atom(s) to which they are bound,
a 4- to 7-membered heterocycle, [0075] in which for its part the 4-
to 7-membered heterocycle can be substituted with 1 or 2
substituents selected independently of one another from the group
fluorine, cyano, trifluoromethyl, (C.sub.1-C.sub.6)-alkyl, hydroxy,
oxo, (C.sub.1-C.sub.6)-alkoxy, trifluoromethoxy,
(C.sub.1-C.sub.6)-alkoxycarbonyl, amino,
mono-(C.sub.1-C.sub.6)-alkylamino and
di(C.sub.1-C.sub.6)-alkylamino, [0076] or [0077] R.sup.10 and
R.sup.11 form, together with the respective atom(s) to which they
are bound, a 4- to 7-membered heterocycle, [0078] in which for its
part the 4- to 7-membered heterocycle can be substituted with 1 or
2 substituents selected independently of one another from the group
cyano, trifluoromethyl, (C.sub.1-C.sub.6)-alkyl, hydroxy, oxo,
(C.sub.1-C.sub.6)-alkoxy, trifluoromethoxy,
(C.sub.1-C.sub.6)-alkoxycarbonyl, amino,
mono-(C.sub.1-C.sub.6)-alkylamino and
di(C.sub.1-C.sub.6)-alkylamino, [0079] in which [0080] R.sup.12
stands for (C.sub.1-C.sub.6)-alkyl or (C.sub.3-C.sub.7)-cycloalkyl,
[0081] and [0082] in which phenyl, 4- to 7-membered heterocyclyl
and 5- or 6-membered heteroaryl for their part can be substituted
with 1 to substituents selected independently of one another from
the group halogen, cyano, difluoromethyl, trifluoromethyl,
(C.sub.1-C.sub.4)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl, hydroxy,
oxo, difluoromethoxy, trifluoromethoxy and
(C.sub.1-C.sub.4)-alkoxy, [0083] or [0084] R.sup.5 and R.sup.6
form, together with the nitrogen atom to which they are bound, a 4-
to 7-membered heterocycle or a 5- or 6-membered heteroaryl, [0085]
in which the 4- to 7-membered heterocycle and the 5- or 6-membered
heteroaryl can be substituted with 1 to 3 substituents selected
independently of one another from the group fluorine, cyano,
difluoromethyl, trifluoromethyl, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl, hydroxy, oxo,
(C.sub.1-C.sub.6)-alkoxy, difluoromethoxy, trifluoromethoxy,
(C.sub.1-C.sub.6)-alkoxycarbonyl,
(C.sub.1-C.sub.6)-alkylcarbonylamino, amino,
mono-(C.sub.1-C.sub.6)-alkylamino, di(C.sub.1-C.sub.6)-alkylamino
and 4- to 7-membered heterocycyl, [0086] and [0087] in which the
aforementioned (C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.8)-cycloalkyl, (C.sub.3-C.sub.7)-cycloalkyl and 4-
to 7-membered heterocyclyl groups, unless stated otherwise, can in
each case be further substituted independently of one another with
1 to 3 substituents selected independently of one another from the
group fluorine, difluoromethyl, trifluoromethyl,
(C.sub.1-C.sub.4)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl, hydroxy,
difluoromethoxy, trifluoromethoxy, alkoxy, hydroxycarbonyl,
(C.sub.1-C.sub.4)-alkoxycarbonyl, amino, phenyl, 4- to 7-membered
heterocyclyl and 5- or 6-membered heteroaryl, [0088] R.sup.1 stands
for fluorine, chlorine, cyano, difluoromethyl, trifluoromethyl,
(C.sub.1-C.sub.4)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl or
(C.sub.1-C.sub.4)-alkoxy, [0089] n stands for a number 0, 1 or 2,
[0090] R.sup.2 stands for trifluoromethyl, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.8)-cycloalkyl, phenyl or 5- or 6-membered
heteroaryl, [0091] wherein (C.sub.1-C.sub.6)-alkyl is substituted
with a substituent selected from the group difluoromethyl and
trifluoromethyl, [0092] wherein (C.sub.1-C.sub.6)-alkyl can be
substituted with 1 to 3 fluorine substituents, [0093] wherein
(C.sub.3-C.sub.8)-cycloalkyl can be substituted with 1 or 2
substituents selected independently of one another from the group
fluorine, methyl and methoxy, [0094] wherein phenyl is substituted
with 1 to 3 fluorine substituents, [0095] wherein phenyl can be
substituted with 1 or 2 substituents selected independently of one
another from the group methyl and methoxy, [0096] and [0097]
wherein 5- and 6-membered heteroaryl can be substituted with 1 or 2
substituents selected independently of one another from the group
fluorine, trifluoromethyl and methyl. and their N-oxides, salts,
solvates, salts of the N-oxides and solvates of the N-oxides and
salts.
[0098] Compounds according to the invention are the compounds of
formula (I) and their N-oxides, salts, solvates and solvates of the
N-oxides and salts, the compounds covered by formula (I) with the
formulae stated hereunder and their N-oxides, salts, solvates and
solvates of the N-oxides and salts and the compounds covered by
formula (I) stated hereunder as practical examples and their
N-oxides, salts, solvates and solvates of the N-oxides and salts,
provided the compounds stated hereunder that are covered by formula
(I) are not already N-oxides, salts, solvates and solvates of the
N-oxides and salts.
[0099] Physiologically harmless salts of the compounds according to
the invention are preferred as salts in the context of the present
invention. Salts that are not suitable themselves for
pharmaceutical applications, but can be used for example for
isolating or purifying the compounds according to the invention,
are also covered.
[0100] Physiologically harmless salts of the compounds according to
the invention comprise acid addition salts of mineral acids,
carboxylic acids and sulphonic acids, e.g. salts of hydrochloric
acid, hydrobromic acid, sulphuric acid, phosphoric acid,
methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid,
benzenesulphonic acid, naphthalene-disulphonic acid, formic acid,
acetic acid, trifluoroacetic acid, propionic acid, lactic acid,
tartaric acid, malic acid, citric acid, fumaric acid, maleic acid
and benzoic acid.
[0101] Physiologically harmless salts of the compounds according to
the invention also comprise salts of usual bases, for example and
preferably alkali metal salts (e.g. sodium and potassium salts),
alkaline-earth salts (e.g. calcium and magnesium salts) and
ammonium salts, derived from ammonia or organic amines with 1 to 16
carbon atoms, for example and preferably ethylamine, diethylamine,
triethylamine, ethyldiisopropylamine, monoethanolamine,
diethanolamine, triethanolamine, dicyclohexylamine,
dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine,
arginine, lysine, ethylenediamine and N-methylpiperidine.
[0102] The term "solvates" denotes, in the context of the
invention, those forms of the compounds according to the invention
that form a complex in the solid or liquid state by coordination
with solvent molecules. Hydrates are a special form of the
solvates, in which coordination takes place with water. Hydrates
are preferred as solvates in the context of the present
invention.
[0103] Depending on their structure, the compounds according to the
invention can exist in various stereoisomeric forms, i.e. in the
form of configurational isomers or optionally also as
conformational isomers (enantiomers and/or diastereomers, including
those that are atropisomers). The present invention therefore
comprises the enantiomers and diastereomers and their respective
mixtures. The stereoisomerically uniform constituents can be
isolated in a known way from said mixtures of enantiomers and/or
diastereomers; chromatographic methods are preferably used for
this, in particular achiral or chiral phase HPLC
chromatography.
[0104] If the compounds according to the invention can exist in
tautomeric forms, the present invention comprises all tautomeric
forms.
[0105] The present invention also comprises all suitable isotopic
variants of the compounds according to the invention. "Isotopic
variant of a compound according to the invention" means a compound
in which at least one atom within the compound according to the
invention is exchanged for another atom of the same atomic number,
but with an atomic mass different from the atomic mass usually or
mainly occurring naturally. Examples of isotopes that can be
incorporated in a compound according to the invention are those of
hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine,
chlorine, bromine and iodine, such as .sup.2H (deuterium), .sup.3H
(tritium), .sup.13C, .sup.14C, .sup.15N, .sup.17O, .sup.18O,
.sup.32P, .sup.33P, .sup.33S, .sup.34S, .sup.35S, .sup.36S,
.sup.18F, .sup.36Cl, .sup.82Br, .sup.123I, .sup.124I, .sup.129I and
.sup.131I. Certain isotopic variants of a compound according to the
invention, such as in particular those in which one or more
radioactive isotopes are incorporated, can be useful for example
for investigating the mechanism of action or the distribution of
active substances in the body; owing to the comparative ease of
production and detection, compounds labelled with .sup.3H- or
.sup.14C-isotopes are particularly suitable for this. Furthermore,
the incorporation of isotopes, for example deuterium, can lead to
certain therapeutic advantages as a result of increased metabolic
stability of the compound, for example a longer half-life in the
body or a decrease in the effective dose required; such
modifications of the compounds according to the invention can
therefore optionally also represent a preferred embodiment of the
present invention. Isotopic variants of the compounds according to
the invention can be produced by methods that are known by a person
skilled in the art, for example the methods described hereunder and
the specifications presented in the practical examples, in which
corresponding isotopic modifications of the respective reagents
and/or starting compounds are used.
[0106] Moreover, the present invention also comprises prodrugs of
the compounds according to the invention. The term "prodrugs"
denotes compounds that can themselves be biologically active or
inactive, but during their residence time in the body they are
converted to compounds according to the invention (for example
metabolically or by hydrolysis).
[0107] In the context of the present invention, the substituents
have the following meanings, unless stated otherwise:
[0108] In the context of the invention, alkyl stands for a linear
or branched alkyl residue with the number of carbon atoms stated in
each case. For example and preferably, we may mention: methyl,
ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl,
tert.-butyl, n-pentyl, iso-pentyl, 1-ethylpropyl, 1-methylbutyl,
2-methylbutyl, 3-methylbutyl, n-hexyl, 1-methylpentyl,
2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 3,3-dimethylbutyl,
1-ethylbutyl and 2-ethylbutyl.
[0109] In the context of the invention, cycloalkyl or carbocycle
stands for a monocyclic, saturated alkyl residue with the number of
carbon atoms stated in each case. For example and preferably, we
may mention: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and
cycloheptyl.
[0110] In the context of the invention, 5- to 7-membered saturated
or partially unsaturated carbocycle stands for a saturated or
partially unsaturated cyclic alkyl residue with the number of
carbon atoms stated in each case. For example and preferably, we
may mention: cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl,
cyclohexenyl and cycloheptenyl.
[0111] In the context of the invention, alkanediyl stands for a
linear or branched divalent alkyl residue with 1 to 4 carbon atoms.
For example and preferably, we may mention: methylene,
ethane-1,2-diyl, ethane-1,1-diyl, propane-1,3-diyl,
propane-1,1-diyl, propane-1,2-diyl, propane-2,2-diyl,
butane-1,4-diyl, butane-1,2-diyl, butane-1,3-diyl and
butane-2,3-diyl.
[0112] In the context of the invention, alkenyl stands for a linear
or branched alkenyl residue with 2 to 4 carbon atoms and a double
bond. For example and preferably, we may mention: vinyl, allyl,
isopropenyl and n-but-2-en-1-yl.
[0113] In the context of the invention, alkoxy stands for a linear
or branched alkoxy residue with 1 to 6 or 1 to 4 carbon atoms. We
may mention, for example: methoxy, ethoxy, n-propoxy, isopropoxy,
1-methylpropoxy, n-butoxy, iso-butoxy, tert.-butoxy, n-pentoxy,
iso-pentoxy, 1-ethylpropoxy, 1-methylbutoxy, 2-methylbutoxy,
3-methylbutoxy and n-hexoxy. A linear or branched alkoxy residue
with 1 to 4 carbon atoms is preferred. For example and preferably,
we may mention: methoxy, ethoxy, n-propoxy, isopropoxy,
1-methylpropoxy, n-butoxy, iso-butoxy, tert.-butoxy.
[0114] In the context of the invention, alkoxycarbonyl stands for a
linear or branched alkoxy residue with 1 to 4 carbon atoms and a
carbonyl group attached to the oxygen. For example and preferably,
we may mention: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl,
isopropoxycarbonyl and tert.-butoxycarbonyl.
[0115] In the context of the invention, alkoxycarbonylamino stands
for an amino group with a linear or branched alkoxycarbonyl
substituent, which has 1 to 4 carbon atoms in the alkyl chain and
is joined to the N-atom via the carbonyl group. For example and
preferably, we may mention: methoxycarbonylamino,
ethoxycarbonylamino, propoxycarbonylamino, n-butoxycarbonylamino,
iso-butoxycarbonylamino and tert.-butoxycarbonylamino.
[0116] In the context of the invention, mono-alkylamino stands for
an amino group with a linear or branched alkyl substituent having 1
to 6 carbon atoms. For example and preferably, we may mention:
methylamino, ethylamino, n-propylamino, isopropylamino and
tert.-butylamino.
[0117] In the context of the invention, di-alkylamino stands for an
amino group with two identical or different linear or branched
alkyl substituents, with in each case 1 to 6 carbon atoms. For
example and preferably, we may mention: N,N-dimethylamino,
N,N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino,
N-isopropyl-N-n-propylamino, N-tert.-butyl-N-methylamino,
N-ethyl-N-n-pentylamino and N-n-hexyl-N-methylamino.
[0118] In the context of the invention, 5- to 7-membered saturated
or partially unsaturated heterocycle stands for a saturated or
partially unsaturated heterocycle with a total of 5 to 7 ring
atoms, which contains a ring-heteroatom from the group N, O, S, SO
and/or SO.sub.2. We may mention, for example: pyrrolidinyl,
tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, dihydropyrrolyl,
dihydropyridyl.
[0119] In the context of the invention, heterocyclyl or heterocycle
stands for a saturated heterocycle with a total of 4 to 7 ring
atoms, which contains one or two ring-heteroatoms from the group N,
O, S, SO and/or SO.sub.2. We may mention, for example: azetidinyl,
oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolinyl,
tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl,
morpholinyl, thiomorpholinyl and dioxidothiomorpholinyl.
Azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl,
tetrahydropyranyl and morpholinyl are preferred.
[0120] In the context of the invention, 5- or 6-membered heteroaryl
stands for a monocyclic aromatic heterocycle (heteroaromatic) with
a total of 5 or 6 ring atoms, which contains up to three identical
or different ring-heteroatoms from the group N, O and/or S and is
joined via a ring carbon atom or optionally via a ring nitrogen
atom. For example and preferably, we may mention: furyl, pyrrolyl,
thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl,
isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl,
pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl. The following
are preferred: pyrazolyl, oxazolyl, thiazolyl, triazolyl,
oxadiazolyl, thiadiazolyl, pyridyl and pyrimidinyl.
[0121] In the context of the invention, 8- or 9-membered heteroaryl
stands for a bicyclic aromatic or partially unsaturated heterocycle
with a total of 8 or 9 ring atoms, which contains at least two
nitrogen atoms and up to two further, identical or different
ring-heteroatoms from the group N, O and/or S. We may mention, for
example: dihydrothienopyrazolyl, thienopyrazolyl,
pyrazolopyrazolyl, imidazothiazolyl, tetrahydrocyclopentapyrazolyl,
dihydrocyclopentapyrazolyl, tetrahydroindazolyl, dihydroindazolyl,
indazolyl, pyrazolopyridyl, tetrahydropyrazolopyridyl,
pyrazolopyrimidinyl, imidazopyridyl and imidazopyridazinyl. The
following are preferred: indazolyl, pyrazolo[3,4-b]pyridyl,
pyrazolo[3,4-b]pyrimidinyl and imidazo[1,5-a]pyridyl.
[0122] In the context of the invention, halogen stands for
fluorine, chlorine, bromine and iodine. Bromine and iodine are
preferred.
[0123] In the context of the invention, an oxo group stands for an
oxygen atom, which is bound to a carbon atom via a double bond.
[0124] In the context of the invention, a thiooxo group stands for
a sulphur atom, which is bound to a carbon atom via a double
bond.
[0125] In the formula of the group for which L or Q can stand, the
end point of the line at which there is the symbol #.sup.1,
#.sup.2, * and ** does not stand for a carbon atom or a CH.sub.2
group, but is a component of the bond to the atom that is
designated in each case, to which L or Q is bound.
[0126] If residues in the compounds according to the invention are
substituted, the residues can, unless stated otherwise, be
substituted one or more times. In the context of the present
invention, for all residues that occur more than once, their
meaning is independent of one another. Substitution with one, two
or three identical or different substituents is preferred.
[0127] In the sense of the present invention, the term "treatment"
or "treat" comprises inhibiting, delaying, maintaining,
alleviating, mitigating, restricting, decreasing, suppressing,
repressing or healing a disease, a condition, an ailment, an injury
or a disorder, the development, the course or the progression of
said states and/or the symptoms of said states. The term "therapy"
is to be understood as a synonym of the term "treatment".
[0128] In the context of the present invention, the terms
"prevention" and "prophylaxis" are used synonymously and denote
avoiding or reducing the risk of acquiring, experiencing, suffering
or having a disease, a condition, an ailment, an injury or a
disorder, development or progression of said states and/or the
symptoms of said states.
[0129] The treatment or the prevention of a disease, a condition,
an ailment, an injury or a disorder can be partial or complete.
[0130] Compounds of formula (I) that are preferred in the context
of the present invention are those in which [0131] L stands for a
group #.sup.1-CR.sup.7AR.sup.7B--(CR.sup.8AR.sup.8B).sub.m-#.sup.2,
[0132] wherein [0133] #.sup.1 stands for the point of attachment to
the carbonyl group, [0134] #.sup.2 stands for the point of
attachment to the pyrimidine ring, [0135] m stands for a number 0,
1 or 2, [0136] R.sup.7A stands for hydrogen, fluorine,
(C.sub.1-C.sub.4)-alkyl, hydroxyl or amino, [0137] in which
(C.sub.1-C.sub.4)-alkyl can be substituted with 1 to 3 substituents
selected independently of one another from the group fluorine,
trifluoromethyl, hydroxy, hydroxycarbonyl,
(C.sub.1-C.sub.4)-alkoxycarbonyl and amino, [0138] R.sup.7B stands
for hydrogen, fluorine, difluoromethyl, trifluoromethyl,
(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.4)-alkoxycarbonylamino,
cyano, (C.sub.3-C.sub.7)-cycloalkyl, difluoromethoxy,
trifluoromethoxy, phenyl or a group of formula -M-R.sup.13, [0139]
in which (C.sub.1-C.sub.6)-alkyl can be substituted with 1 to 3
substituents selected independently of one another from the group
fluorine, cyano, trifluoromethyl, (C.sub.3-C.sub.7)-cycloalkyl,
hydroxy, difluoromethoxy, trifluoromethoxy,
(C.sub.1-C.sub.4)-alkoxy, hydroxycarbonyl,
(C.sub.1-C.sub.4)-alkoxycarbonyl and amino, [0140] and in which
[0141] M stands for a bond or (C.sub.1-C.sub.4)-alkanediyl, [0142]
R.sup.13 stands for --(C.dbd.O).sub.r--OR.sup.14,
--(C.dbd.O).sub.r--NR.sup.14R.sup.15,
--C(.dbd.S)--NR.sup.14R.sup.15, --NR.sup.14--(C.dbd.O)--R.sup.17,
--NR.sup.14--(C.dbd.O)--NR.sup.15R.sup.16,
--NR.sup.14--SO.sub.2--NR.sup.15R.sup.16,
--NR.sup.14--SO.sub.2--R.sup.17, --S(O).sub.s--R.sup.17,
--SO.sub.2--NR.sup.14R.sup.15, 4- to 7-membered heterocyclyl,
phenyl or 5- or 6-membered heteroaryl, [0143] in which [0144] r
denotes the number 0 or 1, [0145] s denotes the number 0, 1 or 2,
[0146] R.sup.14, R.sup.15 and R.sup.16 each stand, independently of
one another, for hydrogen, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.8)-cycloalkyl, 4- to 7-membered heterocyclyl, phenyl
or 5- or 6-membered heteroaryl, [0147] or [0148] R.sup.14 and
R.sup.15 form, together with the respective atom(s) to which they
are bound, a 4- to 7-membered heterocycle, [0149] in which for its
part the 4- to 7-membered heterocycle can be substituted with 1 or
2 substituents selected independently of one another from the group
cyano, trifluoromethyl, (C.sub.1-C.sub.6)-alkyl, hydroxy, oxo,
(C.sub.1-C.sub.6)-alkoxy, trifluoromethoxy,
(C.sub.1-C.sub.6)-alkoxycarbonyl, amino,
mono-(C.sub.1-C.sub.6)-alkylamino and
di(C.sub.1-C.sub.6)-alkylamino, [0150] or [0151] R.sup.15 and
R.sup.16 form, together with the respective atom(s) to which they
are bound, a 4- to 7-membered heterocycle, [0152] in which for its
part the 4- to 7-membered heterocycle can be substituted with 1 or
2 substituents selected independently of one another from the group
cyano, trifluoromethyl, (C.sub.1-C.sub.6)-alkyl, hydroxy, oxo,
(C.sub.1-C.sub.6)-alkoxy, trifluoromethoxy,
(C.sub.1-C.sub.6)-alkoxycarbonyl, amino,
mono-(C.sub.1-C.sub.6)-alkylamino and
di(C.sub.1-C.sub.6)-alkylamino, [0153] R.sup.17 stands for
(C.sub.1-C.sub.6)-alkyl or (C.sub.3-C.sub.7)-cycloalkyl, [0154] or
[0155] R.sup.14 and R.sup.17 form, together with the respective
atom(s) to which they are bound, a 4- to 7-membered heterocycle,
[0156] in which for its part the 4- to 7-membered heterocycle can
be substituted with 1 or 2 substituents selected independently of
one another from the group cyano, trifluoromethyl,
(C.sub.1-C.sub.6)-alkyl, hydroxy, oxo, (C.sub.1-C.sub.6)-alkoxy,
trifluoromethoxy, (C.sub.1-C.sub.6)-alkoxycarbonyl, amino,
mono-(C.sub.1-C.sub.6)-alkylamino and
di(C.sub.1-C.sub.6)-alkylamino, [0157] and [0158] in which for
their part the 4- to 7-membered heterocyclyl, phenyl and 5- or
6-membered heteroaryl can be substituted with 1 to 3 substituents
selected independently of one another from the group halogen,
cyano, difluoromethyl, trifluoromethyl, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl, hydroxy, oxo, thiooxo and
(C.sub.1-C.sub.4)-alkoxy, [0159] and [0160] in which the
aforementioned (C.sub.1-C.sub.4)-alkyl-, (C.sub.1-C.sub.6)-alkyl-,
(C.sub.3-C.sub.8)-cycloalkyl- and 4- to 7-membered heterocyclyl
groups, unless stated otherwise, can in each case be further
substituted independently of one another with 1 to 3 substituents
selected independently of one another from the group fluorine,
difluoromethyl, trifluoromethyl, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl, hydroxy, difluoromethoxy,
trifluoromethoxy, (C.sub.1-C.sub.4)-alkoxy, hydroxycarbonyl,
(C.sub.1-C.sub.4)-alkoxycarbonyl, amino, phenyl, 4- to 7-membered
heterocyclyl and 5- or 6-membered heteroaryl, [0161] or [0162]
R.sup.7A and R.sup.7B together with the carbon atom to which they
are bound, form a (C.sub.2-C.sub.4)-alkenyl group, an oxo group, a
3- to 6-membered carbocycle or a 4- to 7-membered heterocycle,
[0163] in which the 3- to 6-membered carbocycle and the 4- to
7-membered heterocycle can be substituted with 1 or 2 substituents
selected independently of one another from the group fluorine and
(C.sub.1-C.sub.4)-alkyl, [0164] R.sup.8A stands for hydrogen,
fluorine, (C.sub.1-C.sub.4)-alkyl or hydroxy, [0165] R.sup.8B
stands for hydrogen, fluorine, (C.sub.1-C.sub.4)-alkyl or
trifluoromethyl, the ring Q stands for 8- or 9-membered heteroaryl,
[0166] R.sup.3 stands for --OR.sup.4 or --NR.sup.5R.sup.6, [0167]
wherein [0168] R.sup.4 stands for hydrogen,
(C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl, 4- to
7-membered heterocyclyl, phenyl or 5- or 6-membered heteroaryl,
[0169] in which (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl, 4- to 7-membered heterocyclyl, phenyl
and 5- or 6-membered heteroaryl can be substituted with 1 to 3
substituents selected independently of one another from the group
fluorine, difluoromethyl, trifluoromethyl, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.6)-cycloalkyl, difluoromethoxy, trifluoromethoxy,
oxo, --(C.dbd.O).sub.p--OR.sup.9,
--C(.dbd.O).sub.p--NR.sup.9R.sup.10,
--NR.sup.9--(C.dbd.O)--R.sup.10, --NR.sup.9--(C.dbd.O)--OR.sup.10,
--NR.sup.9--(C.dbd.O)--NR.sup.10R.sup.11,
--NR.sup.9--SO.sub.2--R.sup.10, --S(O).sub.q--R.sup.12 and
--SO.sub.2--NR.sup.9R.sup.10, [0170] in which [0171] p denotes the
number 0 or 1, [0172] q denotes the number 0, 1 or 2, [0173]
R.sup.9, R.sup.10 and R.sup.11 each stand, independently of one
another, for hydrogen, (C.sub.1-C.sub.6)-alkyl or
(C.sub.3-C.sub.8)-cycloalkyl, [0174] in which
(C.sub.1-C.sub.6)-alkyl for its part can be substituted with 1 or 2
substituents selected independently of one another from the group
fluorine, difluoromethyl, trifluoromethyl, hydroxy,
(C.sub.1-C.sub.6)-alkoxy, difluoromethoxy, trifluoromethoxy,
(C.sub.1-C.sub.6)-alkoxycarbonyl, amino,
mono-(C.sub.1-C.sub.6)-alkylamino, di(C.sub.1-C.sub.6)-alkylamino
and 4- to 7-membered heterocyclyl, [0175] or [0176] R.sup.9 and
R.sup.10 form, together with the respective atom(s) to which they
are bound, a 4- to 7-membered heterocycle, [0177] in which for its
part the 4- to 7-membered heterocycle can be substituted with 1 or
2 substituents selected independently of one another from the group
fluorine, trifluoromethyl, (C.sub.1-C.sub.6)-alkyl, hydroxy, oxo,
(C.sub.1-C.sub.6)-alkoxy, trifluoromethoxy,
(C.sub.1-C.sub.6)-alkoxycarbonyl, amino,
mono-(C.sub.1-C.sub.6)-alkylamino and
di(C.sub.1-C.sub.6)-alkylamino, [0178] or [0179] R.sup.10 and
R.sup.11 form, together with the respective atom(s) to which they
are bound, a 4- to 7-membered heterocycle, [0180] in which for its
part the 4- to 7-membered heterocycle can be substituted with 1 or
2 substituents selected independently of one another from the group
fluorine, trifluoromethyl, (C.sub.1-C.sub.6)-alkyl, hydroxy, oxo,
(C.sub.1-C.sub.6)-alkoxy, trifluoromethoxy,
(C.sub.1-C.sub.6)-alkoxycarbonyl, amino,
mono-(C.sub.1-C.sub.6)-alkylamino and
di(C.sub.1-C.sub.6)-alkylamino, [0181] and in which [0182] R.sup.12
stands for (C.sub.1-C.sub.6)-alkyl or (C.sub.3-C.sub.7)-cycloalkyl,
[0183] and [0184] in which the aforementioned
(C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.8)-cycloalkyl and 4- to 7-membered heterocyclyl
groups, unless stated otherwise, can in each case be further
substituted independently of one another with 1 to 3 substituents
selected independently of one another from the group fluorine,
difluoromethyl, trifluoromethyl, (C.sub.3-C.sub.7)-cycloalkyl,
hydroxy, difluoromethoxy, trifluoromethoxy,
(C.sub.1-C.sub.4)-alkoxy, hydroxycarbonyl,
(C.sub.1-C.sub.4)-alkoxycarbonyl, amino, phenyl, 4- to 7-membered
heterocyclyl and 5- or 6-membered heteroaryl, [0185] R.sup.5 stands
for hydrogen or (C.sub.1-C.sub.4)-alkyl, [0186] R.sup.6 stands for
(C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl, 4- to
7-membered heterocyclyl, phenyl or 5- or 6-membered heteroaryl,
[0187] in which (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl, 4- to 7-membered heterocyclyl, phenyl
and 5- or 6-membered heteroaryl can be substituted with 1 to 3
substituents selected independently of one another from the group
fluorine, difluoromethyl, trifluoromethyl, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl, difluoromethoxy, trifluoromethoxy,
oxo, --(C.dbd.O).sub.p--OR.sup.9,
--(C.dbd.O).sub.p--NR.sup.9R.sup.10,
--NR.sup.9--(C.dbd.O)--R.sup.10, --NR.sup.9--(C.dbd.O)--OR.sup.10,
--NR.sup.9--(C.dbd.O)--NR.sup.10R.sup.11,
--NR.sup.9--SO.sub.2--R.sup.10, --S(O).sub.q--R.sup.12,
--SO.sub.2--NR.sup.9R.sup.10, phenyl, 4- to 7-membered heterocyclyl
and 5- or 6-membered heteroaryl, [0188] in which [0189] p denotes
the number 0 or 1, [0190] q denotes the number 0, 1 or 2, [0191]
R.sup.9, R.sup.10 and R.sup.11 each stand, independently of one
another, for hydrogen, (C.sub.1-C.sub.6)-alkyl or
(C.sub.3-C.sub.8)-cycloalkyl, [0192] in which
(C.sub.1-C.sub.6)-alkyl for its part can be substituted with 1 to 3
substituents selected independently of one another from the group
fluorine, difluoromethyl, trifluoromethyl,
(C.sub.3-C.sub.7)-cycloalkyl, difluoromethoxy, trifluoromethoxy and
(C.sub.1-C.sub.4)-alkoxy, [0193] or [0194] R.sup.9 and R.sup.10
form, together with the respective atom(s) to which they are bound,
a 4- to 7-membered heterocycle, [0195] in which for its part the 4-
to 7-membered heterocycle can be substituted with 1 or 2
substituents selected independently of one another from the group
fluorine, cyano, trifluoromethyl, (C.sub.1-C.sub.6)-alkyl, hydroxy,
oxo, (C.sub.1-C.sub.6)-alkoxy, trifluoromethoxy,
(C.sub.1-C.sub.6)-alkoxycarbonyl, amino,
mono-(C.sub.1-C.sub.6)-alkylamino and
di(C.sub.1-C.sub.6)-alkylamino, [0196] or [0197] R.sup.10 and
R.sup.11 form, together with the respective atom(s) to which they
are bound, a 4- to 7-membered heterocycle, [0198] in which for its
part the 4- to 7-membered heterocycle can be substituted with 1 or
2 substituents selected independently of one another from the group
cyano, trifluoromethyl, (C.sub.1-C.sub.6)-alkyl, hydroxy, oxo,
(C.sub.1-C.sub.6)-alkoxy, trifluoromethoxy,
(C.sub.1-C.sub.6)-alkoxycarbonyl, amino,
mono-(C.sub.1-C.sub.6)-alkylamino and
di(C.sub.1-C.sub.6)-alkylamino, [0199] in which [0200] R.sup.12
stands for (C.sub.1-C.sub.6)-alkyl or (C.sub.3-C.sub.7)-cycloalkyl,
[0201] and [0202] in which phenyl, 4- to 7-membered heterocyclyl
and 5- or 6-membered heteroaryl for their part can be substituted
with 1 to substituents selected independently of one another from
the group halogen, cyano, difluoromethyl, trifluoromethyl,
(C.sub.1-C.sub.4)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl, hydroxy,
oxo, difluoromethoxy, trifluoromethoxy and
(C.sub.1-C.sub.4)-alkoxy, [0203] or [0204] R.sup.5 and R.sup.6
form, together with the nitrogen atom to which they are bound, a 4-
to 7-membered heterocycle or a 5- or 6-membered heteroaryl, [0205]
in which the 4- to 7-membered heterocycle and the 5- or 6-membered
heteroaryl can be substituted with 1 to 3 substituents selected
independently of one another from the group fluorine, cyano,
difluoromethyl, trifluoromethyl, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl, hydroxy, oxo,
(C.sub.1-C.sub.6)-alkoxy, difluoromethoxy, trifluoromethoxy,
(C.sub.1-C.sub.6)-alkoxycarbonyl, amino,
mono-(C.sub.1-C.sub.6)-alkylamino and
di(C.sub.1-C.sub.6)-alkylamino, [0206] and [0207] in which the
aforementioned (C.sub.1-C.sub.4)-alkyl-, (C.sub.1-C.sub.6)-alkyl-,
(C.sub.3-C.sub.8)-cycloalkyl- and 4- to 7-membered heterocyclyl
groups, unless stated otherwise, can in each case be further
substituted independently of one another with 1 to 3 substituents
selected independently of one another from the group fluorine,
difluoromethyl, trifluoromethyl, (C.sub.3-C.sub.7)-cycloalkyl,
hydroxy, difluoromethoxy, trifluoromethoxy,
(C.sub.1-C.sub.4)-alkoxy, hydroxycarbonyl, alkoxycarbonyl, amino,
phenyl, 4- to 7-membered heterocyclyl and 5- or 6-membered
heteroaryl, [0208] R.sup.1 stands for fluorine, chlorine, cyano,
difluoromethyl, trifluoromethyl, (C.sub.1-C.sub.4)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl or (C.sub.1-C.sub.4)-alkoxy, [0209] n
stands for a number 0, 1 or 2, [0210] R.sup.2 stands for
trifluoromethyl, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.8)-cycloalkyl, phenyl or 5- or 6-membered
heteroaryl, [0211] wherein (C.sub.1-C.sub.6)-alkyl is substituted
with a substituent selected from the group difluoromethyl and
trifluoromethyl, [0212] wherein (C.sub.1-C.sub.6)-alkyl can be
substituted with 1 to 3 fluorine substituents, [0213] wherein
(C.sub.3-C.sub.8)-cycloalkyl can be substituted with 1 or 2
substituents selected independently of one another from the group
fluorine, methyl and methoxy, [0214] wherein phenyl is substituted
with 1 to 3 fluorine substituents, [0215] wherein phenyl can be
substituted with 1 or 2 substituents selected independently of one
another from the group methyl and methoxy, [0216] and [0217]
wherein 5- and 6-membered heteroaryl can be substituted with 1 or 2
substituents selected independently of one another from the group
fluorine, trifluoromethyl and methyl, and their N-oxides, salts,
solvates, salts of the N-oxides and solvates of the N-oxides and
salts.
[0218] In the context of the present invention, compounds of
formula (I) are preferred in which [0219] L stands for a group
#.sup.1-CR.sup.7AR.sup.7B--(CR.sup.8AR.sup.8B).sub.m-#.sup.2,
[0220] wherein [0221] #.sup.1 stands for the point of attachment to
the carbonyl group, [0222] #.sup.2 stands for the attachment to the
pyrimidine ring, [0223] m stands for a number 0 or 1, [0224]
R.sup.7A stands for hydrogen, fluorine, methyl, ethyl, hydroxy or
amino, [0225] R.sup.7B stands for hydrogen, fluorine,
difluoromethyl, trifluoromethyl, (C.sub.1-C.sub.4)-alkyl,
methoxycarbonylamino, cyano, cyclopropyl, cyclobutyl, cyclopentyl,
phenyl or a group of formula -M-R.sup.13, [0226] in which
(C.sub.1-C.sub.4)-alkyl can be substituted with 1 to 3 substituents
selected independently of one another from the group fluorine,
cyano, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl,
hydroxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy,
hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl and amino, [0227]
and in which [0228] M stands for a bond or methylene, [0229]
R.sup.13 stands for --(C.dbd.O).sub.r--NR.sup.14R.sup.15,
--C(.dbd.S)--NR.sup.14R.sup.15, oxadiazolonyl, oxadiazolethionyl,
phenyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, oxadiazolyl,
thiadiazolyl, pyridyl, pyrimidinyl or pyrazinyl, [0230] in which
[0231] r denotes the number 0 or 1, [0232] R.sup.14 and R.sup.15
each stand, independently of one another, for hydrogen, methyl,
ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl,
azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl,
piperidinyl, piperazinyl, morpholinyl, phenyl, pyrazolyl or
pyridyl, [0233] in which methyl, ethyl and iso-propyl can be
further substituted with 1 or 2 substituents selected independently
of one another from the group fluorine, difluoromethyl,
trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxy,
difluoromethoxy, trifluoromethoxy, methoxy, ethoxy,
hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl and amino, [0234]
and [0235] in which oxadiazolonyl, oxadiazolethionyl, phenyl,
oxazolyl, thiazolyl, pyrazolyl, triazolyl, oxadiazolyl,
thiadiazolyl, pyridyl, pyrimidinyl and pyrazinyl for their part can
be substituted with 1 or 2 substituents selected independently of
one another from the group fluorine, chlorine, cyano,
difluoromethyl, trifluoromethyl, methyl, ethyl, isopropyl,
2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, cyclopropyl,
cyclobutyl, cyclopropylmethyl, cyclobutylmethyl, hydroxy, methoxy
and ethoxy, [0236] or [0237] R.sup.7A and R.sup.7B together with
the carbon atom to which they are bound, form a cyclopropyl,
cyclobutyl, cyclopentyl, azetidinyl, tetrahydrofuranyl,
pyrrolidinyl or tetrahydropyranyl ring, [0238] in which the
cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl,
tetrahydrofuranyl, pyrrolidinyl and tetrahydropyranyl ring can be
substituted with 1 or 2 substituents selected independently of one
another from the group fluorine and methyl, [0239] R.sup.8A stands
for hydrogen, fluorine, methyl, ethyl or hydroxy, [0240] R.sup.8B
stands for hydrogen, fluorine, methyl, ethyl or trifluoromethyl,
the ring Q stands for a group of formula
##STR00002## ##STR00003##
[0240] wherein [0241] * stands for the point of attachment to
--CH.sub.2--R.sup.2, [0242] ** stands for the point of attachment
to the pyrimidine, the ring Q.sub.1 together with the atoms to
which it is bound, forms a 5- to 7-membered saturated or partially
unsaturated carbocycle or a 5- to 7-membered saturated or partially
unsaturated heterocycle, [0243] R.sup.1 stands for fluorine,
chlorine or methyl, [0244] n stands for a number 0, 1 or 2, [0245]
A.sup.1, A.sup.2, A.sup.3 and A.sup.4 independently of one another
stand in each case for N, CH or CR.sup.1, [0246] with the proviso
that at most two of the groups A.sup.1, A.sup.2, A.sup.3 and
A.sup.4 stand for N, [0247] R.sup.3 stands for --OR.sup.4 or
--NR.sup.5R.sup.6, [0248] wherein [0249] R.sup.4 stands for
(C.sub.1-C.sub.6)-alkyl, cyclopropyl, cyclobutyl, cyclopentyl,
oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl,
tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl,
pyrazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl,
thiadiazolyl, pyridyl or pyrimidinyl, [0250] in which
(C.sub.1-C.sub.6)-alkyl can be substituted with 1 to 3 substituents
selected independently of one another from the group fluorine,
difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl,
cyclopentyl, difluoromethoxy, trifluoromethoxy,
--(C.dbd.O).sub.p--OR.sup.9, --(C.dbd.O).sub.p--NR.sup.9R.sup.10,
and --NR.sup.9--(C.dbd.O)--R.sup.10, [0251] and [0252] in which
cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl,
tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl,
piperazinyl, morpholinyl, phenyl, pyrazolyl, oxazolyl, thiazolyl,
triazolyl, oxadiazolyl, thiadiazolyl, pyridyl or pyrimidinyl can be
substituted with 1 to 3 substituents selected independently of one
another from the group fluorine, difluoromethyl, trifluoromethyl,
2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, methyl, ethyl,
isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethoxy,
trifluoromethoxy, oxo, --(C.dbd.O).sub.p--OR.sup.9 and
--(C.dbd.O).sub.p--NR.sup.9R.sup.10, [0253] in which [0254] p
denotes the number 0 or 1, [0255] R.sup.9 and R.sup.10 each stand,
independently of one another, for hydrogen, methyl, ethyl,
isopropyl, trifluoromethyl, 2,2,2-trifluoroethyl,
1,1,2,2,2-pentafluoroethyl, cyclopropyl, cyclobutyl or cyclopentyl,
[0256] or [0257] R.sup.9 and R.sup.10 form, together with the
respective atom(s) to which they are bound, an azetidinyl,
pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring, [0258]
in which the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and
morpholinyl ring for its part can be substituted with 1 or 2
substituents selected independently of one another from the group
fluorine, trifluoromethyl, methyl, ethyl, hydroxy, oxo, methoxy,
ethoxy, amino, methylamino, ethylamino, dimethylamino and
diethylamino, [0259] R.sup.5 stands for hydrogen, methyl or ethyl,
[0260] R.sup.6 stands for (C.sub.1-C.sub.6)-alkyl, cyclopropyl,
(C.sub.3-C.sub.6)-cycloalkyl, oxetanyl, azetidinyl,
tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl,
piperazinyl, morpholinyl, phenyl, pyrazolyl, oxazolyl, thiazolyl,
triazolyl, oxadiazolyl, thiadiazolyl, pyridyl or pyrimidinyl,
[0261] in which (C.sub.1-C.sub.6)-alkyl and
(C.sub.3-C.sub.6)-cycloalkyl are substituted with 1 to 3
substituents selected independently of one another from the group
fluorine, difluoromethyl, trifluoromethyl, methyl, ethyl,
cyclopropyl, cyclobutyl, cyclopentyl, difluoromethoxy,
trifluoromethoxy, --(C.dbd.O).sub.p--OR.sup.9,
--(C.dbd.O).sub.p--NR.sup.9R.sup.10,
--NR.sup.9--(C.dbd.O)--R.sup.10, oxetanyl, azetidinyl,
tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl,
piperazinyl, morpholinyl, phenyl, furanyl, pyrazolyl, imidazolyl,
oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl
and pyrimidinyl, [0262] in which cyclopropyl, cyclobutyl,
cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl,
tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl,
furanyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl,
oxadiazolyl, thiadiazolyl, pyridyl and pyrimidinyl for their part
can be substituted with 1 or 2 substituents selected independently
of one another from the group fluorine, chlorine, cyano,
difluoromethyl, trifluoromethyl, methyl, ethyl, cyclopropyl,
cyclobutyl, cyclopentyl, hydroxy, oxo, difluoromethoxy,
trifluoromethoxy, methoxy and ethoxy, [0263] in which oxetanyl,
azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl,
piperidinyl, piperazinyl, morpholinyl, phenyl, pyrazolyl, oxazolyl,
thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl and
pyrimidinyl can be substituted with 1 to 3 substituents selected
independently of one another from the group fluorine,
difluoromethyl, trifluoromethyl, methyl, ethyl, cyclopropyl,
cyclobutyl, cyclopentyl, difluoromethoxy, trifluoromethoxy, oxo,
--(C.dbd.O).sub.p--OR.sup.9 and
--(C.dbd.O).sub.p--NR.sup.9R.sup.10, [0264] in which [0265] p
denotes the number 0 or 1, [0266] R.sup.9 and R.sup.10 each stand,
independently of one another, for hydrogen, methyl, ethyl,
isopropyl, trifluoromethyl, 2,2,2-trifluoroethyl,
1,1,2,2,2-pentafluoroethyl, cyclopropyl, cyclobutyl or cyclopentyl,
[0267] or [0268] R.sup.9 and R.sup.10 form, together with the
respective atom(s) to which they are bound, an azetidinyl,
pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring, [0269]
in which the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and
morpholinyl ring for its part can be substituted with 1 or 2
substituents selected independently of one another from the group
fluorine, trifluoromethyl, methyl, ethyl, hydroxy, oxo, methoxy,
ethoxy, amino, methylamino, ethylamino, dimethylamino and
diethylamino, [0270] or [0271] R.sup.5 and R.sup.6 form, together
with the nitrogen atom to which they are bound, an azetidinyl,
pyrrolidinyl, imidazolidinyl, piperidinyl, dihydropiperidinyl,
piperazinyl, morpholinyl, pyrazolyl, imidazolyl or triazolyl ring,
[0272] in which the azetidinyl, pyrrolidinyl, imidazolidinyl,
piperidinyl, dihydropiperidinyl, piperazinyl, morpholinyl,
pyrazolyl, imidazolyl and triazolyl ring can be substituted with 1
or 2 substituents selected independently of one another from the
group fluorine, cyano, difluoromethyl, trifluoromethyl,
2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, methyl, ethyl,
1-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxy, oxo,
methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, oxetanyl,
azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl,
piperidinyl, piperazinyl and morpholinyl, [0273] R.sup.2 stands for
trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoroprop-1-yl,
2,2,3,3,3-pentafluoroprop-1-yl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl or
pyridazinyl, [0274] wherein phenyl is substituted with 1 to 3
fluorine substituents, [0275] and [0276] wherein cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, pyrimidinyl,
pyrazinyl and pyridazinyl can be substituted with 1 or 2 fluorine
substituents, and their salts, solvates and solvates of the
salts.
[0277] In the context of the present invention, compounds of
formula (I) are preferred in which [0278] L stands for a group
#.sup.1-CR.sup.7AR.sup.7B--(CR.sup.8AR.sup.8B).sub.m-#.sup.2,
[0279] wherein [0280] #.sup.1 stands for the point of attachment to
the carbonyl group, [0281] #.sup.2 stands for the point of
attachment to the pyrimidine ring, [0282] m stands for a number 0
or 1, [0283] R.sup.7A stands for hydrogen, fluorine, methyl, ethyl,
hydroxy or amino, [0284] R.sup.7B stands for hydrogen, fluorine,
difluoromethyl, trifluoromethyl, (C.sub.1-C.sub.4)-alkyl,
methoxycarbonylamino, cyano, cyclopropyl, cyclobutyl, cyclopentyl,
phenyl or a group of formula -M-R.sup.13, [0285] in which
(C.sub.1-C.sub.4)-alkyl can be substituted with 1 to 3 substituents
selected independently of one another from the group fluorine,
cyano, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl,
hydroxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy,
hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl and amino, [0286]
and in which [0287] M stands for a bond or methylene, [0288]
R.sup.3 stands for --(C.dbd.O).sub.r--NR.sup.14R.sup.15,
--C(.dbd.S)--NR.sup.14R.sup.15, oxadiazolonyl, oxadiazolethionyl,
phenyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, oxadiazolyl,
thiadiazolyl, pyridyl, pyrimidinyl or pyrazinyl, [0289] in which
[0290] r denotes the number 0 or 1, [0291] R.sup.14 and R.sup.15
each stand, independently of one another, for hydrogen, methyl,
ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl,
azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl,
piperidinyl, piperazinyl, morpholinyl, phenyl, pyrazolyl or
pyridyl, [0292] in which methyl, ethyl and iso-propyl can be
further substituted with 1 or 2 substituents selected independently
of one another from the group fluorine, difluoromethyl,
trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxy,
difluoromethoxy, trifluoromethoxy, methoxy, ethoxy,
hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl and amino, [0293]
and [0294] in which oxadiazolonyl, oxadiazolethionyl, phenyl,
oxazolyl, thiazolyl, pyrazolyl, triazolyl, oxadiazolyl,
thiadiazolyl, pyridyl, pyrimidinyl and pyrazinyl for their part can
be substituted with 1 or 2 substituents selected independently of
one another from the group fluorine, chlorine, cyano,
difluoromethyl, trifluoromethyl, methyl, ethyl, isopropyl,
2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, cyclopropyl,
cyclobutyl, cyclopropylmethyl, cyclobutylmethyl, hydroxy, methoxy
and ethoxy, [0295] or [0296] R.sup.7A and R.sup.7B together with
the carbon atom to which they are bound, form a cyclopropyl,
cyclobutyl, cyclopentyl, azetidinyl, tetrahydrofuranyl,
pyrrolidinyl or tetrahydropyranyl ring, [0297] in which the
cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl,
tetrahydrofuranyl, pyrrolidinyl and tetrahydropyranyl ring can be
substituted with 1 or 2 substituents selected independently of one
another from the group fluorine and methyl, [0298] R.sup.8A stands
for hydrogen, fluorine, methyl, ethyl or hydroxy, [0299] R.sup.8B
stands for hydrogen, fluorine, methyl, ethyl or trifluoromethyl,
the ring Q stands for a group of formula
##STR00004## ##STR00005## ##STR00006##
[0299] wherein [0300] * stands for the point of attachment to
--CH.sub.2--R.sup.2, [0301] ** stands for the point of attachment
to the pyrimidine, the ring Q.sub.1 together with the atoms to
which it is bound, forms a 5- to 7-membered saturated or partially
unsaturated carbocycle or a 5- to 7-membered saturated or partially
unsaturated heterocycle, [0302] R.sup.1 stands for fluorine,
chlorine or methyl, [0303] n stands for a number 0, 1 or 2, [0304]
A.sup.1, A.sup.2, A.sup.3 and A.sup.4 independently of one another
stand in each case for N, CH or CR.sup.1, [0305] with the proviso
that at most two of the groups A.sup.1, A.sup.2, A.sup.3 and
A.sup.4 stand for N, [0306] R.sup.3 stands for --OR.sup.4 or
--NR.sup.5R.sup.6, [0307] wherein [0308] R.sup.4 stands for
(C.sub.1-C.sub.6)-alkyl, cyclopropyl, cyclobutyl, cyclopentyl,
oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl,
tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl,
pyrazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl,
thiadiazolyl, pyridyl or pyrimidinyl, [0309] in which
(C.sub.1-C.sub.6)-alkyl can be substituted with 1 to 3 substituents
selected independently of one another from the group fluorine,
difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl,
cyclopentyl, difluoromethoxy, trifluoromethoxy,
--(C.dbd.O).sub.p--OR.sup.9, --(C.dbd.O).sub.p--NR.sup.9R.sup.10,
and --NR.sup.9--(C.dbd.O)--R.sup.10, [0310] and [0311] in which
cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl,
tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl,
piperazinyl, morpholinyl, phenyl, pyrazolyl, oxazolyl, thiazolyl,
triazolyl, oxadiazolyl, thiadiazolyl, pyridyl or pyrimidinyl can be
substituted with 1 to 3 substituents selected independently of one
another from the group fluorine, difluoromethyl, trifluoromethyl,
2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, methyl, ethyl,
isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethoxy,
trifluoromethoxy, oxo, --(C.dbd.O).sub.p--OR.sup.9 and
--(C.dbd.O).sub.p--NR.sup.9R.sup.10, [0312] in which [0313] p
denotes the number 0 or 1, [0314] R.sup.9 and R.sup.10 each stand,
independently of one another, for hydrogen, methyl, ethyl,
isopropyl, trifluoromethyl, 2,2,2-trifluoroethyl,
1,1,2,2,2-pentafluoroethyl, cyclopropyl, cyclobutyl or cyclopentyl,
[0315] or [0316] R.sup.9 and R.sup.10 form, together with the
respective atom(s) to which they are bound, an azetidinyl,
pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring, [0317]
in which the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and
morpholinyl ring for its part can be substituted with 1 or 2
substituents selected independently of one another from the group
fluorine, trifluoromethyl, methyl, ethyl, hydroxy, oxo, methoxy,
ethoxy, amino, methylamino, ethylamino, dimethylamino and
diethylamino, [0318] R.sup.5 stands for hydrogen, methyl or ethyl,
[0319] R.sup.6 stands for (C.sub.1-C.sub.6)-alkyl, cyclopropyl,
cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuranyl,
pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl,
morpholinyl, phenyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl,
oxadiazolyl, thiadiazolyl, pyridyl or pyrimidinyl, [0320] in which
(C.sub.1-C.sub.6)-alkyl, cyclopropyl, cyclobutyl and cyclopentyl
are substituted with 1 to 3 substituents selected independently of
one another from the group fluorine, difluoromethyl,
trifluoromethyl methyl, ethyl, cyclopropyl, cyclobutyl,
cyclopentyl, difluoromethoxy, trifluoromethoxy,
--(C.dbd.O).sub.p--OR.sup.9, --(C.dbd.O).sub.p--NR.sup.9R.sup.10,
--NR.sup.9--(C.dbd.O)--R.sup.10, oxetanyl, azetidinyl,
tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl,
piperazinyl, morpholinyl, phenyl, furanyl, pyrazolyl, imidazolyl,
oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl
and pyrimidinyl, [0321] in which oxetanyl, azetidinyl,
tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl,
piperazinyl, morpholinyl, phenyl, furanyl, pyrazolyl, imidazolyl,
oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl
and pyrimidinyl for their part can be substituted with 1 or 2
substituents selected independently of one another from the group
fluorine, chlorine, cyano, difluoromethyl, trifluoromethyl, methyl,
ethyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxy, oxo,
difluoromethoxy, trifluoromethoxy, methoxy and ethoxy, [0322] in
which oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl,
tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl,
pyrazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl,
thiadiazolyl, pyridyl and pyrimidinyl can be substituted with 1 to
3 substituents selected independently of one another from the group
fluorine, difluoromethyl, trifluoromethyl, methyl, ethyl,
cyclopropyl, cyclobutyl, cyclopentyl, difluoromethoxy,
trifluoromethoxy, oxo, --(C.dbd.O).sub.p--OR.sup.9 and
--(C.dbd.O).sub.p--NR.sup.9R.sup.10, [0323] in which [0324] p
denotes the number 0 or 1, [0325] R.sup.9 and R.sup.10 each stand,
independently of one another, for hydrogen, methyl, ethyl,
isopropyl, trifluoromethyl, 2,2,2-trifluoroethyl,
1,1,2,2,2-pentafluoroethyl, cyclopropyl, cyclobutyl or cyclopentyl,
[0326] or [0327] R.sup.9 and R.sup.10 form, together with the
respective atom(s) to which they are bound, an azetidinyl,
pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring, [0328]
in which the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and
morpholinyl ring for its part can be substituted with 1 or 2
substituents selected independently of one another from the group
fluorine, trifluoromethyl, methyl, ethyl, hydroxy, oxo, methoxy,
ethoxy, amino, methylamino, ethylamino, dimethylamino and
diethylamino, [0329] or [0330] R.sup.5 and R.sup.6 form, together
with the nitrogen atom to which they are bound, an azetidinyl,
pyrrolidinyl, imidazolidinyl, piperidinyl, dihydropiperidinyl,
piperazinyl, morpholinyl, pyrazolyl, imidazolyl or triazolyl ring,
[0331] in which the azetidinyl, pyrrolidinyl, imidazolidinyl,
piperidinyl, dihydropiperidinyl, piperazinyl, morpholinyl,
pyrazolyl, imidazolyl and triazolyl ring can be substituted with 1
or 2 substituents selected independently of one another from the
group fluorine, cyano, difluoromethyl, trifluoromethyl,
2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, methyl, ethyl,
1-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxy, oxo,
methoxy, ethoxy, difluoromethoxy and trifluoromethoxy, [0332]
R.sup.2 stands for trifluoromethyl, 2,2,2-trifluoroethyl,
3,3,3-trifluoroprop-1-yl, 2,2,3,3,3-pentafluoroprop-1-yl,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl,
pyrimidinyl, pyrazinyl or pyridazinyl, [0333] wherein phenyl is
substituted with 1 to 3 fluorine substituents, [0334] and [0335]
wherein cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyridyl,
pyrimidinyl, pyrazinyl and pyridazinyl can be substituted with 1 or
2 fluorine substituents, and their salts, solvates and solvates of
the salts.
[0336] In the context of the present invention, compounds of
formula (I) are also preferred in which [0337] L stands for a group
#.sup.1-CR.sup.7AR.sup.7B--(CR.sup.8AR.sup.8B).sub.m-#.sup.2,
[0338] wherein [0339] #.sup.1 stands for the point of attachment to
the carbonyl group, [0340] #.sup.2 stands for the point of
attachment to the pyrimidine ring, [0341] m stands for a number 0,
[0342] R.sup.7A stands for hydrogen, fluorine, methyl, ethyl,
hydroxy or amino, [0343] R.sup.7B stands for hydrogen, fluorine,
difluoromethyl, trifluoromethyl, methyl, ethyl,
methoxycarbonylamino, cyclopropyl, cyclobutyl, cyclopentyl, or a
group of formula -M-R.sup.13, [0344] in which methyl and ethyl can
be substituted with 1 to 3 substituents selected independently of
one another from the group fluorine, cyano, trifluoromethyl,
cyclopropyl, cyclobutyl, hydroxy, difluoromethoxy,
trifluoromethoxy, methoxy, ethoxy, hydroxycarbonyl,
methoxycarbonyl, ethoxycarbonyl and amino, [0345] and in which
[0346] M stands for a bond, [0347] R.sup.13 stands for
--(C.dbd.O).sub.r--NR.sup.14R.sup.15, phenyl, thiazolyl, triazolyl,
oxadiazolyl, thiadiazolyl or pyrimidinyl, [0348] in which [0349] r
denotes the number 1, [0350] R.sup.14 and R.sup.15 independently of
one another stand in each case for hydrogen or cyclopropyl, [0351]
and [0352] in which phenyl, thiazolyl, triazolyl, oxadiazolyl,
thiadiazolyl and pyrimidinyl for their part can be substituted with
1 or 2 substituents selected independently of one another from the
group fluorine, difluoromethyl, trifluoromethyl, methyl, ethyl,
isopropyl, 2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl,
cyclopropyl, cyclobutyl, cyclopropylmethyl and cyclobutylmethyl,
[0353] or [0354] R.sup.7A and R.sup.7B together with the carbon
atom to which they are bound, form a cyclopropyl, cyclobutyl,
cyclopentyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl or
tetrahydropyranyl ring, [0355] in which the cyclopropyl,
cyclobutyl, cyclopentyl, azetidinyl, tetrahydrofuranyl,
pyrrolidinyl and tetrahydropyranyl ring can be substituted with 1
or 2 substituents selected independently of one another from the
group fluorine and methyl, the ring Q stands for a group of
formula
##STR00007##
[0355] wherein [0356] * stands for the point of attachment to
--CH.sub.2--R.sup.2, [0357] ** stands for the point of attachment
to the pyrimidine, [0358] R.sup.1a stands for hydrogen or methyl,
[0359] R.sup.1b stands for hydrogen or fluorine, [0360] R.sup.1c
stands for hydrogen or chlorine, [0361] A.sup.1 stands for N or CH,
[0362] A.sup.3 stands for N, CH or C--F, [0363] R.sup.3 stands for
--OR.sup.4 or --NR.sup.5R.sup.6, [0364] wherein [0365] R.sup.4
stands for (C.sub.1-C.sub.6)-alkyl or pyrazolyl, [0366] in which
(C.sub.1-C.sub.6)-alkyl can be substituted with 1 to 3 substituents
selected independently of one another from the group fluorine,
trifluoromethyl, --(C.dbd.O).sub.p--OR.sup.9 and
--(C.dbd.O).sub.p--NR.sup.9R.sup.10, [0367] in which [0368] p
denotes the number 0 or 1, [0369] R.sup.9 and R.sup.10 each stand,
independently of one another, for hydrogen, or methyl, [0370] and
[0371] in which pyrazolyl can be substituted with 1 or 2
substituents selected independently of one another from the group
fluorine, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl,
1,1,2,2,2-pentafluoroethyl, methyl, cyclopropyl, cyclobutyl,
cyclopentyl. [0372] R.sup.5 stands for hydrogen, methyl or ethyl,
[0373] R.sup.6 stands for (C.sub.1-C.sub.6)-alkyl, oxetanyl,
azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl,
piperidinyl, piperazinyl, morpholinyl, phenyl, pyrazolyl, oxazolyl,
thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl or
pyrimidinyl, [0374] in which (C.sub.1-C.sub.6)-alkyl is substituted
with 1 or 2 substituents selected independently of one another from
the group fluorine, difluoromethyl, trifluoromethyl cyclopropyl,
cyclobutyl, cyclopentyl, trifluoromethoxy,
--(C.dbd.O).sub.p--OR.sup.9, --(C.dbd.O).sub.p--NR.sup.9R.sup.10,
tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, phenyl,
furanyl, pyrazolyl, imidazolyl, triazolyl and pyridyl, [0375] in
which [0376] p denotes the number 0 or 1, [0377] R.sup.9 and
R.sup.10 each stand, independently of one another, for hydrogen,
methyl, ethyl, trifluoromethyl, 2,2,2-trifluoroethyl,
1,1,2,2,2-pentafluoroethyl, cyclopropyl or cyclobutyl, [0378] and
[0379] in which tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl,
phenyl, furanyl, pyrazolyl, imidazolyl, triazolyl and pyridyl for
their part can be substituted with 1 or 2 substituents selected
independently of one another from the group fluorine, chlorine,
cyano, difluoromethyl, trifluoromethyl, methyl, ethyl and oxo,
[0380] in which oxetanyl, azetidinyl, tetrahydrofuranyl,
pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl,
morpholinyl, phenyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl,
oxadiazolyl, thiadiazolyl, pyridyl and pyrimidinyl can be
substituted with 1 or 2 substituents selected independently of one
another from the group fluorine, difluoromethyl, trifluoromethyl,
methyl, ethyl and oxo, [0381] or [0382] R.sup.5 and R.sup.6 form,
together with the nitrogen atom to which they are bound, an
azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl,
dihydropiperidinyl, piperazinyl, morpholinyl, pyrazolyl or
imidazolyl ring, [0383] in which the azetidinyl, pyrrolidinyl,
imidazolidinyl, piperidinyl, dihydropiperidinyl, piperazinyl,
morpholinyl, pyrazolyl and imidazolyl ring can be substituted with
1 or 2 substituents selected independently of one another from the
group fluorine, cyano, difluoromethyl, trifluoromethyl,
2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, methyl, ethyl,
1-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxy, oxo,
methoxy, ethoxy, difluoromethoxy and trifluoromethoxy, [0384]
R.sup.2 stands for 3,3,3-trifluoroprop-1-yl,
2,2,3,3-tetrafluoroprop-1-yl, 2,2,3,3,3-pentafluoroprop-1-yl,
phenyl or pyridyl, [0385] wherein phenyl is substituted with 1 to 3
fluorine substituents, [0386] and [0387] wherein pyridyl can be
substituted with 1 fluorine substituent, and their salts, solvates
and solvates of the salts.
[0388] In the context of the present invention, compounds of
formula (I) are especially preferred in which [0389] L stands for a
group #.sup.1-CR.sup.7AR.sup.7B--(CR.sup.8AR.sup.8B).sub.m-#.sup.2,
[0390] wherein [0391] #.sup.1 stands for the point of attachment to
the carbonyl group, [0392] #.sup.2 stands for the point of
attachment to the pyrimidine ring, [0393] m stands for a number 0,
[0394] R.sup.7A stands for hydrogen, fluorine, methyl or hydroxy,
[0395] R.sup.7B stands for hydrogen, fluorine, trifluoromethyl,
2,2,2-trifluoroethyl or methyl, the ring Q stands for a group of
formula
##STR00008##
[0395] wherein [0396] * stands for the point of attachment to
--CH.sub.2--R.sup.2, [0397] ** stands for the point of attachment
to the pyrimidine, [0398] R.sup.1a stands for hydrogen or methyl,
[0399] R.sup.1b stands for hydrogen or fluorine, [0400] R.sup.1c
stands for hydrogen or chlorine, [0401] A.sup.1 stands for N or CH,
[0402] A.sup.3 stands for N, CH or C--F, [0403] R.sup.3 stands for
--OR.sup.4 or --NR.sup.5R.sup.6, [0404] wherein [0405] R.sup.4
stands for (C.sub.1-C.sub.6)-alkyl or pyrazolyl, [0406] in which
(C.sub.1-C.sub.6)-alkyl can be substituted with 1 to 3 substituents
selected independently of one another from the group fluorine,
trifluoromethyl, --(C.dbd.O).sub.p--OR.sup.9 and
--(C.dbd.O).sub.p--NR.sup.9R.sup.10, [0407] in which [0408] p
denotes the number 0 or 1, [0409] R.sup.9 and R.sup.10
independently of one another stand in each case for hydrogen or
methyl, [0410] and [0411] in which pyrazolyl can be substituted
with 1 or 2 substituents selected independently of one another from
the group fluorine, difluoromethyl, trifluoromethyl,
2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, methyl,
cyclopropyl, cyclobutyl, cyclopentyl, [0412] R.sup.5 stands for
hydrogen, methyl or ethyl, [0413] R.sup.6 stands for
(C.sub.1-C.sub.6)-alkyl, oxetanyl, azetidinyl, tetrahydrofuranyl,
pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl,
morpholinyl, phenyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl,
oxadiazolyl, thiadiazolyl, pyridyl or pyrimidinyl, [0414] in which
(C.sub.1-C.sub.6)-alkyl is substituted with 1 or 2 substituents
selected independently of one another from the group fluorine,
difluoromethyl, trifluoromethyl cyclopropyl, cyclobutyl,
cyclopentyl, trifluoromethoxy, --(C.dbd.O).sub.p--OR.sup.9,
--(C.dbd.O).sub.p--NR.sup.9R.sup.10, tetrahydrofuranyl,
pyrrolidinyl, tetrahydropyranyl, phenyl, furanyl, pyrazolyl,
imidazolyl, triazolyl and pyridyl, [0415] in which [0416] p denotes
the number 0 or 1, [0417] R.sup.9 and R.sup.10 each stand,
independently of one another, for hydrogen, methyl, ethyl,
trifluoromethyl, 2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl,
cyclopropyl or cyclobutyl, [0418] and [0419] in which
tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, phenyl,
furanyl, pyrazolyl, imidazolyl, triazolyl and pyridyl for their
part can be substituted with 1 or 2 substituents selected
independently of one another from the group fluorine, chlorine,
cyano, difluoromethyl, trifluoromethyl, methyl, ethyl and oxo,
[0420] in which oxetanyl, azetidinyl, tetrahydrofuranyl,
pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl,
morpholinyl, phenyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl,
oxadiazolyl, thiadiazolyl, pyridyl and pyrimidinyl can be
substituted with 1 or 2 substituents selected independently of one
another from the group fluorine, difluoromethyl, trifluoromethyl,
methyl, ethyl and oxo, [0421] or [0422] R.sup.5 and R.sup.6 form,
together with the nitrogen atom to which they are bound, an
azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl,
dihydropiperidinyl, piperazinyl, morpholinyl, pyrazolyl or
imidazolyl ring, [0423] in which the azetidinyl, pyrrolidinyl,
imidazolidinyl, piperidinyl, dihydropiperidinyl, piperazinyl,
morpholinyl, pyrazolyl and imidazolyl ring can be substituted with
1 or 2 substituents selected independently of one another from the
group fluorine, cyano, difluoromethyl, trifluoromethyl,
2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, methyl, ethyl,
1-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxy, oxo,
methoxy, ethoxy, difluoromethoxy and trifluoromethoxy, [0424]
R.sup.2 stands for 3,3,3-trifluoroprop-1-yl,
2,2,3,3,3-pentafluoroprop-1-yl, phenyl or pyridyl, [0425] wherein
phenyl is substituted with 1 to 3 fluorine substituents, [0426] and
[0427] wherein pyridyl can be substituted with 1 fluorine
substituent, and their salts, solvates and solvates of the
salts.
[0428] In the context of the present invention, compounds of
formula (I) are also preferred in which [0429] L stands for a group
#.sup.1-CR.sup.7AR.sup.7B--(CR.sup.8AR.sup.8B).sub.m-#.sup.2,
[0430] wherein [0431] #.sup.1 stands for the point of attachment to
the carbonyl group, [0432] #.sup.2 stands for the point of
attachment to the pyrimidine ring, [0433] m stands for a number 0,
[0434] R.sup.7A stands for hydrogen, fluorine, methyl or hydroxy,
[0435] R.sup.7B stands for hydrogen, fluorine, trifluoromethyl,
methyl or 2,2,2-trifluoroethyl, [0436] or [0437] R.sup.7A and
R.sup.7B together with the carbon atom to which they are bound,
form a tetrahydrofuranyl ring, the ring Q stands for a group of
formula
##STR00009##
[0437] wherein [0438] * stands for the point of attachment to
--CH.sub.2--R.sup.2, [0439] ** stands for the point of attachment
to the pyrimidine, [0440] R.sup.1a stands for hydrogen or methyl,
[0441] R.sup.1b stands for hydrogen or fluorine, [0442] R.sup.1c
stands for hydrogen or chlorine, [0443] A.sup.1 stands for N or CH,
[0444] A.sup.3 stands for N, CH or C--F, [0445] R.sup.3 stands for
--NR.sup.5R.sup.6, [0446] wherein [0447] R.sup.5 stands for
hydrogen, [0448] R.sup.6 stands for (C.sub.1-C.sub.6)-alkyl, [0449]
in which (C.sub.1-C.sub.6)-alkyl is substituted with 1 or 2
substituents selected independently of one another from the group
fluorine, difluoromethyl, trifluoromethyl or
--(C.dbd.O).sub.p--OR.sup.9, [0450] in which [0451] p denotes the
number 0, [0452] R.sup.9 stands for hydrogen, [0453] R.sup.2 stands
for 2-fluorophenyl, 2,3-difluorophenyl or 3-fluoropyrid-2-yl, and
their salts, solvates and solvates of the salts.
[0454] In the context of the present invention, compounds of
formula (I) are also especially preferred in which [0455] L stands
for a group
#.sup.1-CR.sup.7AR.sup.7B--(CR.sup.8AR.sup.8B).sub.m-#.sup.2,
[0456] wherein [0457] #.sup.1 stands for the point of attachment to
the carbonyl group, [0458] #.sup.2 stands for the point of
attachment to the pyrimidine ring, [0459] m stands for a number 0,
[0460] R.sup.7A stands for methyl, [0461] R.sup.7B stands for
methyl, the ring Q stands for a group of formula
##STR00010##
[0461] wherein [0462] * stands for the point of attachment to
--CH.sub.2--R.sup.2, [0463] ** stands for the point of attachment
to the pyrimidine, [0464] R.sup.1a stands for hydrogen or methyl,
[0465] R.sup.1b stands for hydrogen or fluorine, [0466] R.sup.1c
stands for hydrogen or chlorine, [0467] A.sup.1 stands for N or CH,
[0468] A.sup.3 stands for N, CH or C--F, [0469] R.sup.3 stands for
--NR.sup.5R.sup.6, [0470] wherein [0471] R.sup.5 stands for
hydrogen, methyl or ethyl, [0472] R.sup.6 stands for
(C.sub.1-C.sub.6)-alkyl, oxetanyl, azetidinyl, tetrahydrofuranyl,
pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl,
morpholinyl, phenyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl,
oxadiazolyl, thiadiazolyl, pyridyl or pyrimidinyl, [0473] in which
(C.sub.1-C.sub.6)-alkyl is substituted with 1 or 2 substituents
selected independently of one another from the group fluorine,
difluoromethyl, trifluoromethyl cyclopropyl, cyclobutyl,
cyclopentyl, trifluoromethoxy, --(C.dbd.O).sub.p--OR.sup.9,
--(C.dbd.O).sub.p--NR.sup.9R.sup.10, tetrahydrofuranyl,
pyrrolidinyl, tetrahydropyranyl, phenyl, furanyl, pyrazolyl,
imidazolyl, triazolyl and pyridyl, [0474] in which [0475] p denotes
the number 0 or 1, [0476] R.sup.9 and R.sup.10 each stand,
independently of one another, for hydrogen, methyl, ethyl,
trifluoromethyl, 2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl,
cyclopropyl or cyclobutyl, [0477] and [0478] in which
tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, phenyl,
furanyl, pyrazolyl, imidazolyl, triazolyl and pyridyl for their
part can be substituted with 1 or 2 substituents selected
independently of one another from the group fluorine, chlorine,
cyano, difluoromethyl, trifluoromethyl, methyl, ethyl and oxo,
[0479] in which oxetanyl, azetidinyl, tetrahydrofuranyl,
pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl,
morpholinyl, phenyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl,
oxadiazolyl, thiadiazolyl, pyridyl and pyrimidinyl can be
substituted with 1 or 2 substituents selected independently of one
another from the group fluorine, difluoromethyl, trifluoromethyl,
methyl, ethyl and oxo, [0480] or [0481] R.sup.5 and R.sup.6 form,
together with the nitrogen atom to which they are bound, an
azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl,
dihydropiperidinyl, piperazinyl, morpholinyl, pyrazolyl or
imidazolyl ring, [0482] in which the azetidinyl, pyrrolidinyl,
imidazolidinyl, piperidinyl, dihydropiperidinyl, piperazinyl,
morpholinyl, pyrazolyl and imidazolyl ring can be substituted with
1 or 2 substituents selected independently of one another from the
group fluorine, cyano, difluoromethyl, trifluoromethyl,
2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, methyl, ethyl,
1-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxy, oxo,
methoxy, ethoxy, difluoromethoxy and trifluoromethoxy, [0483]
R.sup.2 stands for 3,3,3-trifluoroprop-1-yl,
2,2,3,3,3-pentafluoroprop-1-yl, phenyl or pyridyl, [0484] wherein
phenyl is substituted with 1 to 3 fluorine substituents, [0485] and
[0486] wherein pyridyl can be substituted with 1 fluorine
substituent, and their salts, solvates and solvates of the
salts.
[0487] In the context of the present invention, compounds of
formula (I) are also especially preferred in which [0488] L stands
for a group
#.sup.1-CR.sup.7AR.sup.7B--(CR.sup.7AR.sup.8B).sub.m-#.sup.2,
[0489] wherein [0490] #.sup.1 stands for the point of attachment to
the carbonyl group, [0491] #.sup.2 stands for the point of
attachment to the pyrimidine ring, [0492] m stands for a number 0,
[0493] R.sup.7A stands for hydrogen, fluorine, methyl, hydroxy,
[0494] R.sup.7B stands for hydrogen, fluorine, methyl or
trifluoromethyl, [0495] or [0496] R.sup.7A and R.sup.7B together
with the carbon atom to which they are bound, form a
tetrahydrofuranyl ring, the ring Q stands for a group of
formula
##STR00011##
[0496] wherein [0497] * stands for the point of attachment to
--CH.sub.2--R.sup.2, [0498] ** stands for the point of attachment
to the pyrimidine, [0499] R.sup.3 stands for --OR.sup.4 or
--NR.sup.5R.sup.6, [0500] wherein [0501] R.sup.4 stands for
(C.sub.1-C.sub.6)-alkyl or pyrazolyl, [0502] in which
(C.sub.1-C.sub.6)-alkyl can be substituted with 1 to 3 substituents
selected independently of one another from the group fluorine,
trifluoromethyl, --(C.dbd.O).sub.p--OR.sup.9 and
--(C.dbd.O).sub.p--NR.sup.9R.sup.10, [0503] in which [0504] p
denotes the number 0 or 1, [0505] R.sup.9 and R.sup.10
independently of one another stand in each case for hydrogen or
methyl, [0506] and [0507] in which pyrazolyl can be substituted
with 1 or 2 substituents selected independently of one another from
the group fluorine, difluoromethyl, trifluoromethyl,
2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, methyl,
cyclopropyl, cyclobutyl, cyclopentyl. [0508] R.sup.5 stands for
hydrogen, methyl or ethyl, [0509] R.sup.6 stands for
(C.sub.1-C.sub.6)-alkyl, oxetanyl, azetidinyl, tetrahydrofuranyl,
pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl,
morpholinyl, phenyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl,
oxadiazolyl, thiadiazolyl, pyridyl or pyrimidinyl, [0510] in which
(C.sub.1-C.sub.6)-alkyl is substituted with 1 or 2 substituents
selected independently of one another from the group fluorine,
difluoromethyl, trifluoromethyl cyclopropyl, cyclobutyl,
cyclopentyl, trifluoromethoxy, --(C.dbd.O).sub.p--OR.sup.9,
--(C.dbd.O).sub.p--NR.sup.9R.sup.10, tetrahydrofuranyl,
pyrrolidinyl, tetrahydropyranyl, phenyl, furanyl, pyrazolyl,
imidazolyl, triazolyl and pyridyl, [0511] in which [0512] p denotes
the number 0 or 1, [0513] R.sup.9 and R.sup.10 each stand,
independently of one another, for hydrogen, methyl, ethyl,
trifluoromethyl, 2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl,
cyclopropyl or cyclobutyl, [0514] and [0515] in which cyclopropyl,
cyclobutyl, cyclopentyl, tetrahydrofuranyl, pyrrolidinyl,
tetrahydropyranyl, phenyl, furanyl, pyrazolyl, imidazolyl,
triazolyl and pyridyl for their part can be substituted with 1 or 2
substituents selected independently of one another from the group
fluorine, chlorine, cyano, difluoromethyl, trifluoromethyl, methyl,
ethyl, oxo and hydroxy, [0516] in which oxetanyl, azetidinyl,
tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl,
piperazinyl, morpholinyl, phenyl, pyrazolyl, oxazolyl, thiazolyl,
triazolyl, oxadiazolyl, thiadiazolyl, pyridyl and pyrimidinyl can
be substituted with 1 or 2 substituents selected independently of
one another from the group fluorine, difluoromethyl,
trifluoromethyl, methyl, ethyl, oxo, azetidinyl and pyrrolidinyl,
[0517] or [0518] R.sup.5 and R.sup.6 form, together with the
nitrogen atom to which they are bound, an azetidinyl, pyrrolidinyl,
imidazolidinyl, piperidinyl, dihydropiperidinyl, piperazinyl,
morpholinyl, pyrazolyl or imidazolyl ring, [0519] in which the
azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl,
dihydropiperidinyl, piperazinyl, morpholinyl, pyrazolyl and
imidazolyl ring can be substituted with 1 or 2 substituents
selected independently of one another from the group fluorine,
cyano, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl,
1,1,2,2,2-pentafluoroethyl, methyl, ethyl, 1-hydroxyethyl,
cyclopropyl, cyclobutyl, cyclopentyl, hydroxy, oxo, methoxy,
ethoxy, difluoromethoxy and trifluoromethoxy, [0520] R.sup.2 stands
for 2-fluorophenyl, 2,3-difluorophenyl or 3-fluoropyrid-2-yl, and
their salts, solvates and solvates of the salts.
[0521] In the context of the present invention, compounds of
formula (I) are also preferred in which [0522] L stands for a group
#.sup.1-CR.sup.7AR.sup.7B-(CR.sup.8AR.sup.8B).sub.m-#.sup.2, [0523]
wherein [0524] #.sup.1 stands for the point of attachment to the
carbonyl group, [0525] #.sup.2 stands for the point of attachment
to the pyrimidine ring, [0526] m stands for a number 0, 1 or 2,
[0527] R.sup.7A stands for hydrogen, fluorine,
(C.sub.1-C.sub.4)-alkyl, hydroxyl or amino, [0528] in which
(C.sub.1-C.sub.4)-alkyl can be substituted with 1 to 3 substituents
selected independently of one another from the group fluorine,
trifluoromethyl, hydroxy, hydroxycarbonyl,
(C.sub.1-C.sub.4)-alkoxycarbonyl and amino, [0529] R.sup.7B stands
for hydrogen, fluorine, (C.sub.1-C.sub.4)-alkyl, trifluoromethyl,
(C.sub.1-C.sub.4)-alkoxycarbonylamino or phenyl, [0530] in which
(C.sub.1-C.sub.4)-alkyl can be substituted with 1 to 3 substituents
selected independently of one another from the group fluorine,
trifluoromethyl, hydroxy, hydroxycarbonyl,
(C.sub.1-C.sub.4)-alkoxycarbonyl and amino, [0531] or [0532]
R.sup.7A and R.sup.7B together with the carbon atom to which they
are bound, form a (C.sub.2-C.sub.4)-alkenyl group, an oxo group, a
3- to 6-membered carbocycle or a 4- to 7-membered heterocycle,
[0533] in which the 3- to 6-membered carbocycle and the 4- to
7-membered heterocycle can be substituted with 1 or 2 substituents
selected independently of one another from the group fluorine and
(C.sub.1-C.sub.4)-alkyl, [0534] R.sup.8A stands for hydrogen,
fluorine, (C.sub.1-C.sub.4)-alkyl or hydroxy, [0535] R.sup.8B
stands for hydrogen, fluorine, (C.sub.1-C.sub.4)-alkyl or
trifluoromethyl, the ring Q stands for 8- or 9-membered heteroaryl,
[0536] R.sup.3 stands for --OR.sup.4 or --NR.sup.5R.sup.6, [0537]
wherein [0538] R.sup.4 stands for hydrogen,
(C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl, 4- to
7-membered heterocyclyl or 5- or 6-membered heteroaryl, [0539] in
which (C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl, 4- to
7-membered heterocyclyl and 5- or 6-membered heteroaryl can be
substituted with 1 to 3 substituents selected independently of one
another from the group fluorine, difluoromethyl, trifluoromethyl,
(C.sub.3-C.sub.6)-cycloalkyl, difluoromethoxy, trifluoromethoxy,
--(C.dbd.O).sub.p--OR.sup.9, --C(.dbd.O).sub.p--NR.sup.9R.sup.10,
--NR.sup.9--(C.dbd.O)--R.sup.10, --NR.sup.9--(C.dbd.O)--OR.sup.10,
--NR.sup.9--(C.dbd.O)--NR.sup.10R.sup.11,
--NR.sup.9--SO.sub.2--R.sup.10, --S(O).sub.q--R.sup.12 and
--SO.sub.2--NR.sup.9R.sup.10, [0540] in which [0541] p denotes the
number 0 or 1, [0542] q denotes the number 0, 1 or 2, [0543]
R.sup.9, R.sup.10 and R.sup.11 each stand, independently of one
another, for hydrogen, (C.sub.1-C.sub.6)-alkyl or
(C.sub.3-C.sub.8)-cycloalkyl, [0544] in which
(C.sub.1-C.sub.6)-alkyl for its part can be substituted with 1 or 2
substituents selected independently of one another from the group
fluorine, difluoromethyl, trifluoromethyl, hydroxy,
(C.sub.1-C.sub.6)-alkoxy, difluoromethoxy, trifluoromethoxy,
(C.sub.1-C.sub.6)-alkoxycarbonyl, amino,
mono-(C.sub.1-C.sub.6)-alkylamino, di(C.sub.1-C.sub.6)-alkylamino
and 4- to 7-membered heterocyclyl, [0545] or [0546] R.sup.9 and
R.sup.10 form, together with the respective atom(s) to which they
are bound, a 4- to 7-membered heterocycle, [0547] in which for its
part the 4- to 7-membered heterocycle can be substituted with 1 or
2 substituents selected independently of one another from the group
fluorine, trifluoromethyl, (C.sub.1-C.sub.6)-alkyl, hydroxy, oxo,
(C.sub.1-C.sub.6)-alkoxy, trifluoromethoxy,
(C.sub.1-C.sub.6)-alkoxycarbonyl, amino,
mono-(C.sub.1-C.sub.6)-alkylamino and
di(C.sub.1-C.sub.6)-alkylamino, [0548] or [0549] R.sup.10 and
R.sup.11 form, together with the respective atom(s) to which they
are bound, a 4- to 7-membered heterocycle, [0550] in which for its
part the 4- to 7-membered heterocycle can be substituted with 1 or
2 substituents selected independently of one another from the group
fluorine, trifluoromethyl, (C.sub.1-C.sub.6)-alkyl, hydroxy, oxo,
(C.sub.1-C.sub.6)-alkoxy, trifluoromethoxy,
(C.sub.1-C.sub.6)-alkoxycarbonyl, amino,
mono-(C.sub.1-C.sub.6)-alkylamino and
di(C.sub.1-C.sub.6)-alkylamino, [0551] and in which [0552] R.sup.12
stands for (C.sub.1-C.sub.6)-alkyl or (C.sub.3-C.sub.7)-cycloalkyl,
[0553] R.sup.5 stands for hydrogen or (C.sub.1-C.sub.4)-alkyl,
[0554] R.sup.6 stands for (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl, 4- to 7-membered heterocyclyl or 5-
or 6-membered heteroaryl, [0555] in which (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl, 4- to 7-membered heterocyclyl and 5-
or 6-membered heteroaryl can be substituted with 1 to 3
substituents selected independently of one another from the group
fluorine, difluoromethyl, trifluoromethyl, difluoromethoxy,
trifluoromethoxy, --(C.dbd.O).sub.p--OR.sup.9,
--C(.dbd.O).sub.p--NR.sup.9R.sup.10,
--NR.sup.9--(C.dbd.O)--R.sup.10, --NR.sup.9--(C.dbd.O)--OR.sup.10,
--NR.sup.9--(C.dbd.O)--NR.sup.10R.sup.11,
--NR.sup.9--SO.sub.2--R.sup.10, --S(O).sub.q--R.sup.12 and
--SO.sub.2--NR.sup.9R.sup.10, [0556] in which [0557] p denotes the
number 0 or 1, [0558] q denotes the number 0, 1 or 2, [0559]
R.sup.9, R.sup.10 and R.sup.11 each stand, independently of one
another, for hydrogen, (C.sub.1-C.sub.6)-alkyl or
(C.sub.3-C.sub.8)-cycloalkyl, [0560] or [0561] R.sup.9 and R.sup.10
form, together with the respective atom(s) to which they are bound,
a 4- to 7-membered heterocycle, [0562] in which for its part the 4-
to 7-membered heterocycle can be substituted with 1 or 2
substituents selected independently of one another from the group
cyano, trifluoromethyl, (C.sub.1-C.sub.6)-alkyl, hydroxy, oxo,
(C.sub.1-C.sub.6)-alkoxy, trifluoromethoxy,
(C.sub.1-C.sub.6)-alkoxycarbonyl, amino,
mono-(C.sub.1-C.sub.6)-alkylamino and
di(C.sub.1-C.sub.6)-alkylamino, [0563] or [0564] R.sup.10 and
R.sup.11 form, together with the respective atom(s) to which they
are bound, a 4- to 7-membered heterocycle, [0565] in which for its
part the 4- to 7-membered heterocycle can be substituted with 1 or
2 substituents selected independently of one another from the group
cyano, trifluoromethyl, (C.sub.1-C.sub.6)-alkyl, hydroxy, oxo,
(C.sub.1-C.sub.6)-alkoxy, trifluoromethoxy,
(C.sub.1-C.sub.6)-alkoxycarbonyl, amino,
mono-(C.sub.1-C.sub.6)-alkylamino and
di(C.sub.1-C.sub.6)-alkylamino, [0566] and in which [0567] R.sup.12
stands for (C.sub.1-C.sub.6)-alkyl or (C.sub.3-C.sub.7)-cycloalkyl,
[0568] or [0569] R.sup.5 and R.sup.6 form, together with the
nitrogen atom to which they are bound, a 4- to 7-membered
heterocycle, [0570] in which the 4- to 7-membered heterocycle can
be substituted with 1 or 2 substituents selected independently of
one another from the group fluorine, trifluoromethyl,
(C.sub.1-C.sub.6)-alkyl, hydroxy, oxo, (C.sub.1-C.sub.6)-alkoxy,
trifluoromethoxy, (C.sub.1-C.sub.6)-alkoxycarbonyl, amino,
mono-(C.sub.1-C.sub.6)-alkylamino and
di(C.sub.1-C.sub.6)-alkylamino, [0571] R.sup.1 stands for fluorine,
chlorine or methyl, [0572] n stands for a number 0, 1 or 2, [0573]
R.sup.2 stands for (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.8)-cycloalkyl, phenyl or 5- or 6-membered
heteroaryl, [0574] wherein (C.sub.1-C.sub.6)-alkyl is substituted
with a trifluoromethyl substituent, [0575] wherein
(C.sub.1-C.sub.6)-alkyl can be substituted with 1 to 3 fluorine
substituents, [0576] wherein phenyl is substituted with 1 to 3
fluorine substituents, [0577] and [0578] wherein 5- and 6-membered
heteroaryl can be substituted with 1 or 2 substituents selected
independently of one another from the group fluorine and methyl,
and their N-oxides, salts, solvates, salts of the N-oxides and
solvates of the N-oxides and salts.
[0579] In the context of the present invention, compounds of
formula (I) are also preferred in which [0580] L stands for a group
#.sup.1-CR.sup.7AR.sup.7B--(CR.sup.8AR.sup.8B).sub.m-#.sup.2,
[0581] wherein [0582] #.sup.1 stands for the point of attachment to
the carbonyl group, [0583] #.sup.2 stands for the point of
attachment to the pyrimidine ring, [0584] m stands for a number 0
or 1, [0585] R.sup.7A stands for hydrogen, fluorine, methyl, ethyl
or hydroxy, [0586] R.sup.7B stands for hydrogen, fluorine, methyl,
ethyl, trifluoromethyl, methoxycarbonylamino or phenyl, [0587] in
which methyl and ethyl can be substituted with 1 to 3 substituents
selected independently of one another from the group fluorine,
trifluoromethyl and hydroxy, [0588] or [0589] R.sup.7A and R.sup.7B
together with the carbon atom to which they are bound, form a
cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, pyrrolidinyl,
tetrahydrofuranyl, piperidinyl or tetrahydropyranyl ring form,
[0590] in which the cyclopropyl, cyclobutyl, cyclopentyl,
azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl and
tetrahydropyranyl ring can be substituted with 1 or 2 substituents
selected independently of one another from the group fluorine and
methyl, [0591] R.sup.8A stands for hydrogen, fluorine, methyl,
ethyl or hydroxy, [0592] R.sup.8B stands for hydrogen, fluorine,
methyl, ethyl or trifluoromethyl, the ring Q stands for a group of
formula
##STR00012## ##STR00013##
[0592] wherein [0593] * stands for the point of attachment to
--CH.sub.2--R.sup.2, [0594] ** stands for the point of attachment
to the pyrimidine, [0595] R.sup.1 stands for fluorine, chlorine or
methyl, [0596] n stands for a number 0, 1 or 2, [0597] A.sup.1,
A.sup.2, A.sup.3 and A.sup.4 independently of one another stand in
each case for N, CH or CR.sup.1, [0598] with the proviso that at
most two of the groups A.sup.1, A.sup.2, A.sup.3 and A.sup.4 stand
for N, [0599] R.sup.3 stands for --OR.sup.4 or --NR.sup.5R.sup.6,
[0600] wherein [0601] R.sup.4 stands for hydrogen,
(C.sub.1-C.sub.6)-alkyl or (C.sub.3-C.sub.7)-cycloalkyl, [0602] in
which (C.sub.1-C.sub.6)-alkyl can be substituted with 1 or 2
substituents selected independently of one another from the group
fluorine, difluoromethyl, trifluoromethyl, difluoromethoxy,
trifluoromethoxy, --(C.dbd.O).sub.p--OR.sup.9 and
--C(.dbd.O).sub.p--NR.sup.9R.sup.10, [0603] in which [0604] p
denotes the number 0, [0605] R.sup.9 and R.sup.10 each stand,
independently of one another, for hydrogen, methyl or ethyl, [0606]
or [0607] R.sup.9 and R.sup.10 form, together with the nitrogen
atom to which they are bound, an azetidinyl, pyrrolidinyl,
piperidinyl, piperazinyl or morpholinyl ring, [0608] in which the
azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl
ring for its part can be substituted with 1 or 2 substituents
selected independently of one another from the group fluorine,
trifluoromethyl, methyl, ethyl, hydroxy, oxo, methoxy, ethoxy,
amino, methylamino, ethylamino, dimethylamino and diethylamino,
[0609] R.sup.5 stands for hydrogen or methyl, [0610] R.sup.6 stands
for (C.sub.1-C.sub.6)-alkyl or (C.sub.3-C.sub.7)-cycloalkyl, [0611]
in which (C.sub.1-C.sub.6)-alkyl can be substituted with 1 or 2
substituents selected independently of one another from the group
fluorine, difluoromethyl, trifluoromethyl, difluoromethoxy,
trifluoromethoxy, --(C.dbd.O).sub.p--OR.sup.9 and
--C(.dbd.O).sub.p--NR.sup.9R.sup.10, [0612] in which [0613] p
denotes the number 0, [0614] R.sup.9 and R.sup.10 each stand,
independently of one another, for hydrogen, methyl or ethyl, [0615]
or [0616] R.sup.9 and R.sup.10 form, together with the nitrogen
atom to which they are bound, an azetidinyl, pyrrolidinyl,
piperidinyl, piperazinyl or morpholinyl ring, [0617] in which the
azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl
ring for its part can be substituted with 1 or 2 substituents
selected independently of one another from the group fluorine,
trifluoromethyl, methyl, ethyl, hydroxy, oxo, methoxy, ethoxy,
amino, methylamino, ethylamino, dimethylamino and diethylamino,
[0618] or [0619] R.sup.5 and R.sup.6 form, together with the
nitrogen atom to which they are bound, an azetidinyl, pyrrolidinyl,
piperidinyl, piperazinyl or morpholinyl ring, [0620] in which the
azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl
ring for its part can be substituted with 1 or 2 substituents
selected independently of one another from the group fluorine,
trifluoromethyl, methyl, ethyl, hydroxy, oxo, methoxy, ethoxy,
amino, methylamino, ethylamino, dimethylamino and diethylamino,
[0621] R.sup.2 stands for trifluoromethyl, 2,2,2-trifluoroethyl,
3,3,3-trifluoroprop-1-yl, 2,2,3,3,3-pentafluoroprop-1-yl,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl,
pyrimidinyl, pyrazinyl or pyridazinyl, [0622] wherein phenyl is
substituted with 1 to 3 fluorine substituents, [0623] and [0624]
wherein pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl can be
substituted with 1 or 2 fluorine substituents. and their salts,
solvates and solvates of the salts.
[0625] In the context of the present invention, compounds of
formula (I) are also especially preferred in which [0626] L stands
for a group
#.sup.1-CR.sup.7AR.sup.7B--(CR.sup.8AR.sup.8B).sub.m-#.sup.2,
[0627] wherein [0628] #.sup.1 stands for the point of attachment to
the carbonyl group, [0629] #.sup.2 stands for the point of
attachment to the pyrimidine ring, [0630] m stands for a number 0,
[0631] R.sup.7A stands for hydrogen, fluorine, methyl or hydroxy,
[0632] R.sup.7B stands for hydrogen, fluorine, methyl or
trifluoromethyl, [0633] or [0634] R.sup.7A and R.sup.7B together
with the carbon atom to which they are bound, form a cyclopropyl or
cyclobutyl ring, [0635] in which the cyclopropyl and the cyclobutyl
ring can be substituted with 1 or 2 substituents selected
independently of one another from the group fluorine and methyl,
the ring Q stands for a group of formula
##STR00014##
[0635] wherein [0636] * stands for the point of attachment to
--CH.sub.2--R.sup.2, [0637] ** stands for the point of attachment
to the pyrimidine, [0638] R.sup.1a stands for hydrogen or fluorine,
[0639] R.sup.1b stands for hydrogen or methyl, [0640] R.sup.3
stands for --OR.sup.4 or --NR.sup.5R.sup.6, [0641] wherein [0642]
R.sup.4 stands for hydrogen or (C.sub.1-C.sub.6)-alkyl, [0643] in
which (C.sub.1-C.sub.6)-alkyl can be substituted with 1 or 2
substituents selected independently of one another from the group
fluorine, difluoromethyl, trifluoromethyl, difluoromethoxy,
trifluoromethoxy, --(C.dbd.O).sub.p--OR.sup.9 and
--C(.dbd.O).sub.p--NR.sup.9R.sup.10, [0644] in which [0645] p
denotes the number 0, [0646] R.sup.9 and R.sup.10 independently of
one another in each case stand for hydrogen, [0647] R.sup.5 stands
for hydrogen, [0648] R.sup.6 stands for (C.sub.1-C.sub.6)-alkyl,
[0649] in which (C.sub.1-C.sub.6)-alkyl is substituted with 1 or 2
substituents selected independently of one another from the group
fluorine, difluoromethyl, trifluoromethyl, difluoromethoxy,
trifluoromethoxy, --(C.dbd.O).sub.p--OR.sup.9 and
--C(.dbd.O).sub.p--NR.sup.9R.sup.10, [0650] in which [0651] p
denotes the number 0, [0652] R.sup.9 and R.sup.10 independently of
one another in each case stand for hydrogen, [0653] R.sup.2 stands
for 2,2,3,3,3-pentafluoroprop-1-yl, 2-fluorophenyl or
2,3,6-trifluorophenyl, and their salts, solvates and solvates of
the salts.
[0654] In the context of the present invention, compounds of
formula (I) are also preferred in which [0655] R.sup.3 stands for
--OR.sup.4 or --NR.sup.5R.sup.6, [0656] wherein [0657] R.sup.4
stands for (C.sub.1-C.sub.6)-alkyl or (C.sub.3-C.sub.7)-cycloalkyl,
[0658] in which (C.sub.1-C.sub.6)-alkyl can be substituted with 1
or 2 substituents selected independently of one another from the
group fluorine, difluoromethyl, trifluoromethyl, difluoromethoxy,
trifluoromethoxy, --(C.dbd.O).sub.p--OR.sup.9 and
--C(.dbd.O).sub.p--NR.sup.9R.sup.10, [0659] in which [0660] p
denotes the number 0, [0661] R.sup.9 and R.sup.10 each stand,
independently of one another, for hydrogen, methyl or ethyl, [0662]
or [0663] R.sup.9 and R.sup.10 form, together with the nitrogen
atom to which they are bound, an azetidinyl, pyrrolidinyl,
piperidinyl, piperazinyl or morpholinyl ring, [0664] in which the
azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl
ring for its part can be substituted with 1 or 2 substituents
selected independently of one another from the group fluorine,
trifluoromethyl, methyl, ethyl, hydroxy, oxo, methoxy, ethoxy,
amino, methylamino, ethylamino, dimethylamino and diethylamino,
[0665] R.sup.5 stands for hydrogen or methyl, [0666] R.sup.6 stands
for (C.sub.1-C.sub.6)-alkyl or (C.sub.3-C.sub.7)-cycloalkyl, [0667]
in which (C.sub.1-C.sub.6)-alkyl can be substituted with 1 or 2
substituents selected independently of one another from the group
fluorine, difluoromethyl, trifluoromethyl, difluoromethoxy,
trifluoromethoxy, --(C.dbd.O).sub.p--OR.sup.9 and
--C(.dbd.O).sub.p--NR.sup.9R.sup.10, [0668] in which [0669] p
denotes the number 0, [0670] R.sup.9 and R.sup.10 each stand,
independently of one another, for hydrogen, methyl or ethyl, [0671]
or [0672] R.sup.9 and R.sup.10 form, together with the nitrogen
atom to which they are bound, an azetidinyl, pyrrolidinyl,
piperidinyl, piperazinyl or morpholinyl ring, [0673] in which the
azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl
ring for its part can be substituted with 1 or 2 substituents
selected independently of one another from the group fluorine,
trifluoromethyl, methyl, ethyl, hydroxy, oxo, methoxy, ethoxy,
amino, methylamino, ethylamino, dimethylamino and diethylamino,
[0674] or [0675] R.sup.5 and R.sup.6 form, together with the
nitrogen atom to which they are bound, an azetidinyl, pyrrolidinyl,
piperidinyl, piperazinyl or morpholinyl ring, [0676] in which the
azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl
ring for its part can be substituted with 1 or 2 substituents
selected independently of one another from the group fluorine,
trifluoromethyl, methyl, ethyl, hydroxy, oxo, methoxy, ethoxy,
amino, methylamino, ethylamino, dimethylamino and diethylamino,
[0677] n, L, Q, R.sup.1 and R.sup.2 have the respective meanings
given above, and their salts, solvates and solvates of the
salts.
[0678] In the context of the present invention, compounds of
formula (I) are also preferred in which [0679] R.sup.3 stands for
--NR.sup.5R.sup.6, [0680] wherein [0681] R.sup.5 stands for
hydrogen or methyl, [0682] R.sup.6 stands for
(C.sub.1-C.sub.6)-alkyl or (C.sub.3-C.sub.7)-cycloalkyl, [0683] in
which (C.sub.1-C.sub.6)-alkyl can be substituted with 1 or 2
substituents selected independently of one another from the group
fluorine, difluoromethyl, trifluoromethyl, difluoromethoxy,
trifluoromethoxy, --(C.dbd.O).sub.p--OR.sup.9 and
--C(.dbd.O).sub.p--NR.sup.9R.sup.10, [0684] in which [0685] p
denotes the number 0, [0686] R.sup.9 and R.sup.10 each stand,
independently of one another, for hydrogen, methyl or ethyl, [0687]
or [0688] R.sup.9 and R.sup.10 form, together with the nitrogen
atom to which they are bound, an azetidinyl, pyrrolidinyl,
piperidinyl, piperazinyl or morpholinyl ring, [0689] in which the
azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl
ring for its part can be substituted with 1 or 2 substituents
selected independently of one another from the group fluorine,
trifluoromethyl, methyl, ethyl, hydroxy, oxo, methoxy, ethoxy,
amino, methylamino, ethylamino, dimethylamino and diethylamino,
[0690] or [0691] R.sup.5 and R.sup.6 form, together with the
nitrogen atom to which they are bound, an azetidinyl, pyrrolidinyl,
piperidinyl, piperazinyl or morpholinyl ring, [0692] in which the
azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl
ring for its part can be substituted with 1 or 2 substituents
selected independently of one another from the group fluorine,
trifluoromethyl, methyl, ethyl, hydroxy, oxo, methoxy, ethoxy,
amino, methylamino, ethylamino, dimethylamino and diethylamino,
[0693] n, L, Q, R.sup.1 and R.sup.2 have the respective meanings
given above, and their salts, solvates and solvates of the
salts.
[0694] In the context of the present invention, compounds of
formula (I) are also preferred in which [0695] R.sup.3 stands for
--NR.sup.5R.sup.6, [0696] wherein [0697] R.sup.5 stands for
hydrogen or methyl, [0698] R.sup.6 stands for
(C.sub.1-C.sub.6)-alkyl or (C.sub.3-C.sub.7)-cycloalkyl, [0699] in
which (C.sub.1-C.sub.6)-alkyl and (C.sub.3-C.sub.7)-cycloalkyl are
substituted with 1 or 2 substituents selected independently of one
another from the group fluorine, difluoromethyl, trifluoromethyl,
difluoromethoxy, trifluoromethoxy, --(C.dbd.O).sub.p--OR.sup.9 and
--C(.dbd.O).sub.p--NR.sup.9R.sup.10, [0700] in which [0701] p
denotes the number 0, [0702] R.sup.9 and R.sup.10 each stand,
independently of one another, for hydrogen, methyl or ethyl, [0703]
or [0704] R.sup.9 and R.sup.10 form, together with the nitrogen
atom to which they are bound, an azetidinyl, pyrrolidinyl,
piperidinyl, piperazinyl or morpholinyl ring, [0705] in which the
azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl
ring for its part can be substituted with 1 or 2 substituents
selected independently of one another from the group fluorine,
trifluoromethyl, methyl, ethyl, hydroxy, oxo, methoxy, ethoxy,
amino, methylamino, ethylamino, dimethylamino and diethylamino,
[0706] or [0707] R.sup.5 and R.sup.6 form, together with the
nitrogen atom to which they are bound, an azetidinyl, pyrrolidinyl,
piperidinyl, piperazinyl or morpholinyl ring, [0708] in which the
azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl
ring for its part can be substituted with 1 or 2 substituents
selected independently of one another from the group fluorine,
trifluoromethyl, methyl, ethyl, hydroxy, oxo, methoxy, ethoxy,
amino, methylamino, ethylamino, dimethylamino and diethylamino,
[0709] n, L, Q, R.sup.1 and R.sup.2 have the respective meanings
given above, and their salts, solvates and solvates of the
salts.
[0710] In the context of the present invention, compounds of
formula (I) are also preferred in which
the ring Q stands for a group of formula
##STR00015##
wherein [0711] * stands for the point of attachment to
--CH.sub.2--R.sup.2, [0712] ** stands for the point of attachment
to the pyrimidine, [0713] A.sup.1, A.sup.3 and A.sup.4
independently of one another stand in each case for N, CH or
CR.sup.1, [0714] in which [0715] R.sup.1 stands for fluorine,
chlorine or methyl, [0716] n stands for a number 0, 1 or 2, [0717]
with the proviso that at most two of the groups A.sup.1, A.sup.3
and A.sup.4 stand for N, [0718] R.sup.3 stands for
--NR.sup.5R.sup.6, [0719] wherein [0720] R.sup.5 stands for
hydrogen or methyl, [0721] R.sup.6 stands for
(C.sub.1-C.sub.6)-alkyl, [0722] in which (C.sub.1-C.sub.6)-alkyl is
substituted with 1 or 2 substituents selected independently of one
another from the group fluorine, difluoromethyl and
trifluoromethyl, [0723] L and R.sup.2 have the respective meanings
given above, and their salts, solvates and solvates of the
salts.
[0724] In the context of the present invention, compounds of
formula (I) are also preferred in which
the ring Q stands for a group of formula
##STR00016##
wherein [0725] * stands for the point of attachment to
--CH.sub.2--R.sup.2, [0726] ** stands for the point of attachment
to the pyrimidine, [0727] R.sup.1 stands for hydrogen or fluorine,
[0728] R.sup.3 stands for --NR.sup.5R.sup.6, [0729] wherein [0730]
R.sup.5 stands for hydrogen or methyl, [0731] R.sup.6 stands for
(C.sub.1-C.sub.6)-alkyl, [0732] in which (C.sub.1-C.sub.6)-alkyl is
substituted with 1 or 2 substituents selected independently of one
another from the group fluorine, difluoromethyl and
trifluoromethyl, [0733] stands for 2-fluorophenyl or
3-fluoropyrid-2-yl, [0734] and [0735] L and R.sup.2 have the
respective meanings given above, and their salts, solvates and
solvates of the salts.
[0736] In the context of the present invention, compounds of
formula (I) are also preferred in which [0737] R.sup.3 stands for
--NR.sup.5R.sup.6, [0738] wherein [0739] R.sup.5 stands for
hydrogen or methyl, [0740] R.sup.6 stands for
(C.sub.1-C.sub.6)-alkyl, [0741] in which (C.sub.1-C.sub.6)-alkyl is
substituted with 1 or 2 substituents selected independently of one
another from the group fluorine, difluoromethyl and
trifluoromethyl, [0742] n, L, Q, R.sup.1 and R.sup.2 have the
respective meanings given above, and their salts, solvates and
solvates of the salts.
[0743] In the context of the present invention, compounds of
formula (I) are also preferred in which [0744] R.sup.3 stands for
--NR.sup.5R.sup.6, [0745] wherein [0746] R.sup.5 stands for
hydrogen or methyl, [0747] R.sup.6 stands for
(C.sub.1-C.sub.6)-alkyl, [0748] in which (C.sub.1-C.sub.6)-alkyl is
substituted with 1 or 2 substituents selected independently of one
another from the group fluorine, difluoromethyl, trifluoromethyl
and --(C.dbd.O).sub.p--OR.sup.9, [0749] in which [0750] p denotes
the number 0, [0751] R.sup.9 stands for hydrogen, [0752] n, L, Q,
R.sup.1 and R.sup.2 have the respective meanings given above, and
their salts, solvates and solvates of the salts.
[0753] In the context of the present invention, compounds of
formula (I) are also preferred in which [0754] L stands for a group
#.sup.1-CR.sup.7AR.sup.7B--(CR.sup.8AR.sup.8B).sub.m-#.sup.2,
[0755] wherein [0756] #.sup.1 stands for the point of attachment to
the carbonyl group, [0757] #.sup.2 stands for the point of
attachment to the pyrimidine ring, [0758] m stands for a number 0,
[0759] R.sup.7A stands for methyl, [0760] R.sup.7B stands for
methyl, [0761] R.sup.3 stands for --NR.sup.5R.sup.6, [0762] wherein
[0763] R.sup.5 stands for hydrogen or methyl, [0764] R.sup.6 stands
for (C.sub.1-C.sub.6)-alkyl, [0765] in which
(C.sub.1-C.sub.6)-alkyl is substituted with 1 or 2 substituents
selected independently of one another from the group fluorine,
difluoromethyl, trifluoromethyl and --(C.dbd.O).sub.p--OR.sup.9,
[0766] in which [0767] p denotes the number 0, [0768] R.sup.9
stands for hydrogen, [0769] n, Q, R.sup.1 and R.sup.2 have the
respective meanings given above, and their salts, solvates and
solvates of the salts.
[0770] In the context of the present invention, compounds of
formula (I) are also preferred in which [0771] L stands for a group
#.sup.1-CR.sup.7AR.sup.7B--(CR.sup.8AR.sup.8B).sub.m-#.sup.2,
[0772] wherein [0773] #.sup.1 stands for the point of attachment to
the carbonyl group, [0774] #.sup.2 stands for the point of
attachment to the pyrimidine ring, [0775] m stands for a number 0,
[0776] R.sup.7A stands for hydrogen, fluorine, methyl or hydroxy,
[0777] R.sup.7B stands for hydrogen, fluorine, methyl or
trifluoromethyl, [0778] R.sup.3 stands for --NR.sup.5R.sup.6,
[0779] wherein [0780] R.sup.5 stands for hydrogen or methyl, [0781]
R.sup.6 stands for (C.sub.1-C.sub.6)-alkyl, [0782] in which
(C.sub.1-C.sub.6)-alkyl is substituted with 1 or 2 substituents
selected independently of one another from the group fluorine,
difluoromethyl, trifluoromethyl and --(C.dbd.O).sub.p--OR.sup.9,
[0783] in which [0784] p denotes the number 0, [0785] R.sup.9
stands for hydrogen, [0786] n, Q, R.sup.1 and R.sup.2 have the
respective meanings given above, and their salts, solvates and
solvates of the salts.
[0787] In the context of the present invention, compounds of
formula (I) are also preferred in which [0788] R.sup.3 stands for
--OR.sup.4, [0789] wherein [0790] R.sup.4 stands for hydrogen,
(C.sub.1-C.sub.6)-alkyl or (C.sub.3-C.sub.7)-cycloalkyl, [0791] in
which (C.sub.1-C.sub.6)-alkyl can be substituted with 1 or 2
substituents selected independently of one another from the group
fluorine, difluoromethyl, trifluoromethyl, difluoromethoxy,
trifluoromethoxy, --(C.dbd.O).sub.p--OR.sup.9 and
--C(.dbd.O).sub.p--NR.sup.9R.sup.10, [0792] in which [0793] p
denotes the number 0, [0794] R.sup.9 and R.sup.10 each stand,
independently of one another, for hydrogen, methyl or ethyl, [0795]
or [0796] R.sup.9 and R.sup.10 form, together with the nitrogen
atom to which they are bound, an azetidinyl, pyrrolidinyl,
piperidinyl, piperazinyl or morpholinyl ring, [0797] in which the
azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl
ring for its part can be substituted with 1 or 2 substituents
selected independently of one another from the group fluorine,
trifluoromethyl, methyl, ethyl, hydroxy, oxo, methoxy, ethoxy,
amino, methylamino, ethylamino, dimethylamino and diethylamino,
[0798] n, L, Q, R.sup.1 and R.sup.2 have the respective meanings
given above, and their salts, solvates and solvates of the
salts.
[0799] In the context of the present invention, compounds of
formula (I) are also preferred in which [0800] R.sup.3 stands for
--OR.sup.4, [0801] wherein [0802] R.sup.4 stands for hydrogen,
[0803] n, L, Q, R.sup.1 and R.sup.2 have the respective meanings
given above, and their salts, solvates and solvates of the
salts.
[0804] In the context of the present invention, compounds of
formula (I) are also preferred in which
the ring Q stands for a group of formula
##STR00017##
wherein [0805] * stands for the point of attachment to
--CH.sub.2--R.sup.2, [0806] ** stands for the point of attachment
to the pyrimidine, [0807] R.sup.1 stands for hydrogen or fluorine,
[0808] R.sup.3 stands for --OR.sup.4, [0809] wherein [0810] R.sup.4
stands for hydrogen, [0811] n, L, Q, R.sup.1 and R.sup.2 have the
respective meanings given above, and their salts, solvates and
solvates of the salts.
[0812] In the context of the present invention, compounds of
formula (I) are also preferred in which R.sup.1 stands for H, and
their salts, solvates and solvates of the salts.
[0813] In the context of the present invention, compounds of
formula (I) are also preferred in which R.sup.1 stands for fluoro,
and their salts, solvates and solvates of the salts.
[0814] In the context of the present invention, compounds of
formula (I) are also preferred in which R.sup.1 stands for methyl,
and their salts, solvates and solvates of the salts.
[0815] In the context of the present invention, compounds of
formula (I) are also especially preferred in which [0816] R.sup.2
stands for 2,2,3,3,3-pentafluoroprop-1-yl, 2-fluorophenyl,
2,3-difluorophenyl, 2,3,6-trifluorophenyl, 3-fluoropyrid-2-yl or
pyrimidin-2-yl, and their salts, solvates and solvates of the
salts.
[0817] In the context of the present invention, compounds of
formula (I) are also especially preferred in which [0818] R.sup.2
stands for 2-fluorophenyl or 3-fluoropyrid-2-yl, and their salts,
solvates and solvates of the salts.
[0819] In the context of the present invention, compounds of
formula (I) are also especially preferred in which [0820] R.sup.2
stands for 2-fluorophenyl, and their salts, solvates and solvates
of the salts.
[0821] In the context of the present invention, compounds of
formula (I) are also especially preferred in which [0822] R.sup.2
stands for 3-fluoropyrid-2-yl or pyrimidin-2-yl, and their salts,
solvates and solvates of the salts.
[0823] In the context of the present invention, compounds of
formula (I) are also preferred in which [0824] L stands for a group
#.sup.1-CR.sup.7AR.sup.7B--(CR.sup.8AR.sup.8B) #.sup.2, [0825]
wherein [0826] #.sup.1 stands for the point of attachment to the
carbonyl group, [0827] #.sup.2 stands for the point of attachment
to the pyrimidine ring, [0828] m stands for a number 0, [0829]
R.sup.7A stands for hydrogen, fluorine, methyl or hydroxy, [0830]
R.sup.7B stands for hydrogen, fluorine, methyl or trifluoromethyl,
[0831] or [0832] R.sup.7A and R.sup.7B together with the carbon
atom to which they are bound, form a cyclopropyl or cyclobutyl
ring, [0833] in which the cyclopropyl and the cyclobutyl ring can
be substituted with 1 or 2 substituents selected independently of
one another from the group fluorine and methyl, [0834] n, Q,
R.sup.1, R.sup.2 and R.sup.3 have the respective meanings given
above, and their salts, solvates and solvates of the salts.
[0835] In the context of the present invention, compounds of
formula (I) are also preferred in which [0836] L stands for a group
#.sup.1-CR.sup.7AR.sup.7B--(CR.sup.8AR.sup.8B).sub.m-#.sup.2,
[0837] wherein [0838] #.sup.1 stands for the point of attachment to
the carbonyl group, [0839] #.sup.2 stands for the point of
attachment to the pyrimidine ring, [0840] m stands for a number 0,
[0841] R.sup.7A stands for hydrogen, fluorine, methyl or hydroxy,
[0842] R.sup.7B stands for hydrogen, fluorine, methyl or
trifluoromethyl, [0843] n, Q, R.sup.1, R.sup.2 and R.sup.3 have the
respective meanings given above, and their salts, solvates and
solvates of the salts.
[0844] In the context of the present invention, compounds of
formula (I) are also preferred in which [0845] L stands for a group
#.sup.1-CR.sup.7AR.sup.7B--(CR.sup.8AR.sup.8B).sub.m-#.sup.2,
[0846] wherein [0847] #.sup.1 stands for the point of attachment to
the carbonyl group, [0848] #.sup.2 stands for the point of
attachment to the pyrimidine ring, [0849] m stands for a number 0,
[0850] R.sup.7A stands for methyl, [0851] R.sup.7B stands for
methyl, [0852] n, Q, R.sup.1, R.sup.2 and R.sup.3 have the
respective meanings given above, and their salts, solvates and
solvates of the salts.
[0853] In the context of the present invention, compounds of
formula (I) are also preferred in which [0854] L stands for a group
#.sup.1-CR.sup.7AR.sup.7B--(CR.sup.8AR.sup.8B).sub.m-#.sup.2,
[0855] wherein [0856] #.sup.1 stands for the point of attachment to
the carbonyl group, [0857] #.sup.2 stands for the point of
attachment to the pyrimidine ring, [0858] m stands for a number 0,
[0859] R.sup.7A stands for methyl, [0860] R.sup.7B stands for
methyl, [0861] or [0862] R.sup.7A and R.sup.7B together with the
carbon atom to which they are bound, form a tetrahydrofuranyl ring,
[0863] n, Q, R', R.sup.2 and R.sup.3 have the respective meanings
given above, and their salts, solvates and solvates of the
salts.
[0864] In the context of the present invention, compounds of
formula (I) are also preferred in which [0865] L stands for a group
#.sup.1-CR.sup.7AR.sup.7B--(CR.sup.8AR.sup.8B).sub.m-#.sup.2,
[0866] wherein [0867] #.sup.1 stands for the point of attachment to
the carbonyl group, [0868] #.sup.2 stands for the point of
attachment to the pyrimidine ring, [0869] m stands for a number 0,
[0870] R.sup.7A stands for hydrogen, fluorine, methyl, ethyl,
hydroxy or amino, [0871] R.sup.7B stands for a group of formula
-M-R.sup.13, [0872] in which [0873] M stands for a bond, [0874]
R.sup.13 stands for --(C.dbd.O).sub.r--NR.sup.14R.sup.15, phenyl,
thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl or pyrimidinyl,
[0875] in which [0876] r denotes the number 1, [0877] R.sup.14 and
R.sup.15 independently of one another stand in each case for
hydrogen or cyclopropyl, [0878] and [0879] in which phenyl,
thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl and pyrimidinyl for
their part can be substituted with 1 or 2 substituents selected
independently of one another from the group fluorine,
difluoromethyl, trifluoromethyl, methyl, ethyl, isopropyl,
2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, cyclopropyl,
cyclobutyl, cyclopropylmethyl and cyclobutylmethyl, and their
salts, solvates and solvates of the salts.
[0880] In the context of the present invention, compounds of
formula (I) are also preferred in which [0881] R.sup.3 stands for
--NR.sup.5R.sup.6, [0882] wherein [0883] R.sup.5 stands for
hydrogen or methyl, [0884] R.sup.6 stands for
(C.sub.1-C.sub.6)-alkyl or (C.sub.3-C.sub.7)-cycloalkyl, [0885] in
which (C.sub.1-C.sub.6)-alkyl can be substituted with 1 or 2
substituents selected independently of one another from the group
fluorine, difluoromethyl, trifluoromethyl, difluoromethoxy,
trifluoromethoxy, --(C.dbd.O).sub.p--OR.sup.9 and
--C(.dbd.O).sub.p--NR.sup.9R.sup.10, [0886] in which [0887] p
denotes the number 0, [0888] R.sup.9 and R.sup.10 each stand,
independently of one another, for hydrogen, methyl or ethyl, [0889]
or [0890] R.sup.9 and R.sup.10 form, together with the nitrogen
atom to which they are bound, an azetidinyl, pyrrolidinyl,
piperidinyl, piperazinyl or morpholinyl ring, [0891] in which the
azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl
ring for its part can be substituted with 1 or 2 substituents
selected independently of one another from the group fluorine,
trifluoromethyl, methyl, ethyl, hydroxy, oxo, methoxy, ethoxy,
amino, methylamino, ethylamino, dimethylamino and diethylamino,
[0892] or [0893] R.sup.5 and R.sup.6 form, together with the
nitrogen atom to which they are bound, an azetidinyl, pyrrolidinyl,
piperidinyl, piperazinyl or morpholinyl ring, [0894] in which the
azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl
ring for its part can be substituted with 1 or 2 substituents
selected independently of one another from the group fluorine,
trifluoromethyl, methyl, ethyl, hydroxy, oxo, methoxy, ethoxy,
amino, methylamino, ethylamino, dimethylamino and diethylamino, the
ring Q stands for a group of formula
##STR00018##
[0894] wherein [0895] * stands for the point of attachment to
--CH.sub.2--R.sup.2, [0896] ** stands for the point of attachment
to the pyrimidine, [0897] A.sup.1, A.sup.3 and A.sup.4
independently of one another stand in each case for N, CH or
CR.sup.1, [0898] in which [0899] R.sup.1 stands for fluorine,
chlorine or methyl, [0900] n stands for a number 0, 1 or 2, [0901]
with the proviso that at most two of the groups A.sup.1, A.sup.3
and A.sup.4 stand for N, and their salts, solvates and solvates of
the salts.
[0902] In the context of the present invention, compounds of
formula (I) are also preferred in which
the ring Q stands for a group of formula
##STR00019##
[0903] wherein [0904] * stands for the point of attachment to
--CH.sub.2--R.sup.2, [0905] ** stands for the point of attachment
to the pyrimidine, [0906] A.sup.1, A.sup.3 and A.sup.4
independently of one another stand in each case for N, CH or
CR.sup.1, [0907] in which [0908] R.sup.1 stands for fluorine,
chlorine or methyl, [0909] n stands for a number 0, 1 or 2, [0910]
with the proviso that at most two of the groups A.sup.1, A.sup.3
and A.sup.4 stand for N, [0911] R.sup.3 stands for --OR.sup.4 or
--NR.sup.5R.sup.6, [0912] wherein [0913] R.sup.4 stands for
hydrogen or (C.sub.1-C.sub.6)-alkyl, [0914] in which
(C.sub.1-C.sub.6)-alkyl can be substituted with 1 or 2 substituents
selected independently of one another from the group fluorine,
difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy,
--(C.dbd.O).sub.p--OR.sup.9 and
--C(.dbd.O).sub.p--NR.sup.9R.sup.10, [0915] in which [0916] p
denotes the number 0, [0917] R.sup.9 and R.sup.10 independently of
one another in each case stand for hydrogen, [0918] R.sup.5 stands
for hydrogen, [0919] R.sup.6 stands for (C.sub.1-C.sub.6)-alkyl,
[0920] in which (C.sub.1-C.sub.6)-alkyl is substituted with 1 or 2
substituents selected independently of one another from the group
fluorine, difluoromethyl, trifluoromethyl, difluoromethoxy,
trifluoromethoxy, --(C.dbd.O).sub.p--OR.sup.9 and
--C(.dbd.O).sub.p--NR.sup.9R.sup.10, [0921] in which [0922] p
denotes the number 0, [0923] R.sup.9 and R.sup.10 independently of
one another in each case stand for hydrogen, and their salts,
solvates and solvates of the salts.
[0924] In the context of the present invention, compounds of
formula (I) are also preferred in which the ring Q stands for a
group of formula
##STR00020##
wherein [0925] * stands for the point of attachment to
--CH.sub.2--R.sup.2, [0926] ** stands for the point of attachment
to the pyrimidine, [0927] A.sup.1, A.sup.3 and A.sup.4
independently of one another stand in each case for N, CH or
CR.sup.1, [0928] in which [0929] R.sup.1 stands for fluorine,
chlorine or methyl, [0930] n stands for a number 0, 1 or 2, [0931]
with the proviso that at most two of the groups A.sup.1, A.sup.3
and A.sup.4 stand for N, and their salts, solvates and solvates of
the salts.
[0932] In the context of the present invention, compounds of
formula (I) are also preferred in which [0933] L stands for a group
#.sup.1-CR.sup.7AR.sup.7B--(CR.sup.8AR.sup.8B).sub.m-#.sup.2,
[0934] wherein [0935] #.sup.1 stands for the point of attachment to
the carbonyl group, [0936] #.sup.2 stands for the point of
attachment to the pyrimidine ring, [0937] m stands for a number 0,
[0938] R.sup.7A stands for hydrogen, fluorine, methyl or hydroxy,
[0939] R.sup.7B stands for hydrogen, fluorine, trifluoromethyl,
2,2,2-trifluoroethyl or methyl, the ring Q stands for a group of
formula
##STR00021##
[0939] wherein [0940] * stands for the point of attachment to
--CH.sub.2--R.sup.2, [0941] ** stands for the point of attachment
to the pyrimidine, [0942] R.sup.1a stands for hydrogen or methyl,
[0943] R.sup.1b stands for hydrogen or fluorine, [0944] R.sup.1c
stands for hydrogen or chlorine, [0945] A.sup.1 stands for N or CH,
[0946] A.sup.3 stands for N, CH or C--F, [0947] R.sup.2 and R.sup.3
have the respective meanings given above, and their salts, solvates
and solvates of the salts.
[0948] In the context of the present invention, compounds of
formula (I) are also preferred in which [0949] L stands for a group
#.sup.1-CR.sup.7AR.sup.7B--(CR.sup.8AR.sup.8B).sub.m-#.sup.2,
[0950] wherein [0951] #.sup.1 stands for the point of attachment to
the carbonyl group, [0952] #.sup.2 stands for the point of
attachment to the pyrimidine ring, [0953] m stands for a number 0
or 1, [0954] R.sup.7A stands for hydrogen, fluorine, methyl, ethyl,
hydroxy or amino, [0955] R.sup.7B stands for hydrogen, fluorine,
difluoromethyl, trifluoromethyl, methyl, ethyl,
methoxycarbonylamino, cyclopropyl, cyclobutyl, cyclopentyl, or a
group of formula -M-R.sup.13, [0956] in which methyl and ethyl can
be substituted with 1 to 3 substituents selected independently of
one another from the group fluorine, cyano, trifluoromethyl,
cyclopropyl, cyclobutyl, hydroxy, difluoromethoxy,
trifluoromethoxy, methoxy, ethoxy, hydroxycarbonyl,
methoxycarbonyl, ethoxycarbonyl and amino, [0957] and in which
[0958] M stands for a bond, [0959] R.sup.13 stands for
--(C.dbd.O).sub.r--NR.sup.14R.sup.15, phenyl, thiazolyl, triazolyl,
oxadiazolyl, thiadiazolyl or pyrimidinyl, [0960] in which [0961] r
denotes the number 1, [0962] R.sup.14 and R.sup.15 independently of
one another stand in each case for hydrogen or cyclopropyl, [0963]
and [0964] in which phenyl, thiazolyl, triazolyl, oxadiazolyl,
thiadiazolyl and pyrimidinyl for their part can be substituted with
1 or 2 substituents selected independently of one another from the
group fluorine, difluoromethyl, trifluoromethyl, methyl, ethyl,
isopropyl, 2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl,
cyclopropyl, cyclobutyl, cyclopropylmethyl and cyclobutylmethyl,
[0965] or [0966] R.sup.7A and R.sup.7B together with the carbon
atom to which they are bound, form a cyclopropyl, cyclobutyl,
cyclopentyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl or
tetrahydropyranyl ring, [0967] in which the cyclopropyl,
cyclobutyl, cyclopentyl, azetidinyl, tetrahydrofuranyl,
pyrrolidinyl and tetrahydropyranyl ring can be substituted with 1
or 2 substituents selected independently of one another from the
group fluorine and methyl, [0968] R.sup.8A stands for hydrogen,
fluorine, methyl or hydroxy, [0969] R.sup.8B stands for hydrogen,
fluorine, methyl or trifluoromethyl, the ring Q stands for a group
of formula
##STR00022##
[0969] wherein [0970] * stands for the point of attachment to
--CH.sub.2--R.sup.2, [0971] ** stands for the point of attachment
to the pyrimidine, [0972] R.sup.1a stands for hydrogen or methyl,
[0973] R.sup.1b stands for hydrogen or fluorine, [0974] R.sup.1c
stands for hydrogen or chlorine, [0975] A.sup.1 stands for N or CH,
[0976] A.sup.3 stands for N, CH or C--F, [0977] R.sup.2 and R.sup.3
have the respective meanings given above, and their salts, solvates
and solvates of the salts.
[0978] The following compounds of formula (I) are also preferred in
the context of the present invention: [0979]
2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-methoxy-5,5-dimet-
hyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one, [0980]
2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-[(2-hydr-
oxyethyl)amino]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,
[0981]
4-[(2-amino-2-methylpropyl)amino]-2-[5-fluoro-1-(2-fluorobenzyl)-1-
H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]p-
yrimidin-6-one, [0982]
2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-[(2-hydr-
oxy-2-methylpropyl)amino]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimi-
din-6-one, [0983]
2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimeth-
yl-4-[(3,3,3-trifluoropropyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-
-6-one, [0984]
4-[(2,2-difluoroethyl)amino]-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3-
,4-b]pyridin-3-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-o-
ne, [0985]
4-(3-fluoroazetidin-1-yl)-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyr-
azolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimi-
din-6-one, [0986]
4-[(cyclopropylmethyl)amino]-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3-
,4-b]pyridin-3-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-o-
ne, [0987]
2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]--
5,5-dimethyl-4-[(2,2,2-trifluoroethyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-d]-
pyrimidin-6-one, [0988]
2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3--
yl}-5,5-dimethyl-4-[(3,3,3-trifluoropropyl)amino]-5,7-dihydro-6H-pyrrolo[2-
,3-d]pyrimidin-6-one, [0989]
2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3--
yl}-5,5-dimethyl-4-[(2,2,2-trifluoroethyl)amino]-5,7-dihydro-6H-pyrrolo[2,-
3-d]pyrimidin-6-one, [0990]
4-[(cyclopropylmethyl)amino]-2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-
-1H-pyrazolo[3,4-b]pyridin-3-yl}-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d-
]pyrimidin-6-one, [0991]
4-(3-ethyl-2-oxoimidazolidin-1-yl)-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4--
b]pyridin-3-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,
[0992]
2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-(4-hydroxy-
-1H-pyrazol-1-yl)-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-on-
e, [0993]
2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimeth-
yl-4-(1H-pyrazol-4-yloxy)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,
[0994]
2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-[3-(1-hydr-
oxyethyl)-1H-pyrazol-1-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrim-
idin-6-one, [0995]
2-[5-fluoro-3-(2-fluorobenzyl)-1H-indazol-1-yl]-4-hydroxy-5,5-dimethyl-5,-
7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one, [0996]
4-[(cyclopropylmethyl)amino]-2-[5-fluoro-3-(2-fluorobenzyl)-1H-indazol-1--
yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,
[0997]
2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-[(2-hydroxypropyl-
)amino]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,
[0998]
N-(1-{2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl--
6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}pyrrolidin-3-yl)acetamid-
e, [0999]
2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-[(trans--
4-hydroxycyclohexyl)amino]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrim-
idin-6-one, [1000]
2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimeth-
yl-4-[(3,3,3-trifluoro-2-hydroxypropyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-d-
]pyrimidin-6-one (Enantiomer 1), [1001]
2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimeth-
yl-4-[(3,3,3-trifluoro-2-hydroxypropyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-d-
]pyrimidin-6-one (Enantiomer 2), [1002]
4-{[(2,2-difluorocyclopropyl)methyl]amino}-2-[5-fluoro-1-(2-fluorobenzyl)-
-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d-
]pyrimidin-6-one, [1003]
2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-{[(1-hyd-
roxycyclopropyl)methyl]amino}-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]py-
rimidin-6-one, [1004]
ethyl-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-hydroxy-5-m-
ethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxylate,
[1005]
2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-hydroxy--
5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one, [1006]
4-(3-aminopyrrolidin-1-yl)-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridi-
n-3-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,
[1007]
2-[1-(2-fluorobenzyl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5,5-dime-
thyl-4-[(3,3,3-trifluoropropyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimid-
in-6-one, [1008]
2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-hydroxy-5,5-dimet-
hyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one, [1009]
2-[1-(2,3-difluorobenzyl)-5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-hydr-
oxy-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one,
[1010]
2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-(2-hydroxyethoxy)-
-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one, and
their salts, solvates and solvates of the salts.
[1011] Compounds of the present invention according to formula (I)
are also preferred
##STR00023##
in which [1012] L stands for a group
#.sup.1-CR.sup.7AR.sup.7B-(CR.sup.8AR.sup.8B).sub.m-#.sup.2, [1013]
wherein [1014] #.sup.1 stands for the point of attachment to the
carbonyl group, [1015] #.sup.2 stands for the point of attachment
to the pyrimidine ring, [1016] m stands for a number 0, 1 or 2,
[1017] R.sup.7A stands for hydrogen, fluorine,
(C.sub.1-C.sub.4)-alkyl, hydroxyl or amino, [1018] in which
(C.sub.1-C.sub.4)-alkyl can be substituted with 1 to 3 substituents
selected independently of one another from the group fluorine,
trifluoromethyl, hydroxy, hydroxycarbonyl,
(C.sub.1-C.sub.4)-alkoxycarbonyl and amino, [1019] R.sup.7B stands
for hydrogen, fluorine, difluoromethyl, trifluoromethyl,
(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.4)-alkoxycarbonylamino,
cyano, (C.sub.3-C.sub.7)-cycloalkyl, difluoromethoxy,
trifluoromethoxy, phenyl or a group of formula -M-R.sup.13, [1020]
in which (C.sub.1-C.sub.6)-alkyl can be substituted with 1 to 3
substituents selected independently of one another from the group
fluorine, cyano, trifluoromethyl, (C.sub.3-C.sub.7)-cycloalkyl,
hydroxy, difluoromethoxy, trifluoromethoxy,
(C.sub.1-C.sub.4)-alkoxy, hydroxycarbonyl,
(C.sub.1-C.sub.4)-alkoxycarbonyl and amino, [1021] and in which
[1022] M stands for a bond or (C.sub.1-C.sub.4)-alkanediyl, [1023]
R.sup.13 stands for --(C.dbd.O).sub.r--OR.sup.14,
--(C.dbd.O).sub.r--NR.sup.14R.sup.15,
--C(.dbd.S)--NR.sup.14R.sup.15, --NR.sup.14--(C.dbd.O)--R.sup.17,
--NR.sup.14--(C.dbd.O)--NR.sup.15R.sup.16,
--NR.sup.14--SO.sub.2--NR.sup.15R.sup.16,
--NR.sup.14--SO.sub.2--R.sup.17, --S(O).sub.s--R.sup.17,
--SO.sub.2--NR.sup.14R.sup.15, 4- to 7-membered heterocyclyl,
phenyl or 5- or 6-membered heteroaryl, [1024] in which [1025] r
denotes the number 0 or 1, [1026] s denotes the number 0, 1 or 2,
[1027] R.sup.14, R.sup.15 and R.sup.16 each stand, independently of
one another, for hydrogen, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.8)-cycloalkyl, 4- to 7-membered heterocyclyl, phenyl
or 5- or 6-membered heteroaryl, [1028] or [1029] R.sup.14 and
R.sup.15 form, together with the respective atom(s) to which they
are bound, a 4- to 7-membered heterocycle, [1030] in which for its
part the 4- to 7-membered heterocycle can be substituted with 1 or
2 substituents selected independently of one another from the group
cyano, trifluoromethyl, (C.sub.1-C.sub.6)-alkyl, hydroxy, oxo,
(C.sub.1-C.sub.6)-alkoxy, trifluoromethoxy,
(C.sub.1-C.sub.6)-alkoxycarbonyl, amino,
mono-(C.sub.1-C.sub.6)-alkylamino and
di(C.sub.1-C.sub.6)-alkylamino, [1031] or [1032] R.sup.15 and
R.sup.16 form, together with the respective atom(s) to which they
are bound, a 4- to 7-membered heterocycle, [1033] in which for its
part the 4- to 7-membered heterocycle can be substituted with 1 or
2 substituents selected independently of one another from the group
cyano, trifluoromethyl, (C.sub.1-C.sub.6)-alkyl, hydroxy, oxo,
(C.sub.1-C.sub.6)-alkoxy, trifluoromethoxy,
(C.sub.1-C.sub.6)-alkoxycarbonyl, amino,
mono-(C.sub.1-C.sub.6)-alkylamino and
di(C.sub.1-C.sub.6)-alkylamino, [1034] R.sup.17 stands for
(C.sub.1-C.sub.6)-alkyl or (C.sub.3-C.sub.7)-cycloalkyl, [1035] or
[1036] R.sup.14 and R.sup.17 form, together with the respective
atom(s) to which they are bound, a 4- to 7-membered heterocycle,
[1037] in which for its part the 4- to 7-membered heterocycle can
be substituted with 1 or 2 substituents selected independently of
one another from the group cyano, trifluoromethyl,
(C.sub.1-C.sub.6)-alkyl, hydroxy, oxo, (C.sub.1-C.sub.6)-alkoxy,
trifluoromethoxy, (C.sub.1-C.sub.6)-alkoxycarbonyl, amino,
mono-(C.sub.1-C.sub.6)-alkylamino and
di(C.sub.1-C.sub.6)-alkylamino, [1038] and [1039] in which for
their part the 4- to 7-membered heterocyclyl, phenyl and 5- or
6-membered heteroaryl can be substituted with 1 to 3 substituents
selected independently of one another from the group halogen,
cyano, difluoromethyl, trifluoromethyl, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl, hydroxy, oxo, thiooxo and
(C.sub.1-C.sub.4)-alkoxy, [1040] and [1041] in which the
aforementioned (C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.8)-cycloalkyl, (C.sub.3-C.sub.7)-cycloalkyl and 4-
to 7-membered heterocyclyl groups, unless stated otherwise, can in
each case be further substituted independently of one another with
1 to 3 substituents selected independently of one another from the
group fluorine, difluoromethyl, trifluoromethyl,
(C.sub.1-C.sub.4)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl, hydroxy,
difluoromethoxy, trifluoromethoxy, (C.sub.1-C.sub.4)-alkoxy,
hydroxycarbonyl, (C.sub.1-C.sub.4)-alkoxycarbonyl, amino, phenyl,
4- to 7-membered heterocyclyl and 5- or 6-membered heteroaryl,
[1042] or [1043] R.sup.7A and R.sup.7B together with the carbon
atom to which they are bound, form a (C.sub.2-C.sub.4)-alkenyl
group, an oxo group, a 3- to 6-membered carbocycle or a 4- to
7-membered heterocycle, [1044] in which the 3- to 6-membered
carbocycle and the 4- to 7-membered heterocycle can be substituted
with 1 or 2 substituents selected independently of one another from
the group fluorine and (C.sub.1-C.sub.4)-alkyl, [1045] R.sup.8A
stands for hydrogen, fluorine, (C.sub.1-C.sub.4)-alkyl or hydroxy,
[1046] R.sup.8B stands for hydrogen, fluorine,
(C.sub.1-C.sub.4)-alkyl or trifluoromethyl, [1047] the ring Q
stands for 8- or 9-membered heteroaryl, [1048] R.sup.3 stands for
--OR.sup.4 or --NR.sup.5R.sup.6, [1049] wherein [1050] R.sup.4
stands for hydrogen, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl, 4- to 7-membered heterocyclyl, phenyl
or 5- or 6-membered heteroaryl, [1051] in which
(C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl, 4- to
7-membered heterocyclyl, phenyl and 5- or 6-membered heteroaryl can
be substituted with 1 to 3 substituents selected independently of
one another from the group fluorine, difluoromethyl,
trifluoromethyl, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.6)-cycloalkyl, difluoromethoxy, trifluoromethoxy,
oxo, --(C.dbd.O).sub.p--OR.sup.9,
--C(.dbd.O).sub.p--NR.sup.9R.sup.10,
--NR.sup.9--(C.dbd.O)--R.sup.10, --NR.sup.9--(C.dbd.O)--OR.sup.10,
--NR.sup.9--(C.dbd.O)--NR.sup.10R.sup.11,
--NR.sup.9--SO.sub.2--R.sup.10, --S(O).sub.q--R.sup.12 and
--SO.sub.2--NR.sup.9R.sup.10, [1052] in which [1053] p denotes the
number 0 or 1, [1054] q denotes the number 0, 1 or 2, [1055]
R.sup.9, R.sup.10 and R.sup.11 each stand, independently of one
another, for hydrogen, (C.sub.1-C.sub.6)-alkyl or
(C.sub.3-C.sub.8)-cycloalkyl, [1056] in which
(C.sub.1-C.sub.6)-alkyl for its part can be substituted with 1 or 2
substituents selected independently of one another from the group
fluorine, difluoromethyl, trifluoromethyl, hydroxy,
(C.sub.1-C.sub.6)-alkoxy, difluoromethoxy, trifluoromethoxy,
(C.sub.1-C.sub.6)-alkoxycarbonyl, amino,
mono-(C.sub.1-C.sub.6)-alkylamino, di(C.sub.1-C.sub.6)-alkylamino
and 4- to 7-membered heterocyclyl, [1057] or [1058] R.sup.9 and
R.sup.10 form, together with the respective atom(s) to which they
are bound, a 4- to 7-membered heterocycle, [1059] in which for its
part the 4- to 7-membered heterocycle can be substituted with 1 or
2 substituents selected independently of one another from the group
fluorine, trifluoromethyl, (C.sub.1-C.sub.6)-alkyl, hydroxy, oxo,
(C.sub.1-C.sub.6)-alkoxy, trifluoromethoxy,
(C.sub.1-C.sub.6)-alkoxycarbonyl, amino,
mono-(C.sub.1-C.sub.6)-alkylamino and
di(C.sub.1-C.sub.6)-alkylamino, [1060] or [1061] R.sup.10 and
R.sup.11 form, together with the respective atom(s) to which they
are bound, a 4- to 7-membered heterocycle, [1062] in which for its
part the 4- to 7-membered heterocycle can be substituted with 1 or
2 substituents selected independently of one another from the group
fluorine, trifluoromethyl, (C.sub.1-C.sub.6)-alkyl, hydroxy, oxo,
(C.sub.1-C.sub.6)-alkoxy, trifluoromethoxy,
(C.sub.1-C.sub.6)-alkoxycarbonyl, amino,
mono-(C.sub.1-C.sub.6)-alkylamino and
di(C.sub.1-C.sub.6)-alkylamino, [1063] and in which [1064] R.sup.12
stands for (C.sub.1-C.sub.6)-alkyl or (C.sub.3-C.sub.7)-cycloalkyl,
[1065] and [1066] in which the aforementioned
(C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.8)-cycloalkyl, (C.sub.3-C.sub.7)-cycloalkyl and 4-
to 7-membered heterocyclyl groups, unless stated otherwise, can in
each case be further substituted independently of one another with
1 to 3 substituents selected independently of one another from the
group fluorine, difluoromethyl, trifluoromethyl,
(C.sub.1-C.sub.4)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl, hydroxy,
difluoromethoxy, trifluoromethoxy, (C.sub.1-C.sub.4)-alkoxy,
hydroxycarbonyl, (C.sub.1-C.sub.4)-alkoxycarbonyl, amino, phenyl,
4- to 7-membered heterocyclyl and 5- or 6-membered heteroaryl,
[1067] R.sup.5 stands for hydrogen or (C.sub.1-C.sub.4)-alkyl,
[1068] R.sup.6 stands for (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl, 4- to 7-membered heterocyclyl, phenyl
or 5- or 6-membered heteroaryl, [1069] in which
(C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl, 4- to
7-membered heterocyclyl, phenyl and 5- or 6-membered heteroaryl can
be substituted with 1 to 3 substituents selected independently of
one another from the group fluorine, difluoromethyl,
trifluoromethyl, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl, difluoromethoxy, trifluoromethoxy,
oxo, --(C.dbd.O).sub.p--OR.sup.9,
--(C.dbd.O).sub.p--NR.sup.9R.sup.10,
--NR.sup.9--(C.dbd.O)--R.sup.10, --NR.sup.9--(C.dbd.O)--OR.sup.10,
--NR.sup.9--(C.dbd.O)--NR.sup.10R.sup.11,
--NR.sup.9--SO.sub.2--R.sup.10, --S(O).sub.q--R.sup.12,
--SO.sub.2--NR.sup.9R.sup.10, phenyl, 4- to 7-membered heterocyclyl
and 5- or 6-membered heteroaryl, [1070] in which [1071] p denotes
the number 0 or 1, [1072] q denotes the number 0, 1 or 2, [1073]
R.sup.9, R.sup.10 and R.sup.11 each stand, independently of one
another, for hydrogen, (C.sub.1-C.sub.6)-alkyl or
(C.sub.3-C.sub.8)-cycloalkyl, [1074] in which
(C.sub.1-C.sub.6)-alkyl for its part can be substituted with 1 to 3
substituents selected independently of one another from the group
fluorine, difluoromethyl, trifluoromethyl,
(C.sub.3-C.sub.7)-cycloalkyl, difluoromethoxy, trifluoromethoxy and
(C.sub.1-C.sub.4)-alkoxy, [1075] or [1076] R.sup.9 and R.sup.10
form, together with the respective atom(s) to which they are bound,
a 4- to 7-membered heterocycle, [1077] in which for its part the 4-
to 7-membered heterocycle can be substituted with 1 or 2
substituents selected independently of one another from the group
fluorine, cyano, trifluoromethyl, (C.sub.1-C.sub.6)-alkyl, hydroxy,
oxo, (C.sub.1-C.sub.6)-alkoxy, trifluoromethoxy,
(C.sub.1-C.sub.6)-alkoxycarbonyl, amino,
mono-(C.sub.1-C.sub.6)-alkylamino and
di(C.sub.1-C.sub.6)-alkylamino, [1078] or [1079] R.sup.10 and
R.sup.11 form, together with the respective atom(s) to which they
are bound, a 4- to 7-membered heterocycle, [1080] in which for its
part the 4- to 7-membered heterocycle can be substituted with 1 or
2 substituents selected independently of one another from the group
cyano, trifluoromethyl, (C.sub.1-C.sub.6)-alkyl, hydroxy, oxo,
(C.sub.1-C.sub.6)-alkoxy, trifluoromethoxy,
(C.sub.1-C.sub.6)-alkoxycarbonyl, amino,
mono-(C.sub.1-C.sub.6)-alkylamino and
di(C.sub.1-C.sub.6)-alkylamino, [1081] in which [1082] R.sup.12
stands for (C.sub.1-C.sub.6)-alkyl or (C.sub.3-C.sub.7)-cycloalkyl,
[1083] and [1084] in which phenyl, 4- to 7-membered heterocyclyl
and 5- or 6-membered heteroaryl for their part can be substituted
with 1 to substituents selected independently of one another from
the group halogen, cyano, difluoromethyl, trifluoromethyl,
(C.sub.1-C.sub.4)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl, hydroxy,
oxo, difluoromethoxy, trifluoromethoxy and
(C.sub.1-C.sub.4)-alkoxy, [1085] or [1086] R.sup.5 and R.sup.6
form, together with the nitrogen atom to which they are bound, a 4-
to 7-membered heterocycle or a 5- or 6-membered heteroaryl, [1087]
in which the 4- to 7-membered heterocycle and the 5- or 6-membered
heteroaryl can be substituted with 1 to 3 substituents selected
independently of one another from the group fluorine, cyano,
difluoromethyl, trifluoromethyl, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl, hydroxy, oxo,
(C.sub.1-C.sub.6)-alkoxy, difluoromethoxy, trifluoromethoxy,
(C.sub.1-C.sub.6)-alkoxycarbonyl,
(C.sub.1-C.sub.6)-alkylcarbonylamino, amino,
mono-(C.sub.1-C.sub.6)-alkylamino, di(C.sub.1-C.sub.6)-alkylamino
and 4- to 7-membered heterocyclyl, [1088] and [1089] in which the
aforementioned (C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.8)-cycloalkyl, (C.sub.3-C.sub.7)-cycloalkyl and 4-
to 7-membered heterocyclyl groups, unless stated otherwise, can in
each case be further substituted independently of one another with
1 to 3 substituents selected independently of one another from the
group fluorine, difluoromethyl, trifluoromethyl,
(C.sub.1-C.sub.4)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl, hydroxy,
difluoromethoxy, trifluoromethoxy, (C.sub.1-C.sub.4)-alkoxy,
hydroxycarbonyl, (C.sub.1-C.sub.4)-alkoxycarbonyl, amino, phenyl,
4- to 7-membered heterocyclyl and 5- or 6-membered heteroaryl,
[1090] R.sup.1 stands for fluorine, chlorine, cyano,
difluoromethyl, trifluoromethyl, (C.sub.1-C.sub.4)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl or (C.sub.1-C.sub.4)-alkoxy, [1091] n
stands for a number 0, 1 or 2, [1092] R.sup.2 stands for
trifluoromethyl, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.8)-cycloalkyl, phenyl or 5- or 6-membered
heteroaryl, [1093] wherein (C.sub.1-C.sub.6)-alkyl is substituted
with a substituent selected from the group difluoromethyl and
trifluoromethyl, [1094] wherein (C.sub.1-C.sub.6)-alkyl can be
substituted with 1 to 3 fluorine substituents, [1095] wherein
(C.sub.3-C.sub.8)-cycloalkyl can be substituted with 1 or 2
substituents selected independently of one another from the group
fluorine, methyl and methoxy, [1096] wherein phenyl is substituted
with 1 to 3 fluorine substituents, [1097] wherein phenyl can be
substituted with 1 or 2 substituents selected independently of one
another from the group methyl and methoxy, [1098] and [1099]
wherein 5- and 6-membered heteroaryl can be substituted with 1 or 2
substituents selected independently of one another from the group
fluorine, trifluoromethyl and methyl, and their N-oxides, salts,
solvates, salts of the N-oxides and solvates of the N-oxides and
salts.
[1100] Compounds of the present invention according to formula (I)
are also preferred in which [1101] L stands for a group
#.sup.1-CR.sup.7AR.sup.7B--(CR.sup.8AR.sup.8B).sub.m-#.sup.2,
[1102] wherein [1103] #.sup.1 stands for the point of attachment to
the carbonyl group, [1104] #.sup.2 stands for the point of
attachment to the pyrimidine ring, [1105] m stands for a number 0
or 1, [1106] R.sup.7A stands for hydrogen, fluorine, methyl, ethyl,
hydroxy or amino, [1107] R.sup.7B stands for hydrogen, fluorine,
difluoromethyl, trifluoromethyl, (C.sub.1-C.sub.4)-alkyl,
methoxycarbonylamino, cyano, cyclopropyl, cyclobutyl, cyclopentyl,
phenyl or a group of formula -M-R.sup.13, [1108] in which
(C.sub.1-C.sub.4)-alkyl can be substituted with 1 to 3 substituents
selected independently of one another from the group fluorine,
cyano, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl,
hydroxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy,
hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl and amino, [1109]
and in which [1110] M stands for a bond or methylene, [1111]
R.sup.3 stands for --(C.dbd.O).sub.r--NR.sup.14R.sup.15,
--C(.dbd.S)--NR.sup.14R.sup.15, oxadiazolonyl, oxadiazolethionyl,
phenyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, oxadiazolyl,
thiadiazolyl, pyridyl, pyrimidinyl or pyrazinyl, [1112] in which
[1113] r denotes the number 0 or 1, [1114] R.sup.14 and R.sup.15
each stand, independently of one another, for hydrogen, methyl,
ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl,
azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl,
piperidinyl, piperazinyl, morpholinyl, phenyl, pyrazolyl or
pyridyl, [1115] in which methyl, ethyl and iso-propyl can be
further substituted with 1 or 2 substituents selected independently
of one another from the group fluorine, difluoromethyl,
trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxy,
difluoromethoxy, trifluoromethoxy, methoxy, ethoxy,
hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl and amino, [1116]
and [1117] in which oxadiazolonyl, oxadiazolethionyl, phenyl,
oxazolyl, thiazolyl, pyrazolyl, triazolyl, oxadiazolyl,
thiadiazolyl, pyridyl, pyrimidinyl and pyrazinyl for their part can
be substituted with 1 or 2 substituents selected independently of
one another from the group fluorine, chlorine, cyano,
difluoromethyl, trifluoromethyl, methyl, ethyl, isopropyl,
2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, cyclopropyl,
cyclobutyl, cyclopropylmethyl, cyclobutylmethyl, hydroxy, methoxy
and ethoxy, [1118] or [1119] R.sup.7A and R.sup.7B together with
the carbon atom to which they are bound, form a cyclopropyl,
cyclobutyl, cyclopentyl, azetidinyl, tetrahydrofuranyl,
pyrrolidinyl or tetrahydropyranyl ring, [1120] in which the
cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl,
tetrahydrofuranyl, pyrrolidinyl and tetrahydropyranyl ring can be
substituted with 1 or 2 substituents selected independently of one
another from the group fluorine and methyl, [1121] R.sup.8A stands
for hydrogen, fluorine, methyl, ethyl or hydroxy, [1122] R.sup.8B
stands for hydrogen, fluorine, methyl, ethyl or trifluoromethyl,
the ring Q stands for a group of formula
##STR00024## ##STR00025##
[1122] wherein [1123] * stands for the point of attachment to
--CH.sub.2--R.sup.2, [1124] ** stands for the point of attachment
to the pyrimidine, [1125] the ring Q.sub.1 together with the atoms
to which it is bound, forms a 5- to 7-membered saturated or
partially unsaturated carbocycle or a 5- to 7-membered saturated or
partially unsaturated heterocycle, [1126] R.sup.1 stands for
fluorine, chlorine or methyl, [1127] n stands for a number 0, 1 or
2, [1128] A.sup.1, A.sup.2, A.sup.3 and A.sup.4 independently of
one another stand in each case for N, CH or CR.sup.1, [1129] with
the proviso that at most two of the groups A.sup.1, A.sup.2,
A.sup.3 and A.sup.4 stand for N, [1130] R.sup.3 stands for
--OR.sup.4 or --NR.sup.5R.sup.6, [1131] wherein [1132] R.sup.4
stands for (C.sub.1-C.sub.6)-alkyl, cyclopropyl, cyclobutyl,
cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl,
tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl,
pyrazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl,
thiadiazolyl, pyridyl or pyrimidinyl, [1133] in which
(C.sub.1-C.sub.6)-alkyl can be substituted with 1 to 3 substituents
selected independently of one another from the group fluorine,
difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl,
cyclopentyl, difluoromethoxy, trifluoromethoxy,
--(C.dbd.O).sub.p--OR.sup.9, --(C.dbd.O).sub.p--NR.sup.9R.sup.10,
and --NR.sup.9--(C.dbd.O)--R.sup.10, [1134] and [1135] in which
cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl,
tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl,
piperazinyl, morpholinyl, phenyl, pyrazolyl, oxazolyl, thiazolyl,
triazolyl, oxadiazolyl, thiadiazolyl, pyridyl or pyrimidinyl can be
substituted with 1 to 3 substituents selected independently of one
another from the group fluorine, difluoromethyl, trifluoromethyl,
2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, methyl, ethyl,
isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, difluoromethoxy,
trifluoromethoxy, oxo, --(C.dbd.O).sub.p--OR.sup.9 and
--(C.dbd.O).sub.p--NR.sup.9R.sup.10, [1136] in which [1137] p
denotes the number 0 or 1, [1138] R.sup.9 and R.sup.10 each stand,
independently of one another, for hydrogen, methyl, ethyl,
isopropyl, trifluoromethyl, 2,2,2-trifluoroethyl,
1,1,2,2,2-pentafluoroethyl, cyclopropyl, cyclobutyl or cyclopentyl,
[1139] or [1140] R.sup.9 and R.sup.10 form, together with the
respective atom(s) to which they are bound, an azetidinyl,
pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring, [1141]
in which the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and
morpholinyl ring for its part can be substituted with 1 or 2
substituents selected independently of one another from the group
fluorine, trifluoromethyl, methyl, ethyl, hydroxy, oxo, methoxy,
ethoxy, amino, methylamino, ethylamino, dimethylamino and
diethylamino, [1142] R.sup.5 stands for hydrogen, methyl or ethyl,
[1143] R.sup.6 stands for (C.sub.1-C.sub.6)-alkyl, cyclopropyl,
(C.sub.3-C.sub.6)-cycloalkyl, oxetanyl, azetidinyl,
tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl,
piperazinyl, morpholinyl, phenyl, pyrazolyl, oxazolyl, thiazolyl,
triazolyl, oxadiazolyl, thiadiazolyl, pyridyl or pyrimidinyl,
[1144] in which (C.sub.1-C.sub.6)-alkyl and
(C.sub.3-C.sub.6)-cycloalkyl are substituted with 1 to 3
substituents selected independently of one another from the group
fluorine, difluoromethyl, trifluoromethyl methyl, ethyl,
cyclopropyl, cyclobutyl, cyclopentyl, difluoromethoxy,
trifluoromethoxy, --(C.dbd.O).sub.p--OR.sup.9,
--(C.dbd.O).sub.p--NR.sup.9R.sup.10,
--NR.sup.9--(C.dbd.O)--R.sup.10, oxetanyl, azetidinyl,
tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl,
piperazinyl, morpholinyl, phenyl, furanyl, pyrazolyl, imidazolyl,
oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl
and pyrimidinyl, [1145] in which cyclopropyl, cyclobutyl,
cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl,
tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl,
furanyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl,
oxadiazolyl, thiadiazolyl, pyridyl and pyrimidinyl for their part
can be substituted with 1 or 2 substituents selected independently
of one another from the group fluorine, chlorine, cyano,
difluoromethyl, trifluoromethyl, methyl, ethyl, cyclopropyl,
cyclobutyl, cyclopentyl, hydroxy, oxo, difluoromethoxy,
trifluoromethoxy, methoxy and ethoxy, [1146] in which oxetanyl,
azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl,
piperidinyl, piperazinyl, morpholinyl, phenyl, pyrazolyl, oxazolyl,
thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl and
pyrimidinyl can be substituted with 1 to 3 substituents selected
independently of one another from the group fluorine,
difluoromethyl, trifluoromethyl, methyl, ethyl, cyclopropyl,
cyclobutyl, cyclopentyl, difluoromethoxy, trifluoromethoxy, oxo,
--(C.dbd.O).sub.p--OR.sup.9 and
--(C.dbd.O).sub.p--NR.sup.9R.sup.10, [1147] in which [1148] p
denotes the number 0 or 1, [1149] R.sup.9 and R.sup.10 each stand,
independently of one another, for hydrogen, methyl, ethyl,
isopropyl, trifluoromethyl, 2,2,2-trifluoroethyl,
1,1,2,2,2-pentafluoroethyl, cyclopropyl, cyclobutyl or cyclopentyl,
[1150] or [1151] R.sup.9 and R.sup.10 form, together with the
respective atom(s) to which they are bound, an azetidinyl,
pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring, [1152]
in which the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and
morpholinyl ring for its part can be substituted with 1 or 2
substituents selected independently of one another from the group
fluorine, trifluoromethyl, methyl, ethyl, hydroxy, oxo, methoxy,
ethoxy, amino, methylamino, ethylamino, dimethylamino and
diethylamino, [1153] or [1154] R.sup.5 and R.sup.6 form, together
with the nitrogen atom to which they are bound, an azetidinyl,
pyrrolidinyl, imidazolidinyl, piperidinyl, dihydropiperidinyl,
piperazinyl, morpholinyl, pyrazolyl, imidazolyl or triazolyl ring,
[1155] in which the azetidinyl, pyrrolidinyl, imidazolidinyl,
piperidinyl, dihydropiperidinyl, piperazinyl, morpholinyl,
pyrazolyl, imidazolyl and triazolyl ring can be substituted with 1
or 2 substituents selected independently of one another from the
group fluorine, cyano, difluoromethyl, trifluoromethyl,
2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, methyl, ethyl,
1-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxy, oxo,
methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, oxetanyl,
azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl,
piperidinyl, piperazinyl and morpholinyl, [1156] R.sup.2 stands for
trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoroprop-1-yl,
2,2,3,3,3-pentafluoroprop-1-yl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl or
pyridazinyl, [1157] wherein phenyl is substituted with 1 to 3
fluorine substituents, [1158] and [1159] wherein cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, pyrimidinyl,
pyrazinyl and pyridazinyl can be substituted with 1 or 2 fluorine
substituents, and their salts, solvates and solvates of the
salts.
[1160] Compounds of the present invention according to formula (I)
are also preferred in which [1161] L stands for a group
#.sup.1-CR.sup.7AR.sup.7B--(CR.sup.8AR.sup.8B).sub.m-#.sup.2,
[1162] wherein [1163] #.sup.1 stands for the point of attachment to
the carbonyl group, [1164] #.sup.2 stands for the point of
attachment to the pyrimidine ring, [1165] m stands for a number 0,
[1166] R.sup.7A stands for hydrogen, fluorine, methyl or hydroxy,
[1167] R.sup.7B stands for hydrogen, fluorine, trifluoromethyl,
methyl or 2,2,2-trifluoroethyl, [1168] or [1169] R.sup.7A and
R.sup.7B together with the carbon atom to which they are bound,
form a tetrahydrofuranyl ring, the ring Q stands for a group of
formula
##STR00026##
[1169] wherein [1170] * stands for the point of attachment to
--CH.sub.2--R.sup.2, [1171] ** stands for the point of attachment
to the pyrimidine, [1172] R.sup.1a stands for hydrogen or methyl,
[1173] R.sup.1b stands for hydrogen or fluorine, [1174] R.sup.1c
stands for hydrogen or chlorine, [1175] A.sup.1 stands for N or CH,
[1176] A.sup.3 stands for N, CH or C--F, [1177] R.sup.3 stands for
--NR.sup.5R.sup.6, [1178] wherein [1179] R.sup.5 stands for
hydrogen, [1180] R.sup.6 stands for (C.sub.1-C.sub.6)-alkyl, [1181]
in which (C.sub.1-C.sub.6)-alkyl is substituted with 1 or 2
substituents selected independently of one another from the group
fluorine, difluoromethyl, trifluoromethyl or
--(C.dbd.O).sub.p--OR.sup.9, [1182] in which [1183] p denotes the
number 0, [1184] R.sup.9 stands for hydrogen, [1185] R.sup.2 stands
for 2-fluorophenyl, 2,3-difluorophenyl or 3-fluoropyrid-2-yl, and
their salts, solvates and solvates of the salts.
[1186] Compounds of the present invention according to formula (I)
are also preferred in which [1187] L stands for a group
#.sup.1-CR.sup.7AR.sup.7B--(CR.sup.8AR.sup.8B).sub.m-#.sup.2,
[1188] wherein [1189] #.sup.1 stands for the point of attachment to
the carbonyl group, [1190] #.sup.2 stands for the point of
attachment to the pyrimidine ring, [1191] m stands for a number 0,
[1192] R.sup.7A stands for methyl, [1193] R.sup.7B stands for
methyl, the ring Q stands for a group of formula
##STR00027##
[1193] wherein [1194] * stands for the point of attachment to
--CH.sub.2--R.sup.2, [1195] ** stands for the point of attachment
to the pyrimidine, [1196] R.sup.1a stands for hydrogen or methyl,
[1197] R.sup.1b stands for hydrogen or fluorine, [1198] R.sup.1c
stands for hydrogen or chlorine, [1199] A.sup.1 stands for N or CH,
[1200] A.sup.3 stands for N, CH or C--F, [1201] R.sup.3 stands for
--NR.sup.5R.sup.6, [1202] wherein [1203] R.sup.5 stands for
hydrogen, methyl or ethyl, [1204] R.sup.6 stands for
(C.sub.1-C.sub.6)-alkyl, oxetanyl, azetidinyl, tetrahydrofuranyl,
pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl,
morpholinyl, phenyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl,
oxadiazolyl, thiadiazolyl, pyridyl or pyrimidinyl, [1205] in which
(C.sub.1-C.sub.6)-alkyl is substituted with 1 or 2 substituents
selected independently of one another from the group fluorine,
difluoromethyl, trifluoromethyl cyclopropyl, cyclobutyl,
cyclopentyl, trifluoromethoxy, --(C.dbd.O).sub.p--OR.sup.9,
--(C.dbd.O).sub.p--NR.sup.9R.sup.10, tetrahydrofuranyl,
pyrrolidinyl, tetrahydropyranyl, phenyl, furanyl, pyrazolyl,
imidazolyl, triazolyl and pyridyl, [1206] in which [1207] p denotes
the number 0 or 1, [1208] R.sup.9 and R.sup.10 each stand,
independently of one another, for hydrogen, methyl, ethyl,
trifluoromethyl, 2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl,
cyclopropyl or cyclobutyl, [1209] and [1210] in which
tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, phenyl,
furanyl, pyrazolyl, imidazolyl, triazolyl and pyridyl for their
part can be substituted with 1 or 2 substituents selected
independently of one another from the group fluorine, chlorine,
cyano, difluoromethyl, trifluoromethyl, methyl, ethyl and oxo,
[1211] in which oxetanyl, azetidinyl, tetrahydrofuranyl,
pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl,
morpholinyl, phenyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl,
oxadiazolyl, thiadiazolyl, pyridyl and pyrimidinyl can be
substituted with 1 or 2 substituents selected independently of one
another from the group fluorine, difluoromethyl, trifluoromethyl,
methyl, ethyl and oxo, [1212] or [1213] R.sup.5 and R.sup.6 form,
together with the nitrogen atom to which they are bound, an
azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl,
dihydropiperidinyl, piperazinyl, morpholinyl, pyrazolyl or
imidazolyl ring, [1214] in which the azetidinyl, pyrrolidinyl,
imidazolidinyl, piperidinyl, dihydropiperidinyl, piperazinyl,
morpholinyl, pyrazolyl and imidazolyl ring can be substituted with
1 or 2 substituents selected independently of one another from the
group fluorine, cyano, difluoromethyl, trifluoromethyl,
2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, methyl, ethyl,
1-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxy, oxo,
methoxy, ethoxy, difluoromethoxy and trifluoromethoxy, [1215]
R.sup.2 stands for 3,3,3-trifluoroeth-1-yl,
2,2,3,3,3-pentafluoroprop-1-yl, phenyl or pyridyl, [1216] wherein
phenyl is substituted with 1 to 3 fluorine substituents, [1217] and
[1218] wherein pyridyl can be substituted with 1 fluorine
substituent, and their salts, solvates and solvates of the
salts.
[1219] Compounds of the present invention according to formula (I)
are also preferred in which [1220] L stands for a group
#.sup.1-CR.sup.7AR.sup.7B--(CR.sup.8AR.sup.8B).sub.m-#.sup.2,
[1221] wherein [1222] #.sup.1 stands for the point of attachment to
the carbonyl group, [1223] #.sup.2 stands for the point of
attachment to the pyrimidine ring, [1224] m stands for a number 0,
[1225] R.sup.7A stands for hydrogen, fluorine, methyl, hydroxy,
[1226] R.sup.7B stands for hydrogen, fluorine, methyl or
trifluoromethyl, [1227] or [1228] R.sup.7A and R.sup.7B together
with the carbon atom to which they are bound, form a
tetrahydrofuranyl ring, the ring Q stands for a group of
formula
##STR00028##
[1228] wherein [1229] * stands for the point of attachment to
--CH.sub.2--R.sup.2, [1230] ** stands for the point of attachment
to the pyrimidine, [1231] R.sup.3 stands for --OR.sup.4 or
--NR.sup.5R.sup.6, [1232] wherein [1233] R.sup.4 stands for
(C.sub.1-C.sub.6)-alkyl or pyrazolyl, [1234] in which
(C.sub.1-C.sub.6)-alkyl can be substituted with 1 to 3 substituents
selected independently of one another from the group fluorine,
trifluoromethyl, --(C.dbd.O).sub.p--OR.sup.9 and
--(C.dbd.O).sub.p--NR.sup.9R.sup.10, [1235] in which [1236] p
denotes the number 0 or 1, [1237] R.sup.9 and R.sup.10
independently of one another stand in each case for hydrogen or
methyl, [1238] and [1239] in which pyrazolyl can be substituted
with 1 or 2 substituents selected independently of one another from
the group fluorine, difluoromethyl, trifluoromethyl,
2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, methyl,
cyclopropyl, cyclobutyl, cyclopentyl. [1240] R.sup.5 stands for
hydrogen, methyl or ethyl, [1241] R.sup.6 stands for
(C.sub.1-C.sub.6)-alkyl, oxetanyl, azetidinyl, tetrahydrofuranyl,
pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl,
morpholinyl, phenyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl,
oxadiazolyl, thiadiazolyl, pyridyl or pyrimidinyl, [1242] in which
(C.sub.1-C.sub.6)-alkyl is substituted with 1 or 2 substituents
selected independently of one another from the group fluorine,
difluoromethyl, trifluoromethyl cyclopropyl, cyclobutyl,
cyclopentyl, trifluoromethoxy, --(C.dbd.O).sub.p--OR.sup.9,
--(C.dbd.O).sub.p--NR.sup.9R.sup.10, tetrahydrofuranyl,
pyrrolidinyl, tetrahydropyranyl, phenyl, furanyl, pyrazolyl,
imidazolyl, triazolyl and pyridyl, [1243] in which [1244] p denotes
the number 0 or 1, [1245] R.sup.9 and R.sup.10 each stand,
independently of one another, for hydrogen, methyl, ethyl,
trifluoromethyl, 2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl,
cyclopropyl or cyclobutyl, [1246] and [1247] in which cyclopropyl,
cyclobutyl, cyclopentyl, tetrahydrofuranyl, pyrrolidinyl,
tetrahydropyranyl, phenyl, furanyl, pyrazolyl, imidazolyl,
triazolyl and pyridyl for their part can be substituted with 1 or 2
substituents selected independently of one another from the group
fluorine, chlorine, cyano, difluoromethyl, trifluoromethyl, methyl,
ethyl, oxo and hydroxy, [1248] in which oxetanyl, azetidinyl,
tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl,
piperazinyl, morpholinyl, phenyl, pyrazolyl, oxazolyl, thiazolyl,
triazolyl, oxadiazolyl, thiadiazolyl, pyridyl and pyrimidinyl can
be substituted with 1 or 2 substituents selected independently of
one another from the group fluorine, difluoromethyl,
trifluoromethyl, methyl, ethyl, oxo, azetidinyl and pyrrolidinyl,
[1249] or [1250] R.sup.5 and R.sup.6 form, together with the
nitrogen atom to which they are bound, an azetidinyl, pyrrolidinyl,
imidazolidinyl, piperidinyl, dihydropiperidinyl, piperazinyl,
morpholinyl, pyrazolyl or imidazolyl ring, [1251] in which the
azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl,
dihydropiperidinyl, piperazinyl, morpholinyl, pyrazolyl and
imidazolyl ring can be substituted with 1 or 2 substituents
selected independently of one another from the group fluorine,
cyano, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl,
1,1,2,2,2-pentafluoroethyl, methyl, ethyl, 1-hydroxyethyl,
cyclopropyl, cyclobutyl, cyclopentyl, hydroxy, oxo, methoxy,
ethoxy, difluoromethoxy and trifluoromethoxy, [1252] R.sup.2 stands
for 2-fluorophenyl, 2,3-difluorophenyl or 3-fluoropyrid-2-yl, and
their salts, solvates and solvates of the salts.
[1253] Compounds of the present invention according to formula (I)
are also preferred in which [1254] L stands for a group
#.sup.1-CR.sup.7AR.sup.7B--(CR.sup.8AR.sup.8B).sub.m-#.sup.2,
[1255] wherein [1256] #.sup.1 stands for the point of attachment to
the carbonyl group, [1257] #.sup.2 stands for the point of
attachment to the pyrimidine ring, [1258] m stands for a number 0,
[1259] R.sup.7A stands for methyl, [1260] R.sup.7B stands for
methyl, [1261] or [1262] R.sup.7A and R.sup.7B together with the
carbon atom to which they are bound, form a tetrahydrofuranyl ring,
the ring Q stands for a group of formula
##STR00029##
[1262] wherein [1263] * stands for the point of attachment to
--CH.sub.2--R.sup.2, [1264] ** stands for the point of attachment
to the pyrimidine, [1265] R.sup.3 stands for --OR.sup.4 or
--NR.sup.5R.sup.6, [1266] wherein [1267] R.sup.4 stands for
(C.sub.1-C.sub.6)-alkyl or pyrazolyl, [1268] in which
(C.sub.1-C.sub.6)-alkyl can be substituted with 1 to 3 substituents
selected independently of one another from the group fluorine,
trifluoromethyl, --(C.dbd.O).sub.p--OR.sup.9 and
--(C.dbd.O).sub.p--NR.sup.9R.sup.10, [1269] in which [1270] p
denotes the number 0 or 1, [1271] R.sup.9 and R.sup.10
independently of one another stand in each case for hydrogen or
methyl, [1272] and [1273] in which pyrazolyl can be substituted
with 1 or 2 substituents selected independently of one another from
the group fluorine, difluoromethyl, trifluoromethyl,
2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, methyl,
cyclopropyl, cyclobutyl, cyclopentyl, [1274] R.sup.5 stands for
hydrogen, methyl or ethyl, [1275] R.sup.6 stands for
(C.sub.1-C.sub.6)-alkyl, oxetanyl, azetidinyl, tetrahydrofuranyl,
pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl,
morpholinyl, phenyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl,
oxadiazolyl, thiadiazolyl, pyridyl or pyrimidinyl, [1276] in which
(C.sub.1-C.sub.6)-alkyl is substituted with 1 or 2 substituents
selected independently of one another from the group fluorine,
difluoromethyl, trifluoromethyl cyclopropyl, cyclobutyl,
cyclopentyl, trifluoromethoxy, --(C.dbd.O).sub.p--OR.sup.9,
--(C.dbd.O).sub.p--NR.sup.9R.sup.10, tetrahydrofuranyl,
pyrrolidinyl, tetrahydropyranyl, phenyl, furanyl, pyrazolyl,
imidazolyl, triazolyl and pyridyl, [1277] in which [1278] p denotes
the number 0 or 1, [1279] R.sup.9 and R.sup.10 each stand,
independently of one another, for hydrogen, methyl, ethyl,
trifluoromethyl, 2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl,
cyclopropyl or cyclobutyl, [1280] and [1281] in which cyclopropyl,
cyclobutyl, cyclopentyl, tetrahydrofuranyl, pyrrolidinyl,
tetrahydropyranyl, phenyl, furanyl, pyrazolyl, imidazolyl,
triazolyl and pyridyl for their part can be substituted with 1 or 2
substituents selected independently of one another from the group
fluorine, chlorine, cyano, difluoromethyl, trifluoromethyl, methyl,
ethyl, oxo and hydroxy, [1282] in which oxetanyl, azetidinyl,
tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl,
piperazinyl, morpholinyl, phenyl, pyrazolyl, oxazolyl, thiazolyl,
triazolyl, oxadiazolyl, thiadiazolyl, pyridyl and pyrimidinyl can
be substituted with 1 or 2 substituents selected independently of
one another from the group fluorine, difluoromethyl,
trifluoromethyl, methyl, ethyl, oxo, azetidinyl and pyrrolidinyl,
[1283] or [1284] R.sup.5 and R.sup.6 form, together with the
nitrogen atom to which they are bound, an azetidinyl, pyrrolidinyl,
imidazolidinyl, piperidinyl, dihydropiperidinyl, piperazinyl,
morpholinyl, pyrazolyl or imidazolyl ring, [1285] in which the
azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl,
dihydropiperidinyl, piperazinyl, morpholinyl, pyrazolyl and
imidazolyl ring can be substituted with 1 or 2 substituents
selected independently of one another from the group fluorine,
cyano, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl,
1,1,2,2,2-pentafluoroethyl, methyl, ethyl, 1-hydroxyethyl,
cyclopropyl, cyclobutyl, cyclopentyl, hydroxy, oxo, methoxy,
ethoxy, difluoromethoxy and trifluoromethoxy, [1286] R.sup.2 stands
for 2-fluorophenyl, 2,3-difluorophenyl or 3-fluoropyrid-2-yl, and
their salts, solvates and solvates of the salts.
[1287] Compounds of the present invention according to formula (I)
are also preferred that display an action on recombinant guanylate
cyclase reporter cell lines according to the test under B-2 as
minimal effective concentration (MEC) of .ltoreq.3 .mu.m and
display inhibition of human phosphodiesterase 5 (PDE5) according to
the test under B-6 as IC50<100 nm,
and their salts, solvates and solvates of the salts.
[1288] Compounds of the present invention according to claim 1 and
examples 1-117 are especially preferred that display an action on
recombinant guanylate cyclase reporter cell lines according to the
test under B-2 as minimal effective concentration (MEC) of <3
.mu.m and display inhibition of human phosphodiesterase 5 (PDE5)
according to the test under B-6 as IC50<100 nm,
and their salts, solvates and solvates of the salts.
[1289] The definitions of residues given in detail in the
respective combinations or preferred combinations of residues are
also replaced by any definitions of residues of other combinations
independently of the respective combinations stated.
[1290] Combinations of two or more of the aforementioned preferred
ranges are especially preferred.
[1291] The compounds according to the invention of formula (I), in
which R.sup.3 stands for hydroxyl (I-A), can also be in the
tautomeric keto form (I'-A) (see Scheme 7 below); both tautomeric
forms are expressly covered by the present invention.
##STR00030##
[1292] The invention further relates to a method of production of
the compounds according to the invention of formula (I),
characterized in that a compound of formula (II)
##STR00031##
in which n, L, Q, R.sup.1 and R.sup.2 have the respective meanings
given above, is converted in an inert solvent with iso-pentyl
nitrite and a halogen equivalent to a compound of formula (III)
##STR00032##
in which n, L, Q, R.sup.1 and R.sup.2 have the respective meanings
given above and X.sup.1 stands for chlorine, bromine or iodine and
this is then reacted in an inert solvent optionally in the presence
of a suitable base with a compound of formula (IV)
R.sup.3--H (IV),
in which R.sup.3 has the meaning given above, to a compound of
formula (I)
##STR00033##
in which n, L, Q, le, R.sup.2 and R.sup.3 have the respective
meanings given above, and optionally the resultant compounds of
formula (I) are converted optionally with the corresponding (i)
solvents and/or (ii) acids or bases to their solvates, salts and/or
solvates of the salts.
[1293] The process step (II).fwdarw.(III) takes place with or
without solvent. All organic solvents that are inert under the
reaction conditions are suitable as solvent. The preferred solvent
is dimethoxyethane.
[1294] The reaction (II).fwdarw.(III) generally takes place in a
temperature range from +20.degree. C. to +100.degree. C.,
preferably in the range from +50.degree. C. to +100.degree. C.,
optionally in a microwave. The reaction can be carried out at
normal, increased or reduced pressure (e.g. in the range from 0.5
to 5 bar). It is generally carried out at normal pressure.
[1295] For example diiodomethane, a mixture of caesium iodide,
iodine and copper(I) iodide or copper(II) bromide are suitable as
halogen source in the reaction (II).fwdarw.(III).
[1296] Inert solvents for the process step (III)+(IV).fwdarw.(I)
are for example ethers such as diethyl ether, dioxane,
dimethoxyethane, tetrahydrofuran, glycol dimethyl ether or
diethylene glycol dimethyl ether, hydrocarbons such as benzene,
xylene, toluene, hexane, cyclohexane or petroleum fractions, or
other solvents such as dimethylformamide (DMF), dimethylsulphoxide
(DMSO), N,N'-dimethylpropylene urea (DMPU), N-methylpyrrolidone
(NMP), pyridine, acetonitrile or sulpholane. It is also possible to
use mixtures of the aforementioned solvents. NMP is preferred.
[1297] In the case when R.sup.3=--OR.sup.4, the reaction
(III)+(IV).fwdarw.(I) preferably takes place without solvent.
[1298] In the case when R.sup.3=--OR.sup.4, the reaction
(III)+(IV).fwdarw.(I) takes place in the presence of a suitable
copper catalyst, for example copper(I) iodide, with addition of
3,4,7,8-tetramethyl-1,10-phenanthroline, and a suitable base, for
example alkaline-earth carbonates such as lithium, sodium,
potassium, calcium or caesium carbonate, preferably caesium
carbonate.
[1299] Alternatively, in the case when R.sup.3=--OR.sup.4, the
compounds of formula (I) can also be prepared under Mitsunobu
conditions [see: a) Hughes, D. L. "The Mitsunobu reaction," Organic
Reactions; John Wiley & Sons, Ltd, 1992, Vol. 42, p. 335. b)
Hughes, D. L. Org. Prep. Proceed. Int. 1996, 28, 127.] starting
from a compound of formula (I-A)
##STR00034##
in which n, L, Q, R.sup.1 and R.sup.2 have the respective meanings
given above.
[1300] The Mitsunobu reaction takes place herein using triphenyl
phosphine, or tri-n-butylphosphine,
1,2-bis(diphenylphosphino)ethane (DPPE),
diphenyl(2-pyridyl)phosphine (Ph2P-Py),
(p-dimethylaminophenyl)diphenylphosphine (DAP-DP),
Tris(4-dimethylaminophenyl)-phosphine (Tris-DAP) and a suitable
dialkyl azodicarboxylate, for example diethyl azodicarboxylate
(DEAD), diisopropyl azodicarboxylate (DIAD), di-tert-butyl
azodicarboxylate, N,N,N',N'-tetramethyl azodicarboxamide (TMAD),
1,1'-(azodicarbonyl)-dipiperidine (ADDP) or
4,7-dimethyl-3,5,7-hexahydro-1,2,4,7-tetrazocin-3,8-dione (DHTD).
Preferably triphenyl phosphine and diisopropyl azodicarboxylate
(DIAD) are used, or a suitable azodicarbonamide, for example
N,N,N',N'-tetramethyldiazene-1,2-dicarboxamide.
[1301] Inert solvents for the Mitsunobu reaction
(I-A)+(IV).fwdarw.(I) are for example ethers such as
tetrahydrofuran, diethyl ether, hydrocarbons such as benzene,
toluene, xylene, halohydrocarbons such as dichloromethane,
dichloroethane or other solvents such as acetonitrile, DMF or NMP.
It is also possible to use mixtures of the aforementioned solvents.
THF is preferably used.
[1302] The Mitsunobu reaction (III)+(IV).fwdarw.(I) generally takes
place in a temperature range from -78.degree. C. to +180.degree.
C., preferably at 0.degree. C. to +50.degree. C., optionally in a
microwave. The reactions can be carried out at normal, increased or
reduced pressure (e.g. from 0.5 to 5 bar).
[1303] Alternatively, in the case when R.sup.3=--OR.sup.4, the
compounds of formula (I) can also be prepared under alkylation
conditions starting from a compound of formula (I-A). For this, an
alkyl halide, preferably alkyl iodide, is reacted with (I-A) with
addition of a base in an inert solvent.
[1304] Suitable bases for the process step (I-A).fwdarw.(I) are the
usual inorganic or organic bases. These preferably include alkali
hydroxides, for example lithium, sodium or potassium hydroxide,
alkali or alkaline-earth carbonates such as lithium, sodium,
potassium, calcium or caesium carbonate, alkali alcoholates such as
sodium or potassium methanolate, sodium or potassium ethanolate or
sodium or potassium tert.-butylate, alkali hydrides such as sodium
or potassium hydride or amides such as sodium amide, lithium or
potassium bis(trimethylsilyl)amide or lithium diisopropylamide.
Caesium carbonate is preferably used.
[1305] Inert solvents are for example ethers such as
tetrahydrofuran, diethyl ether, hydrocarbons such as benzene,
toluene, xylene, and other solvents such as DMF or NMP. It is also
possible to use mixtures of the aforementioned solvents. DMF is
preferably used.
[1306] The alkylation reaction generally takes place in a
temperature range from -78.degree. C. to +180.degree. C.,
preferably at 0.degree. C. to +130.degree. C., optionally in a
microwave. The reactions can be carried out at normal, increased or
reduced pressure (e.g. from 0.5 to 5 bar).
[1307] In the case when R.sup.3=--NR.sup.5R.sup.6, if R.sup.5 and
R.sup.6, together with the nitrogen atom to which they are bound,
form a 5- or 6-membered heteroaryl, which can be substituted in the
range of meanings stated above, the reaction (III)+(IV).fwdarw.(I)
takes place in the presence of a suitable copper catalyst, for
example copper(I) oxide, with addition of
2-hydroxybenzaldehyde-oxime, and a suitable base, for example
alkaline-earth carbonates such as lithium, sodium, potassium,
calcium or caesium carbonate, preferably caesium carbonate.
[1308] The reaction (III)+(IV).fwdarw.(I) is generally carried out
in a temperature range from +20.degree. C. to +200.degree. C.,
preferably at +150.degree. C. to +200.degree. C., preferably in a
microwave. The reaction can take place at normal, increased or
reduced pressure (e.g. from 0.5 to 5 bar).
[1309] The method of production described can be illustrated for
example by the following synthesis scheme (Scheme 1):
##STR00035##
[1310] Compounds of formula (I-A) are obtained as by-products in
the production of the compounds of formula (III).
[1311] Compounds of formula (I-A) can alternatively also be
obtained starting from compounds of formula (V) by reaction with
compounds of formula (VIII)
##STR00036##
in which L has the meaning given above, T.sup.2 stands for
(C.sub.1-C.sub.4)-alkyl and R' stands for (C.sub.1-C.sub.4)-alkyl,
As described e.g. in Foeldi, et al., Chemische Berichte, 1942, vol.
75, p. 760.
[1312] Compounds of formula (I-A) can also be prepared in another
alternative method starting from compounds of formula (II) by
reaction with nitrites in acids, optionally with addition of water.
Sodium nitrite in a mixture of trifluoroacetic acid and water is
preferred.
[1313] The reaction (II)).fwdarw.(I-A) is generally carried out in
a temperature range from -15.degree. C. to +70.degree. C.,
preferably at 0.degree. C. to +40.degree. C., with addition of the
nitrite in portions. The reaction can take place at normal,
increased or reduced pressure (e.g. from 0.5 to 5 bar).
[1314] The method of production described above can be illustrated
for example by the following synthesis scheme (Scheme 2):
##STR00037##
[1315] The compounds of formula (II) are known from the literature
(see e.g. WO 2010/065275, WO 2011/115804 and WO 2011/149921) or can
be produced by analogy with methods known from the literature.
[1316] The compounds of formula (II) can be produced by reacting a
compound of formula (V)
##STR00038##
in which n, Q.sup.1, R.sup.1 and R.sup.2 have the respective
meanings given above, in an inert solvent in the presence of a
suitable base with a compound of formula (VI)
##STR00039##
in which L has the meaning given above and T.sup.1 stands for
(C.sub.1-C.sub.4)-alkyl, to a compound of formula (II)
##STR00040##
in which n, L, Q.sup.1, R.sup.1 and R.sup.2 have the respective
meanings given above.
[1317] Inert solvents for the process step (V)+(VI).fwdarw.(II) are
for example alcohols such as methanol, ethanol, n-propanol,
isopropanol, n-butanol or tert.-butanol, ethers such as diethyl
ether, dioxane, dimethoxyethane, tetrahydrofuran, glycol dimethyl
ether or diethylene glycol dimethyl ether, hydrocarbons such as
benzene, xylene, toluene, hexane, cyclohexane or petroleum
fractions, or other solvents such as dimethylformamide (DMF),
dimethylsulphoxide (DMSO), N,N'-dimethylpropylene urea (DMPU),
N-methylpyrrolidone (NMP), pyridine, acetonitrile, sulpholane or
also water. It is also possible to use mixtures of the
aforementioned solvents. tert.-Butanol or methanol is
preferred.
[1318] Suitable bases for the process step (V)+(VI).fwdarw.(II) are
alkali hydroxides, for example lithium, sodium or potassium
hydroxide, alkali carbonates such as lithium, sodium, potassium or
caesium carbonate, alkali hydrogen carbonates such as sodium or
potassium hydrogen carbonate, alkali alcoholates such as sodium or
potassium methanolate, sodium or potassium ethanolate or potassium
tert.-butylate, or organic amines such as triethylamine,
diisopropyl ethylamine, pyridine,
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or
1,5-diazabicyclo[4.3.0]non-5-ene (DBN). Potassium tert.-butylate or
sodium methanolate is preferred.
[1319] The reaction (V)+(VI).fwdarw.(II) is generally carried out
in a temperature range from +20.degree. C. to +150.degree. C.,
preferably at +75.degree. C. to +100.degree. C., optionally in a
microwave. The reaction can take place at normal, increased or
reduced pressure (e.g. from 0.5 to 5 bar). It is generally carried
out at normal pressure.
[1320] The method of production described above can be illustrated
for example by the following synthesis scheme (Scheme 3):
##STR00041##
[1321] The compounds of formula (V) are known from the literature
(see e.g. WO 03/095451, example 6A) or can be prepared as in the
following synthesis schemes (Schemes 4 to 6)
##STR00042##
##STR00043##
##STR00044## ##STR00045##
[1322] The compound of formula (VII) is known from the literature
[cf. e.g. Winn M., J. Med. Chem. 1993, 36, 2676-7688; EP 634
413-A1; CN 1613849-A; EP 1626045-A1; WO 2009/018415], can be
prepared by analogy with methods known from the literature or as
shown in the following synthesis scheme (Scheme 7):
##STR00046##
[1323] The compounds of formula (IV) and (VI) are commercially
available, known from the literature or can be prepared by analogy
with methods known from the literature.
[1324] The compounds according to the invention act as potent
stimulators of soluble guanylate cyclase and inhibitors of
phosphodiesterase-5, possess valuable pharmacological properties,
and have an improved therapeutic profile, for example with respect
to their in-vivo properties and/or their pharmacokinetic behaviour
and/or metabolic profile. They are therefore suitable for treating
and/or preventing diseases in humans and animals.
[1325] The compounds according to the invention bring about vessel
relaxation and inhibition of thrombocyte aggregation and lead to a
lowering of blood pressure and to an increase in coronary blood
flow. These effects are due to direct stimulation of soluble
guanylate cyclase and an increase in intracellular cGMP. Moreover,
the compounds according to the invention intensify the action of
substances that raise the cGMP level, for example EDRF
(endothelium-derived relaxing factor), NO donors, protoporphyrin
IX, arachidonic acid or phenylhydrazine derivatives.
[1326] The compounds according to the invention are suitable for
treating and/or preventing cardiovascular, pulmonary,
thromboembolic and fibrotic diseases.
[1327] The compounds according to the invention can therefore be
used in medicinal products for treating and/or preventing
cardiovascular diseases, for example high blood pressure
(hypertension), resistant hypertension, acute and chronic heart
failure, coronary heart disease, stable and unstable angina
pectoris, peripheral and cardiac vascular diseases, arrhythmias,
disturbances of atrial and ventricular rhythm and conduction
disturbances, for example atrioventricular blocks of degree I-III
(AVB I-III), supraventricular tachyarrhythmia, atrial fibrillation,
atrial flutter, ventricular fibrillation, ventricular flutter,
ventricular tachyarrhythmia, torsade-de-pointes tachycardia, atrial
and ventricular extrasystoles, AV-junction extrasystoles,
sick-sinus syndrome, syncopes, AV-node reentry tachycardia,
Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS),
autoimmune heart diseases (pericarditis, endocarditis, valvulitis,
aortitis, cardiomyopathies), shock such as cardiogenic shock,
septic shock and anaphylactic shock, aneurysms, Boxer
cardiomyopathy (premature ventricular contraction (PVC)), for
treating and/or preventing thromboembolic diseases and ischaemias
such as myocardial ischaemia, myocardial infarction, stroke,
cardiac hypertrophy, transient ischaemic attacks, preeclampsia,
inflammatory cardiovascular diseases, spasms of the coronary
arteries and peripheral arteries, development of oedema, for
example pulmonary oedema, cerebral oedema, renal oedema or oedema
due to heart failure, peripheral perfusion disturbances,
reperfusion injury, arterial and venous thromboses,
microalbuminuria, myocardial insufficiency, endothelial
dysfunction, for preventing restenoses such as after thrombolysis
therapies, percutaneous transluminal angioplasty (PTA),
transluminal coronary angioplasty (PTCA), heart transplant and
bypass operations, and micro- and macrovascular damage
(vasculitis), increased level of fibrinogen and of low-density LDL
and increased concentrations of plasminogen activator inhibitor 1
(PAI-1), and for treating and/or preventing erectile dysfunction
and female sexual dysfunction.
[1328] In the sense of the present invention, the term heart
failure comprises both acute and chronic manifestations of heart
failure, as well as more specific or related forms of disease such
as acute decompensated heart failure, right ventricular failure,
left ventricular failure, total heart failure, ischaemic
cardiomyopathy, dilatated cardiomyopathy, hypertrophic
cardiomyopathy, idiopathic cardiomyopathy, congenital heart
defects, heart failure with valvular defects, mitral valve
stenosis, mitral valve insufficiency, aortic valve stenosis, aortic
valve insufficiency, tricuspid stenosis, tricuspid insufficiency,
pulmonary valve stenosis, pulmonary valve insufficiency, combined
valvular defects, heart muscle inflammation (myocarditis), chronic
myocarditis, acute myocarditis, viral myocarditis, diabetic heart
failure, alcoholic cardiomyopathy, storage cardiomyopathies,
diastolic heart failure and systolic heart failure and acute phases
of exacerbation of existing chronic heart failure (worsening heart
failure).
[1329] Furthermore, the compounds according to the invention can
also be used for treating and/or preventing arteriosclerosis,
disturbances of lipid metabolism, hypolipoproteinaemias,
dyslipidaemias, hypertriglyceridaemias, hyperlipidaemias,
hypercholesterolaemias, abetalipoproteinaemia, sitosterolaemia,
xanthomatosis, Tangier disease, adiposity, obesity, and combined
hyperlipidaemias and metabolic syndrome.
[1330] Moreover, the compounds according to the invention can be
used for treating and/or preventing primary and secondary Raynaud
phenomenon, microcirculation disturbances, claudication, peripheral
and autonomic neuropathies, diabetic microangiopathies, diabetic
retinopathy, diabetic limb ulcers, gangrene, CREST syndrome,
erythematous disorders, onychomycosis, rheumatic diseases and for
promoting wound healing.
[1331] Furthermore, the compounds according to the invention are
suitable for treating urological diseases, for example benign
prostatic syndrome (BPS), benign prostatic hyperplasia (BPH),
benign prostatic enlargement (BPE), bladder outlet obstruction
(BOO), lower urinary tract syndromes (LUTS, including feline
urological syndrome (FUS)), diseases of the urogenital system
including neurogenic overactive bladder (OAB) and (IC), urinary
incontinence (UI) for example mixed, urge, stress, or overflow
incontinence (MUI, UUI, SUI, OUI), pelvic pains, benign and
malignant diseases of the organs of the male and female urogenital
system.
[1332] Furthermore, the compounds according to the invention are
suitable for treating and/or preventing kidney diseases, in
particular acute and chronic renal insufficiency, and acute and
chronic renal failure. In the sense of the present invention, the
term renal insufficiency comprises both acute and chronic
manifestations of renal insufficiency, as well as underlying or
related kidney diseases such as renal hypoperfusion, intradialytic
hypotension, obstructive uropathy, glomerulopathies,
glomerulonephritis, acute glomerulonephritis, glomerulosclerosis,
tubulointerstitial diseases, nephropathic diseases such as primary
and congenital kidney disease, nephritis, immunological kidney
diseases such as kidney transplant rejection, immune
complex-induced kidney diseases, nephropathy induced by toxic
substances, contrast medium-induced nephropathy, diabetic and
non-diabetic nephropathy, pyelonephritis, renal cysts,
nephrosclerosis, hypertensive nephrosclerosis and nephrotic
syndrome, which can be characterized diagnostically for example by
abnormally reduced creatinine and/or water excretion, abnormally
increased blood concentrations of urea, nitrogen, potassium and/or
creatinine, altered activity of renal enzymes such as e.g. glutamyl
synthetase, altered urine osmolarity or urine volume, increased
microalbuminuria, macroalbuminuria, lesions of glomeruli and
arterioles, tubular dilatation, hyperphosphataemia and/or need for
dialysis. The present invention also comprises the use of the
compounds according to the invention for treating and/or preventing
sequelae of renal insufficiency, for example pulmonary oedema,
heart failure, uraemia, anaemia, electrolyte disturbances (e.g.
hyperkalaemia, hyponatraemia) and disturbances in bone and
carbohydrate metabolism.
[1333] Furthermore, the compounds according to the invention are
also suitable for treating and/or preventing asthmatic diseases,
pulmonary arterial hypertension (PAH) and other forms of pulmonary
hypertension (PH), comprising pulmonary hypertension associated
with left ventricular disease, HIV, sickle cell anaemia,
thromboembolism (CTEPH), sarcoidosis, COPD or pulmonary fibrosis,
chronic obstructive pulmonary disease (COPD), acute respiratory
distress syndrome (ARDS), acute lung injury (ALI),
alpha-1-antitrypsin deficiency (AATD), pulmonary fibrosis,
pulmonary emphysema (e.g. smoking-induced pulmonary emphysema) and
cystic fibrosis (CF).
[1334] The compounds described in the present invention are also
active substances for combating diseases in the central nervous
system that are characterized by disturbances of the NO/cGMP
system. In particular, they are suitable for improving perception,
capacity for concentration, capacity for learning or memory
performance after cognitive disturbances, such as occur in
particular in situations/diseases/syndromes such as mild cognitive
impairment, age-related learning and memory disturbances,
age-related memory loss, vascular dementia, head injury, stroke,
post-stroke dementia, post-traumatic head injury, general
disturbances of concentration, disturbances of concentration in
children with learning and memory problems, Alzheimer's disease,
Lewy body dementia, dementia with frontal lobe degeneration
including Pick's syndrome, Parkinson's disease, progressive nuclear
palsy, dementia with corticobasal degeneration, amyotrophic lateral
sclerosis (ALS), Huntington's disease, demyelination, multiple
sclerosis, thalamic degeneration, Creutzfeldt-Jakob dementia,
HIV-dementia, schizophrenia with dementia or Korsakoff psychosis.
They are also suitable for treating and/or preventing diseases of
the central nervous system such as anxiety, tension and depression,
CNS-related sexual dysfunctions and sleep disturbances and for
controlling pathological eating disorders and use of luxury foods
and addictive drugs.
[1335] Furthermore, the compounds according to the invention are
also suitable for controlling cerebral perfusion and are effective
agents for combating migraines. They are also suitable for
preventing and combating the consequences of cerebral infarctions
(apoplexia cerebri) such as stroke, cerebral ischaemias and head
injury. The compounds according to the invention can also be used
for combating pain states and tinnitus.
[1336] In addition, the compounds according to the invention
possess anti-inflammatory action and can therefore be used as
anti-inflammatory agents for treating and/or preventing sepsis
(SIRS), multiple organ failure (MODS, MOF), inflammatory diseases
of the kidney, chronic intestinal inflammations (IBD, Crohn's
disease, UC), pancreatitis, peritonitis, rheumatoid diseases,
inflammatory skin diseases and inflammatory eye diseases.
[1337] Moreover, the compounds according to the invention can also
be used for treating and/or preventing autoimmune diseases.
[1338] Furthermore, the compounds according to the invention are
suitable for treating and/or preventing fibrotic diseases of the
internal organs, for example of the lung, heart, kidney, bone
marrow and in particular of the liver, and dermatological fibroses
and fibrotic diseases of the eye. In the sense of the present
invention, the term fibrotic diseases comprises in particular the
following terms: hepatic fibrosis, hepatic cirrhosis, pulmonary
fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis,
interstitial renal fibrosis, fibrotic lesions as a consequence of
diabetes, bone marrow fibrosis and similar fibrotic diseases,
scleroderma, morphea, keloids, hypertrophic scars (including after
surgery), naevi, diabetic retinopathy, proliferative
vitreoretinopathy and connective tissue diseases (e.g.
sarcoidosis).
[1339] Furthermore, the compounds according to the invention are
suitable for combating postoperative scarring, e.g. as a result of
glaucoma operations.
[1340] The compounds according to the invention can also be used
cosmetically for ageing and keratinizing skin.
[1341] Moreover, the compounds according to the invention are
suitable for treating and/or preventing hepatitis, neoplasms,
osteoporosis, glaucoma and gastroparesis.
[1342] The present invention further relates to the use of the
compounds according to the invention for treating and/or preventing
diseases, in particular the aforementioned diseases.
[1343] The present invention further relates to the use of the
compounds according to the invention for treating and/or preventing
heart failure, angina pectoris, hypertension, pulmonary
hypertension, ischaemias, vascular diseases, renal insufficiency,
thromboembolic diseases, fibrotic diseases and
arteriosclerosis.
[1344] The present invention further relates to the compounds
according to the invention for use in a method of treating and/or
preventing heart failure, angina pectoris, hypertension, pulmonary
hypertension, ischaemias, vascular diseases, renal insufficiency,
thromboembolic diseases, fibrotic diseases and
arteriosclerosis.
[1345] The present invention further relates to the use of the
compounds according to the invention for producing a medicinal
product for treating and/or preventing diseases, in particular the
aforementioned diseases.
[1346] The present invention further relates to the use of the
compounds according to the invention for producing a medicinal
product for treating and/or preventing heart failure, angina
pectoris, hypertension, pulmonary hypertension, ischaemias,
vascular diseases, renal insufficiency, thromboembolic diseases,
fibrotic diseases and arteriosclerosis.
[1347] The present invention further relates to a method of
treating and/or preventing diseases, in particular the
aforementioned diseases, using an effective amount of at least one
of the compounds according to the invention.
[1348] The present invention further relates to a method of
treating and/or preventing heart failure, angina pectoris,
hypertension, pulmonary hypertension, ischaemias, vascular
diseases, renal insufficiency, thromboembolic diseases, fibrotic
diseases and arteriosclerosis, using an effective amount of at
least one of the compounds according to the invention.
[1349] The compounds according to the invention can be used alone
or in combination with other active substances if necessary. The
present invention further relates to medicinal products containing
at least one of the compounds according to the invention and one or
more further active substances, in particular for treating and/or
preventing the aforementioned diseases. As suitable combination
active substances, we may mention for example and preferably:
[1350] organic nitrates and NO-donors, for example sodium
nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide
dinitrate, molsidomine or SIN-1, and inhalational NO; [1351]
compounds that inhibit the degradation of cyclic guanosine
monophosphate (cGMP), for example inhibitors of phosphodiesterases
(PDE) 1, 2 and/or 5, in particular PDE-5 inhibitors such as
sildenafil, vardenafil and tadalafil; [1352] antithrombotic agents,
for example and preferably from the group of platelet aggregation
inhibitors, anticoagulants or profibrinolytic substances; [1353]
active substances for lowering blood pressure, for example and
preferably from the group of calcium antagonists, angiotensin AII
antagonists, ACE inhibitors, endothelin antagonists, renin
inhibitors, alpha-blockers, beta-blockers, mineralocorticoid
receptor antagonists and diuretics; and/or [1354] active substances
that alter fat metabolism, for example and preferably from the
group of thyroid receptor agonists, cholesterol synthesis
inhibitors such as for example and preferably HMG-CoA-reductase or
squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors,
MTP inhibitors, PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists,
cholesterol absorption inhibitors, lipase inhibitors, polymeric
bile acid adsorbers, bile acid reabsorption inhibitors and
lipoprotein(a) antagonists.
[1355] Antithrombotic agents are preferably to be understood as
compounds from the group of platelet aggregation inhibitors,
anticoagulants or profibrinolytic substances.
[1356] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with a
platelet aggregation inhibitor, for example and preferably aspirin,
clopidogrel, ticlopidine or dipyridamole.
[1357] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with a
thrombin inhibitor, for example and preferably ximelagatran,
dabigatran, melagatran, bivalirudin or Clexane.
[1358] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with a
GPIIb/IIIa antagonist, for example and preferably tirofiban or
abciximab.
[1359] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with a
factor Xa inhibitor, for example and preferably rivaroxaban (BAY
59-7939), DU-176b, apixaban, otamixaban, fidexaban, razaxaban,
fondaparinux, idraparinux, PMD-3112, YM-150, KFA-1982, EMD-503982,
MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or
SSR-128428.
[1360] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with
heparin or a low molecular weight (LMW) heparin derivative.
[1361] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with a
vitamin K antagonist, for example and preferably coumarin.
[1362] The agents for lowering blood pressure are preferably to be
understood as compounds from the group of calcium antagonists,
angiotensin AII antagonists, ACE inhibitors, endothelin
antagonists, renin inhibitors, alpha-blockers, beta-blockers,
mineralocorticoid-receptor antagonists and diuretics.
[1363] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with a
calcium antagonist, for example and preferably nifedipine,
amlodipine, verapamil or diltiazem.
[1364] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with an
alpha-1-receptor blocker, for example and preferably prazosin.
[1365] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with a
beta-blocker, for example and preferably propranolol, atenolol,
timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol,
metipranolol, nadolol, mepindolol, carazolol, sotalol, metoprolol,
betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol,
carvedilol, adaprolol, landiolol, nebivolol, epanolol or
bucindolol.
[1366] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with an
angiotensin AII antagonist, for example and preferably losartan,
candesartan, valsartan, telmisartan or embursatan.
[1367] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with an
ACE inhibitor, for example and preferably enalapril, captopril,
lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril
or trandopril.
[1368] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with an
endothelin antagonist, for example and preferably bosentan,
darusentan, ambrisentan or sitaxsentan.
[1369] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with a
renin inhibitor, for example and preferably aliskiren, SPP-600 or
SPP-800.
[1370] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with a
mineralocorticoid-receptor antagonist, for example and preferably
spironolactone or eplerenone.
[1371] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with a
loop diuretic, for example furosemide, torasemide, bumetanide and
piretanide, with potassium-sparing diuretics for example amiloride
and triamterene, with aldosterone antagonists, for example
spironolactone, potassium canrenoate and eplerenone and thiazide
diuretics, for example hydrochlorothiazide, chlorthalidone,
xipamide, and indapamide.
[1372] Agents altering fat metabolism are preferably to be
understood as compounds from the group of CETP inhibitors, thyroid
receptor agonists, cholesterol synthesis inhibitors such as
HMG-CoA-reductase or squalene synthesis inhibitors, the ACAT
inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and/or
PPAR-delta agonists, cholesterol-absorption inhibitors, polymeric
bile acid adsorbers, bile acid reabsorption inhibitors, lipase
inhibitors and the lipoprotein(a) antagonists.
[1373] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with a
CETP inhibitor, for example and preferably dalcetrapib, BAY
60-5521, anacetrapib or CETP-vaccine (CETi-1).
[1374] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with a
thyroid receptor agonist, for example and preferably D-thyroxin,
3,5,3'-triiodothyronin (T3), CGS 23425 or axitirome (CGS
26214).
[1375] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with a
HMG-CoA-reductase inhibitor from the class of statins, for example
and preferably lovastatin, simvastatin, pravastatin, fluvastatin,
atorvastatin, rosuvastatin or pitavastatin.
[1376] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with a
squalene synthesis inhibitor, for example and preferably BMS-188494
or TAK-475.
[1377] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with an
ACAT inhibitor, for example and preferably avasimibe, melinamide,
pactimibe, eflucimibe or SMP-797.
[1378] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with an
MTP inhibitor, for example and preferably implitapide, BMS-201038,
R-103757 or ITT-130.
[1379] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with a
PPAR-gamma agonist, for example and preferably pioglitazone or
rosiglitazone.
[1380] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with a
PPAR-delta agonist, for example and preferably GW 501516 or BAY
68-5042.
[1381] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with a
cholesterol-absorption inhibitor, for example and preferably
ezetimibe, tiqueside or pamaqueside.
[1382] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with a
lipase inhibitor, for example and preferably orlistat.
[1383] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with a
polymeric bile acid adsorber, for example and preferably
cholestyramine, colestipol, colesolvam, CholestaGel or
colestimide.
[1384] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with a
bile acid reabsorption inhibitor, for example and preferably
ASBT(=IBAT) inhibitors, e.g. AZD-7806, S-8921, AK-105, BARI-1741,
SC-435 or SC-635.
[1385] In a preferred embodiment of the invention, the compounds
according to the invention are administered in combination with a
lipoprotein(a) antagonist, for example and preferably gemcabene
calcium (CI-1027) or nicotinic acid.
[1386] The present invention further relates to medicinal products
that contain at least one compound according to the invention,
usually together with one or more inert, non-toxic,
pharmaceutically suitable excipients, and use thereof for the
aforementioned purposes.
[1387] The compounds according to the invention can have systemic
and/or local action. For this purpose they can be applied in a
suitable way, e.g. by oral, parenteral, pulmonary, nasal,
sublingual, lingual, buccal, rectal, dermal, transdermal,
conjunctival, or otic administration or as implant or stent.
[1388] For these routes of application, the compounds according to
the invention can be administered in suitable dosage forms.
[1389] Dosage forms functioning according to the prior art, for
rapid and/or modified release of the compounds according to the
invention, which contain the compounds according to the invention
in crystalline and/or amorphized and/or dissolved form, e.g.
tablets (uncoated or coated tablets, for example with enteric
coatings or coatings with delayed dissolution or insoluble
coatings, which control the release of the compound according to
the invention), tablets or films/wafers that disintegrate rapidly
in the oral cavity, films/lyophilizates, capsules (for example hard
or soft gelatin capsules), sugar-coated pills, granules, pellets,
powders, emulsions, suspensions, aerosols or solutions, are
suitable for oral application.
[1390] Parenteral application can take place avoiding an absorption
step (e.g. intravenous, intraarterial, intracardiac, intraspinal or
intralumbar) or including absorption (e.g. intramuscular,
subcutaneous, intracutaneous, percutaneous or intraperitoneal).
Injection and infusion preparations in the form of solutions,
suspensions, emulsions, lyophilizates or sterile powders are
suitable, among others, as dosage forms for parenteral
application.
[1391] Inhaled pharmaceutical forms (including powder inhalers,
nebulizers), nasal drops, solutions or sprays, tablets,
films/wafers or capsules for lingual, sublingual or buccal
application, suppositories, ear or eye preparations, vaginal
capsules, aqueous suspensions (lotions, shaking mixtures),
lipophilic suspensions, ointments, creams, transdermal therapeutic
systems (e.g. patches), milk, pastes, foams, dusting powders,
implants or stents for example are suitable for other routes of
administration.
[1392] Oral or parenteral application is preferred, especially oral
application.
[1393] The compounds according to the invention can be transformed
to the aforementioned dosage forms. This can take place in a manner
known per se by mixing with inert, non-toxic, pharmaceutically
suitable excipients. These excipients include inter alia carriers
(for example microcrystalline cellulose, lactose, mannitol),
solvents (e.g. liquid polyethylene glycols), emulsifiers and
dispersants or wetting agents (for example sodium dodecyl sulphate,
polyoxysorbitan oleate), binders (for example
polyvinylpyrrolidone), synthetic and natural polymers (for example
albumin), stabilizers (e.g. antioxidants such as ascorbic acid),
colorants (e.g. inorganic pigments, for example iron oxides) and
taste and/or odour correctants.
[1394] In general, it has proved advantageous, in the case of
parenteral application, to administer amounts of about 0.001 to 1
mg/kg, preferably about 0.01 to 0.5 mg/kg body weight to achieve
effective results. For oral application, the dosage is about 0.001
to 2 mg/kg, preferably about 0.001 to 1 mg/kg body weight.
[1395] Nevertheless, it may optionally be necessary to deviate from
the stated amounts, namely depending on body weight, route of
application, individual response to the active substance, type of
preparation and time point or interval when application takes
place. Thus, in some cases it may be sufficient to use less than
the aforementioned minimum amount, whereas in other cases the
stated upper limit must be exceeded. When applying larger amounts,
it may be advisable to distribute these in several individual doses
throughout the day.
[1396] The following practical examples explain the invention. The
invention is not limited to the examples.
[1397] The percentages in the following tests and examples are
percentages by weight, unless stated otherwise; parts are parts by
weight. Proportions of solvents, dilution ratios and concentrations
for liquid/liquid solutions refer in each case to the volume.
A. EXAMPLES
Abbreviations and Acronyms
[1398] aq. aqueous solution [1399] calc. calculated [1400] DCI
direct chemical ionization (in MS) [1401] DMF dimethylformamide
[1402] DMSO dimethylsulphoxide [1403] of theor. of theoretical
(referring to yield) [1404] eq. equivalent(s) [1405] ESI
electrospray ionization (in MS) [1406] Et ethyl [1407] h hour(s)
[1408] HPLC high-performance liquid chromatography [1409] HRMS
high-resolution mass spectrometry [1410] conc. concentrated [1411]
LC/MS liquid chromatography-coupled mass spectrometry [1412] LiHMDS
lithium hexamethyl disilazide [1413] Me methyl [1414] min minute(s)
[1415] MS mass spectrometry [1416] NMR nuclear magnetic resonance
spectrometry [1417] Pd/C palladium on activated charcoal (10%)
[1418] Ph phenyl [1419] qt quartet of triplet (NMR) [1420] RT room
temperature [1421] R.sub.t retention time (in HPLC) [1422] t-Bu
tert.-butyl [1423] TFA trifluoroacetic acid [1424] THF
tetrahydrofuran [1425] UV ultraviolet spectrometry [1426] v/v
volume to volume ratio (of a solution) [1427] XPHOS
dicyclohexyl-(2',4',6'-triisopropylbiphenyl-2-yl)-phosphine
[1428] HPLC and LC/MS Methods:
[1429] Method 1 (LC-MS):
[1430] Instrument: Waters ACQUITY SQD UPLC system; column: Waters
ACQUITY UPLC HSS T3 1.8.mu. 50.times.1 mm; eluent A: 1 l water+0.25
ml 99% formic acid, eluent B: 1 l acetonitrile+0.25 ml 99% formic
acid; gradient: 0.0 min 90% A.fwdarw.1.2 min 5% A.fwdarw.2.0 min 5%
A, furnace: 50.degree. C.; flow: 0.40 ml/min; UV-detection: 210-400
nm.
[1431] Method 2 (LC-MS):
[1432] Instrument type MS: Waters ZQ; instrument type HPLC: Agilent
1100 Series; UV DAD; column: Thermo Hypersil GOLD 3.mu. 20
mm.times.4 mm; eluent A: 1 l water+0.5 ml 50% formic acid, eluent
B: 1 l acetonitrile+0.5 ml 50% formic acid; gradient: 0.0 min 100%
A.fwdarw.3.0 min 10% A.fwdarw.4.0 min 10% A, furnace: 55.degree.
C.; flow 2 ml/min; UV-detection: 210 nm.
[1433] Method 3 (LC-MS):
[1434] Instrument: Waters ACQUITY SQD UPLC system; column: Waters
ACQUITY UPLC HSS T3 1.8.mu. 30.times.2 mm; eluent A: 1 l water+0.25
ml 99% formic acid, eluent B: 1 l acetonitrile+0.25 ml 99% formic
acid; gradient: 0.0 min 90% A.fwdarw.1.2 min 5% A.fwdarw.2.0 min 5%
A, furnace: 50.degree. C.; flow: 0.60 ml/min; UV-detection: 208-400
nm.
[1435] Method 4 (LC-MS):
[1436] Instrument: Micromass Quattro Premier with Waters UPLC
ACQUITY; column: Thermo Hypersil GOLD 1.9.mu. 50.times.1 mm; eluent
A: 1 l water+0.5 ml 50% formic acid, eluent B: 1 l acetonitrile+0.5
ml 50% formic acid; gradient: 0.0 min 97% A.fwdarw.0.5 min 97%
A.fwdarw.3.2 min 5% A.fwdarw.4.0 min 5% A, furnace: 50.degree. C.;
flow: 0.3 ml/min; UV-detection: 210 nm.
[1437] Method 5 (LC-MS):
[1438] MS instrument: Waters SQD; HPLC instrument: Waters UPLC;
column: Zorbax SB-Aq (Agilent), 50 mm.times.2.1 mm, 1.8 .mu.m;
eluent A: water+0.025% formic acid, eluent B: acetonitrile
(ULC)+0.025% formic acid; gradient: 0.0 min 98% A--0.9 min 25%
A--1.0 min 5% A--1.4 min 5% A -1.41 min 98% A--1.5 min 98% A;
furnace: 40.degree. C.; flow: 0.600 ml/min; UV-detection: DAD; 210
nm
[1439] Method 6 (prep. HPLC):
[1440] MS instrument: Waters, HPLC instrument: Waters (column
Phenomenex Luna 5.mu. C18(2) 100A, AXIA Tech. 50.times.21.2 mm,
eluent A: water+0.05% formic acid, eluent B: methanol (ULC)+0.05%
formic acid, with gradient, flow: 40 ml/min; UV-detection: DAD;
210-400 nm).
[1441] Method 7 (LC-MS):
[1442] MS instrument: Waters (Micromass) Quattro Micro; HPLC
instrument: Agilent 1100 series; column: YMC-Triart C18 3.mu.
50.times.3 mm; eluent A: 1 l water+0.01 mol ammonium carbonate,
eluent B: 1 l acetonitrile; gradient: 0.0 min 100% A.fwdarw.2.75
min 5% A.fwdarw.4.5 min 5% A; furnace: 40.degree. C.; flow: 1.25
ml/min; UV-detection: 210 nm.
[1443] Method 8 (LC-MS): Method: MCW_SQ-HSST3_long
[1444] Instrument: Waters ACQUITY SQD UPLC system; column: Waters
ACQUITY UPLC HSS T3 1.8.mu. 50.times.1 mm; eluent A: 1 l water+0.25
ml 99% formic acid, eluent B: 1 l acetonitrile+0.25 ml 99% formic
acid; gradient: 0.0 min 95% A.fwdarw.6.0 min 5% A.fwdarw.7.5 min 5%
A, furnace: 50.degree. C.; flow: 0.35 ml/min; UV-detection: 210-400
nm.
Starting Compounds and Intermediates
Example 1A
1-(2-Fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide
hydrochloride
##STR00047##
[1446] The synthesis of this compound is described in WO 03/095451,
example 6A.
Example 2A
2,6-Dichloro-5-fluoronicotinamide
##STR00048##
[1448] A suspension of 25 g (130.90 mmol) of
2,6-dichloro-5-fluoro-3-cyanopyridine in conc. sulphuric acid (125
ml) was stirred for 1 h at 60-65.degree. C. After cooling to RT,
the flask contents were poured into ice water and extracted with
ethyl acetate three times (100 ml each time). The combined organic
phases were washed with water (100 ml) and then with saturated
aqueous sodium hydrogen carbonate solution (100 ml), dried and
concentrated in a rotary evaporator. The material obtained was
dried under high vacuum.
[1449] Yield: 24.5 g (90% of theor.)
[1450] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=7.95 (br s,
1H), 8.11 (br s, 1H), 8.24 (d, 1H).
Example 3A
2-Chloro-5-fluoronicotinamide
##STR00049##
[1452] 44 g (210.58 mmol) of 2,6-dichloro-5-fluoronicotinamide was
added at RT to a suspension of 21.9 g (335.35 mmol) of zinc in
methanol (207 ml). Then acetic acid (18.5 ml) was added and it was
heated under reflux for 24 h, with stirring. Then the flask
contents were decanted from the zinc and ethyl acetate (414 ml) and
saturated aqueous sodium hydrogen carbonate solution (414 ml) were
added and stirred vigorously. Then it was filtered with suction on
diatomaceous earth and washed again three times with ethyl acetate
(517 ml each time). The organic phase was separated and the aqueous
phase was washed with ethyl acetate (258 ml). The combined organic
phases were washed once with saturated aqueous sodium hydrogen
carbonate solution (414 ml), dried and concentrated by vacuum
evaporation. Dichloromethane (388 ml) was added to the crystals
thus obtained, and left to precipitate for 20 min. It was filtered
with suction again and washed with diethyl ether and
suction-dried.
[1453] Yield: 20.2 g (53% of theor.)
[1454] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=7.87 (br s,
1H), 7.99 (dd, 1H), 8.10 (br s, 1H), 8.52 (d, 1H).
Example 4A
2-Chloro-5-fluoronicotinonitrile
##STR00050##
[1456] 81.2 ml (582.25 mmol) of triethylamine was added to a
suspension of 46.2 g (264.66 mmol) of 2-chloro-5-fluoronicotinamide
in dichloromethane (783 ml) and cooled to 0.degree. C. While
stirring, 41.12 ml (291.13 mmol) of trifluoroacetic acid anhydride
was slowly added dropwise and stirred for a further 1.5 h at
0.degree. C. The reaction solution was then washed twice with
saturated aqueous sodium hydrogen carbonate solution (391 ml each
time), dried and concentrated by vacuum evaporation.
[1457] Yield: 42.1 g (90% of theor.).
[1458] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=8.66 (dd, 1H),
8.82 (d, 1H).
Example 5A
5-Fluoro-1H-pyrazolo[3,4-b]pyridin-3-amine
##STR00051##
[1460] A suspension of 38.5 g (245.93 mmol) of
2-chloro-5-fluoronicotinonitrile in 1,2-ethanediol (380 ml) was
prepared and then hydrazine hydrate (119.6 ml) was added. It was
heated under reflux for 4 h, with stirring. On cooling, the product
was precipitated. Water (380 ml) was added to the crystals and it
was left to precipitate for 10 min at RT. Then the suspension was
filtered with suction on a frit, and washed again with water (200
ml) and with cold (-10.degree. C.) THF (200 ml). Drying over
phosphorus pentoxide under high vacuum.
[1461] Yield: 22.8 g (61% of theor.)
[1462] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=5.54 (s, 2H),
7.96 (dd, 1H), 8.38 (m, 1H), 12.07 (m, 1H).
Example 6A
5-Fluoro-3-iodo-1H-pyrazolo[3,4-b]pyridine
##STR00052##
[1464] 10 g (65.75 mmol) of
5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-amine was put in THF (329 ml)
and cooled to 0.degree. C. Then 16.65 ml (131.46 mmol) of boron
trifluoride/diethyl ether complex was slowly added. The reaction
mixture was cooled further to -10.degree. C. Then a solution of
10.01 g (85.45 mmol) of isopentyl nitrite in THF (24.39 ml) was
slowly added and stirred for a further 30 min. The mixture was
diluted with cold diethyl ether (329 ml) and the resultant solid
was filtered off. The resultant diazonium salt was added in
portions to a cold (0.degree. C.) solution of 12.81 g (85.45 mmol)
of sodium iodide in acetone (329 ml) and the mixture was stirred
for a further 30 min at RT. The reaction mixture was added to ice
water (1.8 l) and was extracted twice with ethyl acetate (487 ml
each time). The combined organic phases were washed with saturated
aqueous sodium chloride solution (244 ml), dried, filtered and
concentrated by evaporation. 12.1 g (86% purity, 60% of theor.) of
the title compound was obtained as a solid. The raw product was
reacted without further purification.
[1465] LC-MS (method 2): R.sub.t=1.68 min
[1466] MS (ESIpos): m/z=264 [M+H].sup.+
Example 7A
5-Fluoro-1-(2-fluorobenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridine
##STR00053##
[1468] 12.1 g (approx. 39.65 mmol) of the compound from example 6A
was put in DMF (217 ml) and then 8.25 g (43.62 mmol) of
2-fluorobenzyl bromide and 14.21 g (43.62 mmol) of caesium
carbonate were added. The mixture was stirred for two hours at RT.
Then the reaction mixture was added to water (1.17 l) and was
extracted twice with ethyl acetate (502 ml). The combined organic
phases were washed with saturated aqueous sodium chloride solution
(335 ml), dried, filtered and concentrated by evaporation. The
residue was chromatographed on silica gel (solvent: petroleum
ether/ethyl acetate 97:3) and the product fractions were
concentrated by evaporation. 9.0 g (61% of theor.) of the title
compound was obtained as a solid. The solid was taken up in ethyl
acetate and washed with 10% aqueous sodium thiosulphate solution
and then with saturated aqueous sodium chloride solution, dried and
concentrated by evaporation.
[1469] LC-MS (method 2): R.sub.t=2.57 min
[1470] MS (ESIpos): m/z=372 [M+H].sup.+
[1471] .sup.1H-NMR (400 MHz, DMSO-d6): .delta.=5.73 (s, 2H),
7.13-7.26 (m, 3H), 7.33-7.41 (m, 1H), 7.94 (dd, 1H), 8.69-8.73 (m,
1H).
Example 8A
Ethyl-5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate
##STR00054##
[1473] 13.487 g (51.228 mmol) of
ethyl-5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate
(preparation described for example 20A in WO 00/06569) was put in
300 ml dioxane and 6 g (51.228 mmol) of
3-(dimethylamino)-2-fluoroacrylaldehyde (preparation described in
Justus Liebigs Annalen der Chemie 1970; 99-107) was added at RT.
Then 4.736 ml (61.473 mmol) of trifluoroacetic acid was added and
the mixture was heated under reflux for 3 days, with stirring.
After cooling, it was concentrated by vacuum evaporation and water
and ethyl acetate were added to the residue. The phases were
separated and the organic phase was washed twice with water. The
combined aqueous phases were then extracted twice with ethyl
acetate. The combined organic phases were dried over sodium
sulphate, filtered and concentrated by vacuum evaporation. The
residue (22 g) was then purified by silica gel chromatography
(solvent: dichloromethane). 5.67 g (35% of theor.) of the title
compound was obtained.
[1474] LC-MS (method 1): R.sub.t=1.17 min
[1475] MS (ESIpos): m/z=318 [M+H].sup.+
[1476] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=1.37 (t, 3H),
4.40 (q, 2H), 5.86 (s, 2H), 7.15-7.27 (m, 3H), 7.36-7.41 (m, 1H),
8.25 (d, 1H), 8.78 (s br, 1H).
Example 9A
5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide
##STR00055##
[1478] 1.00 g (3.152 mmol) of the compound obtained in example 8A
was stirred in 10 ml of a 7N solution of ammonia in methanol at RT
for three days. Then it was concentrated by vacuum evaporation. 908
mg (99% of theor.) of the title compound was obtained.
[1479] LC-MS (method 1): R.sub.t=0.85 min
[1480] MS (ESIpos): m/z=289 [M+H].sup.+
[1481] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=5.87 (s, 2H),
7.12-7.26 (m, 3H), 7.34-7.40 (m, 1H), 7.60 (s br, 1H), 7.87 (s br,
1H), 8.28 (dd, 1H), 8.72 (dd, 1H).
Example 10A
5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile
##STR00056##
[1483] Variant A:
[1484] A suspension of 16.03 g (43.19 mmol) of
5-fluoro-1-(2-fluorobenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridine
(example 7A) and 4.25 g (47.51 mmol) of copper(I) cyanide was put
in DMSO (120 ml) and stirred for 2 h at 150.degree. C. After
cooling, the flask contents were cooled to approx. 40.degree. C.,
poured into a solution of conc ammonia water (90 ml) and water (500
ml), ethyl acetate (200 ml) was added and it was left to
precipitate for a short time. The aqueous phase was separated and
extracted two more times with ethyl acetate (200 ml each time). The
combined organic phases were washed twice with 10% aqueous sodium
chloride solution (100 ml each time), dried and concentrated by
vacuum evaporation. The raw product was reacted without further
purification.
[1485] Yield: 11.1 g (91% of theor.)
[1486] Variant B:
[1487] 900 mg (3.122 mmol) of the compound obtained in example 9A
was dissolved in THF (14 ml) and 0.646 ml (7.993 mmol) of pyridine
was added. Then, while stirring, 1.129 ml (7.993 mmol) of
trifluoroacetic acid anhydride was slowly added dropwise and then
it was stirred overnight at RT. Then the reaction mixture was
poured into water and extracted three times with ethyl acetate. The
combined organic phases were extracted with saturated aqueous
sodium hydrogen carbonate solution and 1N hydrochloric acid and
then washed with saturated aqueous sodium chloride solution. The
organic phase was dried over sodium sulphate, filtered and
concentrated by evaporation. 850 mg (99% of theor.) of the title
compound was obtained.
[1488] LC-MS (method 1): R.sub.t=1.06 min
[1489] MS (ESIpos): m/z=271 [M+H].sup.+
[1490] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=5.87 (s, 2H),
7.17-7.42 (m, 4H), 8.52 (dd, 1H), 8.87 (dd, 1H).
Example 11A
5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide
acetate
##STR00057##
[1492] 11.1 g (41.07 mmol) of
5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile
(example 10A) was added to 2.22 g (41.07 mmol) of sodium
methanolate in methanol (270 ml) and stirred for 2 h at RT. Then
2.64 g (49.29 mmol) of ammonium chloride and acetic acid (9.17 ml)
were added and it was heated under reflux overnight. Then the
reaction mixture was evaporated to dryness and the residue was
taken up in water (100 ml) and ethyl acetate (100 ml) and was
adjusted to pH 10 with 2N sodium hydroxide solution. It was stirred
vigorously for approx. 1 h at RT. The suspension obtained was
filtered with suction and was washed with ethyl acetate (100 ml),
water (100 ml) and again with ethyl acetate (100 ml). The residue
is dried over phosphorus pentoxide under high vacuum.
[1493] Yield: 9.6 g (78% of theor.)
[1494] MS (ESIpos): m/z=288 [M+H].sup.+
[1495] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=1.85 (s, 3H),
5.80 (s, 2H), 7.14-7.25 (m, 3H), 7.36 (m, 1H), 8.42 (dd, 1H), 8.72
(dd, 1H).
Example 12A
Methyl-3,3-dicyano-2,2-dimethylpropanoate
##STR00058##
[1497] In THF (91 ml), 3 g (45.411 mmol) of malonic acid dinitrile
was slowly added to 1.816 g (45.411 mmol) of sodium hydride (60% in
mineral oil). Then 5.876 ml (45.411 mmol) of
methyl-2-bromo-2-methylpropanoate was added and it was stirred
overnight at RT. Then a further 5.876 ml (45.411 mmol) of
methyl-2-bromo-2-methylpropanoate was added and it was heated
overnight to 50.degree. C. Then once again, 1.762 ml (13.623 mmol)
of methyl-2-bromo-2-methylpropanoate was added and it was heated
for a further 4 h to 50.degree. C. Saturated aqueous sodium
hydrogen carbonate solution was then added to the mixture and it
was extracted three times with ethyl acetate. The combined organic
phases were washed with saturated aqueous sodium chloride solution,
dried over sodium sulphate, filtered and evaporated to dryness. 8.9
g of raw product was obtained, and was purified by silica gel
chromatography (cyclohexane-ethyl acetate 4:1).
[1498] Yield: 6.47 g (85% of theor.)
[1499] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.40 (s,
6H), 3.74 (s, 3H), 5.27 (s, 1H).
Example 13A
4-Amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-
-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00059##
[1501] 5.887 g (19.256 mmol) of example 1A was put in tert.-butanol
(50 ml) and 2.593 g (23.107 mmol) of potassium tert.-butylate was
added. Then 3.2 g (19.256 mmol) of example 12A in tert.-butanol (25
ml) was added dropwise and the mixture was heated under reflux
overnight. Next day, a further 0.64 g (3.851 mmol) of example 12A
was added and it was heated under reflux for another day. After
cooling, a precipitate was filtered off, and was washed with
diethyl ether. Then it was made into a slurry in water and filtered
off once again and washed with diethyl ether. After drying under
high vacuum, 6.65 g of the title compound was obtained (85% of
theor.).
[1502] LC-MS (method 1): R.sub.t=0.90 min; MS (ESIpos): m/z=404
[M+H].sup.+
[1503] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.35 (s,
6H), 5.82 (s, 2H), 6.82 (br s, 2H), 7.14-7.25 (m, 3H), 7.33-7.40
(m, 2H), 8.63 (dd, 1H), 9.03 (dd, 1H), 10.98 (s br, 1H).
Example 14A
4-Amino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-
-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00060##
[1505] By analogy with the preparation of example 13A, 4.18 g
(12.035 mmol) of example 11A was reacted with 2.20 g (13.239 mmol)
of example 12A. 3.72 g of the title compound was obtained (73% of
theor.).
[1506] LC-MS (method 1): R.sub.t=0.98 min; MS (ESIpos): m/z=422
[M+H].sup.+
[1507] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.34 (s,
6H), 5.81 (s, 2H), 6.85 (br s, 2H), 7.13-7.25 (m, 3H), 7.36 (m,
1H), 8.69 (dd, 1H), 8.84 (dd, 1H), 10.96 (s br, 1H).
[1508] Alternatively, example 73A can also be used instead of
example 11A for production.
Example 15A
2-[1-(2-Fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl--
5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00061##
[1510] 5.00 g (12.394 mmol) of example 13A was put in isopentyl
nitrite (35.87 ml) and diiodomethane (1.16 mol, 93.71 ml) and
heated for 12 h to 85.degree. C. After cooling, the solids were
filtered off, the filtrate was concentrated by evaporation and the
residue was then purified by silica gel chromatography (solvent:
first cyclohexane-dichloromethane gradient, then
dichloromethane-methanol gradient). 5.50 g of the title compound
was obtained (67% of theor.).
[1511] LC-MS (method 1): R.sub.t=1.19 min; MS (ESIpos): m/z=515
[M+H].sup.+
[1512] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.42 (s,
6H), 5.88 (s, 2H), 7.13-7.26 (m, 3H), 7.34-7.38 (m, 1H), 7.48 (dd,
1H), 8.69 (dd, 1H), 8.79 (dd, 1H), 11.78 (s br, 1H).
Example 16A
2-[5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5--
dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00062##
[1514] 3.325 g (7.890 mmol) of example 14A was reacted on the
analogy of example 15A. 3.65 g of the title compound was obtained
(87% of theor., approx. 61% purity according to LC/MS).
[1515] LC-MS (method 1): R.sub.t=1.26 min; MS (ESIpos): m/z=533
[M+H].sup.+
[1516] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.42 (s,
6H), 5.87 (s, 2H), 7.14-7.26 (m, 3H), 7.37 (m, 1H), 8.48 (dd, 1H),
8.77 (dd, 1H), 11.76 (s br, 1H).
[1517] Improved Protocol for Larger Batches:
[1518] 52.6 g (113.585 mmol, 91% purity) of example 14A was stirred
in dioxane (239 ml) with 91.26 g (340.75 mmol) of diiodomethane and
39.91 g (340.75 mmol) of isopentyl nitrite for 2 h at 85.degree.
C.
[1519] After concentration by evaporation, the residue was
chromatographed on silica gel with dichloromethane:acetone (95:5)
as eluent. 29.90 g of the title compound was obtained (49% of
theor.).
Example 17A
5-Fluoro-1-[(3-fluoropyridin-2-yl)methyl]-3-iodo-1H-pyrazolo[3,4-b]pyridin-
e
##STR00063##
[1521] 6.291 g (23.921 mmol) of
5-fluoro-3-iodo-1H-pyrazolo[3,4-b]pyridine and 8.573 g (26.313
mmol) of caesium carbonate were put in DMF (10 ml) and then 5.00 g
(26.313 mmol) of 2-(bromomethyl)-3-fluoropyridine dissolved in DMF
(20 ml) was added dropwise. The mixture was stirred overnight at
RT. Then it was left to cool and was poured into 200 ml water. A
precipitate was filtered off with suction, it was washed with water
and dried overnight under high vacuum. 6.28 g (70% of theor.) of
the title compound was obtained.
[1522] LC-MS (method 4): R.sub.t=2.17 min
[1523] MS (ESIpos): m/z=373 [M+H].sup.+
[1524] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=5.88 (s, 2H),
7.42-7.46 (m, 1H), 7.77 (dd, 1H), 7.93 (dd, 1H), 8.27 (d, 1H), 8.67
(t, 1H).
Example 18A
5-Fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridine-3-car-
bonitrile
##STR00064##
[1526] 6.280 g (16.876 mmol) of example 17A and 1.663 g (18.564
mmol) of copper(I) cyanide were put in DMSO (100 ml) and stirred
for 3 h at 150.degree. C. After cooling, the reaction mixture was
filtered on Celite and washed with ethyl acetate. The filtrate was
extracted four times with saturated aqueous ammonium chloride
solution and conc. ammonia water (3:1 v/v) and the organic phase
was separated. This was then washed with saturated aqueous sodium
chloride solution, dried over sodium sulphate, filtered and
concentrated by vacuum evaporation. 3.97 g (86% of theor.) of the
title compound was obtained.
[1527] LC-MS (method 1): R.sub.t=0.92 min
[1528] MS (ESIpos): m/z=272 [M+H].sup.+
[1529] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=6.04 (s, 2H),
7.44-7.48 (m, 1H), 7.61 (t, 1H), 8.26 (d, 1H), 8.52 (dd, 1H), 8.83
(dd, 1H).
Example 19A
5-Fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridine-3-car-
boximidamide acetate
##STR00065##
[1531] 3.900 g (14.379 mmol) of example 18A in methanol (40 ml) was
added to 777 mg (14.379 mmol) of sodium methanolate in methanol (20
ml) and stirred for 2 h at RT. Then 932 mg (17.255 mmol) of
ammonium chloride and acetic acid (3.210 ml) were added and it was
heated under reflux overnight. Then the reaction mixture was
evaporated to dryness and ethyl acetate and 1N sodium hydroxide
solution were added to the residue and stirred for 2 h at RT. Then
a solid was filtered off, which was washed with ethyl acetate and
water. The solid was dried overnight under high vacuum. 0.56 g (11%
of theor.) of the title compound was obtained. The phases of the
filtrate were separated, and the aqueous phase was extracted twice
with ethyl acetate. The combined organic phases were dried over
sodium sulphate and concentrated by evaporation. A further 1.86 g
(14% of theor., 39% purity) of the title compound was obtained. The
aqueous phase was also concentrated by evaporation, DMF was added
to the residue and it was stirred for 30 min at RT. A precipitate
was filtered off with suction, washed with DMF, the filtrate was
concentrated by evaporation and dried overnight under high vacuum.
A further 1.77 g (35% of theor.) of the title compound is
obtained.
[1532] LC-MS (method 4): R.sub.t=1.25 min
[1533] MS (ESIpos): m/z=289 [M+H].sup.+
Example 20A
4-Amino-2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyr-
idin-3-yl}-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00066##
[1535] 567 mg (1.628 mmol) of example 19A was put in tert.-butanol
(10 ml) and 274 mg (2.442 mmol) of potassium tert.-butylate was
added. Then 324 mg (1.953 mmol) of example 12A in tert.-butanol (5
ml) was added and the mixture was heated under reflux overnight.
After cooling, water and ethanol were added to the reaction
mixture, and it was stirred for 1 h. The resultant precipitate was
filtered with suction and washed with a little ethanol. The solid
was dried under high vacuum. 568 mg of the title compound was
obtained (80% of theor.).
[1536] LC-MS (method 3): R.sub.t=0.82 min; MS (ESIpos): m/z=423
[M+H].sup.+
[1537] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.34 (s,
6H), 5.94 (s, 2H), 6.87 (br s, 2H), 7.42-7.46 (m, 1H), 7.75-7.80
(m, 1H), 8.27 (d, 1H), 8.67 (dd, 1H), 8.83 (dd, 1H), 10.95 (br s,
1H).
Example 21A
2-{5-Fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-y-
l}-4-iodo-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00067##
[1539] 2.040 g (4.830 mmol) of example 20A was put in isopentyl
nitrite (14 ml) and diiodomethane (37 ml) and heated for 1 h to
85.degree. C. After cooling, a solid was filtered off, which was
washed with a little acetonitrile. Then the solid was dried under
high vacuum overnight. 1.83 g of the title compound was obtained
(39% of theor., 55% purity). The raw compound was used in the next
steps without further purification.
[1540] LC-MS (method 1): R.sub.t=1.12 min; MS (ESIpos): m/z=534
[M+H].sup.+
Example 22A
2-[6-Chloro-3-(2,3,6-trifluorobenzyl)imidazo[1,5-a]pyridin-1-yl]-4-iodo-5,-
5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00068##
[1542] 556 mg (1.176 mmol) of
4-amino-2-[6-chloro-3-(2,3,6-trifluorobenzyl)imidazo[1,5-a]pyridin-1-yl]--
5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
(described in WO 2010/065275) was put in 1,2-dimethoxyethane (14
ml), and 305 mg (1.176 mmol) of caesium iodide, 149 mg (0.588 mmol)
of iodine and 67 mg (0.353 mmol) of copper(I) iodide were added at
room temperature. Then isopentyl nitrite (0.933 ml) was added and
it was heated overnight to 60.degree. C. Next day, 305 mg (1.176
mmol) of caesium iodide, 149 mg (0.588 mmol) of iodine and 67 mg
(0.353 mmol) of copper(I) iodide, and isopentyl nitrite (0.933 ml)
were added again and it was heated for 3 days to 60.degree. C.
After cooling, it was combined with a smaller batch (starting from
50 mg
4-amino-2-[6-chloro-3-(2,3,6-trifluorobenzyl)imidazo[1,5-a]pyridin-1-yl]--
5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one). It was
extracted with ethyl acetate and saturated aqueous sodium
thiosulphate and the phases were separated. The organic phase was
extracted twice more with saturated aqueous sodium thiosulphate.
Then the organic phase was washed with saturated aqueous sodium
chloride solution, dried over sodium sulphate, filtered,
concentrated by evaporation and the residue was purified by
preparative HPLC (acetonitrile:water (+0.05% formic acid)
gradient). 236 mg of the title compound was obtained (31% of
theor.).
[1543] LC-MS (method 1): R.sub.t=1.28 min; MS (ESIpos): m/z=584
[M+H].sup.+
[1544] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.37 (s,
6H), 4.57 (s, 2H), 7.19-7.25 (m, 1H), 7.30 (dd, 1H), 7.48-7.56 (m,
1H), 8.43 (d, 1H), 8.87 (s, 1H), 11.58 (s, 1H).
[1545] In addition to the title compound, 27 mg (5% of theor., 90%
purity) of
2-[6-chloro-3-(2,3,6-trifluorobenzyl)imidazo[1,5-a]pyridin-1-yl]-4-hyd-
roxy-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one was
also obtained.
Example 23A
4-(Chloromethyl)-3-fluoropyridine hydrochloride
##STR00069##
[1547] 6.710 g (52.785 mmol) of (3-fluoropyridin-4-yl)methanol was
put in 29 ml acetonitrile and heated to 50.degree. C. Then a
solution of 7.701 ml thionyl chloride in 14.5 ml acetonitrile was
added dropwise and the reaction mixture was stirred for 4 h at
50.degree. C. Then the reaction mixture was concentrated by
evaporation and was co-distilled three times with dichloromethane.
After drying under high vacuum, 10.27 g of the title compound was
obtained, which was used in the next step without further
purification.
Example 24A
5-Fluoro-1-[(3-fluoropyridin-4-yl)methyl]-3-iodo-1H-pyrazolo[3,4-b]pyridin-
e
##STR00070##
[1549] On the analogy of the specification in example 7A, 12.225 g
(46.482 mmol) of 5-fluoro-3-iodo-1H-pyrazolo[3,4-b]pyridine was
reacted with example 23A. 11.34 g (65% of theor.) of the title
compound was obtained.
[1550] LC-MS (method 3): R.sub.t=1.01 min
[1551] MS (ESIpos): m/z=373 [M+H].sup.+
Example 25A
5-Fluoro-1-[(3-fluoropyridin-4-yl)methyl]-1H-pyrazolo[3,4-b]pyridine-3-car-
bonitrile
##STR00071##
[1553] On the analogy of the specification in example 10A, variant
A, 11.340 g (30.474 mmol) of example 24A was reacted. 6.31 g (76%
of theor.) of the title compound was obtained.
[1554] LC-MS (method 3): R.sub.t=0.89 min
[1555] MS (ESIpos): m/z=272 [M+H].sup.+
Example 26A
5-Fluoro-1-[(3-fluoropyridin-4-yl)methyl]-1H-pyrazolo[3,4-b]pyridine-3-car-
boximidamide acetate
##STR00072##
[1557] On the analogy of the specification in example 11A, 6.310 g
(23.264 mmol) of example 25A was reacted. 6.12 g (75% of theor.) of
the title compound was obtained.
[1558] LC-MS (method 1): R.sub.t=0.45 min
[1559] MS (ESIpos): m/z=289 [M+H].sup.+
Example 27A
4-Amino-2-{5-fluoro-1-[(3-fluoropyridin-4-yl)methyl]-1H-pyrazolo[3,4-b]pyr-
idin-3-yl}-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00073##
[1561] On the analogy of the specification in example 13A, 3.050 g
(8.756 mmol) of example 26A was reacted. Purification by
preparative silica gel chromatography (dichloromethane:methanol
gradient). 528 mg of the title compound was obtained (14% of
theor.).
[1562] LC-MS (method 1): R.sub.t=0.80 min; MS (ESIpos): m/z=423
[M+H].sup.+
[1563] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.35 (s,
6H), 5.90 (s, 2H), 6.89 (br s, 2H), 7.11 (t, 1H), 8.35 (d, 1H),
8.59 (d, 1H), 8.70 (dd, 1H), 8.87 (dd, 1H), 10.99 (br s, 1H).
Example 28A
2-{5-Fluoro-1-[(3-fluoropyridin-4-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-y-
l}-4-iodo-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00074##
[1565] On the analogy of the specification in example 21A, 527 mg
(1.248 mmol) of example 27A was reacted. 395 mg of the title
compound was obtained (39% of theor., 66% purity). The raw compound
was used in the next steps without further purification.
[1566] LC-MS (method 3): R.sub.t=1.09 min; MS (ESIpos): m/z=534
[M+H].sup.+
Example 29A
1,4,5,6-Tetrahydrocyclopenta[c]pyrazole-3-carbonitrile
##STR00075##
[1568] Preparation of the compound is described in: Org. Process
Res. Dev. 2009, 13, 543.
Example 30A
1-(2-Fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carbonitrile
##STR00076##
[1570] 10.320 g (77.50 mmol) of
1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carbonitrile was
dissolved in 100 ml DMF, 30.304 g (93.01 mmol) of caesium carbonate
and 16.116 g (85.26 mmol) of 2-fluorobenzyl bromide were added and
it was stirred at RT overnight. The reaction mixture was
concentrated by evaporation and taken up in dichloromethane and
water was added. The organic phase was separated and the aqueous
phase was extracted twice with dichloromethane. The combined
organic phases were washed with saturated aqueous sodium chloride
solution, filtered on a silicone filter and concentrated by
evaporation. The residue was purified by silica-gel flash
chromatography (eluent: hexane/ethyl acetate, gradient). 11.37 g
(60% of theor.) of the target compound was obtained.
[1571] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=2.59-2.64
(m, 4H), 5.33 (s, 2H), 7.15-7.23 (m, 2H), 7.27-7.33 (m, 1H),
7.36-7.43 (m, 1H).
Example 31A
1-(2-Fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta
[c]pyrazole-3-carboximidamide
##STR00077##
[1573] Under nitrogen atmosphere, 3.600 g (14.92 mmol) of
1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carbonitrile
was dissolved in 37 ml of absolute methanol. 1.306 g (24.17 mmol)
of sodium methylate was added and it was stirred for 4 h at RT.
1.452 g (24.17 mmol) of acetic acid and 1.197 g (22.38 mmol) of
ammonium chloride were added and the suspension was stirred
overnight at 50.degree. C. The reaction mixture was concentrated by
evaporation and the residue was suspended in 100 ml water and 25 ml
1N hydrochloric acid. The mixture was extracted with
dichloromethane. The aqueous phase was made basic (pH=12) with 2N
sodium hydroxide solution and extracted three times with a mixture
of dichloromethane/methanol (v/v=8:2). The combined organic phases
were dried over sodium sulphate, concentrated by evaporation,
toluene was added and again evaporated to dryness. 1.94 g (50% of
theor.) of the target compound was obtained.
[1574] LC-MS (method 7): R.sub.t=2.52 min; MS (ESIpos): m/z=259
[M+H].sup.+
Example 32A
4-Amino-2-[1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl]-
-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00078##
[1576] 300 mg (1.15 mmol) of
1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboximidam-
ide was dissolved with 2 ml tert.-butanol, 287 mg (1.38 mmol) of
methyl-3,3-dicyano-2,2-dimethylpropanoate in 2 ml tert.-butanol and
181 mg (1.61 mmol) of potassium tert.-butylate was added and it was
heated under reflux for 72 h. It was evaporated to dryness and the
residue was mixed with water/isopropanol (v/v=3:1). The solid was
filtered off and dried under high vacuum. 385 mg (80% of theor.) of
the target compound was obtained.
[1577] LC-MS (method 1): R.sub.t=0.83 min; MS (ESIpos): m/z=393
[M+H].sup.+
Example 33A
2-[1-(2-Fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl]-4-iodo--
5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00079##
[1579] 285 mg (0.68 mmol) of
4-amino-2-[1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl-
]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-c]pyrimidin-6-one was put
in absolute dimethoxyethane and 800 mg (6.83 mmol) of isopentyl
nitrite, 87 mg (0.34 mmol) of iodine, 39 mg (0.21 mmol) of copper
(I) iodide and 177 mg (0.68 mmol) of caesium iodide were added. The
mixture was stirred for 40 min at 100.degree. C. The mixture was
concentrated in a rotary evaporator, the residue was taken up in
dichloromethane and was washed with 5% aqueous sodium thiosulphate
solution and saturated aqueous sodium chloride solution. The
organic phase was dried over sodium sulphate, concentrated by
evaporation and purified by preparative HPLC (eluent:
acetonitrile/water with 0.1% formic acid, gradient
20:80.fwdarw.100:0). 148 mg (40% of theor.) of the target compound
was obtained.
[1580] LC-MS (method 1): R.sub.t=1.23 min; MS (ESIpos): m/z=504
[M+H].sup.+
Example 34A
1-(2-Bromophenyl)-2-(2-fluorophenyl)ethanone
##STR00080##
[1582] 15.0 g (69.8 mmol) of 2-methyl bromobenzoate and 11.8 g
(76.7 mmol) of 2-fluorophenylacetic acid were put in THF (278 ml)
under argon atmosphere at -70.degree. C. and 174 ml of a 1M
solution of sodium hexamethyldisilazane in THF was added dropwise
in the space of 20 min. The reaction mixture was heated to
0.degree. C., stirred for 30 min at this temperature and 1N
hydrochloric acid (278 ml) was added. After 1 h of vigorous
stirring with evolution of gas (CO.sub.2 cleavage), the reaction
mixture was extracted with ethyl acetate (500 ml). The organic
phase was washed twice with saturated aqueous sodium hydrogen
carbonate solution, once with water and once with saturated aqueous
sodium chloride solution. After drying and removal of the solvent
in the rotary evaporator, 16.8 g of residue was obtained (55%
purity). The residue was dissolved in THF (140 ml), 1N sodium
hydroxide solution (70 ml) was added and it was stirred for 4 h at
RT, in order to saponify excess ester. The THF was removed in the
rotary evaporator, the aqueous phase was extracted with diethyl
ether and the organic phase was washed with saturated aqueous
sodium hydrogen carbonate solution and saturated aqueous sodium
chloride solution. After drying and removal of the solvent, 12.2 g
of residue was obtained (approx. 80% purity). The residue was
dissolved in THF (100 ml), 1N sodium hydroxide solution (40 ml) was
added and it was stirred overnight at RT. The THF was removed in
the rotary evaporator, the aqueous phase was extracted with diethyl
ether and the organic phase was washed with saturated aqueous
sodium hydrogen carbonate solution and saturated aqueous sodium
chloride solution. After drying and removal of the solvent, 7.90 g
(37% of theor.) of the title compound was isolated.
[1583] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=4.35 (s,
2H), 7.14-7.22 (m, 2H), 7.30-7.39 (m, 2H), 7.41-7.47 (m, 1H),
7.49-7.55 (m, 1H), 7.70-7.78 (m, 2H).
Example 35A
2-[1-(2-Bromophenyl)-2-(2-fluorophenyl)ethylidene]hydrazinecarboximidamide
##STR00081##
[1585] 7.80 g (26.6 mmol) of example 34A and 5.88 g (53.2 mmol) of
aminoguanidine hydrochloride were put in ethylene glycol (193 ml)
and 8.50 g (59.9 mmol) of boron trifluoride/diethyl ether complex
was added. The reaction mixture was heated for 2 h at 120.degree.
C. on a distillation bridge. After cooling, again 5.88 g (53.2
mmol) of aminoguanidine hydrochloride and 8.50 g (59.9 mmol) of
boron trifluoride/diethyl ether complex were added and it was
stirred for 3 h at 120.degree. C. After cooling, water (750 ml) was
added and it was adjusted to pH 11-12 with 1N sodium hydroxide
solution. After crystals began to form, 300 g ice was added, it was
stirred for 5 min and the solid was then filtered off. The residue
was washed first with water, then with pentane, and dried under
vacuum. 8.30 g (87% of theor.) of the title compound was
obtained.
[1586] LC-MS (method 1): R.sub.t=0.78 min; MS (ESIpos): m/z
(Br-isotope 1+2)=349+351 [M+H].sup.+
Example 36A
3-(2-Fluorobenzyl)-1H-indazole-1-carboximidamide
##STR00082##
[1588] 320 ml of N-methylpyrrolidone was heated to 140.degree. C.,
8.20 g (23.5 mmol) of example 35A and 4.47 g (23.5 mmol) of
copper(I) iodide were added and it was stirred for 14 min at
170.degree. bath temperature. The reaction mixture was then added
slowly to 1 L of ice water and concentrated aqueous ammonia
solution (350 mL) was added. After stirring for 5 minutes, 1 L of
ethyl acetate was added and the mixture was stirred for 10 min. The
aqueous phase was extracted once with ethyl acetate and the
combined organic phases were washed with water three times. After
drying and removal of the solvent in the rotary evaporator, 7.10 g
(74% of theor., 66% purity) of the title compound was obtained. The
raw product was reacted further without purification.
[1589] LC-MS (method 1): R.sub.t=0.68 min; MS (ESIpos): m/z=269
[M+H].sup.+
Example 37A
4-Amino-2-[3-(2-fluorobenzyl)-1H-indazol-1-yl]-5,5-dimethyl-5,7-dihydro-6H-
-pyrrolo[2,3-d]pyrimidin-6-one
##STR00083##
[1591] 7.00 g (approx. 17.2 mmol, 66% purity) of the raw product
from example 36A and 5.72 g (34.4 mmol) of example 12A were put in
tert.-butanol (77.0 ml) and 3.29 g (29.3 mmol) of potassium
tert.-butylate was added. The reaction mixture was heated under
reflux for 18 h. After cooling, the reaction mixture was diluted
with ethyl acetate and washed with approx. 7% aqueous ammonium
chloride solution. The organic phase was washed with saturated
aqueous sodium chloride solution, dried and the solvent was removed
in the rotary evaporator. The residue was purified
chromatographically on 600 ml silica gel with cyclohexane/ethyl
acetate 2:3. 2.20 g (29% of theor.) of the title compound was
obtained as a solid.
[1592] LC-MS (method 4): R.sub.t=2.19 min; MS (ESIpos): m/z=403
[M+H].sup.+
[1593] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.35 (s,
6H), 4.39 (s, 2H), 6.97 (br s, 2H), 7.11-7.18 (m, 1H), 7.21 (d,
1H), 7.24-7.33 (m, 2H), 7.36 (t, 1H), 7.50 (t, 1H), 7.70 (d, 1H),
8.82 (d, 1H), 11.10 (s, 1H).
Example 38A
2-[3-(2-Fluorobenzyl)-1H-indazol-1-yl]-4-iodo-5,5-dimethyl-5,7-dihydro-6H--
pyrrolo[2,3-d]pyrimidin-6-one
##STR00084##
[1595] 500 mg (1.242 mmol) of example 37A was put in isopentyl
nitrite (3.552 ml) and diiodomethane (9.430 ml) and heated
overnight to 85.degree. C. After cooling, the reaction mixture was
filtered on silica gel (dichloromethane:methanol gradient) and
concentrated by evaporation. Dichloromethane and methanol were
added to the residue and it was stirred for 10 min at room
temperature. The solid that formed was filtered off and then washed
with dichloromethane and methanol. The filtrate was concentrated by
evaporation. Methanol and acetonitrile were then added to this
residue. A precipitate formed again, which was filtered with
suction and was washed again with acetonitrile. After drying under
high vacuum, 127 mg of the title compound was obtained (18% of
theor.). The filtrate was concentrated by evaporation, thus
obtaining a further 334 mg of the title compound at 57% purity (30%
of theor.).
[1596] LC-MS (method 1): R.sub.t=1.31 min; MS (ESIpos): m/z=514
[M+H].sup.+
[1597] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.42 (s,
6H), 4.43 (s, 2H), 7.13-7.23 (m, 2H), 7.29-7.41 (m, 3H), 7.62 (t,
1H), 7.74 (d, 1H), 8.58 (d, 1H), 11.89 (s, 1H).
[1598] In addition to the title compound, 57 mg (9% of theor., 86%
purity) of
2-[3-(2-fluorobenzyl)-1H-indazol-1-yl]-4-hydroxy-5,5-dimethyl-5,7-dihy-
dro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 22) was obtained.
Example 39A
1-(2-Bromo-5-fluorophenyl)-2-(2-fluorophenyl)ethanone
##STR00085##
[1600] 15.0 g (63.1 mmol) of 2-bromo-5-methyl fluorobenzoate and
11.7 g (75.7 mmol) of 2-fluorophenylacetic acid were put in THF
(278 ml) under argon atmosphere at -70.degree. C. and a 1M solution
of sodium hexamethyldisilazane in THF (158 ml) was added dropwise
in the space of 20 min. The reaction mixture was stirred at this
temperature for 30 min, heated to 0.degree. C., stirred for a
further 30 min at 0.degree. C. and then 1N hydrochloric acid (251
ml) was added. After stirring vigorously for 1 h with evolution of
gas (CO.sub.2 cleavage), the reaction mixture was extracted with
ethyl acetate (700 ml). The organic phase was washed twice with
saturated aqueous sodium hydrogen carbonate solution, once with
water and once with saturated aqueous sodium chloride solution.
After drying and removal of the solvent in the rotary evaporator,
16.9 g of residue was obtained (50% purity). The residue was
dissolved in THF (200 ml), 1N sodium hydroxide solution (100 ml)
was added and it was stirred overnight at RT. The THF was removed
in the rotary evaporator, the aqueous phase was extracted with
diethyl ether and the organic phase was washed with saturated
aqueous sodium hydrogen carbonate solution and saturated aqueous
sodium chloride solution. After drying and removal of the solvent
in the rotary evaporator, 9.10 g (42% of theor.) of the title
compound was isolated.
[1601] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=4.36 (s,
2H), 7.14-7.24 (m, 2H), 7.30-7.39 (m, 3H), 7.71-7.80 (m, 2H).
Example 40A
2-[1-(2-Bromo-5-fluorophenyl)-2-(2-fluorophenyl)ethylidene]hydrazinecarbox-
imidamide
##STR00086##
[1603] 9.00 g (28.9 mmol) of example 39A and 6.40 g (58.9 mmol) of
aminoguanidine hydrochloride were put in ethylene glycol (207 ml)
and 9.24 g (65.1 mmol) of boron trifluoride/diethyl ether complex
was added. The reaction mixture was heated for 2 h at 120.degree.
C. on a distillation bridge. After cooling, 6.40 g (58.9 mmol) of
aminoguanidine hydrochloride and 9.24 g (65.1 mmol) of boron
trifluoride/diethyl ether complex were added again and it was
stirred for 3 h at 120.degree. C. After cooling, the reaction
mixture was slowly added to water (800 ml) and was adjusted to pH
11-12 with 1N sodium hydroxide solution. After a precipitate
started to form, 300 g ice was added and it was stirred for 15 min.
Owing to the sticky nature of the precipitate, the water was
decanted off and the residue was precipitated twice more, with 200
ml water each time. The sticky precipitate was dissolved in diethyl
ether, washed with water, the organic phase was dried, the solvent
was removed in the rotary evaporator and 6.00 g (54% of theor.) of
the title compound was isolated as a foam.
[1604] LC-MS (method 1): R.sub.t=0.80 min; MS (ESIpos): m/z=367+369
[M+H].sup.+
Example 41A
5-Fluoro-3-(2-fluorobenzyl)-1H-indazole-1-carboximidamide
##STR00087##
[1606] 222 ml of N-methylpyrrolidone was heated to 140.degree. C.,
6.00 g (16.3 mmol) of example 40A and 3.11 g (16.3 mmol) of
copper(I) iodide were added and it was stirred for 14 min at
170.degree. C. bath temperature. The reaction mixture was then
added slowly to 700 ml ice water, and concentrated aqueous ammonia
solution (230 mL) was added. After stirring for 5 minutes, 700 ml
ethyl acetate was added and it was stirred for 10 min. The aqueous
phase was extracted with ethyl acetate once more and the combined
organic phases were washed with water three times. After drying and
removal of the solvent in the rotary evaporator, 6.00 g (64% of
theor., 50% purity) of product was obtained. The raw product was
reacted further without purification.
[1607] LC-MS (method 3): R.sub.t=1.60 min; MS (ESIpos): m/z=287
[M+H].sup.+
Example 42A
4-Amino-2-[5-fluoro-3-(2-fluorobenzyl)-1H-indazol-1-yl]-5,5-dimethyl-5,7-d-
ihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00088##
[1609] 6.00 g (approx. 10.5 mmol, 50% purity) of the raw product
from example 41A and 5.22 g (31.4 mmol) of example 12A were put in
tert.-butanol (46.0 ml) and 2.00 g (17.8 mmol) of potassium
tert.-butylate was added. The reaction mixture was heated under
reflux for 18 h. After cooling, it was diluted with ethyl acetate
and was extracted with approx. 7% aqueous ammonium chloride
solution. The organic phase was washed with saturated aqueous
sodium chloride solution, dried and the solvent was removed in the
rotary evaporator. The residue was purified by chromatography on
600 ml silica gel with cyclohexane/ethyl acetate 2:3. The
product-containing fractions were concentrated by evaporation and
mixed with approx. 20 ml diethyl ether, filtered with suction and
washed with diethyl ether. 1.80 g (37% of theor.) of the title
compound was obtained as a solid.
[1610] LC-MS (method 1): R.sub.t=1.00 min; MS (ESIpos): m/z=421
[M+H].sup.+
Example 43A
2-[5-Fluoro-3-(2-fluorobenzyl)-1H-indazol-1-yl]-4-iodo-5,5-dimethyl-5,7-di-
hydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00089##
[1612] 500 mg (1.189 mmol) of example 42A was put in isopentyl
nitrite (3.40 ml) and diiodomethane (9.027 ml) and heated overnight
to 85.degree. C. After cooling, it was filtered on silica gel
(dichloromethane:methanol gradient) and concentrated by
evaporation. The residue was purified by preparative HPLC
(acetonitrile:water (+0.05% formic acid) gradient). 274 mg of the
title compound was obtained (43% of theor.).
[1613] LC-MS (method 1): R.sub.t=1.33 min; MS (ESIpos): m/z=532
[M+H].sup.+
[1614] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.41 (s,
6H), 4.41 (s, 2H), 7.14-7.23 (m, 2H), 7.29-7.35 (m, 1H), 7.39-7.43
(ddd, 1H), 7.52-7.61 (m, 2H), 8.58 (d, 1H), 11.91 (s, 1H).
[1615] In addition to the title compound, 72 mg (14% of theor., 83%
purity) of
2-[5-fluoro-3-(2-fluorobenzyl)-1H-indazol-1-yl]-4-hydroxy-5,5-dimethyl-5,-
7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 31) was
obtained.
Example 44A
[1616]
Ethyl-8-(2-fluorobenzyl)imidazo[1,5-a]pyrimidine-6-carboxylate
##STR00090##
[1617] Preparation of the compound is described in: US 2010/29653,
Page 19, example 10A.
Example 45A
8-(2-Fluorobenzyl)imidazo[1,5-a]pyrimidine-6-carboxamide
##STR00091##
[1619] 8.200 g (27.40 mmol) of
ethyl-8-(2-fluorobenzyl)imidazo[1,5-a]pyrimidine-6-carboxylate was
distributed in 8 microwave vessels. Each vessel was charged with 10
ml of 7N solution of ammonia in methanol and stirred for 80 min at
150.degree. C. in the microwave. After cooling, the contents of the
vessels were combined, the resultant precipitate was filtered with
suction, washed with a little methanol and dried under high vacuum.
8.42 g (quant.) of the target compound was obtained.
[1620] LC-MS (method 1) R.sub.t=0.76 min; MS (ESIpos): m/z=271
[M+H].sup.+
Example 46A
8-(2-Fluorobenzyl)imidazo[1,5-a]pyrimidine-6-carbonitrile
##STR00092##
[1622] 150 ml of phosphoryl chloride was added to 9.100 g (33.67
mmol) of 8-(2-fluorobenzyl)imidazo[1,5-a]pyrimidine-6-carboxamide
and it was stirred for 2 h at 120.degree. C. The reaction mixture
was concentrated in the rotary evaporator and the residue was mixed
with water. The solid was filtered with suction, washed with a
little water and dried under high vacuum. 8.02 g (92% of theor.) of
the target compound was obtained.
[1623] LC-MS (method 1) R.sub.t=0.92 min; MS (ESIpos): m/z=253
[M+H].sup.+
Example 47A
8-(2-Fluorobenzyl)imidazo[1,5-a]pyrimidine-6-carboximidamide
##STR00093##
[1625] Under argon atmosphere, 6.98 g (32.30 mmol) of sodium
methylate (25% solution in methanol) was put in 50 ml methanol and
8.000 g (30.76 mmol) of
8-(2-fluorobenzyl)imidazo[1,5-a]pyrimidine-6-carbonitrile dissolved
in 40 ml of absolute methanol was added. The reaction mixture was
stirred for 1 h at RT. 7.205 g (119.98 mmol) of acetic acid and
1.975 g (36.92 mmol) of ammonium chloride were added and the
mixture was stirred for 2 h at 50.degree. C. The reaction mixture
was concentrated by evaporation and the residue was distributed
between 150 ml water and 100 ml ethyl acetate. The aqueous phase
was made basic (pH=10) with 2N sodium hydroxide solution and the
phases were stirred for 1 h at RT. Water was added and it was
extracted three times with ethyl acetate. The combined organic
phases were dried over sodium sulphate, concentrated by evaporation
and the residue was dried under high vacuum. 7.53 g (purity 73%,
66% of theor.) of the target compound was obtained.
[1626] LC-MS (method 1) R.sub.t=0.56 min; MS (ESIpos): m/z=270
[M+H].sup.+
Example 48A
4-Amino-2-[8-(2-fluorobenzyl)imidazo[1,5-a]pyrimidin-6-yl]-5,5-dimethyl-5,-
7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00094##
[1628] 4.000 g (purity 73%, 10.84 mmol) of
8-(2-fluorobenzyl)imidazo[1,5-a]pyrimidine-6-carboximidamide was
put in 25 ml tert.-butanol, 2.162 g (13.01 mmol) of
methyl-3,3-dicyano-2,2-dimethylpropanoate dissolved in 25 ml
tert.-butanol and 1.703 g (15.18 mmol) of potassium tert.-butylate
were added and it was heated under reflux for 18 h. A further 1.802
g (10.84 mmol) of methyl-3,3-dicyano-2,2-dimethylpropanoate was
added and it was boiled under reflux for 5 h. It was evaporated to
dryness and the residue was mixed with water/isopropanol (v/v=4:1).
The solid was filtered off and was mixed with methanol and diethyl
ether. It was filtered with suction and the residue was dried under
high vacuum. 1.90 g (purity 90%, 39% of theor.) of the target
compound was obtained.
[1629] LC-MS (method 1): R.sub.t=0.84 min; MS (ESIpos): m/z=404
[M+H].sup.+
Example 49A
2-[8-(2-Fluorobenzyl)imidazo[1,5-a]pyrimidin-6-yl]-4-iodo-5,5-dimethyl-5,7-
-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00095##
[1631] 1.500 g (3.35 mmol) of
4-amino-2-[8-(2-fluorobenzyl)imidazo[1,5-a]pyrimidin-6-yl]-5,5-dimethyl-5-
,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one was suspended in 6.00
ml (44.56 mmol) of isopentyl nitrite and 4.00 ml (49.66 mmol) of
diiodomethane and it was stirred for 2d at 85.degree. C. 4.00 ml
isopentyl nitrite and 5 ml NMP were added and the solution was
stirred for 4 h at 85.degree. C. The mixture was concentrated by
evaporation in the rotary evaporator except the NMP and was
purified by preparative HPLC (eluent: acetonitrile/water with 0.1%
formic acid, gradient 20:80.fwdarw.100:0). 928 mg (purity 69%, 37%
of theor.) of the target compound was obtained.
[1632] LC-MS (method 1): R.sub.t=1.11 min; MS (ESIpos): m/z=515
[M+H].sup.+
Example 50A
5-Fluoro-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-amine
##STR00096##
[1634] 58 g (340.027 mmol) of
2-chloro-5-fluoro-6-methylnicotinonitrile (preparation described in
WO2007/41052, example U-2, page 80) was put in 1,2-ethanediol (580
ml) and then hydrazine hydrate (24.813 ml) and 56.091 ml (340.027
mmol) of diisopropyl ethylamine were added. The reaction mixture
was heated with stirring for 16 h to 80.degree. C. and then for 66
h to 120.degree. C. After cooling, water (2.5 l) and ethyl acetate
(2.5 l) were added and it was filtered with suction. The solid
obtained was dried. 28.4 g (47% of theor.) of the target compound
was obtained.
[1635] LC-MS (method 7): R.sub.t=1.77 min; MS (ESIpos): m/z=167
[M+H].sup.+
Example 51A
5-Fluoro-3-iodo-6-methyl-1H-pyrazolo[3,4-b]pyridine
##STR00097##
[1637] 28 g (168.513 mmol) of example 50A was reacted, on the
analogy of example 6A. After silica gel chromatography
(cyclohexane:ethyl acetate 9:1), 14.9 g (31% of theor.) of the
title compound was obtained.
[1638] LC-MS (method 1): R.sub.t=0.84 min; MS (ESIpos): m/z=278
[M+H].sup.+
Example 52A
5-Fluoro-1-(2-fluorobenzyl)-3-iodo-6-methyl-1H-pyrazolo[3,4-b]pyridine
##STR00098##
[1640] 13 g (46.925 mmol) of example 51A was reacted, on the
analogy of example 7A. After silica gel chromatography
(cyclohexane:ethyl acetate gradient), 8.4 g (43% of theor.) of the
title compound was obtained.
[1641] LC-MS (method 1): R.sub.t=1.32 min; MS (ESIpos): m/z=386
[M+H].sup.+
Example 53A
5-Fluoro-1-(2-fluorobenzyl)-6-methyl-1H-pyrazolo[3,4-b]pyridine-3-carbonit-
rile
##STR00099##
[1643] 9.3 g (24.146 mmol) of example 52A was reacted, on the
analogy of example 10A, variant A. After silica gel chromatography
(cyclohexane:ethyl acetate gradient), 5.7 g (80% of theor.) of the
title compound was obtained.
[1644] LC-MS (method 1): R.sub.t=1.20 min; MS (ESIpos): m/z=285
[M+H].sup.+
Example 54A
5-Fluoro-1-(2-fluorobenzyl)-6-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxim-
idamide acetate
##STR00100##
[1646] 5.7 g (18.908 mmol, approx. 95%) of example 53A was reacted,
on the analogy of example 11A. 6.6 g (96% of theor.) of the title
compound was obtained.
[1647] LC-MS (method 1): R.sub.t=0.66 min; MS (ESIpos): m/z=302
[M+H].sup.+
Example 55A
4-Amino-2-[5-fluoro-1-(2-fluorobenzyl)-6-methyl-1H-pyrazolo[3,4-b]pyridin--
3-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00101##
[1649] 1 g (2.767 mmol) of example 54A was reacted, on the analogy
of example 13A. 971 mg (80% of theor.) of the title compound was
obtained.
[1650] LC-MS (method 1): R.sub.t=1.05 min; MS (ESIpos): m/z=436
[M+H].sup.+
Example 56A
2-[5-Fluoro-1-(2-fluorobenzyl)-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl]-4--
iodo-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00102##
[1652] 960 mg (2.205 mmol) of example 55A was reacted, on the
analogy of example 15A. 749 mg (62% of theor., 84% purity) of the
title compound was obtained.
[1653] LC-MS (method 1): R.sub.t=1.35 min; MS (ESIpos): m/z=547
[M+H].sup.+.
[1654] In addition to the title compound, 99 mg (10% of theor.) of
2-[5-fluoro-1-(2-fluorobenzyl)-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-
-hydroxy-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-c]pyrimidin-6-one
was obtained in this batch.
Example 57A
4'-Amino-2'-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-
,5-dihydrospiro[furan-3,5'-pyrrolo[2,3-c]pyrimidin]-6'(7'H)-one
##STR00103##
[1656] 1.505 g (4.650 mmol) of example 73A was reacted, on the
analogy of example 13A, with 0.903 g (4.650 mmol) of
methyl-3-(dicyanomethyl)tetrahydrofuran-3-carboxylate (described in
WO 2012/004259, example 12A, page 42). 178 mg (8% of theor.) of the
title compound was obtained.
[1657] LC-MS (method 1): R.sub.t=0.99 min; MS (ESIpos): m/z=450
[M+H].sup.+
Example 58A
2'-[5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4'-iodo-4,-
5-dihydrospiro[furan-3,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one
##STR00104##
[1659] 155 mg (0.345 mmol) of example 57A was reacted, on the
analogy of WO 2012/004258, example 57A, page 97-98. 86 mg (44% of
theor.) of the title compound was obtained.
[1660] LC-MS (method 1): R.sub.t=1.16 min; MS (ESIpos): m/z=561
[M+H].sup.+
Example 59A
[1661]
Ethyl-4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-
-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxylate
##STR00105##
[1662] 4.687 g (15.329 mmol) of example 1A was put in tert.-butanol
(120 ml) and 3.069 g (30.659 mmol) of potassium hydrogen carbonate
was added. Then 4.2 g (17.629 mmol) of
diethyl-(dicyanomethyl)(methyl)malonate was added and the mixture
was heated for 5 h to 85.degree. C. Then water was added, it was
stirred for 30 min at room temperature and then a solid was
filtered with suction. This was washed with a little diethyl ether.
After drying under high vacuum, 6.20 g of the title compound was
obtained (87% of theor.).
[1663] LC-MS (method 1): R.sub.t=0.95 min; MS (ESIpos): m/z=462
[M+H].sup.+
Example 60A
Ethyl-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5-methy-
l-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-c]pyrimidine-5-carboxylate
##STR00106##
[1665] 1.00 g (2.167 mmol) of example 59A was reacted, on the
analogy of the specification in example 15A. 0.887 g of the title
compound was obtained (71% of theor.).
[1666] LC-MS (method 1): R.sub.t=1.22 min; MS (ESIpos): m/z=573
[M+H].sup.+
[1667] In addition to the title compound, 173 mg (17% of theor.) of
ethyl-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-hydroxy-5-m-
ethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxylate
(example 101) was obtained.
Example 61A
tert.-Butyl-(1-{2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5--
dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}pyrrolidin-3-yl-
)carbamate (racemate)
##STR00107##
[1669] 150 mg (0.21 mmol, purity approx. 71%) of
2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-
-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 15A) was
dissolved, in a reaction vessel suitable for a microwave, in
1-methyl-2-pyrrolidone (3.1 ml), and 0.22 ml (1.24 mmol) of
N,N-diisopropyl ethylamine and 154 mg (0.83 mmol) of
tert.-butyl-pyrrolidin-3-ylcarbamate were added. Then the reaction
vessel was sealed with a septum and was heated for 6 h at
150.degree. C. in the microwave. After cooling, water was added to
the reaction mixture, and trifluoroacetic acid extracted three
times with dichloromethane. The combined organic phases were dried
over sodium sulphate, filtered and concentrated by evaporation. The
residue was purified by preparative HPLC (acetonitrile:water (+0.1%
trifluoroacetic acid) gradient). 69 mg of the title compound was
obtained (59% of theor.).
[1670] LC-MS (method 1): R.sub.t=1.17 min; MS (EIpos): m/z=573
[M+H].sup.+.
Example 62A
tert.-Butyl-(1-{2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5--
dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}azetidin-3-yl)c-
arbamate
##STR00108##
[1672] 150 mg (0.21 mmol, purity approx. 71%) of
2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-
-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 15A) was
dissolved, in a reaction vessel suitable for a microwave, in
1-methyl-2-pyrrolidone (3.1 ml), and 0.22 ml (1.24 mmol) of
N,N-diisopropyl ethylamine and 143 mg (0.83 mmol) of
tert.-butyl-azetidin-3-ylcarbamate were added. Then the reaction
vessel was sealed with a septum and heated for 8 h at 150.degree.
C. in the microwave. Then 0.15 ml (0.82 mmol) of N,N-diisopropyl
ethylamine and 107 mg (0.62 mmol) of
tert.-butyl-azetidin-3-ylcarbamate were added again and the
reaction mixture was heated for 3 h at 150.degree. C. in the
microwave. After cooling, water was added to the reaction mixture
and it was purified by preparative HPLC (acetonitrile:water (+0.1%
trifluoroacetic acid) gradient). 81 mg of the title compound was
obtained (64% of theor.; purity 91%).
[1673] LC-MS (method 1): R.sub.t=1.15 min; MS (EIpos): m/z=559
[M+H].sup.+.
Example 63A
4-Chloro-6-methyl-1H-pyrazolo[3,4-d]pyrimidine
##STR00109##
[1675] This compound was prepared according to a modified
specification from: C. C. Cheng, R. K. Robins, J. Org. Chem. 1958,
23, 191.
[1676] 4.878 g (33.2 mmol) of
6-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-ol (J. Org. Chem. 1958, 23,
191) was put in 50 ml toluene, 15.5 ml (165.8 mmol) of phosphoryl
chloride and 12.7 ml (72.9 mmol) of diisopropyl ethylamine were
added and it was stirred for 1 h at 80.degree. C. It was
concentrated by evaporation and distributed between ethyl acetate
and 1 M hydrochloric acid. The organic phase was dried over sodium
sulphate and concentrated by evaporation. The residue (4.464 g, 92%
purity, 73% of theor.) was processed further without
purification.
[1677] LC-MS (method 1): R.sub.t=0.53 min; MS (ESIpos): m/z=169
(M+H).sup.+
Example 64A
6-Methyl-1H-pyrazolo[3,4-d]pyrimidine
##STR00110##
[1679] 4.464 g (approx. 24.28 mmol, purity 92%) of
4-chloro-6-methyl-1H-pyrazolo[3,4-d]pyrimidine was dissolved in 180
ml dioxane and 2.948 g (29.14 mmol) of triethylamine and 5.629 g of
20% palladium hydroxide on charcoal were added and it was
hydrogenated at 3 bar hydrogen pressure and RT for 2 days. 100 ml
ethyl acetate, 2.948 g (29.14 mmol) of triethylamine and 2.000 g of
20% palladium hydroxide on charcoal were added. The mixture was
hydrogenated with hydrogen at 3 bar hydrogen pressure and RT for 3
h. The reaction mixture was filtered on Celite, washed with a
little dioxane/ethyl acetate and the filtrate was concentrated in
the rotary evaporator. 2.180 g (purity 73%, 49% of theor.) of the
target compound was obtained.
[1680] LC-MS (method 4): R.sub.t=0.40 min; MS (ESIpos): m/z=135
(M+H).sup.+
Example 65A
3-Iodo-6-methyl-1H-pyrazolo[3,4-d]pyrimidine
##STR00111##
[1682] 2.180 g (purity 73%, approx. 11.82 mmol) of
6-methyl-1H-pyrazolo[3,4-d]pyrimidine and 3.987 g (17.72 mmol) of
N-iodosuccinimide were dissolved in 30 ml DMF and heated for 2 h at
80.degree. C. After cooling, the mixture was concentrated in the
rotary evaporator and the residue was mixed with dichloromethane,
filtered with suction and dried under high vacuum. 7.950 g (approx.
38% purity) of the target compound was obtained.
[1683] LC-MS (method 1): R.sub.t=0.52 min; MS (ESIpos): m/z=261
(M+H).sup.+
Example 66A
1-(2-Fluorobenzyl)-3-iodo-6-methyl-1H-pyrazolo[3,4-d]pyrimidine
##STR00112##
[1685] 7.950 g (13.76 mmol) of
3-iodo-6-methyl-1H-pyrazolo[3,4-d]pyrimidine and 4.930 g (15.13
mmol) of caesium carbonate were put in 20 ml DMF and 2.860 g (15.13
mmol) of 2-fluorobenzyl bromide dissolved in 5 ml DMF was added.
The reaction mixture was stirred overnight at RT, diluted with 100
ml water and extracted with ethyl acetate. The organic phase was
dried over sodium sulphate and concentrated in a rotary evaporator.
The residue was purified by preparative HPLC (eluent:
acetonitrile/water, gradient 30:70.fwdarw.95:5). 1.030 g of the
target compound was obtained (20% of theor.).
[1686] LC-MS (method 4): R.sub.t=2.27 min; MS (ESIpos): m/z=369
(M+H).sup.+
Example 67A
1-(2-Fluorobenzyl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile
##STR00113##
[1688] 1.485 g (4.03 mmol) of
1-(2-fluorobenzyl)-3-iodo-6-methyl-1H-pyrazolo[3,4-d]pyrimidine and
397 mg (4.44 mmol) of copper(I) cyanide were put in 11 ml of
absolute DMSO and heated for 2 h at 150.degree. C. After cooling,
the reaction mixture was filtered on Celite and then washed with
ethyl acetate and THF. The organic phase was washed with 25%
aqueous ammonia solution, saturated aqueous ammonium chloride
solution and saturated aqueous sodium chloride solution, dried over
sodium sulphate and concentrated in a rotary evaporator. 994 mg
(purity 81%, 75% of theor.) of the target compound was
obtained.
[1689] LC-MS (method 1): R.sub.t=0.96 min; MS (ESIpos): m/z=268
(M+H).sup.+
Example 68A
1-(2-Fluorobenzyl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboximidamide
##STR00114##
[1691] Under an argon atmosphere, 994 mg (purity 81%, approx. 3.01
mmol) of
1-(2-fluorobenzyl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitril-
e was dissolved in 15 ml of absolute methanol. 209 mg (3.72 mmol)
of sodium methylate was added and it was stirred for 1 h at RT.
Then a further 31 mg (0.56 mmol) of sodium methylate was added and
it was stirred for 15 min at RT. 871 mg (14.50 mmol) of acetic acid
and 489 mg (4.46 mmol) of ammonium chloride were added and the
mixture was stirred for 45 min at 45.degree. C. The reaction
mixture was concentrated by evaporation, the residue was mixed with
1N sodium hydroxide solution, the precipitate was filtered with
suction and dried under high vacuum. 918 mg (purity 91%, 97% of
theor.) of the target compound was obtained.
[1692] LC-MS (method 2) R.sub.t=0.53 min; MS (ESIpos): m/z=285
(M+H).sup.+
[1693] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=2.75 (s,
3H), 5.65-5.73 (m, 1H), 5.71 (s, 2H), 7.10-7.18 (m, 2H), 7.19-7.29
(m, 1H), 7.33-7.43 (m, 1H), 9.51 (s, 1H).
Example 69A
4-Amino-2-[1-(2-fluorobenzyl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5-
,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00115##
[1695] 3 ml tert.-butanol, a solution of 146 mg (0.70 mmol) of
methyl-3,3-dicyano-2,2-dimethylpropanoate in 1.5 ml tert.-butanol
and 94 mg (0.84 mmol) of potassium tert.-butylate were added to 200
mg (0.70 mmol) of
1-(2-fluorobenzyl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carbo-
ximidamide and it was heated under reflux for 48 h. Water was added
and the precipitate was filtered off. The filtrate was extracted
with dichloromethane, the organic phase was dried over sodium
sulphate and concentrated in a rotary evaporator. The residue was
mixed with water/ethanol. The solid was filtered off and dried
under high vacuum. 102 mg (34% of theor.) of the target compound
was obtained.
[1696] LC-MS (method 1): R.sub.t=0.81 min; MS (ESIpos): m/z=419
(M+H).sup.+
Example 70A
2-[1-(2-Fluorobenzyl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-4-iodo-5,-
5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00116##
[1698] 3.770 g (14.08 mmol) of diiodomethane and 411 mg (3.51 mmol)
of isopentyl nitrite were added to 70 mg (0.17 mmol) of
4-amino-2-[1-(2-fluorobenzyl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl]--
5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one. The
mixture was stirred for 8 h at 85.degree. C. After cooling, it was
diluted with acetonitrile and the mixture was purified by
preparative HPLC (eluent: acetonitrile/water, gradient
30:70.fwdarw.95:5). 35 mg (24% of theor.) of the target compound
was obtained.
[1699] LC-MS (method 4): R.sub.t=2.37 min; MS (ESIpos): m/z=530
(M+H).sup.+
[1700] In addition, 10 mg (14% of theor.) of
2-[1-(2-fluorobenzyl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-4-hydrox-
y-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one was
obtained.
Example 71A
4-Amino-2-[1-(2,3-difluorobenzyl)-5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl]-
-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00117##
[1702] On the analogy of the preparation of example 13A, 5.00 g
(13.687 mmol) of
1-(2,3-difluorobenzyl)-5-fluoro-1H-pyrazolo[3,4-b]pyridine-3-car-
boximidamide acetate (example 64A from WO 2012/004258, Page
102-103) was reacted. 5.13 g of the title compound was obtained
(85% of theor.).
[1703] LC-MS (method 1) R.sub.t=0.97 min; MS (ESIpos): m/z=440
[M+H].sup.+
Example 72A
2-[1-(2,3-Difluorobenzyl)-5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo--
5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00118##
[1705] On the analogy of the preparation of example 16A, 5.11 g
(11.629 mmol) of example 71A was reacted. 2.39 g of the title
compound was obtained (85% of theor.).
[1706] LC-MS (method 1) R.sub.t=1.25 min; MS (ESIpos): m/z=551
[M+H].sup.+
[1707] In addition to the title compound, 660 mg (12% of theor.) of
2-[1-(2,3-difluorobenzyl)-5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-hydr-
oxy-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
(example 116) was obtained.
Example 73A
5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide
hydrochloride
##STR00119##
[1709] 406.0 g (1.50 mol) of the compound from example 10A was
suspended in 2.08 L ethanol. Then 54.1 g (0.30 mol) of sodium
methanolate in methanol (30%) was added and it was stirred
overnight at room temperature. 88.4 g (1.65 mol) of ammonium
chloride was added, it was heated to 65.degree. C. and stirred for
3.5 h at 65.degree. C. The solvents were distilled off and the
residue was stirred overnight with 1.6 L ethyl acetate. The
precipitated solid was filtered with suction, washed twice with 140
ml ethyl acetate each time and dried in a vacuum drying cabinet at
50.degree. C. under a gentle nitrogen stream. 441.4 g (90.7% of
theor.) of the title compound was obtained.
[1710] MS (ESIpos): m/z=288 (M+H).sup.+
[1711] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=5.90 (s, 2H),
7.15-7.20 (m, 1H), 7.22-7.28 (m, 1H), 7.29-7.35 (m, 1H), 7.36-7.43
(m, 1H), 8.48 (dd, 1H), 8.86 (dd, 1H), 9.35 (br s, 3H) ppm.
Practical Examples
Example 1
2-[1-(2-Fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-methoxy-5,5-dimeth-
yl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00120##
[1713] Methanol (3 ml), 126 mg (0.389 mmol) of caesium carbonate,
3.7 mg (0.019 mmol) of copper(I) iodide and 9 mg (0.039 mmol) of
3,4,7,8-tetramethyl-1,10-phenanthroline were added to 100 mg (0.194
mmol) of example 15A in a reaction vessel suitable for a microwave.
It was rinsed with argon under ultrasonic treatment for 5 min and
then sealed with a suitable septum. Then it was heated in the
microwave in 3 cycles, in each case for 2 h at 140.degree. C. After
cooling, the reaction mixture was filtered, concentrated by
evaporation and the residue was purified by preparative HPLC
(acetonitrile:water (+0.05% formic acid) gradient). 32 mg of the
title compound was obtained (39% of theor.).
[1714] LC-MS (method 1): R.sub.t=1.08 min; MS (EIpos): m/z=419
[M+H].sup.+.
[1715] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.35 (s,
6H), 4.15 (s, 3H), 5.87 (s, 2H), 7.13-7.26 (m, 3H), 7.34-7.38 (m,
1H), 7.45 (dd, 1H), 8.68 (dd, 1H), 8.91 (dd, 1H), 11.44 (s br,
1H).
Example 2
2-[5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-[(2-hydro-
xyethyl)amino]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00121##
[1717] In a reaction vessel suitable for a microwave, 100 mg (0.115
mmol, approx. 61% purity) of example 16A was dissolved in
1-methyl-2-pyrrolidone (2 ml) and 0.75 ml aminoethanol was added.
Then it was sealed with a corresponding septum and was heated in
the microwave for 5 h at 150.degree. C. After cooling, the reaction
mixture was purified by preparative HPLC (acetonitrile:water
(+0.05% formic acid) gradient). 68 mg of the title compound was
obtained (100% of theor., 94% purity according to LC/MS).
[1718] LC-MS (method 3): R.sub.t=0.94 min; MS (EIpos): m/z=466
[M+H].sup.+.
[1719] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.36 (s,
6H), 3.29 (s, signal superimposed with water signal, 2H), 3.64 (s,
2H), 4.82 (t, 1H), 5.83 (s, 2H), 6.65 (t br, 1H), 7.13-7.25 (m,
3H), 7.33-7.39 (m, 1H), 8.55 (dd, 1H), 8.71 (dd, 1H), 11.00 (s br,
1H).
Example 3
4-[(2-Amino-2-methylpropyl)amino]-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazo-
lo[3,4-b]pyridin-3-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-
-6-one
##STR00122##
[1721] 100 mg (0.115 mmol, approx. 61% purity) of example 16A was
dissolved in 1-methyl-2-pyrrolidone (2 ml) in a reaction vessel
suitable for a microwave and 0.75 ml 2-methylpropane-1,2-diamine
was added. Then it was sealed with a corresponding septum and it
was heated in the microwave at 150.degree. C. for 3 h. After
cooling, the reaction mixture was purified by preparative HPLC
(acetonitrile:water (+0.05% formic acid) gradient). 57 mg of the
title compound was obtained (100% of theor.).
[1722] LC-MS (method 3): R.sub.t=0.82 min; MS (EIpos): m/z=493
[M+H].sup.+.
[1723] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.21 (s,
6H), 1.41 (s, 6H), 3.67 (signal superimposed with water signal
probably 2H), 5.84 (s, 2H), 6.98 (m br, 1H), 7.15 (t, 1H),
7.20-7.26 (m, 2H), 7.34-7.39 (m, 1H), 8.56 (dd, 1H), 8.73 (dd, 1H),
signals for --NH--C.dbd.O and --NH.sub.2 not observed.
Example 4
2-[5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-[(2-hydro-
xy-2-methylpropyl)amino]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimid-
in-6-one
##STR00123##
[1725] 100 mg (0.115 mmol, approx. 61% purity) of example 16A was
dissolved in 1-methyl-2-pyrrolidone (2 ml) in a reaction vessel
suitable for a microwave and 0.5 ml of 1-amino-2-methylpropan-2-ol
was added. Then it was sealed with a corresponding septum and it
was heated in the microwave at 150.degree. C. for 3 h. After
cooling, the reaction mixture was purified by preparative HPLC
(acetonitrile:water (+0.05% formic acid) gradient). 56 mg of the
title compound was obtained (100% of theor.).
[1726] LC-MS (method 1): R.sub.t=1.06 min; MS (EIpos): m/z=494
[M+H].sup.+.
[1727] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.15 (s,
6H), 1.39 (s, 6H), 3.60 (d, 2H), 4.76 (s, 1H), 5.82 (s, 2H), 6.41
(t, 1H), 7.15 (t, 1H), 7.20-7.26 (m, 2H), 7.34-7.39 (m, 1H), 8.64
(dd, 1H), 8.72 (dd, 1H), 11.06 (s br, 1H).
Example 5
2-[5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethy-
l-4-[(3,3,3-trifluoropropyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin--
6-one
##STR00124##
[1729] 100 mg (0.115 mmol, approx. 61% purity) of example 16A was
dissolved in 1-methyl-2-pyrrolidone (2 ml) in a reaction vessel
suitable for a microwave and 0.5 ml of
3,3,3-trifluoropropyl-1-amine was added. Then it was sealed with a
corresponding septum and it was heated in the microwave at
150.degree. C. for 3 h. After cooling, the reaction mixture was
purified by preparative HPLC (acetonitrile:water (+0.05% formic
acid) gradient). 60 mg of the title compound was obtained (100% of
theor.).
[1730] LC-MS (method 1): R.sub.t=1.21 min; MS (EIpos): m/z=518
[M+H].sup.+.
[1731] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.35 (s,
6H), 2.64-2.71 (m, 2H), 3.82 (q, 2H), 5.83 (s, 2H), 6.88 (t, 1H),
7.15 (t, 1H), 7.20-7.25 (m, 2H), 7.34-7.40 (m, 1H), 8.48 (dd, 1H),
8.72 (dd, 1H), 11.10 (s, 1H).
Example 6
4-[(2-Amino-3,3,3-trifluoropropyl)amino]-2-[5-fluoro-1-(2-fluorobenzyl)-1H-
-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]py-
rimidin-6-one
##STR00125##
[1733] 100 mg (0.115 mmol, approx. 61% purity) of example 16A was
suspended in 1-methyl-2-pyrrolidone (2 ml) in a reaction vessel
suitable for a microwave, and 1 ml diisopropyl ethylamine and then
300 mg (1.492 mmol) of
1-(trifluoromethyl)ethylene-1,2-diamin-dihydrochloride were added.
Then it was sealed with a corresponding septum and it was heated in
the microwave at 150.degree. C. for 3 h. After cooling, the
reaction mixture was purified by preparative HPLC
(acetonitrile:water (+0.05% formic acid) gradient). 5.7 mg of the
title compound was obtained (9% of theor.).
[1734] LC-MS (method 1): R.sub.t=0.98 min; MS (EIpos): m/z=534
[M+H].sup.+.
[1735] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.37 (d,
6H), 3.47-3.45 (m, 1H), 3.62-3.73 (m, 1H), 3.94-4.00 (m, 1H), 5.83
(s, 2H), 6.82 (t, 1H), 7.15 (t, 1H), 7.20-7.26 (m, 2H), 7.34-7.39
(m, 1H), 8.56 (dd, 1H), 8.72 (br d, 1H), 11.11 (br s, 1H),
--NH.sub.2 not observed
Example 7
4-[(2,2-Difluoroethyl)amino]-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,-
4-b]pyridin-3-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-on-
e
##STR00126##
[1737] 100 mg (0.115 mmol, approx. 61% purity) of example 16A was
dissolved in 1-methyl-2-pyrrolidone (2 ml) in a reaction vessel
suitable for a microwave and 0.5 ml of 2,2-difluoroethylamine was
added. Then it was sealed with a corresponding septum and it was
heated in the microwave at 150.degree. C. for 3 h. After cooling,
the reaction mixture was purified by preparative HPLC
(acetonitrile:water (+0.05% formic acid) gradient). 30 mg of the
title compound was obtained (55% of theor., 100%).
[1738] LC-MS (method 1): R.sub.t=1.15 min; MS (EIpos): m/z=486
[M+H].sup.+.
[1739] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.37 (s,
6H), 3.91-4.00 (m, 2H), 5.83 (s, 2H), 6.13-6.43 (m, 1H), 7.04 (t,
1H), 7.15 (dd, 1H), 7.20-7.25 (m, 2H), 7.34-7.39 (m, 1H), 8.46 (dd,
1H), 8.72 (dd, 1H), 11.13 (s, 1H).
Example 8
4-(3-Fluoroazetidin-1-yl)-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b-
]pyridin-3-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00127##
[1741] 100 mg (0.115 mmol, approx. 61% purity) of example 16A was
dissolved in 1-methyl-2-pyrrolidone (2 ml) in a reaction vessel
suitable for a microwave, and 0.314 ml (1.800 mmol) of
N,N-diisopropyl ethylamine and 200 mg (1.793 mmol) of
3-fluoroazetidine hydrochloride were added. Then it was sealed with
a corresponding septum and it was heated in the microwave at
150.degree. C. for 3 h. After cooling, the reaction mixture was
purified by preparative HPLC (acetonitrile:water (+0.05% formic
acid) gradient). 22 mg of the title compound was obtained (41% of
theor.).
[1742] LC-MS (method 1): R.sub.t=1.19 min; MS (EIpos): m/z=480
[M+H].sup.+.
[1743] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.35 (s,
6H), 4.34-4.42 (m, 2H), 4.63-4.73 (m, 2H), 5.48-5.66 (m, 1H), 5.84
(s, 2H), 7.13-7.25 (m, 3H), 7.34-7.40 (m, 1H), 8.52 (dd, 1H), 8.73
(dd, 1H), 11.27 (s, 1H).
Example 9
4-[(Dicyclopropylmethyl)amino]-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[-
3,4-b]pyridin-3-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6--
one
##STR00128##
[1745] 100 mg (0.115 mmol, approx. 61% purity) of example 16A was
dissolved in 1-methyl-2-pyrrolidone (2 ml) in a reaction vessel
suitable for a microwave and 0.5 ml of dicyclopropylmethylamine was
added. Then it was sealed with a corresponding septum and it was
heated in the microwave at 150.degree. C. for 3 h. After cooling,
the reaction mixture was purified by preparative HPLC
(acetonitrile:water (+0.05% formic acid) gradient). 25 mg of the
title compound was obtained (42% of theor.).
[1746] LC-MS (method 1): R.sub.t=1.34 min; MS (EIpos): m/z=516
[M+H].sup.+.
[1747] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.28-0.41
(m, 6H), 0.49-0.58 (m, 2H), 1.25-1.34 (m, 2H), 1.40 (s, 6H), 3.49
(dd, 1H), 5.81 (s, 2H), 6.40 (d, 1H), 7.14 (t, 1H), 7.20-7.24 (m,
2H), 7.34-7.39 (m, 1H), 8.37 (dd, 1H), 8.72 (m, 1H), 11.02 (s br,
1H).
Example 10
4-[(Cyclopropylmethyl)amino]-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,-
4-b]pyridin-3-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-on-
e
##STR00129##
[1749] 100 mg (0.115 mmol, approx. 61% purity) of example 16A was
dissolved in 1-methyl-2-pyrrolidone (2 ml) in a reaction vessel
suitable for a microwave and 0.5 ml of aminomethylcyclopropane was
added. Then it was sealed with a corresponding septum and it was
heated in the microwave at 150.degree. C. for 3 h. After cooling,
the reaction mixture was purified by preparative HPLC
(acetonitrile:water (+0.05% formic acid) gradient). 45 mg of the
title compound was obtained (82% of theor.).
[1750] LC-MS (method 1): R.sub.t=1.22 min; MS (EIpos): m/z=476
[M+H].sup.+.
[1751] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.31-0.34
(m, 2H), 0.42-0.46 (m, 2H), 1.21-1.26 (m, 1H), 1.37 (s, 6H), 3.45
(t, 2H), 5.83 (s, 2H), 6.88 (t, 1H), 7.15 (t, 1H), 7.21-7.25 (m,
2H), 7.34-7.39 (m, 1H), 8.57 (dd, 1H), 8.72 (m, 1H), 11.02 (s br,
1H).
Example 11
2-[5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethy-
l-4-[(2,2,2-trifluoroethyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-
-one
##STR00130##
[1753] 100 mg (0.115 mmol, approx. 61% purity) of example 16A was
dissolved in 1-methyl-2-pyrrolidone (2 ml) in a reaction vessel
suitable for a microwave and 1 ml of 2,2,2-trifluoroethylamine was
added. Then it was sealed with a corresponding septum and heated in
the microwave at 150.degree. C. for 20 h. After cooling, the
reaction mixture was purified by preparative HPLC
(acetonitrile:water (+0.05% formic acid) gradient). 35 mg of the
title compound was obtained (61% of theor.).
[1754] LC-MS (method 1): R.sub.t=1.12 min; MS (EIpos): m/z=504
[M+H].sup.+.
[1755] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.39 (s,
6H), 4.35-4.43 (m, 2H), 5.84 (s, 2H), 7.15 (t, 1H), 7.20-7.25 (m,
3H), 7.34-7.40 (m, 1H), 8.46 (dd, 1H), 8.73 (m, 1H), 11.22 (s br,
1H).
Example 12
2-{5-Fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-y-
l}-5,5-dimethyl-4-[(3,3,3-trifluoropropyl)amino]-5,7-dihydro-6H-pyrrolo[2,-
3-d]pyrimidin-6-one
##STR00131##
[1757] 350 mg (0.361 mmol, approx. 55% purity) of example 21A was
dissolved in 1-methyl-2-pyrrolidone (4 ml) in a reaction vessel
suitable for a microwave and 1.2 ml of
3,3,3-trifluoropropyl-1-amine was added. Then it was sealed with a
corresponding septum and it was heated in the microwave at
150.degree. C. for 3 h. After cooling, the reaction mixture was
purified by preparative HPLC (acetonitrile:water (+0.05% formic
acid) gradient). 108 mg of the title compound was obtained (57% of
theor.).
[1758] LC-MS (method 1): R.sub.t=1.08 min; MS (EIpos): m/z=519
[M+H].sup.+.
[1759] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.35 (s,
6H), 2.62-2.72 (m, 2H), 3.82 (q, 2H), 5.96 (s, 2H), 6.82 (t, 1H),
7.42-7.45 (m, 1H), 7.76 (t, 1H), 8.27 (d, 1H), 8.48 (dd, 1H), 8.67
(br s, 1H), 11.03 (s, 1H).
Example 13
2-[6-Chloro-3-(2,3,6-trifluorobenzyl)imidazo[1,5-a]pyridin-1-yl]-5,5-dimet-
hyl-4-[(3,3,3-trifluoropropyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidi-
n-6-one
##STR00132##
[1761] 128 mg (0.219 mmol) of example 22A was dissolved in
1-methyl-2-pyrrolidone (2.334 ml) in a reaction vessel suitable for
a microwave and 0.584 ml of 3,3,3-trifluoropropyl-1-amine was
added. Then it was sealed with a corresponding septum and it was
heated in the microwave at 150.degree. C. for 3 h. After cooling,
the reaction mixture was purified by preparative HPLC
(acetonitrile:water (+0.05% formic acid) gradient). 57 mg of the
title compound was obtained (46% of theor.).
[1762] LC-MS (method 1): R.sub.t=1.21 min; MS (EIpos): m/z=569
[M+H].sup.+.
[1763] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.31 (s,
6H), 2.62-2.71 (m, 2H), 3.73 (q, 2H), 4.53 (s, 2H), 6.69 (t, 1H),
7.05 (dd, 1H), 7.17-7.24 (m, 1H), 7.46-7.55 (m, 1H), 8.42 (d, 1H),
8.80 (s, 1H), 10.91 (s, 1H).
Example 14
2-{5-Fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-y-
l}-5,5-dimethyl-4-[(3,3,3-trifluoropropyl)amino]-5,7-dihydro-6H-pyrrolo[2,-
3-d]pyrimidin-6-one
##STR00133##
[1765] 150 mg (0.186 mmol, approx. 66% purity) of the compound
obtained in example 28A was dissolved in 1-methyl-2-pyrrolidone
(3.6 ml) in a reaction vessel suitable for a microwave and 0.9 ml
of 3,3,3-trifluoropropyl-1-amine was added. Then it was sealed with
a corresponding septum and it was heated in the microwave at
150.degree. C. for 3 h. After cooling, the reaction mixture was
purified by preparative HPLC (acetonitrile:water (+0.05% formic
acid) gradient). 33 mg of the title compound was obtained (34% of
theor.).
[1766] LC-MS (method 1): R.sub.t=1.00 min; MS (EIpos): m/z=519
[M+H].sup.+.
[1767] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.36 (s,
6H), 2.61-2.74 (m, 2H), 3.82 (q, 2H), 5.92 (s, 2H), 6.89 (t, 1H),
7.13 (t, 1H), 8.35 (d, 1H), 8.50 (dd, 1H), 8.59 (d, 1H), 8.73 (dd,
1H), 11.10 (s, 1H).
Example 15
4-(3-Fluoroazetidin-1-yl)-2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H--
pyrazolo[3,4-b]pyridin-3-yl}-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyr-
imidin-6-one
##STR00134##
[1769] 150 mg (0.155 mmol, approx. 55% purity) of the compound
obtained in example 21A was dissolved in 1-methyl-2-pyrrolidone
(2.7 ml) in a reaction vessel suitable for a microwave, and 0.423
ml (2.430 mmol) of N,N-diisopropyl ethylamine and 270 mg (2.420
mmol) of 3-fluoroazetidine hydrochloride were added. Then it was
sealed with a corresponding septum and it was heated in the
microwave at 150.degree. C. for 3 h. After cooling, the reaction
mixture was purified by preparative HPLC (acetonitrile:water
(+0.05% formic acid) gradient). 30 mg of the title compound was
obtained (40% of theor.).
[1770] LC-MS (method 1): R.sub.t=0.97 min; MS (EIpos): m/z=481
[M+H].sup.+.
[1771] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.35 (s,
6H), 4.34-4.42 (m, 2H), 4.63-4.73 (m, 2H), 5.48-5.65 (m, 1H), 5.98
(s, 2H), 7.41-7.45 (m, 1H), 7.74-7.79 (m, 1H), 8.24-8.28 (m, 1H),
8.52 (dd, 1H), 8.68 (dd, 1H), 11.22 (s, 1H).
Example 16
2-{5-Fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-y-
l}-5,5-dimethyl-4-[(2,2,2-trifluoroethyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-
-d]pyrimidin-6-one
##STR00135##
[1773] 150 mg (0.155 mmol, approx. 55% purity) of the compound
obtained in example 21A was dissolved in 1-methyl-2-pyrrolidone
(2.7 ml) in a reaction vessel suitable for a microwave and 0.675 ml
2,2,2-trifluoroethylamine was added. Then it was sealed with a
corresponding septum and heated in the microwave at 150.degree. C.
for 21 h. After cooling, the reaction mixture was purified by
preparative HPLC (acetonitrile:water (+0.05% formic acid)
gradient). 31 mg of the title compound was obtained (39% of
theor.).
[1774] LC-MS (method 1): R.sub.t=0.99 min; MS (EIpos): m/z=505
[M+H].sup.+.
[1775] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.39 (s,
6H), 4.35-4.44 (m, 2H), 5.98 (s, 2H), 7.19 (t, 1H), 7.41-7.45 (m,
1H), 7.74-7.79 (m, 1H), 8.24-8.28 (m, 1H), 8.46 (dd, 1H), 8.68 (dd,
1H), 11.16 (s br, 1H).
Example 17
4-[(Cyclopropylmethyl)amino]-2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]--
1H-pyrazolo[3,4-b]pyridin-3-yl}-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]-
pyrimidin-6-one
##STR00136##
[1777] 200 mg (0.206 mmol, approx. 55% purity) of the compound
obtained in example 21A was dissolved in 1-methyl-2-pyrrolidone (4
ml) in a reaction vessel suitable for a microwave and 1 ml of
aminomethylcyclopropane was added. Then it was sealed with a
corresponding septum and it was heated in the microwave at
150.degree. C. for 3 h. After cooling, the reaction mixture was
purified by preparative HPLC (acetonitrile:water (+0.05% formic
acid) gradient). 64 mg of the title compound was obtained (65% of
theor.).
[1778] LC-MS (method 1): R.sub.t=1.09 min; MS (EIpos): m/z=477
[M+H].sup.+.
[1779] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.30-0.33
(m, 2H), 0.42-0.46 (m, 2H), 1.21-1.27 (m, 1H), 1.37 (s, 6H), 3.46
(t, 2H), 5.96 (s, 2H), 6.78-6.85 (m, 1H), 7.41-7.45 (m, 1H), 7.76
(t, 1H), 8.24-8.28 (m, 1H), 8.57 (dd, 1H), 8.67 (dd, 1H), 10.95 (s
br, 1H).
Example 18
2-[5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethy-
l-4-[(4,4,4-trifluorobutyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-
-one
##STR00137##
[1781] 150 mg (0.186 mmol, approx. 66% purity) of the compound
obtained in example 16A was dissolved in 1-methyl-2-pyrrolidone (3
ml) in a reaction vessel suitable for a microwave and 0.4 ml of
4,4,4-trifluorobutylamine was added. Then it was sealed with a
corresponding septum and it was heated in the microwave at
150.degree. C. for 3 h. After cooling, the reaction mixture was
purified by preparative HPLC (acetonitrile:water (+0.05% formic
acid) gradient). 47 mg of the title compound was obtained (48% of
theor.).
[1782] LC-MS (method 1): R.sub.t=1.19 min; MS (EIpos): m/z=532
[M+H].sup.+.
[1783] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.37 (s,
6H), 1.87-1.94 (m, 2H), 2.30-2.43 (m, 2H), 3.63 (q, 2H), 5.83 (s,
2H), 6.81 (t, 1H), 7.12-7.17 (m, 1H), 7.21-7.25 (m, 2H), 7.34-7.39
(m, 1H), 8.47 (dd, 1H), 8.72 (dd, 1H), 11.04 (s, 1H).
Example 19
2-[1-(2-Fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl]-5,5-dim-
ethyl-4-[(2,2,2-trifluoroethyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimid-
in-6-one
##STR00138##
[1785] 50 mg (0.09 mmol) of
2-[1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl]-4-iodo-
-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example
33A) was dissolved in 1 ml of absolute NMP and 336 mg (3.70 mmol)
of 2,2,2-trifluoroethanamine was added. The mixture was heated in
the microwave for 2 h at 150.degree. C., 18 h at 150.degree. C., 2
h at 160.degree. C., 2 h at 170.degree. C. and 5 h at 170.degree.
C. The reaction solution was filtered and purified by preparative
HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient
20:80.fwdarw.100:0). 18 mg (purity 88%, 36% of theor.) of the
target compound was obtained.
[1786] LC-MS (method 1): R.sub.t=1.09 min; MS (ESIpos): m/z=475
[M+H].sup.+
[1787] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.34 (s,
6H), 2.64 (t, 2H), 2.79 (t, 2H), 4.24-4.32 (m, 2H), 5.30 (s, 2H),
7.01 (t, 1H), 7.18-7.28 (m, 3H), 7.36-7.42 (m, 1H), 11.01 (s,
1H).
Example 20
2-[1-(2-Fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl]-5,5-dim-
ethyl-4-[(3,3,3-trifluoropropyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimi-
din-6-one
##STR00139##
[1789] 40 mg (0.07 mmol) of
2-[1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl]-4-iodo-
-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example
33A) was dissolved in 1 ml of absolute NMP and 334 mg (2.96 mmol)
of 3,3,3-trifluoropropan-1-amine was added. The mixture was heated
in the microwave for 2 h at 150.degree. C. and 1 h at 150.degree.
C. The reaction solution was filtered and purified by preparative
HPLC (eluent: acetonitrile/water with 0.1% hydrochloric acid,
gradient 20:80.fwdarw.100:0). 27 mg (purity 93%, 70% of theor.) of
the target compound was obtained.
[1790] LC-MS (method 1): R.sub.t=1.17 min; MS (ESIpos): m/z=489
[M+H].sup.+
[1791] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.32 (s,
6H), 2.57-2.67 (m, 4H), 2.80 (t, 2H), 3.68-3.73 (m, 2H), 5.32 (s,
2H), 6.85 (s br, 1H), 7.19-7.29 (m, 3H), 7.37-7.42 (m, 1H), 10.93
(s, 1H).
Example 21
4-(3-Ethyl-2-oxoimidazolidin-1-yl)-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b-
]pyridin-3-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00140##
[1793] Under argon atmosphere, 150 mg (purity 62%, 0.18 mmol) of
2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-
-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 15A) was
suspended in 2 ml of absolute acetonitrile and 413 mg (3.62 mmol)
of 1-ethylimidazolidin-2-one, 118 mg (0.36 mmol) of caesium
carbonate, 5 mg (0.04 mmol) of copper(I) oxide and 20 mg (0.15
mmol) of 2-hydroxybenzaldehyde-oxime were added. The mixture was
heated in the microwave for 1 h at 200.degree. C. The reaction
solution was filtered and purified by preparative HPLC (eluent:
acetonitrile/water, gradient 20:80.fwdarw.100:0). 35 mg (purity
91%, 35% of theor.) of the target compound was obtained.
[1794] LC-MS (method 1): R.sub.t=1.03 min; MS (ESIpos): m/z=501
[M+H].sup.+
[1795] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.13 (t,
3H), 1.41 (s, 6H), 3.28 (q, 2H), 3.57 (t, 2H), 3.97 (t, 2H), 5.87
(s, 2H), 7.12-7.25 (m, 3H), 7.34-7.38 (m, 1H), 7.44 (dd, 1H), 8.67
(dd, 1H), 8.83 (dd, 1H), 11.63 (s, 1H).
Example 22
2-[3-(2-Fluorobenzyl)-1H-indazol-1-yl]-4-hydroxy-5,5-dimethyl-5,7-dihydro--
6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00141##
[1797] The title compound was obtained as a side component in the
experiment for example 38A. Yield: 57 mg (9% of theor., 86%
purity)
[1798] LC-MS (method 1): R.sub.t=1.03 min; MS (ESIpos): m/z=404
[M+H].sup.+
[1799] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.33 (s,
6H), 4.42 (s, 2H), 7.13-7.23 (m, 2H), 7.28-7.44 (m, 3H), 7.57-7.61
(m, 1H), 7.73 (d, 1H), 3H cannot be ascribed definitely.
Example 23
4-(3,5-Dimethyl-1H-pyrazol-1-yl)-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]p-
yridin-3-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00142##
[1801] Under argon atmosphere, 150 mg (purity 62%, 0.18 mmol) of
2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-
-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 15A) was
suspended in 2 ml of absolute acetonitrile, and 26 mg (0.27 mmol)
of 3,5-dimethyl-1H-pyrazole, 118 mg (0.36 mmol) of caesium
carbonate, 5 mg (0.04 mmol) of copper(I) oxide and 20 mg (0.15
mmol) of 2-hydroxybenzaldehyde-oxime were added. The mixture was
heated in the microwave for 1 h at 150.degree. C. Then 346 mg (3.62
mmol) of 3,5-dimethyl-1H-pyrazole was added and the mixture was
heated in the microwave for 45 min at 200.degree. C. The reaction
solution was filtered and purified by preparative HPLC (eluent:
acetonitrile/water, gradient 20:80.fwdarw.100:0). 20 mg (23% of
theor.) of the target compound was obtained.
[1802] LC-MS (method 1): R.sub.t=1.23 min; MS (ESIpos): m/z=483
[M+H].sup.+
[1803] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.43 (s,
6H), 2.27 (s, 3H), 2.53 (s, 3H), 5.87 (s, 2H), 6.22 (s, 1H), 7.16
(t, 1H), 7.21-7.30 (m, 2H), 7.35-7.39 (m, 1H), 7.46 (dd, 1H), 8.69
(dd, 1H), 8.79 (dd, 1H), 11.76 (s, 1H).
Example 24
2-[1-(2-Fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-(3-fluoro-2-oxopyr-
idin-1(2H)-yl)-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00143##
[1805] Under argon atmosphere, 200 mg (purity 62%, 0.24 mmol) of
2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-
-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 15A) was
suspended in 2.5 ml of absolute acetonitrile, and 545 mg (4.82
mmol) of 3-fluoropyridin-2-ol, 157 mg (0.48 mmol) of caesium
carbonate, 7 mg (0.05 mmol) of copper(I) oxide and 20 mg (0.15
mmol) of 2-hydroxybenzaldehyde-oxime were added. The mixture was
heated in the microwave for 1 h at 200.degree. C. The reaction
solution was filtered and purified by preparative HPLC (eluent:
acetonitrile/water, gradient 20:80.fwdarw.100:0). 20 mg (23% of
theor.) of the target compound was obtained.
[1806] LC-MS (method 1): R.sub.t=1.11 min; MS (ESIpos): m/z=500
[M+H].sup.+
[1807] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.49 (s,
6H), 5.81 (s, 2H), 7.10-7.23 (m, 4H), 7.32-7.38 (m, 1H), 7.61-7.65
(m, 2H), 8.07-8.12 (m, 1H), 8.36 (dd, 1H), 8.59 (dd, 1H), 11.75 (s,
1H).
Example 25
2-[1-(2-Fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-4-[2-ox-
o-4-(trifluoromethyl)pyrrolidin-1-yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimid-
in-6-one
##STR00144##
[1809] Under argon atmosphere, 200 mg (purity 62%, 0.24 mmol) of
2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-
-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 15A) was
suspended in 2.5 ml of absolute acetonitrile, and 738 mg (4.82
mmol) of 4-(trifluoromethyl)pyrrolidin-2-one, 157 mg (0.48 mmol) of
caesium carbonate, 7 mg (0.05 mmol) of copper(I) oxide and 26 mg
(0.19 mmol) of 2-hydroxybenzaldehyde-oxime were added. The mixture
was heated in the microwave for 1 h at 200.degree. C. The reaction
solution was filtered and purified by preparative HPLC (eluent:
acetonitrile/water with 0.1% formic acid, gradient
20:80.fwdarw.100:0). 26 mg (19% of theor.) of the target compound
was obtained.
[1810] LC-MS (method 1): R.sub.t=1.02 min; MS (ESIpos): m/z=540
[M+H].sup.+
[1811] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.32 (s,
3H), 1.36 (s, 3H), 2.70 (dd, 1H), 3.08 (dd, 1H), 3.67-3.75 (m, 1H),
3.87 (dd, 1H), 4.32 (dd, 1H), 5.88 (s, 2H), 7.14 (t, 1H), 7.16-7.25
(m, 2H), 7.34-7.38 (m, 1H), 7.45 (dd, 1H), 8.69 (dd, 1H), 8.84 (dd,
1H), 11.83 (s, 1H).
Example 26
2-[1-(2-Fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-(4-hydroxy-1H-pyra-
zol-1-yl)-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00145##
[1813] Under an argon atmosphere, 150 mg (purity 62%, 0.18 mmol) of
2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-
-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 15A) was
suspended in 2 ml of absolute acetonitrile, and 304 mg (3.62 mmol)
of 1H-pyrazol-4-ol, 118 mg (0.36 mmol) of caesium carbonate, 5 mg
(0.04 mmol) of copper(I) oxide and 20 mg (0.15 mmol) of
2-hydroxybenzaldehyde-oxime were added. The mixture was heated in
the microwave for 1 h at 200.degree. C. The reaction solution was
filtered and purified by preparative HPLC (eluent:
acetonitrile/water with 0.1% formic acid, gradient
20:80.fwdarw.100:0). 20 mg (24% of theor.) of the target compound
was obtained.
[1814] LC-MS (method 1): R.sub.t=1.03 min; MS (ESIpos): m/z=471
[M+H].sup.+
[1815] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.59 (s,
6H), 5.89 (s, 2H), 7.15 (t, 1H), 7.22-7.25 (m, 2H), 7.35-7.39 (m,
1H), 7.51 (dd, 1H), 7.72 (s, 1H), 8.25 (s, 1H), 8.71 (dd, 1H), 8.87
(dd, 1H), 9.37 (s, 1H), 11.75 (s br, 1H).
[1816] In addition,
2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-4-(1H--
pyrazol-4-yloxy)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one was
obtained in this batch (see example 27).
Example 27
2-[1-(2-Fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-4-(1H-p-
yrazol-4-yloxy)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00146##
[1818] Formed during the preparation in example 26 (see example
26). 20 mg (23% of theor.) of the target compound was obtained.
[1819] LC-MS (method 1): R.sub.t=0.94 min; MS (ESIpos): m/z=471
[M+H].sup.+
[1820] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.45 (s,
6H), 5.83 (s, 2H), 7.14 (t, 1H), 7.19-7.25 (m, 3H), 7.33-7.38 (m,
1H), 7.67 (s br, 1H), 8.00 (s br, 1H), 8.22 (d, 1H), 8.62 (dd, 1H),
11.57 (s, 1H), 12.92 (s br, 1H).
Example 28
2-[1-(2-Fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-[3-(1-hydroxyethyl-
)-1H-pyrazol-1-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-o-
ne
##STR00147##
[1822] Under argon atmosphere, 150 mg (purity 62%, 0.18 mmol) of
2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-
-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 15A) was
suspended in 2 ml of absolute acetonitrile, and 405 mg (3.62 mmol)
of 1-(1H-pyrazol-3-yl)ethanol, 118 mg (0.36 mmol) of caesium
carbonate, 5 mg (0.04 mmol) of copper(I) oxide and 20 mg (0.15
mmol) of 2-hydroxybenzaldehyde-oxime were added. The mixture was
heated in the microwave for 1 h at 200.degree. C. The reaction
solution was filtered and purified by preparative HPLC (eluent:
acetonitrile/water with 0.1% formic acid, gradient
20:80.fwdarw.100:0). 20 mg (24% of theor.) of the target compound
was obtained.
[1823] LC-MS (method 1): R.sub.t=0.96 min; MS (ESIpos): m/z=499
[M+H].sup.+
[1824] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.38 (s,
3H), 1.40 (s, 3H), 1.86 (d, 3H), 5.66 (q, 1H), 5.84 (s, 2H), 6.20
(d, 1H), 7.13 (t, 1H), 7.20-7.38 (m, 3H), 7.41 (dd, 1H), 7.63 (s,
1H), 8.28 (d, 1H), 8.69 (dd, 1H), 12.63 (s br, 2H).
Example 29
2-[1-(2-Fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-4-[4-(t-
rifluoromethyl)-1H-pyrazol-1-yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6--
one
##STR00148##
[1826] Under argon atmosphere, 200 mg (purity 62%, 0.24 mmol) of
2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-
-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 15A) was
suspended in 2.5 ml of absolute acetonitrile, and 656 mg (4.82
mmol) of 4-(trifluoromethyl)-1H-pyrazole, 157 mg (0.48 mmol) of
caesium carbonate, 7 mg (0.05 mmol) of copper(I) oxide and 26 mg
(0.19 mmol) of 2-hydroxybenzaldehyde-oxime were added. The mixture
was heated in the microwave for 1 h at 200.degree. C. The reaction
solution was filtered and purified by preparative HPLC (eluent:
acetonitrile/water with 0.1% formic acid, gradient
20:80.fwdarw.100:0). 85 mg (63% of theor.) of the target compound
was obtained.
[1827] LC-MS (method 1): R.sub.t=1.33 min; MS (ESIpos): m/z=523
[M+H].sup.+
[1828] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.56 (s,
6H), 5.91 (s, 2H), 7.15 (t, 1H), 7.20-7.25 (m, 2H), 7.34-7.39 (m,
1H), 7.52 (dd, 1H), 8.51 (s, 1H), 8.71 (dd, 1H), 8.92 (dd, 1H),
9.30 (s, 1H), 11.99 (s, 1H).
Example 30
2-[1-(2-Fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-4-[3-(t-
rifluoromethyl)-1H-pyrazol-1-yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6--
one
##STR00149##
[1830] Under argon atmosphere, 200 mg (purity 62%, 0.24 mmol) of
2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-
-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 15A) was
suspended in 2.5 ml of absolute acetonitrile, and 656 mg (4.82
mmol) of 3-(trifluoromethyl)-1H-pyrazole, 157 mg (0.48 mmol) of
caesium carbonate, 7 mg (0.05 mmol) of copper(I) oxide and 26 mg
(0.19 mmol) of 2-hydroxybenzaldehyde-oxime were added. The mixture
was heated in the microwave for 1 h at 200.degree. C. The reaction
solution was filtered and purified by preparative HPLC (eluent:
acetonitrile/water with 0.1% formic acid, gradient
20:80.fwdarw.100:0). 41 mg (33% of theor.) of the target compound
was obtained.
[1831] LC-MS (method 1): R.sub.t=1.32 min; MS (ESIpos): m/z=523
[M+H].sup.+
[1832] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.55 (s,
6H), 5.90 (s, 2H), 7.15 (t, 1H), 7.21-7.25 (m, 3H), 7.35-7.39 (m,
1H), 7.50 (dd, 1H), 8.72 (dd, 1H), 8.93 (dd, 1H), 9.05 (s, 1H),
12.02 (s, 1H).
Example 31
2-[5-Fluoro-3-(2-fluorobenzyl)-1H-indazol-1-yl]-4-hydroxy-5,5-dimethyl-5,7-
-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00150##
[1834] The title compound was obtained as a side component in the
experiment for example 43A. Yield: 72 mg (14% of theor., 83%
purity).
[1835] LC-MS (method 1): R.sub.t=1.33 min; MS (ESIpos): m/z=422
[M+H].sup.+
[1836] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.33 (s,
6H), 4.40 (s, 2H), 7.14-7.23 (m, 2H), 7.27-7.34 (m, 1H), 7.42 (t,
1H), 7.49-7.58 (m, 2H), 8.75 (s br, 1H), 11.31 (s br, 1H), 12.37 (s
br, 1H).
Example 32
2-[1-(2-Fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-4-[2-(t-
rifluoromethyl)morpholin-4-yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-on-
e
##STR00151##
[1838] Under argon atmosphere, 200 mg (purity 62%, 0.24 mmol) of
2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-
-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 15A) was put
in 4 ml of absolute NMP, and 924 mg (4.82 mmol) of
2-(trifluoromethyl)morpholine and 623 mg (4.82 mmol) of
N,N-diisopropyl ethylamine were added. The mixture was heated in
the microwave at 150.degree. C. for 5 h. The reaction solution was
filtered and purified by preparative HPLC (eluent:
acetonitrile/water with 0.1% formic acid, gradient
20:80.fwdarw.100:0). 60 mg (46% of theor.) of the target compound
was obtained.
[1839] LC-MS (method 1): R.sub.t=1.16 min; MS (ESIpos): m/z=542
[M+H].sup.+
[1840] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.43 (s,
6H), 3.36-3.42 (m, 1H), 3.80 (dt, 1H), 4.13 (dd, 2H), 4.43-4.51 (m,
2H), 5.85 (s, 2H), 7.14 (t, 1H), 7.18-7.24 (m, 2H), 7.34-7.38 (m,
1H), 7.40 (dd, 1H), 8.66 (dd, 1H), 8.75 (dd, 1H), 11.41 (s,
1H).
Example 33
2-[1-(2-Fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-4-[3-(t-
rifluoromethyl)pyrrolidin-1-yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-o-
ne
##STR00152##
[1842] Under an argon atmosphere, 200 mg (purity 62%, 0.24 mmol) of
2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-
-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 15A) was put
in 4 ml of absolute NMP and 671 mg (4.82 mmol) of
3-(trifluoromethyl)pyrrolidine was added. The mixture was heated in
the microwave at 150.degree. C. for 5 h. The reaction solution was
filtered and purified by preparative HPLC (eluent:
acetonitrile/water with 0.1% formic acid, gradient
20:80.fwdarw.100:0). 65 mg (49% of theor.) of the target compound
was obtained.
[1843] LC-MS (method 1): R.sub.t=1.21 min; MS (ESIpos): m/z=526
[M+H].sup.+
[1844] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.42 (s,
3H), 1.43 (s, 3H), 2.15-2.23 (m, 1H), 2.32-2.41 (m, 1H), 3.38-3.48
(m, 1H), 3.79-3.94 (m, 3H), 4.07 (dd, 1H), 5.84 (s, 2H), 7.12-7.25
(m, 3H), 7.33-7.39 (m, 1H), 7.42 (dd, 1H), 8.65 (dd, 1H), 8.81 (dd,
1H), 11.29 (s, 1H).
Example 34
2-[5-Fluoro-3-(2-fluorobenzyl)-1H-indazol-1-yl]-5,5-dimethyl-4-(3,3,3-trif-
luoropropoxy)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00153##
[1846] Under argon, 80 mg (0.19 mmol) of the compound from example
31 was largely dissolved in 2 ml THF, 32.5 mg (0.29 mmol) of
3,3,3-trifluoropropan-1-ol, 75 mg (0.29 mmol) of triphenyl
phosphine and 56 .mu.l (0.29 mmol) of diisopropyl azodicarboxylate
were added and it was stirred for 3 d at RT. A further 11 mg (0.01
mmol) of 3,3,3-trifluoropropan-1-ol, 25 mg (0.01 mmol) of triphenyl
phosphine and 19 .mu.l (0.01 mmol) of diisopropyl azodicarboxylate
were added and it was stirred for 1d at RT. The reaction mixture
was concentrated by evaporation and the residue was purified by
preparative HPLC (Reprosil C18, gradient of acetonitrile/0.01% aq.
formic acid). Yield: 48 mg (49% of theor.)
[1847] LC-MS (method 1): R.sub.t=1.32 min; MS (ESIpos): m/z=518
[M+H].sup.+
[1848] .sup.1H-NMR (500 MHz, DMSO-d.sub.6): .delta. [ppm]=1.34 (s,
6H), 2.82-3.00 (m, 2H), 4.40 (s, 2H), 4.75 (t, 2H), 7.11-7.24 (m,
2H), 7.26-7.32 (m, 1H), 7.37-7.50 (m, 2H), 7.53-7.62 (m, 1H), 8.60
(dd, 1H), 11.53 (br s, 1H).
Example 35
2-[3-(2-Fluorobenzyl)-1H-indazol-1-yl]-5,5-dimethyl-4-[(3,3,3-trifluoropro-
pyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00154##
[1850] 60 mg (0.12 mmol) of the compound from example 38A was
dissolved in 1.2 ml NMP and after adding 0.3 ml of
3,3,3-trifluoropropylamine in a sealed microwave vessel, it was
heated in the microwave at 150.degree. C. for 3 h. The reaction
mixture was purified by preparative HPLC (Reprosil C18, gradient of
acetonitrile/0.01% aq. formic acid). Yield: 38 mg (65% of
theor.)
[1851] LC-MS (method 1): R.sub.t=1.26 min; MS (ESIpos): m/z=499
[M+H].sup.+
[1852] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.36 (s,
6H), 2.58-2.80 (m, 2H), 3.80 (q, 2H), 4.40 (s, 2H), 6.98 (t, 1H),
7.09-7.24 (m, 2H), 7.25-7.33 (m, 2H), 7.38 (t, 1H), 7.50 (t, 1H),
7.74 (d, 1H), 8.59 (d, 1H), 11.19 (s, 1H).
[1853] The compounds listed in Table 3 were prepared on the analogy
of example 35:
TABLE-US-00001 TABLE 3 Example No. Structure Educts; yield Analysis
36 ##STR00155## Example 38A, cyclopropyl- methylamine; 77% of
theor. LC-MS (method 1): R.sub.t = 1.27 min; MS (ESIpos): m/z = 457
[M + H].sup.+ .sup.1H-NMR (500 MHz, DMSO- d.sub.6): .delta. [ppm] =
0.29-0.36 (m, 2H), 0.39-0.48 (m, 2H), 1.15- 1.28 (m, 1H), 1.38 (s,
6H), 3.38-3.50 (m, 2H), 4.39 (s, 2H), 6.85-6.95 (m, 1H), 7.10- 7.22
(m, 2H), 7.23-7.33 (m, 2H), 7.34-7.41 (m, 1H), 7.50- 7.58 (m, 1H),
7.72 (dd, 1H), 8.67 (dd, 1H), 11.08 (s, 1H). 37 ##STR00156##
Example 43A, 3,3,3-trifluoro- propylamine, 82% of theor. LC-MS
(method 1): R.sub.1 = 1.27 min; MS (ESIpos): m/z = 517 [M +
H].sup.+ .sup.1H-NMR (500 MHz, DMSO- d.sub.6): .delta. [ppm] = 1.36
(s, 6H), 2.60-2.75 (m, 2H), 3.78 (q, 2H), 4.38 (s, 2H), 6.96 (t,
1H), 7.12-7.22 (m, 2H), 7.27- 7.44 (m, 3H), 7.54 (dd, 1H),
8.55-8.64 (m, 1H), 11.16 (s, 1H). 38 ##STR00157## Example 43A,
cyclopentyl- methylamine; 74% of theor. LC-MS (method 1): R.sub.t =
1.29 min; MS (ESIpos): m/z = 475 [M + H].sup.+ .sup.1H-NMR (500
MHz, DMSO- d.sub.6): .delta. [ppm] = 0.27-0.35 (m, 2H), 0.38-0.47
(m, 2H), 1.15- 1.27 (m, 1H), 3.43 (t, 2H), 4.38 (s, 2H), 6.87-6.97
(m, 1H), 7.10-7.23 (m, 2H), 7.26- 7.34 (m, 1H), 7.36-7.48 (m, 2H),
7.53 (d, 1H), 8.67 (dd, 1H), 11.09 (br s, 1H).
Example 39
2-[8-(2-Fluorobenzyl)imidazo[1,5-a]pyrimidin-6-yl]-5,5-dimethyl-4-[(3,3,3--
trifluoropropyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00158##
[1855] Under an argon atmosphere, 200 mg (purity 69%, 0.27 mmol) of
2-[8-(2-fluorobenzyl)imidazo[1,5-a]pyrimidin-6-yl]-4-iodo-5,5-dimethyl-5,-
7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 52A) was
suspended in 3.2 ml of absolute NMP and 607 mg (5.37 mmol) of
3,3,3-trifluoropropan-1-amine was added. The mixture was stirred
for 1.5 h at 150.degree. C. in the microwave. The reaction solution
was filtered and purified by preparative HPLC (eluent:
acetonitrile/water with 0.1% hydrochloric acid, gradient
20:80.fwdarw.100:0). 41 mg (31% of theor.) of the target compound
was obtained.
[1856] LC-MS (method 1): R.sub.t=1.09 min; MS (ESIpos): m/z=500
[M+H].sup.+
[1857] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.35 (s,
6H), 2.62-2.74 (m, 2H), 3.77 (q, 2H), 4.33 (s, 2H), 6.87 (t, 1H),
6.96 (dd. 1H), 7.07-7.17 (m, 2H), 7.22-7.27 (m, 1H), 7.32 (t, 1H),
8.34 (d, 1H), 9.83 (d, 1H), 11.10 (s, 1H).
Example 40
2-[1-(2-Fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-4-{[(1--
methyl-1H-pyrazol-5-yl)methyl]amino}-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidi-
n-6-one
##STR00159##
[1859] 111.1 mg (1.0 mmol) of
1-(1-methyl-1H-pyrazol-5-yl)methanamine was put in a vial of a
microwave reactor block and a solution of 51.4 mg (100 .mu.mol) of
2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-
-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 15A) in 0.6
ml of 1-methyl-2-pyrrolidinone was added. Then the reactor block
was sealed and was irradiated for 6 h with microwaves, in order to
reach and maintain a temperature of the mixture of 170.degree. C.
After cooling, it was purified by preparative LC-MS (method 6). The
product-containing fractions were concentrated by evaporation by
means of a centrifugal dryer under vacuum. The residue of the
individual fractions was in each case dissolved in 0.6 ml DMSO and
combined. Then the solvent was evaporated completely in the
centrifugal dryer. 32.7 mg (61% of theor.) of the target product
was obtained.
[1860] LC-MS (method 5): R.sub.t=1.07 min;
[1861] MS (ESIpos): m/z=498 [M+H].sup.+, purity: 93%
[1862] The compounds listed in Table 4 were prepared on the analogy
of example 40.
TABLE-US-00002 TABLE 4 Example Structure No. Yield (% of theor.)
Name Analytical data 41 ##STR00160## 2-[1-(2-fluorobenzyl)-1H-
pyrazolo[3,4-b]pyridin-3- yl]-5,5-dimethyl-4-{[(5- methylfuran-2-
yl)methyl]amino}-5,7- dihydro-6H-pyrrolo[2,3- d]pyrimidin-6-one
LC/MS (method 5): R.sub.t = 1.19 min MS (ESIpos): m/z = 498 [M +
H].sup.+ Purity: 94% 42 ##STR00161## 4-[(2-fluorobenzyl)amino]-
2-[1-(2-fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3-
yl]-5,5-dimethyl-5,7- dihydro-6H-pyrrolo[2,3- b]pyrimidin-6-one
LC/MS (method 5.): R.sub.t = 1.20 min MS (ESIpos): m/z = 512 [M +
H].sup.+ 43 ##STR00162## 4-[(cyclopropylmethyl) amino]-2-[1-(2-
fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3- yl]-5,5-dimethyl-5,7-
dihydro-6H-pyrrolo[2,3- d]pyrimidin-6-one LC/MS (method 5.):
R.sub.t = 1.19 min MS (ESIpos): m/z = 458 [M + H].sup.+ 44
##STR00163## N-[2-({2-[1-(2- fluorobenzyl)-1H-
pyrazolo[3,4-b]pyridin-3- yl]-5,5-dimethyl-6-oxo-6,7-
dihydro-5H-pyrrolo[2,3- d]pyrimidin-4- yl}amino)ethyl]acetamide
LC/MS (method 5.): R.sub.t = 0.99 min MS (ESIpos): m/z = 489 [M +
H].sup.+ 45 ##STR00164## 2-[1-(2-fluorobenzyl)-1H-
pyrazolo[3,4-b]pyridin-3- yl]-5,5-dimethyl-4- [(tetrahydrofuran-3-
ylmethyl)amino]-5,7- dihydro-6H-pyrrolo[2,3- d]pyrimidin-6-one
LC/MS (method 5.): R.sub.t = 1.11 min MS (ESIpos): m/z = 488 [M +
H].sup.+ 46 ##STR00165## 2-[1-(2-fluorobenzyl)-1H-
pyrazolo[3,4-b]pyridin-3- yl]-5,5-dimethyl-4- [(1S,4S)-2-oxa-5-
azabicyclo[2.2.1]hept-5- yl]-5,7-dihydro-6H-
pyrrolo[2,3-d]pyrimidin-6- one LC/MS (method 5.): R.sub.t = 1.10
min MS (ESIpos): m/z = 486 [M + H].sup.+ Purity: 92% 47
##STR00166## 2-[1-(2-fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3-
yl]-5,5-dimethyl-4-{[2- (1H-1,2,3-triazol-1- yl)ethyl]amino}-5,7-
dihydro-6H-pyrrolo[2,3- d]pyrimidin-6-one LC/MS (method 5.):
R.sub.t = 1.02 min MS (ESIpos): m/z = 499 [M + H].sup.+ Purity: 92%
48 ##STR00167## 2-[1-(2-fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3-
yl]-5,5-dimethyl-4-{[(1- methyl-1H-pyrazol-3- yl)methyl]amino}-5,7-
dihydro-6H-pyrrolo[2,3- d]pyrimidin-6-one LC/MS (method 5.):
R.sub.t = 1.05 min MS (ESIpos): m/z = 498 [M + H].sup.+ Purity: 76%
49 ##STR00168## 2-[1-(2-fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3-
yl]-5,5-dmethyl-4- (tetrahydrofuran-3- ylamino)-5,7-dihydro-6H-
pyrrolo[2,3-d]pyrimidin-6- one LC/MS (method 5.): R.sub.t = 0.79
min MS (ESIpos): m/z = 474 [M + H].sup.+ 50 ##STR00169##
4-[(1,5-dimethyl-1H- pyrazol-3-yl)amino]-2-[1- (2-fluorobenzyl)-1H-
pyrazolo[3,4-b]pyridin-3- yl]-5,5-dimethyl-5,7-
dihydro-6H-pyrrolo[2,3- d]pyrimidin-6-one LC/MS (method 5.):
R.sub.t = 1.08 min MS (ESIpos): m/z = 498 [M + H].sup.+ Purity: 95%
51 ##STR00170## 2-[1-(2-fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3-
yl]-5,5-dimethyl-4- (tetrahydro-2H-pyran-3-
ylamino)-5,7-dihydro-6H- pyrrolo[2,3-d]pyrimidin-6- one LC/MS
(method 5.): R.sub.t = 1.14 min MS (ESIpos): m/z = 488 [M +
H].sup.+ Purity: 95% 52 ##STR00171## 2-[1-(2-fluorobenzyl)-1H-
pyrazolo[3,4-b]pyridin-3- yl]-4-(4-hydroxypiperidin-
1-yl)-5,5-dimethyl-5,7- dihydro-6H-pyrrolo[2,3- d]pyrimidin-6-one
LC/MS (method 5.): R.sub.t = 1.04 min MS (ESIpos): m/z = 488 [M +
H].sup.+ 53 ##STR00172## 2-[1-(2-fluorobenzyl)-1H-
pyrazolo[3,4-b]pyridin-3- yl]-4-(3-methoxyazetidin-
1-yl)-5,5-dimethyl-5,7- dihydro-6H-pyrrolo[2,3- d]pyrimidin-6-one
LC/MS (method 5.): R.sub.t = 0.82 min MS (ESIpos): m/z = 474 [M +
H].sup.+ Purity: 83% 54 ##STR00173## 2-[1-(2-fluorobenzyl)-1H-
pyrazolo[3,4-b]pyridin-3- yl]-5,5-dimethyl-4- (piperidin-1-yl)-5,7-
dihydro-6H-pyrrolo[2,3- d]pyrimidin-6-one LC/MS (method 5.):
R.sub.t = 1.26 min MS (ESIpos): m/z = 472 [M + H].sup.+ Purity: 95%
55 ##STR00174## 2-[1-(2-fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3-
yl]-5,5-dimethyl-4- [(pyridin-2- ylmethyl)amino]-5,7-
dihydro-6H-pyrrolo[2,3- d]pyrimidin-6-one LC/MS (method 5.):
R.sub.t = 0.95 min MS (ESIpos): m/z = 495 [M + H].sup.+ Purity: 91%
56 ##STR00175## 2-[1-(2-fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3-
yl]-4-[(2- methoxyethyl)amino]-5,5- dimethyl-5,7-dihydro-6H-
pyrrolo[2,3-d]pyrimidin-6- one LC/MS (method 5.): R.sub.t = 1.09
min MS (ESIpos): m/z = 462 [M + H].sup.+ Purity: 94% 57
##STR00176## 2-[1-(2-fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3-
yl]-4-[(2- hydroxypropyl)amino]-5,5- dimethyl-5,7-dihydro-6H-
pyrrolo[2,3-d]pyrimidin-6- one LC/MS (method 5.): R.sub.t = 1.01
min MS (ESIpos): m/z = 461 [M + H].sup.+ Purity: 95% 58
##STR00177## 2-[1-(2-fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3-
yl]-5,5-dimethyl-4-{[2- (1H-pyrazol-1- yl)ethyl]amino}-5,7-
dihydro-6H-pyrrolo[2,3- d]pyrimidin-6-one LC/MS (method 5.):
R.sub.t = 1.08 min MS (ESIpos): m/z = 498 [M + H].sup.+ 59
##STR00178## 2-[1-(2-fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3-
yl]-5,5-dimethyl-4-{[(1- methyl-1H-pyrazol-4- yl)methyl]amino}-5,7-
dihydro-6H-pyrrolo[2,3- d]pyrimidin-6-one LC/MS (method 5.):
R.sub.t = 1.074 min MS (ESIpos): m/z = 498 [M + H].sup.+ 60
##STR00179## 2-[1-(2-fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3-
yl]-5,5-dimethyl-4-{[(1- methyl-1H-imidazol-2-
yl)methyl]amino}-5,7- dihydro-6H-pyrrolo[2,3- d]pyrimidin-6-one
LC/MS (method 5.): R.sub.t = 0.79 min MS (ESIpos): m/z = 498 [M +
H].sup.+ 61 ##STR00180## 4-[ethyl(2- methoxyethyl)amino]-2-[1-
(2-fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3-
yl]-5,5-dimethyl-5,7- dihydro-6H-pyrrolo[2,3- d]pyrimidin-6-one
LC/MS (method 5.): R.sub.t = 1.19 min MS (ESIpos): m/z = 490 [M +
H].sup.+ 62 ##STR00181## 2-[1-(2-fluorobenzyl)-1H-
pyrazolo[3,4-b]pyridin-3- yl]-5,5-dimethyl-4-(2-
methyl-1H-imidazol-1-yl)- 5,7-dihydro-6H-
pyrrolo[2,3-d]pyrimidin-6- one LC/MS (method 5.): R.sub.t = 0.83
min MS (ESIpos): m/z = 469 [M + H].sup.+ 63 ##STR00182##
2-[1-(2-fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3-
yl]-5,5-dimethyl-4-[(3- methylbutyl)amino]-5,7-
dihydro-6H-pyrrolo[2,3- d]pyrimidin-6-one LC/MS (method 5.):
R.sub.t = 1.25 min MS (ESIpos): m/z = 474 [M + H].sup.+ 64
##STR00183## 2-[1-(2-fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3-
yl]-5,5-dimethyl-4- (pyrrolidin-1-yl)-5,7- dihydro-6H-pyrrolo[2,3-
d]pyrimidin-6-one LC/MS (method 5.): R.sub.t = 1.32 min MS
(ESIpos): m/z = 458 [M + H].sup.+ 65 ##STR00184##
2-[1-(2-fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3-
yl]-5,5-dimethyl-4- (pyridin-3-ylamino)-5,7-
dihydro-6H-pyrrolo[2,3- d]pyrimidin-6-one LC/MS (method 5.):
R.sub.t = 0.78 min MS (ESIpos): m/z = 481 [M + H].sup.+ 66
##STR00185## 2-[1-(2-fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3-
yl]-5,5-dimethyl-4-{[(5- oxopyrrolidin-3- yl)methyl]amino}-5,7-
dihydro-6H-pyrrolo[2,3- d]pyrimidin-6-one LC/MS (method 5.):
R.sub.t = 0.98 min MS (ESIpos): m/z = 501 [M + H].sup.+ Purity: 91%
67 ##STR00186## 2-[1-(2-fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3-
yl]-5,5-dimethyl-4-{[(3- methyloxetan-3- yl)methyl]amino}-5,7-
dihydro-6H-pyrrolo[2,3- d]pyrimidin-6-one LC/MS (method 5.):
R.sub.t = 1.07 min MS (ESIpos): m/z = 488 [M + H].sup.+ Purity: 87%
68 ##STR00187## 4-(4,4-dimethylpiperidin-1-
yl)-2-[1-(2-fluorobenzyl)- 1H-pyrazolo[3,4-b]pyridin-
3-yl]-5,5-dimethyl-5,7- dihydro-6H-pyrrolo[2,3- d]pyrimidin-6-one
LC/MS (method 5.): R.sub.t = 1.31 min MS (ESIpos): m/z = 500 [M +
H].sup.+ Purity: 93% 69 ##STR00188## 2-[1-(2-fluorobenzyl)-1H-
pyrazolo[3,4-b]pyridin-3- yl]-5,5-dimethyl-4-
(pyridin-4-ylamino)-5,7- dihydro-6H-pyrrolo[2,3- d]pyrimidin-6-one
LC/MS (method 5.): R.sub.t = 0.79 min MS (ESIpos): m/z = 481 [M +
H].sup.+ Purity: 90% 70 ##STR00189## 2-[1-(2-fluorobenzyl)-1H-
pyrazolo[3,4-b]pyridin-3- yl]-5,5-dimethyl-4-(4-
methylpiperazin-1-yl)-5,7- dihydro-6H-pyrrolo[2,3-
d]pyrimidin-6-one LC/MS (method 5.): R.sub.t = 0.75 min MS
(ESIpos): m/z = 487 [M + H].sup.+ 71 ##STR00190##
4-[(3-ethoxypropyl)amino]- 2-[1-(2-fluorobenzyl)-1H-
pyrazolo[3,4-b]pyridin-3- yl]-5,5-dimethyl-5,7-
dihydro-6H-pyrrolo[2,3- d]pyrimidin-6-one LC/MS (method 5.):
R.sub.t = 1.17 min MS (ESIpos): m/z = 490 [M + H].sup.+ 72
##STR00191## 2-[1-(2-fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3-
yl]-5,5-dimethyl-4- (morpholin-4-yl)-5,7- dihydro-6H-pyrrolo[2,3-
d]pyrimidin-6-one LC/MS (method 5.): R.sub.t = 1.13 min MS
(ESIpos): m/z = 474 [M + H].sup.+ 73 ##STR00192##
N.sup.3-[2-[1-(2-fluorobenzyl)- 1H-pyrazolo[3,4-b]pyridin-
3-yl]-5,5-dimethyl-6-oxo- 6,7-dihydro-5H-
pyrrolo[2,3-d]pyrimidin-4- yl}-beta-alaninamide LC/MS (method 5.):
R.sub.t = 0.94 min MS (ESIpos): m/z = 475 [M + H].sup.+ 74
##STR00193## 2-{1-(2-fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3-
yl]-4-[(3- methoxypropyl)amino]-5,5- dimethyl-5,7-dihydro-6H-
pyrrolo[2,3-d]pyrimidin-6- one LC/MS (method 5.): R.sub.t = 1.14
min MS (ESIpos): m/z = 476 [M + H].sup.+ 75 ##STR00194##
2-[1-(2-fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3- yl]-4-[(2-
methoxyethyl)(methyl) amino]-5,5-dimethyl-5,7-
dihydro-6H-pyrrolo[2,3- d]pyrimidin-6-one LC/MS (method 5.):
R.sub.t = 1.15 min MS (ESIpos): m/z = 476 [M + H].sup.+ 76
##STR00195## 4-(3,3-difluoropyrrolidin-1-
yl)-2-[1-(2-fluorobenzyl)- 1H-pyrazolo[3,4-b]pyridin-
3-yl]-5,5-dimethyl-5,7- dihydro-6H-pyrrolo[2,3- d]pyrimidin-6-one
LC/MS (method 5.): R.sub.t = 1.19 min MS (ESIpos): m/z = 494 [M +
H].sup.+ 77 ##STR00196## 4-[(4-fluorobenzyl)amino]-
2-[1-(2-fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3-
yl]-5,5-dimethyl-5,7- dihydro-6H-pyrrolo[2,3- d]pyrimidin-6-one
LC/MS (method 5.): R.sub.t = 1.19 min MS (ESIpos): m/z = 512 [M +
H].sup.+ 78 ##STR00197## 4-[(3-fluorobenzyl)amino]-
2-[1-(2-fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3-
yl]-5,5-dimethyl-5,7- dihydro-6H-pyrrolo[2,3- d]pyrimidin-6-one
LC/MS (method 5.): R.sub.t = 1.20 min MS (ESIpos): m/z = 512 [M +
H].sup.+ 79 ##STR00198## N.sub.2-{2-[1-(2-fluorobenzyl)-
1H-pyrazolo[3,4-b]pyridin- 3-yl]-5,5-dimethyl-6-oxo-
6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-4- yl}-L-alaninamide LC/MS
(method 5.): R.sub.t = 0.96 min MS (ESIpos): m/z = 475 [M +
H].sup.+ Purity: 94% 80 ##STR00199## 4-[(cyclopentylmethyl)
amino]-2-[1-(2- fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3-
yl]-5,5-dimethyl-5,7- dihydro-6H-pyrrolo[2,3- d]pyrimidin-6-one
LC/MS (method 5.): R.sub.t = 1.27 min MS (ESIpos): m/z = 486 [M +
H].sup.+ 81 ##STR00200## 2-[1-(2-fluorobenzyl)-1H-
pyrazolo[3,4-b]pyridin-3- yl]-5,5-dimethyl-4-[(2-
oxopiperidin-3-yl)amino]- 5,7-dihydro-6H-
pyrrolo[2,3-d]pyrimidin-6- one LC/MS (method 5.): R.sub.t = 1.01
min MS (ESIpos): m/z = 501 [M + H].sup.+ Purity: 92% 82
##STR00201## 2-[1-(2-fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3-
yl]-5,5-dimethyl-4-(3- oxopiperazin-1-yl)-5,7-
dihydro-6H-pyrrolo[2,3- d]pyrimidin-6-one LC/MS (method 5.):
R.sub.t = 0.98 min MS (ESIpos): m/z = 487 [M + H].sup.+ 83
##STR00202## 4-(benzylamino)-2-[1-(2- fluorobenzyl)-1H-
pyrazolo[3,4-b]pyridin-3- yl]-5,5-dimethyl-5,7-
dihydro-6H-pyrrolo[2,3- d]pyrimidin-6-one LC/MS (method 5.):
R.sub.t = 1.20 min MS (ESIpos): m/z = 494 [M + H].sup.+ 84
##STR00203## 2-[1-(2-fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3-
yl]-5,5-dimethyl-4- [(pyridin-3- ylmethyl)amino]-5,7-
dihydro-6H-pyrrolo[2,3- d]pyrimidin-6-one LC/MS (method 5.):
R.sub.t = 0.91 min MS (ESIpos): m/z = 495 [M + H].sup.+ 85
##STR00204## 2-[1-(2-fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3-
yl]-5,5-dimethyl-4- [(pyridin-4- ylmethyl)amino]-5,7-
dihydro-6H-pyrrolo[2,3- d]pyrimidin-6-one LC/MS (method 5.):
R.sub.t = 0.87 min MS (ESIpos): m/z = 495 [M + H].sup.+ 86
##STR00205## 2-[1-(2-fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3-
yl]-5,5-dimethyl-4- [(tetrahydrofuran-2- ylmethyl)amino]-5,7-
dihydro-6H-pyrrolo[2,3- d]pyrimidin-6-one LC/MS (method 5.):
R.sub.t = 1.12 min MS (ESIpos): m/z = 488 [M + H].sup.+ 87
##STR00206## 2-[1-(2-fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3-
yl]-5,5-dimethyl-4- (phenylamino)-5,7- dihydro-6H-pyrrolo[2,3-
d]pyrimidin-6-one LC/MS (method 5.): R.sub.t = 1.21 min MS
(ESIpos): m/z = 480 [M + H].sup.+
Example 88
4-{[(1R)-1-Cyclopropylethyl]amino}-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyraz-
olo[3,4-b]pyridin-3-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidi-
n-6-one
##STR00207##
[1864] 150 mg (0.186 mmol, approx. 66% purity) of example 16A was
dissolved in 1-methyl-2-pyrrolidone (3.5 ml) in a reaction vessel
suitable for a microwave, and 0.5 ml of (R)-1-cyclopropylethylamine
was added. Then it was sealed with a corresponding septum and it
was heated in the microwave at 150.degree. C. for 3 h. After
cooling, the reaction mixture was purified by preparative HPLC
(acetonitrile:water:water+1% trifluoroacetic acid--(70:24:6). 54 mg
of the title compound was obtained (59% of theor.).
[1865] LC-MS (method 1): R.sub.t=1.29 min; MS (EIpos): m/z=490
[M+H].sup.+.
[1866] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.19-0.25
(m, 1H), 0.35-0.41 (m, 2H), 0.48-0.53 (m, 1H), 1.13-1.21 (m, 1H),
1.35 (d, 3H), 1.39 (2s, 6H), 4.00-4.06 (m, 1H), 5.82 (s, 2H), 6.29
(d, 1H), 7.12-7.16 (m, 1H), 7.19-7.24 (m, 2H), 7.33-7.39 (m, 1H),
8.42 (dd, 1H), 8.71 (dd, 1H), 10.99 (s, 1H).
Example 89
4-{[(1S)-1-Cyclopropylethyl]amino}-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyraz-
olo[3,4-b]pyridin-3-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidi-
n-6-one
##STR00208##
[1868] 150 mg (0.186 mmol, approx. 66% purity) of example 16A was
dissolved in 1-methyl-2-pyrrolidone (3.5 ml) in a reaction vessel
suitable for a microwave and 0.5 ml of (S)-1-cyclopropylethylamine
was added. Then it was sealed with a corresponding septum and it
was heated in the microwave at 150.degree. C. for 3 h. After
cooling, the reaction mixture was purified by preparative HPLC
(acetonitrile:water:water+1% trifluoroacetic acid (70:24:6). 69 mg
of the title compound was obtained (75% of theor.).
[1869] LC-MS (method 1): R.sub.t=1.29 min; MS (EIpos): m/z=490
[M+H].sup.+.
[1870] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.19-0.25
(m, 1H), 0.35-0.41 (m, 2H), 0.48-0.53 (m, 1H), 1.13-1.21 (m, 1H),
1.35 (d, 3H), 1.39 (2s, 6H), 4.00-4.06 (m, 1H), 5.82 (s, 2H), 6.29
(d, 1H), 7.12-7.16 (m, 1H), 7.19-7.24 (m, 2H), 7.33-7.39 (m, 1H),
8.42 (dd, 1H), 8.71 (dd, 1H), 10.99 (s, 1H).
Example 90
2-[5-Fluoro-1-(2-fluorobenzyl)-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,-
5-dimethyl-4-[(3,3,3-trifluoropropyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-d]p-
yrimidin-6-one
##STR00209##
[1872] 150 mg (0.231 mmol, approx. 84% purity) of example 53A was
dissolved in 1-methyl-2-pyrrolidone (3 ml) in a reaction vessel
suitable for a microwave and 1 ml of 3,3,3-trifluoropropyl-1-amine
was added. Then it was sealed with a corresponding septum and it
was heated in the microwave at 150.degree. C. for 3 h. After
cooling, the reaction mixture was purified by preparative HPLC
(acetonitrile:water (+0.05% formic acid) gradient). 89 mg of the
title compound was obtained (73% of theor.).
[1873] LC-MS (method 1): R.sub.t=1.27 min; MS (EIpos):
m/z=532[M+H].sup.+.
[1874] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.35 (s,
6H), 2.62 (d, 3H), 2.64-2.73 (m, 2H), 3.81 (q, 2H), 5.78 (s, 2H),
6.84 (t, 1H), 7.12-7.25 (m, 3H), 7.33-7.39 (m, 1H), 8.36 (d, 1H),
11.05 (s br, 1H).
Example 91
2-[1-(2-Fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-4-[2-ox-
o-5-(trifluoromethyl)piperidin-1-yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidi-
n-6-one
##STR00210##
[1876] Under argon atmosphere, 200 mg (purity 62%, 0.24 mmol) of
2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-
-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 15A) was
suspended in 2.5 ml of absolute acetonitrile, and 806 mg (4.82
mmol) of 5-(trifluoromethyl)piperidin-2-one, 157 mg (0.48 mmol) of
caesium carbonate, 7 mg (0.05 mmol) of copper(I) oxide and 26 mg
(0.19 mmol) of 2-hydroxybenzaldehyde-oxime were added. The mixture
was heated in the microwave for 1 h at 200.degree. C. The reaction
solution was filtered and purified by preparative HPLC (eluent:
acetonitrile/water, gradient 20:80.fwdarw.100:0). 15 mg (11% of
theor.) of the target compound was obtained.
[1877] LC-MS (method 1): R.sub.t=1.07 min; MS (ESIpos): m/z=554
[M+H].sup.+
[1878] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.31 (d,
6H), 1.41 (s, 6H), 2.05-2.24 (m, 2H), 2.59-2.78 (m, 3H), 3.76-3.87
(m, 2H), 5.89 (s, 2H), 7.12-7.18 (m, 2H), 7.23 (t, 1H), 7.33-7.38
(m, 1H), 7.46 (dd, 1H), 8.69 (d, 1H), 8.87 (d, 1H), 11.82 (s,
1H).
Example 92
2-[1-(2-Fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-4-(2-me-
thyl-3-oxopiperazin-1-yl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00211##
[1880] Under argon atmosphere, 200 mg (purity 62%, 0.24 mmol) of
2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-
-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 15A) was
suspended in 4 ml of absolute 1-methyl-2-pyrrolidone and 550 mg
(4.82 mmol) of 3-methylpiperazin-2-one was added. The mixture was
heated in the microwave for 3 h at 150.degree. C. and for 3 h at
220.degree. C. After cooling, the reaction mixture was purified by
preparative HPLC (eluent: acetonitrile/water, gradient
20:80.fwdarw.100:0). 61 mg (purity 100%, 50% of theor.) of the
target compound was obtained.
[1881] LC-MS (method 8): R.sub.t=2.55 min; MS (ESIpos): m/z=501
[M+H].sup.+
[1882] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.42-1.45
(m, 9H), 3.54-3.61 (m, 1H), 4.13-4.18 (m, 1H), 4.97 (q, 1H), 5.86
(s, 2H), 7.12-7.25 (m, 3H), 7.33-7.39 (m, 1H), 7.45 (dd, 1H), 8.09
(s, 1H), 8.67 (dd, 1H), 8.76 (dd, 1H), 11.40 (s br, 1H).
Example 93
4-(1,1-Dioxidothiomorpholin-4-yl)-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]-
pyridin-3-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00212##
[1884] Under argon atmosphere, 200 mg (purity 62%, 0.24 mmol) of
2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-
-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 15A) was
suspended in 4 ml of absolute 1-methyl-2-pyrrolidone and 652 mg
(4.82 mmol) of thiomorpholine-1,1-dioxide was added. The mixture
was heated in the microwave for 3 h at 150.degree. C. and 1 h at
200.degree. C. After cooling, the reaction mixture was purified by
preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid,
gradient 20:80.fwdarw.100:0). 72 mg (57% of theor.) of the target
compound was obtained.
[1885] LC-MS (method 1): R.sub.t=0.96 min; MS (ESIpos): m/z=522
[M+H].sup.+
[1886] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.43 (s,
6H), 3.36-3.39 (m, 4H), 4.14-4.17 (m, 4H), 5.85 (s, 2H), 7.11-7.25
(m, 3H), 7.33-7.39 (m, 1H), 7.44 (dd, 1H), 8.66-8.71 (m, 2H), 11.45
(s, 1H).
Example 94
N-(1-{2-[1-(2-Fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-6-
-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}pyrrolidin-3-yl)acetamide
##STR00213##
[1888] Under argon atmosphere, 200 mg (purity 62%, 0.24 mmol) of
2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-
-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 15A) was
suspended in 4 ml of absolute 1-methyl-2-pyrrolidone and 618 mg
(4.82 mmol) of N-(pyrrolidin-3-yl)acetamide was added. The mixture
was heated in the microwave at 150.degree. C. for 3 h. After
cooling, the reaction mixture was purified by preparative HPLC
(eluent: acetonitrile/water with 0.1% formic acid, gradient
20:80.fwdarw.100:0). 122 mg (98% of theor.) of the target compound
was obtained.
[1889] LC-MS (method 1): R.sub.t=0.91 min; MS (ESIpos): m/z=515
[M+H].sup.+
[1890] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.42 (s,
6H), 1.83 (s, 3H), 1.90-2.01 (m, 1H), 2.17-2.25 (m, 1H), 3.65 (dd,
1H), 3.81-3.97 (m, 3H), 4.33-4.40 (m, 1H), 5.84 (s, 2H), 7.12-7.25
(m, 3H), 7.32-7.40 (m, 1H), 7.43 (dd, 1H), 8.22 (d, 1H), 8.65 (dd,
1H), 8.86 (dd, 1H), 11.21 (s, 1H).
Example 95
2-[1-(2-Fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-[(trans-4-hydroxyc-
yclohexyl)amino]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00214##
[1892] Under argon atmosphere, 200 mg (purity 62%, 0.24 mmol) of
2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-
-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 15A) was
suspended in 4 ml of absolute 1-methyl-2-pyrrolidone and 555 mg
(4.82 mmol) of trans-4-aminocyclohexanol was added. The mixture was
heated in the microwave at 150.degree. C. for 3 h. After cooling,
the reaction mixture was purified by preparative HPLC (eluent:
acetonitrile/water with 0.1% formic acid, gradient
20:80.fwdarw.100:0). 91 mg (73% of theor.) of the target compound
was obtained.
[1893] LC-MS (method 1): R.sub.t=0.92 min; MS (ESIpos): m/z=502
[M+H].sup.+
[1894] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.31-1.41
(m, 2H), 1.36 (s, 6H), 1.49-1.58 (m, 2H), 1.91-1.98 (m, 4H),
3.42-3.51 (m, 1H), 4.12-4.22 (m, 1H), 4.61 (d, 1H), 5.83 (s, 2H),
6.15 (d, 1H), 7.12-7.25 (m, 3H), 7.33-7.38 (m, 1H), 7.41 (dd, 1H),
8.66 (dd, 1H), 8.80 (dd, 1H), 11.21 (s, 1H).
Example 96
2-[5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethy-
l-4-[(3,3,3-trifluoro-2-hydroxypropyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-d]-
pyrimidin-6-one
##STR00215##
[1896] 300 mg (0.372 mmol, purity 66%) of example 16A was dissolved
in 1-methyl-2-pyrrolidone (5 ml) in a reaction vessel suitable for
a microwave and 300 mg (2.324 mmol) of
3-amino-1,1,1-trifluoro-2-propanol was added. Then it was sealed
with a corresponding septum and heated twice in the microwave at
150.degree. C. for 3 h. After cooling, the reaction mixture was
purified by preparative HPLC (acetonitrile:water (+0.05% formic
acid) gradient). 164 mg of the title compound was obtained (83% of
theor.)
[1897] LC-MS (method 1): R.sub.t=1.12 min; MS (EIpos): m/z=534
[M+H].sup.+.
[1898] Separation into Enantiomers:
[1899] 164 mg of the racemate obtained was separated into the
enantiomers by preparative HPLC (solvent: ((iso-hexane:ethanol+0.2%
trifluoroacetic acid+1% water) 80/20), wavelength: 210 nM on chiral
phase (Daicel Chiralpak OZ-H(HPLC), 5 .mu.M 250.times.20 mm)
[1900] Example 96-1 (Enantiomer 1)
[1901] Yield: 42 mg
[1902] ee=99% (analytical HPLC: (solvent: (iso-hexane:ethanol
80/20)+0.2% trifluoroacetic acid+1% water on chiral phase
(Chiralcel OZ-H, 5 .mu.M 250*4.6 mm)
[1903] R.sub.t=5.004 min
[1904] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.36 (s,
3H), 1.37 (s, 3H), 3.61-3.68 (m, 1H), 3.91-3.97 (m, 1H), 4.32-4.42
(m, 1H), 5.82 (s, 2H), 6.56 (d, 1H), 6.90 (t, 1H), 7.13-7.26 (m,
3H), 7.34-7.39 (m, 1H), 8.53 (dd, 1H), 8.71 (dd, 1H), 11.05 (br s,
1H).
Example 96-2
Enantiomer 2
[1905] Yield: 31 mg
[1906] ee=96% (analytical HPLC: (solvent: (iso-hexane:ethanol
80/20)+0.2% trifluoroacetic acid+1% water on chiral phase
(Chiralcel OZ-H, 5 .mu.M 250*4.6 mm)
[1907] R.sub.t=5.044 min
Example 97
4-{[(2,2-Difluorocyclopropyl)methyl]amino}-2-[5-fluoro-1-(2-fluorobenzyl)--
1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]-
pyrimidin-6-one
##STR00216##
[1909] 100 mg (0.115 mmol, purity 61%) of example 16A was dissolved
in 1-methyl-2-pyrrolidone (3 ml) in a reaction vessel suitable for
a microwave and 164 mg (1.146 mmol) of
2,2-difluorocyclopropylmethylamine hydrochloride and 0.24 ml (1.375
mmol) of N,N-diisopropyl ethylamine were added. Then the reaction
vessel was sealed with a septum and was heated in the microwave at
150.degree. C. for 12 h. After cooling, the reaction mixture was
purified by preparative HPLC (acetonitrile:water (+0.05% formic
acid) gradient). 21 mg of the title compound was obtained (35% of
theor.).
[1910] LC-MS (method 1): R.sub.t=1.20 min; MS (EIpos): m/z=512
[M+H].sup.+.
[1911] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.37 (s,
6H), 1.42-1.50 (m, 1H), 1.53-1.61 (m, 1H), 2.12-2.22 (m, 1H),
3.57-3.63 (m, 1H), 3.73-3.79 (m, 1H), 5.83 (s, 2H), 6.98 (t, 1H),
7.13-7.17 (m, 1H), 7.20-7.26 (m, 2H), 7.34-7.39 (m, 1H), 8.51 (dd,
1H), 8.72 (dd, 1H), 11.06 (s, 1H).
Example 98
2-[5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-{[(1-hydr-
oxycyclopropyl)methyl]amino}-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyr-
imidin-6-one
##STR00217##
[1913] 200 mg (0.376 mmol) of example 16A was dissolved in
1-methyl-2-pyrrolidone (3 ml) in a reaction vessel suitable for a
microwave and 98 mg (1.127 mmol) of 1-(aminomethyl)-cyclopropanol
was added. Then the reaction vessel was sealed with a septum and
heated in the microwave at 150.degree. C. for 12 h. After cooling,
the reaction mixture was purified by preparative HPLC
(acetonitrile:water (+0.05% formic acid) gradient). 56 mg of the
title compound was obtained (31% of theor.).
[1914] LC-MS (method 1) R.sub.t=1.07 min; MS (EIpos): m/z=492
[M+H].sup.+.
[1915] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.56-0.63
(m, 4H), 1.37 (s, 6H), 3.77-3.79 (m, 2H), 5.54 (s, 1H), 5.82 (s,
2H), 6.58 (m, 1H), 7.12-7.16 (m, 1H), 7.20-7.25 (m, 2H), 7.34-7.39
(m, 1H), 8.60 (dd, 1H), 8.71 (dd, 1H), 11.02 (s, 1H).
Example 99
4-{[(2,2-Dimethylcyclopropyl)methyl]amino}-2-[5-fluoro-1-(2-fluorobenzyl)--
1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]-
pyrimidin-6-one
##STR00218##
[1917] 200 mg (0.376 mmol) of example 16A was dissolved in a
reaction vessel suitable for a microwave in 1-methyl-2-pyrrolidone
(3 ml) and 254 mg (1.879 mmol) of
1-(2,2-dimethylcyclopropyl)methanamine hydrochloride and 0.393 ml
(2.254 mmol) of N,N-diisopropyl ethylamine were added. Then it was
sealed with a corresponding septum and it was heated in the
microwave at 150.degree. C. for 3 h. After cooling, the reaction
mixture was purified by preparative HPLC (acetonitrile:water
(+0.05% formic acid) gradient). 64 mg of the title compound was
obtained (33% of theor.).
[1918] LC-MS (method 1) R.sub.t=1.38 min; MS (EIpos): m/z=504
[M+H].sup.+.
[1919] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.24 (dd,
1H), 0.43 (dd, 1H), 1.02 (s, 3H), 1.08-1.15 (m, 1H), 1.17 (s, 3H),
1.37 (s, 6H), 3.30-3.41 (m, 1H), 3.70-3.76 (m, 1H), 5.82 (s, 2H),
6.81 (t, 1H), 7.13-7.17 (m, 1H), 7.20-7.26 (m, 2H), 7.34-7.39 (m,
1H), 8.58 (dd, 1H), 8.72 (dd, 1H), 11.01 (s, 1H).
Example 100
[1920]
2'-[5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4'--
[(3,3,3-trifluoropropyl)amino]-4,5-dihydrospiro[furan-3,5'-pyrrolo[2,3-d]p-
yrimidin]-6'(7'H)-one
##STR00219##
[1921] 84 mg (0.150 mmol) of example 58A was dissolved in
1-methyl-2-pyrrolidone (3 ml) in a reaction vessel suitable for a
microwave and 112 mg (0.750 mmol) of 3,3,3-trifluoropropyl-1-amine
hydrochloride and 0.157 ml (0.900 mmol) of N,N-diisopropyl
ethylamine were added. Then the reaction vessel was sealed with a
septum and was heated in the microwave at 150.degree. C. for 3 h.
After cooling, the reaction mixture was purified by preparative
HPLC (acetonitrile:water (+0.05% formic acid) gradient). 27 mg of
the title compound was obtained (33% of theor.).
[1922] LC-MS (method 1): R.sub.t=1.23 min; MS (EIpos):
m/z=546[M+H].sup.+.
[1923] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=2.19-2.29
(m, 2H), 2.63-2.75 (m, 2H), 3.70 (d, 1H), 3.79-3.95 (m, 3H), 4.09
(d, 1H), 4.26-4.32 (m, 1H), 5.84 (s, 2H), 6.41 (t, 1H), 7.13-7.17
(m, 1H), 7.21-7.28 (m, 2H), 7.34-7.39 (m, 1H), 8.48 (dd, 1H), 8.73
(dd, 1H), 11.24 (s, 1H).
Example 101
Ethyl-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-hydroxy-5-me-
thyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxylate
##STR00220##
[1925] 1.00 g (2.167 mmol) of example 59A was reacted on the
analogy of the specification in example 15A. 173 mg (17% of theor.)
of the title compound and 0.887 g of
ethyl-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5-meth-
yl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxylate
(example 60A) were obtained.
[1926] LC-MS (method 1): R.sub.t=0.96 min; MS (EIpos):
m/z=462[M+H].sup.+.
[1927] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.09 (t,
3H), 1.55 (s, 3H), 4.10 (q, 2H), 5.87 (s, 2H), 7.13-7.17 (m, 1H),
7.21-7.26 (m, 1H), 7.36-7.40 (m, 2H), 7.50 (dd, 1H), 8.73-8.78 (m,
2H), 11.48 (br s, 1H), 12.72 (br s, 1H).
Example 102
2-[5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-hydroxy-5-
,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00221##
[1929] 200 mg (0.376 mmol) of example 16A was dissolved in 3 ml
water and 3 ml tetrahydrofuran in a reaction vessel suitable for a
microwave, the reaction vessel was sealed with a septum and was
heated in the microwave for 1 h at 140.degree. C. Then 1.127 ml
(1.127 mmol) of 1M sodium hydroxide solution was added and it was
heated in the microwave for a further 14 h at 140.degree. C. After
cooling, the reaction mixture was purified by preparative HPLC
(acetonitrile:water (+0.05% formic acid) gradient). 24 mg of the
title compound was obtained (15% of theor.).
[1930] LC-MS (method 1): R.sub.t=0.96 min; MS (EIpos):
m/z=423[M+H].sup.+.
[1931] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.33 (s,
6H), 5.85 (s, 2H), 7.14-7.18 (m, 1H), 7.22-7.26 (m, 1H), 7.34-7.41
(m, 2H), 8.55 (br s, 1H), 8.78 (dd, 1H), 11.10 (s br, 1H), 12.11
and 12.61 (s br, together 1H).
Example 103
4-(4,4-Difluoropiperidin-1-yl)-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[-
3,4-b]pyridin-3-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6--
one
##STR00222##
[1933] 100 mg (0.18 mmol) of
2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-
-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example
16A) was dissolved in 1-methyl-2-pyrrolidone (3.1 ml) in a reaction
vessel suitable for a microwave, and 0.19 ml (1.07 mmol) of
N,N-diisopropyl ethylamine and 140 mg (0.89 mmol) of
4,4-difluoropiperidine hydrochloride were added. Then the reaction
vessel was sealed with a septum and was heated in the microwave for
5 h at 150.degree. C. Then the same amounts of N,N-diisopropyl
ethylamine and 4,4-difluoropiperidine hydrochloride were added
again to the reaction solution and the reaction mixture was stirred
for 6 h at 150.degree. C. in the microwave. Water was added to the
reaction mixture, the precipitated solid was stirred for 30 min at
room temperature and then filtered off. The precipitated solid was
stirred with 1 ml acetonitrile, the solid was filtered off and was
washed with 0.5 ml acetonitrile. 63 mg of the target compound (64%
of theor.) was obtained.
[1934] LC-MS (method 1): R.sub.t=1.29 min; MS (EIpos): m/z=526
[M+H].sup.+.
[1935] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.44 (s,
6H), 2.10-2.23 (m, 4H), 3.79-3.90 (m, 4H), 5.84 (s, 2H), 7.10-7.28
(m, 3H), 7.32-7.40 (m, 1H), 8.42-8.48 (m, 1H), 8.70-8.76 (m, 1H),
11.35 (s, 1H).
Example 104
2-[5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-(3-hydrox-
yazetidin-1-yl)-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00223##
[1937] 100 mg (0.18 mmol, approx. 95% purity) of
2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-
-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example
16A) was dissolved in 1-methyl-2-pyrrolidone (3.1 ml) in a reaction
vessel suitable for a microwave, and 0.19 ml (1.07 mmol) of
N,N-diisopropyl ethylamine and 97 mg (0.89 mmol) of azetidin-3-ol
hydrochloride were added. Then the reaction vessel was sealed with
a septum and was heated in the microwave at 150.degree. C. for 3 h.
After cooling, water/trifluoroacetic acid was added to the reaction
mixture and the resultant solid was filtered off. The filtrate was
purified by preparative HPLC (acetonitrile:water (+0.1%
trifluoroacetic acid) gradient). 19 mg of the title compound was
obtained (21% of theor.; purity 93%).
[1938] LC-MS (method 1): R.sub.t=1.01 min; MS (EIpos): m/z=478
[M+H].sup.+.
[1939] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.34 (s,
6H), 4.03-4.09 (m, 2H), 4.50-4.57 (m, 2H), 4.62-4.69 (m, 1H), 5.83
(s, 2H), 7.15 (t, 1H), 7.19-7.26 (m, 2H), 7.33-7.40 (m, 1H), 8.53
(dd, 1H), 8.71-8.73 (m, 1H), 11.19 (s, 1H).
Example 105
2-[1-(2-Fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-4-[3-(p-
yrrolidin-1-yl)azetidin-1-yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00224##
[1941] 150 mg (0.21 mmol, purity approx. 71%) of
2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-
-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 15A) was
dissolved in 1-methyl-2-pyrrolidone (3.1 ml) in a reaction vessel
suitable for a microwave, and 0.29 ml (1.66 mmol) of
N,N-diisopropyl ethylamine and 165 mg (0.83 mmol) of
1-(azetidin-3-yl)pyrrolidine-dihydrochloride were added. Then the
reaction vessel was sealed with a septum and heated in the
microwave at 150.degree. C. for 6 h. After cooling, water was added
to the reaction mixture. It was stirred for 30 min and filtered to
remove the resultant solid. The filtrate was purified by
preparative HPLC (acetonitrile:water (+0.1% trifluoroacetic acid)
gradient). The product fraction was dissolved in dichloromethane
and was washed twice with saturated aqueous sodium hydrogen
carbonate solution. The organic phase was dried over sodium
sulphate, filtered and concentrated by evaporation. 52 mg of the
title compound was obtained (46% of theor.; purity 94%).
[1942] LC-MS (method 1): R.sub.t=0.71 min; MS (EIpos): m/z=513
[M+H].sup.+.
[1943] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.34 (s,
6H), 1.70-1.79 (m, 4H), 2.48-2.57 (m, masked by the DMSO signal),
3.41-3.51 (m, 1H), 4.10-4.18 (m, 2H), 4.37-4.43 (m, 2H), 5.83 (s,
2H), 7.10-7.28 (m, 3H), 7.31-7.46 (m, 2H), 8.62-8.66 (m, 1H),
8.85-8.89 (m, 1H), 11.20 (s, 1H).
Example 106
4-(3-Aminopyrrolidin-1-yl)-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-
-3-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
(racemate)
##STR00225##
[1945] 0.71 ml of a 2N solution of hydrogen chloride in diethyl
ether was added to 81 mg (0.24 mmol) of
tert.-butyl-(1-{2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-
-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}pyrrolidin-3-y-
l)carbamate (racemate, example 61A) and it was stirred for 4 h at
room temperature. The reaction solution was concentrated and was
purified by preparative HPLC (acetonitrile/water (+0.1%
trifluoroacetic acid) gradient). The concentrated fractions were
dissolved in dichloromethane and washed twice with saturated
aqueous sodium hydrogen carbonate solution. The combined aqueous
phases were extracted twice with dichloromethane. The combined
organic phases were dried over sodium sulphate, filtered and
concentrated by evaporation. 37 mg (55% of theor.) of the target
compound was obtained.
[1946] LC-MS (method 1): R.sub.t=0.73 min; MS (ESIpos): m/z=473
[M+H].sup.+
[1947] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.42 (s,
6H), 1.70-1.79 (m, 1H), 2.06-2.16 (m, 1H), 3.39-3.45 (m, 1H),
3.58-3.63 (m, 1H), 3.73-3.82 (m, 1H), 3.83-3.94 (m, 2H), 5.83 (s,
2H), 7.10-7.26 (m, 3H), 7.31-7.39 (m, 1H), 7.42 (dd, 1H), 8.65 (dd,
1H), 8.88 (dd, 1H), 11.29 (br s, 1H).
Example 107
4-(3-Aminoazetidin-1-yl)-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-
-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00226##
[1949] 0.66 ml of a 2N solution of hydrogen chloride in diethyl
ether was added to 81 mg (0.13 mmol; purity 91%) of
tert.-butyl-(1-[2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-
-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]azetidin-3-yl)-
carbamate (example 62A) and it was stirred for 4 h at room
temperature. The reaction solution was concentrated by evaporation
and purified twice by preparative HPLC (acetonitrile/water (+0.1%
trifluoroacetic acid) gradient). The concentrated fractions were
dissolved in dichloromethane and washed twice with saturated
aqueous sodium hydrogen carbonate solution. The combined aqueous
phases were extracted twice with dichloromethane. The combined
organic phases were dried over sodium sulphate, filtered and
concentrated by evaporation. 31 mg (49% of theor.) of the target
compound was obtained.
[1950] LC-MS (method 1): R.sub.t=0.71 min; MS (ESIpos): m/z=459
[M+H].sup.+
[1951] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.33 (s,
6H), 2.22 (br s, 2H), 3.83-3.98 (m, 3H), 4.46 (t, 2H), 5.82 (s,
2H), 7.10-7.27 (m, 3H), 7.31-7.38 (m, 1H), 7.42 (dd, 1H), 8.65 (dd,
1H), 8.88 (dd, 1H), 11.18 (s, 1H).
Example 108
2-[1-(2-Fluorobenzyl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5,5-dimet-
hyl-4-[(3,3,3-trifluoropropyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidi-
n-6-one
##STR00227##
[1953] The title compound was prepared similarly to the
specification for example 35 starting from 100 mg (0.16 mmol) of
example 70A and 372 mg (3.29 mmol) of
3,3,3-trifluoro-propylamine.
[1954] Yield: 38 mg (44% of theor.)
[1955] LC-MS (method 1): R.sub.t=1.11 min; MS (ESIpos): m/z=515
[M+H].sup.+
[1956] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.37 (s,
6H), 2.59-2.74 (m, 2H), 2.78 (s, 3H), 3.83 (q, 2H), 5.75 (s, 2H),
6.89 (t, 1H), 7.10-7.29 (m, 3H), 7.32-7.43 (m, 1H), 9.65 (s, 1H),
11.11 (s, 1H).
Example 109
2-[1-(2-Fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-hydroxy-5,5-dimeth-
yl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00228##
[1958] 6.0 g (14.87 mmol) of example 13A was dissolved in 60 ml of
trifluoroacetic acid (heating) and cooled in an ice bath. While
stirring, 6.7 ml of water and then, in small portions within 1 h,
1.54 g (22.3 mmol) of sodium nitrite, were added. Then the reaction
mixture was poured into 250 ml water and the resultant precipitate
was filtered with suction. The solid was left to precipitate in 50
ml water (adjusted to pH 6 with conc. sodium hydrogen carbonate
solution), filtered with suction again, washed with water and
dried. Yield: 5.75 g (94% of theor.)
[1959] LC-MS (method 1): R.sub.t=0.92 min; MS (ESIpos): m/z=405
[M+H].sup.+
[1960] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.33 (s,
6H), 5.86 (s, 2H), 7.16 (t, 1H), 7.23 (t, 1H), 7.28-7.41 (m, 2H),
7.49 (dd, 1H), 8.61-8.85 (m, 2H), 11.11 (s, 1H), 12.12 (br s,
0.2H), 12.44 (br s, 0.8H).
Example 110
2-[1-(2,3-Difluorobenzyl)-5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dim-
ethyl-4-(3,3,3-trifluoropropoxy)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6--
one
##STR00229##
[1962] Under argon, 80 mg (0.18 mmol) of the compound from example
116 was dissolved in 2 ml THF and 0.4 ml DMF, and 31 mg (0.27 mmol)
of 3,3,3-trifluoropropan-1-ol, 71.5 mg (0.27 mmol) of triphenyl
phosphine and 57 .mu.l (0.27 mmol) of 94% diisopropyl
azodicarboxylate were added and it was stirred overnight at RT. A
further 71.5 mg (0.27 mmol) of triphenyl phosphine was added and it
was treated for 15 min in the ultrasonic bath, then a further 57.5
.mu.l (0.27 mmol) of 94% diisopropyl azodicarboxylate was added
dropwise and it was stirred overnight at RT. Then 31 mg (0.27 mmol)
of 3,3,3-trifluoropropan-1-ol and 71.5 mg (0.27 mmol) of triphenyl
phosphine were added, it was treated for 15 min in the ultrasonic
bath, 57.5 .mu.l (0.27 mmol) of 94% diisopropyl azodicarboxylate
was added and it was stirred overnight at RT. The reaction mixture
was purified by preparative HPLC (Chromatorex C18, gradient of
acetonitrile/0.01% aq. formic acid). Yield: 41 mg (42% of
theor.)
[1963] LC-MS (method 1): R.sub.t=1.46 min; MS (ESIpos): m/z=633
[M+H].sup.+
[1964] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.35 (s,
6H), 2.93 (qt, 2H), 4.79 (t, 2H), 5.92 (s, 2H), 7.01-7.10 (m, 1H),
7.18 (t, 1H), 7.34-7.46 (m, 1H), 8.55 (dd, 1H), 8.76 (dd, 1H),
11.45 (s, 1H).
Example 111
2-[1-(2-Fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-4-propo-
xy-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00230##
[1966] Under argon, 80 mg (0.20 mmol) of the compound from example
109, 13 mg (164.0.22 mmol) of n-propanol and 57 mg (0.22 mmol) of
triphenyl phosphine were suspended in 0.8 ml THF, mixed for 10 min
in the ultrasonic bath and finally 44 mg (43 .mu.l, 0.22 mmol) of
diisopropyl azodicarboxylate was added and it was stirred for 1 h
at RT. The reaction mixture was purified by preparative HPLC
(Reprosil C18, gradient of acetonitrile/0.01% aq. formic acid).
Yield: 48 mg (55% of theor.)
[1967] LC-MS (method 1): R.sub.t=1.28 min; MS (ESIpos): m/z=447
[M+H].sup.+
[1968] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.05 (t,
3H), 1.36 (s, 6H), 1.77-1.91 (m, 2H), 4.54 (t, 2H), 5.86 (s, 2H),
7.11-7.27 (m, 3H), 7.32-7.40 (m, 1H), 7.45 (dd, 1H), 8.68 (dd, 1H),
8.85 (dd, 1H), 11.39 (s, 1H).
Example 112
4-Ethoxy-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethy-
l-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00231##
[1970] Similarly to the specification for example 111, 150 mg (0.37
mmol) of example 109, 24 .mu.l (0.41 mmol) of ethanol and 107 mg
(0.41 mmol) of triphenyl phosphine were mixed in 1.5 ml THF for 10
min in the ultrasonic bath, 82.5 mg (0.41 mmol) of diisopropyl
azodicarboxylate was added and it was stirred overnight at RT. Then
a further 24 .mu.l (0.41 mmol) of ethanol and 107 mg (0.41 mmol) of
triphenyl phosphine were added, mixed for 5 min in the ultrasonic
bath, 82.5 mg (0.41 mmol) of diisopropyl azodicarboxylate was added
and it was stirred for approx. 30 min at RT. The reaction mixture
was purified by preparative HPLC (Reprosil C18, gradient of
acetonitrile/0.01% aq. formic acid). Yield: 25 mg (16% of
theor.).
[1971] LC-MS (method 1): R.sub.t=1.21 min; MS (ESIpos): m/z=433
[M+H].sup.+
[1972] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.35 (s,
6H), 1.43 (t, 3H), 4.62 (q, 2H), 5.86 (s, 2H), 7.09-7.27 (m, 3H),
7.31-7.40 (m, 1H), 7.45 (dd, 1H), 8.68 (dd, 1H), 8.85 (dd, 1H),
11.39 (s, 1H).
Example 113
4-(Cyclopropylmethoxy)-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-y-
l]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00232##
[1974] Similarly to the specification for example 111, 200 mg (0.50
mmol) of example 109, 39 mg (0.54 mmol) of cyclopropanemethanol and
143 mg (0.54 mmol) of triphenyl phosphine were mixed in 2 ml THF
for 10 min in the ultrasonic bath, 110 mg (0.11 ml, 0.54 mmol) of
diisopropyl azodicarboxylate was added and it was stirred overnight
at RT. Then a further 14 mg (0.19 mmol) of cyclopropanemethanol, 48
mg (0.18 mmol) of triphenyl phosphine and 35 ml (0.17 mmol) of
diisopropyl azodicarboxylate were added and it was stirred for 1.5
h at RT. The reaction mixture was purified by preparative HPLC
(Chromatorex C18, gradient of acetonitrile/0.01% aq. formic acid).
Yield: 52 mg (23% of theor.)
[1975] LC-MS (method 1): R.sub.t=1.27 min; MS (ESIpos): m/z=459
[M+H].sup.+
[1976] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=0.40-0.48
(m, 2H), 0.55-0.64 (m, 2H), 1.27-1.43 (m, 7H), 4.44 (d, 2H), 5.86
(s, 2H), 7.09-7.28 (m, 3H), 7.31-7.41 (m, 1H), 7.47 (dd, 1H), 8.68
(dd, 1H), 8.84 (dd, 1H), 11.41 (s, 1H).
Example 114
2-[3-(2-Fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin-1-yl]-5,5-dimethyl-4-(3,3,-
3-trifluoropropoxy)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00233##
[1978] Under argon, 57 mg (0.22 mmol) of triphenyl phosphine was
dissolved in 1.5 ml THF, 43 .mu.l (0.22 mmol) of diisopropyl
azodicarboxylate and 25 mg (0.22 mmol) of
3,3,3-trifluoropropan-1-ol were added and it was stirred for 10
min. Then a suspension of 80 mg of example 109 in 0.5 ml DMF, which
had been treated for 3 min in the ultrasonic bath, was added and
the reaction mixture was stirred overnight at RT (solution). A
further 57 mg (0.22 mmol) of triphenyl phosphine was added, the
mixture was treated for 10 min in the ultrasonic bath, then a
further 43 .mu.l (0.22 mmol) of diisopropyl azodicarboxylate was
added and it was stirred overnight. Then a further 25 mg (0.22
mmol) of 3,3,3-trifluoropropan-1-ol and 57 mg (0.22 mmol) of
triphenyl phosphine were added, the reaction mixture was treated
for 10 min in the ultrasonic bath, then 43 .mu.l (0.22 mmol) of
diisopropyl azodicarboxylate was added and it was stirred for
another night at RT. The reaction mixture was purified by
preparative HPLC (Reprosil C18, gradient of acetonitrile/0.01% aq.
formic acid). Yield: 37 mg (37% of theor.)
[1979] LC-MS (method 1): R.sub.t=1.21 min; MS (ESIpos): m/z=501
[M+H].sup.+
[1980] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.35 (s,
6H), 2.92 (qt, 2H), 4.79 (t, 2H), 5.87 (s, 2H), 7.11-7.27 (m, 3H),
7.32-7.41 (m, 1H), 7.45 (dd, 1H), 8.68 (dd, 1H), 8.86 (dd, 1H),
11.45 (s, 1H).
Example 115
2-[1-(2-Fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-4-(2,2,-
2-trifluoroethoxy)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00234##
[1982] 177 mg (0.54 mmol) of caesium carbonate and 114 mg (0.54
mmol) of 2,2,2-trifluoroethyl iodide were added to a suspension of
200 mg (0.5 mmol) of the compound from example 109 in DMF (1.97 ml)
and it was stirred overnight at RT. Then it was heated in the
microwave to 120.degree. C. for 1 h. The reaction mixture was
purified by preparative HPLC (Chromatorex C18, gradient of
acetonitrile/0.01% aq. formic acid). Yield: 14.5 mg (6% of
theor.).
[1983] LC-MS (method 1): R.sub.t=1.20 min; MS (ESIpos): m/z=487
[M+H].sup.+
[1984] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.36 (s,
6H), 5.30 (q, 2H), 5.88 (s, 2H), 7.10-7.28 (m, 3H), 7.32-7.41 (m,
1H), 7.48 (dd, 1H), 8.69 (dd, 1H), 8.89 (dd, 1H), 11.61 (s,
1H).
Example 116
2-[1-(2,3-Difluorobenzyl)-5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-hydro-
xy-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00235##
[1986] On the analogy of the preparation of example 16A, 5.11 g
(11.629 mmol) of example 69A was reacted. 660 mg (12% of theor.) of
the title compound and 2.39 g of
2-[1-(2,3-difluorobenzyl)-5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-
-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example
70A) were obtained.
[1987] LC-MS (method 1): R.sub.t=0.98 min; MS (ESIpos): m/z=441
[M+H].sup.+
[1988] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.33 (s,
6H), 5.89 (s, 2H), 7.15-7.20 (m, 2H), 7.37-7.45 (m, 1H), 8.58 (br
s, 1H), 8.79 (s, 1H), 11.08 (br s, 1H), 12.58 (br s, 1H).
Example 117
2-[1-(2-Fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-(2-hydroxyethoxy)--
5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
##STR00236##
[1990] Similarly to example 1, 100 mg (0.19 mmol) of example 15A,
121 mg (1.94 mmol) of ethylene glycol, 9 mg (0.039 mmol) of
3,4,7,8-tetramethyl-1,10-phenanthroline, 3.7 mg (0.019 mmol) of
copper(I) iodide and 126 mg (0.39 mmol) of caesium carbonate in 3
ml toluene were heated in the microwave in 4 cycles for in each
case 2 h at 140.degree. C. Yield: 24 mg (28% of theor.)
[1991] LC-MS (method 1): R.sub.t=0.94 min; MS (EIpos): m/z=449
[M+H].sup.+.
[1992] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.37 (s,
6H), 3.82 (q, 2H), 4.58 (t, 2H), 4.94 (t, 1H), 5.86 (s, 2H),
7.10-7.27 (m, 3H), 7.32-7.40 (m, 1H), 7.45 (dd, 1H), 8.68 (dd, 1H),
8.86 (dd, 1H), 11.41 (s, 1H).
B. ASSESSMENT OF PHARMACOLOGICAL EFFICACY
[1993] The following abbreviations are used in the following:
[1994] BSA bovine serum albumin [1995] EDTA
ethylenediaminetetraacetic acid [1996] .mu.Ci microcurie [1997]
Tris Tris(hydroxymethyl)-aminomethane
[1998] The pharmacological action of the compounds according to the
invention can be demonstrated in the following assays:
[1999] B-1. Vessel-Relaxing Action In Vitro
[2000] Rabbits are stunned with a blow on the back of the neck and
exsanguinated. The aorta is removed, freed from adhering tissue,
separated into rings with a width of 1.5 mm, and placed
individually, with preloading, in 5-ml organ baths with
carbogen-gassed Krebs-Henseleit solution at 37.degree. C. with the
following composition (mM in each case): sodium chloride: 119;
potassium chloride: 4.8; calcium chloride dihydrate: 1; magnesium
sulphate heptahydrate: 1.4; potassium dihydrogen phosphate: 1.2;
sodium hydrogen carbonate: 25; glucose: 10. The contraction force
is recorded with Statham UC2 cells, amplified and digitized via an
A/D converter (DAS-1802 HC, Keithley Instruments Munich) and
recorded in parallel on a continuous-line recorder. To produce
contraction, phenylephrine is added to the bath cumulatively in
increasing concentration. After several control cycles, the test
substance is added in increasing dosage in each subsequent pass and
the level of contraction is compared with the level of contraction
reached in the immediately preceding pass. This is used for
calculating the concentration that is required to reduce the level
of the control value by 50% (IC.sub.50 value). The standard
application volume is 5 .mu.l, and the proportion of DMSO in the
bath solution corresponds to 0.1%.
[2001] Representative IC.sub.50 values for the compounds according
to the invention are shown in the following table (Table 1):
TABLE-US-00003 TABLE 1 Example No. IC.sub.50 [nM] 1 114 2 54 3 469
4 62 5 285 6 680 7 200 8 309 9 21000 10 552 11 663 12 631 13 4970
14 1030 15 453 16 126 17 200 18 2720 19 1280 20 1870 21 100 22 530
23 2864 24 573 25 501 26 674 27 1470 28 98 29 11400 30 >10000 31
142 32 9160 33 696 34 6150 35 >10000 36 5490 37 3870 38 10000 39
618 88 1670 89 3880 90 3072 91 517 92 520 93 984 94 277 95 228 96-1
1468 96-2 601 97 1350 98 214 99 10000 100 4758 102 156 103 551 104
482 105 478 106 1454 107 700 108 444 109 81 110 10000 111 1620 112
1620 113 1960 114 1600 115 1634 117 38
[2002] B-2. Action on Recombinant Guanylate Cyclase Reporter Cell
Line
[2003] The cellular action of the compounds according to the
invention is determined on a recombinant guanylate cyclase reporter
cell line, as described in F. Wunder et al., Anal. Biochem. 339,
104-112 (2005).
[2004] Representative values (MEC=minimal effective concentration)
for the compounds according to the invention are shown in the
following table (Table 2):
TABLE-US-00004 TABLE 2 MEC Example [.mu.M] 1 0.1 2 0.3 3 3.0 4 0.1
5 0.03 6 0.1 7 0.1 8 0.3 9 0.1 10 0.3 11 0.3 12 0.1 13 0.1 14 0.3
15 1.0 16 0.1 17 0.1 18 0.03 19 0.3 20 0.3 21 0.03 22 0.03 23 0.1
24 0.1 25 0.1 26 0.03 27 0.1 28 0.3 29 1.0 30 1.0 31 0.01 32 1.0 33
0.3 34 1.0 35 0.3 36 0.3 37 0.3 38 0.3 39 0.1 40 0.1 41 0.01 42 0.1
43 0.03 44 0.1 45 0.1 46 0.1 47 0.1 48 0.1 49 0.3 50 0.1 51 0.03 52
0.01 53 3.0 54 0.03 55 0.03 56 0.03 57 0.1 58 0.03 59 0.1 60 0.3 61
0.03 62 0.1 63 0.03 64 0.1 65 0.1 66 0.1 67 0.03 68 0.1 69 0.3 70
0.03 71 0.01 72 0.1 73 0.3 74 0.01 75 0.03 76 0.03 77 0.1 78 0.03
79 0.1 80 0.03 81 0.03 82 0.1 83 0.03 84 0.1 85 0.3 86 0.01 87 0.03
88 0.1 89 0.03 90 0.3 91 0.03 92 0.3 93 0.3 94 0.1 95 0.1 96-1 0.1
96-2 0.01 97 0.1 98 0.01 99 0.3 100 0.3 101 0.03 102 1 103 1 104
0.1 105 0.3 106 1 107 1 108 0.3 109 0.03 110 1.0 111 0.3 112 0.1
113 0.1 114 0.3 115 0.3 116 0.03 117 0.03
[2005] B-3. Radiotelemetric Blood Pressure Measurement on Awake,
Spontaneously Hypertensive Rats
[2006] The blood pressure measurement on awake rats described below
uses a commercially available telemetry system from the company
DATA SCIENCES INTERNATIONAL DSI, USA.
[2007] The system consists of 3 main components: [2008] implantable
transmitter (Physiotel.RTM. Telemetry Transmitter) [2009] receiver
(Physiotel.RTM. Receiver), which are connected via a multiplexer
(DSI Data Exchange Matrix) to a [2010] data acquisition
computer.
[2011] The telemetry system provides continuous acquisition of
blood pressure, heart rate and body movement on awake animals in
their usual living space.
[2012] Animal Material
[2013] The investigations are carried out on adult female,
spontaneously hypertensive rats (SHR Okamoto) with a body weight of
>200 g. SHR/NCrl from Okamoto Kyoto School of Medicine, 1963
were crossed from male Wistar Kyoto rats with greatly increased
blood pressure and females with slightly raised blood pressure and
were delivered in F13 to the U.S. National Institutes of
Health.
[2014] After transmitter implantation, the experimental animals are
kept individually in Makrolon cages, type 3. They have free access
to standard feed and water.
[2015] The day-night rhythm in the testing laboratory is alternated
by the room lighting at 06:00 hours in the morning and at 19:00
hours in the evening.
[2016] Transmitter Implantation
[2017] The TA11 PA-C40 telemetry transmitters used are implanted
surgically in the experimental animals under aseptic conditions at
least 14 days before the first test. The animals provided with this
instrumentation can be used again after the wound has healed and
the implant has become incorporated.
[2018] For implantation, the fasting animals are anaesthetized with
pentobarbital (Nembutal, Sanofi: 50 mg/kg i.p.) and are shaved and
disinfected on a wide area of the abdomen. After opening the
abdominal cavity along the linea alba, the liquid-filled measuring
catheter of the system is inserted above the bifurcation in the
cranial direction into the aorta descendens and secured with tissue
adhesive (VetBonD.TM., 3M). The transmitter housing is fixed
intraperitoneally on the abdominal wall musculature and the wound
is closed layer by layer.
[2019] Postoperatively, an antibiotic is administered to prevent
infection (Tardomyocel COMP Bayer 1 ml/kg s.c.)
[2020] Substances and Solutions
[2021] Unless described otherwise, the test substances are in each
case administered orally by stomach tube to a group of animals
(n=6). Corresponding to an application volume of 5 ml/kg body
weight, the test substances are dissolved in suitable solvent
mixtures or suspended in 0.5% Tylose.
[2022] A group of animals treated with solvents is used as
control.
[2023] Test Procedure
[2024] The present telemetry measuring device is configured for 24
animals. Each test is recorded under a test number (test year month
day).
[2025] The instrumented rats living in the unit are each assigned
their own receiving antenna (1010 Receiver, DSI).
[2026] The implanted transmitters can be activated from outside by
an in-built magnetic switch. They are switched to transmission at
the start of the tests. The signals emitted can be recorded online
by a data acquisition system (Dataquest.TM. A.R.T. for WINDOWS,
DSI) and processed appropriately. The data are saved in each case
to a folder opened for this, which bears the test number.
[2027] In the standard procedure, the following are measured, in
each case for 10 seconds: [2028] systolic blood pressure (SBP)
[2029] diastolic blood pressure (DBP) [2030] mean arterial pressure
(MAP) [2031] heart rate (HR) [2032] activity (ACT).
[2033] Recording of the measured values is repeated at 5-minute
intervals under computer control. The source data recorded as
absolute value are corrected in the diagram with the currently
measured barometric pressure (Ambient Pressure Reference Monitor;
APR-1) and saved in individual data. Further technical details can
be found in the extensive documentation of the manufacturer
(DSI).
[2034] Unless described otherwise, the test substances are
administered on the test day at 09.00 hours. Following application,
the parameters described above are measured for 24 hours.
[2035] Evaluation
[2036] After the end of the test, the individual data recorded are
sorted with the analysis software (DATAQUEST.TM. A. R.T..TM.
ANALYSIS). The 2 hours before application are taken as the blank
value here, so that the selected data set comprises the period from
07:00 hours on the test day to 09:00 hours on the next day.
[2037] The data are smoothed for a pre-settable time by mean value
determination (15-minute average) and transferred as text file to a
storage medium. The pre-sorted and compressed measured values are
transferred to Excel templates and presented as tables. The data
recorded are saved per test day in a specific folder, which bears
the test number. Results and test protocols are filed in folders,
sorted in paper form by numbers.
[2038] Literature
[2039] Klaus Witte, Kai Hu, Johanna Swiatek, Claudia Mussig, Georg
Ertl and Bjorn Lemmer: Experimental heart failure in rats: effects
on cardiovascular circadian rhythms and on myocardial
.beta.-adrenergic signaling. Cardiovasc Res 47 (2): 203-405, 2000;
Kozo Okamoto: Spontaneous hypertension in rats. Int Rev Exp Pathol
7: 227-270, 1969; Maarten van den Buuse: Circadian Rhythms of Blood
Pressure, Heart Rate, and Locomotor Activity in Spontaneously
Hypertensive Rats as Measured with Radio-Telemetry. Physiology
& Behavior 55(4): 783-787, 1994
[2040] B-4. Determination of Pharmacokinetic Parameters after
Intravenous and Oral Administration
[2041] The pharmacokinetic parameters of the compounds according to
the invention are determined in male CD-1 mice, male Wistar rats
and female beagles. Intravenous administration takes place in mice
and rats using a species-specific plasma/DMSO formulation and in
dogs using a water/PEG400/ethanol formulation. Oral administration
of the dissolved substance by stomach tube is carried out in all
species on the basis of a water/PEG400/ethanol formulation. To
simplify collection of blood, prior to administration of the
substance the rats are fitted with a silicone catheter in the right
vena jugularis externa. The operation is performed at least one day
before the test under isoflurane anaesthesia and with
administration of an analgesic (atropine/Rimadyl (3/1) 0.1 mL
s.c.). Blood collection (as a rule more than 10 time points) takes
place in a time window that includes terminal time points from at
least 24 to max. 72 hours after administration of the substance. On
collection, the blood is led into heparinized tubes. Then the blood
plasma is obtained by centrifugation and optionally stored at
-20.degree. C. until further processing.
[2042] An internal standard (which can also be a chemically
unrelated substance) is added to the samples of the compounds
according to the invention, the calibration samples and the
qualifiers and then protein precipitation is carried out using
acetonitrile in excess. After adding a buffer solution, which is
suitable for the LC conditions, and then vortexing, centrifugation
is carried out at 1000 g. The supernatant is measured by LC-MS/MS
using C18-reversed-phase columns and variable eluent mixtures. The
substances are quantified on the basis of the peak heights or areas
from extracted ion chromatograms of specific selected ion
monitoring experiments.
[2043] The pharmacokinetic parameters such as AUC, C.sub.max,
t.sub.1/2 (terminal half-life), MRT (mean residence time) and CL
(clearance) are calculated from the plasma concentration-time
curves obtained by means of validated pharmacokinetics
software.
[2044] As substance quantification takes place in plasma, the
blood/plasma distribution of the substance must be determined for
appropriate adjustment of the pharmacokinetic parameters. For this,
a defined amount of the substance in heparinized whole blood of the
corresponding species is incubated for 20 min in the tumbling
roller mixer. After centrifugation at 1000 g, the concentration of
the plasma is measured (by LC-MS/MS; see above) and the
C.sub.blood/C.sub.plasma value is determined by finding the
quotient.
[2045] B-5. Investigation of Metabolism
[2046] To determine the metabolism profile of the compounds
according to the invention, these are incubated with recombinant
human cytochrome P450 (CYP) enzymes, liver microsomes or with
primary fresh hepatocytes of various animal species (e.g. rat, dog)
as well as of human origin, in order to obtain and compare
information on hepatic phase I and phase II metabolism that is as
complete as possible and on the enzymes involved in metabolism.
[2047] The compounds according to the invention were incubated at a
concentration of about 0.1-10 .mu.M. For this, stock solutions of
the compounds according to the invention with a concentration of
0.01-1 mM were prepared in acetonitrile, and then pipetted at 1:100
dilution into the incubation preparation. The liver microsomes and
recombinant enzymes were incubated at 37.degree. C. in 50 mM
potassium phosphate buffer pH 7.4 with and without NADPH-generating
system, consisting of 1 mM NADP.sup.+, 10 mM glucose-6-phosphate
and 1 unit of glucose-6-phosphate dehydrogenase. Primary
hepatocytes were also incubated at 37.degree. C. in suspension in
Williams E medium. After an incubation time of 0-4 h, the
incubation assays were stopped with acetonitrile (final
concentration approx. 30%) and the protein was centrifuged off at
approx. 15000.times.g. The samples stopped in this way were either
analysed directly or were stored at -20.degree. C. until
analysis.
[2048] The analysis takes place by high-performance liquid
chromatography with ultraviolet and mass-spectrometry detection
(HPLC-UV-MS/MS). For this, the supernatants of the incubation
samples are chromatographed with suitable C18-reversed-phase
columns and variable eluent mixtures of acetonitrile and 10 mM
aqueous ammonium formate solution or 0.05% formic acid. The UV
chromatograms in conjunction with mass-spectrometry data serve for
identification, structure elucidation and quantitative estimation
of the metabolites, and the quantitative metabolic decrease of the
compound according to the invention in the incubation assays.
[2049] B-6. Inhibition of Human Phosphodiesterase 5 (PDE-5)
[2050] PDE-5 preparations are obtained from human platelets by
lysis (Microfluidizer.RTM., 800 bar, 3 passages), followed by
centrifugation (75000 g, 60 min, 4.degree. C.) and ion-exchange
chromatography of the supernatant on a Mono Q 10/10 column (linear
sodium chloride gradient, elution with a 0.2-0.3M solution of
sodium chloride in buffer (20 mM Hepes pH 7.2, 2 mM magnesium
chloride). Fractions that have PDE-5 activity are combined (PDE-5
preparation) and stored at -80.degree. C.
[2051] For determining their in-vitro action on human PDE-5, the
test substances are dissolved in 100% DMSO and serial dilutions are
prepared. Typically, dilution series (1:3) from 200 .mu.M to 0.091
.mu.M are prepared (resultant final concentrations in the test: 4
.mu.M to 0.0018 .mu.M). In each case 2 .mu.L of the diluted
solutions of the substance are put in the wells of microtitre
plates (Isoplate-96/200W; Perkin-Elmer). Then 50 .mu.L of a
dilution of the PDE-5 preparation described above is added. The
dilution of the PDE-5 preparation is selected so that during
subsequent incubation less than 70% of the substrate is reacted
(typical dilution: 1:100; dilution buffer: 50 mM Tris/hydrochloric
acid pH 7.5, 8.3 mM magnesium chloride, 1.7 mM EDTA, 0.2% BSA). The
substrate [8.sup.-3H]cyclic guanosine-3',5'-monophosphate (1
.mu.Ci/.mu.L; Perkin-Elmer) is diluted 1:2000 with assay buffer (50
mM Tris/hydrochloric acid pH 7.5, 8.3 mM magnesium chloride, 1.7 mM
EDTA) to a concentration of 0.0005 .mu.Ci/.mu.L. The enzyme
reaction is finally started by adding 50 .mu.L (0.025 .mu.Ci) of
the diluted substrate. The test preparations are incubated for 60
min at room temperature and the reaction is stopped by adding 25
.mu.L of a suspension of 18 mg/mL of Yttrium Scintillation
Proximity Beads in water (phosphodiesterase beads for SPA assays,
RPNQ 0150, Perkin-Elmer). The microtitre plates are sealed with
film and left to stand for 60 min at room temperature. Then the
plates are measured for 30 s per well in a Microbeta scintillation
counter (Perkin-Elmer). IC.sub.50 values are determined on the
basis of the graphs plotted of the substance concentration versus
the percentage PDE-5 inhibition.
[2052] Representative IC.sub.50 values for the compounds according
to the invention are presented in the following table (Table
3):
TABLE-US-00005 TABLE 3 Example No. IC.sub.50 [nM] 1 140 2 8.0 3 46
4 6.0 5 130 6 120 7 110 8 400 9 230 10 52 11 48 12 50 13 80 14 130
15 430 16 13 17 24 18 120 19 280 20 900 21 400 22 580 23 1600 24
100 25 320 26 12 27 4.0 28 110 29 >4000 30 >4000 31 500 32
720 33 570 34 550 35 110 36 89 37 100 38 41 39 88 40 11 41 170 42
120 43 410 44 86 45 78 46 35 47 83 48 54 49 50 40 51 5.0 52 34 53
150 54 55 130 56 34 57 16 58 270 59 8.0 60 430 61 100 62 480 63 230
64 980 65 430 66 16 67 68 35 69 46 70 80 71 42 72 110 73 16 74 110
75 210 76 130 77 78 330 79 80 81 290 82 83 230 84 19 85 4.2 86 330
87 210 88 150 89 82 90 230 91 600 92 170 93 120 94 140 95 4.0 96-1
150 96-2 26 97 63 98 4.0 99 440 100 2800 101 870 102 74 103 400 104
80 105 980 106 12 107 100 108 25 109 50 110 840 111 320 112 210 113
120 114 200 115 250 116 83 117 52
[2053] B-7. Determination of the Organ-Protective Effects in the
Long-Term Test on Rats
[2054] The organ-protective effects of the sGC stimulators were
demonstrated in a therapeutically relevant "low nitric oxide
(NO)/high renin" hypertension model in rats. The study was carried
out on the basis of the recent publication (Sharkovska Y, Kalk P,
Lawrenz B, Godes M, Hoffmann L S, Wellkisch K, Geschka S, Relle K,
Hocher B, Stasch J P. NO-independent stimulation of soluble
guanylate cyclase reduces target organ damage in low- and
high-renin models of hypertension. J. Hypertension. 2010; 28:
1666-1675). In this, renin-transgenic rats (TGR(mRen2)27), which
were administered the NO-synthase inhibitor L-NAME in the drinking
water, were treated simultaneously with an sGC stimulator or
vehicle for several weeks. Haemodynamic and renal parameters were
determined during the treatment period. At the end of the long-term
study, organ protection (kidney, lung, heart, aorta) was
demonstrated by histopathological investigations, biomarkers,
expression analyses and cardiovascular plasma parameters.
C. PRACTICAL EXAMPLES OF PHARMACEUTICAL COMPOSITIONS
[2055] The compounds according to the invention can be transformed
as follows into pharmaceutical preparations:
[2056] Tablet:
[2057] Composition:
[2058] 100 mg of the compound according to the invention, 50 mg
lactose (monohydrate), 50 mg maize starch (native), 10 mg
polyvinylpyrrolidone (PVP 25) (from BASF, Ludwigshafen, Germany)
and 2 mg magnesium stearate.
[2059] Tablet weight 212 mg, diameter 8 mm, radius of convexity 12
mm
[2060] Production:
[2061] The mixture of compound according to the invention, lactose
and starch is granulated with a 5% solution (w/w) of PVP in water.
After drying, the granules are mixed with the magnesium stearate
for 5 minutes. This mixture is compressed with a usual tablet press
(see above for tablet format). A pressing force of 15 kN is used as
a guide value for compression.
[2062] Oral Suspension:
[2063] Composition:
[2064] 1000 mg of the compound according to the invention, 1000 mg
ethanol (96%), 400 mg Rhodigel.RTM. (xanthan gum from the company
FMC, Pennsylvania, USA) and 99 g water.
[2065] An individual dose of 100 mg of the compound according to
the invention corresponds to 10 ml of oral suspension.
[2066] Production:
[2067] The Rhodigel is suspended in ethanol, and the compound
according to the invention is added to the suspension. Water is
added while stirring. It is stirred for approx. 6 h, until swelling
of the Rhodigel has ceased.
[2068] Oral Solution:
[2069] Composition:
[2070] 500 mg of the compound according to the invention, 2.5 g
polysorbate and 97 g polyethylene glycol 400. An individual dose of
100 mg of the compound according to the invention corresponds to 20
g of oral solution.
[2071] Production:
[2072] The compound according to the invention is suspended in a
mixture of polyethylene glycol and polysorbate, with stirring.
Stirring is continued until the compound according to the invention
has dissolved completely.
[2073] I.V. Solution:
[2074] The compound according to the invention is dissolved at a
concentration below the saturation solubility in a physiologically
compatible solvent (e.g. isotonic saline, glucose solution 5%
and/or PEG 400 solution 30%). The solution is sterile-filtered and
filled in sterile and pyrogen-free injection containers.
* * * * *