U.S. patent application number 13/672438 was filed with the patent office on 2013-05-09 for novel inhibitor compounds of phosphodiesterase type 10a.
This patent application is currently assigned to AbbVie Inc.. The applicant listed for this patent is Abbott GmbH & Co.KG, AbbVie Inc.. Invention is credited to Jurgen Dinges, Karla Drescher, Herve Geneste, Clarissa Jakob, Michael Ochse.
Application Number | 20130116229 13/672438 |
Document ID | / |
Family ID | 47143131 |
Filed Date | 2013-05-09 |
United States Patent
Application |
20130116229 |
Kind Code |
A1 |
Geneste; Herve ; et
al. |
May 9, 2013 |
NOVEL INHIBITOR COMPOUNDS OF PHOSPHODIESTERASE TYPE 10A
Abstract
The present invention relates to compounds which are inhibitors
of phosphodiesterase type 10A and to their use for the manufacture
of a medicament and which thus are suitable for treating or
controlling of medical disorders selected from neurological
disorders and psychiatric disorders, for ameliorating the symptoms
associated with such disorders and for reducing the risk of such
disorders.
Inventors: |
Geneste; Herve;
(Ludwigshafen, DE) ; Ochse; Michael;
(Ludwigshafen, DE) ; Drescher; Karla;
(Ludwigshafen, DE) ; Dinges; Jurgen; (Abbott Park,
IL) ; Jakob; Clarissa; (Abbott Park, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Abbott GmbH & Co.KG;
AbbVie Inc.; |
Wiesbaden
North Chicago |
IL |
DE
US |
|
|
Assignee: |
AbbVie Inc.
North Chicago
IL
Abbott GmbH & Co. KG
Wiesbaden
|
Family ID: |
47143131 |
Appl. No.: |
13/672438 |
Filed: |
November 8, 2012 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
61557878 |
Nov 9, 2011 |
|
|
|
Current U.S.
Class: |
514/210.18 ;
514/235.2; 514/248; 514/249; 514/253.05; 514/256; 514/300; 514/309;
544/128; 544/237; 544/333; 544/353; 544/363; 546/123; 546/141 |
Current CPC
Class: |
C07D 409/12 20130101;
C07D 217/24 20130101; C07D 471/04 20130101; C07D 413/06 20130101;
A61K 31/47 20130101; A61P 25/28 20180101; C07D 417/12 20130101;
A61P 25/22 20180101; C07D 401/12 20130101; C07D 401/06 20130101;
A61P 3/04 20180101; A61P 25/18 20180101; C07D 401/14 20130101; C07D
237/32 20130101; C07D 417/06 20130101; C07D 409/08 20130101; A61P
25/24 20180101; A61P 25/00 20180101; A61P 43/00 20180101; C07D
217/26 20130101 |
Class at
Publication: |
514/210.18 ;
546/141; 514/309; 544/128; 514/235.2; 544/363; 514/253.05; 544/237;
514/248; 544/333; 514/256; 544/353; 514/249; 546/123; 514/300 |
International
Class: |
C07D 401/06 20060101
C07D401/06; C07D 413/06 20060101 C07D413/06; C07D 471/04 20060101
C07D471/04; C07D 237/32 20060101 C07D237/32; C07D 417/06 20060101
C07D417/06; C07D 409/08 20060101 C07D409/08; C07D 217/26 20060101
C07D217/26; C07D 401/14 20060101 C07D401/14 |
Claims
1. Compound of formula I ##STR00009## where in formula I X.sup.1 is
CH or N, X.sup.2 is C--R.sup.5 or N, Y is O or S, R.sup.1 is
selected from the group consisting of C.sub.2-C.sub.8-alkyl,
C.sub.2-C.sub.8-alkenyl, C.sub.1-C.sub.4-fluoroalkyl,
C.sub.3-C.sub.8-cycloalkyl, C.sub.5-C.sub.8-cycloalkyl carrying a
fused benzene ring, fluorinated C.sub.3-C.sub.8-cycloalkyl,
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl, fluorinated
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl,
hydroxy-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkyl-N(R.sup.b)(R.sup.c) and a moiety
Z.sup.1--Ar.sup.1; R.sup.2 is a radical of the formula
CR.sup.21R.sup.22R.sup.23 or phenyl or 5- or 6-membered hetaryl
having 1, 2 or 3 heteroatoms as ring members which are selected
from O, S and N, where phenyl and monocyclic hetaryl are
unsubstituted or may carry 1, 2 or 3 identical or different
substituents R.sup.a, where R.sup.21 is selected from the group
consisting of hydrogen, C.sub.1-C.sub.8-alkyl, trimethylsilyl,
C.sub.2-C.sub.8-alkenyl, C.sub.1-C.sub.4-fluoroalkyl,
C.sub.3-C.sub.8-cycloalkyl, fluorinated C.sub.3-C.sub.8-cycloalkyl,
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl, fluorinated
C.sub.3-C.sub.8-cyclo alkyl-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl,
hydroxy-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkyl-N(R.sup.b)(R.sup.c),
(CH.sub.2).sub.mC(O)O--R.sup.d,
(CH.sub.2).sub.mC(O)N(R.sup.e)(R.sup.f) and Z.sup.2--Ar.sup.2,
R.sup.22 is selected from the group consisting of hydrogen,
fluorine, C.sub.1-C.sub.8-alkyl, C.sub.2-C.sub.8-alkenyl,
C.sub.1-C.sub.4-fluoroalkyl, C.sub.3-C.sub.8-cycloalkyl,
fluorinated C.sub.3-C.sub.8-cycloalkyl,
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl, fluorinated
C.sub.3-C.sub.8-cyclo alkyl-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl,
hydroxy-C.sub.1-C.sub.4-alkyl and
C.sub.1-C.sub.4-alkyl-N(R.sup.b)(R.sup.c), or R.sup.21 and R.sup.22
together with the carbon atom, to which they are bound form a
saturated 5- to 7-membered carbocyclic ring or a saturated 5- to
7-membered heterocyclic ring which has 1, 2 or 3 heteroatoms or
heteroatom containing groups selected from the group of O, N, S, SO
and SO.sub.2 as ring members, where the carbocyclic ring and the
heterocyclic ring may be unsubstituted or may be substituted by 1,
2 or 3 identical or different substituents R.sup.g, and where the
carbocyclic ring and the heterocyclic ring may carry a fused
benzene ring or a fused 5- or 6-membered heteroaromatic ring, where
the fused rings themselves are unsubstituted or carry 1, 2 or 3
substituents R.sup.h, R.sup.23 is selected from the group
consisting of hydrogen, fluorine, C.sub.1-C.sub.8-alkyl and
C.sub.1-C.sub.4-fluoroalkyl; R.sup.3 is selected from the group
consisting of hydrogen, C.sub.1-C.sub.8-alkyl,
C.sub.2-C.sub.8-alkenyl, C.sub.1-C.sub.4-fluoroalkyl,
C.sub.3-C.sub.8-cycloalkyl,
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl,
hydroxy-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkyl-N(R.sup.b)(R.sup.c), and trimethylsilyl, or
R.sup.2 and R.sup.3 together with the nitrogen atom, to which they
are bound form a saturated 5- to 7-membered heterocyclic ring
which, in addition to the nitrogen atom, may have 1 or 2 further
heteroatoms or heteroatom containing groups selected from the group
of O, N, S, SO and SO.sub.2 as ring members, where the heterocyclic
ring may be unsubstituted or may be substituted by 1, 2 or 3
identical or different substituents R.sup.31, and where the
heterocyclic ring may carry a fused benzene ring or a fused 5- or
6-membered heteroaromatic ring, where the fused rings themselves
are unsubstituted or carry 1, 2 or 3 substituents R.sup.32, where
R.sup.31 is selected from the group consisting of halogen, CN, OH,
C.sub.1-C.sub.4-alkyl, fluorinated C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy, fluorinated C.sub.1-C.sub.4-alkoxy,
N(R.sup.b)(R.sup.c), C(O)O--R.sup.d, C(O)N(R.sup.e)(R.sup.f), where
one radical R.sup.31 may also be a moiety Z.sup.3--Ar.sup.3,
R.sup.32 is selected from the group consisting of halogen, CN, OH,
C.sub.1-C.sub.4-alkyl, fluorinated C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy, fluorinated C.sub.1-C.sub.4-alkoxy,
N(R.sup.b)(R.sub.c), C(O)O--R.sup.d and C(O)N(R.sup.e)(R.sup.f);
R.sup.4 is selected from the group consisting of
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-fluoroalkyl,
C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl and
Z.sup.4--Ar.sup.4., R.sup.5 is selected from the group consisting
of hydrogen, halogen, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-fluoroalkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-fluoroalkoxy, --Z.sup.5--Ar.sup.5,
--O--Z.sup.5--Ar.sup.5, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl,
C.sub.3-C.sub.6-cycloalkoxy and
C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkoxy, where the cyclic
radical in the last four mentioned groups may be unsubstituted,
partially or completely fluorinated or carries 1, 2, 3 or 4 methyl
groups; Ar.sup.1 is selected from the group consisting of phenyl,
monocyclic 5- or 6-membered hetaryl or bicyclic 9- or 10-membered
hetaryl, where hetaryl has 1, 2 or 3 heteroatoms as ring members
which are selected from O, S and N, where phenyl and hetaryl are
unsubstituted or may carry 1, 2 or 3 identical or different
substituents R.sup.h; Ar.sup.2 is phenyl or monocyclic 5- or
6-membered hetaryl having 1, 2 or 3 heteroatoms as ring members
which are selected from O, S and N, where phenyl and monocyclic
hetaryl are unsubstituted or may carry 1, 2 or 3 identical or
different substituents R.sup.h; Ar.sup.3 is phenyl or monocyclic 5-
or 6-membered hetaryl having 1, 2 or 3 heteroatoms as ring members
which are selected from O, S and N, where phenyl and monocyclic
hetaryl are unsubstituted or may carry 1, 2 or 3 identical or
different substituents R.sup.h; Ar.sup.4 and Ar.sup.5 are
independently of each other selected from the group consisting of
phenyl and monocyclic 5- or 6-membered hetaryl having 1, 2 or 3
heteroatoms as ring members which are selected from O, S and N,
where phenyl and monocyclic hetaryl are unsubstituted or may carry
1, 2 or 3 identical or different substituents R.sup.k; Z.sup.1,
Z.sup.4, Z.sup.5 are independently of each other
C.sub.1-C.sub.4-alkylene; Z.sup.2 is a single bond or
C.sub.1-C.sub.4-alkylene; Z.sup.3 is a single bond,
C.sub.1-C.sub.4-alkylene, O, N, S, SO or SO.sub.2; R.sup.a is
selected from the group consisting of halogen, CN, OH, NO.sub.2,
C.sub.1-C.sub.4-alkyl, fluorinated C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy, fluorinated C.sub.1-C.sub.4-alkoxy,
(CH.sub.2).sub.mN(R.sup.b)(R.sup.c), C(O)O--R.sup.d,
C(O)N(R.sup.e)(R.sup.f), N(R.sup.ee)S(O).sub.2(R.sup.ff) and
S(O).sub.2N(R.sup.e)(R.sup.f); R.sup.b, R.sup.c, independently of
each other are selected from the group consisting of hydrogen,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-fluoroalkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkylmethyl and
benzyl or R.sup.b and R.sup.c form together with the N atom to
which they are attached a 3- to 7-membered, nitrogen heterocycle
which may have 1, 2 or 3 further different or identical heteroatoms
or heteroatom containing groups selected from the group of O, N, S,
SO and SO.sub.2 as ring members and which may carry 1, 2, 3, 4, 5
or 6 substituents selected from C.sub.1-C.sub.4-alkyl; R.sup.d is
selected from the group consisting of C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-fluoroalkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-cycloalkylmethyl and benzyl; R.sup.e, R.sup.f,
independently of each other are selected from the group consisting
of hydrogen, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-fluoroalkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkylmethyl and
benzyl or R.sup.e and R.sup.f form together with the N atom to
which they are attached a 3- to 7-membered, nitrogen heterocycle
which may have 1, 2 or 3 further different or identical heteroatoms
or heteroatom containing groups selected from the group of O, N, S,
SO and SO.sub.2 as ring members and which may carry 1, 2, 3, 4, 5
or 6 substituents selected from C.sub.1-C.sub.4-alkyl; R.sup.g is
selected from the group consisting of halogen, CN, OH,
C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl,
C.sub.1-C.sub.4-fluoroalkyl, C.sub.3-C.sub.6-cycloalkyl,
fluorinated C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl, fluorinated
C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl,
hydroxy-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkyl-N(R.sup.b)(R.sup.c), C.sub.1-C.sub.4-alkoxy,
fluorinated C.sub.1-C.sub.4-alkoxy, one R.sup.g together with a
carbon atom to which R.sup.g is attached may also form a carbonyl
group, one R.sup.g may also be phenyl or benzyl, where the phenyl
ring in the last 2 mentioned radicals is unsubstituted or carries
1, 2 or 3 radicals R.sup.h; R.sup.h is selected from the group
consisting of halogen, CN, OH, C.sub.1-C.sub.4-alkyl, fluorinated
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.6-alkoxy, fluorinated
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-alkylsulfanyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkoxy,
C.sub.3-C.sub.6-cycloalkyl, fluorinated C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-cycloalkoxy,
C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkoxy, phenoxy,
N(R.sup.b)(R.sup.c), C.sub.1-C.sub.4-alkyl-N(R.sup.b)(R.sup.c),
C(O)O--R.sup.d, C(O)N(R.sup.e)(R.sup.f),
N(R.sup.ee)S(O).sub.2(R.sup.ff), S(O).sub.2N(R.sup.e)(R.sup.f), 3-
to 7-membered heterocyclyloxy, 3- to 7-membered
heterocyclyl-C.sub.1-C.sub.4-alkoxy, where heterocyclyl in the two
last mentioned radicals has 1, 2 or 3 heteroatoms as ring members
which are selected from O, S and N, and 5- to 6-membered
hetaryl-C.sub.1-C.sub.4-alkoxy, where hetaryl has 1, 2 or 3
heteroatoms as ring members which are selected from O, S and N;
R.sup.k is selected from the group consisting of halogen, CN, OH,
C.sub.1-C.sub.4-alkyl, fluorinated C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy, fluorinated C.sub.1-C.sub.4-alkoxy,
N(R.sup.b)(R.sup.c), C(O)O--R.sup.d, C(O)N(R.sup.e)(R.sup.f),
N(R.sup.ee)S(O).sub.2(R.sup.ff) and S(O).sub.2N(R.sup.e)(R.sup.f)
or two radicals R.sup.k that are bound to adjacent carbon atoms
together with said carbon atoms may form fused benzene ring or a
fused 5- or 6-membered heteroaromatic ring having 1 or 2 ring
members selected from O, N and S, where the fused benzene ring and
the fused heteroaromatic ring are unsubstituted or may carry 1, 2
or 3 radicals R.sup.h; R.sup.ee is selected from the group
consisting of hydrogen, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-fluoroalkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-cycloalkylmethyl and benzyl; R.sup.ff is selected
from the group consisting of C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-fluoroalkyl and phenyl, which is unsubstituted or
carries 1, 2 or 3 radicals R.sup.h; m is 0, 1, 2, 3 or 4, the
N-oxides, hydrates, tautomers, the prodrugs thereof and the
pharmaceutically acceptable salts thereof.
2. The compound of claim 1, where R.sup.h is selected from the
group consisting of halogen, CN, OH, C.sub.1-C.sub.4-alkyl,
fluorinated C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy,
fluorinated C.sub.1-C.sub.4-alkoxy, C.sub.3-C.sub.6-cycloalkyl,
fluorinated C.sub.3-C.sub.6-cycloalkyl, N(R.sup.b)(R.sup.c),
C.sub.1-C.sub.4-alkyl-N(R.sup.b)(R.sup.c), C(O)O--R.sup.d,
C(O)N(R.sup.e)(R.sup.f), N(R.sup.ee)S(O).sub.2(R.sup.ff) and
S(O).sub.2N(R.sup.e)(R.sup.f).
3. The compound of claim 1, where X.sup.1 is C--H.
4. The compound of claim 1, where X.sup.1 is N.
5. The compound of claim 1, where X.sup.2 is C--R.sup.5.
6. The compound of claim 1, where X.sup.2 is N.
7. The compound of claim 1, where Y is O.
8. The compound of claim 1, where R.sup.1 is C.sub.2-C.sub.8-alkyl,
C.sub.3-C.sub.8-cycloalkyl or C.sub.3-C.sub.8-cycloalkylmethyl.
9. The compound of claim 8, where R.sup.1 is a radical of the
formula CHR.sup.1aR.sup.1b, where R.sup.1a is selected from the
group consisting of hydrogen and C.sub.1-C.sub.3-alkyl and where
R.sup.1b is selected from the group consisting of
C.sub.1-C.sub.4-alkyl.
10. The compound of claim 1, where R.sup.1 is a moiety
Z.sup.1--Ar.sup.1.
11. The compound of claim 1, where R.sup.2 is a radical of the
formula CR.sup.21R.sup.22R.sup.23.
12. The compound of claim 11, where R.sup.21 and R.sup.22 together
with the carbon atom, to which they are bound form a saturated 5-
to 7-membered carbocyclic ring or a saturated 5- to 7-membered
heterocyclic ring which has 1, 2 or 3 heteroatoms or heteroatom
containing groups selected from the group of O, N, S, SO and
SO.sub.2 as ring members, where the carbocyclic ring and the
heterocyclic ring may be unsubstituted or may be substituted by 1,
2 or 3 identical or different substituents R.sup.g, and where the
carbocyclic ring and the heterocyclic ring may carry a fused
benzene ring or a fused 5- or 6-membered heteroaromatic ring, where
the fused rings themselves are unsubstituted or carry 1, 2 or 3
substituents R.sup.h, where R.sup.h and R.sup.g are as defined in
claim 1, and where R.sup.23 is hydrogen.
13. The compound of claim 11, where R.sup.21 and R.sup.22 together
with the carbon atom, to which they are bound form a saturated 5-
to 7-membered carbocyclic ring or a 3-tetrahydrofuryl or
3-tetrahydrothienyl, where the 5- to 7-membered carbocyclic ring
and the 3-tetrahydrofuryl or 3-tetrahydrothienyl ring carry a fused
benzene ring or a fused 5- or 6-membered heteroaromatic ring, where
the fused rings themselves are unsubstituted or carry 1, 2 or 3
substituents R.sup.h, where R.sup.h are as defined in claim 1, and
where R.sup.23 is hydrogen.
14. The compound of claim 11, where R.sup.21 is selected from the
group consisting of C.sub.1-C.sub.8-alkyl, trimethylsilyl,
C.sub.2-C.sub.8-alkenyl, C.sub.1-C.sub.4-fluoroalkyl,
C.sub.3-C.sub.8-cycloalkyl, fluorinated C.sub.3-C.sub.8-cycloalkyl,
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl, fluorinated
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl and
Z.sup.2--Ar.sup.2, where Z.sup.2 and Ar.sup.2 are as defined in
claim 1; R.sup.22 is selected from the group consisting of
hydrogen, fluorine, C.sub.1-C.sub.8-alkyl; and R.sup.23 is
hydrogen.
15. The compound of claim 14, where R.sup.21 is a moiety
Z.sup.2--Ar.sup.2, where Z.sup.2 and Ar.sup.2 are as defined in
claim 1.
16. The compound of claim 1, where R.sup.3 is hydrogen or
C.sub.1-C.sub.4-alkyl.
17. The compound of claim 1, where R.sup.2 and R.sup.3 together
with the nitrogen atom, to which they are bound form a saturated 5-
to 7-membered heterocyclic ring which, in addition to the nitrogen
atom, may have 1 or 2 further heteroatoms or heteroatom containing
groups selected from the group of O, N, S, SO and SO.sub.2 as ring
members, where the heterocyclic ring may be unsubstituted or may be
substituted by 1, 2 or 3 identical or different substituents
R.sup.31, and where the heterocyclic ring may carry a fused benzene
ring or a fused 5- or 6-membered heteroaromatic ring, where the
fused rings themselves are unsubstituted or carry 1, 2 or 3
substituents R.sup.32, where R.sup.31 and R.sup.32 are as defined
in claim 1.
18. The compound of claim 1, where R.sup.4 is
C.sub.1-C.sub.4-alkyl.
19. The compound of claim 1, where X.sup.2 is C--R.sup.5 and
R.sup.5 is hydrogen, fluorine, C.sub.1-C.sub.4-alkoxy or a radical
O--Z.sup.5--Ar.sup.5.
20. The compound of claim 19, where R.sup.4 is methyl and R.sup.5
is hydrogen, fluorine or methoxy.
21. The compound of claim 19, where R.sup.4 is methyl and R.sup.5
is O--Z.sup.5--Ar.sup.5.
22. The compound of claim 1 which is a compound of the formula Ia
##STR00010## where R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5
are as defined in claim 1.
23. The compound of claim 1 which is a compound of the formula Ib
##STR00011## where R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5
are as defined in claim 1.
24. The compound of claim 22, where R.sup.1 is a radical of the
formula CHR.sup.1aR.sup.1b, where R.sup.1a is selected from the
group consisting of hydrogen and C.sub.1-C.sub.3-alkyl and where
R.sup.1b is selected from the group consisting of
C.sub.1-C.sub.4-alkyl; R.sup.2 is a radical of the formula
CR.sup.21R.sup.22R.sup.23; R.sup.3 is hydrogen or
C.sub.1-C.sub.4-alkyl; R.sup.4 is C.sub.1-C.sub.4-alkyl, and
R.sup.5 is hydrogen, fluorine, C.sub.1-C.sub.4-alkoxy or a radical
O--Z.sup.5--Ar.sup.5.
25. The compound of claim 22, where R.sup.1 is a moiety
Z.sup.1--Ar.sup.1; R.sup.2 is a radical of the formula
CR.sup.21R.sup.22R.sup.23; R.sup.3 is hydrogen or
C.sub.1-C.sub.4-alkyl; R.sup.4 is C.sub.1-C.sub.4-alkyl, and
R.sup.5 is hydrogen, fluorine or C.sub.1-C.sub.4-alkoxy.
26. The compound of claim 24, where R.sup.21 and R.sup.22 together
with the carbon atom, to which they are bound form a saturated 5-
to 7-membered carbocyclic ring, which carries a fused benzene ring
or a fused 5- or 6-membered heteroaromatic ring, where the fused
rings themselves are unsubstituted or carry 1, 2 or 3 substituents
R.sup.h, where R.sup.h are as defined in claim 1, and where
R.sup.23 is hydrogen.
27. The compound of claim 24, where R.sup.21 is selected from the
group consisting of C.sub.1-C.sub.8-alkyl, trimethylsilyl,
C.sub.2-C.sub.8-alkenyl, C.sub.1-C.sub.4-fluoroalkyl,
C.sub.3-C.sub.8-cycloalkyl, fluorinated C.sub.3-C.sub.8-cycloalkyl,
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl, fluorinated
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl and
Z.sup.2--Ar.sup.2, where Z.sup.2 and Ar.sup.2 are as defined in
claim 1; R.sup.22 is selected from the group consisting of
hydrogen, fluorine, C.sub.1-C.sub.8-alkyl; and R.sup.23 is
hydrogen.
28. The compound of claim 22, where R.sup.4 is methyl and R.sup.5
is hydrogen, fluorine or methoxy.
29. The compound of claim 22, where R.sup.4 is methyl and R.sup.5
is O--Z.sup.5--Ar.sup.5.
30. The compound of claim 1, which is selected from the group
consisting of
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid butylamide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid methylamide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid cyclopropylmethyl-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid methyl-phenethyl-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (2-methoxy-benzyl)-methyl-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (4-methoxy-benzyl)-methyl-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (3-methoxy-benzyl)-methyl-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid methyl-(3-trifluoromethyl-benzyl)-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid benzyl-(2-dimethylamino-ethyl)-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (1-benzyl-piperidin-4-yl)-methyl-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid tert-butylamide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid sec-butylamide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid isobutyl-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid cyclopentylamide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (1-methyl-butyl)-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (1,1-dimethyl-propyl)-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (1,2-dimethyl-propyl)-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (2,2-dimethyl-propyl)-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (1-ethyl-propyl)-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid ethylamide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (2-methyl-butyl)-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid pentylamide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid cyclohexylamide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (1,3-dimethyl-butyl)-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (3,3-dimethyl-butyl)-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (2-ethyl-butyl)-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid benzylamide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid dicyclopropylmethyl-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (2-fluoro-ethyl)-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid cyclohexylmethyl-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (1-phenyl-ethyl)-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid 2-fluoro-benzylamide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid 3-fluoro-benzylamide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid 4-fluoro-benzylamide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid 2,3-difluoro-benzylamide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid 2,4-difluoro-benzylamide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid 2,6-difluoro-benzylamide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid 3,4-difluoro-benzylamide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (2,2,2-trifluoro-ethyl)-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid 3,5-difluoro-benzylamide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid phenethyl-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid [1-(4-fluoro-phenyl)-ethyl]-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid indan-1-ylamide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid indan-2-ylamide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid [1-(4-fluoro-phenyl)-1-methyl-ethyl]-amide,
4-(Azetidine-1-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquinolin-1-one,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid cyclopropylamide,
2-Ethyl-6,7-dimethoxy-4-(2-methyl-pyrrolidine-1-carbonyl)-2H-isoquinolin--
1-one,
2-Ethyl-6,7-dimethoxy-4-(morpholine-4-carbonyl)-2H-isoquinolin-1-on-
e,
2-Ethyl-4-(3-fluoro-pyrrolidine-1-carbonyl)-6,7-dimethoxy-2H-isoquinoli-
n-1-one,
2-Ethyl-6,7-dimethoxy-4-(4-methyl-piperazine-1-carbonyl)-2H-isoqu-
inolin-1-one,
4-(3,3-Difluoro-pyrrolidine-1-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquino-
lin-1-one,
4-(3-Dimethylamino-pyrrolidine-1-carbonyl)-2-ethyl-6,7-dimethox-
y-2H-isoquinolin-1-one,
2-Ethyl-6,7-dimethoxy-4-((R)-2-methoxymethyl-pyrrolidine-1-carbonyl)-2H-i-
soquinolin-1-one,
4-(1,3-Dihydro-isoindole-2-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquinolin-
-1-one,
4-(4,4-Difluoro-piperidine-1-carbonyl)-2-ethyl-6,7-dimethoxy-2H-is-
oquinolin-1-one,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid isopropylamide,
2-Ethyl-4-(4-isopropyl-piperazine-1-carbonyl)-6,7-dimethoxy-2H-isoquinoli-
n-1-one,
4-(4-Dimethylamino-piperidine-1-carbonyl)-2-ethyl-6,7-dimethoxy-2-
H-isoquinolin-1-one,
2-Ethyl-6,7-dimethoxy-4-(2-trifluoromethyl-pyrrolidine-1-carbonyl)-2H-iso-
quinolin-1-one,
4-(4-Cyclopropylmethyl-piperazine-1-carbonyl)-2-ethyl-6,7-dimethoxy-2H-is-
oquinolin-1-one,
2-Ethyl-6,7-dimethoxy-4-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbon-
yl)-2H-isoquinolin-1-one,
2-Ethyl-6,7-dimethoxy-4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-2H-isoq-
uinolin-1-one,
4-[4-(2-Dimethylamino-ethyl)-piperazine-1-carbonyl]-2-ethyl-6,7-dimethoxy-
-2H-isoquinolin-1-one,
4-([1,4']Bipiperidinyl-1'-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquinolin--
1-one,
4-[4-(3-Dimethylamino-propyl)-piperazine-1-carbonyl]-2-ethyl-6,7-di-
methoxy-2H-isoquinolin-1-one,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid propylamide,
2-Ethyl-6,7-dimethoxy-4-[4-(2-pyrrolidin-1-yl-ethyl)-piperazine-1-carbony-
l]-2H-isoquinolin-1-one,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid dimethylamide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid ethyl-methyl-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid isopropyl-methyl-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid diethylamide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid methyl-propyl-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid ethyl-isopropyl-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid tert-butyl-methyl-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid isobutyl-methyl-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid butyl-methyl-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid ethyl-propyl-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (2-dimethylamino-ethyl)-methyl-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid ethyl-(2-methoxy-ethyl)-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid cyclopentyl-methyl-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid butyl-ethyl-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid methyl-pentyl-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid diisopropylamide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid isopropyl-propyl-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid cyclobutylamide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid dipropylamide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (3-dimethylamino-propyl)-methyl-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid cyclohexyl-methyl-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid cyclopropylmethyl-propyl-amide
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid diisobutylamide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid benzyl-methyl-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (2-fluoro-benzyl)-methyl-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (4-fluoro-benzyl)-methyl-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (3-fluoro-benzyl)-methyl-amide,
2-tert-Butyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid butylamide,
2-sec-Butyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid butylamide,
2-Isobutyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid butylamide,
2-Butyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid butylamide,
2-Cyclopropylmethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carbox-
ylic acid butylamide,
2-(2-Dimethylamino-ethyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4--
carboxylic acid butylamide,
2-Cyclopentyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid butylamide,
2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid butylamide,
6,7-Dimethoxy-1-oxo-2-(2,2,2-trifluoro-ethyl)-1,2-dihydro-isoquinoline-4--
carboxylic acid butylamide
6,7-Dimethoxy-1-oxo-2-(2-pyrrolidin-1-yl-ethyl)-1,2-dihydro-isoquinoline--
4-carboxylic acid butylamide,
2-(2-Fluoro-ethyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid butylamide,
2-Benzyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid butylamide,
2-(2,4-Difluoro-benzyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-ca-
rboxylic acid butylamide,
2-Cyclopropyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid butylamide,
6,7-Dimethoxy-1-oxo-2-(2-piperidin-1-yl-ethyl)-1,2-dihydro-isoquinoline-4-
-carboxylic acid butylamide,
6,7-Dimethoxy-1-oxo-2-phenethyl-1,2-dihydro-isoquinoline-4-carboxylic
acid butylamide,
6,7-Dimethoxy-2-(2-methoxy-benzyl)-1-oxo-1,2-dihydro-isoquinoline-4-carbo-
xylic acid butylamide,
2-Indan-1-yl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid butylamide,
2-Isopropyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid butylamide,
6,7-Dimethoxy-1-oxo-2-propyl-1,2-dihydro-isoquinoline-4-carboxylic
acid butylamide,
6,7-Dimethoxy-1-oxo-2-(3,3,3-trifluoro-propyl)-1,2-dihydro-isoquinoline-4-
-carboxylic acid butylamide,
6,7-Dimethoxy-2-(2-methoxy-ethyl)-1-oxo-1,2-dihydro-isoquinoline-4-carbox-
ylic acid butylamide,
2-Cyclobutyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid butylamide,
3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid butylamide,
2-Ethyl-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid
butylamide,
2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid indan-1-ylamide,
2-Ethyl-7-methoxy-1-oxo-6-(2-quinolin-2-yl-ethoxy)-1,2-dihydro-isoquinoli-
ne-4-carboxylic acid butylamide,
2-Ethyl-7-methoxy-1-oxo-6-(3-quinolin-2-yl-propoxy)-1,2-dihydro-isoquinol-
ine-4-carboxylic acid butylamide,
3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid (6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-amide,
3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid (R)-indan-1-ylamide,
2-Ethyl-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylic
acid indan-1-ylamide,
2-Ethyl-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylic
acid butylamide,
2-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid indan-1-ylamide,
3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid (6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl)-amide,
3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid
(1,2,3,4-tetrahydro-naphthalen-2-yl)-amide,
3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid (1,2,3,4-tetrahydro-naphthalen-1-yl)-amide,
3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid (4-bromo-indan-1-yl)-amide,
3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid (5-bromo-indan-1-yl)-amide,
3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid 2-dimethylaminomethyl-benzylamide,
3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid (6,7-dihydro-5H-[1]pyrindin-5-yl)-amide,
3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid (6,7-dihydro-5H-[1]pyrindin-7-yl)-amide,
3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid 3-dimethylaminomethyl-benzylamide,
3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid 4-dimethylaminomethyl-benzylamide,
7-Methoxy-1-oxo-2-(2-quinolin-2-yl-ethyl)-1,2-dihydro-isoquinoline-4-carb-
oxylic acid butylamide,
7-Methoxy-1-oxo-2-(2-quinolin-2-yl-ethyl)-1,2-dihydro-isoquinoline-4-carb-
oxylic acid indan-1-ylamide,
3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid (S)-indan-1-ylamide,
2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid (6,7-dihydro-5H-[1]pyrindin-5-yl)-amide,
2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid 2-dimethylaminomethyl-benzylamide,
2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid 3,5-difluoro-benzylamide,
2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid 3,4-difluoro-benzylamide,
2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid cyclohexylmethyl-amide,
2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid (R)-indan-1-ylamide,
2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid (S)-indan-1-ylamide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (1,2,3,4-tetrahydro-naphthalen-1-yl)-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid pyridin-3-ylamide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (pyrimidin-4-ylmethyl)-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid 2-methoxy-benzylamide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (4-morpholin-4-yl-phenyl)-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid 3-chloro-benzylamide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (pyridin-4-ylmethyl)-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid o-tolylamide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid m-tolylamide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (2-methoxy-phenyl)-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (3-methoxy-phenyl)-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (pyridin-3-ylmethyl)-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (pyridin-2-ylmethyl)-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (3-dimethylamino-propyl)-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid phenylamide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid 4-methoxy-benzylamide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid 3-methyl-benzylamide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid 2-methyl-benzylamide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (2-methoxy-ethyl)-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (4-fluoro-phenyl)-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (4-methoxy-phenyl)-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid p-tolylamide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (3-fluoro-phenyl)-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (2-fluoro-phenyl)-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid 4-methyl-benzylamide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid 2-chloro-benzylamide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid [(R)-1-(4-fluoro-phenyl)-ethyl]-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid pyridin-4-ylamide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid [(S)-1-(4-fluoro-phenyl)-ethyl]-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (6-methyl-indan-1-yl)-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid 2-morpholin-4-ylmethyl-benzylamide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (5-chloro-indan-1-yl)-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (6-chloro-indan-1-yl)-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (6-fluoro-indan-1-yl)-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (4-fluoro-indan-1-yl)-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (4-methyl-indan-1-yl)-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (5-methyl-indan-1-yl)-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (6-methoxy-indan-1-yl)-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (5-fluoro-indan-1-yl)-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid 2-diethylaminomethyl-benzylamide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid 2-pyrrolidin-1-ylmethyl-benzylamide,
2-Ethyl-6,7-dimethoxy-4-(4-methyl-piperidine-1-carbonyl)-2H-isoquinolin-1-
-one,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (tetrahydro-furan-2-ylmethyl)-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (3-methoxy-propyl)-amide,
4-(3,5-Dimethyl-piperidine-1-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquinol-
in-1-one,
2-Ethyl-4-(4-ethyl-piperazine-1-carbonyl)-6,7-dimethoxy-2H-isoqu-
inolin-1-one,
2-Isobutyl-6,7-dimethoxy-4-(4-methyl-piperazine-1-carbonyl)-2H-isoquinoli-
n-1-one,
2-Isobutyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid (2-dimethylamino-ethyl)-amide,
2-Isobutyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid butyl-methyl-amide,
[(2-Isobutyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carbonyl)-ami-
no]-acetic acid methyl ester,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (3-isopropoxy-propyl)-amide,
2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid (5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide,
2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid (2,3-dihydro-benzofuran-3-yl)-amide,
2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid (6-oxo-5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide,
2-Cyclopropyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid indan-1-ylamide,
2-sec-Butyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid indan-1-ylamide,
2-Isopropyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid indan-1-ylamide,
2-(1-Ethyl-propyl)-6,7-dimethoxy-4-(3-phenyl-piperidine-1-carbonyl)-2H-is-
oquinolin-1-one,
2-(1-Ethyl-propyl)-6,7-dimethoxy-4-(3-phenoxy-piperidine-1-carbonyl)-2H-i-
soquinolin-1-one,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (S)indan-1-ylamide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (R)indan-1-ylamide,
2-(1-Ethyl-propyl)-6,7-dimethoxy-4-[3-(3-methoxy-phenyl)-piperazine-1-car-
bonyl]-2H-isoquinolin-1-one,
2-(1-Ethyl-propyl)-6,7-dimethoxy-4-[8-(4-methyl-piperazine-1-sulfonyl)-3,-
4-dihydro-1H-isoquinoline-2-carbonyl]-2H-isoquinolin-1-one,
2-(1-Ethyl-propyl)-6,7-dimethoxy-4-[8-(morpholine-4-sulfonyl)-3,4-dihydro-
-1H-isoquinoline-2-carbonyl]-2H-isoquinolin-1-one,
2-(1-Ethyl-propyl)-6,7-dimethoxy-4-[3-(3-methoxy-phenyl)-4-methyl-piperaz-
ine-1-carbonyl]-2H-isoquinolin-1-one,
2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid ([1,3,4]thiadiazol-2-ylmethyl)-amide,
2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid 2-(morpholine-4-sulfonyl)-benzylamide,
2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid (thiazol-4-ylmethyl)-amide,
2-(1-Ethyl-propyl)-6,7-dimethoxy-4-[(R)-3-(quinoxalin-2-yloxy)-pyrrolidin-
e-1-carbonyl]-2H-isoquinolin-1-one,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (S)(5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide,
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (R)(5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide,
2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid (thiophen-3-ylmethyl)-amide,
4-(7-Amino-3,4-dihydro-1H-isoquinoline-2-carbonyl)-2-(1-ethyl-propyl)-6,7-
-dimethoxy-2H-isoquinolin-1-one,
2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid 3-(4-chloro-benzenesulfonylamino)-benzylamide,
2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid (2,3-dihydro-benzo[b]thiophen-3-yl)-amide,
2-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carbo-
xylic acid (5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide,
2-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carbo-
xylic acid (S)-indan-1-ylamide,
2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid 2-(4-methyl-piperazine-1-sulfonyl)-benzylamide,
2-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carbo-
xylic acid 2-(morpholine-4-sulfonyl)-benzylamide,
2-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carbo-
xylic acid (6,7-dihydro-5H-[1]pyrindin-5-yl)-amide,
2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid 3-(4-methoxy-benzenesulfonylamino)-benzylamide,
2-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carbo-
xylic acid 3,5-difluoro-benzylamide,
2-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carbo-
xylic acid 4-methyl-benzylamide,
2-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carbo-
xylic acid cyclohexylmethyl-amide,
2-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carbo-
xylic acid butylamide,
2-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carbo-
xylic acid (2,3-dihydro-benzofuran-3-yl)-amide,
2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid (thiazol-2-ylmethyl)-amide,
2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid (thiophen-2-ylmethyl)-amide,
2-Ethyl-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylic
acid (5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide,
3-(1-Ethyl-propyl)-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxyl-
ic acid (5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide,
3-(1-Ethyl-propyl)-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxyl-
ic acid (2,3-dihydro-benzofuran-3-yl)-amide,
3-(1-Ethyl-propyl)-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxyl-
ic acid indan-1-ylamide,
3-(1-Ethyl-propyl)-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxyl-
ic acid (6,7-dihydro-5H-[1]pyrindin-5-yl)-amide,
2-(1-Ethyl-propyl)-6,7-dimethoxy-4-(3-phenyl-propionyl)-2H-isoquinolin-1--
one,
2-Ethyl-6,7-dimethoxy-N-(4-nitrophenyl)-1-oxo-1,2-dihydroisoquinoline-
-4-carboxamide, and the N-oxides, the tautomers, the hydrates, the
prodrugs and the pharmaceutically acceptable salts thereof.
31. The compound of claim 1, which is selected from the group
consisting of
6,7-Dimethoxy-1-oxo-2-(pentan-3-yl)-N-(pyridin-3-ylmethyl)-1,2-dihydro-
isoquinoline-4-carboxamide,
6,7-Dimethoxy-N-((5-methylthiophen-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-
-dihydroisoquinoline-4-carboxamide,
N-((3,5-Dimethylisoxazol-4-yl)methyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-
-1,2-dihydroisoquinoline-4-carboxamide,
6,7-dimethoxy-N-((5-methylthiazol-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2--
dihydroisoquinoline-4-carboxamide,
6,7-Dimethoxy-1-oxo-2-(pentan-3-yl)-N-(pyrimidin-4-ylmethyl)-1,2-dihydroi-
soquinoline-4-carboxamide,
6,7-Dimethoxy-N-((3-methylisoxazol-5-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-
-dihydroisoquinoline-4-carboxamide,
N-((2,5-Dimethylthiophen-3-yl)methyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-
-1,2-dihydroisoquinoline-4-carboxamide,
6,7-Dimethoxy-N-((2-methylthiazol-5-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2--
dihydroisoquinoline-4-carboxamide,
6,7-Dimethoxy-N-((5-methylisoxazol-3-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-
-dihydroisoquinoline-4-carboxamide,
(R)--N-(1-(4-Fluorophenyl)ethyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2--
dihydroisoquinoline-4-carboxamide,
(S)--N-(1-(4-Fluorophenyl)ethyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2--
dihydroisoquinoline-4-carboxamide,
6,7-Dimethoxy-N-((4-methylthiazol-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2--
dihydroisoquinoline-4-carboxamide,
6,7-Dimethoxy-N-((2-methylthiazol-4-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2--
dihydroisoquinoline-4-carboxamide,
6,7-Dimethoxy-N-((4-methylthiazol-5-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2--
dihydroisoquinoline-4-carboxamide,
6,7-Dimethoxy-1-oxo-2-(pentan-3-yl)-N-((5-(trifluoromethyl)furan-2-yl)met-
hyl)-1,2-dihydroisoquinoline-4-carboxamide,
6,7-Dimethoxy-N-((5-methylfuran-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-di-
hydroisoquinoline-4-carboxamide,
N-(5-Fluoro-2,3-dihydro-1H-inden-1-yl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl-
)-1,2-dihydroiso-quinoline-4-carboxamide,
6,7-Dimethoxy-N-(5-methyl-2,3-dihydro-1H-inden-1-yl)-1-oxo-2-(pentan-3-yl-
)-1,2-dihydroisoquinoline-4-carboxamide,
6,7-Dimethoxy-N-(4-methyl-2,3-dihydro-1H-inden-1-yl)-1-oxo-2-(pentan-3-yl-
)-1,2-dihydroisoquinoline-4-carboxamide,
N-((2-Ethylthiazol-4-yl)methyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2-d-
ihydroisoquinoline-4-carboxamide,
6,7-Dimethoxy-N-(6-methoxy-2,3-dihydro-1H-inden-1-yl)-1-oxo-2-(pentan-3-y-
l)-1,2-dihydroisoquinoline-4-carboxamide,
6,7-Dimethoxy-N-((4-methylthiophen-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-
-dihydroisoquinoline-4-carboxamide,
6,7-Dimethoxy-N-((3-methylthiophen-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-
-dihydroisoquinoline-4-carboxamide,
6,7-Dimethoxy-N-((5-methyloxazol-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-d-
ihydroisoquinoline-4-carboxamide,
6,7-Dimethoxy-N-(6-methyl-2,3-dihydro-1H-inden-1-yl)-1-oxo-2-(pentan-3-yl-
)-1,2-dihydroisoquinoline-4-carboxamide,
6,7-Dimethoxy-1-oxo-2-(pentan-3-yl)-N-(pyridin-4-ylmethyl)-1,2-dihydroiso-
quinoline-4-carboxamide,
6,7-Dimethoxy-N-(4-methylbenzyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquin-
oline-4-carboxamide,
6,7-Dimethoxy-1-oxo-2-(pentan-3-yl)-N-(pyridin-2-ylmethyl)-1,2-dihydroiso-
quinoline-4-carboxamide,
N-((5-Cyanofuran-2-yl)methyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2-dih-
ydroisoquinoline-4-carboxamide,
N-(4-Chloro-2,3-dihydro-1H-inden-1-yl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl-
)-1,2-dihydroisoquinoline-4-carboxamide,
N-((5-Ethylthiophen-2-yl)methyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2--
dihydroisoquinoline-4-carboxamide,
6,7-Dimethoxy-N-((3-methylfuran-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-di-
hydroisoquinoline-4-carboxamide,
6,7-Dimethoxy-N-((2-methylfuran-3-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-di-
hydroisoquinoline-4-carboxamide,
6,7-Dimethoxy-N-((1-methyl-1H-pyrazol-3-yl)methyl)-1-oxo-2-(pentan-3-yl)--
1,2-dihydroisoquinoline-4-carboxamide,
N-[(3,4-Dimethylphenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4-
-carboxamide,
N-[(2-Chloro-4-methyl-phenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquino-
line-4-carboxamide,
N-[[2-(Dimethylamino)-4-methyl-phenyl]methyl]-2-ethyl-6,7-dimethoxy-1-oxo-
-isoquinoline-4-carboxamide,
2-Ethyl-N-[(2-fluoro-4-methyl-phenyl)methyl]-6,7-dimethoxy-1-oxo-isoquino-
line-4-carboxamide,
2-Ethyl-6,7-dimethoxy-N-[(3-methoxy-4-methyl-phenyl)methyl]-1-oxo-isoquin-
oline-4-carboxamide,
2-Ethyl-6,7-dimethoxy-N-[(4-methyl-2-morpholino-phenyl)methyl]-1-oxo-isoq-
uinoline-4-carboxamide,
N-[(2-tert-Butoxy-4-methyl-phenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo-iso-
quinoline-4-carboxamide,
N-[[2-(1,1-Dimethylpropoxy)-4-methyl-phenyl]methyl]-2-ethyl-6,7-dimethoxy-
-1-oxo-isoquinoline-4-carboxamide,
N-[(2,3-Difluoro-4-methyl-phenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoq-
uinoline-4-carboxamide,
2-Ethyl-N-[(3-fluoro-4-methyl-phenyl)methyl]-6,7-dimethoxy-1-oxo-isoquino-
line-4-carboxamide,
N-[(3-Chloro-4-methyl-phenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquino-
line-4-carboxamide,
2-Ethyl-6,7-dimethoxy-1-oxo-N-[(2,4,6-trimethylphenyl)methyl]isoquinoline-
-4-carboxamide,
N-[(2,4-Dimethylphenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4-
-carboxamide,
2-Ethyl-6,7-dimethoxy-N-[[2-(3-methoxypropoxy)-4-methyl-phenyl]methyl]-1--
oxo-isoquinoline-4-carboxamide,
N-[[2-(2-Ethoxyethoxy)-4-methyl-phenyl]methyl]-2-ethyl-6,7-dimethoxy-1-ox-
o-isoquinoline-4-carboxamide,
N-[[2-(Cyclopentoxy)-4-methyl-phenyl]methyl]-2-ethyl-6,7-dimethoxy-1-oxo--
isoquinoline-4-carboxamide,
2-Ethyl-6,7-dimethoxy-N-[(4-methyl-2-phenoxy-phenyl)methyl]-1-oxo-isoquin-
oline-4-carboxamide,
2-Ethyl-6,7-dimethoxy-N-[[2-(2-methoxy-1-methyl-ethoxy)-4-methyl-phenyl]m-
ethyl]-1-oxo-isoquinoline-4-carboxamide,
2-Ethyl-6,7-dimethoxy-N-[[4-methyl-2-(2,2,2-trifluoroethoxy)phenyl]methyl-
]-1-oxo-isoquinoline-4-carboxamide,
N-[[2-(Cyclohexoxy)-4-methyl-phenyl]methyl]-2-ethyl-6,7-dimethoxy-1-oxo-i-
soquinoline-4-carboxamide,
N-[[2-(Cyclopropylmethoxy)-4-methyl-phenyl]methyl]-2-ethyl-6,7-dimethoxy--
1-oxo-isoquinoline-4-carboxamide,
2-Ethyl-N-[(2-hexoxy-4-methyl-phenyl)methyl]-6,7-dimethoxy-1-oxo-isoquino-
line-4-carboxamide,
2-Ethyl-6,7-dimethoxy-N-[[4-methyl-2-(tetrahydrofuran-3-ylmethoxy)phenyl]-
methyl]-1-oxo-isoquinoline-4-carboxamide,
2-Ethyl-6,7-dimethoxy-N-[[2-(2-methoxyethoxy)-4-methyl-phenyl]methyl]-1-o-
xo-isoquinoline-4-carboxamide,
2-Ethyl-N-(2-isobutoxy-4-methylbenzyl)-6,7-dimethoxy-1-oxo-1,2-dihydroiso-
quinoline-4-carboxamide,
2-Ethyl-N-(2-(furan-2-ylmethoxy)-4-methylbenzyl)-6,7-dimethoxy-1-oxo-1,2--
dihydroisoquinoline-4-carboxamide,
2-Ethyl-6,7-dimethoxy-N-(4-methyl-2-(pentyloxy)benzyl)-1-oxo-1,2-dihydroi-
soquinoline-4-carboxamide,
N-(2-Ethoxy-4-methylbenzyl)-2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydroisoqui-
noline-4-carboxamide,
N-(2-sec-Butoxy-4-methylbenzyl)-2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydrois-
oquinoline-4-carboxamide,
2-Ethyl-N-(2-(isopentyloxy)-4-methylbenzyl)-6,7-dimethoxy-1-oxo-1,2-dihyd-
roisoquinoline-4-carboxamide,
2-Ethyl-6,7-dimethoxy-N-(4-methyl-2-propoxybenzyl)-1-oxo-1,2-dihydroisoqu-
inoline-4-carboxamide,
2-Ethyl-6,7-dimethoxy-N-(4-methyl-2-(methylthio)benzyl)-1-oxo-1,2-dihydro-
isoquinoline-4-carboxamide,
2-Ethyl-N-(2-isopropoxy-4-methylbenzyl)-6,7-dimethoxy-1-oxo-1,2-dihydrois-
oquinoline-4-carboxamide,
2-Ethyl-6,7-dimethoxy-N-(4-methyl-2-(tetrahydrofuran-3-yloxy)benzyl)-1-ox-
o-1,2-dihydroisoquinoline-4-carboxamide,
2-Ethyl-6,7-dimethoxy-1-oxo-N-(2,4,5-trimethylbenzyl)-1,2-dihydroisoquino-
line-4-carboxamide,
2-Ethyl-6,7-dimethoxy-N-(4-methyl-2-((tetrahydrofuran-2-yl)methoxy)benzyl-
)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide,
2-Ethyl-6,7-dimethoxy-N-(4-methyl-2-(4-methylpentan-2-yloxy)benzyl)-1-oxo-
-1,2-dihydroisoquinoline-4-carboxamide,
2-Ethyl-6,7-dimethoxy-N-(4-methyl-2-(4-methylpentyloxy)benzyl)-1-oxo-1,2--
dihydroisoquinoline-4-carboxamide,
2-Ethyl-6,7-dimethoxy-N-(2-methoxy-4-methylbenzyl)-1-oxo-1,2-dihydroisoqu-
inoline-4-carboxamide,
2-Ethyl-6,7-dimethoxy-1-oxo-N-(thiazol-4-ylmethyl)isoquinoline-4-carboxam-
ide,
2-Ethyl-6,7-dimethoxy-1-oxo-N-[[4-(trifluoromethyl)phenyl]methyl]isoq-
uinoline-4-carboxamide,
2-Ethyl-6,7-dimethoxy-1-oxo-N-[(1S)-1-(p-tolyl)ethyl]isoquinoline-4-carbo-
xamide,
2-Ethyl-N-[(4-isopropylphenyl)methyl]-6,7-dimethoxy-1-oxo-isoquino-
line-4-carboxamide,
2-Ethyl-N-[(4-ethylphenyl)methyl]-6,7-dimethoxy-1-oxo-isoquinoline-4-carb-
oxamide,
2-Ethyl-6,7-dimethoxy-1-oxo-N-[(1R)-1-(p-tolyl)ethyl]isoquinoline-
-4-carboxamide,
N-[[4-(Difluoromethyl)phenyl]methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquino-
line-4-carboxamide,
2-Ethyl-6,7-dimethoxy-N-[(2-methylthiazol-4-yl)methyl]-1-oxo-isoquinoline-
-4-carboxamide,
2-Ethyl-6,7-dimethoxy-N-[(4-methyl-2-thienyl)methyl]-1-oxo-isoquinoline-4-
-carboxamide,
N-[(4-Cyclopropylphenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline--
4-carboxamide,
N-Indan-1-yl-6,7-dimethoxy-2-[2-(5-methyl-2-pyridyl)-ethyl]-1-oxo-isoquin-
oline-4-carboxamide,
N-Butyl-6,7-dimethoxy-2-[2-(5-methyl-2-pyridyl)-ethyl]-1-oxo-isoquinoline-
-4-carboxamide,
2-Ethyl-6,7-dimethoxy-N-[2-(6-methoxy-2-pyridyl)-ethyl]-1-oxo-isoquinolin-
e-4-carboxamide,
N-Butyl-6,7-dimethoxy-1-oxo-2-[2-(2-quinolyl)ethyl]isoquinoline-4-carboxa-
mide,
N-Indan-1-yl-6,7-dimethoxy-1-oxo-2-[2-(2-quinolyl)ethyl]isoquinoline-
-4-carboxamide; and the N-oxides, the tautomers, the hydrates, the
prodrugs and the pharmaceutically acceptable salts thereof.
32. The compound of claim 1 for the use in the treatment of a
medical disorder, selected from neurological and psychiatric
disorders which can be treated by modulation of phosphodiesterase
type 10 in a mammalian.
33. The compound of claim 1 for treating, controlling, ameliorating
or reducing the risk of CNS disorders in a mammalian.
34. The compound of claim 1 for treating, controlling, ameliorating
or reducing the risk of schizophrenia in a mammalian.
35. The compound of claim 1 for treating, controlling, ameliorating
or reducing cognitive dysfunction associated with schizophrenia in
a mammalian.
36. The compound of claim 1 for treating, controlling, ameliorating
or reducing the risk of bipolar disorders in a mammalian.
37. The compound of claim 1 for treating, controlling, ameliorating
or reducing the risk of depression in a mammalian.
38. The compound of claim 1 for treating, controlling, ameliorating
or reducing cognitive dysfunction associated with Alzheimer's
disease in a mammalian.
39. The compound of claim 1 for treating, controlling, ameliorating
or reducing the risk of diet-induced obesity in a mammalian.
40. A method for treating a medical disorder, selected from
neurological and psychiatric disorders which can be treated by
modulation of phosphodiesterase type 10, said method comprising
administering an effective amount of at least one compound of claim
1 to a subject in need thereof.
41. Pharmaceutical composition which comprises a carrier and a
compound as claimed in claim 1.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This claims priority to U.S. Provisional Patent Application
No. 61/557,878, filed on Nov. 9, 2011, the contents of which are
herein fully incorporated by reference.
[0002] The present invention relates to compounds which are
inhibitors of phosphodiesterase type 10A and to their use for the
manufacture of a medicament and which thus are suitable for
treating or controlling of medical disorders selected from
neurological disorders and psychiatric disorders, for ameliorating
the symptoms associated with such disorders and for reducing the
risk of such disorders.
BACKGROUND OF THE INVENTION
[0003] Phosphodiesterase type 10A (hereinafter PDE10A) is a
dual-substrate phosphodiesterase that can convert both cAMP to AMP
and cGMP to GMP. PDE10A is highly prominent in the mammalian brain.
In the rat, as well as in other mammalian species, PDE10A and the
mRNA of PDE10A are highly enriched in the GABAergic medium spiny
projection neurons (MSNs) of the striatal complex (caudate nucleus,
nucleus accumbens, and olfactory tubercle) where the output is
regulated by the effect of PDE10A on cAMP and cGMP signalling
cascades (see e.g. C. J. Schmidt et al, The Journal of Pharmacology
and Experimental Therapeutics 325 (2008) 681-690, A. Nishi, The
Journal of Neuroscience 2008, 28, 10450-10471).
[0004] MSNs express two functional classes of neurons: the D.sub.1
class expressing D.sub.1 dopamine receptors and the D.sub.2 class
expressing D.sub.2 dopamine receptors. The D.sub.1 class of neurons
is part of the `direct` striatal output pathway, which broadly
functions to facilitate behavioral responses. The D.sub.2 class of
neurons is part of the `indirect` striatal output pathway, which
functions to suppress behavioral responses that compete with those
being facilitated by the `direct` pathway. PDE10A regulation of
cAMP and/or cGMP signaling in the dendritic compartment of these
neurons may be involved in filtering the cortico/thalamic input
into the MSN. Furthermore, PDE10A may be involved in the regulation
of GABA release in the substantia nigra and globus pallidus
(Seeger, T. F. et al. Brain Research, 2003, 985, 1 13-126)
Inhibition of PDE10A results in striatal activation and behavioral
suppression such as dampened locomotion, inhibition of conditioned
avoidance response (CAR), and activity in the rat auditory gating
model, suggesting that inhibitors of phosphodiesterase type 10A
represent a novel class of antipsychotic agents.
[0005] The hypotheses around the physiological role of PDE10A and
the therapeutic utility of PDE10A inhibitors derive in part from
studies with papaverine (J. A. Siuciak et al. loc. cit.), the first
extensively profiled pharmacological tool compound for this target.
The PDE10A inhibitor papaverine was shown to be active in several
antipsychotic models. Papaverine potentiated the cataleptic effect
of the D.sub.2 receptor antagonist haloperidol in rats, but did not
cause catalepsy on its own (WO 03/093499). Papaverine reduced
hyperactivity in rats induced by PCP, while reduction of
amphetamine-induced hyperactivity was insignificant (WO 03/093499).
These models suggest that PDE10A inhibition has the classic
antipsychotic potential that would be expected from theoretical
considerations. Papaverine, however has significant limitations in
this regard with relatively poor potency and selectivity and a very
short exposure half-life after systemic administration. It was
found that inhibition of PDE10A reverses subchronic PCP-induced
deficits in attentional set-shifting in rats suggesting that PDE10A
inhibitors might alleviate cognitive deficits associated with
schizophrenia. (Rodefer et al., Eur. J. Neurosci., 4 (2005)
1070-1076).
[0006] The discovery of a new class of PDE10A inhibitors with
improved potency, selectivity, and pharmacokinetic properties,
provided an opportunity to further explore the physiology of PDE10A
and the potential therapeutic utility of inhibiting this enzyme.
The new class of inhibitors are exemplified by MP-10 (PF-2545920:
2-{-4-[1-methylpyridine-4-yl-1-H-pyrazol-3-31y]phenoxymethyl}-quinoline)
and TP-10, i.e.
2-{4-[pyridine-4-yl-1-(2,2,2-trifluoroethyl)-1-H-pyrazol-3-31yl]phenoxyme-
thyl}-quinoline. The compounds offer a therapeutic approach to the
treatment of schizophrenia (see C. J. Schmidt et al., loc cit.; S.
M. Grauer et al., Journal of Pharmacology and Experimental
Therapeutics, fast forward DOI 10.1124 JPET 109.155994). Positive
signals in rodent models of schizophrenia include the: attenuation
of conditioned avoidance response (CAR), inhibition of
hyperactivity caused by amphetamine-induced dopamine release or
phencyclidine (PCP) mediated NMDA receptor blockade, attenuation of
pharmacologically impaired social or object recognition, and
antagonism of apomorphine-induced climbing. Taken together, these
data suggest a broad suppression of all 3 symptoms clusters
(positive symptoms, negative symptoms & cognitive dysfunctions)
linked to schizophrenia (see C. J. Schmidt et al., loc cit.; S. M.
Grauer et al., loc. cit).
[0007] Beyond schizophrenia, selective PDE10 inhibitors may have
the potential for the treatment of Huntington's disease (S. H.
Francis et al., Physiol. Rev., 91 (2011) 651-690) and they may be
an therapeutic option for substance abuse disorders (F. Sotty et
al., J. Neurochem., 109 (2009) 766-775). Furthermore, it has been
suggested that PDE10A inhibitors may be useful for treatment of
obesity and non-insulin dependent diabetes (see e.g. WO
2005/120514, WO 2005/012485, Cantin et al, Bioorganic &
Medicinal Chemistry Letters 17 (2007) 2869-2873).
[0008] In summary, inhibitors of PDE10A offer a promising
therapeutic approach to the treatment or prevention of neurological
and psychiatric disorders, in particular schizophrenia and related
disorders, including symptoms linked to schizophrenia such as
cognitive dysfunction.
[0009] Several classes of compounds which are inhibitors of PDE10A
have been described in the art, the recent compound groups are:
[0010] Pyrido[3,2-e]pyridazines--see WO 2007/137819, WO
2007/137820, WO 2009/068246, WO 2009/068320, WO 2009/070583 and WO
2009/070584;
[0011] 4-substituted phthalazines and quinazolines WO 2007/085954,
WO 2007/022280, WO 2007/096743, WO 2007/103370, WO 2008/020302, WO
2008/006372 and WO 2009/036766;
[0012] 4-substituted cinnazolines--see WO 2006/028957, WO
2007/098169, WO 2007/098214, WO 2007/103554, WO 2009/025823 and WO
2009/025839;
[0013] Isoquinolines and isoquinolinones--see WO 2007/100880 and WO
2009/029214;
[0014] MP10 and MP10 like compounds: US 2007/0155779, WO
2008/001182 and WO 2008/004117; and
[0015] Benzodiazepines--see WO 2007/082546.
[0016] For a further review see also T. Chappie et al. Current
Opinion in Drug Discovery & Development 12(4), (2009) 458-467)
and the literature cited therein.
[0017] Although some of the compounds of prior art are known to
inhibit PDE10A effectively having IC.sub.50 values of less than 50
nM, there is still an ongoing need for compounds which inhibit
PDE10A. In particular, there is an ongoing need for compounds which
have one of the following characteristics: [0018] i. Selective
inhibition of PDE10A, in particular vis-a-vis inhibition of other
phosphodisesterases such as PDE3 or PDE4; [0019] ii. metabolic
stability, in particular microsomal stability, e.g. measured in
vitro, in liver microsomes from various species (e.g. rat or human)
in human cells, such as hepatocytes; [0020] iii. no or only low
inhibition of cytochrome P450 (CYP) enzymes: cytochrome P450 (CYP)
is the name for a superfamily of heme proteins having enzymatic
activity (oxidase). They are also particularly important for the
degradation (metabolism) of foreign substances such as drugs or
xenobiotics in mammalian organisms. The principal representatives
of the types and subtypes of CYP in the human body are: CYP 1A2,
CYP 2C9, CYP 2D6 and CYP 3A4. If CYP 3A4 inhibitors (e.g.
grapefruit juice, cimetidine, erythromycin) are used at the same
time as medicinal substances which are degraded by this enzyme
system and thus compete for the same binding site on the enzyme,
the degradation thereof may be slowed down and thus effects and
side effects of the administered medicinal substance may be
undesirably enhanced; [0021] iv. a suitable solubility in water (in
mg/ml); [0022] v. suitable pharmacokinetics (time course of the
concentration of the compound of the invention in plasma or in
tissue, for example brain). The pharmacokinetics can be described
by the following parameters: half-life, volume of distribution (in
lkg.sup.-1), plasma clearance (in lh.sup.-1kg.sup.-1), AUC (area
under the curve, area under the concentration-time curve (in
nghl.sup.-1), oral bioavailability, (the dose-normalized ratio of
AUC after oral administration and AUC after intravenous
administration), the so-called brain-plasma ratio (the ratio of AUC
in brain tissue and AUC in plasma); [0023] vi. no or only low
blockade of the hERG channel: compounds which block the hERG
channel may cause a prolongation of the QT interval and thus lead
to serious disturbances of cardiac rhythm (for example so-called
"torsade de pointes"). The potential of compounds to block the hERG
channel can be determined by means of the displacement assay with
radiolabelled dofetilide which is described in the literature (G.
J. Diaz et al., Journal of Pharmacological and Toxicological
Methods, 50 (2004), 187-199). A smaller IC50 in this dofetilide
assay means a greater probability of potent hERG blockade. In
addition, the blockade of the hERG channel can be measured by
electrophysiological experiments on cells which have been
transfected with the hERG channel, by so-called whole-cell patch
clamping (G. J. Diaz et al., Journal of Pharmacological and
Toxicological Methods, 50 (2004), 187-199). [0024] vii. high free
fraction in brain, i.e. the fraction of the compound bound to
proteins should be low. [0025] viii. low lipophilicity.
BRIEF DESCRIPTION OF THE INVENTION
[0026] The present invention is thus based on the object of
providing compounds which inhibit PDE10A at low concentrations.
[0027] The compounds are further intended to display at least one
of the properties i. to viii. mentioned above, in particular high
selectivity with regard to inhibition of PDE10A, high selectivity
vis-a-vis other phosphodiesterases such as, enhanced metabolic
stability, in particular microsomal and/or cytosolic stability, low
affinity to the HERG receptor, low inhibition of cytochrome P450
(CYP) enzymes, suitable solubility in water and suitable
pharmacokinetics.
[0028] This object and further objects are achieved by the
compounds of the general formula I described below, the N-oxides,
the prodrugs, the hydrates and the tautomers thereof and the
pharmaceutically suitable salts thereof:
##STR00001## [0029] wherein [0030] X.sup.1 is CH or N, [0031]
X.sup.2 is C--R.sup.5 or N, [0032] Y is O or S, [0033] R.sup.1 is
selected from the group consisting of C.sub.2-C.sub.8-alkyl,
C.sub.2-C.sub.8-alkenyl, C.sub.1-C.sub.4-fluoroalkyl,
C.sub.3-C.sub.8-cycloalkyl, C.sub.5-C.sub.8-cycloalkyl carrying a
fused benzene ring, fluorinated C.sub.3-C.sub.8-cycloalkyl,
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl, fluorinated
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl,
hydroxy-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkyl-N(R.sup.b)(R.sup.c) and a moiety
Z.sup.1--Ar.sup.1; [0034] R.sup.2 is a radical of the formula
CR.sup.21R.sup.22R.sup.23 or phenyl or 5- or 6-membered hetaryl
having 1, 2 or 3 heteroatoms as ring members which are selected
from O, S and N, where phenyl and monocyclic hetaryl are
unsubstituted or may carry 1, 2 or 3 identical or different
substituents R.sup.a, where [0035] R.sup.21 is selected from the
group consisting of hydrogen, C.sub.1-C.sub.8-alkyl,
trimethylsilyl, C.sub.2-C.sub.8-alkenyl,
C.sub.1-C.sub.4-fluoroalkyl, C.sub.3-C.sub.8-cycloalkyl,
fluorinated C.sub.3-C.sub.8-cycloalkyl,
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl, fluorinated
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl,
hydroxy-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkyl-N(R.sup.b)(R.sup.c),
(CH.sub.2).sub.mC(O)O--R.sup.d,
(CH.sub.2).sub.mC(O)N(R.sup.e)(R.sup.f) and Z.sup.2--Ar.sup.2,
[0036] R.sup.22 is selected from the group consisting of hydrogen,
fluorine, C.sub.1-C.sub.8-alkyl, C.sub.2-C.sub.8-alkenyl,
C.sub.1-C.sub.4-fluoroalkyl, C.sub.3-C.sub.8-cycloalkyl,
fluorinated C.sub.3-C.sub.8-cycloalkyl,
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl, fluorinated
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl,
hydroxy-C.sub.1-C.sub.4-alkyl and
C.sub.1-C.sub.4-alkyl-N(R.sup.b)(R.sup.c), or [0037] R.sup.21 and
R.sup.22 together with the carbon atom, to which they are bound
form a saturated 5- to 7-membered carbocyclic ring or a saturated
5- to 7-membered heterocyclic ring which has 1, 2 or 3 heteroatoms
or heteroatom containing groups selected from the group of O, N, S,
SO and SO.sub.2 as ring members, where the carbocyclic ring and the
heterocyclic ring may be unsubstituted or may be substituted by 1,
2 or 3 identical or different substituents R.sup.g, and where the
carbocyclic ring and the heterocyclic ring may carry a fused
benzene ring or a fused 5- or 6-membered heteroaromatic ring, where
the fused rings themselves are unsubstituted or carry 1, 2 or 3
substituents R.sup.h, [0038] R.sup.23 is selected from the group
consisting of hydrogen, fluorine, C.sub.1-C.sub.8-alkyl and
C.sub.1-C.sub.4-fluoroalkyl; [0039] R.sup.3 is selected from the
group consisting of hydrogen, C.sub.1-C.sub.8-alkyl,
C.sub.2-C.sub.8-alkenyl, C.sub.1-C.sub.4-fluoroalkyl,
C.sub.3-C.sub.8-cycloalkyl,
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl,
hydroxy-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkyl-N(R.sup.b)(R.sup.c), and trimethylsilyl, or
[0040] R.sup.2 and R.sup.3 together with the nitrogen atom, to
which they are bound form a saturated 5- to 7-membered heterocyclic
ring which, in addition to the nitrogen atom, may have 1 or 2
further heteroatoms or heteroatom containing groups selected from
the group of O, N, S, SO and SO.sub.2 as ring members, where the
heterocyclic ring may be unsubstituted or may be substituted by 1,
2 or 3 identical or different substituents R.sup.31, and where the
heterocyclic ring may carry a fused benzene ring or a fused 5- or
6-membered heteroaromatic ring, where the fused rings themselves
are unsubstituted or carry 1, 2 or 3 substituents R.sup.32, where
[0041] R.sup.31 is selected from the group consisting of halogen,
CN, OH, C.sub.1-C.sub.4-alkyl, fluorinated C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy, fluorinated C.sub.1-C.sub.4-alkoxy,
N(R.sup.b)(R.sup.c), C(O)O--R.sup.d, C(O)N(R.sup.e)(R.sup.f), where
one radical R.sup.31 may also be a moiety Z.sup.3--Ar.sup.3, [0042]
R.sup.32 is selected from the group consisting of halogen, CN, OH,
C.sub.1-C.sub.4-alkyl, fluorinated C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy, fluorinated C.sub.1-C.sub.4-alkoxy,
N(R.sup.b)(R.sup.c), C(O)O--R.sup.d and C(O)N(R.sup.e)(R.sup.f);
[0043] R.sup.4 is selected from the group consisting of
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-fluoroalkyl,
C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl and
Z.sup.4--Ar.sup.4, [0044] R.sup.5 is selected from the group
consisting of hydrogen, halogen, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-fluoroalkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-fluoroalkoxy, --Z.sup.5--Ar.sup.5,
--O--Z.sup.5--Ar.sup.5, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl,
C.sub.3-C.sub.6-cycloalkoxy and
C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkoxy, where the cyclic
radical in the last four mentioned groups may be unsubstituted,
partially or completely fluorinated or carries 1, 2, 3 or 4 methyl
groups; [0045] Ar.sup.1 is selected from the group consisting of
phenyl, monocyclic 5- or 6-membered hetaryl or bicyclic 9- or
10-membered hetaryl, where hetaryl has 1, 2 or 3 heteroatoms as
ring members which are selected from O, S and N, where phenyl and
hetaryl are unsubstituted or may carry 1, 2 or 3 identical or
different substituents R.sup.h; [0046] Ar.sup.2 is phenyl or
monocyclic 5- or 6-membered hetaryl having 1, 2 or 3 heteroatoms as
ring members which are selected from O, S and N, where phenyl and
monocyclic hetaryl are unsubstituted or may carry 1, 2 or 3
identical or different substituents R.sup.h; [0047] Ar.sup.3 is
phenyl or monocyclic 5- or 6-membered hetaryl having 1, 2 or 3
heteroatoms as ring members which are selected from O, S and N,
where phenyl and monocyclic hetaryl are unsubstituted or may carry
1, 2 or 3 identical or different substituents R.sup.h; [0048]
Ar.sup.4 and Ar.sup.5 are independently of each other selected from
the group consisting of phenyl and monocyclic 5- or 6-membered
hetaryl having 1, 2 or 3 heteroatoms as ring members which are
selected from O, S and N, where phenyl and monocyclic hetaryl are
unsubstituted or may carry 1, 2 or 3 identical or different
substituents R.sup.k; [0049] Z.sup.1, Z.sup.4, Z.sup.5 are
independently of each other C.sub.1-C.sub.4-alkylene; [0050]
Z.sup.2 is a single bond or C.sub.1-C.sub.4-alkylene; [0051]
Z.sup.3 is a single bond, C.sub.1-C.sub.4-alkylene, O, N, S, SO or
SO.sub.2; [0052] R.sup.a is selected from the group consisting of
halogen, CN, OH, NO.sub.2, C.sub.1-C.sub.4-alkyl, fluorinated
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, fluorinated
C.sub.1-C.sub.4-alkoxy, (CH.sub.2).sub.mN(R.sup.b)(R.sup.c),
C(O)O--R.sup.d, C(O)N(R.sup.e)(R.sup.f),
N(R.sup.ee)S(O).sub.2(R.sup.ff) and S(O).sub.2N(R.sup.e)(R.sup.f);
[0053] R.sup.b, R.sup.c, independently of each other are selected
from the group consisting of hydrogen, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-fluoroalkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-cycloalkylmethyl and benzyl or R.sup.b and R.sup.c
form together with the N atom to which they are attached a 3- to
7-membered, nitrogen heterocycle which may have 1, 2 or 3 further
different or identical heteroatoms or heteroatom containing groups
selected from the group of O, N, S, SO and SO.sub.2 as ring members
and which may carry 1, 2, 3, 4, 5 or 6 substituents selected from
C.sub.1-C.sub.4-alkyl; [0054] R.sup.d is selected from the group
consisting of C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-fluoroalkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkylmethyl and
benzyl; [0055] R.sup.e, R.sup.f, independently of each other are
selected from the group consisting of hydrogen,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-fluoroalkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkylmethyl and
benzyl or R.sup.e and R.sup.f form together with the N atom to
which they are attached a 3- to 7-membered, nitrogen heterocycle
which may have 1, 2 or 3 further different or identical heteroatoms
or heteroatom containing groups selected from the group of O, N, S,
SO and SO.sub.2 as ring members and which may carry 1, 2, 3, 4, 5
or 6 substituents selected from C.sub.1-C.sub.4-alkyl; [0056]
R.sup.g is selected from the group consisting of halogen, CN, OH,
C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl,
C.sub.1-C.sub.4-fluoroalkyl, C.sub.3-C.sub.6-cycloalkyl,
fluorinated C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl, fluorinated
C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl,
hydroxy-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkyl-N(R.sup.b)(R.sup.c), C.sub.1-C.sub.4-alkoxy,
fluorinated C.sub.1-C.sub.4-alkoxy, one R.sup.g together with a
carbon atom to which R.sup.g is attached may also form a carbonyl
group, one R.sup.g may also be phenyl or benzyl, where the phenyl
ring in the last 2 mentioned radicals is unsubstituted or carries
1, 2 or 3 radicals R.sup.h; [0057] R.sup.h is selected from the
group consisting of halogen, CN, OH, C.sub.1-C.sub.4-alkyl,
fluorinated C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.6-alkoxy,
fluorinated C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-alkylsulfanyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkoxy,
C.sub.3-C.sub.6-cycloalkyl, fluorinated C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-cycloalkoxy,
C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkoxy, phenoxy,
N(R.sup.b)(R.sup.c), C.sub.1-C.sub.4-alkyl-N(R.sup.b)(R.sup.c),
C(O)O--R.sup.d, C(O)N(R.sup.e)(R.sup.f),
N(R.sup.ee)S(O).sub.2(R.sup.ff), S(O).sub.2N(R.sup.e)(R.sup.f), 3-
to 7-membered heterocyclyloxy, 3- to 7-membered
heterocyclyl-C.sub.1-C.sub.4-alkoxy, where heterocyclyl in the two
last mentioned radicals has 1, 2 or 3 heteroatoms as ring members
which are selected from O, S and N, and 5- to 6-membered
hetaryl-C.sub.1-C.sub.4-alkoxy, where hetaryl has 1, 2 or 3
heteroatoms as ring members which are selected from O, S and N;
[0058] R.sup.k is selected from the group consisting of halogen,
CN, OH, C.sub.1-C.sub.4-alkyl, fluorinated C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy, fluorinated C.sub.1-C.sub.4-alkoxy,
N(R.sup.b)(R.sup.c), C(O)O--R.sup.d, C(O)N(R.sup.e)(R.sup.f),
N(R.sup.ee)S(O).sub.2(R.sup.ff) and S(O).sub.2N(R.sup.e)(R.sup.f)
or two radicals R.sup.k that are bound to adjacent carbon atoms
together with said carbon atoms may form fused benzene ring or a
fused 5- or 6-membered heteroaromatic ring having 1 or 2 ring
members selected from O, N and S, where the fused benzene ring and
the fused heteroaromatic ring are unsubstituted or may carry 1, 2
or 3 radicals R.sup.h; [0059] R.sup.ee is selected from the group
consisting of hydrogen, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-fluoroalkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-cycloalkylmethyl and benzyl; [0060] R.sup.ff is
selected from the group consisting of C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-fluoroalkyl and phenyl, which is unsubstituted or
carries 1, 2 or 3 radicals R.sup.h; [0061] m is 0, 1, 2, 3 or
4.
[0062] The present invention therefore relates to the compounds of
the general formula I, the N-oxides, the tautomers and the hydrates
thereof, the pharmaceutically acceptable salts of the compounds of
formula I, the prodrugs of the compounds of formula I and the
pharmaceutically acceptable salts of said N-oxides, prodrugs,
tautomers or hydrates of the compounds of formula I.
[0063] The present invention also relates to the compounds of the
general formula I, the N-oxides, the tautomers and the hydrates
thereof, the pharmaceutically acceptable salts of the compounds of
formula I, the prodrugs of the compounds of formula I and the
pharmaceutically acceptable salts of said N-oxides, prodrugs,
tautomers or hydrates of the compounds of formula I for the use in
the treatment of a medical disorder, selected from neurological and
psychiatric disorders which can be treated by modulation of
phosphodiesterase type 10.
[0064] The compounds of the formula I, their pharmaceutically
acceptable salts, their N-oxides, their prodrugs, their hydrates
and their tautomers and the pharmaceutically acceptable salts of
said N-oxides, prodrugs, tautomers or hydrates effectively inhibit
PDE10A even at low concentrations. They are additionally
distinguished by a high selectivity in relation to the inhibition
of the PDE10A vis-a-vis inhibition of other phosphodiesterease,
such as PDE3 or PDE4. The compounds of the invention may
additionally have one or more of the properties ii. to viii.
mentioned above.
[0065] The compounds of the formula I, their pharmaceutically
acceptable salts, their N-oxides, their prodrugs, their hydrates
and their tautomers and the pharmaceutically acceptable salts of
said N-oxides, prodrugs, tautomers or hydrates are therefore
particularly suitable for treating disorders and conditions in
creatures, especially human creatures, which can be treated or
controlled by inhibition of phosphodiesterase type 10A.
[0066] The invention therefore also relates to the use of the
compounds of the formula I, their N-oxides, their tautomers, their
hydrates and their pharmaceutically acceptable salts and the
pharmaceutically acceptable salts of said N-oxides, prodrugs,
tautomers or hydrates for the manufacture of a medicament, in
particular of a medicament which is suitable for the treatment of a
disorder or a condition which can be treated by inhibition of
phosphodiesterase type 10A.
[0067] The invention further relates to a medicament, in particular
a medicament which is suitable for the treatment of a disorder or a
condition which can be treated by inhibition of phosphodiesterase
type 10A. The medicament comprises at least one compound of the
formula I, as described herein, or an N-oxide, a tautomer, or a
hydrate or a prodrug of said compound I, or a pharmaceutically
acceptable salt of the compound of the formula I or a
pharmaceutically acceptable salt of the N-oxide, the tautomer, the
hydrate or the prodrug of compound of the formula I.
DETAILED DESCRIPTION OF THE INVENTION
[0068] The terms "compound of the formula I" and "compounds I" are
used as synonyms. The term "prodrugs" means compounds which are
metabolized in vivo to the compounds I of the invention. Typical
examples of prodrugs are described in C. G. Wermuth (editor): The
Practice of Medicinal Chemistry, Academic Press, San Diego, 1996,
pages 671-715. These include for example phosphates, carbamates,
amino acids, esters, amides, peptides, ureas and the like. Suitable
prodrugs in the present case may be for example derivatives of
those compounds I carrying an OH or NH.sub.2-group, where the OH or
NH.sub.2-group forms an ester/amide/peptide linkage, i.e. where one
of the hydrogen atoms of the OH or NH.sub.2-group is substituted by
a C.sub.1-C.sub.4-alkylcarbonyl group, e.g. by acetyl, propionyl,
n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl or
tert-butylcarbonyl (pivaloyl), by benzoyl, or by an acyl group
derived from an amino acid, e.g. glycine, alanine, serine,
phenylalanine and the like, which is linked to the oxygen or
nitrogen of the OH or NH.sub.2-group via the carbonyl group of the
amino acid. Further suitable prodrugs are alkylcarbonyloxyalkyl
carbonates or carbamates of compounds I carrying an OH-- or
NH.sub.2-group in which one of the hydrogen atoms of the OH-- or
NH.sub.2-group has been replaced by a group of the formula
--C(.dbd.O)--O--CHR.sup.p--O--C(.dbd.O)--R.sup.q in which R.sup.p
and R.sup.q are independently of one another C.sub.1-C.sub.4-alkyl.
Such carbonates and carbamates are described for example in J.
Alexander, R. Cargill, S. R. Michelson, H. Schwam, J. Medicinal
Chem. 1988, 31(2), 318-322. These groups can then be eliminated
under metabolic conditions and result in compounds I. Therefore,
said prodrugs and their pharmaceutically acceptable salts are also
part of the invention.
[0069] The term "pharmaceutically acceptable salts" refers to
cationic or anionic salts compounds, wherein the counter ion is
derived from pharmaceutically acceptable non-toxic bases or acids
including inorganic or organic bases and inorganic or organic
acids.
[0070] When the compound of formula I or its prodrug, tautomer,
hydrate or N-oxide is acidic, salts may be prepared from
pharmaceutically acceptable non-toxic bases, including inorganic
and organic bases. Salts derived from inorganic bases include
salts, wherein the counter ion is aluminium, ammonium, calcium,
copper, ferric, ferrous, lithium, magnesium, manganic, manganous,
potassium, sodium, zinc ion and the like. Particularly preferred
are the ammonium, calcium, magnesium, potassium, and sodium ions.
Salts derived from pharmaceutically acceptable organic non-toxic
bases include salts of primary, secondary, and tertiary amines,
substituted amines including naturally occurring substituted
amines, cyclic amines, and basic ion exchange resins, such as
arginine, betaine, caffeine, choline, dibenzylethylene-diamine,
diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,
ethanolamine, ethylenediamine, N-ethyl-morpholine,
N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine,
isopropylamine, lysine, methylglucamine, morpholine, piperazine,
piperidine, polyamine resins, procaine, purines, theobromine,
triethylamine, trimethylamine, tripropylamine, tromethamine, and
the like.
[0071] When the compound of formula I or its prodrug, tautomer,
hydrate or N-oxide is basic, salts may be prepared from
pharmaceutically acceptable non-toxic acids, including inorganic
and organic acids. Such acids include acetic, trifluoroacetic acid,
benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic,
fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic,
lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric,
pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,
p-toluenesulfonic acid, and the like. Particularly preferred are
citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric,
fumaric, and tartaric acids. It will be understood that, as used
herein, references to the compounds of formula I are meant to also
include the pharmaceutically acceptable salts.
[0072] The compounds of the invention may be in the form of a
mixture of diastereomers, or of a mixture of diastereomers in which
one of the two diastereomers is enriched, or of essentially
diastereomerically pure compounds (diastereomeric excess de
>90%). The compounds are preferably in the form of essentially
diastereomerically pure compounds (diastereomeric excess de
>90%). The compounds I of the invention may furthermore be in
the form of a mixture of enantiomers (for example as racemate), of
a mixture of enantiomers in which one of the two enantiomers is
enriched, or essentially in enantiomerically pure compounds
(enantiomeric excess ee >90%). However, the compounds of the
invention are frequently prone to racemization in relation to the
stereochemistry of the carbon atom which carries the radical
R.sup.1, so that mixtures are frequently obtained in relation to
this carbon atom, or compounds which exhibit a uniform
stereochemistry in relation to this C atom form mixtures under
physiological conditions. However, in relation to other
stereocenters and the occurrence, associated therewith, of
enantiomers and diastereomers, it is preferred to employ the
compounds enantiomerically pure or diastereomerically pure.
[0073] The present invention moreover relates to compounds as
defined herein, wherein one or more of the atoms depicted in
formula I have been replaced by its stable, preferably
non-radioactive isotope (e.g., hydrogen by deuterium, .sup.12C by
.sup.13C, .sup.14N by .sup.15N, .sup.16O by .sup.18O) and
preferably wherein at least one hydrogen atom has been replaced by
a deuterium atom. Of course, the compounds according to the
invention contain more of the respective isotope than this
naturally occurs and thus is anyway present in the compounds I.
[0074] The compounds of the formula I and their salts in the solid
form may exist in more than one crystal structure (polymorphism),
and may also be in the form of hydrates or other solvates. The
present invention includes any polymorph of the compound I or its
salt as well as any hydrate or other solvate.
[0075] In the context of the present description, unless stated
otherwise, the terms "alkyl", "alkenyl", "alkoxy", "alkenyloxy",
"fluoroalkyl", "fluoroalkoxy", "cycloalkyl", "fluorinated
cycloalkyl", "alkylene", "alkandiyl", "hetaryl" and radicals
derived therefrom, such as "hydroxylalkyl", "alkoxylalkyl",
"alkoxyalkoxy", "cycloalkylalkyl" and "fluorinated cycloalkylalkyl"
and "hetarylalkyl" represent groups of individual radicals. The
groups of noncyclic radicals "alkyl", "alkenyl", "alkoxy",
"alkenyloxy", "fluoroalkyl", "fluoroalkoxy", "alkylene",
"alkandiyl", and the groups of radicals derived therefrom always
include both unbranched and branched "alkyl", "alkenyl", "alkoxy",
"alkenyloxy", "fluoroalkyl", "fluoroalkoxy", "alkylene" and
"alkandiyl", respectively.
[0076] The prefix C.sub.n-C.sub.m- indicates the respective number
of carbons in the hydrocarbon unit. Unless indicated otherwise,
fluorinated substituents preferably have one to five identical or
different fluorine atoms.
[0077] The term "halogen" designates in each case, fluorine,
bromine, chlorine or iodine, specifically fluorine, chlorine or
bromine
[0078] Examples of other meanings are:
[0079] Alkyl, and the alkyl moieties for example in alkylcarbonyl,
alkylsulfanyl, alkylsulfonyl, alkylsulfanylalkyl and
alkylsulfanylalkoxy: saturated, straight-chain or branched
hydrocarbon radicals having one or more C atoms, e.g. 1 to 10, 1 to
8, 1 to 6 or 1 to 4 carbon atoms. Examples of C.sub.1-C.sub.4-alkyl
are methyl, ethyl, propyl, 1-methylethyl, n-butyl, 1-methylpropyl,
2-methylpropyl and 1,1-dimethylethyl. C.sub.1-C.sub.6-alkyl are,
apart those mentioned for C.sub.1-C.sub.4-alkyl, n-pentyl,
1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl,
1-ethylpropyl, n-hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl,
1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,
1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,
2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl,
1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl,
1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and
1-ethyl-2-methylpropyl. Examples for C.sub.1-C.sub.8-alkyl or
C.sub.2-C.sub.9-alkyl are, apart those mentioned for
C.sub.1-C.sub.6-alkyl, n-heptyl, 1-methylhexyl, 2-methylhexyl,
3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1-ethylpentyl,
2-ethylpentyl, 3-ethylpentyl, n-octyl, 1-methyloctyl,
2-methylheptyl, 1-ethylhexyl, 2-ethylhexyl, 1,2-dimethylhexyl and
1-propylpentyl, 2-propylpentyl.
[0080] Fluoroalkyl and the fluoroalkyl moieties for example in
fluoroalkylsulfonyl: an alkyl radical having ordinarily 1 to 4 C
atoms, in particular 1 or 2 C-atoms (C.sub.1-C.sub.2-fluoroalkyl)
as mentioned above, whose hydrogen atoms are partly or completely
replaced by fluorine atoms such as fluoromethyl, difluoromethyl,
trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl,
2,2,2-trifluoroethyl, pentafluoroethyl, 2-fluoro-1-methylethyl,
2,2-difluoro-1-methylethyl, 2,2-trifluoro-1-methylethyl,
2-fluoropropyl, 3-fluoropropyl, 2,2-difluoropropyl,
2,3-difluoropropyl, 3,3,3-trifluoropropyl,
2,3,3,3-pentafluoropropyl, heptafluoropropyl,
1-(fluoromethyl)-2-fluoroethyl, 4-fluorobutyl, and
nonafluorobutyl.
[0081] Cycloalkyl, and the cycloalkyl moieties for example in
cycloalkoxy, cycloalkyl-C.sub.1-C.sub.4-alkyl or
cycloalkyl-C.sub.1-C.sub.4-alkoxy: monocyclic, saturated
hydrocarbon groups having three or more C atoms, e.g. 3, 4, 5, 6, 7
or 8 carbon ring members, such as cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl and cycloheptyl.
[0082] Fluorinated cycloalkyl, and the flourinted cycloalkyl
moieties for example in fluorinated cycloalkoxy or fluorinated
cycloalkyl-C.sub.1-C.sub.4-alkyl: monocyclic, saturated hydrocarbon
groups having three or more C atoms, e.g. 3, 4, 5, 6, 7 or 8 carbon
ring members, such as cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl and cycloheptyl, wherein at least one, e.g. 1, 2, 3, 4,
5 or 6 of the hydrogen atoms are replaced by fluorine atoms,
examples including 1-fluorocyclopropyl, 2-fluorocyclopropyl,
2,2-difluorocyclopropyl, 1,2-difluorocyclopropyl,
2,3-difluorocyclopropyl, etc.
[0083] Cycloalkoxy: a cycloalkyl radical as defined above which is
linked via an oxygen atom, e.g. cyclopropyloxy, cyclobutyloxy,
cyclopentyloxy or cyclohexyloxy.
[0084] Cycloalkylalkyl: a cycloalkyl radical as defined above which
is linked via an alkylene group, in particular via a methylene,
1,1-ethylene or 1,2-ethylene group, e.g. cyclopropylmethyl,
cyclobutylmethyl, cyclopentylmethy, cyclohexylmethyl,
1-cyclopropylethyl, 1-cyclobutylethyl, 1-cyclopentylethyl,
1-cyclohexylethyl, 2-cyclopropylethyl, 2-cyclobutylethyl,
2-cyclopentylethyl or 2-cyclohexylethyl.
[0085] Fluorinated cycloalkylalkyl: a fluorinated cycloalkyl
radical as defined above which is linked via an alkylene group, in
particular via a methylene, 1,1-ethylene or 1,2-ethylene group,
e.g. 1-fluorocyclopropylmethyl, 2-fluorocyclopropylmethyl,
2,2-difluorocyclopropylmethyl, 1,2-difluorocyclopropylmethyl,
2,3-difluorocyclopropylmethyl, 1-(1-fluorocyclopropyl)ethyl,
1-(2-fluorocyclopropyl)ethyl, 1-(2,2-difluorocyclopropyl)ethyl,
1-(1,2-difluorocyclopropyl)ethyl, 1-(2,3-difluorocyclopropyl)ethyl,
2-(1-fluorocyclopropyl)ethyl, 2-(2-fluorocyclopropyl)ethyl,
2-(2,2-difluorocyclopropyl)ethyl, 2-(1,2-difluorocyclopropyl)ethyl
or 2-(2,3-difluorocyclopropyl)ethyl.
[0086] Alkenyl, and alkenyl moieties for example in alkenyloxy:
monounsaturated, straight-chain or branched hydrocarbon radicals
having two or more C atoms, e.g. 2 to 4 carbon atoms and one
C.dbd.C-double bond in any position, e.g. C.sub.2-C.sub.4-alkenyl
such as ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl,
1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl,
2-methyl-1-propenyl, 1-methyl-2-propenyl and
2-methyl-2-propenyl.
[0087] Alkoxy or alkoxy moieties for example in alkoxyalkyl and
alkoxyalkoxy:
[0088] an alkyl radical as defined above ordinarily having 1 to 6 C
atoms, preferably 1 to 4 C atoms, which is connected to the
remainder of the molecule via an O atom: e.g. methoxy, ethoxy,
n-propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy
or 1,1-dimethylethoxy.
[0089] Fluoroalkoxy: alkoxy as described above, in which the
hydrogen atoms of these groups are partly or completely replaced by
fluorine atoms, i.e. for example C.sub.1-C.sub.4-fluoroalkoxy, in
particular C.sub.1-C.sub.2-fluoroalkoxy, such as fluoromethoxy,
difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy,
2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy,
2-fluoropropoxy, 3-fluoropropoxy, 2,2-difluoropropoxy,
2,3-difluoropropoxy, 3,3,3-trifluoropropoxy,
2,2,3,3,3-pentafluoropropoxy, heptafluoropropoxy,
1-(fluoromethyl)-2-fluoroethoxy, specifically fluoromethoxy,
difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, or
2,2,2-trifluoroethoxy.
[0090] Hydroxyalkyl: an alkyl radical ordinarily having 1 to 4 C
atoms, in which one hydrogen atom is replaced by an OH radical.
Examples thereof are CH.sub.2--OH, 1-hydroxyethyl, 2-hydroxyethyl,
1-hydroxypropyl, 2-hydroxypropyl, 1-methyl-1-hydroxyethyl,
1-methyl-2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxybutyl,
3-hydroxybutyl, 4-hydroxybutyl, 1-methyl-2-hydroxypropyl,
1,1-dimethyl-2-hydroxyetyl, 1-methyl-1-hydroxypropyl etc.
[0091] Alkylsulfanyl: alkyl as defined above preferably having 1 to
4 C atoms, which is connected via a sulfur atom to the remainder of
the molecule, e.g. methylsulfanyl, ethylsulfanyl, n-propylsulfanyl
and the like.
[0092] Alkoxyalkyl: an alkyl radical ordinarily having 1 to 4 C
atoms, in which one hydrogen atom is replaced by an alkoxy radical
ordinarily having 1 to 4 C atoms. Examples thereof are
CH.sub.2--OCH.sub.3, CH.sub.2--OC.sub.2H.sub.5, n-propoxymethyl,
CH.sub.2--OCH(CH.sub.3).sub.2, n-butoxymethyl,
(1-methylpropoxy)methyl, (2-methylpropoxy)methyl,
CH.sub.2--OC(CH.sub.3).sub.3, 2-(methoxy)ethyl, 2-(ethoxy)ethyl,
2-(n-propoxy)ethyl, 2-(1-methylethoxy)ethyl, 2-(n-butoxy)ethyl,
2-(1-methylpropoxy)ethyl, 2-(2-methylpropoxy)ethyl,
2-(1,1-dimethylethoxy)ethyl, 2-(methoxy)propyl, 2-(ethoxy)propyl,
2-(n-propoxy)propyl, 2-(1-methylethoxy)propyl, 2-(n-butoxy)propyl,
2-(1-methylpropoxy)propyl, 2-(2-methylpropoxy)propyl,
2-(1,1-dimethylethoxy)propyl, 3-(methoxy)propyl, 3-(ethoxy)propyl,
3-(n-propoxy)propyl, 3-(1-methylethoxy)propyl, 3-(n-butoxy)propyl,
3-(1-methylpropoxy)propyl, 3-(2-methylpropoxy)propyl,
3-(1,1-dimethylethoxy)propyl, 2-(methoxy)butyl, 2-(ethoxy)butyl,
2-(n-propoxy)butyl, 2-(1-methylethoxy)butyl, 2-(n-butoxy)butyl,
2-(1-methylpropoxy)butyl, 2-(2-methylpropoxy)butyl,
2-(1,1-dimethylethoxy)butyl, 3-(methoxy)butyl, 3-(ethoxy)butyl,
3-(n-propoxy)butyl, 3-(1-methylethoxy)butyl, 3-(n-butoxy)butyl,
3-(1-methylpropoxy)butyl, 3-(2-methylpropoxy)butyl,
3-(1,1-dimethylethoxy)butyl, 4-(methoxy)butyl, 4-(ethoxy)butyl,
4-(n-propoxy)butyl, 4-(1-methylethoxy)butyl, 4-(n-butoxy)butyl,
4-(1-methylpropoxy)butyl, 4-(2-methylpropoxy)butyl,
4-(1,1-dimethylethoxy)butyl, etc.
[0093] Alkoxyalkoxy: an alkoxyalkyl radical as defined above
ordinarily having 1 to 4 C atoms both in the alkoxy and the alkyl
moiety which is connected to the remainder of the molecule via an O
atom: Examples thereof are OCH.sub.2--OCH.sub.3,
OCH.sub.2--OC.sub.2H.sub.5, n-propoxymethoxy,
OCH.sub.2--OCH(CH.sub.3).sub.2, n-butoxymethoxy,
(1-methylpropoxy)methoxy, (2-methylpropoxy)methoxy,
OCH.sub.2--OC(CH.sub.3).sub.3, 2-(methoxy)ethoxy, 2-(ethoxy)ethoxy,
2-(n-propoxy)ethoxy, 2-(1-methylethoxy)ethoxy, 2-(n-butoxy)ethoxy,
2-(1-methylpropoxy)ethoxy, 2-(2-methylpropoxy)ethoxy,
2-(1,1-dimethyl-ethoxy)ethoxy, etc.
[0094] Cycloalkylalkoxy: an alkoxy radical ordinarily having 1 to 4
C atoms, preferably 1 to 2 C atoms, in which one hydrogen atom is
replaced by a cycloalkyl radical ordinarily having 3 to 6 C atoms
as defined above. Examples thereof are cyclopropylmethoxy,
cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy,
cyclopropylethoxy, cyclobutylethoxy, cyclopentylethoxy,
cyclohexylethoxy and the like.
[0095] "Alkylen" or "alkanediyl": a saturated hydrocarbon chain
having ordinarily from 1 to 4 carbon atoms, such as methylen
(--CH.sub.2--), 1,2-ethylen (--CH.sub.2CH.sub.2--), 1,1-ethanediyl
(--CH(CH.sub.3)--), 1,2-propanediyl, 1,3-propanediyl,
1,4-butanediyl, 1,2-butanediyl, 1,3-butanediyl,
1-methyl-1,2-propanediyl, 2-methyl-1,3-propanediyl,
1-methyl-1,1-ethanediyl, 1-methyl-1,2-propanediyl etc.
[0096] Saturated or partially unsaturated 5- to 7-membered
monocarbocyclic radicals include cycloalkyl as defined above and
cycloalkenyl having ordinarily from 4 to 7 carbon atoms as ring
members, e.g. 1-cyclobuten-1-yl, 2-cyclobutenyl, 1-cyclopentenyl,
2-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl,
1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl.
[0097] Heterocyclyl: a heterocyclic radical which may be saturated
or partly unsaturated and which may be a monocyclic heterocyclic
radical ordinarily having 3, 4, 5, 6, 7 or 8 ring atoms or a
heterobicyclic radical ordinarily having 7, 8, 9 or 10 ring atoms,
where ordinarily 1, 2, 3 or 4, in particular 1, 2 or 3, of the ring
atoms are heteroatoms such as N, S or O, or heteroatom groups such
as S(.dbd.O) or S(.dbd.O).sub.2 besides carbon atoms as ring
members.
[0098] Examples of saturated heteromonocycles are in particular:
[0099] Saturated heteromonocyclic radical which ordinarily has 3,
4, 5, 6 or 7 ring atoms, where ordinarily 1, 2 or 3 of the ring
atoms are heteroatoms such as N, S or O, besides carbon atoms as
ring members. These include for example: [0100] C-bonded, 3- or
4-membered saturated rings such as [0101] 2-oxiranyl, 2-oxetanyl,
3-oxetanyl, 2-aziridinyl, 3-thiethanyl, 1-azetidinyl, 2-azetidinyl.
[0102] C-bonded, 5-membered saturated rings such as [0103]
tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl,
tetrahydrothien-3-yl, tetrahydropyrrol-2-yl, tetrahydropyrrol-3-yl,
tetrahydropyrazol-3-yl, tetrahydropyrazol-4-yl,
tetrahydroisoxazol-3-yl, tetrahydroisoxazol-4-yl,
tetrahydroisoxazol-5-yl, 1,2-oxathiolan-3-yl, 1,2-oxathiolan-4-yl,
1,2-oxathiolan-5-yl, tetrahydroisothiazol-3-yl,
tetrahydroisothiazol-4-yl, tetrahydroisothiazol-5-yl,
1,2-dithiolan-3-yl, 1,2-dithiolan-4-yl, tetrahydroimidazol-2-yl,
tetrahydroimidazol-4-yl, tetrahydrooxazol-2-yl,
tetrahydrooxazol-4-yl, tetrahydrooxazol-5-yl,
tetrahydrothiazol-2-yl, tetrahydrothiazol-4-yl,
tetrahydrothiazol-5-yl, 1,3-dioxolan-2-yl, 1,3-dioxolan-4-yl,
1,3-oxathiolan-2-yl, 1,3-oxathiolan-4-yl, 1,3-oxathiolan-5-yl,
1,3-dithiolan-2-yl, 1,3-dithiolan-4-yl, 1,3,2-dioxathiolan-4-yl.
[0104] C-bonded, 6-membered saturated rings such as: [0105]
tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl,
piperidin-2-yl, piperidin-3-yl, piperidin-4-yl,
tetrahydrothiopyran-2-yl, tetrahydrothiopyran-3-yl,
tetrahydrothiopyran-4-yl, 1,3-dioxan-2-yl, 1,3-dioxan-4-yl,
1,3-dioxan-5-yl, 1,4-dioxan-2-yl, 1,3-dithian-2-yl,
1,3-dithian-4-yl, 1,3-dithian-5-yl, 1,4-dithian-2-yl,
1,3-oxathian-2-yl, 1,3-oxathian-4-yl, 1,3-oxathian-5-yl,
1,3-oxathian-6-yl, 1,4-oxathian-2-yl, 1,4-oxathian-3-yl,
1,2-dithian-3-yl, 1,2-dithian-4-yl, hexahydropyrimidin-2-yl,
hexahydropyrimidin-4-yl, hexahydropyrimidin-5-yl,
hexahydropyrazin-2-yl, hexahydropyridazin-3-yl,
hexahydropyridazin-4-yl, tetrahydro-1,3-oxazin-2-yl,
tetrahydro-1,3-oxazin-4-yl, tetrahydro-1,3-oxazin-5-yl,
tetrahydro-1,3-oxazin-6-yl, tetrahydro-1,3-thiazin-2-yl,
tetrahydro-1,3-thiazin-4-yl, tetrahydro-1,3-thiazin-5-yl,
tetrahydro-1,3-thiazin-6-yl, tetrahydro-1,4-thiazin-2-yl,
tetrahydro-1,4-thiazin-3-yl, tetrahydro-1,4-oxazin-2-yl,
tetrahydro-1,4-oxazin-3-yl, tetrahydro-1,2-oxazin-3-yl,
tetrahydro-1,2-oxazin-4-yl, tetrahydro-1,2-oxazin-5-yl,
tetrahydro-1,2-oxazin-6-yl. [0106] N-bonded, 5-membered saturated
rings such as: [0107] tetrahydropyrrol-1-yl,
tetrahydropyrazol-1-yl, tetrahydroisoxazol-2-yl,
tetrahydroisothiazol-2-yl, tetrahydroimidazol-1-yl,
tetrahydrooxazol-3-yl, tetrahydrothiazol-3-yl. [0108] N-bonded,
6-membered saturated rings such as: piperidin-1-yl,
hexahydropyrimidin-1-yl, hexahydropyrazin-1-yl,
hexahydro-pyridazin-1-yl, tetrahydro-1,3-oxazin-3-yl,
tetrahydro-1,3-thiazin-3-yl, tetrahydro-1,4-thiazin-4-yl,
tetrahydro-1,4-oxazin-4-yl, tetrahydro-1,2-oxazin-2-yl. [0109]
Unsaturated heteromonocyclic radicals which ordinarily have 4, 5, 6
or 7 ring atoms, where ordinarily 1, 2 or 3 of the ring atoms are
heteroatoms such as N, S or O, besides carbon atoms as ring
members. These include for example: [0110] C-bonded, 5-membered,
partially unsaturated rings such as: 2,3-dihydrofuran-2-yl,
2,3-dihydrofuran-3-yl, 2,5-dihydrofuran-2-yl,
2,5-dihydrofuran-3-yl, 4,5-dihydrofuran-2-yl,
4,5-dihydrofuran-3-yl, 2,3-dihydrothien-2-yl,
2,3-dihydrothien-3-yl, 2,5-dihydrothien-2-yl,
2,5-dihydrothien-3-yl, 4,5-dihydrothien-2-yl,
4,5-dihydrothien-3-yl, 2,3-dihydro-1H-pyrrol-2-yl,
2,3-dihydro-1H-pyrrol-3-yl, 2,5-dihydro-1H-pyrrol-2-yl,
2,5-dihydro-1H-pyrrol-3-yl, 4,5-dihydro-1H-pyrrol-2-yl,
4,5-dihydro-1H-pyrrol-3-yl, 3,4-dihydro-2H-pyrrol-2-yl,
3,4-dihydro-2H-pyrrol-3-yl, 3,4-dihydro-5H-pyrrol-2-yl,
3,4-dihydro-5H-pyrrol-3-yl, 4,5-dihydro-1H-pyrazol-3-yl,
4,5-dihydro-1H-pyrazol-4-yl, 4,5-dihydro-1H-pyrazol-5-yl,
2,5-dihydro-1H-pyrazol-3-yl, 2,5-dihydro-1H-pyrazol-4-yl,
2,5-dihydro-1H-pyrazol-5-yl, 4,5-dihydroisoxazol-3-yl,
4,5-dihydroisoxazol-4-yl, 4,5-dihydroisoxazol-5-yl,
2,5-dihydroisoxazol-3-yl, 2,5-dihydroisoxazol-4-yl,
2,5-dihydroisoxazol-5-yl, 2,3-dihydroisoxazol-3-yl,
2,3-dihydroisoxazol-4-yl, 2,3-dihydroisoxazol-5-yl,
4,5-dihydroisothiazol-3-yl, 4,5-dihydroisothiazol-4-yl,
4,5-dihydroisothiazol-5-yl, 2,5-dihydroisothiazol-3-yl,
2,5-dihydroisothiazol-4-yl, 2,5-dihydroisothiazol-5-yl,
2,3-dihydroisothiazol-3-yl, 2,3-dihydroisothiazol-4-yl,
2,3-dihydroisothiazol-5-yl, 4,5-dihydro-1H-imidazol-2-yl,
4,5-dihydro-1H-imidazol-4-yl, 4,5-dihydro-1H-imidazol-5-yl,
2,5-dihydro-1H-imidazol-2-yl, 2,5-dihydro-1H-imidazol-4-yl,
2,5-dihydro-1H-imidazol-5-yl, 2,3-dihydro-1H-imidazol-2-yl,
2,3-dihydro-1H-imidazol-4-yl, 4,5-dihydrooxazol-2-yl,
4,5-dihydrooxazol-4-yl, 4,5-dihydrooxazol-5-yl,
2,5-dihydrooxazol-2-yl, 2,5-dihydrooxazol-4-yl,
2,5-dihydrooxazol-5-yl, 2,3-dihydrooxazol-2-yl,
2,3-dihydrooxazol-4-yl, 2,3-dihydrooxazol-5-yl,
4,5-dihydrothiazol-2-yl, 4,5-dihydrothiazol-4-yl,
4,5-dihydrothiazol-5-yl, 2,5-dihydrothiazol-2-yl,
2,5-dihydrothiazol-4-yl, 2,5-dihydrothiazol-5-yl,
2,3-dihydrothiazol-2-yl, 2,3-dihydrothiazol-4-yl,
2,3-dihydrothiazol-5-yl, 1,3-dioxol-2-yl, 1,3-dioxol-4-yl,
1,3-dithiol-2-yl, 1,3-dithiol-4-yl, 1,3-oxathiol-2-yl,
1,3-oxathiol-4-yl, 1,3-oxathiol-5-yl. [0111] C-bonded, 6-membered,
partially unsaturated rings such as: 2H-3,4-dihydropyran-6-yl,
2H-3,4-dihydropyran-5-yl, 2H-3,4-dihydropyran-4-yl,
2H-3,4-dihydropyran-3-yl, 2H-3,4-dihydropyran-2-yl,
2H-3,4-dihydrothiopyran-6-yl, 2H-3,4-dihydrothiopyran-5-yl,
2H-3,4-dihydrothiopyran-4-yl, 2H-3,4-dihydrothiopyran-3-yl,
2H-3,4-dihydrothiopyran-2-yl, 1,2,3,4-tetrahydropyridin-6-yl,
1,2,3,4-tetrahydropyridin-5-yl, 1,2,3,4-tetrahydropyridin-4-yl,
1,2,3,4-tetra-hydropyridin-3-yl, 1,2,3,4-tetrahydropyridin-2-yl,
2H-5,6-dihydropyran-2-yl, 2H-5,6-dihydropyran-3-yl,
2H-5,6-dihydropyran-4-yl, 2H-5,6-dihydropyran-5-yl,
2H-5,6-dihydropyran-6-yl, 2H-5,6-dihydrothiopyran-2-yl,
2H-5,6-dihydrothiopyran-3-yl, 2H-5,6-dihydrothiopyran-4-yl,
2H-5,6-dihydrothiopyran-5-yl, 2H-5,6-dihydrothiopyran-6-yl,
1,2,5,6-tetrahydropyridin-2-yl, 1,2,5,6-tetrahydropyridin-3-yl,
1,2,5,6-tetrahydropyridin-4-yl, 1,2,5,6-tetrahydropyridin-5-yl,
1,2,5,6-tetra-hydropyridin-6-yl, 2,3,4,5-tetrahydropyridin-2-yl,
2,3,4,5-tetrahydropyridin-3-yl, 2,3,4,5-tetrahydropyridin-4-yl,
2,3,4,5-tetrahydropyridin-5-yl, 2,3,4,5-tetrahydropyridin-6-yl,
4H-pyran-2-yl, 4H-pyran-3-yl, 4H-pyran-4-yl, 4H-thiopyran-2-yl,
4H-thiopyran-3-yl, 4H-thiopyran-4-yl, 1,4-dihydropyridin-2-yl,
1,4-dihydropyridin-3-yl, 1,4-dihydropyridin-4-yl, 2H-pyran-2-yl,
2H-pyran-3-yl, 2H-pyran-4-yl, 2H-pyran-5-yl, 2H-pyran-6-yl,
2H-thiopyran-2-yl, 2H-thiopyran-3-yl, 2H-thiopyran-4-yl,
2H-thiopyran-5-yl, 2H-thiopyran-6-yl, 1,2-dihydropyridin-2-yl,
1,2-dihydropyridin-3-yl, 1,2-dihydropyridin-4-yl,
1,2-dihydropyridin-5-yl, 1,2-dihydropyridin-6-yl,
3,4-dihydropyridin-2-yl, 3,4-dihydropyridin-3-yl,
3,4-dihydropyridin-4-yl, 3,4-dihydropyridin-5-yl,
3,4-dihydropyridin-6-yl, 2,5-dihydropyridin-2-yl,
2,5-dihydropyridin-3-yl, 2,5-dihydropyridin-4-yl,
2,5-dihydropyridin-5-yl, 2,5-dihydropyridin-6-yl,
2,3-dihydropyridin-2-yl, 2,3-dihydropyridin-3-yl,
2,3-dihydropyridin-4-yl, 2,3-dihydropyridin-5-yl,
2,3-dihydropyridin-6-yl, 2H-5,6-dihydro-1,2-oxazin-3-yl,
2H-5,6-dihydro-1,2-oxazin-4-yl, 2H-5,6-dihydro-1,2-oxazin-5-yl,
2H-5,6-dihydro-1,2-oxazin-6-yl, 2H-5,6-dihydro-1,2-thiazin-3-yl,
2H-5,6-dihydro-1,2-thiazin-4-yl, 2H-5,6-dihydro-1,2-thiazin-5-yl,
2H-5,6-dihydro-1,2-thiazin-6-yl, 4H-5,6-dihydro-1,2-oxazin-3-yl,
4H-5,6-dihydro-1,2-oxazin-4-yl, 4H-5,6-dihydro-1,2-oxazin-5-yl,
4H-5,6-dihydro-1,2-oxazin-6-yl, 4H-5,6-dihydro-1,2-thiazin-3-yl,
4H-5,6-dihydro-1,2-thiazin-4-yl, 4H-5,6-dihydro-1,2-thiazin-5-yl,
4H-5,6-dihydro-1,2-thiazin-6-yl, 2H-3,6-dihydro-1,2-oxazin-3-yl,
2H-3,6-dihydro-1,2-oxazin-4-yl, 2H-3,6-dihydro-1,2-oxazin-5-yl,
2H-3,6-dihydro-1,2-oxazin-6-yl, 2H-3,6-dihydro-1,2-thiazin-3-yl,
2H-3,6-dihydro-1,2-thiazin-4-yl, 2H-3,6-dihydro-1,2-thiazin-5-yl,
2H-3,6-dihydro-1,2-thiazin-6-yl, 2H-3,4-dihydro-1,2-oxazin-3-yl,
2H-3,4-dihydro-1,2-oxazin-4-yl, 2H-3,4-dihydro-1,2-oxazin-5-yl,
2H-3,4-dihydro-1,2-oxazin-6-yl, 2H-3,4-dihydro-1,2-thiazin-3-yl,
2H-3,4-dihydro-1,2-thiazin-4-yl, 2H-3,4-dihydro-1,2-thiazin-5-yl,
2H-3,4-dihydro-1,2-thiazin-6-yl, 2,3,4,5-tetrahydropyridazin-3-yl,
2,3,4,5-tetrahydropyridazin-4-yl, 2,3,4,5-tetrahydropyridazin-5-yl,
2,3,4,5-tetrahydropyridazin-6-yl, 3,4,5,6-tetrahydropyridazin-3-yl,
3,4,5,6-tetrahydropyridazin-4-yl, 1,2,5,6-tetrahydropyridazin-3-yl,
1,2,5,6-tetrahydropyridazin-4-yl, 1,2,5,6-tetrahydropyridazin-5-yl,
1,2,5,6-tetrahydropyridazin-6-yl, 1,2,3,6-tetrahydropyridazin-3-yl,
1,2,3,6-tetrahydropyridazin-4-yl, 4H-5,6-dihydro-1,3-oxazin-2-yl,
4H-5,6-dihydro-1,3-oxazin-4-yl, 4H-5,6-dihydro-1,3-oxazin-5-yl,
4H-5,6-dihydro-1,3-oxazin-6-yl, 4H-5,6-dihydro-1,3-thiazin-2-yl,
4H-5,6-dihydro-1,3-thiazin-4-yl, 4H-5,6-dihydro-1,3-thiazin-5-yl,
4H-5,6-dihydro-1,3-thiazin-6-yl, 3,4,5-6-tetrahydropyrimidin-2-yl,
3,4,5,6-tetrahydropyrimidin-4-yl,
3,4,5,6-tetra-hydropyrimidin-5-yl,
3,4,5,6-tetrahydropyrimidin-6-yl, 1,2,3,4-tetrahydropyrazin-2-yl,
1,2,3,4-tetrahydropyrazin-5-yl, 1,2,3,4-tetrahydropyrimidin-2-yl,
1,2,3,4-tetrahydropyrimidin-4-yl, 1,2,3,4-tetrahydropyrimidin-5-yl,
1,2,3,4-tetrahydropyrimidin-6-yl, 2,3-dihydro-1,4-thiazin-2-yl,
2,3-dihydro-1,4-thiazin-3-yl, 2,3-dihydro-1,4-thiazin-5-yl,
2,3-dihydro-1,4-thiazin-6-yl, 2H-1,3-oxazin-2-yl,
2H-1,3-oxazin-4-yl, 2H-1,3-oxazin-5-yl, 2H-1,3-oxazin-6-yl,
2H-1,3-thiazin-2-yl, 2H-1,3-thiazin-4-yl, 2H-1,3-thiazin-5-yl,
2H-1,3-thiazin-6-yl, 4H-1,3-oxazin-2-yl, 4H-1,3-oxazin-4-yl,
4H-1,3-oxazin-5-yl, 4H-1,3-oxazin-6-yl, 4H-1,3-thiazin-2-yl,
4H-1,3-thiazin-4-yl, 4H-1,3-thiazin-5-yl, 4H-1,3-thiazin-6-yl,
6H-1,3-oxazin-2-yl, 6H-1,3-oxazin-4-yl, 6H-1,3-oxazin-5-yl,
6H-1,3-oxazin-6-yl, 6H-1,3-thiazin-2-yl, 6H-1,3-oxazin-4-yl,
6H-1,3-oxazin-5-yl, 6H-1,3-thiazin-6-yl, 2H-1,4-oxazin-2-yl,
2H-1,4-oxazin-3-yl, 2H-1,4-oxazin-5-yl, 2H-1,4-oxazin-6-yl,
2H-1,4-thiazin-2-yl, 2H-1,4-thiazin-3-yl, 2H-1,4-thiazin-5-yl,
2H-1,4-thiazin-6-yl, 4H-1,4-oxazin-2-yl, 4H-1,4-oxazin-3-yl,
4H-1,4-thiazin-2-yl, 4H-1,4-thiazin-3-yl,
1,4-dihydropyridazin-3-yl, 1,4-dihydropyridazin-4-yl,
1,4-dihydropyridazin-5-yl, 1,4-dihydropyridazin-6-yl,
1,4-dihydropyrazin-2-yl, 1,2-dihydropyrazin-2-yl,
1,2-dihydropyrazin-3-yl, 1,2-dihydropyrazin-5-yl,
1,2-dihydropyrazin-6-yl, 1,4-dihydropyrimidin-2-yl,
1,4-dihydropyrimidin-4-yl, 1,4-dihydropyrimidin-5-yl,
1,4-dihydropyrimidin-6-yl, 3,4-dihydropyrimidin-2-yl,
3,4-dihydropyrimidin-4-yl, 3,4-dihydropyrimidin-5-yl or
3,4-dihydropyrimidin-6-yl. N-bonded, 5-membered, partially
unsaturated rings such as: 2,3-dihydro-1H-pyrrol-1-yl,
2,5-dihydro-1H-pyrrol-1-yl, 4,5-dihydro-1H-pyrazol-1-yl,
2,5-dihydro-1H-pyrazol-1-yl, 2,3-dihydro-1H-pyrazol-1-yl,
2,5-dihydroisoxazol-2-yl, 2,3-dihydroisoxazol-2-yl,
2,5-dihydroisothiazol-2-yl, 2,3-dihydroisoxazol-2-yl,
4,5-dihydro-1H-imidazol-1-yl, 2,5-dihydro-1H-imidazol-1-yl,
2,3-dihydro-1H-imidazol-1-yl, 2,3-dihydrooxazol-3-yl,
2,3-dihydrothiazol-3-yl. [0112] N-bonded, 6-membered, partially
unsaturated rings such as: [0113] 1,2,3,4-tetrahydropyridin-1-yl,
1,2,5,6-tetrahydropyridin-1-yl, 1,4-dihydropyridin-1-yl,
1,2-dihydropyridin-1-yl, 2H-5,6-dihydro-1,2-oxazin-2-yl,
2H-5,6-dihydro-1,2-thiazin-2-yl, 2H-3,6-dihydro-1,2-oxazin-2-yl,
2H-3,6-dihydro-1,2-thiazin-2-yl, 2H-3,4-dihydro-1,2-oxazin-2-yl,
2H-3,4-dihydro-1,2-thiazin-2-yl, 2,3,4,5-tetrahydropyridazin-2-yl,
1,2,5,6-tetrahydropyridazin-1-yl, 1,2,5,6-tetrahydropyridazin-2-yl,
1,2,3,6-tetrahydropyridazin-1-yl, 3,4,5,6-tetrahydropyrimidin-3-yl,
1,2,3,4-tetrahydropyrazin-1-yl, 1,2,3,4-tetrahydropyrimidin-1-yl,
1,2,3,4-tetrahydro-pyrimidin-3-yl, 2,3-dihydro-1,4-thiazin-4-yl,
2H-1,2-oxazin-2-yl, 2H-1,2-thiazin-2-yl, 4H-1,4-oxazin-4-yl,
4H-1,4-thiazin-4-yl, 1,4-dihydropyridazin-1-yl,
1,4-dihydropyrazin-1-yl, 1,2-dihydropyrazin-1-yl,
1,4-dihydropyrimidin-1-yl or 3,4-dihydropyrimidin-3-yl.
[0114] Heterocyclyloxy: a heterocyclyl radical as defined above
which is attached to the remainder of the molecule via an oxygen
atom. The heterocyclyl radical ordinarily has 3, 4, 5, 6 or 7 ring
atoms, in which besides carbon atoms as ring members ordinarily 1,
2 or 3, in particular 1 or 2, of the ring atoms are heteroatoms
such as N, S or O, in particular 5- to 7-membered heterocycloyloxy,
where heterocyclyl has 1 or 2 heteroatoms selected from O, S and N
as ring members, for example tetrahydrofuran-2-yloxy,
tetrahydrofuran-3-yloxy, tetrahydrothiophen-2-yloxy or
tetrahydrothiophen-3-yloxy.
[0115] Heterocyclyl-C.sub.1-C.sub.4-alkoxy: a
C.sub.1-C.sub.4-alkoxy group as defined above in which one hydrogen
atom is replaced by a heterocyclyl radical as defined above. The
heterocyclyl radical ordinarily has 3, 4, 5, 6 or 7 ring atoms, in
which besides carbon atoms as ring members ordinarily 1, 2 or 3, in
particular 1 or 2, of the ring atoms are heteroatoms such as N, S
or O. In particular, 5- to 7-membered
heterocyclyl-C.sub.1-C.sub.2-alkoxy, where heterocyclyl has 1 or 2
heteroatoms selected from O, S and N as ring members, for example
tetrahydrofuran-2-yl-methoxy, tetrahydrofuran-2-yl-ethoxy,
tetrahydrofuran-3-ylmethoxy, tetrahydrofuran-3-ylethoxy,
tetrahydrothiophen-2-ylmethoxy, tetrahydrothiophen-2-ylethoxy,
tetrahydrothiophen-3-ylmethoxy, tetrahydrothiophen-3-ylethoxy.
[0116] Hetaryl: a 5- or 6-membered aromatic heteromonocyclic
radical (also termed 5- or 6-membered monocyclic hetaryl) which
ordinarily has 1, 2, 3 or 4 heteroatoms as ring members, which are
selected from O, S and N, and which has in particular 1, 2, 3 or 4
nitrogen atoms or a heteroatom selected from oxygen and sulfur and,
if appropriate, 1 or 2 nitrogen atoms as ring members besides
carbon atoms as ring members and a 8-, 9- or 10-membered aromatic
heterobicyclic radical (also termed 8-, 9- or 10-membered bicyclic
hetaryl) which ordinarily has 1, 2, 3 or 4 heteroatoms as ring
members, which are selected from O, S and N, and which has in
particular 1, 2, 3 or 4 nitrogen atoms or a heteroatom selected
from oxygen and sulfur and, if appropriate, 1 or 2 nitrogen atoms
as ring members besides carbon atoms as ring members: for example
[0117] C-bonded, 5-membered monocyclic hetaryl having 1, 2 or 3 or
4 nitrogen atoms or a heteroatom selected from oxygen and sulfur
and, if appropriate, having 1, 2 or 3 nitrogen atoms as ring
members, such as: [0118] 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,
pyrrol-2-yl, pyrrol-3-yl, pyrazol-3-yl, pyrazol-4-yl,
isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, isothiazol-3-yl,
isothiazol-4-yl, isothiazol-5-yl, imidazol-2-yl, imidazol-4-yl,
oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-2-yl, thiazol-4-yl,
thiazol-5-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl,
1,2,4-oxadiazol-3-yl, 1,2,4,-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl,
1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl,
1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl,
1,3,4-thiadiazolyl-2-yl, 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl,
tetrazol-5-yl. [0119] C-bonded, 6-membered monocyclic hetaryl
having 1, 2 or 3 nitrogen atoms as ring members, such as: [0120]
pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazin-3-yl,
pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl,
pyrazin-2-yl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl,
1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl, 1,2,4,5-tetrazin-3-yl.
[0121] N-bonded, 5-membered heteroaromatic radicals having 1, 2, 3
or 4 nitrogen atoms as ring members, such as: [0122] pyrrol-1-yl,
pyrazol-1-yl, imidazol-1-yl, 1,2,3-triazol-1-yl,
1,2,4-triazol-1-yl, tetrazol-1-yl. [0123] bicyclic 8-, 9-
10-membered hetaryl, hetaryl which has one of the aforementioned 5-
or 6-membered heteroaromatic rings and a further aromatic
carbocycle or 5- or 6-membered heterocycle fused thereto, for
example a fused benzene, thiophene, furane, pyrrole, pyrazole,
imidazole, pyridine or pyrimidine ring. These bicyclic hetaryl
include for example quinolinyl, isoquinolinyl, cinnolinyl, indolyl,
indolizynyl, isoindolyl, indazolyl, benzofuryl, benzothienyl,
benzo[b]thiazolyl, benzoxazolyl, benzthiazolyl, benzimidazolyl,
imidazo[1,2-a]pyridine-2-yl, thieno[3,2-b]pyridine-5-yl,
imidazo-[2,1-b]-thiazol-6-yl and
1,2,4-triazolo[1,5-a]pyridine-2-yl.
[0124] Hetarylalkyl: a hetaryl radical as defined above which is
linked via an alkylene group, in particular via a methylene,
1,1-ethylene or 1,2-ethylene group, to the remainder of the
molecule.
[0125] 5- to 6-membered hetaryl-C.sub.1-C.sub.4-alkoxy: a
C.sub.1-C.sub.4-alkoxy group as defined above which carries a 5- to
6-membered hetaryl radical as defined above, where the hetaryl
radical has ordinarily 1, 2 or 3, in particular 1 or 2, heteroatoms
as ring members which are selected from O, S and N. Examples are
furan-2-ylmethoxy, furan-3-ylmethoxy, furan-2-ylethoxy,
furan-3-ylethoxy, thiophen-2-ylmethoxy, thiophen-3-ylmethoxy,
thiophen-2-ylethoxy and thiophen-3-ylethoxy. The expression
"optionally substituted" in the context of the present invention
means that the respective moiety is unsubstituted or has 1, 2 or 3,
in particular 1, substituents which are selected from halogen,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, OH, SH, CN,
CF.sub.3, O--CF.sub.3, COOH, O--CH.sub.2--COOH,
C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.4-haloalkoxy,
C.sub.1-C.sub.6-alkylthio, C.sub.3-C.sub.7-cycloalkyl,
COO--C.sub.1-C.sub.6-alkyl, CONH.sub.2,
CONH--C.sub.1-C.sub.6-alkyl, SO.sub.2NH--C.sub.1-C.sub.6-alkyl,
CON--(C.sub.1-C.sub.6-alkyl).sub.2,
SO.sub.2N--(C.sub.1-C.sub.6-alkyl).sub.2,
NH--SO.sub.2--C.sub.1-C.sub.6-alkyl, NH--CO--C.sub.1-C.sub.6-alkyl,
SO.sub.2--C.sub.1-C.sub.6-alkyl, O-phenyl, O--CH.sub.2-phenyl,
CONH-phenyl, SO.sub.2NH-phenyl, CONH-hetaryl, SO.sub.2NH-hetaryl,
SO.sub.2-phenyl, NH--SO.sub.2-phenyl, NH--CO-phenyl,
NH--SO.sub.2-hetaryl and NH--CO-hetaryl, where phenyl and hetaryl
in the last 11 radicals mentioned are unsubstituted or may have 1,
2 or 3 substituents which are selected from halogen,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.1-C.sub.4-alkoxy and C.sub.1-C.sub.4-haloalkoxy.
[0126] In particular embodiments of the invention, R.sup.h is
selected from the group consisting of halogen, CN, OH,
C.sub.1-C.sub.4-alkyl, fluorinated C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy, fluorinated C.sub.1-C.sub.4-alkoxy,
C.sub.3-C.sub.6-cycloalkyl, fluorinated C.sub.3-C.sub.6-cycloalkyl,
N(RNRc), C.sub.1-C.sub.4-alkyl-N(R.sup.b)(R.sup.c), C(O)O--R.sup.d,
C(O)N(R.sup.e)(R.sup.f), N(R.sup.ee)S(O).sub.2(R.sup.ff) and
S(O).sub.2N(R.sup.e)(R.sup.f).
[0127] In relation to their use as inhibitors of PDE10A, the
variables X.sup.1, X.sup.2, Y, R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 in formula I preferably have the following meanings, where
these represent, both considered on their own and in combination
with at least one other or all, special embodiments of the
compounds of the formula I:
[0128] R.sup.1 is preferably C.sub.2-C.sub.8-alkyl,
C.sub.3-C.sub.8-cycloalkyl or C.sub.3-C.sub.8-cycloalkylmethyl, in
particular C.sub.3-C.sub.8-cycloalkylmethyl or especially
C.sub.2-C.sub.8-alkyl. Particularly, R.sup.1 is alkyl of the
formula CHR.sup.1aR.sup.1b, where R.sup.1a is selected from the
group consisting of hydrogen and C.sub.1-C.sub.3-alkyl, in
particular methyl, ethyl, n-propyl and where R.sup.1b is selected
from the group consisting of C.sub.1-C.sub.4-alkyl, in particular
methyl, ethyl, n-propyl or n-butyl. Particular examples of R.sup.1
are selected from the group consisting of ethyl, isopropyl,
1-methylpropyl and 1-ethylpropyl.
[0129] Particular embodiments of the invention also relate to
compounds, where R.sup.1 is a moiety Z.sup.1--Ar.sup.1, where
Z.sup.1 and Ar.sup.1 are as defined above and where Z.sup.1 is
preferably 1,2-ethanediyl or 1,3-propanediyl, wherein 1, 2, 3 or 4
hydrogen atoms may be replaced by a fluorine atom. According to a
specific embodiment, Z.sup.1 is 1,2-ethanediyl which is
unsubstituted or 1,3-propanediyl which is unsubstituted. In these
embodiments, Ar.sup.1 is preferably monocyclic 6-membered hetaryl
or bicyclic 9- or 10-membered hetaryl, where hetaryl has 1, 2 or 3
heteroatoms as ring members which are selected from O, S and N,
where mono- and bicyclic hetaryl are unsubstituted or may carry 1,
2 or 3 identical or different substituents R.sup.h.
[0130] An is preferably selected from the group consisting of
C-bound 6-membered monocyclic hetaryl, which has 1 or 2 nitrogen
atoms as ring members, and C-bound, fused bicyclic hetaryl, which
has 1 or 2 nitrogen atoms as ring members and optionally a further
heteroatom selected from O, S and N as ring member, where
monocyclic hetaryl and bicyclic hetaryl may be unsubstituted or may
carry 1, 2 or 3 substituents R.sup.h, in particular 0, 1 or 2
substituents R.sup.h. In this regard, R.sup.h is preferably
selected from halogen, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.2-fluoroalkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.2-fluoralkoxy, C.sub.3-C.sub.6-cycloalkyl, and
fluorinated C.sub.3-C.sub.6-cycloalkyl. In this regard, R.sup.h is
in particular selected from fluorine, chlorine, methyl,
fluoromethyl, difluoromethyl, trifluoromethyl, methoxy,
fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl and
fluorinated cyclopropyl.
[0131] Ar.sup.1 is in particular selected from the group consisting
of fused bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring
members and optionally a further heteroatom selected from O, S and
N as ring member and which may be unsubstituted or may carry 1, 2
or 3 substituents R.sup.h, in particular 0, 1 or 2 substituents
R.sup.h as defined above. Amongst these, particular preference is
given to those compounds, where the Ar.sup.1 radical has at least
one imino-nitrogen as ring member, which is located in the position
adjacent to carbon atom bound to the group Z.sup.1. Amongst these,
particular preference is given to those, where Ar.sup.1 is selected
from the group consisting of C-bound, fused bicyclic hetaryl, which
has 1 or 2 nitrogen atoms as ring members and optionally a further
heteroatom selected from O, S and N as ring member, where bicyclic
hetaryl may be unsubstituted or may carry 1, 2 or 3 substituents
R.sup.h, in particular 0, 1 or 2 substituents R.sup.h. In this
regard, R.sup.h is preferably selected from halogen,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.2-fluoroalkyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.2-fluoralkoxy,
C.sub.3-C.sub.6-cycloalkyl and fluorinated
C.sub.3-C.sub.6-cycloalkyl. In this regard, R.sup.h is in
particular selected from fluorine, chlorine, methyl, fluoromethyl,
difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy,
difluoromethoxy, trifluoromethoxy, cyclopropyl and fluorinated
cyclopropyl.
[0132] Particular examples of Ar.sup.1 are selected from the group
consisting of 2-benzofuryl, 2-pyridyl, 2-pyrimidinyl,
4-pyrimidinyl, 2-pyrazinyl, 3-pyridazinyl, 2-quinolinyl,
3-isoquinolinyl, 2-quinazolinyl, 2-quinoxalinyl,
1,5-naphthyridin-2-yl, 1,8-naphthyridin-2-yl, benzothiazol-1-yl,
benzoxazol-1-yl, benzimidazol-2-yl, 1-methylbenzimidazol-2-yl,
imidazo[1,2-a]pyridine-2-yl, thieno[3,2-b]pyridine-5-yl,
imidazo-[2,1-b]-thiazol-6-yl and
1,2,4-triazolo[1,5-a]pyridine-2-yl, where the aforementioned
radicals are unsubstituted or may carry 1, 2 or 3 radicals R.sup.h
as defined above, which are in particular selected from the group
consisting of fluorine, chlorine, methyl, fluoromethyl,
difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy,
difluoromethoxy, trifluoromethoxy, and fluorinated cyclopropyl.
[0133] In particular embodiments, R.sup.2 is a radical of the
formula CR.sup.21R.sup.22R.sup.23, where R.sup.21, R.sup.22 and
R.sup.23 are as defined above and where R.sup.21 is in particular
different from hydrogen.
[0134] In other particular embodiments, R.sup.2 is a phenyl or 5-
or 6-membered hetaryl radical having 1, 2 or 3 heteroatoms as ring
members which are selected from O, S and N, where phenyl and
monocyclic hetaryl are unsubstituted or may carry 1, 2 or 3
identical or different substituents R.sup.a as defined above.
[0135] In the particular embodiments, where R.sup.2 is a radical of
the formula CR.sup.21R.sup.22R.sup.23, where R.sup.21, R.sup.22 and
R.sup.23 are as defined above or where R.sup.2 is a phenyl or 5- or
6-membered hetaryl radical having 1, 2 or 3 heteroatoms as ring
members which are selected from O, S and N, where phenyl and
monocyclic hetaryl are unsubstituted or may carry 1, 2 or 3
identical or different substituents R.sup.a as defined above, the
radical R.sup.3 is preferably selected from the group consisting of
hydrogen and C.sub.1-C.sub.4-alkyl. In these embodiments, R.sup.3
is in particular hydrogen.
[0136] In the particular embodiments, where R.sup.2 is a radical of
the formula CR.sup.21R.sup.22R.sup.23, a particular group of
embodiments relates to compounds, where the radicals R.sup.21,
R.sup.22 and R.sup.23 have the following meanings: [0137] R.sup.21
is selected from the group consisting of C.sub.1-C.sub.8-alkyl,
trimethylsilyl, C.sub.2-C.sub.8-alkenyl,
C.sub.1-C.sub.4-fluoroalkyl, C.sub.3-C.sub.8-cycloalkyl,
fluorinated C.sub.3-C.sub.8-cycloalkyl,
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl, fluorinated
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl,
hydroxy-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkyl-N(R.sup.b)(R.sup.c),
(CH.sub.2).sub.mC(O)O--R.sup.d,
(CH.sub.2).sub.mC(O)N(R.sup.e)(R.sup.f) and Z.sup.2--Ar.sup.2,
[0138] R.sup.22 is selected from the group consisting of hydrogen,
fluorine, C.sub.1-C.sub.8-alkyl, C.sub.2-C.sub.8-alkenyl,
C.sub.1-C.sub.4-fluoroalkyl, C.sub.3-C.sub.8-cycloalkyl,
fluorinated C.sub.3-C.sub.8-cycloalkyl,
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl, fluorinated
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl,
hydroxy-C.sub.1-C.sub.4-alkyl and
C.sub.1-C.sub.4-alkyl-N(R.sup.b)(R.sup.c), or [0139] R.sup.23 is
selected from the group consisting of hydrogen, fluorine,
C.sub.1-C.sub.8-alkyl and C.sub.1-C.sub.4-fluoroalkyl;
[0140] In the particular embodiments, where R.sup.2 is a radical of
the formula CR.sup.21R.sup.22R.sup.23, a particular group of
embodiments relates to compounds, where the radicals R.sup.21,
R.sup.22 and R.sup.23 preferably have the following meanings, both
considered on their own and in combination with at least one other
or all: [0141] R.sup.21 is selected from the group consisting of
C.sub.2-C.sub.8-alkyl, trimethylsilyl, C.sub.2-C.sub.8-alkenyl,
C.sub.1-C.sub.4-fluoroalkyl, C.sub.3-C.sub.8-cycloalkyl,
fluorinated C.sub.3-C.sub.8-cycloalkyl,
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl, fluorinated
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl and
Z.sup.2--Ar.sup.2, where Z.sup.2 and Ar.sup.2, where Z.sup.2 and
Ar.sup.2 are as defined above and where Z.sup.2 is preferably a
single bond or CH.sub.2 and Ar.sup.2 is preferably phenyl, pyridyl,
pyrimidinyl, thienyl, thiazolyl or thiadiazolyl, which are
unsubstituted or which carry 1, 2 or 3 identical or different
substituents R.sup.h; [0142] R.sup.22 is selected from the group
consisting of hydrogen, fluorine, C.sub.1-C.sub.8-alkyl, in
particular hydrogen; and [0143] R.sup.23 is hydrogen or
C.sub.1-C.sub.4-alkyl, such as methyl, or especially hydrogen.
[0144] In the particular embodiments, where R.sup.2 is a radical of
the formula CR.sup.21R.sup.22R.sup.23, a particular group of
embodiments relates to compounds, where the radicals R.sup.21,
R.sup.22 and R.sup.23 preferably have the following meanings, both
considered on their own and in combination with at least one other
or all: [0145] R.sup.21 is selected from the group consisting of
C.sub.2-C.sub.8-alkyl, trimethylsilyl, C.sub.2-C.sub.8-alkenyl,
C.sub.1-C.sub.4-fluoroalkyl, C.sub.3-C.sub.8-cycloalkyl,
fluorinated C.sub.3-C.sub.8-cycloalkyl,
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl, fluorinated
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl, and where
R.sup.21 is in particular C.sub.2-C.sub.4-alkyl; [0146] R.sup.22 is
selected from the group consisting of hydrogen, fluorine,
C.sub.1-C.sub.8-alkyl, in particular methyl or hydrogen; and [0147]
R.sup.23 is hydrogen or C.sub.1-C.sub.4-alkyl, such as methyl, or
especially hydrogen.
[0148] In the particular embodiments, where R.sup.2 is a radical of
the formula CR.sup.21R.sup.22R.sup.23, another particular group of
embodiments relates to compounds, where the radicals R.sup.21,
R.sup.22 and R.sup.23 preferably have the following meanings, both
considered on their own and in combination with at least one other
or all: [0149] R.sup.21 is a radical Z.sup.2--Ar.sup.2, where
Z.sup.2 and Ar.sup.2 are as defined above and where Z.sup.2 is
preferably a single bond or CH.sub.2 and Ar.sup.2 is preferably
phenyl, pyridyl, pyrimidinyl, thienyl, thiazolyl or thiadiazolyl,
which are unsubstituted or which carry 1, 2 or 3 identical or
different substituents R.sup.h, particular examples of R.sup.21
being 2-, 3- or 4-fluorophenyl, 2-, 3- or 4-methylphenyl, 2-, 3- or
4-methoxyphenyl, 2,3-difluorophenyl, 3,5-difluorophenyl,
3,4-difluorophenyl, thiazol-2-yl, thiazol-4-yl,
1,3,4-thiadiazol-2-yl, 2-(1-morpholinosulfonyl)phenyl,
3-(1-morpholinosulfonyl)phenyl,
2-(4-methylpiperazin-1-ylsulfonyl)phenyl or
3-(4-methylpiperazin-1-ylsulfonyl)phenyl. [0150] R.sup.22 is
selected from the group consisting of hydrogen, fluorine,
C.sub.1-C.sub.8-alkyl, in particular methyl or hydrogen; and [0151]
R.sup.23 is hydrogen or C.sub.1-C.sub.4-alkyl, such as methyl, or
especially hydrogen.
[0152] In the particular embodiments, where R.sup.2 is a radical of
the formula CR.sup.21R.sup.22R.sup.23, a further group of
embodiments relates to compounds, where the radicals R.sup.21 and
R.sup.22 together with the carbon atom, to which they are bound
form a saturated 5-, 6- or 7-membered carbocyclic ring, such as
cyclopentyl, cyclohexyl or cycloheptyl, especially cyclopentyl, or
a saturated 5-, 6- or 7-membered heterocyclic ring which has 1, 2
or 3 heteroatoms or heteroatom containing groups selected from the
group of O, N, S, SO and SO.sub.2 as ring members, especially 2- or
3-tetrahydrofuryl or 2- or 3-tetrahydrothienyl, where the
carbocyclic ring and the heterocyclic ring may be unsubstituted or
may be substituted by 1, 2 or 3 identical or different substituents
R.sup.g, and where the carbocyclic ring and the heterocyclic ring
may carry a fused benzene ring or a fused 5- or 6-membered
heteroaromatic ring, where the fused rings themselves are
unsubstituted or carry 1, 2 or 3 substituents R.sup.h, and where
R.sup.g, R.sup.h and R.sup.23 are as defined above and where
R.sup.23 is in particular hydrogen or C.sub.1-C.sub.4-alkyl, such
as methyl, or especially hydrogen.
[0153] In the particular embodiments, where R.sup.2 is a radical of
the formula CR.sup.21R.sup.22R.sup.23, a further particular group
of embodiments relates to compounds, where the radicals R.sup.21,
R.sup.22 and R.sup.23 preferably have the following meanings, both
considered on their own and in combination with at least one other
or all: [0154] R.sup.21 and R.sup.22 together with the carbon atom,
to which they are bound form a saturated 5-, 6- or 7-membered
carbocyclic radical, namely a cyclopentyl, cyclohexyl or
cycloheptyl radical or a 3-tetrahydrofuryl or 3-tetrahydrothienyl,
where the 5- to 7-membered carbocyclic ring and the
3-tetrahydrofuryl or 3-tetrahydrothienyl ring carry a fused benzene
ring or a fused 5- or 6-membered heteroaromatic ring, such as a
fused thiophene or pyridine ring, where the fused rings themselves
are unsubstituted or carry 1, 2 or 3 substituents R.sup.h, and
where R.sup.21 and R.sup.22 in particular form a bicyclic radical
selected from the group consisting of 5-indanyl, 6-indanyl,
5,6,7,8-tetrahydronaphthalin-5-yl,
5,6,7,8-tetrahydronaphthalin-6-yl,
6,7,8,9-tetrahydro-5H-benzocycloheptene-5-yl,
6,7,8,9-tetrahydro-5H-benzocycloheptene-6-yl,
5,6-dihydro-4H-cyclopenta[b]thiophene-4-yl,
6,7-dihydro-5H-[1]-pyrindin-6-yl, 3,4-dihydrobenzofuran-3-yl,
2,3-dihydrobenzothiophen-3-yl or where these bicyclic radicals are
in particular unsubstituted or where the aromatic moiety of these
rings carry 1, 2 or 3 substituents R.sup.h; [0155] R.sup.23 is
hydrogen or C.sub.1-C.sub.4-alkyl, such as methyl, or especially
hydrogen.
[0156] In further particular embodiments of the invention R.sup.2
and R.sup.3 together with the nitrogen atom, to which they are
bound form a saturated 4-, 5-, 6- or 7-membered heterocyclic ring
which, in addition to the nitrogen atom, may have 1 or 2 further
heteroatoms or heteroatom containing groups selected from the group
of O, N, S, SO and SO.sub.2 as ring members, e.g. a pyrrolidine,
piperidine, morpholine, thiomorpholine or piperazine ring, where
the heterocyclic ring may be unsubstituted or may be substituted by
1, 2 or 3 identical or different substituents R.sup.31, and where
the heterocyclic ring may carry a fused benzene ring or a fused 5-
or 6-membered heteroaromatic ring, such as a thiophene or pyridine
ring, where the fused rings themselves are unsubstituted or carry
1, 2 or 3 substituents R.sup.32, where R.sup.31 and R.sup.32 are as
defined defined above.
[0157] R.sup.31 is in particular selected from the group consisting
of C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, halogen, phenyl
and phenoxy, where the phenylring in the last two mentioned
radicals itself is unsubstituted or carries 1 or 2 radicals
selected from the group consisting of C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy, halogen.
[0158] R.sup.32 is in particular selected from the group consisting
of C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy and halogen.
[0159] R.sup.4 is preferably C.sub.1-C.sub.4-alkyl and especially
methyl.
[0160] Y is preferably O.
[0161] A particular group of embodiments of the invention relates
to compounds of the formula I, to their salts, N-oxides, tautomers,
hydrates and prodrugs and to the salts of said N-oxides, tautomers,
hydrates and prodrugs, where X.sup.2 is C--R.sup.5. In this
particular group of embodiments R.sup.5 is preferably selected from
the group consisting of hydrogen, fluorine, C.sub.1-C.sub.4-alkoxy
or a radical O--Z.sup.5--Ar.sup.5, especially hydrogen, fluorine,
methoxy or a radical O--Z.sup.5--Ar.sup.5. Amongst these compounds
a first embodiment relates to compounds of the formula I, to their
salts, tautomers, hydrates and prodrugs and to the salts of said
tautomers, hydrates and prodrugs, where R.sup.5 is hydrogen,
fluorine, OH or C.sub.1-C.sub.4-alkoxy, especially hydrogen,
fluorine, OH or methoxy, with methoxy being particularly
preferred.
[0162] Amongst these compounds a second embodiment relates to
compounds of the formula I, to their salts, tautomers, hydrates and
prodrugs and to the salts of said tautomers, hydrates and prodrugs,
where R.sup.5 is a radical O--Z.sup.5--Ar.sup.5. In this second
embodiment R.sup.4 is in particular C.sub.1-C.sub.4-alkyl,
especially methyl.
[0163] In the second embodiment, Z.sup.5 is preferably
1,2-ethanediyl or 1,3-propanediyl, wherein 1, 2, 3 or 4 hydrogen
atoms may be replaced by a fluorine atom. According to a specific
embodiment, Z.sup.5 is 1,2-ethanediyl which is unsubstituted or
1,3-propanediyl which is unsubstituted.
[0164] In the second embodiment, Ar.sup.5 is preferably selected
from the group consisting of C-bound 6-membered monocyclic hetaryl,
which has 1 or 2 nitrogen atoms as ring members, and C-bound, fused
bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members
and optionally a further heteroatom selected from O, S and N as
ring member, where monocyclic hetaryl may be unsubstituted or may
carry 1, 2 or 3 identical or different substituents R.sup.k, in
particular 0, 1 or 2 substituents R.sup.k and bicyclic hetaryl may
be unsubstituted or may carry 1 substituent R.sup.k, and 0, 1, 2 or
3 substituents R.sup.h, in particular 0, 1 or 2 substituents
R.sup.h. In this regard, R.sup.h is preferably selected from
halogen, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.2-fluoroalkyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.2-fluoralkoxy,
C.sub.3-C.sub.6-cycloalkyl, and fluorinated
C.sub.3-C.sub.6-cycloalkyl. In this regard, R.sup.h is in
particular selected from fluorine, chlorine, methyl, fluoromethyl,
difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy,
difluoromethoxy, trifluoromethoxy, cyclopropyl and fluorinated
cyclopropyl.
[0165] Ar.sup.5 is in particular selected from the group consisting
of fused bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring
members and optionally a further heteroatom selected from O, S and
N as ring member and which may be unsubstituted or may carry 1
substituent R.sup.k and/or may carry 1, 2 or 3 substituents
R.sup.h, in particular 0, 1 or 2 substituents R.sup.h as defined
above. Amongst these, particular preference is given to those
compounds, where the Ar.sup.5 radical has at least one
imino-nitrogen as ring member, which is located in the position
adjacent to carbon atom bound to the group Z.sup.5. Amongst these,
particular preference is given to those, where Ar.sup.5 is selected
from the group consisting of C-bound, fused bicyclic hetaryl, which
has 1 or 2 nitrogen atoms as ring members and optionally a further
heteroatom selected from O, S and N as ring member, where bicyclic
hetaryl may be unsubstituted or may carry 1 substituent R.sup.k
and/or may carry 1, 2 or 3 substituents R.sup.h, in particular 0, 1
or 2 substituents R.sup.h. In this regard, R.sup.h is preferably
selected from halogen, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.2-fluoroalkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.2-fluoralkoxy, C.sub.3-C.sub.6-cycloalkyl and
fluorinated C.sub.3-C.sub.6-cycloalkyl. In this regard, R.sup.h is
in particular selected from fluorine, chlorine, methyl,
fluoromethyl, difluoromethyl, trifluoromethyl, methoxy,
fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl and
fluorinated cyclopropyl.
[0166] Particular examples of Ar.sup.y are selected from the group
consisting of 2-benzofuryl, 2-pyridyl, 2-pyrimidinyl,
4-pyrimidinyl, 2-pyrazinyl, 3-pyridazinyl, 2-quinolinyl,
3-isoquinolinyl, 2-quinazolinyl, 2-quinoxalinyl,
1,5-naphthyridin-2-yl, 1,8-naphthyridin-2-yl, benzothiazol-1-yl,
benzoxazol-1-yl, benzimidazol-2-yl, 1-methylbenzimidazol-2-yl,
imidazo[1,2-a]pyridine-2-yl, thieno[3,2-b]pyridine-5-yl,
imidazo-[2,1-b]-thiazol-6-yl and
1,2,4-triazolo[1,5-a]pyridine-2-yl, where the aforementioned
radicals are unsubstituted or may carry 1, 2 or 3 radicals R.sup.h
as defined above, which are in particular selected from the group
consisting of fluorine, chlorine, methyl, fluoromethyl,
difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy,
difluoromethoxy, trifluoromethoxy, and fluorinated cyclopropyl.
[0167] Amongst these compounds a third embodiment relates to
compounds of the formula I, to their salts, tautomers, hydrates and
prodrugs and to the salts of said tautomers, hydrates and prodrugs,
where R.sup.4 is a radical Z.sup.4--Ar.sup.4. In this third
embodiment R.sup.5 is in particular hydrogen, fluorine or
C.sub.1-C.sub.4-alkoxy, especially methoxy.
[0168] In the third embodiment, Z.sup.4 is preferably
1,2-ethanediyl or 1,3-propanediyl, wherein 1, 2, 3 or 4 hydrogen
atoms may be replaced by a fluorine atom. According to a specific
embodiment, Z.sup.4 is 1,2-ethanediyl which is unsubstituted or
1,3-propanediyl which is unsubstituted.
[0169] In the third embodiment, Ar.sup.4 is preferably selected
from the group consisting of C-bound 6-membered monocyclic hetaryl,
which has 1 or 2 nitrogen atoms as ring members, and C-bound, fused
bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members
and optionally a further heteroatom selected from O, S and N as
ring member, where monocyclic hetaryl may be unsubstituted or may
carry 1, 2 or 3 identical or different substituents R.sup.k, in
particular 0, 1 or 2 substituents R.sup.k and bicyclic hetaryl may
be unsubstituted or may carry 1 substituent R.sup.k, and 0, 1, 2 or
3 substituents R.sup.h, in particular 0, 1 or 2 substituents
R.sup.h. In this regard, R.sup.h is preferably selected from
halogen, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.2-fluoroalkyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.2-fluoralkoxy,
C.sub.3-C.sub.6-cycloalkyl, and fluorinated
C.sub.3-C.sub.6-cycloalkyl. In this regard, R.sup.h is in
particular selected from fluorine, chlorine, methyl, fluoromethyl,
difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy,
difluoromethoxy, trifluoromethoxy, cyclopropyl and fluorinated
cyclopropyl.
[0170] Ar.sup.4 is in particular selected from the group consisting
of fused bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring
members and optionally a further heteroatom selected from O, S and
N as ring member and which may be unsubstituted or may carry 1
substituent R.sup.k and/or may carry 1, 2 or 3 substituents
R.sup.h, in particular 0, 1 or 2 substituents R.sup.h as defined
above. Amongst these, particular preference is given to those
compounds, where the Ar.sup.4 radical has at least one
imino-nitrogen as ring member, which is located in the position
adjacent to carbon atom bound to the group Z.sup.4. Amongst these,
particular preference is given to those, where Ar.sup.4 is selected
from the group consisting of C-bound, fused bicyclic hetaryl, which
has 1 or 2 nitrogen atoms as ring members and optionally a further
heteroatom selected from O, S and N as ring member, where bicyclic
hetaryl may be unsubstituted or may carry 1 substituent R.sup.k
and/or may carry 1, 2 or 3 substituents R.sup.h, in particular 0, 1
or 2 substituents R.sup.h. In this regard, R.sup.h is preferably
selected from halogen, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.2-fluoroalkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.2-fluoralkoxy, C.sub.3-C.sub.6-cycloalkyl and
fluorinated C.sub.3-C.sub.6-cycloalkyl. In this regard, R.sup.h is
in particular selected from fluorine, chlorine, methyl,
fluoromethyl, difluoromethyl, trifluoromethyl, methoxy,
fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl and
fluorinated cyclopropyl.
[0171] Particular examples of Ar.sup.4 are selected from the group
consisting of 2-benzofuryl, 2-pyridyl, 2-pyrimidinyl,
4-pyrimidinyl, 2-pyrazinyl, 3-pyridazinyl, 2-quinolinyl,
3-isoquinolinyl, 2-quinazolinyl, 2-quinoxalinyl,
1,5-naphthyridin-2-yl, 1,8-naphthyridin-2-yl, benzothiazol-1-yl,
benzoxazol-1-yl, benzimidazol-2-yl, 1-methylbenzimidazol-2-yl,
imidazo[1,2-a]pyridine-2-yl, thieno[3,2-b]pyridine-5-yl,
imidazo-[2,1-b]-thiazol-6-yl and
1,2,4-triazolo[1,5-a]pyridine-2-yl, where the aforementioned
radicals are unsubstituted or may carry 1, 2 or 3 radicals R.sup.h
as defined above, which are in particular selected from the group
consisting of fluorine, chlorine, methyl, fluoromethyl,
difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy,
difluoromethoxy, trifluoromethoxy, and fluorinated cyclopropyl.
[0172] A first group of embodiments of the invention relates to
compounds of the formula I, to their salts, N-oxides, tautomers,
hydrates and prodrugs and to the salts of said N-oxides, tautomers,
hydrates and prodrugs, where X.sup.1 is C--H and X.sup.2 is
C--R.sup.5. In this first group, Y, R.sup.1, R.sup.2, R.sup.3,
R.sup.4 and R.sup.5 are as defined above and preferably have the
preferred or particular or special meanings given above. Amongst
these compounds, a particular group of embodiments is represented
by the following formula Ia
##STR00002##
where R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as defined
above.
[0173] A second group of embodiments of the invention relates to
compounds of the formula I, to their salts, N-oxides, tautomers,
hydrates and prodrugs and to the salts of said N-oxides, tautomers,
hydrates and prodrugs, where X.sup.1 is N and X.sup.2 is
C--R.sup.5. In this second group, Y, R.sup.1, R.sup.2, R.sup.3,
R.sup.4 and R.sup.5 are as defined above and preferably have the
preferred or particular or special meanings given above. Amongst
these compounds, a particular group of embodiments is represented
by the following formula Ib
##STR00003##
where R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as defined
above.
[0174] A particular group of embodiments of the invention relates
to compounds of the formulae Ia and Ib, to their salts, N-oxides,
tautomers, hydrates and prodrugs and to the salts of said N-oxides,
tautomers, hydrates and prodrugs, where R.sup.5 is preferably
selected from the group consisting of hydrogen, fluorine,
C.sub.1-C.sub.4-alkoxy or a radical O--Z.sup.5--Ar.sup.5,
especially hydrogen, fluorine, methoxy or a radical
O--Z.sup.5--Ar.sup.5. Amongst these compounds a first embodiment
relates to compounds of the formulae Ia and Ib, to their salts,
tautomers, hydrates and prodrugs and to the salts of said
tautomers, hydrates and prodrugs, where R.sup.5 is hydrogen,
fluorine, OH or C.sub.1-C.sub.4-alkoxy, especially hydrogen,
fluorine, OH or methoxy, with methoxy being particularly
preferred.
[0175] Amongst these compounds a second embodiment relates to
compounds of the formula Ia and Ib, to their salts, tautomers,
hydrates and prodrugs and to the salts of said tautomers, hydrates
and prodrugs, where R.sup.5 is a radical O--Z.sup.5--Ar.sup.5,
where Z.sup.5 and Ar.sup.5 are as defined above and having in
particular the preferred, particular or special meanings given
above. In this second embodiment R.sup.4 is in particular
C.sub.1-C.sub.4-alkyl, especially methyl.
[0176] In the second embodiment of formulae Ia and Ib, Z.sup.5 is
preferably 1,2-ethanediyl or 1,3-propanediyl, wherein 1, 2, 3 or 4
hydrogen atoms may be replaced by a fluorine atom. According to a
specific embodiment, Z.sup.5 is 1,2-ethanediyl which is
unsubstituted or 1,3-propanediyl which is unsubstituted.
[0177] In the second embodiment of formulae Ia and Ib, Ar.sup.5 is
preferably selected from the group consisting of C-bound 6-membered
monocyclic hetaryl, which has 1 or 2 nitrogen atoms as ring
members, and C-bound, fused bicyclic hetaryl, which has 1 or 2
nitrogen atoms as ring members and optionally a further heteroatom
selected from O, S and N as ring member, where monocyclic hetaryl
may be unsubstituted or may carry 1, 2 or 3 identical or different
substituents R.sup.k, in particular 0, 1 or 2 substituents R.sup.k
and bicyclic hetaryl may be unsubstituted or may carry 1
substituent R.sup.k, and 0, 1, 2 or 3 substituents R.sup.h, in
particular 0, 1 or 2 substituents R.sup.h. In this regard, R.sup.h
is preferably selected from halogen, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.2-fluoroalkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.2-fluoralkoxy, C.sub.3-C.sub.6-cycloalkyl, and
fluorinated C.sub.3-C.sub.6-cycloalkyl. In this regard, R.sup.h is
in particular selected from fluorine, chlorine, methyl,
fluoromethyl, difluoromethyl, trifluoromethyl, methoxy,
fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl and
fluorinated cyclopropyl.
[0178] In the second embodiment of formulae Ia and Ib, Ar.sup.5 is
in particular selected from the group consisting of fused bicyclic
hetaryl, which has 1 or 2 nitrogen atoms as ring members and
optionally a further heteroatom selected from O, S and N as ring
member and which may be unsubstituted, or may carry 1 substituent
R.sup.k and/or may carry 1, 2 or 3 substituents R.sup.h, in
particular 0, 1 or 2 substituents R.sup.h as defined above. Amongst
these, particular preference is given to those compounds, where the
Ar.sup.5 radical has at least one imino-nitrogen as ring member,
which is located in the position adjacent to carbon atom bound to
the group Z.sup.5. Amongst these, particular preference is given to
those, where Ar.sup.5 is selected from the group consisting of
C-bound, fused bicyclic hetaryl, which has 1 or 2 nitrogen atoms as
ring members and optionally a further heteroatom selected from O, S
and N as ring member, where bicyclic hetaryl may be unsubstituted,
or may carry 1 substituent R.sup.k and/or may carry 1, 2 or 3
substituents R.sup.h, in particular 0, 1 or 2 substituents R.sup.h.
In this regard, R.sup.h is preferably selected from halogen,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.2-fluoroalkyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.2-fluoralkoxy,
C.sub.3-C.sub.6-cycloalkyl and fluorinated
C.sub.3-C.sub.6-cycloalkyl. In this regard, R.sup.h is in
particular selected from fluorine, chlorine, methyl, fluoromethyl,
difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy,
difluoromethoxy, trifluoromethoxy, cyclopropyl and fluorinated
cyclopropyl.
[0179] In the second embodiment of formulae Ia and Ib, Ar.sup.5 is
e.g. selected from the group consisting of 2-benzofuryl, 2-pyridyl,
2-pyrimidinyl, 4-pyrimidinyl, 2-pyrazinyl, 3-pyridazinyl,
2-quinolinyl, 3-isoquinolinyl, 2-quinazolinyl, 2-quinoxalinyl,
1,5-naphthyridin-2-yl, 1,8-naphthyridin-2-yl, benzothiazol-1-yl,
benzoxazol-1-yl, benzimidazol-2-yl, 1-methylbenzimidazol-2-yl,
imidazo[1,2-a]pyridine-2-yl, thieno[3,2-b]pyridine-5-yl,
imidazo-[2,1-b]-thiazol-6-yl and
1,2,4-triazolo[1,5-a]pyridine-2-yl, where the aforementioned
radicals are unsubstituted or may carry 1, 2 or 3 radicals R.sup.h
as defined above, which are in particular selected from the group
consisting of fluorine, chlorine, methyl, fluoromethyl,
difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy,
difluoromethoxy, trifluoromethoxy, and fluorinated cyclopropyl.
[0180] Amongst these compounds a third embodiment relates to
compounds of the formula Ia and Ib, to their salts, tautomers,
hydrates and prodrugs and to the salts of said tautomers, hydrates
and prodrugs, where R.sup.4 is a radical Z.sup.4--Ar.sup.4, where
Z.sup.4 and Ar.sup.4 are as defined above and having in particular
the preferred, particular or special meanings given above. In this
third embodiment R.sup.5 is in particular hydrogen, fluorine or in
particular C.sub.1-C.sub.4-alkoxy, especially methoxy.
[0181] In the third embodiment of formulae Ia and Ib, Z.sup.4 is
preferably 1,2-ethanediyl or 1,3-propanediyl, wherein 1, 2, 3 or 4
hydrogen atoms may be replaced by a fluorine atom. According to a
specific embodiment, Z.sup.4 is 1,2-ethanediyl which is
unsubstituted or 1,3-propanediyl which is unsubstituted.
[0182] In the third embodiment of formulae Ia and Ib, Ar.sup.4 is
preferably selected from the group consisting of C-bound 6-membered
monocyclic hetaryl, which has 1 or 2 nitrogen atoms as ring
members, and C-bound, fused bicyclic hetaryl, which has 1 or 2
nitrogen atoms as ring members and optionally a further heteroatom
selected from O, S and N as ring member, where monocyclic hetaryl
may be unsubstituted or may carry 1, 2 or 3 substituents R.sup.k,
in particular 0, 1 or 2 substituents R.sup.k and bicyclic hetaryl
may be unsubstituted or may carry 1 substituent R.sup.k, and 0, 1,
2 or 3 substituents R.sup.h, in particular 0, 1 or 2 substituents
R.sup.h. In this regard, R.sup.h is preferably selected from
halogen, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.2-fluoroalkyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.2-fluoralkoxy,
C.sub.3-C.sub.6-cycloalkyl, and fluorinated
C.sub.3-C.sub.6-cycloalkyl. In this regard, R.sup.h is in
particular selected from fluorine, chlorine, methyl, fluoromethyl,
difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy,
difluoromethoxy, trifluoromethoxy, cyclopropyl and fluorinated
cyclopropyl.
[0183] In the third embodiment of formulae Ia and Ib, Ar.sup.4 is
in particular selected from the group consisting of fused bicyclic
hetaryl, which has 1 or 2 nitrogen atoms as ring members and
optionally a further heteroatom selected from O, S and N as ring
member and which may be unsubstituted, or may carry 1 substituent
R.sup.k and/or may carry 1, 2 or 3 substituents R.sup.h, in
particular 0, 1 or 2 substituents R.sup.h as defined above. Amongst
these, particular preference is given to those compounds, where the
Ar.sup.4 radical has at least one imino-nitrogen as ring member,
which is located in the position adjacent to carbon atom bound to
the group Z.sup.4. Amongst these, particular preference is given to
those, where Ar.sup.4 is selected from the group consisting of
C-bound, fused bicyclic hetaryl, which has 1 or 2 nitrogen atoms as
ring members and optionally a further heteroatom selected from O, S
and N as ring member, where bicyclic hetaryl may be unsubstituted,
or may carry 1 substituent R.sup.k and/or may carry 1, 2 or 3
substituents R.sup.h, in particular 0, 1 or 2 substituents R.sup.h.
In this regard, R.sup.h is preferably selected from halogen,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.2-fluoroalkyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.2-fluoralkoxy,
C.sub.3-C.sub.6-cycloalkyl and fluorinated
C.sub.3-C.sub.6-cycloalkyl. In this regard, R.sup.h is in
particular selected from fluorine, chlorine, methyl, fluoromethyl,
difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy,
difluoromethoxy, trifluoromethoxy, cyclopropyl and fluorinated
cyclopropyl.
[0184] In the third embodiment of formulae Ia and Ib, Ar.sup.4 is
e.g. selected from the group consisting of 2-benzofuryl, 2-pyridyl,
2-pyrimidinyl, 4-pyrimidinyl, 2-pyrazinyl, 3-pyridazinyl,
2-quinolinyl, 3-isoquinolinyl, 2-quinazolinyl, 2-quinoxalinyl,
1,5-naphthyridin-2-yl, 1,8-naphthyridin-2-yl, benzothiazol-1-yl,
benzoxazol-1-yl, benzimidazol-2-yl, 1-methylbenzimidazol-2-yl,
imidazo[1,2-a]pyridine-2-yl, thieno[3,2-b]pyridine-5-yl,
imidazo-[2,1-b]-thiazol-6-yl and
1,2,4-triazolo[1,5-a]pyridine-2-yl, where the aforementioned
radicals are unsubstituted or may carry 1, 2 or 3 radicals R.sup.h
as defined above, which are in particular selected from the group
consisting of fluorine, chlorine, methyl, fluoromethyl,
difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy,
difluoromethoxy, trifluoromethoxy, and fluorinated cyclopropyl.
[0185] A third group of embodiments of the invention relates to
compounds of the formula I, to their salts, N-oxides, tautomers,
hydrates and prodrugs and to the salts of said N-oxides, tautomers,
hydrates and prodrugs, where X.sup.1 is C--H and X.sup.2 is N. In
this third group, Y, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as
defined above and preferably have the preferred or particular or
special meanings given above. Amongst these compounds, a particular
group of embodiments is represented by the following formula Ic
##STR00004##
where R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined
above.
[0186] A fourth group of embodiments of the invention relates to
compounds of the formula I, to their salts, N-oxides, tautomers,
hydrates and prodrugs and to the salts of said N-oxides, tautomers,
hydrates and prodrugs, where X.sup.1 is N and X.sup.2 is N. In this
second group, Y, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as
defined above and preferably have the preferred or particular or
special meanings given above. Amongst these compounds, a particular
group of embodiments is represented by the following formula Id
##STR00005##
where R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as defined
above.
[0187] In relation to their use as inhibitors of PDE10A, the
variables R.sup.1, R.sup.2, R.sup.3 and R.sup.4 in formulae Ia, Ib,
Ic and Id preferably have the following meanings, where these
represent, both considered on their own and in combination with at
least one other or all, special embodiments of the compounds of the
formula I:
[0188] In formulae Ia, Ib, Ic and Id, R.sup.1 is preferably
C.sub.2-C.sub.8-alkyl, C.sub.3-C.sub.8-cycloalkyl or
C.sub.3-C.sub.8-cycloalkylmethyl, in particular
C.sub.3-C.sub.8-cycloalkylmethyl or especially
C.sub.2-C.sub.8-alkyl. Particularly, R.sup.1 is alkyl of the
formula CHR.sup.1aR.sup.1b, where R.sup.1a is selected from the
group consisting of hydrogen and C.sub.1-C.sub.3-alkyl, in
particular methyl, ethyl, n-propyl and where R.sup.1b is selected
from the group consisting of C.sub.1-C.sub.4-alkyl, in particular
methyl, ethyl, n-propyl or n-butyl. Particular examples of R.sup.1
are selected from the group consisting of ethyl, isopropyl,
1-methylpropyl and 1-ethylpropyl.
[0189] In formulae Ia, Ib, Ic and Id, R.sup.1 is likewise
preferably a moiety Z.sup.1--Ar.sup.1, where Z.sup.1 and Ar.sup.1
are as defined above and where Z.sup.1 is preferably 1,2-ethanediyl
or 1,3-propanediyl, wherein 1, 2, 3 or 4 hydrogen atoms may be
replaced by a fluorine atom. According to a specific embodiment,
Z.sup.1 is 1,2-ethanediyl which is unsubstituted or 1,3-propanediyl
which is unsubstituted.
[0190] In formulae Ia, Ib, Ic and Id, where R.sup.1 is a moiety
Z.sup.1--Ar.sup.1, Ar.sup.1 is preferably selected from the group
consisting of C-bound 6-membered monocyclic hetaryl, which has 1 or
2 nitrogen atoms as ring members, and C-bound, fused bicyclic
hetaryl, which has 1 or 2 nitrogen atoms as ring members and
optionally a further heteroatom selected from O, S and N as ring
member, where monocyclic hetaryl and bicyclic hetaryl may be
unsubstituted or may carry 1, 2 or 3 substituents R.sup.h, in
particular 0, 1 or 2 substituents R.sup.h. Ar.sup.1 is in
particular selected from the group consisting of fused bicyclic
hetaryl, which has 1 or 2 nitrogen atoms as ring members and
optionally a further heteroatom selected from O, S and N as ring
member and which may be unsubstituted or may carry 1, 2 or 3
substituents R.sup.h, in particular 0, 1 or 2 substituents R.sup.h
as defined above. Amongst these, particular preference is given to
those compounds, where the Ar.sup.1 radical has at least one
imino-nitrogen as ring member, which is located in the position
adjacent to carbon atom bound to the group Z.sup.1. Amongst these,
particular preference is given to those, where Ar.sup.1 is selected
from the group consisting of C-bound, fused bicyclic hetaryl, which
has 1 or 2 nitrogen atoms as ring members and optionally a further
heteroatom selected from O, S and N as ring member, where bicyclic
hetaryl may be unsubstituted or may carry 1, 2 or 3 substituents
R.sup.h, in particular 0, 1 or 2 substituents R.sup.h. In this
regard, R.sup.h is preferably selected from halogen,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.2-fluoroalkyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.2-fluoralkoxy,
C.sub.3-C.sub.6-cycloalkyl and fluorinated
C.sub.3-C.sub.6-cycloalkyl. In this regard, R.sup.h is in
particular selected from fluorine, chlorine, methyl, fluoromethyl,
difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy,
difluoromethoxy, trifluoromethoxy, cyclopropyl and fluorinated
cyclopropyl.
[0191] In particular embodiments of formulae Ia, Ib, Ic and Id,
R.sup.2 is a radical of the formula CR.sup.21R.sup.22R.sup.23,
where R.sup.21, R.sup.22 and R.sup.23 are as defined above and
where R.sup.21 is in particular different from hydrogen.
[0192] In other particular embodiments of formulae Ia, Ib, Ic and
Id, R.sup.2 is a phenyl or 5- or 6-membered hetaryl radical having
1, 2 or 3 heteroatoms as ring members which are selected from O, S
and N, where phenyl and monocyclic hetaryl are unsubstituted or may
carry 1, 2 or 3 identical or different substituents R.sup.a as
defined above.
[0193] In the particular embodiments of formulae Ia, Ib, Ic and Id,
where R.sup.2 is a radical of the formula
CR.sup.21R.sup.22R.sup.23, where R.sup.21, R.sup.22 and R.sup.23
are as defined above or where R.sup.2 is a phenyl or 5- or
6-membered hetaryl radical having 1, 2 or 3 heteroatoms as ring
members which are selected from O, S and N, where phenyl and
monocyclic hetaryl are unsubstituted or may carry 1, 2 or 3
identical or different substituents R.sup.a as defined above, the
radical R.sup.3 is preferably selected from the group consisting of
hydrogen and C.sub.1-C.sub.4-alkyl. In these embodiments, R.sup.3
is in particular hydrogen.
[0194] In the particular embodiments of formulae Ia, Ib, Ic and Id,
where R.sup.2 is a radical of the formula
CR.sup.21R.sup.22R.sup.23, a particular group of embodiments
relates to compounds, where the radicals R.sup.21, R.sup.22 and
R.sup.23 have the following meanings: [0195] R.sup.21 is selected
from the group consisting of C.sub.1-C.sub.8-alkyl, trimethylsilyl,
C.sub.2-C.sub.8-alkenyl, C.sub.1-C.sub.4-fluoroalkyl,
C.sub.3-C.sub.8-cycloalkyl, fluorinated C.sub.3-C.sub.8-cycloalkyl,
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl, fluorinated
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl,
hydroxy-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkyl-N(R.sup.b)(R.sup.c),
(CH.sub.2).sub.mC(O)O--R.sup.d,
(CH.sub.2).sub.mC(O)N(R.sup.e)(R.sup.f) and Z.sup.2--Ar.sup.2,
[0196] R.sup.22 is selected from the group consisting of hydrogen,
fluorine, C.sub.1-C.sub.8-alkyl, C.sub.2-C.sub.8-alkenyl,
C.sub.1-C.sub.4-fluoroalkyl, C.sub.3-C.sub.8-cycloalkyl,
fluorinated C.sub.3-C.sub.8-cycloalkyl,
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl, fluorinated
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl,
hydroxy-C.sub.1-C.sub.4-alkyl and
C.sub.1-C.sub.4-alkyl-N(R.sup.b)(R.sup.c), or [0197] R.sup.23 is
selected from the group consisting of hydrogen, fluorine,
C.sub.1-C.sub.8-alkyl and C.sub.1-C.sub.4-fluoroalkyl;
[0198] In the particular embodiments of formulae Ia, Ib, Ic and Id,
where R.sup.2 is a radical of the formula
CR.sup.21R.sup.22R.sup.23, a particular group of embodiments
relates to compounds, where the radicals R.sup.21, R.sup.22 and
R.sup.23 preferably have the following meanings, both considered on
their own and in combination with at least one other or all: [0199]
R.sup.21 is selected from the group consisting of
C.sub.2-C.sub.8-alkyl, trimethylsilyl, C.sub.2-C.sub.8-alkenyl,
C.sub.1-C.sub.4-fluoroalkyl, C.sub.3-C.sub.8-cycloalkyl,
fluorinated C.sub.3-C.sub.8-cycloalkyl,
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl, fluorinated
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl and
Z.sup.2--Ar.sup.2, where Z.sup.2 and Ar.sup.2, where Z.sup.2 and
Ar.sup.2 are as defined above and where Z.sup.2 is preferably a
single bond or CH.sub.2 and Ar.sup.2 is preferably phenyl, pyridyl,
pyrimidinyl, thienyl, thiazolyl or thiadiazolyl, which are
unsubstituted or which carry 1, 2 or 3 identical or different
substituents R.sup.h; [0200] R.sup.22 is selected from the group
consisting of hydrogen, fluorine, C.sub.1-C.sub.8-alkyl, in
particular hydrogen; and [0201] R.sup.23 is hydrogen or
C.sub.1-C.sub.4-alkyl, such as methyl, or especially hydrogen.
[0202] In the particular embodiments of formulae Ia, Ib, Ic and Id,
where R.sup.2 is a radical of the formula
CR.sup.21R.sup.22R.sup.23, a particular group of embodiments
relates to compounds, where the radicals R.sup.21, R.sup.22 and
R.sup.23 preferably have the following meanings, both considered on
their own and in combination with at least one other or all: [0203]
R.sup.21 is selected from the group consisting of
C.sub.2-C.sub.8-alkyl, trimethylsilyl, C.sub.2-C.sub.8-alkenyl,
C.sub.1-C.sub.4-fluoroalkyl, C.sub.3-C.sub.8-cycloalkyl,
fluorinated C.sub.3-C.sub.8-cycloalkyl,
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl, fluorinated
C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.4-alkyl, and where
R.sup.21 is in particular C.sub.2-C.sub.4-alkyl; [0204] R.sup.22 is
selected from the group consisting of hydrogen, fluorine,
C.sub.1-C.sub.8-alkyl, in particular methyl or hydrogen; and [0205]
R.sup.23 is hydrogen or C.sub.1-C.sub.4-alkyl, such as methyl, or
especially hydrogen.
[0206] In the particular embodiments of formulae Ia, Ib, Ic and Id,
where R.sup.2 is a radical of the formula
CR.sup.21R.sup.22R.sup.23, another particular group of embodiments
relates to compounds, where the radicals R.sup.21, R.sup.22 and
R.sup.23 preferably have the following meanings, both considered on
their own and in combination with at least one other or all: [0207]
R.sup.21 is a radical Z.sup.2--Ar.sup.2, where Z.sup.2 and
Ar.sup.2, where Z.sup.2 and Ar.sup.2 are as defined above and where
Z.sup.2 is preferably a single bond or CH.sub.2 and Ar.sup.2 is
preferably phenyl, pyridyl, pyrimidinyl, thienyl, thiazolyl or
thiadiazolyl, which are unsubstituted or which carry 1, 2 or 3
identical or different substituents R.sup.h, particular examples of
R.sup.21 being 2-, 3- or 4-fluorophenyl, 2-, 3- or 4-methylphenyl,
2-, 3- or 4-methoxyphenyl, 2,3-difluorophenyl, 3,5-difluorophenyl,
3,4-difluorophenyl, thiazol-2-yl, thiazol-4-yl,
1,3,4-thiadiazol-2-yl, 2-(1-morpholinosulfonyl)phenyl,
3-(1-morpholinosulfonyl)phenyl,
2-(4-methylpiperazin-1-ylsulfonyl)phenyl or
3-(4-methylpiperazin-1-ylsulfonyl)phenyl. [0208] R.sup.22 is
selected from the group consisting of hydrogen, fluorine,
C.sub.1-C.sub.8-alkyl, in particular methyl or hydrogen; and [0209]
R.sup.23 is hydrogen or C.sub.1-C.sub.4-alkyl, such as methyl, or
especially hydrogen.
[0210] In the particular embodiments of formulae Ia, Ib, Ic and Id,
where R.sup.2 is a radical of the formula
CR.sup.21R.sup.22R.sup.23, a further group of embodiments relates
to compounds, where the radicals R.sup.21 and R.sup.22 together
with the carbon atom, to which they are bound form a saturated 5-,
6- or 7-membered carbocyclic ring, such as cyclopentyl, cyclohexyl
or cycloheptyl, especially cyclopentyl, or a saturated 5-, 6- or
7-membered heterocyclic ring which has 1, 2 or 3 heteroatoms or
heteroatom containing groups selected from the group of O, N, S, SO
and SO.sub.2 as ring members, especially 2- or 3-tetrahydrofuryl or
2- or 3-tetrahydrothienyl, where the carbocyclic ring and the
heterocyclic ring may be unsubstituted or may be substituted by 1,
2 or 3 identical or different substituents R.sup.g, and where the
carbocyclic ring and the heterocyclic ring may carry a fused
benzene ring or a fused 5- or 6-membered heteroaromatic ring, where
the fused rings themselves are unsubstituted or carry 1, 2 or 3
substituents R.sup.h, and where R.sup.g, R.sup.h and R.sup.23 are
as defined above and where R.sup.23 is in particular hydrogen or
C.sub.1-C.sub.4-alkyl, such as methyl, or especially hydrogen.
[0211] In the particular embodiments of formulae Ia, Ib, Ic and Id,
where R.sup.2 is a radical of the formula
CR.sup.21R.sup.22R.sup.23, a further particular group of
embodiments relates to compounds, where the radicals R.sup.21,
R.sup.22 and R.sup.23 preferably have the following meanings, both
considered on their own and in combination with at least one other
or all: [0212] R.sup.21 and R.sup.22 together with the carbon atom,
to which they are bound form a saturated 5-, 6- or 7-membered
carbocyclic radical, namely a cyclopentyl, cyclohexyl or
cycloheptyl radical or a 3-tetrahydrofuryl or 3-tetrahydrothienyl,
where the 5 to 7 membered carbocyclic ring and the
3-tetrahydrofuryl or 3-tetrahydrothienyl ring carry a fused benzene
ring or a fused 5- or 6-membered heteroaromatic ring, such as a
fused thiophene or pyridine ring, where the fused rings themselves
are unsubstituted or carry 1, 2 or 3 substituents R.sup.h, and
where R.sup.21 and R.sup.22 in particular form a bicyclic radical
selected from the group consisting of 5-indanyl, 6-indanyl,
5,6,7,8-tetrahydronaphthalin-5-yl,
5,6,7,8-tetrahydronaphthalin-6-yl,
6,7,8,9-tetrahydro-5H-benzocycloheptene-5-yl,
6,7,8,9-tetrahydro-5H-benzocycloheptene-6-yl,
5,6-dihydro-4H-cyclopenta[b]thiophene-4-yl,
6,7-dihydro-5H-[1]-pyrindin-6-yl, 3,4-dihydrobenzofuran-3-yl,
2,3-dihydrobenzothiophen-3-yl or where these bicyclic radicals are
in particular unsubstituted or where the aromatic moiety of these
rings carry 1, 2 or 3 substituents R.sup.h; [0213] R.sup.23 is
hydrogen or C.sub.1-C.sub.4-alkyl, such as methyl, or especially
hydrogen.
[0214] In further particular embodiments of the invention R.sup.2
and R.sup.3 together with the nitrogen atom, to which they are
bound form a saturated 4-, 5-, 6- or 7-membered heterocyclic ring
which, in addition to the nitrogen atom, may have 1 or 2 further
heteroatoms or heteroatom containing groups selected from the group
of O, N, S, SO and SO.sub.2 as ring members, e.g. a pyrrolidine,
piperidine, morpholine, thiomorpholine or piperazine ring, where
the heterocyclic ring may be unsubstituted or may be substituted by
1, 2 or 3 identical or different substituents R.sup.31, and where
the heterocyclic ring may carry a fused benzene ring or a fused 5-
or 6-membered heteroaromatic ring, such as a thiophene or pyridine
ring, where the fused rings themselves are unsubstituted or carry
1, 2 or 3 substituents R.sup.32, where R.sup.31 and R.sup.32 are as
defined defined above.
[0215] R.sup.31 is in particular selected from the group consisting
of C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, halogen, phenyl
and phenoxy, where the phenylring in the last two mentioned
radicals itself is unsubstituted or carries 1 or 2 radicals
selected from the group consisting of C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.4-alkoxy, halogen.
[0216] R.sup.32 is in particular selected from the group consisting
of C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy and halogen.
[0217] In formulae Ia, Ib, Ic and Id, a particular embodiment
relates to compounds where R.sup.4 is C.sub.1-C.sub.4-alkyl and
especially methyl.
[0218] In formulae Ia, Ib, Ic and Id, another particular embodiment
relates to compounds where R.sup.4 is a radical Z.sup.4--Ar.sup.4,
where Z.sup.4 and Ar.sup.4 are as defined above and having in
particular the preferred, particular or special meanings given
above. In this embodiment in formulae Ia and Ib R.sup.5 is in
particular hydrogen, fluorine or in particular
C.sub.1-C.sub.4-alkoxy, especially methoxy.
[0219] In this embodiment of formulae Ia, Ib, Ic and Id, Z.sup.4 is
preferably 1,2-ethanediyl or 1,3-propanediyl, wherein 1, 2, 3 or 4
hydrogen atoms may be replaced by a fluorine atom. According to a
specific embodiment, Z.sup.4 is 1,2-ethanediyl which is
unsubstituted or 1,3-propanediyl which is unsubstituted.
[0220] In this embodiment of formulae Ia, Ib, Ic and Id, Ar.sup.4
is preferably selected from the group consisting of C-bound
6-membered monocyclic hetaryl, which has 1 or 2 nitrogen atoms as
ring members, and C-bound, fused bicyclic hetaryl, which has 1 or 2
nitrogen atoms as ring members and optionally a further heteroatom
selected from O, S and N as ring member, where monocyclic hetaryl
may be unsubstituted or may carry 1, 2 or 3 identical or different
substituents R.sup.k, in particular 0, 1 or 2 substituents R.sup.k
and bicyclic hetaryl may be unsubstituted or may carry 1
substituent R.sup.k, and 0, 1, 2 or 3 substituents R.sup.h, in
particular 0, 1 or 2 substituents R.sup.h. In this regard, R.sup.h
is preferably selected from halogen, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.2-fluoroalkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.2-fluoralkoxy, C.sub.3-C.sub.6-cycloalkyl, and
fluorinated C.sub.3-C.sub.6-cycloalkyl. In this regard, R.sup.h is
in particular selected from fluorine, chlorine, methyl,
fluoromethyl, difluoromethyl, trifluoromethyl, methoxy,
fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl and
fluorinated cyclopropyl.
[0221] In this embodiment of formulae Ia, Ib, Ic and Id, Ar.sup.4
is in particular selected from the group consisting of fused
bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members
and optionally a further heteroatom selected from O, S and N as
ring member and which may be unsubstituted, or may carry 1
substituent R.sup.k and/or may carry 1, 2 or 3 substituents
R.sup.h, in particular 0, 1 or 2 substituents R.sup.h as defined
above. Amongst these, particular preference is given to those
compounds, where the Ar.sup.4 radical has at least one
imino-nitrogen as ring member, which is located in the position
adjacent to carbon atom bound to the group Z.sup.4. Amongst these,
particular preference is given to those, where Ar.sup.4 is selected
from the group consisting of C-bound, fused bicyclic hetaryl, which
has 1 or 2 nitrogen atoms as ring members and optionally a further
heteroatom selected from O, S and N as ring member, where bicyclic
hetaryl may be unsubstituted or may carry 1 substituent R.sup.k
and/or may carry 1, 2 or 3 substituents R.sup.h, in particular 0, 1
or 2 substituents R.sup.h. In this regard, R.sup.h is preferably
selected from halogen, C.sub.1-C.sub.4-alkyl,
C.sub.1-C.sub.2-fluoroalkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.2-fluoralkoxy, C.sub.3-C.sub.6-cycloalkyl and
fluorinated C.sub.3-C.sub.6-cycloalkyl. In this regard, R.sup.h is
in particular selected from fluorine, chlorine, methyl,
fluoromethyl, difluoromethyl, trifluoromethyl, methoxy,
fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl and
fluorinated cyclopropyl.
[0222] In this embodiment of formulae Ia, Ib, Ic and Id, Ar.sup.4
is e.g. selected from the group consisting of 2-benzofuryl,
2-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 2-pyrazinyl,
3-pyridazinyl, 2-quinolinyl, 3-isoquinolinyl, 2-quinazolinyl,
2-quinoxalinyl, 1,5-naphthyridin-2-yl, 1,8-naphthyridin-2-yl,
benzothiazol-1-yl, benzoxazol-1-yl, benzimidazol-2-yl,
1-methylbenzimidazol-2-yl, imidazo[1,2-a]pyridine-2-yl,
thieno[3,2-b]pyridine-5-yl, imidazo-[2,1-b]-thiazol-6-yl and
1,2,4-triazolo[1,5-a]pyridine-2-yl, where the aforementioned
radicals are unsubstituted or may carry 1, 2 or 3 radicals R.sup.h
as defined above, which are in particular selected from the group
consisting of fluorine, chlorine, methyl, fluoromethyl,
difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy,
difluoromethoxy, trifluoromethoxy, and fluorinated cyclopropyl.
[0223] Apart from that, the variables Ar.sup.3, Z.sup.3, Z.sup.4,
R.sup.a, R.sup.b, R.sup.c, R.sup.d, R.sup.e, R.sup.f, R.sup.g,
R.sup.h and R.sup.k preferably have, irrespectively of their
occurrence and with regard to the formulae I, Ia, Ib, Ic and Id and
with regard to each of the above mentioned embodiments groups of
embodiments one of the following meanings:
[0224] Ar.sup.3 is preferably phenyl, which is unsubstituted or
substituted by 1, 2 or 3 radicals R.sup.h.
[0225] Z.sup.3 is preferably a single bond, CH.sub.2 or
CH.sub.2CH.sub.2.
[0226] Z.sup.4 is preferably CH.sub.2 or CH.sub.2CH.sub.2.
[0227] R.sup.a is preferably halogen, in particular fluorine,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-fluoroalkyl, C.sub.1-C.sub.4-fluoroalkoxy,
N(R.sup.b)(R.sup.c), CH.sub.2N(R.sup.b)(R.sup.c), or
S(O).sub.2N(R.sup.e)(R.sup.f),
[0228] R.sup.b is preferably hydrogen or C.sub.1-C.sub.4-alkyl;
[0229] R.sup.c is preferably hydrogen or C.sub.1-C.sub.4-alkyl;
or
[0230] R.sup.b and R.sup.c together with the nitrogen atom to which
they are bound may also form a saturated N-bound heterocyclic
radical, selected from the group consisting of pyrrolidin-1-yl,
piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl
and 4-methylpiperazin-1-yl, where the 6 aforementioned heterocyclic
radicals may carry 1, 2, 3 or 4 substituents, selected from methyl
and fluorine.
[0231] R.sup.d is preferably C.sub.1-C.sub.4-alkyl.
[0232] R.sup.e is preferably hydrogen or C.sub.1-C.sub.4-alkyl;
[0233] R.sup.f is preferably hydrogen or C.sub.1-C.sub.4-alkyl;
or
[0234] R.sup.e and R.sup.f together with the nitrogen atom to which
they are bound may also form a saturated N-bound heterocyclic
radical, selected from the group consisting of pyrrolidin-1-yl,
piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl
and 4-methylpiperazin-1-yl, where the 6 aforementioned heterocyclic
radicals may carry 1, 2, 3 or 4 substituents, selected from methyl
and fluorine.
[0235] R.sup.g is preferably halogen, in particular fluorine,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-fluoroalkyl or C.sub.1-C.sub.4-fluoroalkoxy.
[0236] R.sup.h is preferably halogen, in particular fluorine,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-fluoroalkyl, C.sub.1-C.sub.4-fluoroalkoxy,
C.sub.3-C.sub.6-cycloalkyl, fluorinated C.sub.3-C.sub.6-cycloalkyl,
N(R.sup.b)(R.sup.c), CH.sub.2N(R.sup.b)(R.sup.c) or
S(O).sub.2N(R.sup.e)(R.sup.f). In addition, R.sup.h is preferably
C.sub.1-C.sub.2-alkylsulfanyl,
C.sub.1-C.sub.2-alkoxy-C.sub.1-C.sub.4-alkoxy,
C.sub.3-C.sub.6-cycloalkoxy,
C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.2-alkoxy, phenoxy, 3- to
7-membered heterocyclyloxy, 3- to 7-membered
heterocyclyl-C.sub.1-C.sub.2-alkoxy, where heterocyclyl in the two
last mentioned radicals has 1 or 2 heteroatoms as ring members
which are selected from O, S and N, and 5- to 6-membered
hetaryl-C.sub.1-C.sub.2-alkoxy, where hetaryl has 1 or 2
heteroatoms as ring members which are selected from O, S and N.
R.sup.h is in particular selected from halogen,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.2-fluoroalkyl,
C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.2-fluoralkoxy,
C.sub.3-C.sub.6-cycloalkyl and fluorinated
C.sub.3-C.sub.6-cycloalkyl. R.sup.h is especially selected from
fluorine, chlorine, methyl, fluoromethyl, difluoromethyl,
trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy,
trifluoromethoxy, cyclopropyl and fluorinated cyclopropyl.
[0237] R.sup.k is preferably halogen, in particular fluorine,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy,
C.sub.1-C.sub.4-fluoroalkyl or C.sub.1-C.sub.4-fluoroalkoxy.
[0238] Particular embodiments of the invention relates to the
compounds of formula I, to the N-oxides, the prodrugs, the hydrates
and the tautomers thereof and to the pharmaceutically suitable
salts thereof, where the compounds of the formula I are selected
from the group consisting of: [0239]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid butylamide, [0240]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid methylamide, [0241]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid cyclopropylmethyl-amide, [0242]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid methyl-phenethyl-amide, [0243]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (2-methoxy-benzyl)-methyl-amide, [0244]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (4-methoxy-benzyl)-methyl-amide, [0245]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (3-methoxy-benzyl)-methyl-amide, [0246]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid methyl-(3-trifluoromethyl-benzyl)-amide, [0247]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid benzyl-(2-dimethylamino-ethyl)-amide, [0248]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (1-benzyl-piperidin-4-yl)-methyl-amide, [0249]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid tert-butylamide, [0250]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid sec-butylamide, [0251]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid isobutyl-amide, [0252]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid cyclopentylamide, [0253]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (1-methyl-butyl)-amide, [0254]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (1,1-dimethyl-propyl)-amide, [0255]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (1,2-dimethyl-propyl)-amide, [0256]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (2,2-dimethyl-propyl)-amide, [0257]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (1-ethyl-propyl)-amide, [0258]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid ethylamide, [0259]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (2-methyl-butyl)-amide, [0260]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid pentylamide, [0261]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid cyclohexylamide, [0262]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (1,3-dimethyl-butyl)-amide, [0263]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (3,3-dimethyl-butyl)-amide, [0264]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (2-ethyl-butyl)-amide, [0265]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid benzylamide, [0266]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid dicyclopropylmethyl-amide, [0267]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (2-fluoro-ethyl)-amide, [0268]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid cyclohexylmethyl-amide, [0269]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (1-phenyl-ethyl)-amide, [0270]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid 2-fluoro-benzylamide, [0271]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid 3-fluoro-benzylamide, [0272]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid 4-fluoro-benzylamide, [0273]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid 2,3-difluoro-benzylamide, [0274]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid 2,4-difluoro-benzylamide, [0275]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid 2,6-difluoro-benzylamide, [0276]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid 3,4-difluoro-benzylamide, [0277]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (2,2,2-trifluoro-ethyl)-amide, [0278]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid 3,5-difluoro-benzylamide, [0279]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid phenethyl-amide, [0280]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid [1-(4-fluoro-phenyl)-ethyl]-amide, [0281]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid indan-1-ylamide, [0282]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid indan-2-ylamide, [0283]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid [1-(4-fluoro-phenyl)-1-methyl-ethyl]-amide, [0284]
4-(azetidine-1-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquinolin-1-one,
[0285]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid cyclopropylamide, [0286]
2-ethyl-6,7-dimethoxy-4-(2-methyl-pyrrolidine-1-carbonyl)-2H-isoquinolin--
1-one, [0287]
2-ethyl-6,7-dimethoxy-4-(morpholine-4-carbonyl)-2H-isoquinolin-1-one,
[0288]
2-ethyl-4-(3-fluoro-pyrrolidine-1-carbonyl)-6,7-dimethoxy-2H-isoqu-
inolin-1-one, [0289]
2-ethyl-6,7-dimethoxy-4-(4-methyl-piperazine-1-carbonyl)-2H-isoquinolin-1-
-one, [0290]
4-(3,3-difluoro-pyrrolidine-1-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquino-
lin-1-one, [0291]
4-(3-dimethylamino-pyrrolidine-1-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoqu-
inolin-1-one, [0292]
2-ethyl-6,7-dimethoxy-4-((R)-2-methoxymethyl-pyrrolidine-1-carbonyl)-2H-i-
soquinolin-1-one, [0293]
4-(1,3-dihydro-isoindole-2-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquinolin-
-1-one, [0294]
4-(4,4-difluoro-piperidine-1-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquinol-
in-1-one, [0295]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid isopropylamide, [0296]
2-ethyl-4-(4-isopropyl-piperazine-1-carbonyl)-6,7-dimethoxy-2H-isoquinoli-
n-1-one, [0297]
4-(4-dimethylamino-piperidine-1-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoqui-
nolin-1-one, [0298]
2-ethyl-6,7-dimethoxy-4-(2-trifluoromethyl-pyrrolidine-1-carbonyl)-2H-iso-
quinolin-1-one, [0299]
4-(4-cyclopropylmethyl-piperazine-1-carbonyl)-2-ethyl-6,7-dimethoxy-2H-is-
oquinolin-1-one, [0300]
2-ethyl-6,7-dimethoxy-4-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbon-
yl)-2H-isoquinolin-1-one, [0301]
2-ethyl-6,7-dimethoxy-4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-2H-isoq-
uinolin-1-one, [0302]
4-[4-(2-dimethylamino-ethyl)-piperazine-1-carbonyl]-2-ethyl-6,7-dimethoxy-
-2H-isoquinolin-1-one, [0303]
4-([1,4']bipiperidinyl-1'-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquinolin--
1-one, [0304]
4-[4-(3-dimethylamino-propyl)-piperazine-1-carbonyl]-2-ethyl-6,7-dimethox-
y-2H-isoquinolin-1-one, [0305]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid propylamide, [0306]
2-ethyl-6,7-dimethoxy-4-[4-(2-pyrrolidin-1-yl-ethyl)-piperazine-1-carbony-
l]-2H-isoquinolin-1-one, [0307]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid dimethylamide, [0308]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid ethyl-methyl-amide, [0309]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid isopropyl-methyl-amide, [0310]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid diethylamide, [0311]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid methyl-propyl-amide, [0312]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid ethyl-isopropyl-amide, [0313]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid tert-butyl-methyl-amide, [0314]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid isobutyl-methyl-amide, [0315]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid butyl-methyl-amide, [0316]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid ethyl-propyl-amide, [0317]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (2-dimethylamino-ethyl)-methyl-amide, [0318]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid ethyl-(2-methoxy-ethyl)-amide, [0319]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid cyclopentyl-methyl-amide, [0320]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid butyl-ethyl-amide, [0321]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid methyl-pentyl-amide, [0322]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid diisopropylamide, [0323]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid isopropyl-propyl-amide, [0324]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid cyclobutylamide, [0325]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid dipropylamide, [0326]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (3-dimethylamino-propyl)-methyl-amide, [0327]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid cyclohexyl-methyl-amide, [0328]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid cyclopropylmethyl-propyl-amide [0329]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid diisobutylamide, [0330]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid benzyl-methyl-amide, [0331]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (2-fluoro-benzyl)-methyl-amide, [0332]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (4-fluoro-benzyl)-methyl-amide, [0333]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (3-fluoro-benzyl)-methyl-amide, [0334]
2-tert-butyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid butylamide, [0335]
2-sec-butyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid butylamide, [0336]
2-isobutyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid butylamide, [0337]
2-butyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid butylamide, [0338]
2-cyclopropylmethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carbox-
ylic acid butylamide, [0339]
2-(2-dimethylamino-ethyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4--
carboxylic acid butylamide, [0340]
2-cyclopentyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid butylamide, [0341]
2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid butylamide, [0342]
6,7-dimethoxy-1-oxo-2-(2,2,2-trifluoro-ethyl)-1,2-dihydro-isoquinoline-4--
carboxylic acid butylamide [0343]
6,7-dimethoxy-1-oxo-2-(2-pyrrolidin-1-yl-ethyl)-1,2-dihydro-isoquinoline--
4-carboxylic acid butylamide, [0344]
2-(2-fluoro-ethyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid butylamide, [0345]
2-benzyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid butylamide, [0346]
2-(2,4-difluoro-benzyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-ca-
rboxylic acid butylamide, [0347]
2-cyclopropyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid butylamide, [0348]
6,7-dimethoxy-1-oxo-2-(2-piperidin-1-yl-ethyl)-1,2-dihydro-isoquinoline-4-
-carboxylic acid butylamide, [0349]
6,7-dimethoxy-1-oxo-2-phenethyl-1,2-dihydro-isoquinoline-4-carboxylic
acid butylamide, [0350]
6,7-dimethoxy-2-(2-methoxy-benzyl)-1-oxo-1,2-dihydro-isoquinoline-4-carbo-
xylic acid butylamide, [0351]
2-indan-1-yl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid butylamide, [0352]
2-isopropyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid butylamide, [0353]
6,7-dimethoxy-1-oxo-2-propyl-1,2-dihydro-isoquinoline-4-carboxylic
acid butylamide, [0354]
6,7-dimethoxy-1-oxo-2-(3,3,3-trifluoro-propyl)-1,2-dihydro-isoquinoline-4-
-carboxylic acid butylamide, [0355]
6,7-dimethoxy-2-(2-methoxy-ethyl)-1-oxo-1,2-dihydro-isoquinoline-4-carbox-
ylic acid butylamide, [0356]
2-Cyclobutyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid butylamide, [0357]
3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid butylamide, [0358]
2-ethyl-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid
butylamide, [0359]
2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid indan-1-ylamide, [0360]
2-ethyl-7-methoxy-1-oxo-6-(2-quinolin-2-yl-ethoxy)-1,2-dihydro-isoquinoli-
ne-4-carboxylic acid butylamide, [0361]
2-ethyl-7-methoxy-1-oxo-6-(3-quinolin-2-yl-propoxy)-1,2-dihydro-isoquinol-
ine-4-carboxylic acid butylamide, [0362]
3-ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid (6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-amide, [0363]
3-ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid
(R)-indan-1-ylamide, [0364]
2-ethyl-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylic
acid indan-1-ylamide, [0365]
2-ethyl-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylic
acid butylamide, [0366]
2-(1-ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid indan-1-ylamide, [0367]
3-ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid (6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl)-amide, [0368]
3-ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid (1,2,3,4-tetrahydro-naphthalen-2-yl)-amide, [0369]
3-ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid (1,2,3,4-tetrahydro-naphthalen-1-yl)-amide, [0370]
3-ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid (4-bromo-indan-1-yl)-amide, [0371]
3-ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid (5-bromo-indan-1-yl)-amide, [0372]
3-ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid 2-dimethylaminomethyl-benzylamide, [0373]
3-ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid (6,7-dihydro-5H-[1]pyrindin-5-yl)-amide, [0374]
3-ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid (6,7-dihydro-5H-[1]pyrindin-7-yl)-amide, [0375]
3-ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid 3-dimethylaminomethyl-benzylamide, [0376]
3-ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid 4-dimethylaminomethyl-benzylamide, [0377]
7-methoxy-1-oxo-2-(2-quinolin-2-yl-ethyl)-1,2-dihydro-isoquinoline-4-carb-
oxylic acid butylamide, [0378]
7-methoxy-1-oxo-2-(2-quinolin-2-yl-ethyl)-1,2-dihydro-isoquinoline-4-carb-
oxylic acid indan-1-ylamide, [0379]
3-ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid (S)-indan-1-ylamide, [0380]
2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid (6,7-dihydro-5H-[1]pyrindin-5-yl)-amide, [0381]
2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid 2-dimethylaminomethyl-benzylamide, [0382]
2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid 3,5-difluoro-benzylamide, [0383]
2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid 3,4-difluoro-benzylamide,
[0384]
2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4--
carboxylic acid cyclohexylmethyl-amide, [0385]
2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid (R)-indan-1-ylamide, [0386]
2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid (S)-indan-1-ylamide, [0387]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (1,2,3,4-tetrahydro-naphthalen-1-yl)-amide, [0388]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid pyridin-3-ylamide, [0389]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (pyrimidin-4-ylmethyl)-amide, [0390]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid 2-methoxy-benzylamide, [0391]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (4-morpholin-4-yl-phenyl)-amide, [0392]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid 3-chloro-benzylamide, [0393]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (pyridin-4-ylmethyl)-amide, [0394]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid o-tolylamide, [0395]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid m-tolylamide, [0396]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (2-methoxy-phenyl)-amide, [0397]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (3-methoxy-phenyl)-amide, [0398]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (pyridin-3-ylmethyl)-amide, [0399]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (pyridin-2-ylmethyl)-amide, [0400]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (3-dimethylamino-propyl)-amide, [0401]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid phenylamide, [0402]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid 4-methoxy-benzylamide, [0403]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid 3-methyl-benzylamide, [0404]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid 2-methyl-benzylamide, [0405]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (2-methoxy-ethyl)-amide, [0406]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (4-fluoro-phenyl)-amide, [0407]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (4-methoxy-phenyl)-amide, [0408]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid p-tolylamide, [0409]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (3-fluoro-phenyl)-amide, [0410]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (2-fluoro-phenyl)-amide, [0411]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid 4-methyl-benzylamide, [0412]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid 2-chloro-benzylamide, [0413]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid [(R)-1-(4-fluoro-phenyl)-ethyl]-amide, [0414]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid pyridin-4-ylamide, [0415]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid [(S)-1-(4-fluoro-phenyl)-ethyl]-amide, [0416]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (6-methyl-indan-1-yl)-amide, [0417]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid 2-morpholin-4-ylmethyl-benzylamide, [0418]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (5-chloro-indan-1-yl)-amide, [0419]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (6-chloro-indan-1-yl)-amide, [0420]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (6-fluoro-indan-1-yl)-amide, [0421]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide, [0422]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (4-fluoro-indan-1-yl)-amide, [0423]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (4-methyl-indan-1-yl)-amide, [0424]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (5-methyl-indan-1-yl)-amide, [0425]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (6-methoxy-indan-1-yl)-amide, [0426]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (5-fluoro-indan-1-yl)-amide, [0427]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid 2-diethylaminomethyl-benzylamide, [0428]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid 2-pyrrolidin-1-ylmethyl-benzylamide, [0429]
2-ethyl-6,7-dimethoxy-4-(4-methyl-piperidine-1-carbonyl)-2H-isoquinolin-1-
-one, [0430]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (tetrahydro-furan-2-ylmethyl)-amide, [0431]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (3-methoxy-propyl)-amide, [0432]
4-(3,5-dimethyl-piperidine-1-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquinol-
in-1-one, [0433]
2-ethyl-4-(4-ethyl-piperazine-1-carbonyl)-6,7-dimethoxy-2H-isoquinolin-1--
one, [0434]
2-isobutyl-6,7-dimethoxy-4-(4-methyl-piperazine-1-carbonyl)-2H-isoquinoli-
n-1-one, [0435]
2-isobutyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (2-dimethylamino-ethyl)-amide, [0436]
2-isobutyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid butyl-methyl-amide, [0437]
[(2-isobutyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carbonyl)-ami-
no]-acetic acid methyl ester, [0438]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (3-isopropoxy-propyl)-amide, [0439]
2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid (5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide, [0440]
2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid (2,3-dihydro-benzofuran-3-yl)-amide, [0441]
2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid (6-oxo-5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide,
[0442]
2-cyclopropyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid indan-1-ylamide, [0443]
2-sec-butyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid indan-1-ylamide, [0444]
2-isopropyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid indan-1-ylamide, [0445]
2-(1-ethyl-propyl)-6,7-dimethoxy-4-(3-phenyl-piperidine-1-carbonyl)-2H-is-
oquinolin-1-one, [0446]
2-(1-ethyl-propyl)-6,7-dimethoxy-4-(3-phenoxy-piperidine-1-carbonyl)-2H-i-
soquinolin-1-one, [0447]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid
[0448] (S)indan-1-ylamide, [0449]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid
[0450] (R)indan-1-ylamide, [0451]
2-(1-ethyl-propyl)-6,7-dimethoxy-4-[3-(3-methoxy-phenyl)-piperazine-1-car-
bonyl]-2H-isoquinolin-1-one, [0452]
2-(1-ethyl-propyl)-6,7-dimethoxy-4-[8-(4-methyl-piperazine-1-sulfonyl)-3,-
4-dihydro-1H-isoquinoline-2-carbonyl]-2H-isoquinolin-1-one, [0453]
2-(1-ethyl-propyl)-6,7-dimethoxy-4-[8-(morpholine-4-sulfonyl)-3,4-dihydro-
-1H-isoquinoline-2-carbonyl]-2H-isoquinolin-1-one, [0454]
2-(1-ethyl-propyl)-6,7-dimethoxy-4-[3-(3-methoxy-phenyl)-4-methyl-piperaz-
ine-1-carbonyl]-2H-isoquinolin-1-one, [0455]
2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid ([1,3,4]thiadiazol-2-ylmethyl)-amide, [0456]
2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid 2-(morpholine-4-sulfonyl)-benzylamide, [0457]
2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid (thiazol-4-ylmethyl)-amide, [0458]
2-(1-ethyl-propyl)-6,7-dimethoxy-4-[(R)-3-(quinoxalin-2-yloxy)-pyrrolidin-
e-1-carbonyl]-2H-isoquinolin-1-one, [0459]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (S)(5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide, [0460]
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (R)(5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide, [0461]
2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid (thiophen-3-ylmethyl)-amide, [0462]
4-(7-Amino-3,4-dihydro-1H-isoquinoline-2-carbonyl)-2-(1-ethyl-propyl)-6,7-
-dimethoxy-2H-isoquinolin-1-one, [0463]
2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid 3-(4-chloro-benzenesulfonylamino)-benzylamide, [0464]
2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid (2,3-dihydro-benzo[b]thiophen-3-yl)-amide, [0465]
2-(1-ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carbo-
xylic acid (5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide,
[0466]
2-(1-ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carbo-
xylic acid (S)-indan-1-ylamide, [0467]
2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid 2-(4-methyl-piperazine-1-sulfonyl)-benzylamide, [0468]
2-(1-ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carbo-
xylic acid 2-(morpholine-4-sulfonyl)-benzylamide, [0469]
2-(1-ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carbo-
xylic acid (6,7-dihydro-5H-[1]pyrindin-5-yl)-amide, [0470]
2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid 3-(4-methoxy-benzenesulfonylamino)-benzylamide, [0471]
2-(1-ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carbo-
xylic acid 3,5-difluoro-benzylamide, [0472]
2-(1-ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carbo-
xylic acid 4-methyl-benzylamide, [0473]
2-(1-ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carbo-
xylic acid cyclohexylmethyl-amide, [0474]
2-(1-ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carbo-
xylic acid butylamide, [0475]
2-(1-ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carbo-
xylic acid (2,3-dihydro-benzofuran-3-yl)-amide, [0476]
2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid (thiazol-2-ylmethyl)-amide, [0477]
2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid (thiophen-2-ylmethyl)-amide, [0478]
2-ethyl-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylic
acid (5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide, [0479]
3-(1-ethyl-propyl)-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxyl-
ic acid (5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide, [0480]
3-(1-ethyl-propyl)-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxyl-
ic acid (2,3-dihydro-benzofuran-3-yl)-amide, [0481]
3-(1-ethyl-propyl)-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxyl-
ic acid indan-1-ylamide, [0482]
3-(1-ethyl-propyl)-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxyl-
ic acid (6,7-dihydro-5H-[1]pyrindin-5-yl)-amide, [0483]
2-(1-ethyl-propyl)-6,7-dimethoxy-4-(3-phenyl-propionyl)-2H-isoquinolin-1--
one, and [0484]
2-ethyl-6,7-dimethoxy-N-(4-nitrophenyl)-1-oxo-1,2-dihydroisoquinoline-4-c-
arboxamide.
[0485] Particular embodiments of the invention also relates to the
compounds of formula I, to the N-oxides, the prodrugs, the hydrates
and the tautomers thereof and to the pharmaceutically suitable
salts thereof, where the compounds of the formula I are selected
from the group consisting of: [0486]
6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-N-(pyridin-3-ylmethyl)-1,2-dihydroiso-
quinoline-4-carboxamide, [0487]
6,7-dimethoxy-N-((5-methylthiophen-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-
-dihydroisoquinoline-4-carboxamide, [0488]
N-((3,5-dimethylisoxazol-4-yl)methyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-
-1,2-dihydroisoquinoline-4-carboxamide, [0489]
6,7-dimethoxy-N-((5-methylthiazol-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2--
dihydroisoquinoline-4-carboxamide, [0490]
6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-N-(pyrimidin-4-ylmethyl)-1,2-dihydroi-
soquinoline-4-carboxamide, [0491]
6,7-dimethoxy-N-((3-methylisoxazol-5-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-
-dihydroisoquinoline-4-carboxamide, [0492]
N-((2,5-dimethylthiophen-3-yl)methyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-
-1,2-dihydroisoquinoline-4-carboxamide, [0493]
6,7-dimethoxy-N-((2-methylthiazol-5-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2--
dihydroisoquinoline-4-carboxamide, [0494]
6,7-dimethoxy-N-((5-methylisoxazol-3-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-
-dihydroisoquinoline-4-carboxamide, [0495]
(R)--N-(1-(4-fluorophenyl)ethyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2--
dihydroisoquinoline-4-carboxamide, [0496]
(S)--N-(1-(4-fluorophenyl)ethyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2--
dihydroisoquinoline-4-carboxamide, [0497]
6,7-dimethoxy-N-((4-methylthiazol-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2--
dihydroisoquinoline-4-carboxamide, [0498]
6,7-dimethoxy-N-((2-methylthiazol-4-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2--
dihydroisoquinoline-4-carboxamide, [0499]
6,7-dimethoxy-N-((4-methylthiazol-5-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2--
dihydroisoquinoline-4-carboxamide, [0500]
6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-N-((5-(trifluoromethyl)furan-2-yl)met-
hyl)-1,2-dihydroisoquinoline-4-carboxamide, [0501]
6,7-dimethoxy-N-((5-methylfuran-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-di-
hydroisoquinoline-4-carboxamide, [0502]
N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl-
)-1,2-dihydroiso-quinoline-4-carboxamide, [0503]
6,7-dimethoxy-N-(5-methyl-2,3-dihydro-1H-inden-1-yl)-1-oxo-2-(pentan-3-yl-
)-1,2-dihydroisoquinoline-4-carboxamide, [0504]
6,7-dimethoxy-N-(4-methyl-2,3-dihydro-1H-inden-1-yl)-1-oxo-2-(pentan-3-yl-
)-1,2-dihydroisoquinoline-4-carboxamide, [0505]
N-((2-ethylthiazol-4-yl)methyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2-d-
ihydroisoquinoline-4-carboxamide, [0506]
6,7-dimethoxy-N-(6-methoxy-2,3-dihydro-1H-inden-1-yl)-1-oxo-2-(pentan-3-y-
l)-1,2-dihydroisoquinoline-4-carboxamide, [0507]
6,7-dimethoxy-N-((4-methylthiophen-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-
-dihydroisoquinoline-4-carboxamide, [0508]
6,7-dimethoxy-N-((3-methylthiophen-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-
-dihydroisoquinoline-4-carboxamide, [0509]
6,7-dimethoxy-N-((5-methyloxazol-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-d-
ihydroisoquinoline-4-carboxamide, [0510]
6,7-dimethoxy-N-(6-methyl-2,3-dihydro-1H-inden-1-yl)-1-oxo-2-(pentan-3-yl-
)-1,2-dihydroisoquinoline-4-carboxamide, [0511]
6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-N-(pyridin-4-ylmethyl)-1,2-dihydroiso-
quinoline-4-carboxamide, [0512]
6,7-dimethoxy-N-(4-methylbenzyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquin-
oline-4-carboxamide, [0513]
6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-N-(pyridin-2-ylmethyl)-1,2-dihydroiso-
quinoline-4-carboxamide, [0514]
N-((5-cyanofuran-2-yl)methyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2-dih-
ydroisoquinoline-4-carboxamide, [0515]
N-(4-chloro-2,3-dihydro-1H-inden-1-yl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl-
)-1,2-dihydroisoquinoline-4-carboxamide, [0516]
N-((5-ethylthiophen-2-yl)methyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2--
dihydroisoquinoline-4-carboxamide, [0517]
6,7-dimethoxy-N-((3-methylfuran-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-di-
hydroisoquinoline-4-carboxamide, [0518]
6,7-dimethoxy-N-((2-methylfuran-3-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-di-
hydroisoquinoline-4-carboxamide, [0519]
6,7-dimethoxy-N-((1-methyl-1H-pyrazol-3-yl)methyl)-1-oxo-2-(pentan-3-yl)--
1,2-dihydroisoquinoline-4-carboxamide, [0520]
N-[(3,4-dimethylphenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4-
-carboxamide, [0521]
N-[(2-chloro-4-methyl-phenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquino-
line-4-carboxamide, [0522]
N-[[2-(dimethylamino)-4-methyl-phenyl]methyl]-2-ethyl-6,7-dimethoxy-1-oxo-
-isoquinoline-4-carboxamide, [0523]
2-ethyl-N-[(2-fluoro-4-methyl-phenyl)methyl]-6,7-dimethoxy-1-oxo-isoquino-
line-4-carboxamide, [0524]
2-ethyl-6,7-dimethoxy-N-[(3-methoxy-4-methyl-phenyl)methyl]-1-oxo-isoquin-
oline-4-carboxamide, [0525]
2-ethyl-6,7-dimethoxy-N-[(4-methyl-2-morpholino-phenyl)methyl]-1-oxo-isoq-
uinoline-4-carboxamide, [0526]
N-[(2-tert-butoxy-4-methyl-phenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo-iso-
quinoline-4-carboxamide, [0527]
N-[[2-(1,1-dimethylpropoxy)-4-methyl-phenyl]methyl]-2-ethyl-6,7-dimethoxy-
-1-oxo-isoquinoline-4-carboxamide, [0528]
N-[(2,3-difluoro-4-methyl-phenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoq-
uinoline-4-carboxamide, [0529]
2-ethyl-N-[(3-fluoro-4-methyl-phenyl)methyl]-6,7-dimethoxy-1-oxo-isoquino-
line-4-carboxamide, [0530]
N-[(3-chloro-4-methyl-phenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquino-
line-4-carboxamide, [0531]
2-ethyl-6,7-dimethoxy-1-oxo-N-[(2,4,6-trimethylphenyl)methyl]isoquinoline-
-4-carboxamide, [0532]
N-[(2,4-dimethylphenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4-
-carboxamide, [0533]
2-ethyl-6,7-dimethoxy-N-[[2-(3-methoxypropoxy)-4-methyl-phenyl]methyl]-1--
oxo-isoquinoline-4-carboxamide, [0534]
N-[[2-(2-ethoxyethoxy)-4-methyl-phenyl]methyl]-2-ethyl-6,7-dimethoxy-1-ox-
o-isoquinoline-4-carboxamide, [0535]
N-[[2-(cyclopentoxy)-4-methyl-phenyl]methyl]-2-ethyl-6,7-dimethoxy-1-oxo--
isoquinoline-4-carboxamide, [0536]
2-ethyl-6,7-dimethoxy-N-[(4-methyl-2-phenoxy-phenyl)methyl]-1-oxo-isoquin-
oline-4-carboxamide, [0537]
2-ethyl-6,7-dimethoxy-N-[[2-(2-methoxy-1-methyl-ethoxy)-4-methyl-phenyl]m-
ethyl]-1-oxo-isoquinoline-4-carboxamide, [0538]
2-ethyl-6,7-dimethoxy-N-[[4-methyl-2-(2,2,2-trifluoroethoxy)phenyl]methyl-
]-1-oxo-isoquinoline-4-carboxamide, [0539]
N-[[2-(cyclohexoxy)-4-methyl-phenyl]methyl]-2-ethyl-6,7-dimethoxy-1-oxo-i-
soquinoline-4-carboxamide, [0540]
N-[[2-(cyclopropylmethoxy)-4-methyl-phenyl]methyl]-2-ethyl-6,7-dimethoxy--
1-oxo-isoquinoline-4-carboxamide, [0541]
2-ethyl-N-[(2-hexoxy-4-methyl-phenyl)methyl]-6,7-dimethoxy-1-oxo-isoquino-
line-4-carboxamide, [0542]
2-ethyl-6,7-dimethoxy-N-[[4-methyl-2-(tetrahydrofuran-3-ylmethoxy)phenyl]-
methyl]-1-oxo-isoquinoline-4-carboxamide, [0543]
2-ethyl-6,7-dimethoxy-N-[[2-(2-methoxyethoxy)-4-methyl-phenyl]methyl]-1-o-
xo-isoquinoline-4-carboxamide, [0544]
2-ethyl-N-(2-isobutoxy-4-methylbenzyl)-6,7-dimethoxy-1-oxo-1,2-dihydroiso-
quinoline-4-carboxamide, [0545]
2-ethyl-N-(2-(furan-2-ylmethoxy)-4-methylbenzyl)-6,7-dimethoxy-1-oxo-1,2--
dihydroisoquinoline-4-carboxamide, [0546]
2-ethyl-6,7-dimethoxy-N-(4-methyl-2-(pentyloxy)benzyl)-1-oxo-1,2-dihydroi-
soquinoline-4-carboxamide, [0547]
N-(2-ethoxy-4-methylbenzyl)-2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydroisoqui-
noline-4-carboxamide, [0548]
N-(2-sec-butoxy-4-methylbenzyl)-2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydrois-
oquinoline-4-carboxamide, [0549]
2-ethyl-N-(2-(isopentyloxy)-4-methylbenzyl)-6,7-dimethoxy-1-oxo-1,2-dihyd-
roisoquinoline-4-carboxamide, [0550]
2-ethyl-6,7-dimethoxy-N-(4-methyl-2-propoxybenzyl)-1-oxo-1,2-dihydroisoqu-
inoline-4-carboxamide, [0551]
2-ethyl-6,7-dimethoxy-N-(4-methyl-2-(methylthio)benzyl)-1-oxo-1,2-dihydro-
isoquinoline-4-carboxamide, [0552]
2-ethyl-N-(2-isopropoxy-4-methylbenzyl)-6,7-dimethoxy-1-oxo-1,2-dihydrois-
oquinoline-4-carboxamide, [0553]
2-ethyl-6,7-dimethoxy-N-(4-methyl-2-(tetrahydrofuran-3-yloxy)benzyl)-1-ox-
o-1,2-dihydroisoquinoline-4-carboxamide, [0554]
2-ethyl-6,7-dimethoxy-1-oxo-N-(2,4,5-trimethylbenzyl)-1,2-dihydroisoquino-
line-4-carboxamide, [0555]
2-ethyl-6,7-dimethoxy-N-(4-methyl-2-((tetrahydrofuran-2-yl)methoxy)benzyl-
)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide, [0556]
2-ethyl-6,7-dimethoxy-N-(4-methyl-2-(4-methylpentan-2-yloxy)benzyl)-1-oxo-
-1,2-dihydroisoquinoline-4-carboxamide, [0557]
2-ethyl-6,7-dimethoxy-N-(4-methyl-2-(4-methylpentyloxy)benzyl)-1-oxo-1,2--
dihydroisoquinoline-4-carboxamide, [0558]
2-ethyl-6,7-dimethoxy-N-(2-methoxy-4-methylbenzyl)-1-oxo-1,2-dihydroisoqu-
inoline-4-carboxamide, [0559]
2-ethyl-6,7-dimethoxy-1-oxo-N-(thiazol-4-ylmethyl)isoquinoline-4-carboxam-
ide, [0560]
2-ethyl-6,7-dimethoxy-1-oxo-N-[[4-(trifluoromethyl)phenyl]methyl]isoquino-
line-4-carboxamide, [0561]
2-ethyl-6,7-dimethoxy-1-oxo-N-[(1S)-1-(p-tolyl)ethyl]isoquinoline-4-carbo-
xamide, [0562]
2-ethyl-N-[(4-isopropylphenyl)methyl]-6,7-dimethoxy-1-oxo-isoquinoline-4--
carboxamide, [0563]
2-ethyl-N-[(4-ethylphenyl)methyl]-6,7-dimethoxy-1-oxo-isoquinoline-4-carb-
oxamide, [0564]
2-ethyl-6,7-dimethoxy-1-oxo-N-[(1R)-1-(p-tolyl)ethyl]isoquinoline-4-carbo-
xamide, [0565]
N-[[4-(difluoromethyl)phenyl]methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquino-
line-4-carboxamide, [0566]
2-ethyl-6,7-dimethoxy-N-[(2-methylthiazol-4-yl)methyl]-1-oxo-isoquinoline-
-4-carboxamide, [0567]
2-ethyl-6,7-dimethoxy-N-[(4-methyl-2-thienyl)methyl]-1-oxo-isoquinoline-4-
-carboxamide, [0568]
N-[(4-cyclopropylphenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline--
4-carboxamide, [0569]
N-indan-1-yl-6,7-dimethoxy-2-[2-(5-methyl-2-pyridyl)ethyl]-1-oxo-isoquino-
line-4-carboxamide, [0570]
N-butyl-6,7-dimethoxy-2-[2-(5-methyl-2-pyridyl)ethyl]-1-oxo-isoquinoline--
4-carboxamide, [0571]
2-ethyl-6,7-dimethoxy-N-[2-(6-methoxy-2-pyridyl)ethyl]-1-oxo-isoquinoline-
-4-carboxamide, [0572]
N-butyl-6,7-dimethoxy-1-oxo-2-[2-(2-quinolyl)ethyl]isoquinoline-4-carboxa-
mide, and [0573]
N-indan-1-yl-6,7-dimethoxy-1-oxo-2-[2-(2-quinolyl)ethyl]iso-quinoline-4-c-
arboxamide.
[0574] In particular embodiments, the compounds of the present
invention are distinct from the group of the following compounds:
[0575]
1-[(2-ethyl-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoquinolinyl)carbonyl]-(3--
ethoxycarbonyl)piperidine, [0576]
1-[(2-(2-methylpropyl)-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoquinolinyl)-c-
arbonyl]-(3-ethoxycarbonyl)piperidine, [0577]
2-{[(2-ethyl-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoquinolinyl)carbonyl]ami-
no}-benzoic acid ethyl ester, [0578]
N-cycloheptyl-2-ethyl-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoquinoline
carboxamide, [0579]
N-(3-ethoxypropyl)-2-ethyl-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoquinoline
carboxamide, [0580]
N-(3-(1-methylethoxy)propyl)-2-ethyl-1,2-dihydro-6,7-dimethoxy-1-oxo-4-is-
oquinoline carboxamide, [0581]
N-(3-(1-methylethoxy)propyl)-2-(2-methylpropyl)-1,2-dihydro-6,7-dimethoxy-
-1-oxo-4-isoquinoline carboxamide, [0582]
N-(3-ethoxypropyl)-2-(2-methylpropyl)-1,2-dihydro-6,7-dimethoxy-1-oxo-4-i-
soquinoline carboxamide, [0583]
N-[3-(4-methyl-1-piperidinyl)propyl]-2-ethyl-1,2-dihydro-6,7-dimethoxy-1--
oxo-4-isoquinoline carboxamide, [0584]
N-[3-(2-ethyl-1-piperidinyl)propyl]-2-(2-methylpropyl)-1,2-dihydro-6,7-di-
methoxy-1-oxo-4-isoquinoline carboxamide, [0585]
N-[3-(3,5-dimethyl-1-piperidinyl)propyl]-2-ethyl-1,2-dihydro-6,7-dimethox-
y-1-oxo-4-isoquinoline carboxamide, [0586]
N-[3-(3,5-dimethyl-1-piperidinyl)propyl]-2-(2-methylpropyl)-1,2-dihydro-6-
,7-dimethoxy-1-oxo-4-isoquinoline carboxamide, [0587]
N-(3-acetylaminophenyl)-2-ethyl-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoquin-
oline carboxamide, [0588]
N,N-diethyl-2-ethyl-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoquinoline
carboxamide, [0589]
N-(5-methyl-2-furanylmethyl)-2-ethyl-1,2-dihydro-6,7-dimethoxy-1-oxo-4-is-
oquinoline carboxamide, [0590]
N-(5-methyl-2-furanylmethyl)-2-(2-methylpropyl)-1,2-dihydro-6,7-dimethoxy-
-1-oxo-4-isoquinoline carboxamide, [0591]
N-(2-furanylmethyl)-2-ethyl-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoquinolin-
e carboxamide, [0592]
N-(tetrahydro-2-furanylmethyl)-2-ethyl-1,2-dihydro-6,7-dimethoxy-1-oxo-4--
isoquinoline carboxamide, [0593]
N-(2-pyridylmethyl)-2-(2-methylpropyl)-1,2-dihydro-6,7-dimethoxy-1-oxo-4--
isoquinoline carboxamide, [0594]
N-(3-pyridylmethyl)-2-ethyl-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoquinolin-
e carboxamide, [0595]
N-(1,3-benzodioxol-5-ylmethyl)-2-ethyl-1,2-dihydro-6,7-dimethoxy-1-oxo-4--
isoquinoline carboxamide, [0596]
N-(1,3-benzodioxol-5-ylmethyl)-2-(2-methylpropyl)-1,2-dihydro-6,7-dimetho-
xy-1-oxo-4-isoquinoline carboxamide, [0597]
N-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-2-ethyl-1,2-dihydro-6,7-dimeth-
oxy-1-oxo-4-isoquinoline carboxamide, [0598]
N-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-ethyl-1,2-dihydro-6,7-dimethoxy-1--
oxo-4-isoquinoline carboxamide, [0599]
N-ethyl-N-(2-methylphenyl)-2-ethyl-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoq-
uinoline carboxamide, [0600]
N-ethyl-N-(2-ethylphenyl)-2-ethyl-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoqu-
inoline carboxamide, [0601]
N-(3,4-dimethoxyphenyl)-2-ethyl-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoquin-
oline carboxamide, [0602]
N-(3-chlorophenyl)-2-(2-methylpropyl)-1,2-dihydro-6,7-dimethoxy-1-oxo-4-i-
soquinoline carboxamide, [0603]
4-[(4-propyl-1-piperazinyl)carbonyl]-2-(2-methylpropyl)-1,2-dihydro-6,7-d-
imethoxy-4-isoquinolin-1-one, [0604]
4-[(4-cyclohexyl-1-piperazinyl)carbonyl]-2-ethyl-1,2-dihydro-6,7-dimethox-
y-4-isoquinolin-1-one, [0605]
4-[(4-cyclohexyl-1-piperazinyl)carbonyl]-2-(2-methylpropyl)-1,2-dihydro-6-
,7-dimethoxy-4-isoquinolin-1-one, [0606]
4-[(4-(2-pyridyl)-1-piperazinyl)carbonyl]-2-(2-methylpropyl)-1,2-dihydro--
6,7-dimethoxy-4-isoquinolin-1-one, [0607]
4-[(4-(3-chlorophenyl)-1-piperazinyl)carbonyl]-2-ethyl-1,2-dihydro-6,7-di-
methoxy-4-isoquinolin-1-one, [0608]
4-{[4-(2-furanylcarbonyl)-1-piperazinyl]carbonyl}-2-ethyl-1,2-dihydro-6,7-
-dimethoxy-4-isoquinolin-1-one, [0609]
4-[(3,4-dihydro-1(2H)quinolinyl)carbonyl]-2-ethyl-1,2-dihydro-6,7-dimetho-
xy-4-isoquinolin-1-one, [0610]
N-[(2-ethyl-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoquinolinyl)carbonyl]glyc-
ine methyl ester, [0611]
N-[(2-(2-methylpropyl)-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoquinolinyl)ca-
rbonyl]glycine methyl ester, [0612]
N-[(2-ethyl-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoquinolinyl)carbonyl]glyc-
ine ethyl ester,
[0613] the pharmaceutically acceptable salts thereof, the N-oxides
thereof, the prodrugs thereof, the hydrates thereof, the tautomers
the and the pharmaceutically acceptable salts of said N-oxides,
prodrugs, tautomers or hydrates.
[0614] The compounds of the invention of the general formulae I,
Ia, Ib, Ic and Id and the starting materials used to prepare them
can be prepared in analogy to known processes of organic chemistry
as are described in standard works of organic chemistry, e.g.
Houben-Weyl, "Methoden der Organischen Chemie", Thieme-Verlag,
Stuttgart, Jerry March "Advanced Organic Chemistry", 5.sup.th
edition, Wiley & Sons and the literature cited therein, and R.
Larock, "Comprehensive Organic Transformations", 2.sup.nd edition,
Weinheim, 1999 and the literature cited therein. The compounds of
the invention of the general formula I are advantageously prepared
by the methods described below and/or in the experimental
section.
[0615] Compounds of the formula I, wherein Y is oxygen, can be
prepared e.g. by reacting a compound of the formula II with an
amine of the formula III, as depicted in scheme 1.
##STR00006##
[0616] where, X.sup.1, X.sup.2, R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 are as defined above. Q is a suitable leaving group such as
chlorine, bromine or OH or a radical of an activated ester such as
para-nitrophenoxy, pentafluorophenoxy, N-hydroxysuccinimide or
hydroxybenzotriazol-1-yl. suitable reaction conditions have been
described e.g. in Houben-Weyl: "Methoden der organ. Chemie"
[Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart,
N.Y. 1985, Volume E5, pp. 941-1045).
[0617] The reaction of II with III may be performed in the presence
of a base. Suitable base include but are not limited to
[0618] If Q is OH, the reaction may be performed in the presence of
a coupling agent.
[0619] Suitable coupling agents are, for example: [0620] coupling
agents based on carbodiimides, for example
N,N'-dicyclohexylcarbodiimide [J. C. Sheehan, G. P. Hess, J. Am.
Chem. Soc. 1955, 77, 1067],
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide; [0621] coupling
agents which form mixed anhydrides with carbonic esters, for
example 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline [B. Belleau,
G. Malek, J. Amer. Chem. Soc. 1968, 90, 1651],
2-isobutyloxy-1-isobutyloxycarbonyl-1,2-dihydroquinoline [Y. Kiso,
H. Yajima, J. Chem. Soc., Chem. Commun 1972, 942]; [0622] coupling
agents based on phosphonium salts, for example
(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium
hexafluorophosphate [B. Castro, J. R. Domoy, G. Evin, C. Selve,
Tetrahedron Lett. 1975, 14, 1219],
(benzotriazol-1-yl-oxy)tripyrrolidinophosphonium
hexafluorophosphate [J. Coste et al., Tetrahedron Lett. 1990, 31,
205]; [0623] coupling agents based on uronium salts or having a
guanidinium N-oxide structure, for example
N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium
hexafluorophosphate [R. Knorr, A. Trzeciak, W. Bannwarth, D.
Gillessen, Tetrahedron Lett. 1989, 30, 1927],
N,N,N',N'-tetramethyl-O-(benzotriazol-1-yl)uronium
tetrafluoroborate, (benzotriazol-1-yloxy)dipiperidinocarbenium
hexafluorophosphate [S. Chen, J. Xu, Tetrahedron Lett. 1992, 33,
647]; [0624] coupling agents which form acid chlorides, for example
bis-(2-oxo-oxazolidinyl)phosphinic chloride [J. Diago-Mesequer,
Synthesis 1980, 547].
[0625] Apart from that, compounds of the formula I and likewise
compounds of the formula II, where Q is S can be prepared by
successively reacting compounds of the formulae I and II, where Q
is O with a suitable sulfurizing agent, such as Lawenson's reagent
or P.sub.2S.sub.5.
[0626] The N-oxides of compound I may be prepared from the
compounds of formula I according to conventional oxidation methods,
for example by treating said compounds with an organic peracid;
such as metachloroperbenzoic acid or 3-chloroperbenzoic acid
[Journal of Medicinal Chemistry 38(11), 1892-1903 (1995), WO
03/64572]; or with inorganic oxidizing agents; such as hydrogen
peroxide [cf. Journal of Heterocyclic Chemistry 18 (7), 1305-1308
(1981)] or oxone [cf. Journal of the American Chemical Society
123(25), 5962-5973 (2001)]. The oxidation may lead to pure
mono-N-oxides or to a mixture of different N-oxides, which can be
separated by conventional methods; such as chromatography.
[0627] The compounds of the formulae II and III are well known in
the art or can be prepared by anology to well established reactions
of organic synthetic chemistry or by analogy to the methods as
described in standard works of organic chemistry, e.g. Houben-Weyl,
"Methoden der Organischen Chemie", Thieme-Verlag, Stuttgart, Jerry
March "Advanced Organic Chemistry", 5.sup.th edition, Wiley &
Sons and the literature cited therein, and R. Larock,
"Comprehensive Organic Transformations", 2.sup.nd edition,
Weinheim, 1999 and the literature cited therein.
[0628] The compounds of the formula II, where Q is OH can be easily
transformed into compounds of the formula II, where Q is halogen,
in particular chlorine by a suitable chlorination agent such as
thionylchloride or oxalyl chloride.
[0629] Compounds of the formula II, where X.sup.2 is C--R.sup.5,
where R.sup.5 is a radical O--Z.sup.5--Ar.sup.5 can be prepared
e.g. by reacting compounds of the formula II, where X.sup.2 is
C--OH with a compound of formula HO--Z.sup.5--Ar.sup.5 (formula IV)
in terms of a Mitsunobu reaction, i.e. in the presence of dialkyl
azodicarboxylate and triphenylphosphine (for suitable reaction
conditions see e.g. A. J. Reynolds et al. Curr. Org. Chem. 13(16)
(2009) pp. 1610-16-32; K. C. Swamy et al., Chem. Rev. 109(6)
(2009), pp. 2551-2651; D. L. Hughes, Organic Preparations and
Procedures International 28 (2) (1996), pp. 127-164.
[0630] Compounds of the formula II, where X.sup.1 is CH and Q is OH
(compounds Ha), can be prepared e.g. according to the following
reaction scheme 2:
##STR00007##
[0631] In scheme 2, X.sup.2, R.sup.1 and R.sup.4 are as defined
above. R is C.sub.1-C.sub.4-alkyl, in particular methyl.
[0632] Step a) is performed by reacting a compound of the formula V
with dimethoxymethyl dimethylamine (also termed dimethylformamide
dimethylacetal). Thereby the compound of formula VI is obtained,
which can be cyclised in step b) to the compound of formula II,
where Q is methoxy, by reaction with a primary amine of the formula
H.sub.2N--R.sup.1 (compound VII). Subsequent hydrolysis of the
primarily obtained ester in step c) yields the compound of the
formula II, where X.sup.1 is CH and Q is OH.
[0633] Compounds of the formula II, where X.sup.1 is N and Q is OH
(compounds IIb), can be prepared e.g. according to the following
reaction scheme 3:
##STR00008##
[0634] In scheme 3, X.sup.2, R.sup.1 and R.sup.4 are as defined
above.
[0635] Step d) is performed by reacting a compound of the formula
VIII with an excess of a suitable oxidising agent in the presence
of water, e.g. aqueous potassium permanganate. Thereby the compound
of formula IX is obtained, which can be cyclised in step e) to a
phthalazinone or phthalazinone analogue by reaction with hydrazine.
Subsequent alkylation with an alkylating agent of formula
R.sup.1-Q' in step f) yields the compound of the formula II, where
X.sup.1 is CH and Q is OH.
[0636] The reactions are usually performed in an organic solvent,
including aprotic organic solvent, e.g. substituted amides,
lactames and ureas; such as dimethylformamide, dimethylacetamide,
N-methylpyrrolidone, tetramethyl urea, cyclic ethers; such as
dioxane, tetrahydrofurane, halogenated hydrocarbons; such as
dichloromethane, and mixtures thereof as well as mixtures thereof
with C.sub.1-C.sub.6-alkanols and/or water.
[0637] The reactions described above will be usually performed at
temperatures ranging from -10.degree. C. to 100.degree. C.,
depending on the reactivity of the used compounds.
[0638] The reaction mixtures are worked up in a conventional way,
e.g. by mixing with water, separating the phases and, where
appropriate, purifying the crude products by chromatography. The
intermediates and final products in some cases result in the form
of colorless or pale brownish, viscous oils which are freed of
volatiles or purified under reduced pressure and at moderately
elevated temperature. If the intermediates and final products are
obtained as solids, the purification can also take place by
recrystallization or digestion.
[0639] Due to their capability of inhibiting PDE10A at low
concentrations, the compounds of the formula I, their N-oxides,
their hydrates, their tautomers and their prodrugs and the
pharmaceutically acceptable salts thereof, are particularly
suitable for treating disorders or conditions, which can be treated
by inhibition of phosphodiesterase type 10A. The terms "treating"
and "treatment" in terms of the present invention have to be
understood to include both curative treatment of the cause of a
disease or disorder, the treatment of the symptoms associated with
a disease or disorder, i.e. controlling the disease or disorder or
ameliorating the conditions or symptoms associated with a disease
or disorder, and prophylactic treatment, i.e. a treatment for
reducing the risk of a disease or disorder.
[0640] Neurological and psychiatric disorders or conditions which
can be treated by inhibition of PDE10A, including curative
treatment, control or amelioration and prophylaxis, include CNS
disorders, in particular schizophrenia, depression, bipolar
disorders, cognitive dysfunctions associated with schizophrenia,
cognitive dysfunctions associated with Alzheimer's disease,
Huntington's disease (Huntington chorea), anxiety and
substance-related disorders, especially substance use disorder,
substance tolerance conditions associated with substance
withdrawal. Disorders or conditions which can be treated by
inhibition of PDE10A, including curative treatment, control or
amelioration and prophylaxis, also include treatment of diet
induced obesity.
[0641] Thus, the invention relates to the use of compounds of
formula I, their N-oxides, their hydrates, their tautomers and
their prodrugs and the pharmaceutically acceptable salts thereof,
for treatment of disorders or conditions, which can be treated by
inhibition of phosphodiesterase type 10A, i.e. the invention
relates to the use of such compounds for curative treatment of such
a disease or disorder, controlling such a disease or disorder,
ameliorating the symptoms associated with such a disease or
disorder and reducing the risk for such a disease or disorder.
[0642] The present invention also relates to a method for the
treatment of a medical disorder, selected from neurological and
psychiatric disorders which can be treated by inhibition of
phosphodiesterase type 10A, said method comprising administering an
effective amount of at least one compound, selected from the group
of compounds of formula I, their N-oxides, their hydrates, their
tautomers, their prodrugs and the pharmaceutically acceptable salts
thereof, to a mammal in need thereof.
[0643] The present invention in particular relates to: [0644] a
method for treating, controlling, ameliorating or reducing the risk
of schizophrenia in a mammalian; [0645] a method for treating,
controlling, ameliorating or reducing the risk of cognitive
disturbances associated with schizophrenia in a mammalian; [0646] a
method for treating, controlling, ameliorating or reducing the risk
of depression in a mammalian; [0647] a method for treating,
controlling, ameliorating or reducing the risk of bipolar disorders
in a mammalian; [0648] a method for treating or ameliorating the
symptoms associated with substance use disorders in a mammalian;
[0649] a method for treating or ameliorating the symptoms
associated with diet-induced obesity in a mammalian; [0650] a
method for treating, controlling, ameliorating or reducing the risk
of cognitive disturbances associated with Alzheimer's disease in a
mammalian; [0651] a method for treating, controlling, ameliorating
or reducing the risk of behavioral symptoms in Alzheimer's disease;
[0652] a method for treating, controlling, ameliorating or reducing
the risk of anxiety in a mammalian; [0653] a method for treating,
controlling, ameliorating or reducing the risk of Huntington's
disease in a mammalian;
[0654] which methods comprising administering an effective amount
of at least one compound, selected from the group of compounds of
formula I, their N-oxides, their hydrates, their tautomers, their
prodrugs and the pharmaceutically acceptable salts thereof, to a
mammal in need thereof.
[0655] The subject treated in the present methods is generally a
mammal, preferably a human being, male or female, in whom
inhibition of PDE10A is desired. The terms "effective amount" and
"therapeutically effective amount" mean the amount of the subject
compound that will elicit the biological or medical response of a
tissue, system, animal or human that is being sought by the
researcher, veterinarian, medical doctor or other clinician. It is
recognized that one skilled in the art may affect the neurological
and psychiatric disorders by treating a patient presently afflicted
with the disorders or by prophylactically treating a patient
afflicted with the disorders with an effective amount of the
compound of the present invention. As used herein, the terms
"treatment" and "treating" refer to all processes, wherein there
may be a slowing, interrupting, arresting, controlling, or stopping
of the progression of the disorders described herein, but does not
necessarily indicate a total elimination of all disorder symptoms,
as well as the prophylactic therapy of the mentioned conditions,
particularly in a patient who is predisposed to such disease or
disorder. The term "composition" as used herein is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly
or indirectly, from combination of the specified ingredients in the
specified amounts. Such term in relation to pharmaceutical
composition, is intended to encompass a product comprising the
active ingredient(s), and the inert ingredient(s) that make up the
carrier, as well as any product which results, directly or
indirectly, from combination, complexation or aggregation of any
two or more of the ingredients, or from dissociation of one or more
of the ingredients, or from other types of reactions or
interactions of one or more of the ingredients. Accordingly, the
pharmaceutical compositions of the present invention encompass any
composition made by admixing a compound of the present invention
and a pharmaceutically acceptable carrier. By "pharmaceutically
acceptable" it is meant the carrier, diluent or excipient must be
compatible with the other ingredients of the formulation and not
deleterious to the recipient thereof.
[0656] The terms "administration of and or "administering a"
compound should be understood to mean providing a compound of the
invention or a prodrug of a compound of the invention to the
individual in need of treatment.
[0657] A preferred embodiment of the present invention provides a
method for treating schizophrenia, comprising: administering to a
patient in need thereof an effective amount of at least one
compound, selected from the group of compounds of formula I, their
N-oxides, their hydrates, their tautomers, their prodrugs and the
pharmaceutically acceptable salts thereof.
[0658] In another preferred embodiment, the present invention
provides a method for treating cognitive disturbances associated
with schizophrenia, comprising:
administering to a patient in need thereof an effective amount of
at least one compound, selected from the group of compounds of
formula I, their N-oxides, their hydrates, their tautomers, their
prodrugs and the pharmaceutically acceptable salts thereof.
[0659] At present, the fourth edition of the Diagnostic and
Statistical Manual of Mental Disorders (DSM-IV) (1994, American
Psychiatric Association, Washington, D.C.), provides a diagnostic
tool including schizophrenia and other psychotic disorders. These
include: disorders having psychotic symptoms as the defining
feature. The term psychotic refers to delusions, prominent
hallucinations, disorganized speech, disorganized or catatonic
behavior. The disorder includes: paranoid, disorganized, catatonic,
undifferentiated, and residual schizophrenia, schizophreniform
disorder, schizoaffective disorder, delusional disorder, brief
psychotic disorder, shared psychotic disorder, psychotic disorder
due to a general medical condition, substance-induced psychotic
disorder, and psychotic disorder not otherwise specified. The
skilled artisan will recognize that there are alternative
nomenclatures, nosologies, and classification systems for
neurological and psychiatric disorders, and particular
schizophrenia, and that these systems evolve with medical
scientific progress. Thus, the term "schizophrenia" is intended to
include like disorders that are described in other diagnostic
sources.
[0660] In another preferred embodiment, the present invention
provides a method for treating substance-related disorders,
comprising: administering to a patient in need thereof an effective
amount of at least one compound, selected from the group of
compounds of formula I, their N-oxides, their hydrates, their
tautomers, their prodrugs and the pharmaceutically acceptable salts
thereof.
[0661] In another preferred embodiment, the present invention
provides a method for treating anxiety, comprising: administering
to a patient in need thereof an effective amount of at least one
compound, selected from the group of compounds of formula I, their
N-oxides, their hydrates, their tautomers, their prodrugs and the
pharmaceutically acceptable salts thereof. At present, the fourth
edition of the Diagnostic and Statistical Manual of Mental
Disorders (DSM-IV) (1994, American Psychiatric Association,
Washington, D.C.), provides a diagnostic tool including anxiety and
related disorders. These include: panic disorder with or without
agoraphobia, agoraphobia without history of panic disorder,
specific phobia, social phobia, obsessive-compulsive disorder,
post-traumatic stress disorder, acute stress disorder, generalized
anxiety disorder, anxiety disorder due to a general medical
condition, substance-induced anxiety disorder and anxiety disorder
not otherwise specified. As used herein the term "anxiety" includes
treatment of those anxiety disorders and related disorder as
described in the DSM-IV. The skilled artisan will recognize that
there are alternative nomenclatures, nosologies, and classification
systems for neurological and psychiatric disorders, and particular
anxiety, and that these systems evolve with medical scientific
progress. Thus, the term "anxiety" is intended to include like
disorders that are described in other diagnostic sources.
[0662] In another preferred embodiment, the present invention
provides a method for treating depression, comprising:
administering to a patient in need thereof an effective amount of
at least one compound, selected from the group of compounds of
formula I, their N-oxides, their hydrates, their tautomers, their
prodrugs and the pharmaceutically acceptable salts thereof. At
present, the fourth edition of the Diagnostic and Statistical
Manual of Mental Disorders (DSM-IV) (1994, American Psychiatric
Association, Washington, D.C.), provides a diagnostic tool
including depression and related disorders. Depressive disorders
include, for example, single episodic or recurrent major depressive
disorders, and dysthymic disorders, depressive neurosis, and
neurotic depression; melancholic depression including anorexia,
weight loss, insomnia and early morning waking, and psychomotor
retardation; atypical depression (or reactive depression) including
increased appetite, hypersomnia, psychomotor agitation or
irritability, anxiety and phobias; seasonal affective disorder; or
bipolar disorders or manic depression, for example, bipolar I
disorder, bipolar II disorder and cyclothymic disorder. As used
herein the term "depression" includes treatment of those depression
disorders and related disorder as described in the DSM-1V.
[0663] In another preferred embodiment, the present invention
provides a method for treating substance-related disorders,
especially substance dependence, substance abuse, substance
tolerance, and substance withdrawal, comprising: administering to a
patient in need thereof an effective amount at least one compound,
selected from the group of compounds of formula I, their N-oxides,
their hydrates, their tautomers, their prodrugs and the
pharmaceutically acceptable salts thereof. At present, the fourth
edition of the Diagnostic and Statistical Manual of Mental
Disorders (DSM-IV) (1994, American Psychiatric Association,
Washington, D.C.), provides a diagnostic tool including disorders
related to taking a drug of abuse (including alcohol), to the side
effects of a medication, and to toxin exposure. Substances include
alcohol, amphetamine and similarly acting sympathomimetics,
caffeine, cannabis, cocaine, hallucinogens, inhalants, nicotine,
opioids, phencyclidine (PCP) or similarly acting
arylcyclohexylamines, and sedatives, hypnotics, or anxiolytics.
Also, polysubstance dependence and other unknown substance-related
disorders are included. The skilled artisan will recognize that
there are alternative nomenclatures, nosologies, and classification
systems for neurological and psychiatric disorders, and particular
substance-related disorders, and that these systems evolve with
medical scientific progress. Thus, the term "substance-related
disorder" is intended to include like disorders that are described
in other diagnostic sources.
[0664] In the treatment, prevention, control, amelioration, or
reduction of risk of conditions which require inhibition of PDE10A
an appropriate dosage level will generally be about 0.01 to 500 mg
per kg patient body weight per day which can be administered in
single or multiple doses. Preferably, the dosage level will be
about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to
about 100 mg/kg per day. A suitable dosage level may be about 0.01
to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1
to 50 mg/kg per day. Within this range the dosage may be 0.05 to
0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral administration,
the compositions are preferably provided in the form of tablets
containing 1.0 to 1000 milligrams of the active ingredient,
particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0,
150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0,
900.0, and 1000.0 milligrams of the active ingredient for the
symptomatic adjustment of the dosage to the patient to be treated.
The compounds may be administered on a regimen of 1 to 4 times per
day, preferably once or twice per day. When treating, preventing,
controlling, ameliorating, or reducing the risk of neurological and
psychiatric disorders or other diseases for which compounds of the
present invention are indicated, generally satisfactory results are
obtained when the compounds of the present invention are
administered at a daily dosage of from about 0.1 milligram to about
100 milligram per kilogram of animal body weight, preferably given
as a single daily dose or in divided doses two to six times a day,
or in sustained release form. For most large mammals, the total
daily dosage is from about 1.0 milligrams to about 1000 milligrams,
preferably from about 1 milligram to about 50 milligrams, in the
case of a 70 kg adult human, the total daily dose will generally be
from about 7 milligrams to about 350 milligrams. This dosage
regimen may be adjusted to provide the optimal therapeutic
response. It will be understood, however, that the specific dose
level and frequency of dosage for any particular patient may be
varied and will depend upon a variety of factors including the
activity of the specific compound employed, the metabolic stability
and length of action of that compound, the age, body weight,
general health, sex, diet, mode and time of administration, rate of
excretion, drug combination, the severity of the particular
condition, and the host undergoing therapy.
[0665] The compounds of the present invention may be administered
by conventional routes of administration, including parenteral
(e.g., intramuscular, intrapentoneal, intravenous, ICV,
intracisternal injection or infusion, subcutaneous injection, or
implant), oral, by inhalation spray, nasal, vaginal, rectal,
sublingual, or topical routes of administration.
[0666] The compounds according to the present invention are further
useful in a method for the prevention, treatment, control,
amelioration, or reduction of risk of the aforementioned diseases,
disorders and conditions in combination with other agents.
[0667] The compounds of the present invention may be used in
combination with one or more other drugs in the treatment,
prevention, control, amelioration, or reduction of risk of diseases
or conditions for which compounds of Formula I or the other drugs
may have utility, where the combination of the drugs together are
safer or more effective than either drug alone. Such other drug(s)
may be administered, by a route and in an amount commonly used
therefore, contemporaneously or sequentially with a compound of
Formula I. When a compound of formula I is used contemporaneously
with one or more other drugs, a pharmaceutical composition in unit
dosage form containing such other drugs and the compound of formula
I is preferred. However, the combination therapy may also include
therapies in which the compound of formula I and one or more other
drugs are administered on different overlapping schedules. It is
also contemplated that when used in combination with one or more
other active ingredients, the compounds of the present invention
and the other active ingredients may be used in lower doses than
when each is used singly. Accordingly, the pharmaceutical
compositions of the present invention include those that contain
one or more other active ingredients, in addition to a compound of
formula I. The above combinations include combinations of a
compound of the present invention not only with one other active
compound, but also with two or more other active compounds.
[0668] Likewise, compounds of the present invention may be used in
combination with other drugs that are used in the prevention,
treatment, control, amelioration, or reduction of risk of the
diseases or conditions for which compounds of the present invention
are useful. Such other drugs may be administered, by a route and in
an amount commonly used therefore, contemporaneously or
sequentially with a compound of the present invention. When a
compound of the present invention is used contemporaneously with
one or more other drugs, a pharmaceutical composition containing
such other drugs in addition to the compound of the present
invention is preferred. Accordingly, the pharmaceutical
compositions of the present invention include those that also
contain one or more other active ingredients, in addition to a
compound of the present invention.
[0669] The weight ratio of the compound of the compound of the
present invention to the second active ingredient may be varied and
will depend upon the effective dose of each ingredient. Generally,
an effective dose of each will be used. Thus, for example, when a
compound of the present invention is combined with another agent,
the weight ratio of the compound of the present invention to the
other agent will generally range from about 1000:1 to about 1:1000,
preferably about 200:1 to about 1:200. Combinations of a compound
of the present invention and other active ingredients will
generally also be within the aforementioned range, but in each
case, an effective dose of each active ingredient should be used.
In such combinations the compound of the present invention and
other active agents may be administered separately or in
conjunction. In addition, the administration of one element may be
prior to, concurrent to, or subsequent to the administration of
other agent(s).
[0670] The present invention also relates to pharmaceutical
compositions (i.e. medicaments) which comprise at least one
compound of the present invention and, where appropriate, one or
more suitable excipients.
[0671] These excipients/drug carriers are chosen according to the
pharmaceutical form and the desired mode of administration.
[0672] The compounds of the present invention can be used to
manufacture pharmaceutical compositions for parenteral (e.g.,
intramuscular, intrapentoneal, intravenous, ICV, intracisternal
injection or infusion, subcutaneous injection, or implant), oral,
sublingual, intratracheal, intranasal, topical, transdermal,
vaginal or rectal administration, and be administered to animals or
humans in unit dose forms, mixed with conventional pharmaceutical
carriers, for the prophylaxis or treatment of the above impairments
or diseases.
[0673] In the pharmaceutical compositions, the at least one
compound of the present invention may be formulated alone or
together with further active compounds, in suitable dosage unit
formulations containing conventional excipients, which generally
are non-toxic and/or pharmaceutically acceptable. Carriers or
excipients can be solid, semisolid or liquid materials which serve
as vehicles, carriers or medium for the active compound. Suitable
excipients are listed in the specialist medicinal monographs. In
addition, the formulations can comprise pharmaceutically acceptable
carriers or customary auxiliary substances, such as glidants;
wetting agents; emulsifying and suspending agents; preservatives;
antioxidants; antiirritants; chelating agents; coating auxiliaries;
emulsion stabilizers; film formers; gel formers; odor masking
agents; taste corrigents; resin; hydrocolloids; solvents;
solubilizers; neutralizing agents; diffusion accelerators;
pigments; quaternary ammonium compounds; refatting and overfatting
agents; raw materials for ointments, creams or oils; silicone
derivatives; spreading auxiliaries; stabilizers; sterilants;
suppository bases; tablet auxiliaries, such as binders, fillers,
glidants, disintegrants or coatings; propellants; drying agents;
opacifiers; thickeners; waxes; plasticizers and white mineral oils.
A formulation in this regard is based on specialist knowledge as
described, for example, in Fiedler, H. P., Lexikon der Hilfsstoffe
fur Pharmazie, Kosmetik and angrenzende Gebiete [Encyclopedia of
auxiliary substances for pharmacy, cosmetics and related fields],
4.sup.th edition, Aulendorf: ECV-Editio-Kantor-Verlag, 1996.
[0674] Suitable unit dose forms include forms for oral
administration, such as tablets, gelatin capsules, powders,
granules and solutions or suspensions for oral intake, forms for
sublingual, buccal, intratracheal or intranasal administration,
aerosols, implants, forms of subcutaneous, intramuscular or
intravenous administration and forms of rectal administration.
[0675] The compounds of the invention can be used in creams,
ointments or lotions for topical administration.
[0676] If a solid composition is prepared in the form of tablets,
the main ingredient is mixed with a pharmaceutical carrier such as
gelatin, starch, lactose, magnesium stearate, talc, silicon dioxide
or the like.
[0677] The tablets may be coated with sucrose, a cellulose
derivative or another suitable substance or be treated otherwise in
order to display a prolonged or delayed activity and in order to
release a predetermined amount of the active basic ingredient
continuously.
[0678] A preparation in the form of gelatin capsules is obtained by
mixing the active ingredient with an extender and taking up the
resulting mixture in soft or hard gelatin capsules.
[0679] A preparation in the form of a syrup or elixir or for
administration in the form of drops may comprise active ingredients
together with a sweetener, which is preferably calorie-free,
methylparaben or propylparaben as antiseptics, a flavoring and a
suitable coloring.
[0680] The water-dispersible powders or granules may comprise the
active ingredients mixed with dispersants, wetting agents or
suspending agents such as polyvinylpyrrolidones, and sweeteners or
taste improvers.
[0681] Rectal administration is achieved by the use of
suppositories which are prepared with binders which melt at the
rectal temperature, for example cocobutter or polyethylene glycols.
Parenteral administration is effected by using aqueous suspensions,
isotonic salt solutions or sterile and injectable solutions which
comprise pharmacologically suitable dispersants and/or wetting
agents, for example propylene glycol or polyethylene glycol.
[0682] The active basic ingredient may also be formulated as
microcapsules or liposomes/centrosomes, if suitable with one or
more carriers or additives.
[0683] In addition to the compounds of the general formula I, their
prodrugs, their N-oxides, their tautomers, their hydrates or their
pharmaceutically suitable salts, the compositions of the invention
may comprise further active basic ingredients which may be
beneficial for the treatment of the impairments or diseases
indicated above.
[0684] The present invention thus further relates to pharmaceutical
compositions in which a plurality of active basic ingredients are
present together, where at least one thereof is a compound of the
invention.
[0685] When producing the pharmaceutical compositions, the
compounds according to the invention are optionally mixed or
diluted with one or more carriers.
[0686] The following examples are intended for further illustration
of the present invention.
EXAMPLES
[0687] The compounds were either characterized via proton-NMR in
d.sub.6-dimethylsulfoxide or d-chloroform on a 400 MHz or 500 MHz
NMR instrument (Bruker AVANCE), or by mass spectrometry, generally
recorded via HPLC-MS in a fast gradient on C18-material
(electrospray-ionisation (ESI) mode), or melting point.
[0688] The magnetic nuclear resonance spectral properties (NMR)
refer to the chemical shifts (.delta.) expressed in parts per
million (ppm). The relative area of the shifts in the .sup.1H-NMR
spectrum corresponds to the number of hydrogen atoms for a
particular functional type in the molecule. The nature of the
shift, as regards multiplicity, is indicated as singlet (s), broad
singlet (s. br.), doublet (d), broad doublet (d br.), triplet (t),
broad triplet (t br.), quartet (q), quintet (quint.) and multiplet
(m).
ABBREVIATIONS
[0689] DMSO dimethylsulfoxide [0690] DMF dimethylformamide [0691]
DMA dimethylacetamide [0692] MeOH methanol [0693] EtOH ethanol
[0694] AcOH acetic acid [0695] EtOAc ethyl acetate [0696] DCM
dichloromethane [0697] DIPEA or DIEA diisoproylethyl amine [0698]
TFA trifluoroacetic acid [0699] HATU
2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium
hexafluorophosphate methanaminium [0700] PS-TFP
4-hydroxy-2,3,5,6-tetrafluorobenzamidomethyl polystyrene [0701]
r.t. room temperature [0702] RT retention time [0703] Prep-TLC
preperative thin layer chromatography
I. Preparation Examples
Example 1
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid butylamide
1.1 2-(2-Carboxy-4,5-dimethoxy-phenyl)-malonic acid dimethyl
ester
[0704] To rapidly stirred cold (0.degree. C.) dimethyl malonate (20
mL) was added sodium (423 mg, 18.38 mmol) in portions. After the
addition was complete, the mixture was stirred until the sodium
disappeared and the mixture turned to a white colloidal suspension.
Cuprous bromide (110 mg, 0.7660 mmol) and
2-bromo-4,5-dimethoxybenzoic acid (2.00 g, 7.760 mmol) were added.
The mixture was heated at 70.degree. C. for 6 h. The reaction
mixture was dissolved in water and extracted with toluene and
EtOAc. The aqueous layer was acidified with HCl (2 N). The mixture
was then extracted with EtOAc, dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo to give the product as an oil.
After standing overnight the title compound was obtained as a solid
(1.3 g, yield 54%).
[0705] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.58 (s, 1H,
ArH), 6.92 (s, 1H, ArH), 5.98 (s, 1H, CH), 3.87 (s, 3H, CH.sub.3),
3.72 (s, 3H, CH.sub.3).
[0706] LCMS (ESI+): m/z 313 (M+H).sup.+, RT: 1.29 min.
1.2 2-(2-Carboxy-4,5-dimethoxy-phenyl)-malonic acid
[0707] A solution of sodium hydroxide (1.92 g, 48.03 mmol) in water
(20 mL) was added over 30 min to a solution of the compound
obtained in step 1.1 (3.0 g, 9.6 mmol) in methanol (30 mL) at room
temperature. After stirred for 3 h, methanol was removed under
reduced pressure, and the contents were acidified with HCl (conc.)
at r.t. to pH 3. The resulting white aqueous suspension was
extracted twice with EtOAc (100 mL), and the organic layer was
dried over Na.sub.2SO.sub.4. After filtration and concentration in
vacuo the title product was obtained as a white solid (1.8 g,
67%).
[0708] .sup.1H NMR (DMSO-d.sub.6/TMS, 400 MHz) .delta.: 12.67 (s,
3H, COOH), 7.48 (s, 1H, ArH), 6.88 (s, 1H, ArH), 5.76 (s, 1H, CH),
3.81 (s, 3H, CH.sub.3), 3.78 (s, 3H, CH.sub.3).
[0709] LCMS (ESI+): m/z 307 (M+Na).sup.+, RT: 0.71 min.
1.3 2-Carboxymethyl-4,5-dimethoxy-benzoic acid
[0710] The product obtained in step 1.2 (1.8 g, 6.4 mmol) was
suspended in toluene (40 mL), and the suspension was heated at
105.degree. C. overnight. The precipitates were removed by
filtration. The filtrate was concentrated to afford the title
product as a white solid. This was used in the next step without
further purification.
[0711] LCMS (ESI+): m/z 263 (M+Na).sup.+, RT: 1.32 min.
1.4 4,5-Dimethoxy-2-methoxycarbonylmethyl-benzoic acid methyl
ester
[0712] Thionyl chloride (0.74 g, 6.245 mmol) was added dropwise to
a solution of the compound obtained in step 1.3 (0.50 g, 2.082
mmol) in methanol (5 mL) at ambient temperature. After the addition
was completed, the mixture was then heated at 65.degree. C.
overnight. The solvent was concentrated in vacuo. The concentrate
was diluted with EtOAc (50 mL) and washed with saturated aqueous
NaHCO.sub.3 (10 mL), water (10 mL) and brine (10 mL). The organic
layer was dried over Na.sub.2SO.sub.4, filtered and concentrated.
The residue was purified on silica gel column (petrol
ether:EtOAc=5:1) to afford the title product as a white solid (0.5
g, 60%).
[0713] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.56 (s, 1H,
ArH), 6.72 (s, 1H, ArH), 3.97 (s, 2H, CH.sub.2), 3.93 (s, 3H,
CH.sub.3), 3.92 (s, 3H, CH.sub.3), 3.86 (s, 3H, CH.sub.3), 3.71 (s,
3H, CH.sub.3).
[0714] LCMS (ESI+): m/z 269 (M+H).sup.+, RT: 1.69 min
1.5
2-(2-Dimethylamino-1-methoxycarbonylvinyl)-4,5-dimethoxy-benzoic
acid methyl ester
[0715] A mixture of the compound obtained in step 1.4 (2.05 g,
7.641 mmol) in DMF-DMA (20 mL) was heated at 90.degree. C.
overnight. The reaction mixture was concentrated in vacuo. The
residue was diluted with EtOAc and washed with brine. The organic
layer was dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The residue was purified on silica gel column (petrol
ether:EtOAc=3:1) to afford the title product as a white solid (0.78
g, 32%).
[0716] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.43 (s, 1H,
ArH), 7.38 (s, 1H, ArH), 6.59 (s, 1H, CH), 3.86 (s, 3H, CH.sub.3),
3.84 (s, 3H, CH.sub.3), 3.73 (s, 3H, CH.sub.3), 3.53 (s, 3H,
CH.sub.3), 2.61 (s, 6H, N(CH.sub.3).sub.2).
[0717] LCMS (ESI+): m/z 265 (M+H).sup.+, RT: 1.52 min
1.6
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-carboxylic
acid methyl ester
[0718] A mixture of the compound obtained in step 1.5 (80 mg,
0.2474 mmol), ethylamine hydrochloride (61 mg, 0.7423 mmol) and
DIPEA (1 mL) in methanol (5 mL) was heated at reflux overnight. The
solvent was removed under reduced pressure. The residue was diluted
with EtOAc (50 mL) and washed with HCl (2 N, 10 mL) and brine (10
ML). The organic layer was dried over Na.sub.2SO.sub.4, filtered
and concentrated in vacuo to afford the title product as a white
solid (68 mg, yield 95%). The product was pure enough to be used in
the next step without further purification.
[0719] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 8.40 (s, 1H,
ArH), 8.13 (s, 1H, ArH), 7.83 (s, 1H, ArH), 4.12 (q, J=6.8 Hz,
J=7.2 Hz, 2H, CH.sub.2), 4.05 (s, 3H, CH.sub.3), 4.01 (s, 3H,
CH.sub.3), 3.91 (s, 3H, CH.sub.3), 1.43 (t, J=7.6 Hz, 3H,
CH.sub.3).
[0720] LCMS (ESI+): m/z 292 (M+H).sup.+, RT: 1.75 min
1.7
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-carboxylic
acid
[0721] A mixture of the compound obtained in step 1.6 (254 mg,
0.8720 mmol) and sodium hydroxide (42 mg, 1.046 mmol) in methanol
(6 mL) and water (2 mL) was heated at 40.degree. C. for 6 h. The
reaction mixture was concentrated in vacuo. The concentrate was
acidified with HCl (conc.) to pH=2-3. The resulting precipitates
were collected by filtration. The solid was dried in vacuo and used
in the next step without further purification (200 mg, yield
83%).
[0722] LCMS (ESI+): m/z 278 (M+H).sup.+, RT: 1.50 min
1.8
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid butylamide
[0723] A suspension of the compound obtained in step 1.7 (50 mg,
0.1803 mmol) and thionyl chloride (64 mg, 0.5409 mmol) in DCM (3
mL) was refluxed for 3 h. The mixture was concentrated in vacuo and
diluted in DCM (3 mL). The solution was added dropwise to a mixture
of n-butylamine (26 mg, 0.3606 mmol) and triethylamine (55 mg,
0.5409 mmol) in DCM (4 mL) at ambient temperature. The reaction
mixture was stirred at r.t. for another 3 h. Then the solvent was
removed under reduced pressure, the residue was diluted with EtOAc
and washed with HCl (2 N), NaOH (2 N) and brine successively. The
organic layer was dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. The residue was purified on silica gel
column (eluted with DCM/EtOAc=4:1, v/v) to afford the title product
as a white solid (53 mg, yield 88%).
[0724] LCMS: 1.70 min; M+H, 333.1
[0725] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.80 (s, 1H,
ArH), 7.57 (s, 1H, ArH), 7.35 (s, 1H, ArH), 5.96 (s, 1H, NH), 4.05
(q, J=7.6 Hz, 2H, CH.sub.2), 4.01 (s, 3H, OCH.sub.3), 3.99 (s, 3H,
OCH.sub.3), 3.48 (q, J=5.6 Hz, 2H, CH.sub.2), 1.59-1.69 (m, 2H,
CH.sub.2), 1.41-1.51 (m, 2H, CH.sub.2), 1.39 (t, J=6.8 Hz, 3H,
CH.sub.3), 0.99 (t, J=7.2 Hz, 3H, CH.sub.3).
[0726] The following compounds were synthesized analogously, using
in the last reaction step the respective amine.
Example 2
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid methylamide
[0727] LCMS: 1.54 min; M+H: 291
[0728] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.72 (s, 1H),
7.52 (s, 1H), 7.29 (s, 1H), 5.97 (s, 1H), 3.96 (m, 2H), 3.93 (s,
3H), 3.92 (s, 3H), 2.97 (d, J=4.8 Hz, 2H), 1.31 (t, J=7.2 Hz,
3H).
Example 3
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid ethylamide
[0729] LCMS: 1.62 min; M+H: 305
[0730] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.80 (s, 1H),
7.59 (s, 1H), 7.35 (s, 1H), 5.94 (s, 1H), 4.04 (m, 2H), 4.00 (s,
3H), 3.99 (s, 3H), 3.52 (m, 2H), 1.39 (t, J=7.2 Hz, 3H), 1.30 (t,
J=7.4 Hz, 3H).
Example 4
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (2-fluoro-ethyl)-amide
[0731] LCMS: 1.56 min; M+H: 323
[0732] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.75 (s, 1H),
7.53 (s, 1H), 7.37 (s, 1H), 6.26 (s, 1H), 4.66 (t, J=4.6 Hz, 1H),
4.54 (t, J=4.8 Hz, 1H), 3.99 (m, 2H), 3.94 (s, 3H), 3.92 (s, 3H),
3.77 (m, 1H), 3.70 (m, 1H), 1.33 (t, J=7.2 Hz).
Example 5
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (2,2,2-trifluoro-ethyl)-amide
[0733] LCMS: 1.77 min; M+H: 359
[0734] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.81 (s, 1H),
7.52 (s, 1H), 7.46 (s, 1H), 6.21 (s, 1H), 4.13-4.18 (m, 2H), 4.06
(m, 2H), 4.01 (s, 3H), 3.99 (s, 3H), 1.41 (t, J=5.6 Hz, 3H).
Example 6
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid cyclopropylamide
[0735] LCMS: 1.50 min; M+H: 317
[0736] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.71 (s, 1H),
7.56 (s, 1H), 7.24 (s, 1H), 6.06 (s, 1H), 3.96 (m, 2H), 3.93 (s,
3H), 3.92 (s, 3H), 2.85-2.88 (m, 1H), 1.31 (t, J=7.4 Hz, 3H),
0.83-0.86 (m, 2H), 0.57-0.62 (m, 2H).
Example 7
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid isopropylamide
[0737] LCMS: 1.58 min; M+H: 319
[0738] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.75 (s, 1H),
7.51 (s, 1H), 7.27 (s, 1H), 5.65 (s, 1H), 4.20-4.29 (m, 1H),
3.97-4.03 (m, 2H), 3.94 (s, 3H), 3.92 (s, 3H), 1.33 (t, J=7.2 Hz,
3H), 1.24 (d, J=6.4 Hz, 6H).
Example 8
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid propylamide
[0739] LCMS: 1.59 min; M+H: 319
[0740] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.75 (s, 1H),
7.52 (s, 1H), 7.30 (s, 1H), 5.85 (s, 1H), 3.97-4.03 (m, 2H), 3.94
(s, 3H), 3.92 (s, 3H), 3.38 (br, 2H), 1.59-1.65 (m, 2H), 1.33 (t,
J=6.8 Hz, 3H), 0.97 (t, J=7.4 Hz, 3H).
Example 9
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid cyclobutylamide
[0741] LCMS: 1.74 min; M+H: 331
[0742] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.84 (s, 1H),
7.60 (s, 1H), 7.40 (s, 1H), 6.02 (s, 1H), 4.63 (br, 1H), 4.10 (br,
2H), 4.01 (s, 3H), 4.00 (s, 3H), 2.48 (br, 2H), 1.99 (m, 2H), 1.80
(br, 2H), 1.41 (br, 3H).
Example 10
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid cyclopropylmethyl-amide
[0743] LCMS: 1.72 min; M+H: 331
[0744] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.76 (s, 1H),
7.54 (s, 1H), 7.34 (s, 1H), 5.94 (s, 1H), 3.99-4.04 (m, 2H), 3.94
(s, 3H), 3.93 (s, 3H), 3.26-3.29 (m, 2H), 1.34 (t, J=7.2 Hz, 3H),
0.98-1.07 (m, 1H), 0.51-0.55 (m, 2H), 0.23-0.27 (m, 2H).
Example 11
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid tert-butylamide
[0745] LCMS: 1.72 min; M+H: 333
[0746] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.75 (s, 1H),
7.45 (s, 1H), 7.26 (s, 1H), 5.66 (s, 1H), 3.97-4.01 (m, 2H), 3.94
(s, 3H), 3.92 (s, 3H), 1.44 (s, 9H), 1.33 (t, J=7.0 Hz, 3H).
Example 12
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid sec-butylamide
[0747] LCMS: 1.67 min; M+H: 333
[0748] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.75 (s, 1H),
7.49 (s, 1H), 7.28 (s, 1H), 5.63 (s, 1H), 4.08 (m, 1H), 3.98-4.01
(m, 2H), 3.94 (s, 3H), 3.92 (s, 3H), 1.49-1.55 (m, 2H), 1.33 (t,
J=7.0 Hz, 3H), 1.21 (d, J=6.8 Hz, 3H), 0.95 (t, J=7.4 Hz, 3H).
Example 13
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid isobutyl-amide
[0749] LCMS: 1.69 min; M+H: 333
[0750] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.75 (s, 1H),
7.50 (s, 1H), 7.29 (s, 1H), 5.88 (s, 1H), 3.97-4.02 (m, 2H), 3.94
(s, 3H), 3.92 (s, 3H), 3.25 (t, J=6.4 Hz, 2H), 1.84-1.90 (m, 1H),
1.33 (t, J=7.2 Hz, 3H), 0.96 (d, J=6.4 Hz, 6H).
Example 14
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid cyclopentylamide
[0751] LCMS: 1.71 min; M+H: 345
[0752] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.75 (s, 1H),
7.50 (s, 1H), 7.27 (s, 1H), 5.77 (s, 1H), 4.34-4.39 (m, 1H),
3.97-4.02 (m, 2H), 3.94 (s, 3H), 3.92 (s, 3H), 2.05-2.10 (m, 2H),
1.61-1.69 (m, 4H), 1.43-1.46 (m, 2H), 1.33 (t, J=7.2 Hz, 3H).
Example 15
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (1-methyl-butyl)-amide
[0753] LCMS: 1.88 min; M+H: 347
[0754] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.82 (s, 1H),
7.56 (s, 1H), 7.34 (s, 1H), 5.67 (s, 1H), 4.21-4.27 (m, 1H),
4.05-4.09 (m, 2H), 4.01 (s, 3H), 3.99 (s, 3H), 1.52-1.59 (m, 2H),
1.43-1.48 (m, 2H), 1.40 (t, J=5.4 Hz, 3H), 1.28 (d, J=5.2 Hz, 3H),
0.98 (t, J=5.6 Hz, 3H).
Example 16
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (1,1-dimethyl-propyl)-amide
[0755] LCMS: 1.91 min; M+H: 347
[0756] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.86 (s, 1H),
7.53 (s, 1H), 7.41 (s, 1H), 5.63 (s, 1H), 4.13 (m, 2H), 4.03 (s,
3H), 4.00 (s, 3H), 1.88-1.93 (m, 2H), 1.46 (s, 6H), 1.41 (br, 3H),
0.97 (t, J=5.8 Hz, 3H).
Example 17
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (1,2-dimethyl-propyl)-amide
[0757] LCMS: 1.86 min; M+H: 347
[0758] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.76 (s, 1H),
7.48 (s, 1H), 7.27 (s, 1H), 5.61 (s, 1H), 3.96-4.03 (m, 3H), 3.94
(s, 3H), 3.92 (s, 3H), 1.77 (m, 1H), 1.34 (t, J=7.2 Hz, 3H), 1.16
(d, J=6.8 Hz, 3H), 0.94 (d, J=4.0 Hz, 3H), 0.93 (d, J=4.0 Hz,
3H).
Example 18
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (2,2-dimethyl-propyl)-amide
[0759] LCMS: 1.89 min; M+H: 347
[0760] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.83 (s, 1H),
7.55 (s, 1H), 7.37 (s, 1H), 5.99 (s, 1H), 4.07 (br, 2H), 4.01 (s,
3H), 3.98 (s, 3H), 3.31 (s, 2H), 1.40 (s, 3H), 1.03 (s, 9H).
Example 19
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (1-ethyl-propyl)-amide
[0761] LCMS: 1.86 min; M+H: 347
[0762] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.83 (s, 1H),
7.55 (s, 1H), 7.35 (s, 1H), 5.55 (s, 1H), 4.03-4.09 (m, 3H), 4.01
(s, 3H), 3.98 (s, 3H), 1.64-1.70 (m, 2H), 1.51-1.55 (m, 2H), 1.41
(t, J=7.0 Hz, 3H), 1.02 (t, J=7.4 Hz, 6H).
Example 20
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (2-methyl-butyl)-amide
[0763] LCMS: 1.89 min; M+H: 347
[0764] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.76 (s, 1H),
7.50 (s, 1H), 7.29 (s, 1H), 5.83 (s, 1H), 3.98-4.03 (m, 2H), 3.94
(s, 3H), 3.92 (s, 3H), 3.33-3.39 (m, 1H), 3.21-3.27 (m, 1H),
1.61-1.68 (m, 1H), 1.41-1.47 (m, 1H), 1.33 (t, J=5.6 Hz, 3H),
1.16-1.22 (m, 1H), 0.94 (d, J=5.6 Hz, 3H), 0.90 (t, J=6.0 Hz,
3H).
Example 21
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid pentylamide
[0765] LCMS: 1.91 min; M+H: 347
[0766] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.84 (s, 1H),
7.61 (s, 1H), 7.40 (s, 1H), 5.92 (s, 1H), 4.08-4.11 (m, 2H), 4.03
(s, 3H), 4.01 (s, 3H), 3.47-3.51 (s, 2H), 1.68 (m, 2H), 1.42 (m,
7H), 0.96 (t, J=7.2 Hz, 3H).
Example 22
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid cyclohexylamide
[0767] LCMS: 1.90 min; M+H: 359
[0768] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.75 (s, 1H),
7.51 (s, 1H), 7.29 (s, 1H), 5.69 (s, 1H), 3.98-4.02 (m, 3H), 3.94
(s, 3H), 3.92 (s, 3H), 2.01-2.03 (m, 2H), 1.71-1.73 (m, 2H),
1.38-1.42 (m, 2H), 1.33 (t, J=4.8 Hz, 3H), 1.16-1.22 (m, 4H).
Example 23
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (1,3-dimethyl-butyl)-amide
[0769] LCMS: 1.97 min; M+H: 361
[0770] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.74 (s, 1H),
7.45 (s, 1H), 7.25 (s, 1H), 5.62 (s, 1H), 4.23-4.27 (m, 1H),
3.96-4.02 (m, 2H), 3.94 (s, 3H), 3.92 (s, 3H), 1.65 (m, 1H), 1.41
(m, 1H), 1.33 (m, 4H), 1.21 (d, J=6.4 Hz, 3H), 0.93 (d, J=6.4 Hz,
3H), 0.90 (d, J=6.8 Hz, 3H).
Example 24
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (3,3-dimethyl-butyl)-amide
[0771] LCMS: 1.98 min; M+H: 361
[0772] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.75 (s, 1H),
7.54 (s, 1H), 7.28 (s, 1H), 5.71 (s, 1H), 3.98-4.02 (m, 2H), 3.94
(s, 3H), 3.93 (s, 3H), 3.42 (s, 2H), 1.48 (m, 2H), 1.33 (t, J=5.4
Hz, 3H), 0.93 (s, 9H).
Example 25
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (2-ethyl-butyl)-amide
[0773] LCMS: 1.98 min; M+H: 361
[0774] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.84 (s, 1H),
7.56 (s, 1H), 7.38 (s, 1H), 5.87 (s, 1H), 4.06-4.10 (m, 2H), 4.02
(s, 3H), 3.99 (s, 3H), 3.44-3.46 (m, 2H), 1.52-1.55 (m, 1H),
1.40-1.45 (m, 7H), 0.96 (t, J=6.4 Hz, 3H).
Example 26
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid benzylamide
[0775] LCMS: 1.84 min; M+H: 367
[0776] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.82 (s, 1H),
7.56 (s, 1H), 7.33-7.42 (m, 6H), 6.16 (s, 1H), 4.67 (s, 2H),
4.03-4.07 (m, 2H), 4.00 (s, 3H), 3.90 (s, 3H), 1.39 (m, 3H).
Example 27
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid dicyclopropylmethyl-amide
[0777] LCMS: 1.91 min; M+H: 371
[0778] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.77 (s, 1H),
7.48 (s, 1H), 7.32 (s, 1H), 5.85 (s, 1H), 4.00-4.04 (m, 2H), 3.94
(s, 3H), 3.92 (s, 3H), 3.26 (m, 1H), 1.34 (t, J=7.0 Hz, 3H), 0.93
(m, 2H), 0.54 (m, 2H), 0.37-0.45 (m, 6H).
Example 28
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid cyclohexylmethyl-amide
[0779] LCMS: 2.00 min; M+H: 373
[0780] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.82 (s, 1H),
7.57 (s, 1H), 7.36 (s, 1H), 5.95 (s, 1H), 4.04-4.08 (m, 2H), 4.01
(s, 3H), 3.99 (s, 3H), 3.33 (s, 2H), 1.76-1.84 (m, 4H), 1.68-1.72
(m, 2H), 1.40 (s, 3H), 1.21-1.29 (m, 3H), 1.02-1.06 (m, 2H).
Example 29
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (1-phenyl-ethyl)-amide
[0781] LCMS: 1.89 min; M+H: 381
[0782] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.69 (s, 1H),
7.38-7.40 (m, 2H), 7.31-7.35 (m, 4H), 7.22-7.25 (m, 1H), 6.25 (s,
1H), 5.33 (s, 1H), 3.92-3.96 (m, 2H), 3.89 (s, 3H), 3.76 (s, 3H),
1.59 (d, J=5.2 Hz, 3H), 1.31 (s, 3H).
Example 30
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid 2-fluoro-benzylamide
[0783] LCMS: 1.86 min; M+H: 385
[0784] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.81 (s, 1H),
7.53 (s, 1H), 7.46-7.49 (m, 1H), 7.41 (s, 1H), 7.30.7.33 (m, 1H),
7.15-7.18 (m, 1H), 7.08-7.12 (m, 1H), 6.28 (s, 1H), 4.72 (d, J=4.4
Hz, 2H), 4.03-4.08 (m, 2H), 4.00 (s, 3H), 3.92 (s, 3H), 1.38 (d,
J=5.8 Hz, 3H).
Example 31
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid 3-fluoro-benzylamide
[0785] LCMS: 1.87 min; M+H: 385
[0786] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.82 (s, 1H),
7.58 (s, 1H), 7.42 (s, 1H), 7.33-7.37 (m, 1H), 7.18 (d, J=6.0 Hz,
1H), 7.13 (d, J=8.0 Hz, 1H), 7.00-7.04 (m, 1H), 6.22 (s, 1H), 4.67
(d, J=4.8 Hz, 2H), 4.04-4.08 (m, 2H), 4.00 (s, 3H), 3.94 (s, 3H),
1.39 (d, J=5.2 Hz, 3H).
Example 32
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid 4-fluoro-benzylamide
[0787] LCMS: 1.86 min; M+H: 385
[0788] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.78 (s, 1H),
7.55 (s, 1H), 7.38-7.41 (m, 3H), 7.05-7.09 (m, 2H), 6.32 (s, 1H),
4.63 (d, J=4.4 Hz, 2H), 4.00-4.04 (m, 2H), 3.98 (s, 3H), 3.92 (s,
3H), 1.37 (d, J=5.6 Hz, 3H).
Example 33
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid 2,3-difluoro-benzylamide
[0789] LCMS: 1.90 min; M+H: 403
[0790] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.81 (s, 1H),
7.54 (s, 1H), 7.41 (s, 1H), 7.24 (m, 1H), 7.08-7.16 (m, 2H), 6.29
(s, 1H), 4.73 (d, J=5.6 Hz, 2H), 4.04-4.07 (m, 2H), 4.00 (s, 3H),
3.94 (s, 3H), 1.39 (t, J=7.2 Hz, 3H).
Example 34
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid 2,4-difluoro-benzylamide
[0791] LCMS: 1.90 min; M+H: 403
[0792] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.74 (s, 1H),
7.47 (s, 1H), 7.36-7.43 (m, 1H), 7.32 (s, 1H), 6.76-6.85 (m, 2H),
6.17 (s, 1H), 4.59 (d, J=5.6 Hz, 2H), 3.96-4.01 (m, 2H), 3.93 (s,
3H), 3.87 (s, 3H), 1.32 (t, J=7.2 Hz, 3H).
Example 35
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid 2,6-difluoro-benzylamide
[0793] LCMS: 1.86 min; M+H: 403
[0794] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.75 (s, 1H),
7.47 (s, 1H), 7.25 (s, 1H), 7.19 (m, 1H), 6.88 (m, 2H), 6.16 (s,
1H), 4.71 (d, J=5.2 Hz, 2H), 3.96-4.01 (m, 2H), 3.93 (s, 3H), 3.87
(s, 3H), 1.32 (t, J=7.2 Hz, 3H).
Example 36
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid 3,4-difluoro-benzylamide
[0795] LCMS: 1.91 min; M+H: 403
[0796] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.74 (s, 1H),
7.51 (s, 1H), 7.33 (s, 1H), 7.06-7.17 (m, 3H), 6.17 (s, 1H), 4.55
(d, J=5.6 Hz, 2H), 3.96-4.02 (m, 2H), 3.93 (s, 3H), 3.88 (s, 3H),
1.32 (t, J=7.2 Hz, 3H).
Example 37
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid 3,5-difluoro-benzylamide
[0797] LCMS: 1.92 min; M+H: 403
[0798] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.74 (s, 1H),
7.51 (s, 1H), 7.35 (s, 1H), 6.85-6.89 (m, 2H), 6.67-6.72 (m, 1H),
6.24 (s, 1H), 4.58 (d, J=6.0 Hz, 2H), 3.97-4.02 (m, 2H), 3.93 (s,
3H), 3.89 (s, 3H), 1.33 (t, J=7.0 Hz, 3H).
Example 38
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid phenethyl-amide
[0799] LCMS: 1.88 min; M+H: 381
[0800] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.79 (s, 1H),
7.55 (s, 1H), 7.33-7.36 (s, 2H), 7.25-7.28 (m, 3H), 7.16 (s, 1H),
5.88 (s, 1H), 3.93-4.01 (m, 8H), 3.76 (s, 2H), 3.00 (t, J=5.2 Hz,
3H), 1.36 (t, J=4.8 Hz, 3H).
Example 39
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid [1-(4-fluoro-phenyl)-ethyl]-amide
[0801] LCMS: 1.92 min; M+H: 399
[0802] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.77 (s, 1H),
7.41-7.44 (m, 3H), 7.35 (s, 1H), 7.07 (m, 2H), 6.23 (s, 1H), 5.37
(s, 1H), 4.01-4.04 (m, 2H), 3.97 (s, 3H), 3.88 (s, 3H), 1.64 (d,
J=5.6 Hz, 2H), 1.38 (t, J=5.2 Hz, 3H).
Example 40
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid indan-1-ylamide
[0803] LCMS: 1.94 min; M+H: 393
[0804] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.75 (s, 1H),
7.58 (s, 1H), 7.34-7.38 (m, 2H), 7.17-7.23 (m, 3H), 6.05 (m, 1H),
5.66 (s, 1H), 3.96-4.00 (m, 2H), 3.93 (s, 3H), 3.90 (s, 3H),
2.97-3.03 (m, 1H), 2.86-2.71 (m, 1H), 2.64-2.71 (m, 1H), 1.89-1.95
(m, 1H), 1.32 (t, J=5.2 Hz, 3H).
Example 41
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid indan-2-ylamide
[0805] LCMS: 1.93 min; M+H: 393
[0806] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.80 (s, 1H),
7.47 (s, 1H), 7.39 (s, 1H), 7.28-7.30 (m, 2H), 7.20-7.22 (m, 2H),
6.15 (s, 1H), 4.96 (s, 1H), 3.98-4.05 (m, 5H), 3.83 (s, 3H),
3.43-3.48 (m, 2H), 2.96-3.01 (m, 2H), 1.37 (s, 3H).
Example 42
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid [1-(4-fluoro-phenyl)-1-methyl-ethyl]-amide
[0807] LCMS: 1.98 min; M+H: 413
[0808] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.82 (s, 1H),
7.44-7.47 (m, 3H), 7.39 (s, 1H), 7.03-7.07 (m, 2H), 6.18 (s, 1H),
4.06-4.10 (m, 2H), 4.00 (s, 3H), 3.92 (s, 3H), 1.84 (s, 6H), 1.42
(s, 3H).
Example 43
4-(Azetidine-1-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquinolin-1-one
[0809] LCMS: 1.58 min; M+H: 317
[0810] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.76 (s, 1H),
7.42 (s, 1H), 7.20 (s, 1H), 4.13 (t, J=7.6 Hz, 4H), 3.98-4.03 (m,
2H), 3.94 (s, 6H), 2.24-2.32 (m, 2H), 1.32 (t, J=7.2 Hz, 3H).
Example 44
2-Ethyl-6,7-dimethoxy-4-(2-methyl-pyrrolidine-1-carbonyl)-2H-isoquinolin-1-
-one
[0811] LCMS: 1.74 min; M+H: 345
[0812] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.84 (s, 1H),
7.18 (s, 1H), 7.03 (br, 1H), 4.41 (br, 1H), 4.03-4.07 (m, 2H), 4.01
(s, 3H), 3.95 (s, 3H), 3.38 (br, 2H), 1.63-2.13 (m, 4H), 1.39 (t,
J=5.6 Hz, 3H), 1.15-1.41 (br, 3H).
Example 45
2-Ethyl-6,7-dimethoxy-4-(morpholine-4-carbonyl)-2H-isoquinolin-1-one
[0813] LCMS: 1.54 min; M+H: 347
[0814] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.78 (s, 1H),
7.10 (s, 1H), 6.87 (s, 1H), 3.97-4.03 (m, 2H), 3.94 (s, 3H), 3.91
(s, 3H), 3.48-3.64 (br, 8H), 1.33 (t, J=7.4 Hz, 3H).
Example 46
2-Ethyl-4-(3-fluoro-pyrrolidine-1-carbonyl)-6,7-dimethoxy-2H-isoquinolin-1-
-one
[0815] LCMS: 1.61 min; M+H: 349
[0816] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.77 (s, 1H),
7.17 (s, 1H), 6.94 (s, 1H), 5.22-5.34 (br, 1H), 3.98-4.03 (m, 2H),
3.94 (s, 3H), 3.88 (s, 3H), 3.44-3.76 (br, 4H), 2.25 (br, 1H),
1.95-2.06 (br, 1H), 1.33 (t, J=7.0 Hz, 3H).
Example 47
2-Ethyl-6,7-dimethoxy-4-(4-methyl-piperazine-1-carbonyl)-2H-isoquinolin-1--
one
[0817] LCMS: 1.52 min; M+H: 360
[0818] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.77 (s, 1H),
7.09 (s, 1H), 6.86 (s, 1H), 3.97-4.01 (m, 2H), 3.94 (s, 3H), 3.91
(s, 3H), 3.61 (br, 4H), 2.41 (br, 4H), 2.30 (s, 3H), 1.33 (t, J=7.2
Hz, 3H).
Example 48
4-(3,3-Difluoro-pyrrolidine-1-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquinol-
in-1-one
[0819] LCMS: 1.74 min; M+H: 367
[0820] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.85 (s, 1H),
7.23 (s, 1H), 7.00 (s, 1H), 4.06-4.10 (m, 2H), 4.02 (s, 3H), 3.97
(s, 3H), 3.86 (br, 4H), 2.43 (s, 2H), 1.40 (t, J=6.0 Hz, 3H).
Example 49
4-(3-Dimethylamino-pyrrolidine-1-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoqui-
nolin-1-one
[0821] LCMS: 1.55 min; M+H: 374
[0822] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.84 (s, 1H),
7.22 (s, 1H), 7.03 (s, 1H), 4.04-4.09 (m, 2H), 4.01 (s, 3H), 3.97
(s, 3H), 2.81-3.57 (br, 4H), 1.61-2.33 (m, 9H), 1.39 (t, J=5.6 Hz,
3H).
Example 50
2-Ethyl-6,7-dimethoxy-4-((R)-2-methoxymethyl-pyrrolidine-1-carbonyl)-2H-is-
oquinolin-1-one
[0823] LCMS: 1.72 min; M+H: 375
[0824] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.84 (s, 1H),
7.25 (s, 1H), 7.13 (s, 1H), 4.45 (br, 1H), 4.06-4.10 (m, 2H), 4.01
(s, 3H), 3.97 (s, 3H), 3.37-3.49 (m, 5H), 1.76-2.08 (m, 4H), 1.41
(s, 3H).
Example 51
4-(1,3-Dihydro-isoindole-2-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquinolin--
1-one
[0825] LCMS: 1.86 min; M+H: 379
[0826] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.87 (s, 1H),
7.27-7.37 (m, 4H), 7.16 (s, 1H), 7.01 (s, 1H), 5.07 (s, 2H), 4.75
(s, 2H), 4.07-4.11 (m, 2H), 4.02 (s, 3H), 3.90 (s, 3H), 1.42 (t,
J=5.2 Hz, 3H).
Example 52
4-(4,4-Difluoro-piperidine-1-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquinoli-
n-1-one
[0827] LCMS: 1.80 min; M+H: 381
[0828] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.85 (s, 1H),
7.19 (s, 1H), 6.90 (s, 1H), 5.07 (s, 2H), 4.75 (s, 2H), 4.04-4.07
(m, 2H), 4.02 (s, 3H), 3.96 (s, 3H), 3.73 (br, 4H), 2.02 (br, 4H),
1.40 (t, J=5.4 Hz, 3H).
Example 53
2-Ethyl-4-(4-isopropyl-piperazine-1-carbonyl)-6,7-dimethoxy-2H-isoquinolin-
-1-one
[0829] LCMS: 1.70 min; M+H: 388
[0830] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.84 (s, 1H),
7.16 (s, 1H), 6.93 (s, 1H), 4.03-4.08 (m, 2H), 4.01 (s, 3H), 3.97
(s, 3H), 3.29-3.79 (br, 4H), 2.73 (s, 1H), 2.51 (br, 4H), 1.40 (t,
J=5.6 Hz, 3H), 1.05 (d, J=4.8 Hz, 6H).
Example 54
4-(4-Dimethylamino-piperidine-1-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquin-
olin-1-one
[0831] LCMS: 1.50 min; M+H: 388
[0832] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.84 (s, 1H),
7.14 (s, 1H), 6.92 (s, 1H), 4.08 (m, 2H), 4.01 (s, 3H), 3.96 (s,
3H), 2.96 (s, 2H), 2.35-2.43 (br, 7H), 1.97 (br, 2H), 1.53 (br,
4H), 1.39 (t, J=7.0 Hz, 3H).
Example 55
2-Ethyl-6,7-dimethoxy-4-(2-trifluoromethyl-pyrrolidine-1-carbonyl)-2H-isoq-
uinolin-1-one
[0833] LCMS: 1.89 min; M+H: 399
[0834] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.83 (s, 1H),
7.32 (s, 1H), 7.09 (s, 1H), 5.16 (s, 1H), 4.02-4.12 (m, 2H), 4.01
(s, 3H), 3.94 (s, 3H), 3.47 (t, J=5.6 Hz, 2H), 2.15-2.25 (m, 2H),
2.04-2.09 (m, 1H), 1.88-1.93 (m, 1H), 1.41 (t, J=5.8 Hz, 3H).
Example 56
4-(4-Cyclopropylmethyl-piperazine-1-carbonyl)-2-ethyl-6,7-dimethoxy-2H-iso-
quinolin-1-one
[0835] LCMS: 1.74 min; M+H: 400
[0836] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.84 (s, 1H),
7.16 (s, 1H), 6.93 (s, 1H), 4.02-4.08 (m, 2H), 4.01 (s, 3H), 3.97
(s, 3H), 3.63 (br, 4H), 2.55 (br, 4H), 2.31 (s, 2H), 1.40 (t, J=6.4
Hz, 3H), 0.87 (s, 1H), 0.54 (s, 2H), 0.12 (s, 2H).
Example 57
2-Ethyl-6,7-dimethoxy-4-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbony-
l)-2H-isoquinolin-1-one
[0837] LCMS: 1.65 min; M+H: 414
[0838] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.84 (s, 1H),
7.26 (s, 1H), 7.05 (s, 1H), 4.59 (br, 1H), 4.04-4.42 (m, 2H), 4.01
(s, 3H), 3.96 (s, 3H), 3.45 (br, 2H), 2.76 (br, 6H), 1.38-2.05 (m,
8H), 1.40 (t, J=5.8 Hz, 3H).
Example 58
2-Ethyl-6,7-dimethoxy-4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-2H-isoqu-
inolin-1-one
[0839] LCMS: 1.58 min; M+H: 414
[0840] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.84 (s, 1H),
7.13 (s, 1H), 6.92 (s, 1H), 4.66 (br, 1H), 4.05 (s, 2H), 4.01 (s,
3H), 3.97 (s, 3H), 3.02 (br, 4H), 2.64 (br, 4H), 2.36 (br, 2H),
2.00 (br, 2H), 1.85 (br, 4H), 1.38 (t, J=6.0 Hz, 3H).
Example 59
4-[4-(2-Dimethylamino-ethyl)-piperazine-1-carbonyl]-2-ethyl-6,7-dimethoxy--
2H-isoquinolin-1-one
[0841] LCMS: 1.46 min; M+H: 417
[0842] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.84 (s, 1H),
7.15 (s, 1H), 6.92 (s, 1H), 4.07 (s, 2H), 4.01 (s, 3H), 3.97 (s,
3H), 3.67 (br, 4H), 2.53-2.68 (m, 14H), 1.39 (t, J=5.6 Hz, 3H).
Example 60
4-([1,4']Bipiperidinyl-1'-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquinolin-1-
-one
[0843] LCMS: 1.66 min; M+H: 428
[0844] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.84 (s, 1H),
7.14 (br, 1H), 6.89 (br, 1H), 3.79-4.83 (b, 10H), 2.93 (br, 4H),
2.55 (br, 4H), 1.97 (br, 4H), 1.63 (br, 5H), 1.39 (t, J=5.6 Hz,
3H).
Example 61
4-[4-(3-Dimethylamino-propyl)-piperazine-1-carbonyl]-2-ethyl-6,7-dimethoxy-
-2H-isoquinolin-1-one
[0845] LCMS: 1.45 min; M+H: 431
[0846] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.84 (s, 1H),
7.14 (s, 1H), 6.92 (s, 1H), 4.06 (br, 2H), 4.01 (s, 3H), 3.97 (s,
3H), 3.63 (br, 4H), 2.80 (br, 2H), 2.59 (br, 6H), 2.46 (br, 6H),
1.92 (br, 2H), 1.39 (t, J=6.0 Hz, 3H).
Example 62
2-Ethyl-6,7-dimethoxy-4-[4-(2-pyrrolidin-1-yl-ethyl)-piperazine-1-carbonyl-
]-2H-isoquinolin-1-one
[0847] LCMS: 1.48 min; M+H: 443
[0848] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.77 (s, 1H),
7.08 (s, 1H), 6.85 (s, 1H), 3.99 (m, 2H), 3.94 (s, 3H), 3.90 (s,
3H), 3.56 (br, 4H), 2.45-2.67 (br, 11H), 1.81 (br, 5H), 1.32 (t,
J=7.2 Hz, 3H).
Example 63
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid dimethylamide
[0849] LCMS: 1.55 min; M+H: 305
[0850] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.85 (s, 1H),
7.15 (s, 1H), 6.90 (s, 1H), 4.07 (br, 2H), 4.01 (s, 3H), 3.96 (s,
3H), 3.10 (br, 6H), 1.39 (t, J=4.8 Hz, 3H).
Example 64
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid ethyl-methyl-amide
[0851] LCMS: 1.63 min; M+H: 319
[0852] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.85 (s, 1H),
7.12 (s, 1H), 6.87 (s, 1H), 4.04-4.09 (m, 2H), 4.01 (s, 3H), 3.95
(s, 3H), 3.50 (br, 2H), 3.04 (br, 3H), 1.39 (t, J=7.2 Hz, 3H), 1.21
(br, 3H).
Example 65
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid isopropyl-methyl-amide
[0853] LCMS: 1.73 min; M+H: 333
[0854] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.78 (s, 1H),
7.02 (s, 1H), 6.76 (s, 1H), 3.99 (m, 3H), 3.94 (s, 3H), 3.87 (s,
3H), 2.85 (br, 3H), 1.32 (t, J=7.2 Hz, 3H), 1.14 (s, 6H).
Example 66
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid diethylamide
[0855] LCMS: 1.72 min; M+H: 333
[0856] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.85 (s, 1H),
7.10 (s, 1H), 6.85 (s, 1H), 4.08 (br, 2H), 4.01 (s, 3H), 3.94 (s,
3H), 3.56 (br, 4H), 3.04 (br, 3H), 1.40 (br, 3H), 1.21 (br,
6H).
Example 67
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid methyl-propyl-amide
[0857] LCMS: 1.73 min; M+H: 333
[0858] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.85 (s, 1H),
7.11 (s, 1H), 6.88 (s, 1H), 4.07 (br, 2H), 4.02 (s, 3H), 3.95 (s,
3H), 3.42 (br, 2H), 3.02 (br, 3H), 1.63 (br, 2H), 1.39 (br, 3H),
0.89 (br, 3H).
Example 68
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid ethyl-isopropyl-amide
[0859] LCMS: 1.81 min; M+H: 347
[0860] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.85 (s, 1H),
7.06 (s, 1H), 6.85 (s, 1H), 4.07 (br, 3H), 4.01 (s, 3H), 3.93 (s,
3H), 3.34-3.60 (br, 2H), 1.39 (t, J=5.6 Hz, 3H), 1.19 (br, 9H).
Example 69
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid tert-butyl-methyl-amide
[0861] LCMS: 1.87 min; M+H: 347
[0862] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.77 (s, 1H),
7.13 (s, 1H), 6.98 (s, 1H), 4.00 (m, 2H), 3.94 (s, 3H), 3.89 (s,
3H), 2.80 (s, 3H), 1.51 (s, 9H), 1.33 (t, J=6.8 Hz, 3H).
Example 70
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid isobutyl-methyl-amide
[0863] LCMS: 1.83 min; M+H: 347
[0864] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.78 (s, 1H),
7.03 (s, 1H), 6.82 (s, 1H), 4.00 (m, 2H), 3.94 (s, 3H), 3.87 (s,
3H), 3.36 (br, 2H), 2.95 (br, 3H), 1.95 (br, 1H), 1.32 (t, J=6.8
Hz, 3H), 0.78-0.91 (br, 6H).
Example 71
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid butyl-methyl-amide
[0865] LCMS: 1.84 min; M+H: 347
[0866] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.85 (s, 1H),
7.11 (s, 1H), 6.87 (s, 1H), 4.04-4.09 (m, 2H), 4.01 (s, 3H), 3.95
(s, 3H), 3.44 (br, 2H), 3.03 (br, 3H), 1.65 (br, 2H), 1.39 (t,
J=5.8 Hz, 3H), 1.19 (br, 2H), 0.82 (br, 3H).
Example 72
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid ethyl-propyl-amide
[0867] LCMS: 1.82 min; M+H: 347
[0868] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.77 (s, 1H),
7.01 (s, 1H), 6.78 (s, 1H), 4.01 (m, 2H), 3.94 (s, 3H), 3.86 (s,
3H), 3.26-3.43 (br, 4H), 1.61 (br, 2H), 1.32 (t, J=7.2 Hz, 3H),
1.10 (br, 3H), 0.81 (br, 3H).
Example 73
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (2-dimethylamino-ethyl)-methyl-amide
[0869] LCMS: 1.56 min; M+H: 362
[0870] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.84 (s, 1H),
7.20 (s, 1H), 7.00 (s, 1H), 4.04-4.10 (m, 2H), 4.01 (s, 3H), 3.96
(s, 3H), 3.47-3.71 (br, 2H), 3.01 (s, 3H), 2.58 (br, 2H), 2.28 (br,
6H), 1.40 (t, J=7.2 Hz, 3H).
Example 74
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid ethyl-(2-methoxy-ethyl)-amide
[0871] LCMS: 1.70 min; M+H: 363
[0872] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.77 (s, 1H),
7.10 (s, 1H), 6.87 (s, 1H), 3.96-4.02 (m, 2H), 3.94 (s, 3H), 3.88
(s, 3H), 3.29-3.52 (br, 9H), 1.32 (t, J=7.2 Hz, 3H), 1.07 (br,
3H).
Example 75
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid cyclopentyl-methyl-amide
[0873] LCMS: 1.86 min; M+H: 359
[0874] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.85 (s, 1H),
7.11 (s, 1H), 6.84 (s, 1H), 4.07 (br, 3H), 4.02 (s, 3H), 3.94 (s,
3H), 2.95 (br, 3H), 1.59-1.72 (m, 6H), 1.56 (br, 2H), 1.40 (br,
3H).
Example 76
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid ethyl-butyl-amide
[0875] LCMS: 1.93 min; M+H: 361
[0876] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.78 (s, 1H),
7.01 (s, 1H), 6.78 (s, 1H), 3.97-4.02 (m, 2H), 3.94 (s, 3H), 3.87
(s, 3H), 3.20-3.48 (br, 4H), 1.44 (br, 4H), 1.32 (t, J=5.4 Hz, 3H),
0.78-1.11 (br, 6H).
Example 77
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid methyl-pentyl-amide
[0877] LCMS: 1.94 min; M+H: 361
[0878] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.85 (s, 1H),
7.12 (s, 1H), 6.87 (s, 1H), 4.07 (br, 2H), 4.01 (s, 3H), 3.95 (s,
3H), 2.97-3.59 (br, 5H), 1.60 (br, 4H), 1.39 (br, 3H), 1.23 (br,
2H), 0.87 (br, 3H).
Example 78
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid diisopropylamide
[0879] LCMS: 1.92 min; M+H: 361
[0880] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.84 (s, 1H),
6.99 (s, 1H), 6.86 (s, 1H), 4.02-4.08 (m, 2H), 4.01 (s, 3H), 3.94
(s, 3H), 3.74 (br, 2H), 1.38 (t, J=7.2 Hz, 3H), 1.36 (br, 12H).
Example 79
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid isopropyl-propyl-amide
[0881] LCMS: 1.91 min; M+H: 361
[0882] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.85 (s, 1H),
7.05 (s, 1H), 6.85 (s, 1H), 4.06 (br, 3H), 4.01 (s, 3H), 3.93 (s,
3H), 3.18-3.44 (br, 2H), 1.69 (br, 2H), 1.38 (t, J=5.8 Hz, 3H),
0.98-1.17 (br, 9H).
Example 80
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid dipropylamide
[0883] LCMS: 1.92 min; M+H: 361
[0884] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.65 (s, 1H),
7.51 (s, 1H), 6.75 (s, 1H), 3.97-4.03 (m, 2H), 3.88 (s, 3H), 3.81
(s, 3H), 3.42 (s, 2H), 3.13 (s, 2H), 1.47-1.67 (br, 4H), 1.23 (t,
J=7.0 Hz, 3H), 0.66-0.95 (br, 6H).
Example 81
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (3-dimethylamino-propyl)-methyl-amide
[0885] LCMS: 1.48 min; M+H: 376
[0886] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.77 (s, 1H),
7.09 (s, 1H), 6.81 (s, 1H), 3.97-4.03 (m, 2H), 3.94 (s, 3H), 3.88
(s, 3H), 3.44 (br, 3H), 3.00 (s, 3H), 1.84-2.17 (br, 9H), 1.32 (t,
J=7.2 Hz, 3H).
Example 82
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid cyclohexyl-methyl-amide
[0887] LCMS: 1.93 min; M+H: 373
[0888] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.78 (s, 1H),
7.02 (s, 1H), 6.78 (s, 1H), 3.97-4.03 (m, 3H), 3.94 (s, 3H), 3.87
(s, 3H), 2.73-2.95 (br, 3H), 1.51-1.74 (br, 8H), 1.32 (t, J=5.8 Hz,
3H), 1.01 (br, 2H).
Example 83
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid cyclopropylmethyl-propyl-amide
[0889] LCMS: 1.94 min; M+H: 373
[0890] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.77 (s, 1H),
7.03 (s, 1H), 6.83 (s, 1H), 3.97-4.03 (m, 2H), 3.94 (s, 3H), 3.87
(s, 3H), 3.28 (br, 4H), 1.52 (br, 1H), 1.32 (t, J=7.2 Hz, 3H), 0.81
(br, 4H), 0.48 (s, 2H).
Example 84
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid diisobutylamide
[0891] LCMS: 2.08 min; M+H: 389
[0892] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.85 (s, 1H),
7.06 (s, 1H), 6.93 (s, 1H), 4.04-4.09 (m, 2H), 4.02 (s, 3H), 3.93
(s, 3H), 3.07-3.42 (br, 4H), 1.88-2.15 (br, 2H), 1.39 (t, J=5.6 Hz,
3H), 1.05 (br, 6H), 0.77 (br, 6H).
Example 85
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid benzyl-methyl-amide
[0893] LCMS: 1.88 min; M+H: 381
[0894] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.75 (s, 1H),
7.24-7.32 (m, 4H), 7.08 (s, 2H), 6.70 (br, 1H), 4.65 (br, 2H),
3.65-3.93 (br, 8H), 2.86 (br, 3H), 1.26 (s, 3H).
Example 86
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (2-fluoro-benzyl)-methyl-amide
[0895] LCMS: 1.89 min; M+H: 399
[0896] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.82 (s, 1H),
7.40 (br, 1H), 7.29-7.34 (m, 1H), 7.15-7.18 (m, 2H), 7.06-7.10 (m,
1H), 6.79 (br, 1H), 4.79 (br, 2H), 4.02-4.06 (m, 2H), 4.00 (s, 3H),
3.79 (br, 3H), 2.97 (br, 3H), 1.36 (br, 3H).
Example 87
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (4-fluoro-benzyl)-methyl-amide
[0897] LCMS: 1.90 min; M+H: 399
[0898] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.83 (s, 1H),
7.40 (br, 1H), 7.15 (br, 2H), 7.06 (m, 2H), 6.73 (br, 1H), 4.70
(br, 2H), 4.04 (br, 2H), 4.00 (s, 3H), 3.79 (br, 3H), 2.93 (br,
3H), 1.35 (br, 3H).
Example 88
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (3-fluoro-benzyl)-methyl-amide
[0899] LCMS: 1.90 min; M+H: 399
[0900] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.83 (s, 1H),
7.32-7.36 (m, 1H), 6.82-7.16 (m, 5H), 4.74 (br, 2H), 4.04 (br, 2H),
4.00 (s, 3H), 3.80 (br, 3H), 2.93 (br, 3H), 1.36 (br, 3H).
Example 89
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid methyl-phenethyl-amide
[0901] LCMS: 1.89 min; M+H: 395
[0902] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.75 (s, 1H),
7.19 (br, 5H), 7.02 (br, 1H), 6.72 (br, 1H), 3.93 (s, 3H), 3.87
(br, 2H), 3.82 (s, 3H), 3.44 (br, 2H), 2.86-3.08 (br, 5H), 1.26 (t,
J=7.0 Hz, 3H).
Example 90
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (2-methoxy-benzyl)-methyl-amide
[0903] LCMS: 1.89 min; M+H: 411
[0904] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.75 (s, 1H),
7.24 (s, 1H), 6.80-7.06 (m, 5H), 4.45-4.75 (br, 2H), 3.65-3.93 (m,
11H), 2.83-3.06 (m, 3H), 1.18 (br, 3H).
Example 91
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (4-methoxy-benzyl)-methyl-amide
[0905] LCMS: 1.86 min; M+H: 411
[0906] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.83 (s, 1H),
7.38 (br, 1H), 6.72-7.15 (m, 5H), 3.72-4.69 (m, 13H), 2.88 (br,
3H), 1.35 (br, 3H).
Example 92
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (3-methoxy-benzyl)-methyl-amide
[0907] LCMS: 1.88 min; M+H: 411
[0908] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.76 (s, 1H),
7.22 (m, 2H), 6.76-7.09 (m, 4H), 4.60 (br, 2H), 3.73-3.93 (m, 11H),
2.85 (br, 3H), 1.27 (br, 3H).
Example 93
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid methyl-(3-trifluoromethyl-benzyl)-amide
[0909] LCMS: 202 min; M+H: 449
[0910] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.76 (s, 1H),
7.52 (m, 3H), 7.45 (m, 1H), 7.09 (s, 1H), 6.75 (s, 1H), 4.71 (s,
2H), 3.96 (s, 2H), 3.93 (s, 3H), 3.74 (s, 3H), 2.91 (s, 3H), 1.27
(s, 3H).
Example 94
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid benzyl-(2-dimethylamino-ethyl)-amide
[0911] LCMS: 1.88 min; M+H: 438
[0912] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.75 (s, 1H),
7.23-7.27 (m, 4H), 7.08 (br, 3H), 4.47 (br, 2H), 3.17-3.93 (m,
10H), 1.98-2.53 (m, 8H), 1.22 (s, 3H).
Example 95
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (1-benzyl-piperidin-4-yl)-methyl-amide
[0913] LCMS: 1.94 min; M+H: 464
[0914] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.84 (s, 1H),
7.29 (br, 4H), 7.25 (br, 1H), 7.10 (s, 1H), 6.81 (s, 1H), 4.02-4.08
(m, 3H), 4.01 (s, 3H), 3.91 (s, 3H), 3.50 (br, 2H), 2.96 (br, 5H),
1.72-2.17 (m, 6H), 1.38 (t, J=5.8 Hz, 3H).
[0915] The compounds of the following examples 96 to 118 were
prepared in analogy to example 1, where however, in step 1.6,
ethylamine was replaced by the respective amine and in step 1.8
butylamine was used instead of methylamine.
Example 96
6,7-Dimethoxy-1-oxo-2-(2,2,2-trifluoro-ethyl)-1,2-dihydro-isoquinoline-4-c-
arboxylic acid butylamide
[0916] LCMS: 1.94 min; M+H: 387
[0917] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.82 (s, 1H),
7.58 (s, 1H), 7.31 (s, 1H), 5.85 (s, 1H), 4.68 (q, J=7.6 Hz, 2H),
4.01 (s, 3H), 4.00 (s, 3H), 3.48 (q, J=5.6 Hz, 2H), 1.64 (m, 2H),
1.45 (m, 2H), 0.99 (t, J=7.2 Hz, 3H).
Example 97
2-(2-Fluoro-ethyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxyl-
ic acid butylamide
[0918] LCMS: 1.77 min; M+H: 351
[0919] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.80 (s, 1H),
7.66 (s, 1H), 7.39 (s, 1H), 5.84 (s, 1H), 4.84 (s, 1H), 4.71 (s,
1H), 4.37 (s, 1H), 4.28 (s, 1H), 4.01 (s, 6H), 3.46 (d, J=5.2 Hz,
2H), 1.61-1.65 (m, 2H), 1.41-1.48 (m, 2H), 0.99 (t, J=7.6 Hz,
3H).
Example 98
2-Cyclopropyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid butylamide
[0920] LCMS: 1.81 min; M+H: 345
[0921] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.79 (s, 1H),
7.53 (s, 1H), 7.38 (s, 1H), 6.10 (br, 1H), 4.01 (s, 3H), 4.00 (s,
3H), 3.47-3.53 (m, 2H), 3.32-3.36 (m, 1H), 1.64-1.71 (m, 2H),
1.45-1.53 (m, 2H), 1.14-1.20 (m, 2H), 0.99 (t, J=7.2 Hz, 3H),
0.89-0.94 (m, 2H).
Example 99
2-Isopropyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid butylamide
[0922] LCMS: 1.85 min; M+H: 347
[0923] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.84 (s, 1H),
7.56 (s, 1H), 7.40 (s, 1H), 5.83 (br, 1H), 5.31-5.40 (m, 1H), 4.01
(s, 3H), 3.99 (s, 3H), 3.46-3.53 (m, 2H), 1.60-1.69 (m, 2H),
1.41-1.49 (m, 2H), 1.41 (d, J=6.8 Hz, 6H), 0.99 (t, J=7.2 Hz,
3H).
Example 100
6,7-Dimethoxy-1-oxo-2-propyl-1,2-dihydro-isoquinoline-4-carboxylic
acid butylamide
[0924] LCMS: 1.86 min; M+H: 347
[0925] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.83 (s, 1H),
7.61 (s, 1H), 7.36 (s, 1H), 5.83 (br, 1H), 3.98-4.03 (m, 8H),
3.45-3.52 (m, 2H), 1.82 (br, 2H), 1.60-1.68 (m, 2H), 1.41-1.50 (m,
2H), 0.99 (t, J=7.2 Hz, 3H).
Example 101
6,7-Dimethoxy-1-oxo-2-(3,3,3-trifluoro-propyl)-1,2-dihydro-isoquinoline-4--
carboxylic acid butylamide
[0926] LCMS: 1.94 min; M+H: 401
[0927] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.79 (s, 1H),
7.61 (s, 1H), 7.32 (s, 1H), 5.81 (br, 1H), 4.22 (t, J=6.6 Hz, 2H),
4.01 (s, 6H), 3.45-3.51 (m, 2H), 2.60-73 (m, 2H), 1.60-1.68 (m,
2H), 1.41-1.49 (m, 2H), 0.99 (t, J=7.4 Hz, 3H).
Example 102
6,7-Dimethoxy-2-(2-methoxy-ethyl)-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid butylamide
[0928] LCMS: 1.76 min; M+H: 363
[0929] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.81 (s, 1H),
7.69 (s, 1H), 7.45 (s, 1H), 5.88 (br, 1H), 4.20 (t, J=4.8 Hz, 2H),
4.00 (s, 6H), 3.72 (t, J=4.8 Hz, 2H), 3.43-3.51 (m, 2H), 3.33 (s,
3H), 1.58-1.67 (m, 2H), 1.41-1.49 (m, 2H), 0.99 (t, J=7.4 Hz,
3H).
Example 103
2-Cyclobutyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid butylamide
[0930] LCMS: 1.90 min; M+H: 359
[0931] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.81 (s, 1H),
7.56 (s, 1H), 7.50 (s, 1H), 5.85 (br, 1H), 5.16-5.23 (m, 1H), 4.00
(s, 6H), 3.46-3.53 (m, 2H), 2.53 (br, 2H), 2.25-2.29 (m, 2H),
1.88-1.92 (m, 2H), 1.60-1.69 (m, 2H), 1.43-1.51 (m, 2H), 1.00 (t,
J=7.2 Hz, 3H).
Example 104
2-tert-Butyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid butylamide
[0932] LCMS: 1.97 min; M+H: 361
[0933] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.76 (s, 1H),
7.60 (s, 1H), 7.43 (s, 1H), 5.75 (br, 1H), 3.93 (s, 3H), 3.92 (s,
3H), 3.38-3.42 (m, 2H), 1.53-1.59 (m, 2H), 1.35-1.41 (m, 2H), 1.18
(s, 9H), 0.92 (t, J=7.4 Hz, 3H).
Example 105
2-sec-Butyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid butylamide
[0934] LCMS: 1.93 min; M+H: 361
[0935] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.84 (s, 1H),
7.57 (s, 1H), 7.33 (s, 1H), 5.85 (br, 1H), 5.14-5.20 (m, 1H), 4.01
(s, 3H), 3.99 (s, 3H), 3.46-3.51 (m, 2H), 1.73-1.78 (m, 2H),
1.61-1.67 (m, 2H), 1.43-1.49 (m, 2H), 1.39 (d, J=7.2, 3H), 0.99 (t,
J=7.4 Hz, 3H), 0.89 (t, J=7.4 Hz, 3H).
Example 106
2-Isobutyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid butylamide
[0936] LCMS: 1.94 min; M+H: 361
[0937] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.82 (s, 1H),
7.61 (s, 1H), 7.30 (s, 1H), 5.85 (br, 1H), 4.01 (s, 3H), 4.00 (s,
3H), 3.82 (d, J=7.6 Hz, 2H), 3.45-3.50 (m, 2H), 2.17-2.23 (m, 1H),
1.61-1.67 (m, 2H), 1.42-1.49 (m, 2H), 0.96-1.01 (m, 9H).
Example 107
2-Butyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid butylamide
[0938] LCMS: 1.98 min; M+H: 361
[0939] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.82 (s, 1H),
7.60 (s, 1H), 7.34 (s, 1H), 5.83 (br, 1H), 3.99-4.03 (m, 8H),
3.45-3.50 (m, 2H), 1.73-1.78 (m, 2H), 1.61-1.67 (m, 2H), 1.39-1.49
(m, 4H), 0.95-1.01 (m, 6H).
Example 108
2-Cyclopropylmethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid butylamide
[0940] LCMS: 1.88 min; M+H: 359
[0941] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.83 (s, 1H),
7.61 (s, 1H), 7.46 (s, 1H), 5.83 (br, 1H), 4.01 (s, 3H), 4.00 (s,
3H), 3.90 (d, J=6.8 Hz, 2H), 3.45-3.51 (m, 2H), 1.60-1.66 (m, 2H),
1.42-1.50 (m, 2H), 1.23-1.29 (m, 1H), 0.99 (t, J=7.4 Hz, 3H),
0.60-0.64 (m, 2H), 0.41-0.46 (m, 2H).
Example 109
2-Cyclopentyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid butylamide
[0942] LCMS: 1.97 min; M+H: 373
[0943] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.83 (s, 1H),
7.55 (s, 1H), 7.40 (s, 1H), 5.79 (br, 1H), 5.34-5.38 (m, 1H), 4.01
(s, 3H), 3.99 (s, 3H), 3.46-3.52 (m, 2H), 2.18-2.22 (m, 2H), 1.89
(br, 2H), 1.73-1.78 (m, 4H), 1.61-1.67 (m, 2H), 1.42-1.50 (m, 2H),
0.99 (t, J=7.4 Hz, 3H).
Example 110
2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxyl-
ic acid butylamide
[0944] LCMS: 1.99 min; M+H: 375
[0945] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.86 (s, 1H),
7.59 (s, 1H), 7.26 (s, 1H), 5.78 (br, 1H), 5.03 (br, 1H), 4.01 (s,
3H), 3.99 (s, 3H), 3.45-3.51 (m, 2H), 1.81-1.87 (m, 2H), 1.61-1.67
(m, 4H), 1.43-1.49 (m, 2H), 0.99 (t, J=7.2 Hz, 3H), 0.86 (t, J=7.2
Hz, 6H).
Example 111
6,7-Dimethoxy-2-(2-methoxy-benzyl)-1-oxo-1,2-dihydro-isoquinoline-4-carbox-
ylic acid butylamide
[0946] LCMS: 2.00 min; M+H: 425
[0947] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.84 (s, 1H),
7.64 (s, 1H), 7.57 (s, 1H), 7.33-7.36 (m, 1H), 7.25 (br, 1H),
6.89-6.95 (m, 2H), 5.77 (br, 1H), 5.22 (s, 2H), 3.99 (s, 6H), 3.88
(s, 3H), 3.43-3.47 (m, 2H), 1.58-1.62 (m, 2H), 1.41-1.47 (m, 2H),
0.98 (t, J=7.4 Hz, 3H).
Example 112
2-Indan-1-yl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid butylamide
[0948] LCMS: 2.05 min; M+H: 421
[0949] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.89 (s, 1H),
7.61 (s, 1H), 7.30-7.38 (m, 2H), 7.11 (s, 1H), 7.00 (s, 1H), 6.68
(br, 1H), 5.53 (br, 1H), 4.03 (s, 4H), 3.99 (s, 3H), 3.36 (br, 2H),
3.05-3.14 (m, 2H), 2.82 (br, 1H), 2.05 (br, 1H), 1.41-1.51 (m, 2H),
1.25-1.33 (m, 2H), 0.91 (t, J=6.8 Hz, 3H).
Example 113
[0950]
2-(2-Dimethylamino-ethyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquin-
oline-4-carboxylic acid butylamide
Example 114
[0950] [0951]
6,7-Dimethoxy-1-oxo-2-(2-pyrrolidin-1-yl-ethyl)-1,2-dihydro-isoquinoline--
4-carboxylic acid butylamide
Example 115
[0951] [0952]
2-Benzyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid butylamide
Example 116
[0952] [0953]
2-(2,4-Difluoro-benzyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-ca-
rboxylic acid butylamide
Example 117
[0953] [0954]
6,7-Dimethoxy-1-oxo-2-(2-piperidin-1-yl-ethyl)-1,2-dihydro-isoquinoline-4-
-carboxylic acid butylamide
Example 118
[0954] [0955]
6,7-Dimethoxy-1-oxo-2-phenethyl-1,2-dihydro-isoquinoline-4-carboxylic
acid butylamide
Example 119
[0955] [0956]
3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid butylamide
119.1 1-(4,5-Dimethoxy-2-methyl-phenyl)-ethanone
[0957] A solution of 1,2-dimethoxy-4-methylbenzene in CS.sub.2 (20
mL) was added dropwise to a mixture of acetyl chloride (2.063 g,
26.3 mmol) and aluminium trichloride (3.50 g, 26.3 mmol) in
CS.sub.2 (80 mL). The reaction mixture was stirred for 12 h at
25.degree. C., then poured into ice-water and extracted with DCM.
The organic layer was separated and concentrated. The obtained
residue was purified by column chromatography on silica gel (PE:
EtOAc=20:1) to give the title compound (3.2 g, 62%) as a yellow
oil.
[0958] LCMS (ESI+): m/z 195 (M+H).sup.+, RT: 0.776 min.
119.2 4,5-Dimethoxy-2-oxalyl-benzoic acid
[0959] A solution of potassium permanganate (11.39 g, 72.1 mmol) in
water (45 mL) was added dropwise to a mixture of
1-(4,5-dimethoxy-2-methyl-phenyl)-ethanone obtained in step 119.1
(2 g, 10.30 mmol) and potassium carbonate (2.135 g, 15.45 mmol) in
H.sub.2O (5 mL), and the reaction mixture was stirred for 3 hat
50.degree. C. Then ethanol was added and the resulting mixture was
stirred for 30 min The solid was filtered off, the filtrate was
adjusted to pH=2 with conc. HCl, EtOAc was added, and the organic
layer was separated and concentrated to give the title compound
(1.7 g, 64.9%) as a white solid.
[0960] LCMS (ESI+): m/z 255 (M+H).sup.+, RT: 0.524 min
119.3 6,7-Dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid
[0961] A solution of 4,5-dimethoxy-2-oxalyl-benzoic acid obtained
in step 119.2 (1.15 g, 4.52 mmol) and hydrazine hydrate (254 mg,
4.98 mmol) in ethanol (20 mL) was stirred for 2 h at 75.degree. C.
The solid was filtered to give the title compound (910 mg, 80%) as
a white solid.
[0962] LCMS (ESI+): m/z 251 (M+H).sup.+, RT: 0.587 min
119.4
3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid ethyl ester
[0963] A mixture of
6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid
obtained in step 119.3 (500 mg, 1.998 mmol), cesium carbonate (1954
mg, 6.00 mmol) and iodoethane (768 mg, 4.92 mmol) in DMF (8 mL) was
stirred at 65.degree. C. for 12 h. Water was added, and the solid
was filtered to give the title compound (300 mg, 49.0%) as a white
solid.
[0964] LCMS (ESI+): m/z 307 (M+H).sup.+, RT: 0.839 min
119.5
3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid
[0965] A solution of
3-ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid ethyl ester obtained in step 119.4 (400 mg, 1.306 mmol) and
lithium hydroxide (46.9 mg, 1.959 mmol) in ethanol and water (2 mL)
was stirred at 35.degree. C. for 3 h. The reaction solution was
adjusted to pH=4 with dilute HCl, and the solid was filtered and
washed with water to give the title compound (280 mg, 77%) as a
white solid.
[0966] LCMS (ESI+): m/z 279 (M+H).sup.+, RT: 0.862 min
119.6
3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid butylamide
[0967] A solution of
3-ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid obtained in step 119.5 (200 mg, 0.719 mmol) in SOCl.sub.2 (2
mL) was stirred at 76.degree. C. for 2 h. Then SOCl.sub.2 was
removed and the residue was dissolved in DCM (5 mL).
[0968] Butan-1-amine (79 mg, 1.078 mmol) and triethylamine (109 mg,
1.078 mmol) were added dropwise and the resulting reaction was
stirred at r.t. for 3 h. The solvent was removed and the obtained
residue was washed with EtOAc to give the title compound (140 mg,
58.4%) as a white solid.
[0969] LCMS (ESI+): m/z 334 (M+H).sup.+, RT: 1.910 min
[0970] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. 8.75 (s, 1H),
7.78 (s, 1H), 7.37 (br, 1H), 4.33 (t, J=7.2 Hz, 2H), 4.06 (s, 6H),
3.47 (t, J=7.2 Hz, 2H), 1.65 (t, J=7.2 Hz, 2H), 1.47-1.42 (m, 5H),
0.98 (t, J=7.2 Hz, 3H).
[0971] The compounds of the following examples 120 to 132 were
prepared in analogy to example 119.
Example 120
3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid (6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-amide
[0972] ESI-MS: [M+Na.sup.+]=444.20, [M+H.sup.+]=422.20;
Example 121
3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid (R)-indan-1-ylamide
[0973] ESI-MS: [M+Na.sup.+]=416.10, [M+H.sup.+]=394.10;
Example 122
3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid (1,2,3,4-tetrahydro-naphthalen-1-yl)-amide
[0974] ESI-MS: [M+Na.sup.+]=430.10, [M+H.sup.+]=408.10;
Example 123
3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid (R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amide
[0975] ESI-MS: [M+Na.sup.+]=430.10, [M+H.sup.+]=408.10;
Example 124
3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid (6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl)-amide
[0976] ESI-MS: [M+Na.sup.+]=444.10, [M+H.sup.+]=422.10;
Example 125
3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid (1,2,3,4-tetrahydro-naphthalen-2-yl)-amide
[0977] ESI-MS: [M+Na.sup.+]=430.10, [M+H.sup.+]=408.10;
Example 126
3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid (4-bromo-indan-1-yl)-amide
[0978] ESI-MS: 495.10, [M+Na.sup.+]=494.10, 474.10,
[M.sup.+]=472.10;
Example 127
3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid (5-bromo-indan-1-yl)-amide
[0979] ESI-MS: 496.00, [M+Na.sup.+]=494.00, 474.00,
[M.sup.+]=472.00;
Example 128
3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid 2-dimethylaminomethyl-benzylamide
[0980] ESI-MS: [M+H.sup.+]=425.20;
Example 129
3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid (6,7-dihydro-5H-[1]pyrindin-5-yl)-amide
[0981] ESI-MS: [M+Na.sup.+]=417.10, [M+H.sup.+]=395.10;
Example 130
3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid (6,7-dihydro-5H-[1]pyrindin-7-yl)-amide
[0982] ESI-MS: [M+H.sup.+]=395.10;
Example 131
3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid 3-dimethylaminomethyl-benzylamide
[0983] ESI-MS: [M+Na.sup.+]=447.20, [M+H.sup.+]=425.20;
Example 132
3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid 4-dimethylaminomethyl-benzylamide
[0984] ESI-MS: [M+Na.sup.+]=447.20, [M+H.sup.+]=425.20;
Example 133
2-Ethyl-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid
butylamide
133.1 2-(2-Carboxy-4-methoxy-phenyl)-malonic acid dimethyl
ester
[0985] To a solution of dimethyl malonate (45 mL) was added sodium
(0.915 g, 39.8 mmol), and the resulting mixture was stirred until
sodium had disappeared. Then copper(I) bromide (0.248 g, 1.731
mmol) and 2-bromo-5-methoxy-benzoic acid (4 g, 17.31 mmol) were
added and the resulting reaction was stirred at 70.degree. C. for
12 h. Water and EtOAc were added and the organic layer was
separated off. The aqueous layer was acidified with conc. HCl, then
EtOAc was added and the organic layer was separated and
concentrated to give the title compound (3.2 g, 65.5%) as a yellow
solid.
[0986] LCMS (ESI+): m/z 283 (M+H).sup.+, RT: 0.724 min
133.2 2-(2-Carboxy-4-methoxy-phenyl)-malonic acid
[0987] A solution of 2-(2-carboxy-4-methoxy-phenyl)-malonic acid
dimethyl ester obtained in step 133.1 (2.5 g, 8.86 mmol) and
lithium hydroxide (1.061 g, 44.3 mmol) in CH.sub.3OH (30 mL) and
water (8 mL) was stirred for 12 h at 40.degree. C. The solvent was
removed, the residue was adjusted pH=4 with dilute HCl, EtOAc was
added, and the organic layer was separated and concentrated to give
the title compound (1.67 g, 74.2%) as a white solid.
[0988] LCMS (ESI+): m/z 255 (M+H).sup.+, RT: 0.453 min
133.3 2-Carboxymethyl-5-methoxy-benzoic acid
[0989] A suspension of 2-(2-carboxy-4-methoxy-phenyl)-malonic acid
obtained in step 133.2 (200 mg, 0.787 mmol) in toluene (8 mL) was
stirred for 12 h at 105.degree. C. The solid was filtered to give
the title compound (100 mg, 60.5%) as a white solid.
[0990] LCMS (ESI+): m/z 211 (M+H).sup.+, RT: 0.630 min
133.4 5-Methoxy-2-methoxycarbonylmethyl-benzoic acid methyl
ester
[0991] A mixture of 2-carboxymethyl-5-methoxy-benzoic acid obtained
in step 133.3 (100 mg, 0.476 mmol) and sulfurous dichloride (170
mg, 1.427 mmol) in CH.sub.3OH (10 mL) was stirred at 65.degree. C.
for 12 h. The solvent was removed to give the crude title compound
(100 mg, 88%) as a yellow oil.
[0992] LCMS (ESI+): m/z 239 (M+H).sup.+, RT: 0.820 min
133.5 2-(2-Dimethylamino-1-methoxycarbonyl-vinyl)-5-methoxy-benzoic
acid methyl ester
[0993] A solution of 5-methoxy-2-methoxycarbonylmethyl-benzoic acid
methyl ester obtained in step 133.4 (700 mg, 2.94 mmol) and HOAc
(0.5 mL) in DMF-DMA (15 mL) was stirred 12 h at 90.degree. C., then
poured to water and extracted with EtOAc. The organic layer was
separated and concentrated to give a residue which was purified by
Prep-TLC (PE: EtOAc=1:1) to give the title compound (600 mg, 69.6%)
as a yellow oil.
[0994] LCMS (ESI+): m/z 267 (M-27).sup.+, RT: 0.735 min.
133.6 2-Ethyl-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid methyl ester
[0995] A solution of
2-(2-dimethylamino-1-methoxycarbonyl-vinyl)-5-methoxy-benzoic acid
methyl ester obtained in step 133.5 (500 mg, 1.705 mmol),
ethanamine (231 mg, 5.11 mmol) and DIPEA (1.5 ml) in MeOH (15 mL)
was stirred at 65.degree. C. for 12 h. The solvent was removed,
water and EtOAc were added to the residue, the organic layer was
separated and concentrated to give the crude title compound (420
mg, 94%) as a white solid.
[0996] LCMS (ESI+): m/z 262 (M+H).sup.+, RT: 0.867 min
133.7 2-Ethyl-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid
[0997]
2-Ethyl-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid
methyl ester obtained in step 133.6 and lithium hydroxide (77 mg,
3.22 mmol) in CH.sub.3OH (15 mL) and water (2 mL) were stirred at
35.degree. C. for 5 h. The reaction solution was concentrated and
the obtained residue was dissolved in water and adjusted pH=4 with
dilute HCl. The solid was filtered to give the title compound (362
mg, 91%) as white solid.
[0998] LCMS (ESI+): m/z 248 (M+H).sup.+, RT: 0.737 min
133.8 2-Ethyl-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid butylamide
[0999] A solution of
2-ethyl-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid
obtained in step 133.7 (300 mg, 1.209 mmol) in SOCl.sub.2 (4 mL)
was stirred at 76.degree. C. for 2 h; then SOCl.sub.2 was removed.
The obtained residue was dissolved in DCM (6 mL) and butan-1-amine
(133 mg, 1.813 mmol) and triethylamine (183 mg, 1.813 mmol) were
added dropwise. The resulting reaction was stirred at RT for 3 h.
The solvent was removed and the obtained residue was washed with
EtOAc to give the title compound (200 mg, 0.659 mmol, 54.6%
yield).
[1000] .sup.1H-NMR (400 MHz, MeOD): 7.93 (d, J=8.8 Hz, 1H), 7.68
(d, J=2.8 Hz, 1H), 7.44 (s, 1H), 7.25 (dd, 9.2 Hz, 2.8 Hz, 1H),
4.01 (t, J=7.2 Hz, 2H), 3.81 (s, 3H), 3.28 (t, J=7.6 Hz, 2H),
1.56-1.51 (m, 2H), 1.39-1.32 (m, 2H), 1.28 (t, J=7.6 Hz, 3H), 0.89
(t, J=7.6 Hz, 3H).
[1001] The compounds of the following examples 134 to 136 were
prepared in analogy to example 133.
Example 134
2-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid indan-1-ylamide
[1002] ESI-MS: [M+Na.sup.+]=427.10, [M.sup.+]=405.10;
Example 135
2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxyl-
ic acid indan-1-ylamide
135.1
2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-ca-
rboxylic acid methyl ester
[1003] A solution of
2-(2-dimethylamino-1-methoxycarbonylvinyl)-4,5-dimethoxy-benzoic
acid methyl ester obtained in step 1.5 (800 mg, 2.474 mmol),
pentan-3-amine (323 mg, 3.71 mmol) and HOAc (1.5 mL) in MeOH (15
mL) was stirred at 65.degree. C. for 12
h. The solvent was removed and water and EtOAc were added to the
obtained residue. The organic layer was separated and concentrated
to give the title compound (750 mg, 91%) as a white solid.
[1004] LCMS (ESI+): m/z 334 (M+H).sup.+, RT: 0.941 min
135.2
2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-ca-
rboxylic acid
[1005] A mixture of
2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid methyl ester obtained in step 135.1 (750 mg, 2.250 mmol)
and lithium hydroxide (108 mg, 4.50 mmol) in CH.sub.3OH (8 mL) and
water (2 mL) was stirred at 35.degree. C. for 5 h. The reaction
solution was concentrated and the obtained residue was dissolved in
water and adjusted pH=4 with dilute HCl. The solid was filtered to
give the title compound (700 mg, 97%) as a white solid.
[1006] LCMS (ESI+): m/z 320 (M+H).sup.+, RT: 0.804 min
135.3
2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-ca-
rboxylic acid indan-1-ylamide
[1007] A solution of
2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxy-
lic acid obtained in step 135.2 (300 mg, 0.939 mmol) in SOCl.sub.2
(5 mL) was stirred at 76.degree. C. for 2 h. SOCl.sub.2 was
removed. The obtained residue was dissolved in DCM (5 mL),
2,3-dihydro-1H-inden-1-amine (188 mg, 1.409 mmol) was added
dropwise and the resulting reaction was stirred at RT for 3 h. The
solvent was removed and the obtained residue was washed with EtOAc
to give the title compound (200 mg, 49%) as a yellow solid.
[1008] LCMS (ESI+): m/z 435 (M+H).sup.+, RT: 2.084 min
[1009] .sup.1H-NMR (400 MHz, MeOD): .delta. 7.61 (s, 1H), 7.49 (s,
1H), 7.43 (m, 1H), 7.28-7.22 (m, 3H), 5.67 (t, J=7.6 Hz, 1H), 3.95
(s, 3H), 3.94 (s, 3H), 3.09-3.05 (m, 1H), 2.97-2.91 (m, 1H),
2.65-2.60 (m, 1H), 2.08-2.01 (m, 1H), 1.88-1.77 (m, 4H), 1.29 (m,
1H), 0.84 (t, J=1.6 Hz, 6H).
Example 136
2-Ethyl-7-methoxy-1-oxo-6-(2-quinolin-2-yl-ethoxy)-1,2-dihydro-isoquinolin-
e-4-carboxylic acid butylamide
136.1 1-Bromo-4-methoxy-2-methyl-benzene
[1010] To a solution of 1-methoxy-3-methylbenzene (51.6 ml, 405
mmol) in DCM (300 mL), 1-bromopyrrolidine-2,5-dione (72.1 g, 405
mmol) was added. The resulting reaction was stirred at about
20.degree. C. overnight. The reaction mixture was diluted with
30-60.degree. C. petroleum ether (200 mL). The mixture was stirred
for 30 min. The reaction mixture was filtered. The filtrate was
concentrated under reduced pressure to provide the desired product
(80 g, 98%) as a yellow oil, which was used in next step without
further purification.
136.2 1-Bromo-4-methoxy-2-methyl-5-nitro-benzene
[1011] 1-Bromo-4-methoxy-2-methylbenzene obtained in step 136.1 (60
g, 298 mmol) was dissolved in acetic acid (150 ml) and TFA (150
ml). The mixture was cooled to -5.degree. C. in an ice bath. Fuming
nitric acid (14.56 ml, 328 mmol) was added slowly to the reaction.
The resulting mixture was stirred at -5.degree. C. for about 2 h.
The reaction mixture was diluted with water (100 ml). The aqueous
layer was extracted with ethyl acetate (3.times.100 mL) and washed
with sat. NaCl (100 mL), sat. NaHCO.sub.3 (100 mL) and sat. NaCl
(100 mL). The organic layer was dried with Na.sub.2SO.sub.4,
filtered and concentrated. The resulting solid was purified with
silica gel column chromatography (hexane/EtOAc=50:1). The proper
fractions were collected and concentrated to give the title
compound (20 g, 27%).
136.3 1-Bromo-4-methoxy-5-nitro-benzoic acid
[1012] In a 1 L round-bottomed flask,
1-bromo-4-methoxy-2-methyl-5-nitro-benzene obtained in step 136.2
(70 g, 0.28 mol) and KMnO.sub.4 (270 g, 1.707 mol) were dissolved
in water (500 ml) and pyridine (250 ml) and the mixture was stirred
and heated to about 110.degree. C. over night. The reaction was
cooled to ambient temperature and filtered through a sintered glass
funnel. The aqueous layer was adjusted to pH=2 and extracted with
ethyl acetate (2.times.750 mL). The organic layer was washed with
sat. NaCl (300 mL), dried with Na.sub.2SO.sub.4, filtered and
concentrated to afford the crude title compound (60 g). This was
recrystallized in ethanol to afford the pure title compound (38 g,
48.4%).
[1013] LCMS (ESI+): m/z 263 (M+Na).sup.+, RT: 1.32 min.
[1014] .sup.1H NMR (MeOD/TMS, 400 MHz) .delta.: 8.09 (s, 1H), 7.64
(s, 1H), 4.00 (s, 3H).
136.4 2-(2-Carboxy-4-methoxy-5-nitro-phenyl)-malonic acid diethyl
ester
[1015] To rapidly stirred diethyl malonate (58.0 g, 362 mmol) was
added sodium (0.999 g, 43.5 mmol) in portions at r.t. After the
addition was complete, the mixture was stirred at 50.degree. C.
until the sodium had disappeared. Copper(I) bromide (0.260 g, 1.811
mmol) and then 2-bromo-5-methoxy-4-nitro-benzoic acid obtained in
step 136.3 (5.0 g, 18.11 mmol) were added. The mixture was heated
at 70.degree. C. overnight. The reaction mixture was dissolved in
water and extracted with toluene and EtOAc. The aqueous layer was
acidified with HCl (2 N). The mixture was then extracted with EtOAc
and dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The residue was purified on a silica gel column
(DCM/MeOH=10:1, v/v) to afford the title compound as a yellow solid
(5.02 g, 78%).
[1016] LCMS (ESI+): m/z 356 (M+H).sup.+, RT: 1.56 min
[1017] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.95 (s, 1H),
7.80 (s, 1H), 5.62 (s, 1H), 4.25-4.28 (m, 4H), 4.03 (s, 3H),
1.27-1.33 (m, 6H).
136.5 2-Carboxymethyl-5-methoxy-4-nitro-benzoic acid
[1018] NaOH (3.05 g, 76 mmol) in water (15 mL) was added over 30
min to a solution of 2-(2-carboxy-4-methoxy-5-nitro-phenyl)-malonic
acid diethyl ester obtained in step 136.4 (5.42 g, 15.25 mmol) in
EtOH (40 mL) at room temperature. The mixture was then stirred at
50.degree. C. overnight, the solvent was removed under reduced
pressure, the contents were acidified with HCl (conc.) at r.t. to
pH=3 and the resulting white aqueous suspension was extracted twice
with EtOAc (100 mL). The organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue
was dissolved in toluene (50 mL), and the mixture was heated at
105.degree. C. The mixture was concentrated under reduced pressure
and the concentrate was used in the next step without further
purification.
136.6 5-Methoxy-2-methoxycarbonylmethyl-4-nitro-benzoic acid methyl
ester
[1019] SOCl.sub.2 (17.16 mL, 235 mmol) was added dropwise to a
solution of 2-carboxymethyl-5-methoxy-4-nitrobenzoic acid obtained
in step 136.5 (20.0 g, 78 mmol) in MeOH (150 mL) at ambient
temperature. After the addition was completed, the mixture was
heated at 65.degree. C. overnight. The mixture was concentrated in
vacuo. The residue was diluted with EtOAc (200 mL) and washed with
saturated aqueous NaHCO.sub.3 (60 mL), water (60 mL) and brine (60
mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered
and concentrated. The residue was purified on a silica gel column
(PE/EtOAc=5:1, v/v) to afford the title compound (20.7 g, 93%) as a
yellow solid.
[1020] LCMS (ESI+): m/z 284 (M+H).sup.+, RT: 1.95 min
[1021] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.72 (s, 2H),
4.01 (s, 3H), 3.97 (s, 2H), 3.92 (s, 3H), 3.71 (s, 3H).
136.7
2-((Z)-2-Dimethylamino-1-methoxycarbonyl-vinyl)-5-methoxy-4-nitro-be-
nzoic acid methyl ester
[1022] A mixture of methyl
5-methoxy-2-methoxycarbonylmethyl-4-nitro-benzoic acid methyl ester
obtained in step 136.6 (250 mg, 0.883 mmol) in DMF-DMA (5.909 ml,
44.1 mmol) was heated at 90.degree. C. overnight. The reaction
mixture was concentrated under reduced pressure. The residue was
diluted with EtOAc (20 mL) and washed with brine (6 mL*3). The
organic layer was dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. The crude oil was pure enough for next
step.
[1023] LCMS (ESI+): m/z 339 (M+H).sup.+, RT: 1.93 min
136.8
2-Ethyl-7-methoxy-6-nitro-1-oxo-1,2-dihydro-isoquinoline-4-carboxyli-
c acid methyl ester
[1024] A mixture of
2-((Z)-2-dimethylamino-1-methoxycarbonyl-vinyl)-5-methoxy-4-nitro-benzoic
acid methyl ester obtained in step 136.7 (237 mg, 0.701 mmol),
ethanamine (95 mg, 2.102 mmol) and DIPEA (0.734 mL, 4.20 mmol) in
MeOH (5 mL) was heated at reflux overnight. The solvent was removed
under reduced pressure. The residue was diluted with EtOAc (50 mL)
and washed with HCl (2 N, 10 mL) and brine (10 mL). The organic
layer was dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The residue was purified on a silica column (PE/EtOAc=5:1,
v/v) to afford the title compound (200 mg, 93%) as a yellow
solid.
[1025] LCMS (ESI+): m/z 207 (M+H).sup.+, RT: 2.05 min
[1026] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 9.24 (s, 1H),
8.16 (s, 1H), 8.04 (s, 1H), 4.14 (q, 2H), 4.06 (s, 3H), 3.93 (s,
3H), 1.45 (t, J=7.2 Hz, 3H).
136.9
6-Amino-2-ethyl-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxyli-
c acid methyl ester
[1027] To a suspension of
2-ethyl-7-methoxy-6-nitro-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid methyl ester obtained in step 136.8 (200 mg, 0.653 mmol) in
ethanol (10 mL) and saturated NH.sub.4Cl solution (2 mL) was added
zinc (427 mg, 6.53 mmol) in one portion. The mixture was stirred at
r.t. for 30 min, then filtered. The filtrate was concentrated in
vacuo. The residue was diluted with EtOAc (20 mL) and washed with
brine (6*2 mL). The organic layer was dried over Na.sub.2SO.sub.4,
filtered and concentrated to afford the title compound (163 mg,
90%) as a white solid.
[1028] LCMS (ESI+): m/z 277 (M+H).sup.+, RT: 1.83 min
[1029] .sup.1H NMR (DMSO-d.sub.6/TMS, 400 MHz) .delta.: 8.22 (s,
1H), 7.87 (s, 1H), 7.50 (s, 1H), 5.86 (br, 2H), 4.00-4.04 (q, 2H),
3.88 (s, 3H), 3.81 (s, 3H), 1.24 (t, J=7.2 Hz, 3H).
136.10
6-Bromo-2-ethyl-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxyl-
ic acid methyl ester
[1030] To a suspension of
6-amino-2-ethyl-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid methyl ester obtained in step 136.9 (1.20 g, 4.34 mmol) in 2 N
H.sub.2SO.sub.4 solution (25 mL) was added a solution of sodium
nitrite (0.899 g, 13.03 mmol) in water (5 mL) dropwise at 0.degree.
C. The mixture was stirred at 0.degree. C. for 2 h, then it was
added dropwise to a solution of copper(I) bromide (2.492 g, 17.37
mmol) in HBr (48%, 5 mL). The mixture was stirred for another 1 h
at 0.degree. C., diluted with EtOAc (100 mL) and washed with brine
(30 mL*3). The organic layer was dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo. The residue was purified on a
silica column (PE/EtOAc=5:1, v/v) to afford the title compound
(1.31 g, 89%).
[1031] LCMS (ESI+): m/z 340 (M+H).sup.+, RT: 2.04 min
[1032] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 9.02 (s, 1H),
8.01 (s, 1H), 7.76 (s, 1H), 4.01-4.07 (q, 2H), 3.95 (s, 3H), 3.85
(s, 3H), 1.36 (t, J=7.2 Hz, 3H).
136.11
2-Ethyl-7-methoxy-4-(methoxycarbonyl)-1-oxo-1,2-dihydroisoquinolin--
6-yl-boronic acid
[1033] A mixture of
6-bromo-2-ethyl-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid methyl ester obtained in step 136.10 (1.31 g, 3.85 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.174
g, 4.62 mmol), potassium acetate (1.134 g, 11.55 mmol) and
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (0.314 g, 0.385 mmol) in
DMF (100 mL) was stirred at 90.degree. C. overnight. The mixture
was diluted with EtOAc (200 mL) and washed with brine (60
mL.times.4). The organic layer was dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo. The residue was used in the
next step directly without further purification.
[1034] LCMS (ESI+): m/z 306 (M+H).sup.+, RT: 1.82 min
136.12
2-Ethyl-6-hydroxy-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4-carbox-
ylic acid methyl ester
[1035] A mixture of
2-ethyl-7-methoxy-4-(methoxycarbonyl)-1-oxo-1,2-dihydroisoquinolin-6-yl-b-
oronic acid obtained in step 136.11 (838 mg, 2.75 mmol), water (32
mL), acetone (4 mL), NaOH (110 mg, 2.75 mmol) and sodium
bicarbonate (231 mg, 2.75 mmol) was warmed to 50.degree. C. for 1
h. After cooling to r.t., 30% H.sub.2O.sub.2 (0.337 mL, 10.99 mmol)
was added dropwise. The reaction was stirred at r.t. overnight,
then it was acidified to pH=4 by dropwise addition of 2 N HCl, and
extracted with DCM (50 mL*3). The DCM layer was washed with brine
(50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The residue was purified on a silica column (PE/EtOAc=2:1,
v/v) to afford the title compound (220 mg, 28.9%) as a white
solid.
[1036] LCMS (ESI+): m/z 278 (M+H).sup.+, RT: 1.87 min
[1037] .sup.1H NMR (DMSO-d.sub.6/TMS, 400 MHz) .delta.: 10.27 (s,
1H), 8.30 (s, 1H), 8.15 (s, 1H), 7.64 (s, 1H), 4.04-4.08 (m, 2H),
3.88 (s, 3H), 3.82 (s, 3H), 1.26 (t, J=7.2 Hz, 3H).
136.13
2-Ethyl-7-methoxy-1-oxo-6-(2-quinolin-2-yl-ethoxy)-1,2-dihydro-isoq-
uinoline-4-carboxylic acid methyl ester
[1038] To a solution of
2-ethyl-6-hydroxy-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid methyl ester of step 136.12 (50 mg, 0.180 mmol),
2-(quinolin-2-yl)ethanol (31.2 mg, 0.180 mmol) and Ph.sub.3P (142
mg, 0.541 mmol) in anhydrous THF (3 mL) was added DEAD (0.086 mL,
0.541 mmol) dropwise at 0.degree. C. The mixture was stirred at
0.degree. C. for 30 min Then it was allowed to warm to ambient
temperature and stirred overnight. The mixture was diluted with
EtOAc (20 mL) and washed with 2 N HCl (10 mL*3). The aqueous layer
was basified with 2 N NaOH to pH=10, then extracted with EtOAc (15
mL*3). The organic layer was dried over Na.sub.2SO.sub.4, filtered
and concentrated in vacuo. The residue was purified by prep-TLC
(PE/EtOAc=1:1, v/v) to afford the title compound (55 mg,
47.3%).
[1039] LCMS (ESI+): m/z 433 (M+H).sup.+, RT: 1.91 min
[1040] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 8.43 (s, 1H),
8.09-8.13 (m, 3H), 7.80 (s, 1H), 7.65-7.70 (m, 2H), 7.47-7.51 (m,
2H), 4.69 (t, J=6.8 Hz, 2H), 4.08-4.12 (m, 2H), 3.97 (s, 3H), 3.88
(s, 3H), 3.62 (t, J=6.8 Hz, 2H), 1.41 (t, J=7.2 Hz, 3H).
136.14
2-Ethyl-7-methoxy-1-oxo-6-(2-quinolin-2-yl-ethoxy)-1,2-dihydro-isoq-
uinoline-4-carboxylic acid
[1041] A mixture of methyl
2-ethyl-7-methoxy-1-oxo-6-(2-quinolin-2-yl-ethoxy)-1,2-dihydro-isoquinoli-
ne-4-carboxylic acid ethyl ester obtained in step 136.13 (55 mg,
0.085 mmol) and NaOH (10.22 mg, 0.256 mmol) in MeOH (3 mL) and
water (1 mL) was heated at 50.degree. C. for 3 h. The reaction
mixture was concentrated in vacuo. The residue was dissolved in
water (5 mL) and acidified with HCl (2 N) to pH=5-6. The aqueous
solution was extracted with EtOAc (15 mL*3). The organic layer was
dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo.
The residue was used in the next step without further
purification.
[1042] LCMS (ESI+): m/z 419 (M+H).sup.+, RT: 2.08 min
136.15
2-Ethyl-7-methoxy-1-oxo-6-(2-quinolin-2-yl-ethoxy)-1,2-dihydro-isoq-
uinoline-4-carboxylic acid butylamide
[1043] A suspension of
2-ethyl-7-methoxy-1-oxo-6-(2-quinolin-2-yl-ethoxy)-1,2-dihydro-isoquinoli-
ne-4-carboxylic acid obtained in step 136.14 (80 mg, 0.080 mmol),
DMF (6.22 .mu.L, 0.080 mmol) and SOCl.sub.2 (0.018 mL, 0.241 mmol)
in DCM (2 mL) was refluxed for 3 h. The mixture was concentrated in
vacuo. The residue was dissolved in DCM (2 mL). The solution was
added dropwise to a mixture of butan-1-amine (11.75 mg, 0.161 mmol)
and Et.sub.3N (0.034 mL, 0.241 mmol) in DCM (2 mL) at ambient
temperature. The reaction mixture was stirred at r.t. for another 3
h. Then the solvent was removed under reduced pressure, the residue
was diluted with EtOAc (15 mL) and washed with brine (5 mL*3). The
organic layer was dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. The residue was purified on a silica column
(PE/EtOAc=1:1, v/v) to afford the title compound as a white solid
(50 mg), (purity 94.6% by LCMS). Further purification pre-HPLC
afford the title compound (12 mg, 31.6%) as a white solid.
[1044] .sup.1H NMR (CDCl.sub.3/TMS, 400 MHz) .delta.: 7.35-8.17 (m,
9H), 5.88 (s, 1H), 4.65 (m, 2H), 4.03-4.08 (m, 2H), 3.95 (s, 3H),
3.41-3.66 (m, 4H), 1.60-1.63 (m, 2H), 1.37-1.44 (m, 5H), 0.93 (t,
J=7.2 Hz, 3H).
[1045] LCMS (ESI+): m/z 474 (M+H).sup.+, RT: 2.05 min
Example 137
2-Ethyl-7-methoxy-1-oxo-6-(3-quinolin-2-yl-propoxy)-1,2-dihydro-isoquinoli-
ne-4-carboxylic acid butyl amide
137.1 (E)-3-Quinolin-2-yl-acrylic acid ethyl ester
[1046] (2-Ethoxy-2-oxoethyl) triphenylphosphonium bromide (16.8 g,
39.1 mmol) and quinoline-2-carbaldehyde (5.8 g, 36.9 mmol) were
dissolved in EtOH (100 ml). The mixture was heated at about
80.degree. C. over night. The solvent was removed under reduced
pressure, and the residue was purified with silica column (eluted
with 5:1 hexane/EtOAc). The proper fractions were collected and
concentrated to give the title compound (6.8 g, 76%) as yellow
oil.
[1047] LCMS (ESI+): m/z 228 (M+H).sup.+, RT: 1.871 min
137.2 3-Quinolin-2-yl-propan-1-ol
[1048] To a suspension of LiAlH.sub.4 (0.534 g, 14.05 mmol) in THF
(10 ml), at -78.degree. C. was added (E)-3-quinolin-2-yl-acrylic
acid ethyl ester obtained in step 137.1 (1.6 g, 7.04 mmol) slowly.
The mixture was allowed to warm to room temperature and stirred for
3 h. Water (0.1 ml) was added slowly. The reaction mixture was
filtered through a pad of celite. The solvent was removed under
reduced pressure to provide the desired crude product as an
off-white solid. The crude product was purified with plate TLC
(eluted with 1:1 hexane/EtOAc) to give the title compound (55 mg,
4.2%).
[1049] LCMS (ESI+): m/z 188 (M+H).sup.+, RT: 1.074 min
137.3
2-Ethyl-7-methoxy-1-oxo-6-(3-quinolin-2-yl-propoxy)-1,2-dihydro-isoq-
uinoline-4-carboxylic acid methyl ester
[1050] To a solution of
2-ethyl-6-hydroxy-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid methyl ester obtained in step 136.12 (148 mg, 0.534 mmol) and
Ph.sub.3P (420 mg, 1.602 mmol) in anhydrous THF (3 mL) was added
DEAD (0.254 mL, 1.602 mmol) dropwise at -30.degree. C. The mixture
was stirred at -30.degree. C. for 30 min Then a solution of
3-quinolin-2-yl-propan-1-ol obtained in step 137.2 (100 mg, 0.534
mmol) in anhydrous THF (2 mL) was added. The reaction mixture was
allowed to warm to ambient temperature and stirred overnight. The
mixture was diluted with EtOAc (10 mL) and washed with 2 N HCl (5
mL*3). The aqueous layer was basified with 2 N NaOH to pH=10, then
extracted with EtOAc (10 mL*3). The organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue
was purified by pre-TLC (PE/EtOAc=1:1, v/v) to afford the title
compound (43 mg, 11.36%).
[1051] LCMS (ESI+): m/z 447 (M+H).sup.+, RT: 2.08 min
137.4
2-Ethyl-7-methoxy-1-oxo-6-(3-quinolin-2-yl-propoxy)-1,2-dihydro-isoq-
uinoline-4-carboxylic acid
[1052] A mixture of
2-ethyl-7-methoxy-1-oxo-6-(3-quinolin-2-yl-propoxy)-1,2-dihydro-isoquinol-
ine-4-carboxylic acid methyl ester obtained in step 137.3 (43 mg,
0.061 mmol) and sodium hydroxide (7.28 mg, 0.182 mmol) in MeOH (3
mL) and water (1 mL) was heated at 50.degree. C. for 3 h. The
reaction mixture was acidified with HCl (2 N) to pH=4-5. The
aqueous solution was concentrated in vacuo. and re-evaporated with
MeOH (5 mL*3). The residue was used in the next step without
further purification.
[1053] LCMS (ESI+): m/z 433 (M+H).sup.+, RT: 1.39 min
137.5
2-Ethyl-7-methoxy-1-oxo-6-(3-quinolin-2-yl-propoxy)-1,2-dihydro-isoq-
uinoline-4-carboxylic acid butylamide
[1054] A suspension of
2-ethyl-7-methoxy-1-oxo-6-(3-quinolin-2-yl-propoxy)-1,2-dihydro-isoquinol-
ine-4-carboxylic acid obtained in step 137.4 (23 mg, 0.023 mmol),
DMF (3.54 .mu.L, 0.046 mmol) and sulfurous dichloride (8.16 mg,
0.069 mmol) in DCM (2 mL) was refluxed for 3 h. The mixture was
concentrated in vacuo. The residue was dissolved in DCM (2 mL). The
solution was added dropwise to a mixture of butan-1-amine (1.673
mg, 0.023 mmol) and Et.sub.3N (9.56 .mu.L, 0.069 mmol) in DCM (2
mL) at ambient temperature. The reaction mixture was stirred at
r.t. for another 3 h. Then the solvent was removed under reduced
pressure, the residue was diluted with EtOAc (15 mL) and washed
with brine (5 mL*3). The organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue
was purified by pre-HPLC to afford the title compound (3 mg, 26.9%)
as a white solid.
[1055] .sup.1H NMR (MeOD/TMS, 400 MHz) .delta.: 8.15 (d, J=8.0 Hz,
1H), 7.87 (d, J=8.0 Hz, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.61-7.64 (m,
2H), 7.52 (s, 1H), 7.49 (s, 1H), 7.41-7.45 (m, 1H), 7.40 (d, J=8.4
Hz, 1H), 4.12 (t, J=5.8 Hz, 2H), 3.99-4.02 (m, 2H), 3.76 (s, 3H),
3.25-3.29 (m, 2H), 3.12 (t, J=7.6 Hz, 2H), 2.30 (m, 2H), 1.49-1.53
(m, 2H), 1.26-1.34 (m, 5H), 0.86 (t, J=7.4 Hz, 3H).
[1056] LCMS (ESI+): m/z 488 (M+H).sup.+, RT: 2.08 min
[1057] The compounds of the following examples 138 to 166 were
prepared according to following general procedure:
[1058] A 4 ml scintillation vial was charged with a stir bar, a
solution of
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-carboxylic
acid as prepared in step 1.7 (16.57 mg, 0.059 mmol) in 1.0 mL of
N,N-dimethylacetamide (DMA), a solution of the respective amine
(1.2 eq, 0.0717 mmol) in DMA, a solution of HATU (27.26 mg, 0.0717
mmol, 1.2 eq) in DMA, and DIEA (3 eq, 0.179 mmol, 18.27 mg) neat.
The mixture was capped and placed in the Anton Paar Synthos 3000
optimizer at 150.degree. C. for 30 minutes. The vial was decapped
and placed to concentrate to dryness. An additional 1.4 mL of
DMSO/MeOH (1:1 v/v) was added for dissolution and submission for
reverse phase HPLC purification.
Example 138
2-Ethyl-6,7-dimethoxy-1-oxo-N-(pyridin-3-yl)-1,2-dihydroisoquinoline-4-car-
boxamide
[1059] ESI-MS [M+H.sup.+]=353.9 m/z.
[1060] .sup.1H NMR (500 MHz, DMSO/D.sub.2O) .delta. ppm 1.33 (t,
3H) 3.85-3.87 (m, 3H) 3.89-3.91 (m, 3H) 4.07 (q, 1H) 7.50 (dd,
J=8.39, 4.73 Hz, 1H) 7.69 (s, 1H) 7.74 (s, 1H) 8.06 (s, 1H) 8.21
(d, 1H) 8.35 (s, 1H) 8.90 (s, 1H).
Example 139
2-Ethyl-6,7-dimethoxy-1-oxo-N-(pyrimidin-4-ylmethyl)-1,2-dihydroisoquinoli-
ne-4-carboxamide
[1061] ESI-MS [M+H.sup.+]=368.15 m/z.
[1062] .sup.1H NMR (500 MHz, DMSO/D.sub.2O) .delta. ppm 1.32 (t,
J=7.17 Hz, 3H) 3.84 (s, 3H) 3.88 (s, 3H) 4.05 (q, J=7.02 Hz, 3H)
4.57 (s, 2H) 7.56 (dd, J=5.19, 1.22 Hz, 1H) 7.67 (s, 1H) 7.77 (s,
1H) 7.92 (s, 1H) 8.77 (d, J=5.19 Hz, 1H) 9.13 (d, J=1.22 Hz,
1H).
Example 140
2-Ethyl-6,7-dimethoxy-4-(2-methoxybenzylamino)carbonyl)isoquinolin-1(2H)-o-
ne
[1063] ESI-MS [M+H.sup.+]=397.0 m/z.
[1064] .sup.1H NMR (500 MHz, DMSO/D.sub.2O) .delta. ppm 1.30 (t,
J=7.02 Hz, 3H) 3.83 (d, J=10.07 Hz, 6H) 3.88 (s, 3H) 4.03 (d,
J=7.02 Hz, 2H) 4.46 (s, 2H) 6.96 (t, 1H) 7.03 (d, 1H) 7.30 (q, 2H)
7.66 (s, 1H) 7.71 (s, 1H) 7.80 (s, 1H)
Example 141
2-Ethyl-6,7-dimethoxy-N-(4-morpholinophenyl)-1-oxo-1,2-dihydroisoquinoline-
-4-carboxamide
[1065] ESI-MS [M+H.sup.+]=438.0 m/z.
[1066] .sup.1H NMR (500 MHz, DMSO/D.sub.2O) .delta. ppm 1.33 (t,
J=7.17 Hz, 3H) 3.11-3.14 (m, 4H) 3.76-3.79 (m, 4H) 3.85 (s, 3H)
3.89 (s, 3H) 4.06 (q, J=7.12 Hz, 2H) 7.03 (d, J=8.85 Hz, 2H) 7.61
(d, J=8.85 Hz, 2H) 7.68 (s, 1H) 7.71 (s, 1H) 7.92 (s, 1H)
Example 142
N-(3-Chlorobenzyl)-2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-c-
arboxamide
[1067] ESI-MS [M+H.sup.+]=400.9 m/z.
[1068] .sup.1H NMR (500 MHz, DMSO/D.sub.2O) .delta. ppm 1.30 (t,
J=7.02 Hz, 3H) 3.83 (s, 3H) 3.88 (s, 3H) 4.03 (q, J=7.12 Hz, 2H)
4.49 (s, 2H) 7.32-7.44 (m, 4H) 7.66 (s, 1H) 7.70 (s, 1H) 7.82 (s,
1H).
Example 143
2-Ethyl-6,7-dimethoxy-1-oxo-N-(pyridin-4-ylmethyl)-1,2-dihydroisoquinoline-
-4-carboxamide
[1069] ESI-MS [M+H.sup.+]=368.0 m/z.
[1070] .sup.1H NMR (500 MHz, DMSO/D.sub.2O) .delta. ppm 1.33 (t,
J=7.17 Hz, 3H) 3.83 (s, 3H) 3.88 (s, 3H) 4.03-4.10 (m, 2H) 4.69 (s,
2H) 7.67 (s, 1H) 7.75 (s, 1H) 7.88 (d, J=5.80 Hz, 2H) 7.97 (s, 1H)
8.76 (s, 2H).
Example 144
2-Ethyl-6,7-dimethoxy-1-oxo-N-o-tolyl-1,2-dihydroisoquinoline-4-carboxamid-
e
[1071] ESI-MS [M+H.sup.+]=367.0 m/z.
[1072] .sup.1H NMR (500 MHz, DMSO/D.sub.2O) .delta. ppm 1.33 (t,
J=7.17 Hz, 3H) 2.29 (s, 3H) 3.85 (s, 3H) 3.89 (s, 3H) 4.07 (q,
J=7.12 Hz, 2H) 7.17-7.22 (m, 1H) 7.23-7.28 (m, 1H) 7.30 (d, J=7.63
Hz, 1H) 7.37-7.41 (m, 1H) 7.69 (s, 1H) 7.76 (s, 1H) 8.00 (s,
1H)
Example 145
2-Ethyl-6,7-dimethoxy-1-oxo-N-m-tolyl-1,2-dihydroisoquinoline-4-carboxamid-
e
[1073] ESI-MS [M+H.sup.+]=367.0 m/z.
[1074] .sup.1H NMR (500 MHz, DMSO/D.sub.2O) .delta. ppm 1.33 (t,
J=7.17 Hz, 3H) 2.33 (s, 3H) 3.87 (d, 6H) 4.06 (q, J=7.02 Hz, 2H)
6.96 (d, J=7.63 Hz, 1H) 7.26 (t, J=7.93 Hz, 1H) 7.50 (d, J=8.24 Hz,
1H) 7.55 (s, 1H) 7.70 (d, J=14.34 Hz, 2H) 7.95 (s, 1H)
Example 146
2-Ethyl-6,7-dimethoxy-N-(2-methoxyphenyl)-1-oxo-1,2-dihydroisoquinoline-4--
carboxamide
[1075] ESI-MS [M+H.sup.+]=383.0 m/z.
[1076] .sup.1H NMR (500 MHz, DMSO/D.sub.2O) .delta. ppm 1.32 (t,
J=7.17 Hz, 3H) 3.84 (d, J=10.68 Hz, 6H) 3.89 (s, 3H) 4.06 (q,
J=7.02 Hz, 2H) 6.97-7.02 (m, 1H) 7.11 (d, J=7.32 Hz, 1H) 7.18-7.24
(m, 1H) 7.68 (s, 1H) 7.73-7.79 (m, 2H) 7.96 (s, 1H)
Example 147
2-Ethyl-6,7-dimethoxy-N-(3-methoxyphenyl)-1-oxo-1,2-dihydroisoquinoline-4--
carboxamide
[1077] ESI-MS [M+H.sup.+]=383.0 m/z.
[1078] .sup.1H NMR (500 MHz, DMSO/D.sub.2O) .delta. ppm 1.33 (t,
J=7.17 Hz, 3H) 3.77 (s, 3H) 3.86 (s, 3H) 3.89 (s, 3H) 4.06 (q,
J=7.22 Hz, 2H) 6.70-6.75 (m, 1H) 7.28-7.30 (m, 2H) 7.38 (d, J=1.83
Hz, 1H) 7.69 (d, J=6.41 Hz, 2H) 7.95 (s, 1H)
Example 148
2-Ethyl-6,7-dimethoxy-1-oxo-N-(pyridin-3-ylmethyl)-1,2-dihydroisoquinoline-
-4-carboxamide
[1079] ESI-MS [M+H.sup.+]=368.0 m/z.
[1080] .sup.1H NMR (500 MHz, DMSO/D.sub.2O) .delta. ppm 1.31 (t,
J=7.02 Hz, 3H) 3.83 (s, 3H) 3.88 (s, 3H) 4.04 (q, J=7.02 Hz, 2H)
4.63 (s, 2H) 7.66 (s, 1H) 7.73 (s, 1H) 7.88-7.94 (m, 2H) 8.40 (d,
J=7.93 Hz, 1H) 8.73 (d, J=5.19 Hz, 1H) 8.83 (s, 1H)
Example 149
2-Ethyl-6,7-dimethoxy-1-oxo-N-(pyridin-2-ylmethyl)-1,2-dihydroisoquinoline-
-4-carboxamide
[1081] ESI-MS [M+H.sup.+]=368.0 m/z.
[1082] .sup.1H NMR (500 MHz, DMSO/D.sub.2O) .delta. ppm 1.31 (t,
J=7.02 Hz, 3H) 3.83 (s, 3H) 3.88 (s, 3H) 4.04 (q, J=7.02 Hz, 2H)
4.63 (s, 2H) 7.66 (s, 1H) 7.73 (s, 1H) 7.88-7.94 (m, 2H) 8.40 (d,
J=7.93 Hz, 1H) 8.73 (d, J=5.19 Hz, 1H) 8.83 (s, 1H)
Example 150
N-(3-(Dimethylamino)propyl)-2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydroisoquin-
oline-4-carboxamide
[1083] ESI-MS [M+H.sup.+]=362.0
[1084] .sup.1H NMR (500 MHz, DMSO/D.sub.2O) .delta. ppm 1.30 (t,
J=7.17 Hz, 3H) 1.87-1.96 (m, 2H) 2.81 (s, 6H) 3.11-3.18 (m, 2H)
3.34 (t, J=6.56 Hz, 2H) 3.87 (d, J=7.93 Hz, 6H) 4.02 (q, J=7.22 Hz,
2H) 7.66 (s, 1H) 7.74 (s, 1H) 7.77 (s, 1H)
Example 151
2-Ethyl-6,7-dimethoxy-1-oxo-N-phenyl-1,2-dihydroisoquinoline-4-carboxamide
[1085] ESI-MS [M+H.sup.+]=353.0 m/z.
[1086] .sup.1H NMR (500 MHz, DMSO/D.sub.2O) .delta. ppm 1.33 (t,
J=7.17 Hz, 3H) 3.86 (s, 3H) 3.89 (s, 3H) 4.06 (q, J=7.02 Hz, 2H)
7.14 (t, J=7.48 Hz, 1H) 7.37-7.41 (m, 2H) 7.68-7.73 (m, 4H) 7.97
(s, 1H)
Example 152
2-Ethyl-6,7-dimethoxy-N-(4-methoxybenzyl)-1-oxo-1,2-dihydroisoquinoline-4--
carboxamide
[1087] ESI-MS [M+H.sup.+]=397.0 m/z.
[1088] .sup.1H NMR (500 MHz, DMSO/D.sub.2O) .delta. ppm 1.29 (t,
J=7.17 Hz, 3H) 3.74 (s, 3H) 3.82 (s, 3H) 3.88 (s, 3H) 4.01 (q,
J=7.02 Hz, 2H) 4.42 (d, J=5.80 Hz, 2H) 6.91-6.95 (m, 2H) 7.31-7.34
(m, 2H) 7.65 (s, 1H) 7.70 (s, 1H) 7.75 (s, 1H) 8.86 (t, J=5.80 Hz,
1H)
Example 153
2-Ethyl-6,7-dimethoxy-N-(4-methylbenzyl)-1-oxo-1,2-dihydroisoquinoline-4-c-
arboxamide
[1089] ESI-MS [M+H.sup.+]=381.0 m/z.
[1090] .sup.1H NMR (500 MHz, DMSO/D.sub.2O) .delta. ppm 1.29 (t,
J=7.17 Hz, 3H) 2.31 (s, 3H) 3.82 (s, 3H) 3.88 (s, 3H) 4.02 (q,
J=7.22 Hz, 2H) 4.45 (d, J=5.80 Hz, 2H) 7.09 (d, J=7.63 Hz, 1H)
7.16-7.21 (m, 2H) 7.23-7.28 (m, 1H) 7.66 (s, 1H) 7.71 (s, 1H) 7.78
(s, 1H) 8.90 (t, J=5.95 Hz, 1H)
Example 154
2-Ethyl-6,7-dimethoxy-N-(2-methylbenzyl)-1-oxo-1,2-dihydroisoquinoline-4-c-
arboxamide
[1091] ESI-MS [M+H.sup.+]=381.0 m/z.
[1092] .sup.1H NMR (500 MHz, DMSO/D.sub.2O) .delta. ppm 1.29 (t,
J=7.17 Hz, 3H) 2.35 (s, 3H) 3.81 (s, 3H) 3.88 (s, 3H) 4.02 (q,
J=7.22 Hz, 2H) 4.47 (s, 2H) 7.18-7.22 (m, 3H) 7.33 (t, J=3.51 Hz,
1H) 7.66 (s, 1H) 7.70 (s, 1H) 7.78 (s, 1H)
Example 155
2-Ethyl-6,7-dimethoxy-N-(2-methoxyethyl)-1-oxo-1,2-dihydroisoquinoline-4-c-
arboxamide
[1093] ESI-MS [M+H.sup.+]=335.0 m/z.
[1094] .sup.1H NMR (500 MHz, DMSO/D.sub.2O) .delta. ppm 1.29 (t,
J=7.02 Hz, 3H) 3.30 (s, 3H) 3.44 (t, J=5.49 Hz, 2H) 3.51 (t, J=5.80
Hz, 2H) 3.87 (d, J=7.63 Hz, 6H) 4.01 (q, J=7.02 Hz, 2H) 7.65 (s,
1H) 7.72 (d, J=2.75 Hz, 2H)
Example 156
2-Ethyl-N-(4-fluorophenyl)-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-c-
arboxamide
[1095] ESI-MS [M+H.sup.+]=371.0 m/z.
[1096] .sup.1H NMR (500 MHz, DMSO/D.sub.2O) .delta. ppm 1.33 (t,
J=7.02 Hz, 3H) 3.86 (s, 3H) 3.89 (s, 3H) 4.06 (q, J=7.22 Hz, 2H)
7.19-7.27 (m, 2H) 7.68 (s, 1H) 7.71-7.75 (m, 3H) 7.97 (s, 1H)
Example 157
2-Ethyl-6,7-dimethoxy-N-(4-nitrophenyl)-1-oxo-1,2-dihydroisoquinoline-4-ca-
rboxamide
[1097] ESI-MS [M+H.sup.+]=383.0 m/z.
[1098] .sup.1H NMR (500 MHz, DMSO/D.sub.2O) .delta. ppm 1.33 (t,
J=7.17 Hz, 3H) 3.76 (s, 3H) 3.85 (s, 3H) 3.89 (s, 3H) 4.06 (q,
J=7.22 Hz, 2H) 6.96 (tt, 2H) 7.62 (dt, 2H) 7.68 (s, 1H) 7.71 (s,
1H) 7.93 (s, 1H)
Example 158
2-Ethyl-6,7-dimethoxy-1-oxo-N-p-tolyl-1,2-dihydroisoquinoline-4-carboxamid-
e
[1099] ESI-MS [M+H.sup.+]=367.0 m/z.
[1100] .sup.1H NMR (500 MHz, DMSO/D.sub.2O) .delta. ppm 1.33 (t,
J=7.17 Hz, 3H) 2.30 (s, 3H) 3.85 (s, 3H) 3.89 (s, 3H) 4.06 (q,
J=7.22 Hz, 2H) 7.19 (d, J=8.24 Hz, 2H) 7.59 (dd, J=8.39, 2.59 Hz,
2H) 7.68 (s, 1H) 7.71 (s, 1H) 7.94 (s, 1H)
Example 159
2-Ethyl-N-(3-fluorophenyl)-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-c-
arboxamide
[1101] ESI-MS [M+H.sup.+]=371.0 m/z.
[1102] .sup.1H NMR (500 MHz, DMSO/D.sub.2O) .delta. ppm 1.33 (t,
J=7.02 Hz, 3H) 3.86 (s, 3H) 3.89 (s, 3H) 4.06 (q, J=7.02 Hz, 2H)
6.93-6.99 (m, 1H) 7.39-7.45 (m, 1H) 7.46-7.50 (m, 1H) 7.66-7.72 (m,
3H) 8.00 (s, 1H)
Example 160
2-Ethyl-N-(2-fluorophenyl)-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-c-
arboxamide
[1103] ESI-MS [M+H.sup.+]=371.0 m/z.
[1104] .sup.1H NMR (500 MHz, DMSO/D.sub.2O) .delta. ppm 1.33 (t,
J=7.17 Hz, 3H) 3.85 (s, 3H) 3.89 (s, 3H) 4.07 (d, J=7.32 Hz, 2H)
7.22-7.35 (m, 3H) 7.66-7.72 (m, 2H) 7.78 (s, 1H) 8.01 (s, 1H)
Example 161
2-Ethyl-6,7-dimethoxy-N-(4-methylbenzyl)-1-oxo-1,2-dihydroisoquinoline-4-c-
arboxamide
[1105] ESI-MS [M+H.sup.+]=381.0 m/z.
[1106] .sup.1H NMR (500 MHz, DMSO/D.sub.2O) .delta. ppm 1.29 (t,
J=7.02 Hz, 3H) 2.29 (s, 3H) 3.81 (s, 3H) 3.88 (s, 3H) 4.02 (q,
J=7.22 Hz, 2H) 4.44 (d, J=5.19 Hz, 2H) 7.17 (d, J=7.63 Hz, 2H) 7.28
(d, J=7.93 Hz, 2H) 7.65 (s, 1H) 7.70 (s, 1H) 7.77 (s, 1H)
Example 162
N-(2-Chlorobenzyl)-2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-c-
arboxamide
[1107] ESI-MS [M+H.sup.+]=401.0 m/z.
[1108] .sup.1H NMR (500 MHz, DMSO/D.sub.2O) .delta. ppm 1.31 (t,
J=7.17 Hz, 3H) 3.82 (s, 3H) 3.88 (s, 3H) 4.04 (q, J=7.22 Hz, 2H)
4.56 (d, J=5.49 Hz, 2H) 7.31-7.41 (m, 2H) 7.49 (dd, J=7.78, 1.37
Hz, 2H) 7.66 (s, 1H) 7.71 (s, 1H) 7.85 (s, 1H) 8.93 (t, J=5.80 Hz,
1H)
Example 163
(R)-2-Ethyl-N-(1-(4-fluorophenyl)ethyl)-6,7-dimethoxy-1-oxo-1,2-dihydroiso-
quinoline-4-carboxamide
[1109] ESI-MS [M+H.sup.+]=399.0 m/z.
[1110] .sup.1H NMR (500 MHz, DMSO/D.sub.2O) .delta. ppm (t, J=7.17
Hz, 3H) 1.48 (d, J=7.32 Hz, 3H) 3.79 (s, 3H) 3.87 (s, 3H) 4.04 (q,
J=7.02 Hz, 2H) 5.14 (q, J=6.92 Hz, 1H) 7.14-7.21 (m, 2H) 7.44-7.50
(m, 2H) 7.60 (s, 1H) 7.65 (s, 1H) 7.78 (s, 1H)
Example 164
2-Ethyl-6,7-dimethoxy-1-oxo-N-(pyridin-4-yl)-1,2-dihydroisoquinoline-4-car-
boxamide
[1111] ESI-MS [M+H.sup.+]=353.9 m/z.
[1112] .sup.1H NMR (500 MHz, DMSO/D.sub.2O) .delta. ppm 1.35 (t,
J=7.17 Hz, 3H) 3.88 (s, 3H) 3.90 (s, 3H) 4.09 (q, J=7.02 Hz, 2H)
7.70 (s, 1H) 7.79 (s, 1H) 8.17 (d, J=7.32 Hz, 2H) 8.24 (s, 1H) 8.70
(d, J=7.32 Hz, 2H).
Example 165
(S)-2-Ethyl-N-(1-(4-fluorophenyl)ethyl)-6,7-dimethoxy-1-oxo-1,2-dihydroiso-
quinoline-4-carboxamide
[1113] ESI-MS [M+H.sup.+]=399.0 m/z.
[1114] .sup.1H NMR (500 MHz, DMSO/D.sub.2O) .delta. ppm 1.31 (t,
J=7.17 Hz, 3H) 1.48 (d, J=7.32
[1115] Hz, 3H) 3.79 (s, 3H) 3.87 (s, 3H) 4.00-4.07 (m, 2H) 5.14 (q,
J=7.12 Hz, 1H) 7.15-7.21 (m, 2H) 7.45-7.49 (m, 2H) 7.60 (s, 1H)
7.65 (s, 1H) 7.78 (s, 1H).
Example 166
2-Ethyl-6,7-dimethoxy-1-oxo-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,8a-
-tetrahydroisoquinoline-4-carboxamide
[1116] ESI-MS [M+H.sup.+]=407.2 m/z.
[1117] .sup.1H NMR (500 MHz, DMSO/D.sub.2O) .delta. ppm 1.28 (t,
J=7.17 Hz, 3H) 1.75-1.88 (m, 2H) 1.93-2.00 (m, 1H) 2.01-2.08 (m,
1H) 2.72-2.85 (m, 2H) 3.87 (s, 3H) 3.89 (s, 3H) 4.00 (q, J=7.12 Hz,
2H) 5.24 (q, 1H) 7.13-7.16 (m, 1H) 7.17-7.21 (m, 2H) 7.31-7.35 (m,
1H) 7.67 (s, 1H) 7.71 (s, 1H) 7.74 (s, 1H).
[1118] The compounds of the following examples 167 to 179 were
prepared according to following general procedure:
[1119] In a 4 ml microwave vial was added
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydroiso-quinoline-4-carboxylic
acid as prepared in step 1.7 (25 mg, 0.09 mmol), followed by
2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium
hexafluorophosphate methanaminium (HATU; 42 mg, 0.10 mmol),
triethylamine (37 .mu.l, 0.27 mmol) and the respective amine (0.11
mmol). This mixture was placed in Anton Par with stir bar and
heated at 150.degree. C. for 30 minutes. The crude mixture was
checked via LCMS for completion and concentrated to dryness. The
residue was then dissolved in 1.4 mL of DMSO:MeOH (1:1) and
purified through reverse phase HPLC (TFA method using MeOH) to
afford pure products.
Example 167
2-Ethyl-6,7-dimethoxy-N-(6-methyl-2,3-dihydro-1H-inden-1-yl)-1-oxo-1,2-dih-
ydroisoquinoline-4-carboxamide
[1120] .sup.1H NMR (500 MHz) .delta. ppm 1.28 (t, J=7.02 Hz, 3H)
1.95 (dd, J=12.66, 8.09 Hz, 1H) 2.29 (s, 3H) 2.74-2.85 (m, 1H)
2.90-3.02 (m, 1H) 3.88 (d, J=3.97 Hz, 6H) 4.01 (q, J=7.22 Hz, 2H)
5.50 (t, J=7.78 Hz, 1H) 7.06 (d, J=7.63 Hz, 1H) 7.17 (d, 2H) 7.66
(s, 1H) 7.78 (d, J=11.90 Hz, 2H).
[1121] MS (ESI+) M/Z 407 [M+H].sup.+.
Example 168
2-Ethyl-6,7-dimethoxy-N-(2-(morpholinomethyl)benzyl)-1-oxo-1,2-dihydroiso--
quinoline-4-carboxamide
[1122] .sup.1H NMR (500 MHz.delta. ppm 1.24-1.33 (m, 4H) 3.40 (d,
4H) 3.81 (s, 3H) 3.87-3.89 (m, 3H) 4.04 (q, J=7.02 Hz, 4H) 4.58 (d,
J=11.60 Hz, 4H) 7.43 (t, J=7.48, 1.37 Hz, 1H) 7.50-7.57 (m, 2H)
7.60-7.67 (m, 3H) 7.84 (s, 1H).
[1123] MS (ESI+) M/Z 466 [M+H].sup.+.
Example 169
N-(5-Chloro-2,3-dihydro-1H-inden-1-yl)-2-ethyl-6,7-dimethoxy-1-oxo-1,2-dih-
ydroisoquinoline-4-carboxamide
[1124] .sup.1H NMR (500 MHz) .delta. ppm 1.28 (t, J=7.02 Hz, 3H)
2.00 (dd, J=12.82, 7.93 Hz, 1H) 2.88 (d, J=8.24 Hz, 1H) 2.97-3.06
(m, 1H) 3.87 (d, J=6.10 Hz, 6H) 4.00 (q, J=7.02 Hz, 2H) 5.50 (t,
J=7.78 Hz, 1H) 7.28 (dd, J=8.09, 1.98 Hz, 1H) 7.37 (t, 2H) 7.66 (s,
1H) 7.77 (d, J=3.36 Hz, 2H).
[1125] MS (ESI+) M/Z 427 [M+H].sup.+.
Example 170
N-(6-Chloro-2,3-dihydro-1H-inden-1-yl)-2-ethyl-6,7-dimethoxy-1-oxo-1,2-dih-
ydroisoquinoline-4-carboxamide
[1126] .sup.1H NMR (500 MHz) .delta. ppm 1.28 (t, J=7.17 Hz, 3H)
2.01 (dd, J=12.66, 8.09 Hz, 1H) 2.77-2.87 (m, 1H) 2.92-3.06 (m, 1H)
3.88 (d, J=1.22 Hz, 6H) 4.01 (q, J=7.02
[1127] Hz, 2H) 5.52 (t, J=7.78 Hz, 1H) 7.27-7.34 (m, 2H) 7.39 (s,
1H) 7.66 (s, 1H) 7.77 (d, J=18.92 Hz, 2H).
[1128] MS (ESI+) M/Z 427 [M+H].sup.+.
Example 171
2-Ethyl-N-(6-fluoro-2,3-dihydro-1H-inden-1-yl)-6,7-dimethoxy-1-oxo-1,2-dih-
ydroisoquinoline-4-carboxamide
[1129] .sup.1H NMR (500 MHz) .delta. ppm 1.28 (t, J=7.02 Hz, 3H)
1.96-2.06 (m, 1H) 2.77-2.88 (m, 1H) 2.93-3.01 (m, 1H) 3.88 (d,
J=4.88 Hz, 6H) 4.01 (q, J=7.02 Hz, 2H) 5.52 (t, J=7.78 Hz, 1H) 7.06
(t, 1H) 7.16 (dd, J=8.85, 2.14 Hz, 1H) 7.30 (dd, J=8.24, 5.19 Hz,
1H) 7.66 (s, 1H) 7.78 (d, J=13.43 Hz, 2H).
[1130] MS (ESI+) M/Z 411 [M+H].sup.+.
Example 172
N-(5,6-Dihydro-4H-cyclopenta[b]thiophen-4-yl)-2-ethyl-6,7-dimethoxy-1-oxo--
1,2-dihydroisoquinoline-4-carboxamide
[1131] .sup.1H NMR (500 MHz, Solvent) .delta. ppm 1.27 (t, J=7.02
Hz, 3H) 2.33-2.41 (m, 1H) 2.82-2.95 (m, 2H) 3.03 (d, 1H) 3.87 (d,
J=6.71 Hz, 6H) 3.99 (q, J=7.02 Hz, 2H) 5.37 (t, 1H) 6.99 (d, J=5.19
Hz, 1H) 7.39 (d, J=5.19 Hz, 1H) 7.65 (s, 1H) 7.73 (d, J=13.12 Hz,
2H).
[1132] MS (ESI+) M/Z 399 [M+H].sup.+.
Example 173
2-Ethyl-N-(4-fluoro-2,3-dihydro-1H-inden-1-yl)-6,7-dimethoxy-1-oxo-1,2-dih-
ydroisoquinoline-4-carboxamide
[1133] .sup.1H NMR (500 MHz) .delta. ppm 1.28 (t, J=7.17 Hz, 3H)
2.03 (dd, J=12.66, 8.39 Hz, 1H) 2.79-2.96 (m, 1H) 3.04 (d, J=5.19
Hz, 1H) 3.87 (d, J=7.02 Hz, 6H) 4.01 (q, J=7.02 Hz, 2H) 5.58 (d,
J=7.93 Hz, 1H) 6.93-7.14 (m, 1H) 7.16-7.36 (m, 2H) 7.66 (s, 1H)
7.77 (d, J=1.22 Hz, 2H) 8.78 (d, J=8.24 Hz, 1H).
[1134] MS (ESI+) M/Z 411 [M+H].sup.+.
Example 174
2-Ethyl-6,7-dimethoxy-N-(4-methyl-2,3-dihydro-1H-inden-1-yl)-1-oxo-1,2-dih-
ydroisoquinoline-4-carboxamide
[1135] .sup.1H NMR (500 MHz) .delta. ppm 1.28 (t, J=7.17 Hz, 3H)
1.96 (dd, J=12.51, 8.54 Hz, 1
[1136] H) 2.25 (s, 3H) 2.71-2.81 (m, 1H) 2.94 (dd, J=8.85, 3.36 Hz,
1H) 3.87 (d, J=7.93 Hz, 6H) 4.00 (q, J=7.12 Hz, 2H) 5.54 (t, J=7.78
Hz, 1H) 7.07 (d, J=7.32 Hz, 1H) 7.10-7.24 (m, 2H) 7.66 (s, 1H) 7.76
(d, J=14.34 Hz, 2H).
[1137] MS (ESI+) M/Z 407 [M+H].sup.+.
Example 175
2-Ethyl-6,7-dimethoxy-N-(5-methyl-2,3-dihydro-1H-inden-1-yl)-1-oxo-1,2-dih-
ydroisoquinoline-4-carboxamide
[1138] .sup.1H NMR (500 MHz) .delta. ppm 1.27 (t, J=7.17 Hz, 3H)
1.89-2.02 (m, 1H) 2.30 (s, 3H) 2.76-2.87 (m, 1H) 2.91-3.01 (m, 1H)
3.87 (d, J=7.63 Hz, 6H) 4.00 (q, J=7.12 Hz, 2H) 5.48 (t, J=7.63 Hz,
1H) 6.98-7.14 (m, 2H) 7.25 (d, J=7.63 Hz, 1H) 7.66 (s, 1H) 7.76 (d,
J=15.56 Hz, 2H).
[1139] MS (ESI+) M/Z 407 [M+H].sup.+.
Example 176
2-Ethyl-6,7-dimethoxy-N-(6-methoxy-2,3-dihydro-1H-inden-1-yl)-1-oxo-1,2-di-
hydroisoquinoline-4-carboxamide
[1140] .sup.1H NMR (500 MHz) .delta. ppm 1.28 (t, J=7.17 Hz, 3H)
1.97 (dd, J=12.51, 7.93 Hz, 1H) 2.70-2.85 (m, 1H) 2.91 (dd, J=8.85,
3.36 Hz, 1H) 3.72 (s, 3H) 3.87 (d, J=9.76 Hz, 6H) 4.01 (q, J=7.02
Hz, 2H) 5.49 (t, J=7.93 Hz, 1H) 6.82 (dd, J=7.93, 2.14 Hz, 1H) 6.92
(d, J=2.14 Hz, 1H) 7.19 (d, J=8.24 Hz, 1H) 7.66 (s, 1H) 7.78 (d,
J=5.80 Hz, 2H).
[1141] MS (ESI+) M/Z 423 [M+H].sup.+.
Example 177
2-Ethyl-N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-6,7-dimethoxy-1-oxo-1,2-dih-
ydroisoquinoline-4-carboxamide
[1142] .sup.1H NMR (500 MHz) .delta. ppm 1.28 (t, J=7.17 Hz, 3H)
2.01 (dd, J=12.51, 7.93 Hz, 1H) 2.76-2.93 (m, 1H) 2.96-3.13 (m, 1H)
3.87 (d, J=6.10 Hz, 6H) 4.00 (q, J=7.02
[1143] Hz, 2H) 5.50 (d, J=7.63 Hz, 1H) 6.95-7.19 (m, 2H) 7.38 (dd,
J=8.09, 5.34 Hz, 1H) 7.66 (s, 1H) 7.77 (d, J=6.10 Hz, 2H) 8.73 (d,
J=8.24 Hz, 1H).
[1144] MS (ESI+) M/Z 411 [M+H].sup.+.
Example 178
N-(24(Diethylamino)methyl)benzyl)-2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydroi-
soquinoline-4-carboxamide
[1145] .sup.1H NMR (500 MHz) .delta. ppm 1.18-1.45 (m, 9H) 3.25 (q,
4H) 3.79 (s, 3H) 3.87 (s, 3H) 4.04 (q, J=7.02 Hz, 2H) 4.53 (d,
J=14.04 Hz, 4H) 7.43 (t, J=7.48, 1.37 Hz, 1H) 7.50-7.57 (m, 2H)
7.59 (t, 2H) 7.65 (s, 1H) 7.85 (s, 1H).
[1146] MS (ESI+) M/Z 452 [M+H].sup.+.
Example 179
2-Ethyl-6,7-dimethoxy-1-oxo-N-(2-(pyrrolidin-1-ylmethyl)benzyl)-1,2-dihydr-
oisoquinoline-4-carboxamide
[1147] .sup.1H NMR (500 MHz) .delta. ppm 1.22-1.34 (m, 4H)
1.89-1.97 (m, 2H) 2.08-2.16 (m, 2H) 3.19-3.26 (m, 2H) 3.47-3.55 (m,
2H) 3.80 (s, 3H) 3.86-3.89 (m, 4H) 3.97-4.07 (m, 2H) 4.58 (d,
J=3.36 Hz, 4H) 7.41 (t, 1H) 7.49-7.58 (m, 3H) 7.65 (d, 2H) 7.83 (s,
1H).
[1148] MS (ESI+) M/Z 450 [M+H].sup.+.
[1149] The compounds of the following examples 180 and 181 were
prepared by analogy to example 133 starting from
2-ethyl-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-2-carboxylic
acid, which in turn was prepared by analogy to steps 133.1-133.7 of
example 133 starting from commercially available
5-bromo-2-methoxy-isonicotinic acid.
Example 180
2-Ethyl-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylic
acid indan-1-ylamide
[1150] ESI-MS: [M+Na.sup.+]=386.20, [M+H.sup.+]=364.10.
Example 181
2-Ethyl-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylic
acid butylamide
[1151] ESI-MS: [2M+Na.sup.+]=629.20, [M+H.sup.+]=304.10.
[1152] The compound of the following example 182 was prepared
according to example 133 starting from (Z)-methyl
2-(1-(dimethylamino)-3-methoxy-3-oxoprop-1-en-2-yl)-5-methoxybenzoate,
which in turn was prepared according to step 133.6 of example 133
starting from starting from 2-(quinolin-2-yl)ethanamine.
Example 182
7-Methoxy-1-oxo-2-(2-quinolin-2-yl-ethyl)-1,2-dihydro-isoquinoline-4-carbo-
xylic acid butylamide
[1153] ESI-MS: [M+H.sup.+]=430.20.
[1154] The following compounds were prepared in analogy to the
above examples.
Example 183
7-Methoxy-1-oxo-2-(2-quinolin-2-yl-ethyl)-1,2-dihydro-isoquinoline-4-carbo-
xylic acid indan-1-ylamide
[1155] ESI-MS: [M+H.sup.+]=490.20.
Example 184
(S)-3-ethyl-6,7-dimethoxy-4-oxo-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-3,4--
dihydrophthalazine-1-carboxamide
[1156] ESI-MS: [M+Na.sup.+]=430.20, [M+H.sup.+]=408.20.
Example 185
3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic
acid (S)-indan-1-ylamide
[1157] ESI-MS: [M+Na.sup.+]=416.20, [M+H.sup.+]=394.20.
Example 186
2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxyl-
ic acid (6,7-dihydro-5H-[1]pyrindin-5-yl)-amide
[1158] ESI-MS: [M+H.sup.+]=436.20.
Example 187
2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxyl-
ic acid 2-dimethylaminomethyl-benzylamide hydrochloride
[1159] ESI-MS: [M+H.sup.+]=466.30.
Example 188
2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxyl-
ic acid 3,5-difluoro-benzylamide
[1160] ESI-MS: [M+H.sup.+]=445.20;
Example 189
2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxyl-
ic acid 3,4-difluoro-benzylamide
[1161] ESI-MS: [M+H.sup.+]=445.20.
Example 190
2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxyl-
ic acid cyclohexylmethyl-amide
[1162] ESI-MS: [M+H.sup.+]=415.30;
Example 191
2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxyl-
ic acid (R)-indan-1-ylamide
[1163] ESI-MS: [M+H.sup.+]=435.30.
Example 192
2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxyl-
ic acid (S)-indan-1-ylamide
[1164] ESI-MS: [M+H.sup.+]=435.30.
Example 193
2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxyl-
ic acid (5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide
[1165] ESI-MS: 442.10, [M+H.sup.+]=441.10.
Example 194
2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxyl-
ic acid (2,3-dihydro-benzofuran-3-yl)-amide
[1166] ESI-MS: [N+Na.sup.+]=459.15, 438.20, [M+H.sup.+]=437.15.
Example 195
2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxyl-
ic acid (6-oxo-5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide
[1167] ESI-MS: [N+Na.sup.+]=477.05, 456.10, [M+H.sup.+]=455.10.
Example 196
2-Cyclopropyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid indan-1-ylamide
[1168] ESI-MS: 406.10, [M+H.sup.+]=405.10.
Example 197
2-sec-Butyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid indan-1-ylamide
[1169] ESI-MS: 422.15, [M+H.sup.+]=421.10.
Example 198
2-Isopropyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid indan-1-ylamide
[1170] ESI-MS: 408.20, [M+H.sup.+]=407.15;
Example 199
(+)-2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carb-
oxylic acid (6,7-dihydro-5H-[1]pyrindin-5-yl)-amide
[1171] ESI-MS: 437.20, [M+H.sup.+]=436.20.
Example 200
(-)-2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carb-
oxylic acid (6,7-dihydro-5H-[1]pyrindin-5-yl)-amide
[1172] ESI-MS: 437.20, [M+H.sup.+]=436.20.
Example 201
2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxyl-
ic acid ([1,3,4]thiadiazol-2-ylmethyl)-amide
[1173] ESI-MS: 418.20, [M+H.sup.+]=417.10.
Example 202
2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxyl-
ic acid 2-(morpholine-4-sulfonyl)-benzylamide
[1174] ESI-MS: 560.20, 559.20, [M+H.sup.+]=558.20;
Example 203
2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxyl-
ic acid (thiazol-4-ylmethyl)-amide
[1175] ESI-MS: 417.10, [M+H.sup.+]=416.10.
Example 204
(+)-2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide
[1176] ESI-MS: [M+H.sup.+]=399.10.
Example 205
(-)-2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic
acid (5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide
[1177] ESI-MS: [M+H.sup.+]=399.10.
Example 206
2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxyl-
ic acid (thiophen-3-ylmethyl)-amide
[1178] ESI-MS: 416.10, [M+H.sup.+]=415.10.
Example 207
2-(1-Ethyl-propyl)-6,7-dimethoxy-4-(3-phenyl-piperidine-1-carbonyl)-2H-iso-
quinolin-1-one
[1179] ESI-MS: [M+H.sup.+]=463.10.
Example 208
2-(1-Ethyl-propyl)-6,7-dimethoxy-4-(3-phenoxy-piperidine-1-carbonyl)-2H-is-
oquinolin-1-one
[1180] ESI-MS: [M+H.sup.+]=479.20.
Example 209
2-(1-Ethyl-propyl)-6,7-dimethoxy-4-[3-(3-methoxy-phenyl)-piperazine-1-carb-
onyl]-2H-isoquinolin-1-one
[1181] ESI-MS: [M+H.sup.+]=494.20.
Example 210
2-(1-Ethyl-propyl)-6,7-dimethoxy-4-[8-(4-methyl-piperazine-1-sulfonyl)-3,4-
-dihydro-1H-isoquinoline-2-carbonyl]-2H-isoquinolin-1-one
[1182] ESI-MS: [M+H.sup.+]=597.20.
Example 211
2-(1-Ethyl-propyl)-6,7-dimethoxy-4-[8-(morpholine-4-sulfonyl)-3,4-dihydro--
1H-isoquinoline-2-carbonyl]-2H-isoquinolin-1-one
[1183] ESI-MS: [M+H.sup.+]=584.20.
Example 212
2-(1-Ethyl-propyl)-6,7-dimethoxy-4-[3-(3-methoxy-phenyl)-4-methyl-piperazi-
ne-1-carbonyl]-2H-isoquinolin-1-one
[1184] ESI-MS: [M+H.sup.+]=508.30.
Example 213
2-(1-Ethyl-propyl)-6,7-dimethoxy-4-[(R)-3-(quinoxalin-2-yloxy)-pyrrolidine-
-1-carbonyl]-2H-isoquinolin-1-one
[1185] ESI-MS: [M+H].sup.+=517.20.
Example 214
4-(7-Amino-3,4-dihydro-1H-isoquinoline-2-carbonyl)-2-(1-ethyl-propyl)-6,7--
dimethoxy-2H-isoquinolin-1-one trifluoroacetate
[1186] ESI-MS: [M+H].sup.+=450.20.
Example 215
2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxyl-
ic acid 3-(4-chloro-benzenesulfonylamino)-benzylamide
[1187] ESI-MS: [M].sup.+=598.20.
Example 216
2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxyl-
ic acid (2,3-dihydro-benzo[b]thiophen-3-yl)-amide
[1188] ESI-MS: [M+Na].sup.+=475.20, [M+H.sup.+]=453.20.
Example 217
2-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carbox-
ylic acid (5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide
[1189] ESI-MS: [M+Na].sup.+=434.10, [M+H.sup.+]=412.10.
Example 218
2-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carbox-
ylic acid (S)-indan-1-ylamide
[1190] ESI-MS: [M+Na].sup.+=428.10, [M+H.sup.+]=406.20.
Example 219
2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxyl-
ic acid 2-(4-methyl-piperazine-1-sulfonyl)-benzylamide
[1191] ESI-MS: [M+H].sup.+=571.30.
Example 220
2-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carbox-
ylic acid 2-(morpholine-4-sulfonyl)-benzylamide
[1192] ESI-MS: [M+Na].sup.+=551.20, [M+H].sup.+=529.20.
Example 221
2-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carbox-
ylic acid (6,7-dihydro-5H-[1]pyrindin-5-yl)-amide
[1193] ESI-MS: [M+Na].sup.+=429.15, [M+H].sup.+=407.20.
Example 222
2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxyl-
ic acid 3-(4-methoxy-benzenesulfonylamino)-benzylamide
[1194] ESI-MS: [M+Na].sup.+=616.20, [M+H].sup.+=594.30.
Example 223
2-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carbox-
ylic acid 3,5-difluoro-benzylamide
[1195] ESI-MS: [M+Na].sup.+=438.15, [M+H].sup.+=416.10
Example 224
2-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carbox-
ylic acid 4-methyl-benzylamide
[1196] ESI-MS: [M+Na].sup.+=416.20, [M+H].sup.+=394.20.
Example 225
2-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carbox-
ylic acid cyclohexylmethyl-amide
[1197] ESI-MS: [M+Na].sup.+=408.20, [M+H].sup.+=386.20.
Example 226
2-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carbox-
ylic acid butylamide
[1198] ESI-MS: [M+H].sup.+=346.20.
Example 227
2-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carbox-
ylic acid (2,3-dihydro-benzofuran-3-yl)-amide
[1199] ESI-MS: [M+Na].sup.+=430.20, [M+H].sup.+=408.20.
Example 228
2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxyl-
ic acid (thiazol-2-ylmethyl)-amide
[1200] ESI-MS: [M+Na].sup.+=438.10, [M+H].sup.+=416.10.
Example 229
2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxyl-
ic acid (thiophen-2-ylmethyl)-amide
[1201] ESI-MS: [M+Na].sup.+=437.10, [M+H].sup.+=415.10.
Example 230
2-Ethyl-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylic
acid (5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide
[1202] ESI-MS: [M+Na].sup.+=392.10, [M+H].sup.+=370.10.
Example 231
3-(1-Ethyl-propyl)-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxyli-
c acid (5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide
trifluoroacetate
[1203] ESI-MS: [M+Na].sup.+=464.10, [M+H].sup.+=442.15.
Example 232
3-(1-Ethyl-propyl)-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxyli-
c acid (2,3-dihydro-benzofuran-3-yl)-amide trifluoroacetate
[1204] ESI-MS: [M+Na].sup.+=460.20, [M+H].sup.+=438.20.
Example 233
3-(1-Ethyl-propyl)-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxyli-
c acid (6,7-dihydro-5H-[1]pyrindin-5-yl)-amide
[1205] ESI-MS: [M+Na.sup.+]=459.20, [M+H].sup.+=437.20.
Example 234
2-(1-Ethyl-propyl)-6,7-dimethoxy-4-(3-phenyl-propionyl)-2H-isoquinolin-1-o-
ne
[1206] ESI-MS: [M+Na].sup.+=430.20, [M+H].sup.+=408.20
Example 235
3-(1-Ethyl-propyl)-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxyli-
c acid indan-1-ylamide
[1207] ESI-MS: [M+Na].sup.+=458.20, [M+H].sup.+=436.20.
Example 236
6,7-Dimethoxy-1-oxo-2-(pentan-3-yl)-N-(pyridin-3-ylmethyl)-1,2-dihydroisoq-
uinoline-4-carboxamide
[1208] A microwave vial was charged with a stir bar and 284 mg of
PS-TFP (10 eq.). To the vessel were added
6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxylic
acid (29 mg, 0.09 mmol) dissolved in dry THF (1.0 mL) and
CCl.sub.3CN (36 .mu.L, 0.36 mmol) dissolved in dry THF (0.5 mL).
The reaction vessel was sealed and heated to 120.degree. C. for
1800 seconds. Then pyridin-3-ylmethanamine (15 mg, 0.135 mmol)
dissolved in THF (0.5 mL) was added followed by DIEA (47 .mu.L,
0.27 mmol). The mixture was heated again to 150.degree. C. for 1800
seconds. After cooling the reaction mixture was filtered and
products were collected and concentrated to dryness. The residues
were dissolved in 1:1 DMSO/MeOH. Purification by reverse phase HPLC
provided the title compound (14.7 mg, 31%).
[1209] ESI-MS=410 [M+H].sup.+;
[1210] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 25.degree. C.)
.delta. ppm 8.86 (s, 1H) 8.76 (d, J=5.49 Hz, 1H) 8.47 (d, J=7.93
Hz, 1H) 7.97 (dd, J=7.93, 5.49 Hz, 1H) 7.74 (s, 1H) 7.67 (d,
J=10.99 Hz, 2H) 4.86 (s, 1H) 4.65 (s, 2H) 3.86 (d, J=28.08 Hz, 6H)
1.69-1.90 (m, 4H) 0.74 (t, J=7.32 Hz, 6H).
[1211] The following compounds of examples 237 to 244 were prepared
in an analogous manner to the process described in example 236.
Example 237
6,7-Dimethoxy-N-((5-methylthiophen-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2--
dihydroisoquinoline-4-carboxamide
[1212] ESI-MS=429 [M+H].sup.+;
[1213] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 25.degree. C.)
.delta. ppm 7.72 (s, 1H) 7.67 (s, 1H) 7.50 (s, 1H) 6.83 (d, J=3.36
Hz, 1H) 6.65 (d, J=2.14 Hz, 1H) 4.85 (s, 1H) 4.55 (s, 2H) 3.86 (d,
J=21.36 Hz, 6H) 2.39 (s, 3H) 1.65-1.85 (m, 4H) 0.72 (t, J=7.32 Hz,
6H).
Example 238
N-((3,5-Dimethylisoxazol-4-yl)methyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)--
1,2-dihydroisoquinoline-4-carboxamide
[1214] ESI-MS=428[M+H].sup.+;
[1215] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 25.degree. C.)
.delta. ppm 7.67 (s, 1H) 7.63 (s, 1H) 7.45 (s, 1H) 4.83 (s, 1H)
4.26 (s, 2H) 3.85 (d, J=28.99 Hz, 6H) 2.43 (s, 3H) 2.26 (s, 3H)
1.65-1.85 (m, 4H) 0.72 (t, J=7.17 Hz, 6H).
Example 239
6,7-Dimethoxy-N-((5-methylthiazol-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-d-
ihydroisoquinoline-4-carboxamide
[1216] ESI-MS=430 [M+H].sup.+;
[1217] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 25.degree. C.)
.delta. ppm 7.80 (s, 1H) 7.69 (s, 1H) 7.60 (s, 1H) 7.42 (s, 1H)
4.87 (s, 1H) 4.68 (s, 2H) 3.88 (d, J=14.04 Hz, 6H) 2.42 (s, 3H)
1.68-1.88 (m, 4H) 0.74 (t, J=7.32 Hz, 6H).
Example 240
6,7-Dimethoxy-1-oxo-2-(pentan-3-yl)-N-(pyrimidin-4-ylmethyl)-1,2-dihydrois-
oquinoline-4-carboxamide
[1218] ESI-MS=411 [M+H].sup.+;
[1219] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 25.degree. C.)
.delta. ppm 9.13 (s, 1H) 8.76-8.79 (m, 1H) 7.77-7.81 (m, 1H)
7.67-7.70 (m, 2H) 7.55 (d, J=4.88 Hz, 1H) 4.87 (s, 1H) 4.56-4.61
(m, 2H) 3.89 (s, 3H) 3.84 (s, 3H) 1.77-1.86 (m, 4H) 0.75 (t, J=7.32
Hz, 6H).
Example 241
6,7-Dimethoxy-N-((3-methylisoxazol-5-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2--
dihydroisoquinoline-4-carboxamide
[1220] ESI-MS=414 [M+H].sup.+;
[1221] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 25.degree. C.)
.delta. ppm 7.75 (s, 1H) 7.68 (s, 1H) 7.58 (s, 1H) 6.30 (s, 1H)
4.85 (s, 1H) 4.57 (s, 2H) 3.87 (d, J=16.48 Hz, 6H) 2.22 (s, 3H)
1.71-1.87 (m, 4H) 0.73 (t, J=7.32 Hz, 6H).
Example 242
N-((2,5-dimethylthiophen-3-yl)methyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)--
1,2-dihydroisoquinoline-4-carboxamide
[1222] ESI-MS=443 [M+H].sup.+;
[1223] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 25.degree. C.)
.delta. ppm 7.67 (s, 1H) 7.63 (s, 1H) 7.47 (s, 1H) 6.69 (s, 1H)
4.84 (s, 1H) 4.30 (s, 2H) 3.85 (d, J=30.21 Hz, 6H) 2.31-2.39 (m,
6H) 1.67-1.84 (m, 4H) 0.72 (t, J=7.32 Hz, 6H).
Example 243
6,7-Dimethoxy-N-((2-methylthiazol-5-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-d-
ihydroisoquinoline-4-carboxamide
[1224] ESI-MS=430 [M+H].sup.+;
[1225] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 25.degree. C.)
.delta. ppm 7.73 (s, 1H) 7.67 (s, 1H) 7.58 (s, 1H) 7.51 (s, 1H)
4.84 (s, 2H) 4.60 (s, 2H) 3.87 (d, 6H) 2.62 (s, 3H) 1.66-1.85 (m,
4H) 0.72 (t, J=7.32 Hz, 6H).
Example 244
6,7-Dimethoxy-N-((5-methylisoxazol-3-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2--
dihydroisoquinoline-4-carboxamide
[1226] ESI-MS=414 [M+H].sup.+;
[1227] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 25.degree. C.)
.delta. ppm 7.78 (s, 1H) 7.68 (s, 1H) 7.55-7.59 (m, 1H) 6.25 (s,
1H) 4.85 (s, 1H) 4.48 (s, 2H) 3.87 (d, J=10.38 Hz, 6H) 2.39 (s, 3H)
1.70-1.85 (m, 4H) 0.73 (t, J=7.32 Hz, 6H).
Example 245
(R)--N-(1-(4-fluorophenyl)ethyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2-d-
ihydroisoquinoline-4-carboxamide
[1228] The title compound was prepared in analogy to the process
described in example 236 but using (R)-1-(4-fluorophenyl)ethanamine
instead of pyridine-3-ylmethanamine.
[1229] ESI-MS=441 [M+H].sup.+;
[1230] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 25.degree. C.)
.delta. ppm 7.67 (s, 1H) 7.43-7.53 (m, 4H) 7.19 (t, J=8.85 Hz, 2H)
5.17 (q, J=6.92 Hz, 1H) 4.84 (s, 1H) 3.83 (d, J=50.35 Hz, 6H)
1.67-1.88 (m, 4H) 1.50 (d, J=7.32 Hz, 3H) 0.69-0.78 (m, 6H).
Example 246
[1231]
(S)--N-(1-(4-fluorophenyl)ethyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl-
)-1,2-dihydroisoquinoline-4-carboxamide
[1232] The title compound was prepared in analogy to the process
described in example 236 but using (S)-1-(4-fluorophenyl)ethanamine
instead of pyridine-3-ylmethanamine.
[1233] ESI-MS=441 [M+H].sup.+;
[1234] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 25.degree. C.)
.delta. ppm 7.67 (s, 1H) 7.42-7.55 (m, 4H) 7.19 (t, J=8.85 Hz, 2H)
5.17 (q, J=7.02 Hz, 1H) 4.84 (s, 1H) 3.83 (d, J=50.35 Hz, 6H)
1.67-1.90 (m, 4H) 1.50 (d, J=7.32 Hz, 3H) 0.68-0.78 (m, 6H).
[1235] The compounds of examples 247 to 269 were prepared in an
analogous manner to the process described in example 236.
Example 247
6,7-Dimethoxy-N-((4-methylthiazol-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-d-
ihydroisoquinoline-4-carboxamide
[1236] ESI-MS=430 [M+H].sup.+;
[1237] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 25.degree. C.)
.delta. ppm 7.78 (s, 1H) 7.69 (s, 1H) 7.62 (s, 1H) 7.20 (s, 1H)
4.81-4.94 (m, J=10.38 Hz, 1H) 4.72 (s, 2H) 3.87 (d, J=19.53 Hz, 6H)
2.36 (s, 3H) 1.68-1.87 (m, 4H) 0.74 (t, J=7.32 Hz, 6H).
Example 248
6,7-Dimethoxy-N-((2-methylthiazol-4-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-d-
ihydroisoquinoline-4-carboxamide
[1238] ESI-MS=430 [M+H].sup.+;
[1239] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 25.degree. C.)
.delta. ppm 7.75 (s, 1H) 7.68 (s, 1H) 7.60 (s, 1H) 7.32 (s, 1H)
4.85 (s, 1H) 4.53 (s, 2H) 3.86 (d, J=20.45 Hz, 6H) 2.66 (s, 3H)
1.67-1.87 (m, 4H) 0.73 (t, J=7.32 Hz, 6H).
Example 249
6,7-Dimethoxy-N-((4-methylthiazol-5-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-d-
ihydroisoquinoline-4-carboxamide
[1240] ESI-MS=430[M+H].sup.+;
[1241] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 25.degree. C.)
.delta. ppm 8.96 (s, 1H) 7.68 (d, J=8.54 Hz, 2H) 7.50 (s, 1H) 4.85
(s, 1H) 4.61 (s, 2H) 3.86 (d, J=22.28 Hz, 6H) 2.45 (s, 3H)
1.67-1.89 (m, 4H) 0.73 (t, J=7.32 Hz, 6H).
Example 250
6,7-Dimethoxy-1-oxo-2-(pentan-3-yl)-N-((5-(trifluoromethyl)furan-2-yl)meth-
yl)-1,2-dihydroisoquinoline-4-carboxamide
[1242] ESI-MS=467 [M+H].sup.+;
[1243] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 25.degree. C.)
.delta. ppm 7.72 (s, 1H) 7.68 (s, 1H) 7.56 (s, 1H) 7.17 (d, J=2.14
Hz, 1H) 6.58 (d, J=3.05 Hz, 1H) 4.85 (s, 1H) 4.56 (s, 2H) 3.86 (d,
6H) 1.67-1.87 (m, 4H) 0.73 (t, J=7.32 Hz, 6H).
Example 251
6,7-Dimethoxy-N-((5-methylfuran-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-dih-
ydroisoquinoline-4-carboxamide
[1244] ESI-MS=413 [M+H].sup.+;
[1245] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 25.degree. C.)
.delta. ppm 7.73 (s, 1H) 7.67 (s, 1H) 7.53 (s, 1H) 6.21 (d, J=2.75
Hz, 1H) 6.03 (d, J=2.14 Hz, 1H) 4.85 (s, 1H) 4.42 (s, 2H) 3.86 (d,
J=20.14 Hz, 6H) 2.24 (s, 3H) 1.66-1.87 (m, 4H) 0.73 (t, J=7.32 Hz,
6H).
Example 252
N-(5-Fluoro-2,3-dihydro-1H-inden-1-yl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-
-1,2-dihydroisoquinoline-4-carboxamide
[1246] ESI-MS [M+H].sup.+=453 [M+H].sup.+;
[1247] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 25.degree. C.)
.delta. ppm 7.73 (s, 1H) 7.68 (s, 1H) 7.52 (s, 1H) 7.38 (dd,
J=8.24, 5.49 Hz, 1H) 7.10-7.13 (m, 1H) 7.02-7.07 (m, 1H) 5.53 (t,
J=7.78 Hz, 1H) 4.83 (s, 1H) 3.87 (d, J=11.90 Hz, 6H) 2.96-3.05 (m,
1H) 2.81-2.92 (m, 1H) 2.54-2.59 (m, 1H) 1.96-2.10 (m, 1H) 1.65-1.86
(m, 4H) 0.73 (q, J=7.02 Hz, 6H).
Example 253
6,7-Dimethoxy-N-(5-methyl-2,3-dihydro-1H-inden-1-yl)-1-oxo-2-(pentan-3-yl)-
-1,2-dihydroisoquinoline-4-carboxamide
[1248] ESI-MS=449 [M+H].sup.+;
[1249] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 25.degree. C.)
.delta. ppm 7.73 (s, 1H) 7.68 (s, 1H) 7.50 (s, 1H) 7.24 (d, J=7.63
Hz, 1H) 7.10 (s, 1H) 7.05 (d, J=7.63 Hz, 1H) 5.52 (t, J=7.78 Hz,
1H) 4.83 (s, 1H) 3.87 (d, J=14.34 Hz, 6H) 2.92-3.02 (m, 1H)
2.77-2.89 (m, 1H) 2.46-2.51 (m, 1H) 2.30 (s, 3H) 1.91-2.03 (m, 1H)
1.65-1.85 (m, 4H) 0.73 (q, J=7.02 Hz, 6H).
Example 254
6,7-Dimethoxy-N-(4-methyl-2,3-dihydro-1H-inden-1-yl)-1-oxo-2-(pentan-3-yl)-
-1,2-dihydroisoquinoline-4-carboxamide
[1250] ESI-MS=449 [M+H].sup.+;
[1251] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 25.degree. C.)
.delta. ppm 7.74 (s, 1H) 7.68 (s, 1H) 7.51 (s, 1H) 7.12-7.21 (m,
2H) 7.07 (d, J=7.32 Hz, 1H) 5.57 (t, J=7.93 Hz, 1H) 4.84 (s, 1H)
3.87 (d, J=14.34 Hz, 6H) 2.90-3.02 (m, 1H) 2.72-2.83 (m, 1H)
2.55-2.59 (m, 1H) 2.25 (s, 3H) 1.92-2.04 (m, 1H) 1.66-1.83 (m, 4H)
0.68-0.77 (m, 6H).
Example 255
N-((2-Ethylthiazol-4-yl)methyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2-di-
hydroisoquinoline-4-carboxamide
[1252] ESI-MS=444 [M+H].sup.+;
[1253] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 25.degree. C.)
.delta. ppm 7.75 (s, 1H) 7.68 (s, 1H) 7.60 (s, 1H) 7.33 (s, 1H)
4.86 (s, 1H) 4.54 (s, 2H) 3.86 (d, J=21.06 Hz, 6H) 2.98 (q, J=7.53
Hz, 2H) 1.70-1.86 (m, 4H) 1.30 (t, J=7.48 Hz, 3H) 0.73 (t, J=7.32
Hz, 6H).
Example 256
6,7-Dimethoxy-N-(6-methoxy-2,3-dihydro-1H-inden-1-yl)-1-oxo-2-(pentan-3-yl-
)-1,2-dihydroisoquinoline-4-carboxamide
[1254] ESI-MS=465 [M+H].sup.+;
[1255] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 25.degree. C.)
.delta. ppm 7.75 (s, 1H) 7.68 (s, 1H) 7.54 (s, 1H) 7.20 (d, J=8.24
Hz, 1H) 6.90 (d, J=1.83 Hz, 1H) 6.83 (dd, J=8.24, 2.44 Hz, 1H) 5.52
(t, J=7.93 Hz, 1H) 4.84 (s, 1H) 3.87 (d, J=16.17 Hz, 6H) 3.72 (s,
3H) 2.89-2.99 (m, 1H) 2.74-2.83 (m, 1H) 2.47-2.52 (m, 1H) 1.95-2.04
(m, 1H) 1.67-1.85 (m, 4H) 0.73 (q, J=7.02 Hz, 6H).
Example 257
6,7-Dimethoxy-N-((4-methylthiophen-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2--
dihydroisoquinoline-4-carboxamide
[1256] ESI-MS=429 [M+H].sup.+;
[1257] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 25.degree. C.)
.delta. ppm 7.72 (s, 1H) 7.67 (s, 1H) 7.51 (s, 1H) 6.97 (s, 1H)
6.88 (s, 1H) 4.85 (s, 1H) 4.58 (s, 2H) 3.80-3.90 (m, 6H) 2.16-2.19
(m, 3H) 1.66-1.87 (m, 4H) 0.73 (t, J=7.32 Hz, 6H).
Example 258
6,7-Dimethoxy-N-((3-methylthiophen-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2--
dihydroisoquinoline-4-carboxamide
[1258] ESI-MS=429 [M+H].sup.+;
[1259] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 25.degree. C.)
.delta. ppm 7.68 (d, J=6.10 Hz, 2H) 7.46-7.51 (m, 1H) 7.30 (d,
J=4.88 Hz, 1H) 6.86 (d, J=4.88 Hz, 1H) 4.85 (s, 1H) 4.57 (s, 2H)
3.79-3.91 (m, 6H) 2.24 (s, 3H) 1.63-1.86 (m, 4H) 0.73 (t, J=7.32
Hz, 6H).
Example 259
6,7-Dimethoxy-N-((5-methyloxazol-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-di-
hydroisoquinoline-4-carboxamide
[1260] ESI-MS=414 [M+H].sup.+;
[1261] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 25.degree. C.)
.delta. ppm 7.81 (s, 1H) 7.68 (s, 1H) 7.60 (s, 1H) 6.79 (d, J=1.22
Hz, 1H) 4.86 (s, 1H) 4.54 (s, 2H) 3.88 (d, J=10.38 Hz, 6H) 2.28 (s,
3H) 1.66-1.88 (m, 4H) 0.73 (t, J=7.32 Hz, 6H).
Example 260
6,7-Dimethoxy-N-(6-methyl-2,3-dihydro-1H-inden-1-yl)-1-oxo-2-(pentan-3-yl)-
-1,2-dihydroisoquinoline-4-carboxamide
[1262] ESI-MS=449 [M+H].sup.+;
[1263] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 25.degree. C.)
.delta. ppm 7.74 (s, 1H) 7.69 (s, 1H) 7.52 (s, 1H) 7.14-7.20 (m,
2H) 7.06 (d, J=7.93 Hz, 1H) 5.54 (t, J=7.93 Hz, 1H) 4.84 (s, 1H)
3.88 (d, J=11.29 Hz, 6H) 2.88-3.01 (m, 1H) 2.74-2.87 (m, 1H)
2.46-2.51 (m, 1H) 2.28 (s, 3H) 1.92-2.01 (m, 1H) 1.66-1.85 (m, 4H)
0.73 (q, J=7.63 Hz, 6H).
Example 261
6,7-Dimethoxy-1-oxo-2-(pentan-3-yl)-N-(pyridin-4-ylmethyl)-1,2-dihydroisoq-
uinoline-4-carboxamide
[1264] ESI-MS=410 [M+H].sup.+;
[1265] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 25.degree. C.)
.delta. ppm 8.81 (d, J=6.71 Hz, 2H) 7.96 (d, J=6.41 Hz, 2H) 7.77
(s, 1H) 7.73 (s, 1H) 7.69 (s, 1H) 4.80-4.95 (m, J=6.10 Hz, 1H) 4.73
(s, 2H) 3.84 (d, 6H) 1.70-1.89 (m, 4H) 0.75 (t, J=7.32 Hz, 6H).
Example 262
6,7-Dimethoxy-N-(4-methylbenzyl)-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquino-
line-4-carboxamide
[1266] ESI-MS=423 [M+H].sup.+;
[1267] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 25.degree. C.)
.delta. ppm 7.69 (d, J=10.99 Hz, 2H) 7.54 (s, 1H) 7.27 (d, J=7.93
Hz, 2H) 7.18 (d, J=7.93 Hz, 2H) 4.85 (s, 1H) 4.45 (s, 2H) 3.85 (d,
6H) 2.29 (s, 3H) 1.67-1.87 (m, 4H) 0.73 (t, J=7.32 Hz, 6H).
Example 263
6,7-Dimethoxy-1-oxo-2-(pentan-3-yl)-N-(pyridin-2-ylmethyl)-1,2-dihydroisoq-
uinoline-4-carboxamide
[1268] ESI-MS=410 [M+H].sup.+;
[1269] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 25.degree. C.)
.delta. ppm 8.73 (d, J=4.88 Hz, 1H) 8.28-8.34 (m, 1H) 7.85 (d,
J=7.93 Hz, 1H) 7.78 (s, 1H) 7.72-7.76 (m, 2H) 7.69 (s, 1H) 4.88 (s,
1H) 4.74 (s, 2H) 3.85 (d, J=31.43 Hz, 6H) 1.68-1.92 (m, 4H) 0.75
(t, J=7.32 Hz, 6H).
Example 264
N-((5-Cyanofuran-2-yl)methyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2-dihy-
droisoquinoline-4-carboxamide
[1270] ESI-MS=424 [M+H].sup.+;
[1271] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 27.degree. C.)
.delta. ppm 7.71 (s, 1H) 7.68 (s, 1H) 7.57 (s, 1H) 7.54 (d, J=3.66
Hz, 1H) 6.64 (d, J=3.66 Hz, 1H) 4.84 (s, 1H) 4.56 (s, 2H) 3.87 (d,
J=14.04 Hz, 6H) 1.67-1.89 (m, J=12.82 Hz, 4H) 0.73 (t, J=7.32 Hz,
6H).
Example 265
N-(4-Chloro-2,3-dihydro-1H-inden-1-yl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-
-1,2-dihydroisoquinoline-4-carboxamide
[1272] ESI-MS=469 [M+H].sup.+;
[1273] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 27.degree. C.)
.delta. ppm 7.67-7.74 (m, J=17.70 Hz, 2H) 7.52 (s, 1H) 7.25-7.37
(m, 3H) 5.64 (q, J=7.93 Hz, 1H) 4.83 (s, 1H) 3.87 (d, J=10.68 Hz,
6H) 3.00-3.10 (m, 1H) 2.83-2.95 (m, 1H) 2.55-2.62 (m, 1H) 1.97-2.12
(m, 1H) 1.64-1.86 (m, 4H) 0.67-0.79 (m, 6H).
Example 266
N-((5-Ethylthiophen-2-yl)methyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2-d-
ihydroisoquinoline-4-carboxamide
[1274] ESI-MS=443 [M+H].sup.+;
[1275] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 27.degree. C.)
.delta. ppm 7.72 (s, 1H) 7.67 (s, 1H) 7.51 (s, 1H) 6.85 (d, J=3.36
Hz, 1H) 6.68 (d, J=3.36 Hz, 1H) 4.84 (s, 1H) 4.57 (s, 2H) 3.86 (d,
J=16.78 Hz, 6H) 2.76 (q, J=7.43 Hz, 2H) 1.64-1.90 (m, 4H) 1.21 (t,
J=7.63 Hz, 3H) 0.73 (t, J=7.32 Hz, 6H).
Example 267
6,7-Dimethoxy-N-((3-methylfuran-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-dih-
ydroisoquinoline-4-carboxamide
[1276] ESI-MS=413 [M+H].sup.+;
[1277] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 27.degree. C.)
.delta. ppm 7.68 (d, J=8.24 Hz, 2H) 7.44-7.52 (m, 2H) 6.32 (d,
J=1.83 Hz, 1H) 4.83 (s, 1H) 4.45 (s, 2H) 3.85 (d, J=18.62 Hz, 6H)
2.06 (s, 3H) 1.65-1.85 (m, 4H) 0.72 (t, J=7.32 Hz, 6H).
Example 268
6,7-Dimethoxy-N-((2-methylfuran-3-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2-dih-
ydroisoquinoline-4-carboxamide
[1278] ESI-MS=413 [M+H].sup.+;
[1279] .sup.1H NMR (500 MHz, DMSO-D.sub.2 0, T: 27.degree. C.)
.delta. ppm 7.67 (s, 2H) 7.42-7.48 (m, 2H) 6.44 (d, J=1.53 Hz, 1H)
4.83 (s, 1H) 4.25 (s, 2H) 3.85 (d, J=19.84 Hz, 6H) 2.30 (s, 3H)
1.59-1.89 (m, 4H) 0.72 (t, J=7.32 Hz, 6H).
Example 269
6,7-Dimethoxy-N-((1-methyl-1H-pyrazol-3-yl)methyl)-1-oxo-2-(pentan-3-yl)-1-
,2-dihydroisoquinoline-4-carboxamide
[1280] ESI-MS=413 [M+H].sup.+;
[1281] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 27.degree. C.)
.delta. ppm 7.75 (s, 1H) 7.68 (s, 1H) 7.62 (d, J=2.14 Hz, 1H) 7.55
(s, 1H) 6.22 (d, J=2.14 Hz, 1H) 4.84 (s, 1H) 4.43 (s, 2H) 3.87 (d,
J=14.04 Hz, 6H) 3.80 (s, 3H) 1.65-1.86 (m, 4H) 0.73 (t, J=7.17 Hz,
6H).
Example 270
N-[(3,4-Dimethylphenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4--
carboxamide
[1282] To a solution of
2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-carboxylic
acid (25 mg, 0.09 mmol) in DMA (1.0 mL) was added a solution of
HATU (41 mg, 0.1 mmol) in DMA (0.5 mL). The reaction mixture was
placed to shake for 45 minutes at room temperature. Then a solution
of (3,4-dimethylphenyl)methanamine (18 mg, 0.13 mmol) dissolved in
DMA (0.4 mL) was added followed by triethylamine neat (40 mL, 0.27
mmol). The reaction was shaken at 65.degree. C. overnight. The
reaction was checked by LC/MS and concentrated to dryness. The
residues were dissolved in 1:1 DMSO/MeOH. Purification by reverse
phase HPLC provided the titled compound (17.9 mg, 50%)
[1283] ESI-MS: m/z 395 [M+H].sup.+;
[1284] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 27.degree. C.)
.delta. ppm 7.75 (s, 1H) 7.70 (s, 1H) 7.65 (s, 1H) 7.15 (s, 1H)
7.11 (s, 2H) 4.41 (s, 2H) 4.02 (q, J=7.12 Hz, 2H) 3.88 (s, 3H) 3.81
(s, 3H) 2.21 (d, J=6.10 Hz, 6H) 1.29 (t, J=7.17 Hz, 3H).
[1285] The compounds of examples 271 to 292 were prepared in
analogy to the process described in example 270.
Example 271
N-[(2-Chloro-4-methyl-phenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinol-
ine-4-carboxamide
[1286] ESI-MS: m/z 415 [M+H].sup.+
[1287] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 27.degree. C.)
.delta. ppm 7.81 (s, 1H) 7.71 (s, 1H) 7.66 (s, 1H) 7.36 (d, J=7.63
Hz, 1H) 7.31 (s, 1H) 7.18 (d, J=8.24 Hz, 1H) 4.51 (s, 2H) 4.03 (q,
J=7.12 Hz, 2H) 3.88 (s, 3H) 3.82 (s, 3H) 2.30 (s, 3H) 1.30 (t,
J=7.17 Hz, 3H).
Example 272
N-[[2-(Dimethylamino)-4-methyl-phenyl]methyl]-2-ethyl-6,7-dimethoxy-1-oxo--
isoquinoline-4-carboxamide
[1288] ESI-MS: m/z 424 [M+H].sup.+.
[1289] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 27.degree. C.)
.delta. ppm 8.75 (t, J=5.80 Hz, 1H) 7.78 (s, 1H) 7.75 (s, 1H) 7.66
(s, 1H) 7.22 (d, J=7.63 Hz, 1H) 6.96 (s, 1H) 6.87 (d, J=7.93 Hz,
1H) 4.53 (d, J=5.49 Hz, 2H) 4.02 (q, J=7.22 Hz, 2H) 3.88 (s, 3H)
3.81-3.85 (m, 3H) 2.66 (s, 6H) 2.28 (s, 3H) 1.29 (t, J=7.17 Hz,
3H);
Example 273
2-Ethyl-N-[(2-fluoro-4-methyl-phenyl)methyl]-6,7-dimethoxy-1-oxo-isoquinol-
ine-4-carboxamide
[1290] ESI-MS: m/z 399 [M+H].sup.+
[1291] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 27.degree. C.)
.delta. ppm 8.86 (t, J=5.65 Hz, 1H) 7.77 (s, 1H) 7.69 (s, 1H) 7.65
(s, 1H) 7.34 (t, J=8.09 Hz, 1H) 7.01-7.06 (m, 2H) 4.43-4.50 (m, 2H)
4.02 (q, J=7.02 Hz, 2H) 3.88 (s, 3H) 3.82 (s, 3H) 2.31 (s, 3H) 1.29
(t, J=7.17 Hz, 3H).
Example 274
2-Ethyl-6,7-dimethoxy-N-[(3-methoxy-4-methyl-phenyl)methyl]-1-oxo-isoquino-
line-4-carboxamide
[1292] ESI-MS: m/z 411 [M+H].sup.+;
[1293] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 27.degree. C.)
.delta. ppm 7.77 (s, 1H) 7.71 (s, 1H) 7.66 (s, 1H) 7.11 (d, J=7.93
Hz, 1H) 6.95 (s, 1H) 6.84-6.90 (m, 1H) 4.45 (s, 2H) 4.02 (q, J=7.12
Hz, 2H) 3.88 (s, 3H) 3.81 (s, 3H) 3.78 (s, 3H) 2.13 (s, 3H) 1.29
(t, J=7.17 Hz, 3H).
Example 275
2-Ethyl-6,7-dimethoxy-N-[(4-methyl-2-morpholino-phenyl)methyl]-1-oxo-isoqu-
inoline-4-carboxamide
[1294] ESI-MS: m/z 466 [M+H].sup.+.
[1295] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 27.degree. C.)
.delta. ppm 7.76 (d, J=7.02 Hz, 2H) 7.65-7.68 (m, 1H) 7.26 (d,
J=7.63 Hz, 1H) 6.97 (s, 1H) 6.94 (d, J=7.93 Hz, 1H) 4.55 (s, 2H)
4.02 (q, J=7.02 Hz, 2H) 3.88 (s, 3H) 3.84 (s, 3H) 3.75-3.79 (m,
J=4.27 Hz, 4H) 2.83-2.90 (m, 4H) 2.29 (s, 3H) 1.29 (t, 3H).
Example 276
N-[(2-tert-Butoxy-4-methyl-phenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoq-
uinoline-4-carboxamide
[1296] ESI-MS: m/z 453 [M+H].sup.+
[1297] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 27.degree. C.)
.delta. ppm 7.76 (s, 1H) 7.72 (s, 1H) 7.66 (s, 1H) 7.22 (d, J=7.93
Hz, 1H) 6.91 (s, 1H) 6.86 (d, J=7.63 Hz, 1H) 4.45 (s, 2H) 4.02 (q,
J=7.02 Hz, 2H) 3.88 (s, 3H) 3.83 (s, 3H) 2.28 (s, 3H) 1.38 (s, 9H)
1.29 (t, J=7.17 Hz, 3H).
Example 277
N-[[2-(1,1-Dimethylpropoxy)-4-methyl-phenyl]methyl]-2-ethyl-6,7-dimethoxy--
1-oxo-isoquinoline-4-carboxamide
[1298] ESI-MS: m/z 467 [M+H].sup.+;
[1299] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 27.degree. C.)
.delta. ppm 7.77 (s, 1H) 7.73 (s, 1H) 7.66 (s, 1H) 7.20 (d, J=7.93
Hz, 1H) 6.88 (s, 1H) 6.84 (d, J=7.63 Hz, 1H) 4.44 (s, 2H) 4.02 (q,
J=7.22 Hz, 2H) 3.88 (s, 3H) 3.83 (s, 3H) 2.28 (s, 3H) 1.75 (q,
J=7.63 Hz, 2H) 1.32 (s, 6H) 1.29 (t, J=7.17 Hz, 3H) 0.97 (t, J=7.32
Hz, 3H).
Example 278
N-[(2,3-Difluoro-4-methyl-phenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoqu-
inoline-4-carboxamide
[1300] ESI-MS: m/z 417 [M+H].sup.+
[1301] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 27.degree. C.)
.delta. ppm 7.78 (s, 1H) 7.69 (s, 1H) 7.65 (s, 1H) 7.17 (t, J=7.93
Hz, 1H) 7.11 (t, J=7.32 Hz, 1H) 4.51 (s, 2H) 3.98-4.07 (m, 2H) 3.88
(s, 3H) 3.82 (s, 3H) 2.27 (d, J=1.83 Hz, 3H) 1.30 (t, 3H).
Example 279
2-Ethyl-N-[(3-fluoro-4-methyl-phenyl)methyl]-6,7-dimethoxy-1-oxo-isoquinol-
ine-4-carboxamide
[1302] ESI-MS: m/z 399 [M+H]+
[1303] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 27.degree. C.)
.delta. ppm 7.80 (s, 1H) 7.70 (s, 1H) 7.66 (s, 1H) 7.27 (t, J=8.09
Hz, 1H) 7.10-7.15 (m, 2H) 4.45 (s, 2H) 4.03 (q, J=7.12 Hz, 2H) 3.88
(s, 3H) 3.82 (s, 3H) 2.22 (d, J=1.22 Hz, 3H) 1.29 (t, J=7.02 Hz,
3H).
Example 280
N-[(3-chloro-4-methyl-phenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinol-
ine-4-carboxamide
[1304] ESI-MS: m/z 413 [M+H].sup.-
[1305] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 27.degree. C.)
.delta. ppm 7.79 (s, 1H) 7.69 (s, 1H) 7.66 (s, 1H) 7.41 (d, J=1.53
Hz, 1H) 7.32-7.36 (m, 1H) 7.24-7.28 (m, 1H) 4.44 (s, 2H) 4.02 (q,
J=7.22 Hz, 2H) 3.88 (s, 3H) 3.82 (s, 3H) 2.31 (s, 3H) 1.30 (t,
3H).
Example 281
2-Ethyl-6,7-dimethoxy-1-oxo-N-[(2,4,6-trimethylphenyl)methyl]isoquinoline--
4-carboxamide
[1306] ESI-MS: m/z 409 [M+H].sup.+;
[1307] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 27.degree. C.)
.delta. ppm 7.64 (s, 2H) 7.61 (s, 1H) 6.87 (s, 2H) 4.47 (s, 2H)
3.97 (q, J=7.12 Hz, 2H) 3.87 (s, 3H) 3.80 (s, 3H) 2.33-2.36 (m, 6H)
2.22 (s, 3H) 1.25 (t, J=7.02 Hz, 3H).
Example 282
N-[(2,4-Dimethylphenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4--
carboxamide
[1308] ESI-MS: m/z 395 [M+H].sup.+;
[1309] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 27.degree. C.)
.delta. ppm 7.74 (s, 1H) 7.69 (s, 1H) 7.65 (s, 1H) 7.21 (d, J=7.63
Hz, 1H) 6.98-7.03 (m, 2H) 4.43 (s, 2H) 3.95-4.06 (m, 2H) 3.88 (s,
3H) 3.80-3.82 (m, 3H) 2.31 (s, 3H) 2.26 (s, 3H) 1.29 (t, J=7.17 Hz,
3H).
Example 283
2-Ethyl-6,7-dimethoxy-N-[[2-(3-methoxypropoxy)-4-methyl-phenyl]methyl]-1-o-
xo-isoquinoline-4-carboxamide
[1310] ESI-MS: m/z 469 [M+H].sup.+;
[1311] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 27.degree. C.)
.delta. ppm 7.76 (s, 1H) 7.72 (s, 1H) 7.66 (s, 1H) 7.17 (d, J=7.63
Hz, 1H) 6.83 (s, 1H) 6.75 (d, J=7.63 Hz, 1H) 4.42 (s, 2H) 3.97-4.07
(m, 4H) 3.88 (s, 3H) 3.81 (s, 3H) 3.50 (t, J=6.26 Hz, 2H) 3.20 (s,
3H) 2.29 (s, 3H) 1.93-2.03 (m, 2H) 1.29 (t, J=7.17 Hz, 3H).
Example 284
N-[[2-(2-Ethoxyethoxy)-4-methyl-phenyl]methyl]-2-ethyl-6,7-dimethoxy-1-oxo-
-isoquinoline-4-carboxamide
[1312] ESI-MS: m/z 469 [M+H].sup.+
[1313] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 27.degree. C.)
.delta. ppm 7.76 (s, 1H) 7.69 (s, 1H) 7.66 (s, 1H) 7.18 (d, J=7.63
Hz, 1H) 6.86 (s, 1H) 6.77 (d, J=7.63 Hz, 1H) 4.43 (s, 2H) 4.10-4.15
(m, 2H) 4.02 (q, J=7.22 Hz, 2H) 3.88 (s, 3H) 3.81 (s, 3H) 3.74 (s,
2H) 3.48 (q, J=7.02 Hz, 2H) 2.29 (s, 3H) 1.29 (t, J=7.02 Hz, 3H)
1.05 (t, J=7.02 Hz, 3H).
Example 285
N-[[2-(Cyclopentoxy)-4-methyl-phenyl]methyl]-2-ethyl-6,7-dimethoxy-1-oxo-i-
soquinoline-4-carboxamide
[1314] ESI-MS: m/z 465 [M+H].sup.+;
[1315] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 27.degree. C.)
.delta. ppm 7.74 (d, J=4.58 Hz, 2H) 7.66 (s, 1H) 7.15 (d, J=7.63
Hz, 1H) 6.81 (s, 1H) 6.73 (d, J=7.63 Hz, 1H) 4.82-4.90 (m, 1H) 4.38
(s, 2H) 4.01 (q, J=7.22 Hz, 2H) 3.88 (s, 3H) 3.82 (s, 3H) 2.29 (s,
3H) 1.82-1.97 (m, 2H) 1.64-1.81 (m, 4H) 1.50-1.64 (m, 2H) 1.29 (t,
J=7.17 Hz, 3H).
Example 286
2-Ethyl-6,7-dimethoxy-N-[(4-methyl-2-phenoxy-phenyl)methyl]-1-oxo-isoquino-
line-4-carboxamide
[1316] ESI-MS: m/z 473 [M+H].sup.+;
[1317] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 27.degree. C.)
.delta. ppm 7.70 (s, 1H) 7.64 (d, J=3.36
[1318] Hz, 2H) 7.35-7.42 (m, 3H) 7.11 (t, J=7.32 Hz, 1H) 6.95-7.05
(m, 3H) 6.73 (s, 1H) 4.45 (s, 2H) 3.97 (q, J=7.12 Hz, 2H) 3.87 (s,
3H) 3.80 (s, 3H) 2.26 (s, 3H) 1.27 (t, J=7.02 Hz, 3H).
Example 287
2-Ethyl-6,7-dimethoxy-N-[[2-(2-methoxy-1-methyl-ethoxy)-4-methyl-phenyl]me-
thyl]-1-oxo-isoquinoline-4-carboxamide
[1319] ESI-MS: m/z 469 [M+H].sup.+
[1320] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 27.degree. C.)
.delta. ppm 7.75 (s, 1H) 7.70 (s, 1H) 7.66 (s, 1H) 7.17 (d, J=7.63
Hz, 1H) 6.88 (s, 1H) 6.75 (d, J=7.32 Hz, 1H) 4.57-4.67 (m, 1H)
4.33-4.49 (m, 2H) 4.02 (q, J=7.02 Hz, 2H) 3.88 (s, 3H) 3.81 (s, 3H)
3.42-3.55 (m, 2H) 3.23 (s, 3H) 2.29 (s, 3H) 1.22-1.34 (m, 6H).
Example 288
2-Ethyl-6,7-dimethoxy-N-[[4-methyl-2-(2,2,2-trifluoroethoxy)phenyl]methyl]-
-1-oxo-isoquinoline-4-carboxamide
[1321] ESI-MS: m/z 479 [M+H].sup.+;
[1322] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 27.degree. C.)
.delta. ppm 7.78 (s, 1H) 7.73 (s, 1H) 7.66 (s, 1H) 7.23 (d, J=7.63
Hz, 1H) 6.96 (s, 1H) 6.88 (d, J=7.32 Hz, 1H) 4.75 (q, J=8.65 Hz,
2H) 4.44 (s, 2H) 4.02 (q, J=7.22 Hz, 2H) 3.88 (s, 3H) 3.83 (s, 3H)
2.31 (s, 3H) 1.29 (t, J=7.17 Hz, 3H).
Example 289
N-[[2-(Cyclohexyloxy)-4-methyl-phenyl]methyl]-2-ethyl-6,7-dimethoxy-1-oxo--
isoquinoline-4-carboxamide
[1323] ESI-MS: m/z 479 [M+H].sup.+;
[1324] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 27.degree. C.)
.delta. ppm 7.76 (d, J=6.10 Hz, 2H) 7.66 (s, 1H) 7.16 (d, J=7.93
Hz, 1H) 6.84 (s, 1H) 6.73 (d, J=7.63 Hz, 1H) 4.37-4.46 (m, 3H) 4.01
(q, J=7.22 Hz, 2H) 3.88 (s, 3H) 3.82 (s, 3H) 2.25-2.31 (m, 3H)
1.83-1.93 (m, J=7.93, 3.97 Hz, 2H) 1.64-1.76 (m, 2H) 1.44-1.58 (m,
3H) 1.32-1.45 (m, 2H) 1.29 (t, J=7.17 Hz, 4H).
Example 290
N-[[2-(Cyclopropylmethoxy)-4-methyl-phenyl]methyl]-2-ethyl-6,7-dimethoxy-1-
-oxo-isoquinoline-4-carboxamide
[1325] ESI-MS: m/z 451 [M+H].sup.+;
[1326] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 27.degree. C.)
.delta. ppm 7.79 (s, 1H) 7.73 (s, 1H) 7.66 (s, 1H) 7.17 (d, J=7.63
Hz, 1H) 6.81 (s, 1H) 6.75 (d, J=7.02 Hz, 1H) 4.44 (s, 2H) 4.02 (q,
J=7.02 Hz, 2H) 3.85-3.90 (m, 5H) 3.82 (s, 3H) 2.28 (s, 3H)
1.19-1.35 (m, 4H) 0.51-0.61 (m, 2H) 0.31-0.37 (m, 2H).
Example 291
2-Ethyl-N-[(2-hexoxy-4-methyl-phenyl)methyl]-6,7-dimethoxy-1-oxo-isoquinol-
ine-4-carboxamide
[1327] ESI-MS: m/z 481 [M+H].sup.+;
[1328] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 27.degree. C.)
.delta. ppm 7.77 (s, 1H) 7.74 (s, 1H) 7.66 (s, 1H) 7.16 (d, J=7.63
Hz, 1H) 6.82 (s, 1H) 6.74 (d, J=7.63 Hz, 1H) 4.41 (s, 2H) 3.92-4.09
(m, 4H) 3.88 (s, 3H) 3.81 (s, 3H) 2.29 (s, 3H) 1.66-1.76 (m, 2H)
1.36-1.49 (m, 2H) 1.15-1.34 (m, 7H) 0.81 (t, 3H).
Example 292
2-Ethyl-6,7-dimethoxy-N-[[4-methyl-2-(tetrahydrofuran-3-ylmethoxy)phenyl]m-
ethyl]-1-oxo-isoquinoline-4-carboxamide
[1329] ESI-MS: m/z 481 [M+H].sup.+
[1330] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 27.degree. C.)
.delta. ppm 7.77 (s, 1H) 7.73 (s, 1H) 7.66 (s, 1H) 7.17 (d, J=7.63
Hz, 1H) 6.85 (s, 1H) 6.76 (d, J=7.93 Hz, 1H) 4.42 (s, 2H) 3.96-4.08
(m, 3H) 3.89-3.95 (m, 1H) 3.88 (s, 3H) 3.81 (s, 3H) 3.76-3.80 (m,
2H) 3.62-3.69 (m, 1H) 3.55-3.62 (m, J=8.54, 5.49 Hz, 1H) 2.62-2.75
(m, 1H) 2.29 (s, 3H) 1.98-2.10 (m, 1H) 1.66-1.76 (m, 1H) 1.29 (t,
J=7.17 Hz, 3H).
Example 293
2-Ethyl-6,7-dimethoxy-N-[[2-(2-methoxyethoxy)-4-methyl-phenyl]methyl]-1-ox-
o-isoquinoline-4-carboxamide
[1331]
2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-carboxylic
acid (22 mg, 0.08 mmol) dissolved in N,N-dimethylacetamide (1.0 mL)
was added to a 4 mL vial charged with a stir bar followed by a
solution of HATU (36 mg, 0.09 mmol) dissolved in
N,N-dimethylacetamide (1.0 mL). This was placed to shake for one
hour at room temperature. Then a solution of
(2-(2-methoxyethoxy)-4-methylphenyl)methanamine (19.5 mg, 0.1 mmol)
dissolved in N,N-dimethylacetamide (0.4 mL) was added followed by
triethylamine neat (33 .mu.L, 0.24 mmol) and the mixture was
stirred and heated at 65.degree. C. overnight. The reaction was
controlled by LC/MS and concentrated to dryness. The residue was
dissolved in 1:1 MeOH:DMSO. Purification by reverse phase HPLC gave
16.5 mg of the title compound (46%).
[1332] ESI-MS: m/z 455 [M+H].sup.+;
[1333] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 25.degree. C.)
.delta. ppm 7.77 (s, 1H) 7.70 (s, 1H) 7.66 (s, 1H) 7.18 (d, J=7.63
Hz, 1H) 6.85 (s, 1H) 6.77 (d, J=7.63 Hz, 1H) 4.39-4.45 (m, 2H)
4.11-4.17 (m, 2H) 4.02 (q, J=7.12 Hz, 2H) 3.88 (s, 3H) 3.81 (s, 3H)
3.67-3.71 (m, 2H) 3.27 (s, 3H) 2.29 (s, 3H) 1.29 (t, J=7.02 Hz,
3H).
[1334] The compounds of the following examples 294 to 323 were
prepared in analogy to the processes described in the examples
above.
Example 294
2-Ethyl-N-(2-isobutoxy-4-methylbenzyl)-6,7-dimethoxy-1-oxo-1,2-dihydroisoq-
uinoline-4-carboxamide
[1335] ESI-MS: m/z 453 [M+H].sup.+;
[1336] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 25.degree. C.)
.delta. ppm 7.78 (s, 1H) 7.74 (s, 1H) 7.66 (s, 1H) 7.16 (d, J=7.63
Hz, 1H) 6.81 (s, 1H) 6.75 (d, J=7.63 Hz, 1H) 4.42-4.46 (m, 2H) 4.01
(q, J=7.22 Hz, 2H) 3.88 (s, 3H) 3.82 (s, 3H) 3.78 (d, J=6.41 Hz,
2H) 2.29 (s, 3H) 2.00-2.12 (m, 1H) 1.29 (t, J=7.02 Hz, 3H) 1.00 (d,
J=6.71 Hz, 6H).
Example 295
2-Ethyl-N-(2-(furan-2-ylmethoxy)-4-methylbenzyl)-6,7-dimethoxy-1-oxo-1,2-d-
ihydroisoquinoline-4-carboxamide
[1337] ESI-MS: m/z 477 [M+H].sup.+
[1338] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 25.degree. C.)
.delta. ppm 7.77 (s, 1H) 7.71 (s, 1H) 7.65 (s, 2H) 7.19 (d, J=7.63
Hz, 1H) 7.01 (s, 1H) 6.80 (d, J=7.63 Hz, 1H) 6.60 (d, J=3.05 Hz,
1H) 6.42-6.51 (m, 1H) 5.11 (s, 2H) 4.35-4.43 (m, 2H) 4.02 (q,
J=7.02 Hz, 2H) 3.88 (s, 3H) 3.81 (s, 3H) 2.31 (s, 3H) 1.29 (t,
J=7.02 Hz, 3H).
Example 296
2-Ethyl-6,7-dimethoxy-N-(4-methyl-2-(pentyloxy)benzyl)-1-oxo-1,2-dihydrois-
oquinoline-4-carboxamide
[1339] ESI-MS: m/z 467 [M+H].sup.+;
[1340] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 25.degree. C.)
.delta. ppm 7.78 (s, 1H) 7.74 (s, 1H) 7.66 (s, 1H) 7.16 (d, J=7.63
Hz, 1H) 6.82 (s, 1H) 6.74 (d, J=7.63 Hz, 1H) 4.40-4.44 (m, 2H)
3.96-4.06 (m, 4H) 3.88 (s, 3H) 3.82 (s, 3H) 2.29 (s, 3H) 1.68-1.77
(m, 2H) 1.36-1.46 (m, 2H) 1.26-1.34 (m, 5H) 0.83 (t, J=7.17 Hz,
3H).
Example 297
N-(2-Ethoxy-4-methylbenzyl)-2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydroisoquin-
oline-4-carboxamide
[1341] ESI-MS: m/z 425 [M+H].sup.+;
[1342] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 25.degree. C.)
.delta. ppm 7.77 (s, 1H) 7.72 (s, 1H) 7.66 (s, 1H) 7.17 (d, J=7.63
Hz, 1H) 6.82 (s, 1H) 6.75 (d, J=7.32 Hz, 1H) 4.39-4.45 (m, 2H)
3.98-4.10 (m, 4H) 3.88 (s, 3H) 3.82 (s, 3H) 2.29 (s, 3H) 1.35 (t,
J=6.87 Hz, 3H) 1.29 (t, J=7.17 Hz, 3H).
Example 298
N-(2-sec-Butoxy-4-methylbenzyl)-2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydroiso-
quinoline-4-carboxamide
[1343] ESI-MS: m/z 453 [M+H].sup.+
[1344] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 25.degree. C.)
.delta. ppm 7.76 (s, 1H) 7.74 (s, 1H) 7.66 (s, 1H) 7.16 (d, J=7.63
Hz, 1H) 6.83 (s, 1H) 6.73 (d, J=7.63 Hz, 1H) 4.38-4.47 (m, 3H) 4.01
(q, J=7.02 Hz, 2H) 3.88 (s, 3H) 3.82 (s, 3H) 2.29 (s, 3H) 1.56-1.76
(m, 2H) 1.29 (t, J=7.17 Hz, 3H) 1.25 (d, J=6.10 Hz, 3H) 0.93 (t,
J=7.32 Hz, 3H).
Example 299
2-Ethyl-N-(2-(isopentyloxy)-4-methylbenzyl)-6,7-dimethoxy-1-oxo-1,2-dihydr-
oisoquinoline-4-carboxamide
[1345] ESI-MS: m/z 467 [M+H]+
[1346] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 25.degree. C.)
.delta. ppm 7.78 (s, 1H) 7.74 (s, 1H) 7.66 (s, 1H) 7.16 (d, J=7.63
Hz, 1H) 6.84 (s, 1H) 6.75 (d, J=7.63 Hz, 1H) 4.38-4.44 (m, 2H) 4.01
(q, J=6.82 Hz, 4H) 3.88 (s, 3H) 3.82 (s, 3H) 2.29 (s, 3H) 1.75-1.86
(m, 1H) 1.64 (q, J=6.41 Hz, 2H) 1.29 (t, J=7.17 Hz, 3H) 0.90 (d,
J=6.71 Hz, 6H).
Example 300
2-Ethyl-6,7-dimethoxy-N-(4-methyl-2-propoxybenzyl)-1-oxo-1,2-dihydroisoqui-
noline-4-carboxamide
[1347] ESI-MS: m/z 439 [M+H].sup.+;
[1348] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 25.degree. C.)
.delta. ppm 7.77 (s, 1H) 7.73 (s, 1H) 7.66 (s, 1H) 7.16 (d, J=7.63
Hz, 1H) 6.82 (s, 1H) 6.75 (d, J=7.63 Hz, 1H) 4.43 (s, 2H) 4.02 (q,
J=7.02 Hz, 2H) 3.96 (t, J=6.26 Hz, 2H) 3.88 (s, 3H) 3.82 (s, 3H)
2.29 (s, 3H) 1.69-1.84 (m, 2H) 1.29 (t, J=7.02 Hz, 3H) 1.00 (t,
J=7.32 Hz, 3H).
Example 301
2-Ethyl-6,7-dimethoxy-N-(4-methyl-2-(methylthio)benzyl)-1-oxo-1,2-dihydroi-
soquinoline-4-carboxamide
[1349] ESI-MS: m/z 427 [M+H].sup.+
[1350] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 25.degree. C.)
.delta. ppm 7.80 (s, 1H) 7.73 (s, 1H) 7.66 (s, 1H) 7.23 (d, J=7.63
Hz, 1H) 7.13 (s, 1H) 7.00 (d, J=7.93 Hz, 1H) 4.45 (s, 2H) 4.02 (q,
J=7.02 Hz, 2H) 3.88 (s, 3H) 3.82 (s, 3H) 2.49 (s, 3H) 2.31 (s, 3H)
1.30 (t, J=7.02 Hz, 3H).
Example 302
2-Ethyl-N-(2-isopropoxy-4-methylbenzyl)-6,7-dimethoxy-1-oxo-1,2-dihydroiso-
quinoline-4-carboxamide
[1351] ESI-MS: m/z 439 [M+H].sup.+
[1352] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 25.degree. C.)
.delta. ppm 7.76 (s, 1H) 7.73 (s, 1H) 7.66 (s, 1H) 7.16 (d, J=7.63
Hz, 1H) 6.84 (s, 1H) 6.73 (d, J=7.93 Hz, 1H) 4.56-4.68 (m, 1H) 4.40
(s, 2H) 4.02 (q, J=7.02 Hz, 2H) 3.88 (s, 3H) 3.82 (s, 3H) 2.29 (s,
3H) 1.24-1.34 (m, 9H).
Example 303
2-Ethyl-6,7-dimethoxy-N-(4-methyl-2-(tetrahydrofuran-3-yloxy)benzyl)-1-oxo-
-1,2-dihydroisoquinoline-4-carboxamide
[1353] ESI-MS: m/z 467 [M+H].sup.+;
[1354] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 25.degree. C.)
.delta. ppm 7.75 (s, 1H) 7.73 (s, 1H) 7.65 (s, 1H) 7.19 (d, J=7.63
Hz, 1H) 6.82 (s, 1H) 6.77 (d, J=7.63 Hz, 1H) 5.07 (dd, J=5.80, 4.58
Hz, 1H) 4.39 (s, 2H) 4.01 (q, J=7.02 Hz, 2H) 3.73-3.95 (m, 10H)
2.30 (s, 3H) 2.16-2.27 (m, 1H) 2.03 (dd, J=12.51, 6.10 Hz, 1H) 1.29
(t, J=7.17 Hz, 3H).
Example 304
2-Ethyl-6,7-dimethoxy-1-oxo-N-(2,4,5-trimethylbenzyl)-1,2-dihydroisoquinol-
ine-4-carboxamide
[1355] ESI-MS: m/z 409 [M+H].sup.+;
[1356] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 25.degree. C.)
.delta. ppm 7.73 (s, 1H) 7.69 (s, 1H) 7.65 (s, 1H) 7.07 (s, 1H)
6.96 (s, 1H) 4.40 (s, 2H) 4.01 (q, J=7.22 Hz, 2H) 3.88 (s, 3H) 3.80
(s, 3H) 2.27 (s, 3H) 2.17 (s, 6H) 1.28 (t, J=7.17 Hz, 3H).
Example 305
2-Ethyl-6,7-dimethoxy-N-(4-methyl-2-((tetrahydrofuran-2-yl)methoxy)benzyl)-
-1-oxo-1,2-dihydroisoquinoline-4-carboxamide
[1357] ESI-MS: m/z 481 [M+H].sup.+;
[1358] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 25.degree. C.)
.delta. ppm 7.77 (s, 1H) 7.70 (s, 1H) 7.65 (s, 1H) 7.17 (d, J=7.63
Hz, 1H) 6.85 (s, 1H) 6.77 (d, J=7.32 Hz, 1H) 4.42 (s, 2H) 4.16-4.24
(m, 1H) 3.98-4.06 (m, 3H) 3.92-3.97 (m, 1H) 3.88 (s, 3H) 3.81 (s,
3H) 3.67-3.71 (m, 1H) 3.59-3.67 (m, 1H) 2.29 (s, 3H) 1.95-2.05 (m,
1H) 1.68-1.93 (m, 3H) 1.29 (t, J=7.17 Hz, 3H).
Example 306
2-Ethyl-6,7-dimethoxy-N-(4-methyl-2-(4-methylpentan-2-yloxy)benzyl)-1-oxo--
1,2-dihydroisoquinoline-4-carboxamide
[1359] ESI-MS: m/z 481 [M+H].sup.+;
[1360] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 25.degree. C.)
.delta. ppm 7.76 (s, 1H) 7.75 (s, 1H) 7.66 (s, 1H) 7.16 (d, J=7.63
Hz, 1H) 6.84 (s, 1H) 6.72 (d, J=7.32 Hz, 1H) 4.50-4.58 (m, 1H) 4.39
(s, 2H) 3.96-4.06 (m, 2H) 3.88 (s, 3H) 3.82 (s, 3H) 2.29 (s, 3H)
1.70-1.82 (m, 1H) 1.61-1.70 (m, 1H) 1.34-1.44 (m, 1H) 1.29 (t,
J=7.02 Hz, 3H) 1.24 (d, J=5.80 Hz, 3H) 0.87 (dd, J=8.54, 6.71 Hz,
6H).
Example 307
2-Ethyl-6,7-dimethoxy-N-(4-methyl-2-(4-methylpentyloxy)benzyl)-1-oxo-1,2-d-
ihydroisoquinoline-4-carboxamide
[1361] ESI-MS: m/z 481 [M+H].sup.+;
[1362] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 25.degree. C.)
.delta. ppm 7.78 (s, 1H) 7.75 (s, 1H) 7.65 (s, 1H) 7.16 (d, J=7.63
Hz, 1H) 6.82 (s, 1H) 6.74 (d, J=7.32 Hz, 1H) 4.41 (s, 2H) 3.94-4.06
(m, 4H) 3.88 (s, 3H) 3.81 (s, 3H) 2.25-2.31 (m, 3H) 1.66-1.80 (m,
2H) 1.47-1.60 (m, 1H) 1.26-1.34 (m, 5H) 0.83 (d, J=6.71 Hz,
6H).
Example 308
2-Ethyl-6,7-dimethoxy-N-(2-methoxy-4-methylbenzyl)-1-oxo-1,2-dihydroisoqui-
noline-4-carboxamide
[1363] ESI-MS: m/z 411 [M+H].sup.+;
[1364] .sup.1H NMR (500 MHz, DMSO-D.sub.2O, T: 25.degree. C.)
.delta. ppm 7.77 (s, 1H) 7.71 (s, 1H) 7.66 (s, 1H) 7.17 (d, J=7.63
Hz, 1H) 6.84 (s, 1H) 6.76 (d, J=7.32 Hz, 1H) 4.40 (s, 2H) 4.02 (q,
J=7.22 Hz, 2H) 3.88 (s, 3H) 3.82 (s, 6H) 2.30 (s, 3H) 1.29 (t,
J=7.17 Hz, 3H).
Example 309
2-Ethyl-6,7-dimethoxy-1-oxo-N-(thiazol-4-ylmethyl)isoquinoline-4-carboxami-
de
[1365] ESI-MS: m/z 374.1 [M+H].sup.+
Example 310
2-Ethyl-6,7-dimethoxy-1-oxo-N-[[4-(trifluoromethyl)phenyl]-methyl]isoquino-
line-4-carboxamide
[1366] .sup.1H NMR (DMSO-d.sub.6,600 MHz): .delta.=8.99 (br. s.,
1H), 7.89 (s, 1H), 7.78 (s, 1H), 7.73 (m, 2H), 7.63 (m, 3H), 4.57
(br. S., 2H), 4.03 (m, 2H), 3.87 (s, 3H), 3.81 (s, 3H), 1.27-1.32
(m, 3H).
Example 311
2-Ethyl-6,7-dimethoxy-1-oxo-N-[(1S)-1-(p-tolyl)ethyl]isoquinoline-4-carbox-
amide
[1367] ESI-MS: m/z 395.2 [M+H].sup.+
Example 312
2-Ethyl-N-[(4-isopropylphenyl)methyl]-6,7-dimethoxy-1-oxo-isoquinoline-4-c-
arboxamide
[1368] ESI-MS: m/z 409.2 [M+H].sup.+
Example 313
2-Ethyl-N-[(4-ethylphenyl)methyl]-6,7-dimethoxy-1-oxo-isoquinoline-4-carbo-
xamide
[1369] ESI-MS: m/z 395.2 [M+H].sup.+
Example 314
2-Ethyl-6,7-dimethoxy-1-oxo-N-[(1R)-1-(p-tolyl)ethyl]isoquinoline-4-carbox-
amide
[1370] ESI-MS: m/z 395.2 [M+H].sup.+
Example 315
N-[[4-(Difluoromethyl)phenyl]methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinol-
ine-4-carboxamide
[1371] ESI-MS: m/z 417.1 [M+H].sup.+
Example 316
2-Ethyl-6,7-dimethoxy-N-[(2-methylthiazol-4-yl)methyl]-1-oxo-isoquinoline--
4-carboxamide
[1372] ESI-MS: m/z 388.1 [M+H].sup.+
Example 317
2-Ethyl-6,7-dimethoxy-N-[(4-methyl-2-thienyl)methyl]-1-oxo-isoquinoline-4--
carboxamide
[1373] ESI-MS: m/z 387.1 [M+H].sup.+
Example 318
N-[(4-Cyclopropylphenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4-
-carboxamide
[1374] ESI-MS: m/z 407.2 [M+H].sup.+
Example 319
N-Indan-1-yl-6,7-dimethoxy-2-[2-(5-methyl-2-pyridyl)ethyl]-1-oxo-isoquinol-
ine-4-carboxamide
[1375] ESI-MS: m/z 484.20 [M+H].sup.+
Example 320
N-Butyl-6,7-dimethoxy-2-[2-(5-methyl-2-pyridyl)ethyl]-1-oxo-isoquinoline-4-
-carboxamide
[1376] ESI-MS: m/z 424.20 [M+H].sup.+
Example 321
2-Ethyl-6,7-dimethoxy-N-[2-(6-methoxy-2-pyridyl)ethyl]-1-oxo-isoquinoline--
4-carboxamide; 2,2,2-trifluoroacetic acid
[1377] ESI-MS: m/z 412.10 [M+H].sup.+
Example 322
N-Butyl-6,7-dimethoxy-1-oxo-2-[2-(2-quinolyl)ethyl]isoquinoline-4-carboxam-
ide; 2,2,2-trifluoroacetic acid
[1378] ESI-MS: m/z 460.20 [M+H].sup.+
Example 323
N-Indan-1-yl-6,7-dimethoxy-1-oxo-2-[2-(2-quinolyl)ethyl]isoquinoline-4-car-
boxamide; 2,2,2-trifluoroacetic acid
[1379] ESI-MS: m/z 520.20 [M+H].sup.+
Biological Tests
A) Measurement of PDE Activity
[1380] The recombinant PDE proteins are used in in vitro enzymatic
reaction for measurement of PDE activity. These recombinant
proteins, including PDE10A (human, rat and mouse PDE10) and
isoforms of PDEs 1, 3, 4, and 5, were purchased from commercial
vendor BPS Bioscience. The enzymatic activity of PDEs was
determined by cAMP measurement kit from CisBio (IBA) using HTRF
technology.
[1381] The PDE enzymatic reaction was carried out in assay buffer
(20 mM Tris-HCl pH7.5, 10 mM MgCl.sub.2, 0.1% bovine serum albumin)
containing enzyme and substrate. The PDE enzymes concentration
ranged from 10 pM-250 pM, depending on each enzyme's specific
activity. The substrate cyclic nucleotide (cAMP or cGMP)
concentration used in the assay was 20 nM for PDE10, and 100 nM for
other PDEs. The inhibitory effect of compound was determined by
incubating various concentration of inhibitor in the enzymatic
assay. Typically, compound was serial diluted in DMSO then further
diluted in assay buffer. Next, the compound at varying
concentration was mixed with PDE enzyme. The reaction was initiated
by addition of cyclic nucleotide substrate, and incubated for 60
minutes at 29 C. The reaction was stopped by addition of lysis
buffer from assay kit. The cAMP-d2 and anti-cAMP cryptate in the
lysis buffer detected the level of cAMP left from the PDE
hydrolysis reaction. The PDE activity is reversely correlated with
the amount of cAMP left in the reaction and can be converted to the
percent activity of an uninhibited control (100%). Thus, IC.sub.50
value of inhibitor can be obtained by plotting inhibitor
concentration against PDE activity at that concentration. The
results are shown in Table 1.
TABLE-US-00001 TABLE 1 Example IC.sub.50.sup.1) 1 ++ 15 + 20 + 21 +
23 + 24 + 26 ++ 28 + 29 + 30 + 31 + 32 + 33 + 34 + 35 + 36 ++ 37 ++
39 ++ 40 ++ 51 + 129 +++ 135 +++ 136 +++ 139 + 140 + 141 ++ 142 ++
145 + 146 + 147 ++ 148 + 149 + 151 + 152 + 153 ++ 154 ++ 156 + 158
++ 161 +++ 162 + 164 + 165 ++ 167 + 168 + 169 + 171 + 172 ++ 173 +
174 + 175 + 176 + 177 + 182 ++ 186 ++ 187 + 188 ++ 189 ++ 190 ++
191 + 192 +++ 193 +++ 194 +++ 195 ++ 197 ++ 198 + 199 + 200 + 201 +
202 +++ 205 + 216 +++ 219 +++ 228 ++ 230 ++ 233 ++ 236 ++ 237 ++
238 ++ 239 ++ 241 ++ 242 + 244 + 246 ++ 247 ++ 248 ++ 249 + 251 ++
252 ++ 253 +++ 254 +++ 255 + 256 +++ 257 ++ 258 ++ 259 + 260 ++ 261
+ 262 ++ 263 ++ 264 + 265 + 266 + 267 ++ 268 + 269 + 273 + 276 +
277 + 278 + 288 + 290 + 293 + 298 + 302 + 303 + 305 + 308 + 309 +
311 + 313 + 316 + 317 ++ 318 + 322 +++ 323 + .sup.1)+++: IC.sub.50
< 100 nM ++: 100 nM .ltoreq. IC.sub.50 .ltoreq. 200 nM +: 200 nM
< IC.sub.50 < 500 nM
b) Determination of the Microsomal Half-Life:
[1382] The metabolic stability of the compounds of the invention
was determined in the following assay.
[1383] The test substances were incubated in a concentration of 0.5
.mu.M as follows:
[1384] 0.5 .mu.M test substance are preincubated together with
liver microsomes from different species (from rat, human or other
species) (0.25 mg of microsomal protein/ml) in 0.05 M potassium
phosphate buffer of pH 7.4 in microtiter plates at 37.degree. C.
for 5 min The reaction is started by adding NADPH (1 mg/mL). After
0, 5, 10, 15, 20 and 30 min, 50 .mu.l aliquots are removed, and the
reaction is immediately stopped and cooled with the same volume of
acetonitrile. The samples are frozen until analyzed. The remaining
concentration of undegraded test substance is determined by MSMS.
The half-life (T1/2) is determined from the gradient of the signal
of test substance/unit time plot, it being possible to calculate
the half-life of the test substance, assuming first order kinetics,
from the decrease in the concentration of the compound with time.
The microsomal clearance (mCl) is calculated from mCl=ln
2/T1/2/(content of microsomal protein in mg/ml).times.1000
[ml/min/mg] (modified from references: Di, The Society for
Biomoleculur Screening, 2003, 453-462; Obach, DMD, 1999 vol 27. N
11, 1350-1359). The results are shown in Table 2.
TABLE-US-00002 TABLE 2 Rat mCl.sup.2) Human mCl.sup.2) Ex. [.mu.l
min.sup.-1 mg.sup.-1] [.mu.l min.sup.-1 mg.sup.-1] 40 ++ ++ 136
.smallcircle. + 141 ++ ++ 147 ++ ++ 158 ++ ++ 161 ++ ++ 165 ++ ++
171 ++ ++ 172 ++ ++ 186 ++ ++ 190 + .smallcircle. 192 +
.smallcircle. 195 + + 196 ++ ++ 197 + .smallcircle. 198 ++ + 199 ++
++ 200 ++ ++ 201 ++ ++ 202 + .smallcircle. 203 ++ ++ 204 ++ + 205
++ ++ 219 + + 228 ++ ++ 236 ++ + 238 + ++ 239 + + 241 + ++ 244 ++
++ 246 + .smallcircle. 247 ++ + 248 ++ + 251 .smallcircle. + 256 +
.smallcircle. 263 ++ ++ 267 .smallcircle. + 309 nd ++ 310 ++ ++ 311
nd ++ 312 ++ + 313 ++ ++ 314 ++ ++ 315 ++ ++ 316 ++ ++ 317 + ++ 318
++ ++ Ex. Example mCl mikrosomal clearance .sup.2)++: <100 .mu.l
min.sup.-1 mg.sup.-1 +: 100-220 .mu.l min.sup.-1 mg.sup.-1
.smallcircle.: >220 .mu.l min.sup.-1 mg.sup.-1 nd: not
determined
* * * * *