U.S. patent application number 14/407134 was filed with the patent office on 2015-04-23 for novel 1,3-dihydro-2h-benzimidazol-2-one derivatives substituted with heterocycles as respiratory syncytial virus antiviral agents.
This patent application is currently assigned to Jansen R&D Ireland. The applicant listed for this patent is Jansen R&D Ireland. Invention is credited to Ludwig Paul Cooymans, Samuel Dominique Demin, Lili Hu, Tim Hugo Maria Jonckers, Pierre Jean-Marie Bernard Raboisson, Abdellah Tahri, Sandrine Marie Helene Vendeville.
Application Number | 20150111868 14/407134 |
Document ID | / |
Family ID | 48613635 |
Filed Date | 2015-04-23 |
United States Patent
Application |
20150111868 |
Kind Code |
A1 |
Tahri; Abdellah ; et
al. |
April 23, 2015 |
NOVEL 1,3-DIHYDRO-2H-BENZIMIDAZOL-2-ONE DERIVATIVES SUBSTITUTED
WITH HETEROCYCLES AS RESPIRATORY SYNCYTIAL VIRUS ANTIVIRAL
AGENTS
Abstract
The present invention is concerned with novel
1,3-dihydro-2H-benzimidazol-2-one derivatives substituted with
heterocycles having formula (I) ##STR00001## stereoisomeric forms
thereof, and the pharmaceutically acceptable addition salts, and
the solvates thereof, wherein R.sup.4, R.sup.5, Z and Het have the
meaning defined in the claims. The compounds according to the
present invention are useful as inhibitors on the replication of
the respiratory syncytial virus (RSV). The invention further
concerns the preparation of such novel compounds, compositions
comprising these compounds, and the compounds for use in the
treatment of respiratory syncytial virus infection.
Inventors: |
Tahri; Abdellah;
(Anderlecht, BE) ; Jonckers; Tim Hugo Maria;
(Heist-op-den-Berg, BE) ; Raboisson; Pierre Jean-Marie
Bernard; (Rosieres, BE) ; Vendeville; Sandrine Marie
Helene; (Woluwe-Saint-Pierre, BE) ; Hu; Lili;
(Mechelen, BE) ; Demin; Samuel Dominique;
(Antwerpen, BE) ; Cooymans; Ludwig Paul; (Beerse,
BE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Jansen R&D Ireland |
Co Cork |
|
IE |
|
|
Assignee: |
Jansen R&D Ireland
New Brunswick
NJ
|
Family ID: |
48613635 |
Appl. No.: |
14/407134 |
Filed: |
June 14, 2013 |
PCT Filed: |
June 14, 2013 |
PCT NO: |
PCT/EP2013/062322 |
371 Date: |
December 11, 2014 |
Current U.S.
Class: |
514/210.18 ;
514/210.21; 514/256; 514/275; 514/303; 514/371; 544/328; 544/331;
546/118; 548/196; 548/305.1 |
Current CPC
Class: |
C07D 471/04 20130101;
A61P 31/16 20180101; C07D 417/14 20130101; A61P 31/14 20180101;
A61P 31/12 20180101; A61P 31/00 20180101; C07D 519/00 20130101;
C07D 403/14 20130101 |
Class at
Publication: |
514/210.18 ;
546/118; 548/305.1; 514/303; 514/210.21; 544/331; 514/275; 544/328;
514/256; 548/196; 514/371 |
International
Class: |
C07D 471/04 20060101
C07D471/04; C07D 417/14 20060101 C07D417/14; C07D 403/14 20060101
C07D403/14 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 15, 2012 |
EP |
EP12172271.4 |
Aug 31, 2012 |
EP |
EP12182550.9 |
Claims
1. A compound of Formula (I), ##STR00164## or a stereoisomeric form
thereof, wherein Het is a heterocycle having formula (b), (c), (d)
or (e) ##STR00165## each X independently is C or N; provided that
at least one X is N; R.sup.1b is present when Het has formula (b)
and X is C; each R.sup.1b is selected independently from the group
consisting of H, halogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkyloxy,
N(R.sup.6).sub.2, CO(R.sup.7), CH.sub.2NH.sub.2, CH.sub.2OH, CN,
C(.dbd.NOH)NH.sub.2, C(.dbd.NOCH.sub.3)NH.sub.2,
C(.dbd.NH)NH.sub.2, CF.sub.3, OCF.sub.3, B(OH).sub.2 and
B(O--C.sub.1-C.sub.6alkyl).sub.2; R.sup.1b is absent when the X to
which it is bound is N; R.sup.2b is
--(CR.sup.8R.sup.9).sub.m--R.sup.10b; each R.sup.6 is independently
selected from the group consisting of H, C.sub.1-C.sub.6alkyl,
COOCH.sub.3 and CONHSO.sub.2CH.sub.3; each R.sup.7 is independently
selected from the group consisting of OH, C.sub.1-C.sub.6alkyloxy,
NH.sub.2, NHSO.sub.2N(C.sub.1-C.sub.6alkyl).sub.2,
NHSO.sub.2NHCH.sub.3, NHSO.sub.2(C.sub.1-C.sub.6alkyl),
NHSO.sub.2(C.sub.3-C.sub.7cycloalkyl) and
N(C.sub.1-C.sub.6-alkyl).sub.2; each R.sup.8 and R.sup.9 are
independently chosen from the group consisting of H,
C.sub.1-C.sub.10alkyl and C.sub.3-C.sub.7cycloalkyl; or R.sup.8 and
R.sup.9 taken together form a 4 to 6 membered aliphatic ring that
optionally contains one or more heteroatoms selected from the group
consisting of N, S and O; R.sup.10b is selected from the group
consisting of H, R.sup.11, OH, CN, F, CF.sub.2H, CF.sub.3,
CONR.sup.8R.sup.9, COOR.sup.8, CON(R.sup.8)SO.sub.2R.sup.9,
CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9), NR.sup.8R.sup.9,
NR.sup.8COOR.sup.9, OCOR.sup.8, O-Benzyl, NR.sup.8SO.sub.2R.sup.9,
SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8, OCONR.sup.8R.sup.9,
OCONR.sup.8R.sup.12, N(R.sup.8)CON(R.sup.8R.sup.9),
N(R.sup.8)COOR.sup.12, and a 4 to 6 membered saturated ring
containing one oxygen atom; m is an integer from 2 to 6; R.sup.11
is selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.7cycloalkyl, phenyl, pyridinyl and pyrazolyl; each
optionally substituted with one or more substituents each
independently selected from the group consisting of CF.sub.3,
CH.sub.3, OCH.sub.3, OCF.sub.3 and halogen; R.sup.12 is selected
from the group consisting of phenyl, pyridinyl and pyrazolyl; each
optionally substituted with one or more substituents each
independently selected from the group consisting of CF.sub.3,
CH.sub.3, OCH.sub.3, OCF.sub.3 and halogen; or R.sup.12 is
C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.7cycloalkyl; each
substituted with one or more substituents each independently
selected from the group consisting of CF.sub.3, CH.sub.3,
OCH.sub.3, OCF.sub.3 and halogen; R.sup.1c is present when Het has
formula (c); each R.sup.1c is selected independently from the group
consisting of H, halogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkyloxy,
N(R.sup.6).sub.2, CO(R.sup.7c), CH.sub.2NH.sub.2, CH.sub.2OH, CN,
C(.dbd.NOH)NH.sub.2, C(.dbd.NOCH.sub.3)NH.sub.2,
C(.dbd.NH)NH.sub.2, CF.sub.3, OCF.sub.3, B(OH).sub.2 and
B(O--C.sub.1-C.sub.6alkyl).sub.2; R.sup.3c is selected from the
group consisting of H, halogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkyloxy and
CO(R.sup.7c).sub.m--R.sup.10c; R.sup.2c is
--(CR.sup.8R.sup.9).sub.m--R.sup.10c; R.sup.7c is selected from the
group consisting of OH, O(C.sub.1-C.sub.6alkyl), NH.sub.2,
NHSO.sub.2N(C.sub.1-C.sub.6alkyl).sub.2, NHSO.sub.2NHCH.sub.3,
NHSO.sub.2(C.sub.1-C.sub.6alkyl),
NHSO.sub.2(C.sub.3-C.sub.7cycloalkyl),
N(C.sub.1-C.sub.6-alkyl).sub.2, NR.sup.8R.sup.9 and
NR.sup.9R.sup.10c; R.sup.10c is selected from the group consisting
of H, R.sup.11, OH, CN, F, CF.sub.2H, CF.sub.3,
C(.dbd.NOH)NH.sub.2, CONR.sup.8R.sup.9, COOR.sup.8,
CONR.sup.8SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sup.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8
and a 4 to 6 membered saturated ring containing one oxygen atom;
R.sup.1d is present when Het has formula (d) and X is C; each
R.sup.1d is selected independently from the group consisting of H,
OH, halogen, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, N(R.sup.6).sub.2, CO(R.sup.7),
CH.sub.2NH.sub.2, CH.sub.2OH, C(.dbd.NOH)NH.sub.2,
C(.dbd.NOCH.sub.3)NH.sub.2, C(.dbd.NH)NH.sub.2, CF.sub.3,
OCF.sub.3, B(OH).sub.2 and B(O--C.sub.1-C.sub.6alkyl).sub.2;
R.sup.1d is absent when the X to which it is bound is N; R.sup.3d
is selected from the group consisting of H, halogen,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, and CO(R.sup.7); R.sup.2d is
--(CR.sup.8R.sup.9).sub.m--R.sup.10d; R.sup.10d is selected from
the group consisting of H, R.sup.11, OH, CN, F, CF.sub.2H,
CF.sub.3, CONR.sup.8R.sup.9, COOR.sup.8, CONR.sup.8SO.sub.2R.sup.9,
CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9), NR.sup.8R.sup.9,
NR.sup.8COOR.sub.9, OCOR.sup.8, NR.sup.8SO.sub.2R.sup.9,
SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8 and a 4 to 6 membered
saturated ring containing one oxygen atom; each Y independently is
C or N; R.sup.1e is present when Het has formula (e) and Y is C;
each R.sup.1e is selected independently from the group consisting
of H, halogen, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, N(R.sup.6).sub.2, CO(R.sup.7),
CH.sub.2NH.sub.2, CH.sub.2OH, CN, C(.dbd.NOH)NH.sub.2,
C(.dbd.NOCH.sub.3)NH.sub.2, C(.dbd.NH)NH.sub.2, CF.sub.3,
OCF.sub.3, B(OH).sub.2 and B(O--C.sub.1-C.sub.6alkyl).sub.2;
R.sup.1e is absent when the Y to which it is bound is N; R.sup.3e
is selected from the group consisting of H, halogen,
--(CR.sup.8R.sup.9).sub.m--R.sup.10e,
C.ident.C--CH.sub.2--R.sup.10e, C.ident.C--R.sup.10e and
C.dbd.C--R.sup.10e; R.sup.10e is selected from the group consisting
of H, R.sup.11, C.sub.1-C.sub.6alkyloxy, OH, CN, F, CF.sub.2H,
CF.sub.3, CONR.sup.8R.sup.9, COOR.sup.8,
CON(R.sup.8)SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sup.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8
and a 4 to 6 membered saturated ring containing one oxygen atom;
R.sup.4 is selected from the group consisting of tert-butyl,
Het.sup.1, aryl, Het.sup.2, CH(CH.sub.3)(CF.sub.3), and
C.sub.3-C.sub.7cycloalkyl substituted with one or more substituents
selected from the group consisting of halo and
C.sub.1-C.sub.4alkyl; aryl represents phenyl or naphthalenyl; said
aryl optionally being substituted with one or more substituents
each independently selected from the group consisting of halo,
C.sub.1-C.sub.4alkyloxy, C.sub.1-C.sub.4alkyl, OH, CN, CF.sub.2H,
CF.sub.3, CF.sub.3O, CONR.sup.8R.sup.9, COOR.sup.8,
CON(R.sup.8)SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sup.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8,
OCONR.sup.8R.sup.9, OCONR.sup.8R.sup.12,
N(R.sup.8)CON(R.sup.8R.sup.9), N(R.sup.8)COOR.sup.12; or
C.sub.1-4alkyloxyC.sub.1-4alkyloxy; Het.sup.1 represents a 4 to 6
membered saturated ring containing one N atom, optionally being
substituted with one or more substituents each independently
selected from the group consisting of halo,
C.sub.1-C.sub.4alkyloxy, SO.sub.2R.sup.8,
C.sub.1-C.sub.4alkylcarbonyl, CO(aryl), COHet.sup.2,
C.sub.1-C.sub.4alkyloxycarbonyl, pyridinyl, CF.sub.3,
SO.sub.2N(C.sub.1-C.sub.4alkyl).sub.2,
SO.sub.2NH(C.sub.1-C.sub.4alkyl), (C.dbd.O)NH(C.sub.1-4 alkyl),
(C.dbd.S)NH(C.sub.1-4alkyl), C.sub.1-C.sub.4alkyl and
C.sub.1-C.sub.4alkyl substituted with one hydroxy; or Het.sup.1
represents a 4 to 6 membered saturated ring containing one O atom,
substituted with one or more substituents each independently
selected from the group consisting of halo,
C.sub.1-C.sub.4alkyloxy, CF.sub.3, NH(C.dbd.O)(C.sub.1-4alkyl),
(C.dbd.O)NH(C.sub.1-4alkyl) and C.sub.1-C.sub.4alkyl; or Het.sup.1
represents a bicyclic 7 to 11 membered non-aromatic heterocycle
containing one or two heteroatoms each independently selected from
the group consisting of O, S and N, optionally substituted with one
or more substituents each independently selected from the group
consisting of halo, C.sub.1-C.sub.4alkyloxy, SO.sub.2R.sup.8,
C.sub.1-C.sub.4alkylcarbonyl, CO(aryl), COHet.sup.2,
C.sub.1-C.sub.4alkyloxycarbonyl, pyridinyl, CF.sub.3,
SO.sub.2N(C.sub.1-C.sub.4alkyl).sub.2,
SO.sub.2NH(C.sub.1-C.sub.4alkyl), (C.dbd.O)NH(C.sub.1-4alkyl),
(C.dbd.S)NH(C.sub.1-4alkyl), C.sub.1-C.sub.4alkyl and
C.sub.1-C.sub.4alkyl substituted with one hydroxy; Het.sup.2
represents a monocyclic 5 to 6 membered aromatic heterocycle
containing one or more heteroatoms each independently selected from
the group consisting of O, S and N; or a bicyclic 8 to 12 membered
aromatic heterocycle containing one or more heteroatoms each
independently selected from the group consisting of O, S and N;
said Het.sup.2 optionally being substituted with one or more
substituents each independently selected from the group consisting
of halo, C.sub.1-C.sub.4alkyloxy, C.sub.1-C.sub.4alkyl, OH, CN,
CF.sub.2H, CF.sub.3, CONR.sup.8R.sup.9, COOR.sup.8,
CON(R.sup.8)SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sup.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8,
OCONR.sup.8R.sup.9, OCONR.sup.8R.sup.12,
N(R.sup.8)CON(R.sup.8R.sup.9), N(R.sup.8)COOR.sup.12; Z is C or N;
R.sup.5 is present where Z is C, whereby R.sup.5 is selected form
the group consisting of hydrogen, CF.sub.3 and halogen; R.sup.5 is
absent where Z is N; or a pharmaceutically acceptable addition salt
or a solvate thereof.
2. The compound according to claim 1, wherein Het is a heterocycle
having formula (b), (c), (d) or (e); each X independently is C or
N; provided that at least one X is N; R.sup.1b is present when Het
has formula (b) and X is C; each R.sup.1b is selected independently
from the group consisting of H, halogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkyloxy, CF.sub.3 and
OCF.sub.3; R.sup.1b is absent when the X to which it is bound is N;
R.sup.2b is --(CR.sup.8R.sup.9).sub.m--R.sup.10b; each R.sup.8 and
R.sup.9 are independently chosen from the group consisting of H and
C.sub.1-C.sub.10alkyl; R.sup.10b is selected from the group
consisting of H, R.sup.11, OH, CN, F, CF.sub.2H, CF.sub.3,
NR.sup.8R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8; m is an
integer from 2 to 6; R.sup.11 is selected from the group consisting
of C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7cycloalkyl, phenyl,
pyridinyl and pyrazolyl; each optionally substituted with one or
more substituents each independently selected from the group
consisting of CF.sub.3, CH.sub.3, OCH.sub.3, OCF.sub.3 and halogen;
R.sup.12 is selected from the group consisting of phenyl, pyridinyl
and pyrazolyl; each optionally substituted with one or more
substituents each independently selected from the group consisting
of CF.sub.3, CH.sub.3, OCH.sub.3, OCF.sub.3 and halogen; or
R.sup.12 is C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.7cycloalkyl;
each substituted with one or more substituents each independently
selected from the group consisting of CF.sub.3, CH.sub.3,
OCH.sub.3, OCF.sub.3 and halogen; R.sup.1c is present when Het has
formula (c); each R.sup.1c is selected independently from the group
consisting of H, halogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkyloxy, CF.sub.3 and
OCF.sub.3; R.sup.3c is selected from the group consisting of H,
halogen, C.sub.1-C.sub.6alkyl; R.sup.2c is
--(CR.sup.8R.sup.9).sub.m--R.sup.10c; R.sup.10c is selected from
the group consisting of H, C.sub.1-C.sub.6alkyl, OH, CN, F,
CF.sub.2H, CF.sub.3, NR.sup.8R.sup.9, SO.sub.2NR.sup.8R.sup.9,
SO.sub.2R.sup.8; R.sup.1d is present when Het has formula (d) and X
is C; each R.sup.1d is selected independently from the group
consisting of H, halogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkyloxy, CF.sub.3 and
OCF.sub.3; R.sup.1d is absent when the X to which it is bound is N;
R.sup.3d is selected from the group consisting of H, halogen,
C.sub.1-C.sub.6alkyl; R.sup.2d is
--(CR.sup.8R.sup.9).sub.m--R.sup.10d; R.sup.10d is selected from
the group consisting of H, C.sub.1-C.sub.6alkyl, OH, CN, F,
CF.sub.2H, CF.sub.3, NR.sup.8R.sup.9, SO.sub.2NR.sup.8R.sup.9,
SO.sub.2R.sup.8; each Y independently is C or N; R.sup.1e is
present when Het has formula (e) and Y is C; each R.sup.1e is
selected independently from the group consisting of H, halogen,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, CF.sub.3 and OCF.sub.3; R.sup.1e is absent
when the Y to which it is bound is N; R.sup.3e is selected from the
group consisting of H, halogen; R.sup.4 is selected from the group
consisting of tert-butyl, Het', aryl, Het.sup.2,
CH(CH.sub.3)(CF.sub.3), and C.sub.3-C.sub.7cycloalkyl substituted
with one or more substituents selected from the group consisting of
halo and C.sub.1-C.sub.4alkyl; aryl represents phenyl or
naphthalenyl; said aryl optionally being substituted with one or
more substituents each independently selected from the group
consisting of halo, C.sub.1-C.sub.4alkyloxy, C.sub.1-C.sub.4alkyl,
OH, CN, CF.sub.2H, CF.sub.3, CONR.sup.8R.sup.9, NR.sup.8R.sup.9,
NR.sup.8COOR.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8,
OCONR.sup.8R.sup.9, OCONR.sup.8R.sup.12, N(R.sup.8)COOR.sup.12;
Het.sup.1 represents a 4 to 6 membered saturated ring containing
one N atom, optionally being substituted with one or more
substituents each independently selected from the group consisting
of halo, C.sub.1-C.sub.4alkyloxy, CF.sub.3, SO.sub.2R.sup.8,
C.sub.1-C.sub.4alkylcarbonyl, C.sub.1-C.sub.4alkyloxycarbonyl,
pyridinyl, SO.sub.2N(C.sub.1-C.sub.4alkyl).sub.2,
SO.sub.2NH(C.sub.1-C.sub.4alkyl), (C.dbd.O)NH(C.sub.1-4alkyl),
(C.dbd.S)NH(C.sub.1-4alkyl), C.sub.1-C.sub.4alkyl and
C.sub.1-C.sub.4alkyl substituted with one hydroxy; or Het.sup.1
represents a 4 to 6 membered saturated ring containing one O atom,
substituted with one or more substituents each independently
selected from the group consisting of halo,
C.sub.1-C.sub.4alkyloxy, CF.sub.3, NH(C.dbd.O)(C.sub.1-4alkyl),
(C.dbd.O)NH(C.sub.1-4alkyl) and C.sub.1-C.sub.4alkyl; Het.sup.2
represents a monocyclic 5 to 6 membered aromatic heterocycle
containing one or more heteroatoms each independently selected from
the group consisting of O, S and N; or a bicyclic 8 to 12 membered
aromatic heterocycle containing one or more heteroatoms each
independently selected from the group consisting of O, S and N;
said Het.sup.2 optionally being substituted with one or more
substituents each independently selected from the group consisting
of halo, C.sub.1-C.sub.4alkyloxy, C.sub.1-C.sub.4alkyl, OH, CN,
CF.sub.2H, CF.sub.3, CONR.sup.8R.sup.9, NR.sup.8R.sup.9,
NR.sup.8COOR.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8,
OCONR.sup.8R.sup.9, OCONR.sup.8R.sup.12, N(R.sup.8)COOR.sup.12; Z
is C or N; R.sup.5 is present where Z is C, whereby R.sup.5 is
selected form the group consisting of hydrogen, CF.sub.3 and
halogen; R.sup.5 is absent where Z is N; and the pharmaceutically
acceptable addition salts, and the solvates thereof.
3. The compound according to claim 1, wherein Het is a heterocycle
having formula (b), (d) or (e).
4. The compound according to claim 1, wherein Het is a heterocycle
having formula (c).
5. The compound according to claim 1, wherein Z is N and R.sup.5 is
absent.
6. The compound according to claim 1, wherein Z is C and R.sup.5 is
halogen.
7. The compound according to claim 1, wherein R.sup.4 is selected
from the group consisting of Het % aryl, Het.sup.2, and
C.sub.3-C.sub.7cycloalkyl substituted with one or more substituents
selected from the group consisting of halo and
C.sub.1-C.sub.4alkyl.
8. The compound according to claim 7 wherein R.sup.4 is
Het.sup.1.
9. The compound according to claim 7 wherein R.sup.4 is
Het.sup.2.
10. The compound according to claim 7 wherein R.sup.4 is aryl.
11. The compound according to claim 10 wherein aryl is phenyl
optionally being substituted with one or more substituents each
independently selected from the group consisting of halo,
C.sub.1-C.sub.4alkyloxy, C.sub.1-C.sub.4alkyl, CN,
CONR.sup.8R.sup.9, COOR.sup.8, SO.sub.2R.sup.8.
12. The compound according to claim 11 wherein aryl is phenyl
substituted with two substituents each independently selected from
the group consisting of halo, C.sub.1-C.sub.4alkyloxy or
C.sub.1-C.sub.4alkyl.
13. The compound according to claim 12 wherein Het is of formula
(c-1a) ##STR00166## wherein R.sup.3c is H and R.sup.2c is
--(CR.sup.8R.sup.9).sub.m--R.sup.10c wherein R.sup.8 and R.sup.9
are each H, m is 3 and R.sup.10c represents CN or
SO.sub.2CH.sub.3.
14. The compound according to claim 1 wherein aryl is phenyl
optionally being substituted with one or more substituents each
independently selected from the group consisting of halo,
C.sub.1-C.sub.4alkyloxy, C.sub.1-C.sub.4alkyl, CN,
CONR.sup.8R.sup.9, COOR.sup.8, SO.sub.2R.sup.8, CF.sub.3 0 or
C.sub.1-4alkyloxyC.sub.1-4alkyloxy.
15. The compound according to claim 1 wherein the compound is
##STR00167##
16. (canceled)
17. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier, and as active ingredient a therapeutically
effective amount of a compound as defined in claim 1.
18. (canceled)
19. A method of treating a respiratory syncytial viral (RSV)
infection comprising administering to a subject in need of
treatment an anti-virally effective amount of a compound as claimed
in claim 1.
Description
FIELD OF THE INVENTION
[0001] The invention concerns novel
1,3-dihydro-2H-benzimidazol-2-one derivatives substituted with
heterocycles having antiviral activity, in particular, having an
inhibitory activity on the replication of the respiratory syncytial
virus (RSV). The invention further concerns the preparation of such
novel compounds, compositions comprising these compounds, and the
compounds for use in the treatment of respiratory syncytial virus
infection.
BACKGROUND
[0002] Human RSV or Respiratory Syncytial Virus is a large RNA
virus, member of the family of Paramyxoviridae, subfamily
pneumoviridae together with bovine RSV virus. Human RSV is
responsible for a spectrum of respiratory tract diseases in people
of all ages throughout the world. It is the major cause of lower
respiratory tract illness during infancy and childhood. Over half
of all infants encounter RSV in their first year of life, and
almost all within their first two years. The infection in young
children can cause lung damage that persists for years and may
contribute to chronic lung disease in later life (chronic wheezing,
asthma). Older children and adults often suffer from a (bad) common
cold upon RSV infection. In old age, susceptibility again
increases, and RSV has been implicated in a number of outbreaks of
pneumonia in the aged resulting in significant mortality.
[0003] Infection with a virus from a given subgroup does not
protect against a subsequent infection with an RSV isolate from the
same subgroup in the following winter season. Re-infection with RSV
is thus common, despite the existence of only two subtypes, A and
B.
[0004] Today only three drugs have been approved for use against
RSV infection. A first one is ribavirin, a nucleoside analogue that
provides an aerosol treatment for serious RSV infection in
hospitalized children. The aerosol route of administration, the
toxicity (risk of teratogenicity), the cost and the highly variable
efficacy limit its use. The other two drugs, RespiGam.RTM. (RSV-IG)
and Synagis.RTM. (palivizumab), polyclonal and monoclonal antibody
immunostimulants, are intended to be used in a preventive way. Both
are very expensive, and require parenteral administration.
[0005] Other attempts to develop a safe and effective RSV vaccine
have all met with failure thus far. Inactivated vaccines failed to
protect against disease, and in fact in some cases enhanced disease
during subsequent infection. Life attenuated vaccines have been
tried with limited success. Clearly there is a need for an
efficacious non-toxic and easy to administer drug against RSV
replication. It would be particularly preferred to provide drugs
against RSV replication that could be administered perorally.
[0006] A reference on benzimidazole antiviral agents is
WO-01/95910. Herein compounds are presented to have antiviral
activity, yet with EC.sub.50 values over a wide range of from 0.001
.mu.m to as high as 50 .mu.M (which does not normally represent the
desired biological activity). Another reference, relating to
substituted 2-methyl-benzimidazole RSV antiviral agents, in the
same range of activities is WO-03/053344. Another related
background reference on compounds in the same range of activities,
is WO-02/26228 regarding benzimidazolone antiviral agents. A
reference on structure-activity relations, in respect of RSV
inhibition, of 5-substituted benzimidazole compounds is Kuo-Long Yu
et al., Bioorganic and Medicinal Chemistry Letters 14 (2004)
1133-1137, Kuo-Long Yu et al., Bioorganic and Medicinal Chemistry
Letters 17 (2007) 895-901, and X. A. Wang et al., Bioorganic and
Medicinal Chemistry Letters 17 (2007) 4592-4598.
[0007] WO-2004/069256 discloses 2-cyanopyrrolopyrimidines as
capthepsin K or S inhibitors useful in the treatment of various
pain disorders. WO-2008/147697 discloses benzimidazole derivatives
as chymase inhibitors.
[0008] WO-2012/080446, WO-2012/080447, WO-2012/080449,
WO-2012/080450 and WO-2012/080481 all filed on 16 Dec. 2011 and
published on 21 Jun. 2012 disclose benzimidazole derivatives having
antiviral activity against respiratory syncytial virus.
[0009] It is desired to provide new drugs that have antiviral
activity. Particularly, it would be desired to provide new drugs
that have RSV replication inhibitory activity. Further, it would be
desired to retrieve compound structures that allow obtaining
antiviral biological activities of the order of magnitude in the
stronger regions of the prior art (i.e. at the bottom of the
above-mentioned range of up to 50 .mu.M), and preferably at a level
of about the most active, more preferably of even stronger
activity, than the compounds disclosed in the art. A further desire
is to find compounds having oral antiviral activity.
SUMMARY OF THE INVENTION
[0010] In order to better address one or more of the foregoing
desires, the invention, in one aspect, presents antiviral compounds
represented by formula (I),
##STR00002##
and stereoisomeric forms thereof, wherein Het is a heterocycle
having formula (b), (c), (d) or (e)
##STR00003##
each X independently is C or N; provided that at least one X is N;
[0011] R.sup.1b is present when Het has formula (b) and X is C;
each R.sup.1b is selected independently from the group consisting
of H, halogen, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, N(R.sup.6).sub.2, CO(R.sup.7),
CH.sub.2NH.sub.2, CH.sub.2OH, CN, C(.dbd.NOH)NH.sub.2,
C(.dbd.NOCH.sub.3)NH.sub.2, C(.dbd.NH)NH.sub.2, CF.sub.3,
OCF.sub.3, B(OH).sub.2 and B(O--C.sub.1-C.sub.6alkyl).sub.2;
R.sup.1b is absent when the X to which it is bound is N; [0012]
R.sup.2b is --(CR.sup.8R.sup.9).sub.m--R.sup.10b; [0013] each
R.sup.6 is independently selected from the group consisting of H,
C.sub.1-C.sub.6alkyl, COOCH.sub.3 and CONHSO.sub.2CH.sub.3; [0014]
each R.sup.7 is independently selected from the group consisting of
OH, C.sub.1-C.sub.6alkyloxy, NH.sub.2,
NHSO.sub.2N(C.sub.1-C.sub.6alkyl).sub.2, NHSO.sub.2NHCH.sub.3,
NHSO.sub.2(C.sub.1-C.sub.6alkyl),
NHSO.sub.2(C.sub.3-C.sub.7cycloalkyl) and
N(C.sub.1-C.sub.6-alkyl).sub.2; [0015] each R.sup.8 and R.sup.9 are
independently chosen from the group consisting of H,
C.sub.1-C.sub.10alkyl and C.sub.3-C.sub.7cycloalkyl; or R.sup.8 and
R.sup.9 taken together form a 4 to 6 membered aliphatic ring that
optionally contains one or more heteroatoms selected from the group
consisting of N, S and O; [0016] R.sup.10b is selected from the
group consisting of H, R.sup.11, OH, CN, F, CF.sub.2H, CF.sub.3,
CONR.sup.8R.sup.9, COOR.sup.8, CON(R.sup.8)SO.sub.2R.sup.9,
CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9), NR.sup.8R.sup.9,
NR.sup.8COOR.sup.9, OCOR.sup.8, O-Benzyl, NR.sup.8SO.sub.2R.sup.9,
SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8, OCONR.sup.8R.sup.9,
OCONR.sup.8R.sup.12, N(R.sup.8)CON(R.sup.8R.sup.9),
N(R.sup.8)COOR.sup.12, and a 4 to 6 membered saturated ring
containing one oxygen atom; [0017] m is an integer from 2 to 6;
[0018] R.sup.11 is selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7cycloalkyl, phenyl, pyridinyl
and pyrazolyl; each optionally substituted with one or more
substituents each independently selected from the group consisting
of CF.sub.3, CH.sub.3, OCH.sub.3, OCF.sub.3 and halogen; [0019]
R.sup.12 is selected from the group consisting of phenyl, pyridinyl
and pyrazolyl; each optionally substituted with one or more
substituents each independently selected from the group consisting
of CF.sub.3, CH.sub.3, OCH.sub.3, OCF.sub.3 and halogen; [0020] or
R.sup.12 is C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.7cycloalkyl;
each substituted with one or more substituents each independently
selected from the group consisting of CF.sub.3, CH.sub.3,
OCH.sub.3, OCF.sub.3 and halogen; [0021] R.sup.1c is present when
Het has formula (c); [0022] each R.sup.1c is selected independently
from the group consisting of H, halogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkyloxy,
N(R.sup.6).sub.2, CO(R.sup.7c), CH.sub.2NH.sub.2, CH.sub.2OH, CN,
C(.dbd.NOH)NH.sub.2, C(.dbd.NOCH.sub.3)NH.sub.2,
C(.dbd.NH)NH.sub.2, CF.sub.3, OCF.sub.3, B(OH).sub.2 and
B(O--C.sub.1-C.sub.6alkyl).sub.2; [0023] R.sup.3c is selected from
the group consisting of H, halogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkyloxy and
CO(R.sup.7c); [0024] R.sup.2c is
--(CR.sup.8R.sup.9).sub.m--R.sup.10c; [0025] R.sup.7c is selected
from the group consisting of OH, O(C.sub.1-C.sub.6alkyl), NH.sub.2,
NHSO.sub.2N(C.sub.1-C.sub.6alkyl).sub.2, NHSO.sub.2NHCH.sub.3,
NHSO.sub.2(C.sub.1-C.sub.6alkyl),
NHSO.sub.2(C.sub.3-C.sub.7cycloalkyl),
N(C.sub.1-C.sub.6-alkyl).sub.2, NR.sup.8R.sup.9 and
NR.sup.9R.sup.10c; [0026] R.sup.10c is selected from the group
consisting of H, R.sup.11, OH, CN, F, CF.sub.2H, CF.sub.3,
C(.dbd.NOH)NH.sub.2, CONR.sup.8R.sup.9, COOR.sup.8,
CONR.sup.8SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sup.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8
and a 4 to 6 membered saturated ring containing one oxygen atom;
[0027] R.sup.1d is present when Het has formula (d) and X is C;
each R.sup.1d is selected independently from the group consisting
of H, OH, halogen, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, N(R.sup.6).sub.2, CO(R.sup.7),
CH.sub.2NH.sub.2, CH.sub.2OH, C(.dbd.NOH)NH.sub.2,
C(.dbd.NOCH.sub.3)NH.sub.2, C(.dbd.NH)NH.sub.2, CF.sub.3,
OCF.sub.3, B(OH).sub.2 and B(O--C.sub.1-C.sub.6alkyl).sub.2;
R.sup.1d is absent when the X to which it is bound is N; [0028]
R.sup.3d is selected from the group consisting of H, halogen,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, and CO(R.sup.7); [0029] R.sup.2d is
--(CR.sup.8R.sup.9).sub.m--R.sup.10d; [0030] R.sup.10d is selected
from the group consisting of H, R.sup.11, OH, CN, F, CF.sub.2H,
CF.sub.3, CONR.sup.8R.sup.9, COOR.sup.8, CONR.sup.8SO.sub.2R.sup.9,
CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9), NR.sup.8R.sup.9,
NR.sup.8COOR.sub.9, OCOR.sup.8, NR.sup.8SO.sub.2R.sup.9,
SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8 and a 4 to 6 membered
saturated ring containing one oxygen atom; [0031] each Y
independently is C or N; [0032] R.sup.1e is present when Het has
formula (e) and Y is C; each R.sup.1e is selected independently
from the group consisting of H, halogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkyloxy,
N(R.sup.6).sub.2, CO(R.sup.7), CH.sub.2NH.sub.2, CH.sub.2OH, CN,
C(.dbd.NOH)NH.sub.2, C(.dbd.NOCH.sub.3)NH.sub.2,
C(.dbd.NH)NH.sub.2, CF.sub.3, OCF.sub.3, B(OH).sub.2 and
B(O--C.sub.1-C.sub.6alkyl).sub.2; R.sup.1e is absent when the Y to
which it is bound is N; [0033] R.sup.3e is selected from the group
consisting of H, halogen, --(CR.sup.8R.sup.9).sub.m--R.sup.10e,
C.ident.C--CH.sub.2--R.sup.10e, C.ident.C--R.sup.10e and
C.dbd.C--R.sup.10e; [0034] R.sup.10e is selected from the group
consisting of H, R.sup.11, C.sub.1-C.sub.6alkyloxy, OH, CN, F,
CF.sub.2H, CF.sub.3, CONR.sup.8R.sup.9, COOR.sup.8,
CON(R.sup.8)SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sup.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8
and a 4 to 6 membered saturated ring containing one oxygen atom;
[0035] R.sup.4 is selected from the group consisting of tert-butyl,
Het.sup.1, aryl, Het.sup.2, CH(CH.sub.3)(CF.sub.3), and
C.sub.3-C.sub.7cycloalkyl substituted with one or more substituents
selected from the group consisting of halo and
C.sub.1-C.sub.4alkyl; [0036] aryl represents phenyl or
naphthalenyl; said aryl optionally being substituted with one or
more substituents each independently selected from the group
consisting of halo, C.sub.1-C.sub.4alkyloxy, C.sub.1-C.sub.4alkyl,
OH, CN, CF.sub.2H, CF.sub.3, CF.sub.3O, CONR.sup.8R.sup.9,
COOR.sup.8, CON(R.sup.8)SO.sub.2R.sup.9,
CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9), NR.sup.8R.sup.9,
NR.sup.8COOR.sup.9, OCOR.sup.8, NR.sup.8SO.sub.2R.sup.9,
SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8, OCONR.sup.8R.sup.9,
OCONR.sup.8R.sup.12, N(R.sup.8)CON(R.sup.8R.sup.9),
N(R.sup.8)COOR.sup.12, or C.sub.1-4alkyloxyC.sub.1-4alkyloxy;
[0037] Het.sup.1 represents a 4 to 6 membered saturated ring
containing one N atom, optionally being substituted with one or
more substituents each independently selected from the group
consisting of halo, C.sub.1-C.sub.4alkyloxy, SO.sub.2R.sup.8,
C.sub.1-C.sub.4alkylcarbonyl, CO(aryl), COHet.sup.2,
C.sub.1-C.sub.4alkyloxycarbonyl, pyridinyl, CF.sub.3,
SO.sub.2N(C.sub.1-C.sub.4alkyl).sub.2,
SO.sub.2NH(C.sub.1-C.sub.4alkyl), (C.dbd.O)NH(C.sub.1-4alkyl),
(C.dbd.S)NH(C.sub.1-4alkyl), C.sub.1-C.sub.4alkyl and
C.sub.1-C.sub.4alkyl substituted with one hydroxy; or [0038]
Het.sup.1 represents a 4 to 6 membered saturated ring containing
one O atom, substituted with one or more substituents each
independently selected from the group consisting of halo,
C.sub.1-C.sub.4alkyloxy, CF.sub.3, NH(C.dbd.O)(C.sub.1-4alkyl),
(C.dbd.O)NH(C.sub.1-4alkyl) and C.sub.1-C.sub.4alkyl; or [0039]
Het.sup.1 represents a bicyclic 7 to 11 membered non-aromatic
heterocycle containing one or two heteroatoms each independently
selected from the group consisting of O, S and N, optionally
substituted with one or more substituents each independently
selected from the group consisting of halo,
C.sub.1-C.sub.4alkyloxy, SO.sub.2R.sup.8,
C.sub.1-C.sub.4alkylcarbonyl, CO(aryl), COHet.sup.2,
C.sub.1-C.sub.4alkyloxycarbonyl, pyridinyl, CF.sub.3,
SO.sub.2N(C.sub.1-C.sub.4alkyl).sub.2,
SO.sub.2NH(C.sub.1-C.sub.4alkyl), (C.dbd.O)NH(C.sub.1-4alkyl),
(C.dbd.S)NH(C.sub.1-4alkyl), C.sub.1-C.sub.4alkyl and
C.sub.1-C.sub.4alkyl substituted with one hydroxy; [0040] Het.sup.2
represents a monocyclic 5 to 6 membered aromatic heterocycle
containing one or more heteroatoms each independently selected from
the group consisting of O, S and N; or a bicyclic 8 to 12 membered
aromatic heterocycle containing one or more heteroatoms each
independently selected from the group consisting of O, S and N;
said Het.sup.2 optionally being substituted with one or more
substituents each independently selected from the group consisting
of halo, C.sub.1-C.sub.4alkyloxy, C.sub.1-C.sub.4alkyl, OH, CN,
CF.sub.2H, CF.sub.3, CONR.sup.8R.sup.9, COOR.sup.8,
CON(R.sup.8)SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sup.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8,
OCONR.sup.8R.sup.9, OCONR.sup.8R.sup.12,
N(R.sup.8)CON(R.sup.8R.sup.9), N(R.sup.8)COOR.sup.12; [0041] Z is C
or N; R.sup.5 is present where Z is C, whereby R.sup.5 is selected
form the group consisting of hydrogen, CF.sub.3 and halogen;
R.sup.5 is absent where Z is N; and the pharmaceutically acceptable
addition salts, and the solvates thereof.
[0042] In another aspect, the invention relates to the foregoing
compounds for use in the treatment of RSV infections in
warm-blooded animals, preferably humans. In yet another aspect, the
invention presents a method of treatment of viral RSV infections in
a subject in need thereof, comprising administering to said subject
an effective amount of a compound as defined above. In still
another aspect, the invention resides in the use of a compound as
defined above, for the manufacture of a medicament in the treatment
of RSV infections.
[0043] In a further aspect, the invention relates to a
pharmaceutical composition comprising a compound as defined above,
and a pharmaceutically acceptable excipient.
[0044] In a still further aspect, the invention provides methods
for preparing the compounds defined above.
DETAILED DESCRIPTION OF THE INVENTION
[0045] The invention, in a broad sense, is based on the judicious
recognition that the compounds of Formula (I) generally possess an
interesting RSV inhibitory activity. Moreover, these compounds
enable access to anti-RSV activities at the higher regions (lower
end of the EC.sub.50 values) of the range available in the
aforementioned references. Particularly, on the basis of these
compounds, molecular structures can be uncovered that even
outperform the reference compounds in terms of biological
activities.
[0046] The present invention will further be described with respect
to particular embodiments and with reference to certain examples
but the invention is not limited thereto but only by the claims.
Where the term "comprising" is used in the present description and
claims, it does not exclude other elements or steps. Where an
indefinite or definite article is used when referring to a singular
noun e.g. "a" or "an", "the", this includes a plural of that noun
unless something else is specifically stated.
[0047] Whenever the term "substituted" is used in the present
invention, it is meant, unless otherwise is indicated or is clear
from the context, to indicate that one or more hydrogens, in
particular from 1 to 4 hydrogens, preferably from 1 to 3 hydrogens,
more preferably 1 hydrogen, on the atom or radical indicated in the
expression using "substituted" are replaced with a selection from
the indicated group, provided that the normal valency is not
exceeded, and that the substitution results in a chemically stable
compound, i.e. a compound that is sufficiently robust to survive
isolation to a useful degree of purity from a reaction mixture, and
formulation into a therapeutic agent.
[0048] As used herein "C.sub.1-C.sub.4alkyl" or "C.sub.1-4alkyl" as
a group or part of a group defines straight or branched chain
saturated hydrocarbon radicals having from 1 to 4 carbon atoms such
as methyl, ethyl, propyl, 1-methylethyl, butyl and the like.
[0049] As used herein "C.sub.1-C.sub.6alkyl" as a group or part of
a group defines straight or branched chain saturated hydrocarbon
radicals having from 1 to 6 carbon atoms such as methyl, ethyl,
propyl, 1-methylethyl, butyl, pentyl, hexyl, 2-methylbutyl and the
like.
[0050] "C.sub.1-C.sub.10alkyl" as a group or part of a group
defines straight or branched chain saturated hydrocarbon radicals
having from 1 to 10 carbon atoms such as the groups defined for
C.sub.1-C.sub.6alkyl and heptyl, octyl, nonyl, 2-methylhexyl,
2-methylheptyl, decyl, 2-methylnonyl, and the like.
[0051] The term "C.sub.2-C.sub.10alkenyl" used herein as a group or
part of a group is meant to comprise straight or branched chain
unsaturated hydrocarbon radicals having at least one double bond,
and preferably having one double bond, and from 2 to 10 carbon
atoms such as ethenyl, propenyl, buten-1-yl, buten-2-yl,
penten-1-yl, penten-2-yl, hexen-1-yl, hexen-2-yl, hexen-3-yl,
2-methylbuten-1-yl, hepten-1-yl, hepten-2-yl, hepten-3-yl,
hepten-4-yl, 2-methylhexen-1-yl, octen-1-yl, octen-2-yl,
octen-3-yl, octen-4-yl, 2-methylhepten-1-yl, nonen-1-yl,
nonen-2-yl, nonen-3-yl, nonen-4-yl, nonen-5-yl, 2-methylocten-1-yl,
decen-1-yl, decen-2-yl, decen-3-yl, decen-4-yl, decen-5-yl,
2-methylnonen-1-yl, and the like.
[0052] Whenever a "C.sub.2-C.sub.10alkenyl" group is linked to a
heteroatom it preferably is linked via a saturated carbon atom.
[0053] "C.sub.1-C.sub.4alkyloxy" or "C.sub.1-C.sub.4alkoxy", as a
group or part of a group defines an O--C.sub.1-C.sub.4alkyl
radical, wherein C.sub.1-C.sub.4alkyl has, independently, the
meaning given above.
[0054] "C.sub.1-C.sub.6alkyloxy" or "C.sub.1-C.sub.6alkoxy", as a
group or part of a group defines an O--C.sub.1-C.sub.6alkyl
radical, wherein C.sub.1-C.sub.6alkyl has, independently, the
meaning given above.
[0055] The term "C.sub.3-C.sub.7cycloalkyl" alone or in
combination, refers to a cyclic saturated hydrocarbon radical
having from 3 to 7 carbon atoms. Non-limiting examples of suitable
C.sub.3-C.sub.7cycloalkyl include cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl and cycloheptyl.
[0056] The term "--(CR.sup.8R.sup.9).sub.m--" used herein defines m
repetitions of the CR.sup.8R.sup.9 subgroup, wherein each of these
subgroups is independently defined.
[0057] The term "halo" or "halogen" as a group or part of a group
is generic for fluoro, chloro, bromo, iodo unless otherwise is
indicated or is clear from the context.
[0058] A term of the form NRCOOR is identical to N(R)COOR.
[0059] Examples of (but not limited to) a 4 to 6 membered aliphatic
ring optionally containing one or more heteroatoms selected from
the group consisting of N, S and O, as used in the definitions of
R.sup.8 and R.sup.9, are cyclobutyl, cyclopentyl, cyclohexyl,
piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl,
piperidinyl, azetidinyl, thiolanyl, piperazinyl, pyrrolidinyl.
[0060] An example of (but not limited to) Het.sup.2 is thiazolyl or
quinolinyl.
[0061] An example of (but not limited to) Het.sup.1 is
azetidinyl.
[0062] It should be noted that the radical positions on any
molecular moiety used in the definitions may be anywhere on such
moiety as long as it is chemically stable. Radicals used in the
definitions of the variables include all possible isomers unless
otherwise indicated. For instance pentyl includes 1-pentyl,
2-pentyl and 3-pentyl.
[0063] When any variable occurs more than one time in any
constituent, each definition is independent.
[0064] Hereinbefore and hereinafter, the term "compound of formula
(I)" or "compounds of formula (I)" is meant to include the
stereoisomeric forms thereof, and the pharmaceutically acceptable
addition salts, and the solvates thereof.
[0065] The terms "stereoisomers", "stereoisomeric forms" or
"stereochemically isomeric forms" hereinbefore or hereinafter are
used interchangeably.
[0066] The term "stereochemically isomeric forms" as used
hereinbefore defines all the possible compounds made up of the same
atoms bonded by the same sequence of bonds but having different
three-dimensional structures which are not interchangeable, which
the compounds of formula (I) may possess.
[0067] It will be appreciated that some of the compounds of formula
(I) may contain one or more centers of chirality and exist as
stereochemically isomeric forms.
[0068] The invention includes all stereoisomers of the compound of
Formula (I), either as a pure stereoisomer or as a mixture of two
or more stereoisomers.
[0069] Enantiomers are stereoisomers that are non-superimposable
mirror images of each other. A 1:1 mixture of a pair of enantiomers
is a racemate or racemic mixture. Diastereomers (or
diastereoisomers) are stereoisomers that are not enantiomers, i.e.
they are not related as mirror images. If a compound contains a
double bond, the substituents may be in the E or the Z
configuration. Substituents on bivalent cyclic (partially)
saturated radicals may have either the cis- or trans-configuration;
for example if a compound contains a disubstituted cycloalkyl
group, the substituents may be in the cis or trans configuration.
Therefore, the invention includes enantiomers, diastereomers,
racemates, E isomers, Z isomers, cis isomers, trans isomers and
mixtures thereof, whenever chemically possible.
[0070] The absolute configuration is specified according to the
Cahn-Ingold-Prelog system. The configuration at an asymmetric atom
is specified by either R or S. Resolved compounds whose absolute
configuration is not known can be designated by (+) or (-)
depending on the direction in which they rotate plane polarized
light.
[0071] When a specific stereoisomer is identified, this means that
said stereoisomer is substantially free, i.e. associated with less
than 50%, preferably less than 20%, more preferably less than 10%,
even more preferably less than 5%, in particular less than 2% and
most preferably less than 1%, of the other isomers. Thus, when a
compound of formula (I) is for instance specified as (R), this
means that the compound is substantially free of the (S) isomer;
when a compound of formula (I) is for instance specified as E, this
means that the compound is substantially free of the Z isomer; when
a compound of formula (I) is for instance specified as cis, this
means that the compound is substantially free of the trans
isomer.
[0072] Some of the compounds according to formula (I) may also
exist in their tautomeric form. Such forms although not explicitly
indicated in the above formula are intended to be included within
the scope of the present invention.
[0073] Unless otherwise mentioned or indicated, the chemical
designation of a compound encompasses the mixture of all possible
stereochemically isomeric forms which said compound may possess.
Said mixture may contain all diastereomers and/or enantiomers of
the basic molecular structure of said compound. All
stereochemically isomeric forms of the compounds of the present
invention both in pure form or in admixture with each other are
intended to be embraced within the scope of the present
invention.
[0074] Pure stereoisomeric forms of the compounds and intermediates
of this invention may be obtained by the application of art-known
procedures. For instance, enantiomers may be separated from each
other by the selective crystallization of their diastereomeric
salts with optically active acids or bases. Examples thereof are
tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid and
camphosulfonic acid. Alternatively, enantiomers may be separated by
chromatographic techniques using chiral stationary phases. Said
pure stereochemically isomeric forms may also be derived from the
corresponding pure stereochemically isomeric forms of the
appropriate starting materials, provided that the reaction occurs
stereospecifically. Preferably, if a specific stereoisomer is
desired, said compound will be synthesized by stereospecific
methods of preparation. These methods will advantageously employ
enantiomerically pure starting materials.
[0075] The diastereomeric racemates of formula (I) can be obtained
separately by conventional methods. Appropriate physical separation
methods that may advantageously be employed are, for example,
selective crystallization and chromatography, e.g. column
chromatography.
[0076] For some of the compounds of formula (I) and stereoisomeric
forms thereof, and the pharmaceutically acceptable addition salts,
and the solvates thereof; and intermediates used in the preparation
thereof, the absolute stereochemical configuration was not
experimentally determined. A person skilled in the art is able to
determine the absolute configuration of such compounds using
art-known methods such as, for example, X-ray diffraction.
[0077] The present invention is also intended to include all
isotopes of atoms occurring on the present compounds. Isotopes
include those atoms having the same atomic number but different
mass numbers. By way of general example and without limitation,
isotopes of hydrogen include tritium and deuterium. Isotopes of
carbon include C-13 and C-14.
[0078] For therapeutic use, salts of the compounds of formula (I)
are those wherein the counterion is pharmaceutically acceptable.
However, salts of acids and bases which are non-pharmaceutically
acceptable may also find use, for example, in the preparation or
purification of a pharmaceutically acceptable compound. All salts,
whether pharmaceutically acceptable or not are included within the
ambit of the present invention.
[0079] The pharmaceutically acceptable acid and base addition salts
as mentioned hereinabove are meant to comprise the therapeutically
active non-toxic acid and base addition salt forms which the
compounds of formula (I) are able to form. The pharmaceutically
acceptable acid addition salts can conveniently be obtained by
treating the base form with such appropriate acid. Appropriate
acids comprise, for example, inorganic acids such as hydrohalic
acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric,
phosphoric and the like acids; or organic acids such as, for
example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic
(i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid),
maleic, fumaric, malic (i.e. hydroxybutanedioic acid), tartaric,
citric, methanesulfonic, ethanesulfonic, benzenesulfonic,
p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic
and the like acids.
[0080] Conversely said salt forms can be converted by treatment
with an appropriate base into the free base form.
[0081] The compounds of formula (I) containing an acidic proton may
also be converted into their non-toxic metal or amine addition salt
forms by treatment with appropriate organic and inorganic bases.
Appropriate base salt forms comprise, for example, the ammonium
salts, the alkali and earth alkaline metal salts, e.g. the lithium,
sodium, potassium, magnesium, calcium salts and the like, salts
with organic bases, e.g. the benzathine, N-methyl-D-glucamine,
hydrabamine salts, and salts with amino acids such as, for example,
arginine, lysine and the like.
[0082] The term solvate comprises the hydrates and solvent addition
forms which the compounds of Formula (I) are able to form, as well
as the salts thereof. Examples of such forms are e.g. hydrates,
alcoholates and the like.
[0083] It will be appreciated that the compounds of the invention,
with reference to the aforementioned left- and right-hand parts of
formula I, present a wide variety of modification.
[0084] Without detracting from the overall scope of the invention,
certain embodiments are discussed in more detail below.
[0085] A compound according to the invention therefore inherently
comprises a compound with one or more isotopes of one or more
element, and mixtures thereof, including a radioactive compound,
also called radiolabelled compound, wherein one or more
non-radioactive atoms has been replaced by one of its radioactive
isotopes. By the term "radiolabelled compound" is meant any
compound according to Formula (I) which contains at least one
radioactive atom. For example, a compound can be labelled with
positron or with gamma emitting radioactive isotopes. For
radioligand-binding techniques, the .sup.3H-atom or the
.sup.125I-atom is the atom of choice to be replaced. For imaging,
the most commonly used positron emitting (PET) radioactive isotopes
are .sup.11C, .sup.18F, .sup.15O and .sup.13N, all of which are
accelerator produced and have half-lives of 20, 100, 2 and 10
minutes (min) respectively. Since the half-lives of these
radioactive isotopes are so short, it is only feasible to use them
at institutions which have an accelerator on site for their
production, thus limiting their use. The most widely used of these
are .sup.18F, .sup.99mTc, .sup.201Tl and .sup.123I. The handling of
these radioactive isotopes, their production, isolation and
incorporation in a molecule are known to the skilled person.
[0086] In particular, the radioactive atom is selected from the
group of hydrogen, carbon, nitrogen, sulfur, oxygen and halogen. In
particular, the radioactive isotope is selected from the group of
.sup.3H, .sup.11C, .sup.18F, .sup.122I, .sup.123I, .sup.125I,
.sup.131I, .sup.75Br, .sup.76Br, .sup.77Br and .sup.82Br.
[0087] The terms described above and others used in the
specification are well understood to those in the art.
[0088] Preferred features of the compounds of this invention are
now set forth.
[0089] In an embodiment, the present invention concerns novel
compounds of Formula (I) and stereoisomeric forms thereof, wherein
Het is a heterocycle having formula (b), (c), (d) or (e); [0090]
each X independently is C or N; provided that at least one X is N;
[0091] R.sup.1b is present when Het has formula (b) and X is C;
each R.sup.1b is selected independently from the group consisting
of H, halogen, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, N(R.sup.6).sub.2, CO(R.sup.7),
CH.sub.2NH.sub.2, CH.sub.2OH, CN, C(.dbd.NOH)NH.sub.2,
C(.dbd.NOCH.sub.3)NH.sub.2, C(.dbd.NH)NH.sub.2, CF.sub.3,
OCF.sub.3, B(OH).sub.2 and B(O--C.sub.1-C.sub.6alkyl).sub.2;
R.sup.1b is absent when the X to which it is bound is N; [0092]
R.sup.2b is --(CR.sup.8R.sup.9).sub.m--R.sup.10b; [0093] each
R.sup.6 is independently selected from the group consisting of H,
C.sub.1-C.sub.6alkyl, COOCH.sub.3 and CONHSO.sub.2CH.sub.3; [0094]
each R.sup.7 is independently selected from the group consisting of
OH, C.sub.1-C.sub.6alkyloxy, NH.sub.2,
NHSO.sub.2N(C.sub.1-C.sub.6alkyl).sub.2, NHSO.sub.2NHCH.sub.3,
NHSO.sub.2(C.sub.1-C.sub.6alkyl);
NHSO.sub.2(C.sub.3-C.sub.7cycloalkyl) and
N(C.sub.1-C.sub.6-alkyl).sub.2; [0095] each R.sup.8 and R.sup.9 are
independently chosen from the group consisting of H,
C.sub.1-C.sub.10alkyl and C.sub.3-C.sub.7cycloalkyl; or R.sup.8 and
R.sup.9 taken together form a 4 to 6 membered aliphatic ring that
optionally contains one or more heteroatoms selected from the group
consisting of N, S and O; [0096] R.sup.10b is selected from the
group consisting of H, R.sup.11, OH, CN, F, CF.sub.2H, CF.sub.3,
CONR.sup.8R.sup.9, COOR.sup.8, CON(R.sup.8)SO.sub.2R.sup.9,
CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9), NR.sup.8R.sup.9,
NR.sup.8COOR.sup.9, OCOR.sup.8, O-Benzyl, NR.sup.8SO.sub.2R.sup.9,
SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8, OCONR.sup.8R.sup.9,
OCONR.sup.8R.sup.12, N(R.sup.8)CON(R.sup.8R.sup.9),
N(R.sup.8)COOR.sup.12, and a 4 to 6 membered saturated ring
containing one oxygen atom; [0097] m is an integer from 2 to 6;
[0098] R.sup.11 is selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7cycloalkyl, phenyl, pyridinyl
and pyrazolyl; each optionally substituted with one or more
substituents each independently selected from the group consisting
of CF.sub.3, CH.sub.3, OCH.sub.3, OCF.sub.3 and halogen; [0099]
R.sup.12 is selected from the group consisting of phenyl, pyridinyl
and pyrazolyl; each optionally substituted with one or more
substituents each independently selected from the group consisting
of CF.sub.3, CH.sub.3, OCH.sub.3, OCF.sub.3 and halogen; [0100] or
R.sup.12 is C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.7cycloalkyl;
each substituted with one or more substituents each independently
selected from the group consisting of CF.sub.3, CH.sub.3,
OCH.sub.3, OCF.sub.3 and halogen; [0101] R.sup.1c is present when
Het has formula (c); [0102] each R.sup.1c is selected independently
from the group consisting of H, halogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkyloxy,
N(R.sup.6).sub.2, CO(R.sup.7c), CH.sub.2NH.sub.2, CH.sub.2OH, CN,
C(.dbd.NOH)NH.sub.2, C(.dbd.NOCH.sub.3)NH.sub.2,
C(.dbd.NH)NH.sub.2, CF.sub.3, OCF.sub.3, B(OH).sub.2 and
B(O--C.sub.1-C.sub.6alkyl).sub.2; [0103] R.sup.3c is selected from
the group consisting of H, halogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkyloxy and
CO(R.sup.7c); [0104] R.sup.2c is
--(CR.sup.8R.sup.9).sub.m--R.sup.10c; [0105] R.sup.7 is selected
from the group consisting of OH, O(C.sub.1-C.sub.6alkyl), NH.sub.2,
NHSO.sub.2N(C.sub.1-C.sub.6alkyl).sub.2, NHSO.sub.2NHCH.sub.3,
NHSO.sub.2(C.sub.1-C.sub.6alkyl),
NHSO.sub.2(C.sub.3-C.sub.7cycloalkyl),
N(C.sub.1-C.sub.6-alkyl).sub.2, NR.sup.8R.sup.9 and
NR.sup.9R.sup.10c; [0106] R.sup.10c is selected from the group
consisting of H, C.sub.1-C.sub.6alkyl, OH, CN, F, CF.sub.2H,
CF.sub.3, C(.dbd.NOH)NH.sub.2, CONR.sup.8R.sup.9, COOR.sup.8,
CONR.sup.8SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sup.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8
and a 4 to 6 membered saturated ring containing one oxygen atom;
[0107] R.sup.1d is present when Het has formula (d) and X is C;
each R.sup.1d is selected independently from the group consisting
of H, OH, halogen, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, N(R.sup.6).sub.2, CO(R.sup.7),
CH.sub.2NH.sub.2, CH.sub.2OH, CN, C(.dbd.NOH)NH.sub.2,
C(.dbd.NOCH.sub.3)NH.sub.2, C(.dbd.NH)NH.sub.2, CF.sub.3,
OCF.sub.3, B(OH).sub.2 and B(O--C.sub.1-C.sub.6alkyl).sub.2;
R.sup.1d is absent when the X to which it is bound is N; [0108]
R.sup.3d is selected from the group consisting of H, halogen,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, and CO(R.sup.7); [0109] R.sup.2d is
--(CR.sup.8R.sup.9).sub.m--R.sup.10d; [0110] R.sup.10d is selected
from the group consisting of H, C.sub.1-C.sub.6alkyl, OH, CN, F,
CF.sub.2H, CF.sub.3, CONR.sup.8R.sup.9, COOR.sup.8,
CONR.sup.8SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sub.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8
and a 4 to 6 membered saturated ring containing one oxygen atom;
[0111] each Y independently is C or N; [0112] R.sup.1e is present
when Het has formula (e) and Y is C; each R.sup.1e is selected
independently from the group consisting of H, halogen,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, N(R.sup.6).sub.2, CO(R.sup.7),
CH.sub.2NH.sub.2, CH.sub.2OH, CN, C(.dbd.NOH)NH.sub.2,
C(.dbd.NOCH.sub.3)NH.sub.2, C(.dbd.NH)NH.sub.2, CF.sub.3,
OCF.sub.3, B(OH).sub.2 and B(O--C.sub.1-C.sub.6alkyl).sub.2;
R.sup.1e is absent when the Y to which it is bound is N; [0113]
R.sup.3e is selected from the group consisting of H, halogen,
--(CR.sup.8R.sup.9).sub.m--R.sup.10e,
C.ident.C--CH.sub.2--R.sup.10e; C.ident.C--R.sup.10e and
C.dbd.C--R.sup.10e; [0114] R.sup.10e is selected from the group
consisting of H, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy,
C.sub.3-C.sub.7cycloalkyl, OH, CN, F, CF.sub.2H, CF.sub.3,
CONR.sup.8R.sup.9, COOR.sup.8, CON(R.sup.8)SO.sub.2R.sup.9,
CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9), NR.sup.8R.sup.9,
NR.sup.8COOR.sup.9, OCOR.sup.8, NR.sup.8SO.sub.2R.sup.9,
SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8 and a 4 to 6 membered
saturated ring containing one oxygen atom; [0115] R.sup.4 is
selected from the group consisting of tert-butyl, Het.sup.1, aryl,
Het.sup.2, CH(CH.sub.3)(CF.sub.3), and C.sub.3-C.sub.7cycloalkyl
substituted with one or more substituents selected from the group
consisting of halo and C.sub.1-C.sub.4alkyl; [0116] aryl represents
phenyl or naphthalenyl; said aryl optionally being substituted with
one or more substituents each independently selected from the group
consisting of halo, C.sub.1-C.sub.4alkyloxy, C.sub.1-C.sub.4alkyl,
OH, CN, CF.sub.2H, CF.sub.3, CONR.sup.8R.sup.9, COOR.sup.8,
CON(R.sup.8)SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sup.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8,
OCONR.sup.8R.sup.9, OCONR.sup.8R.sup.12,
N(R.sup.8)CON(R.sup.8R.sup.9), N(R.sup.8)COOR.sup.12; [0117]
Het.sup.1 represents a 4 to 6 membered saturated ring containing
one N atom, optionally being substituted with one or more
substituents each independently selected from the group consisting
of halo, C.sub.1-C.sub.4alkyloxy, SO.sub.2R.sup.8,
C.sub.1-C.sub.4alkylcarbonyl, CO(aryl), COHet.sup.2,
C.sub.1-C.sub.4alkyloxycarbonyl, pyridinyl, CF.sub.3,
SO.sub.2N(C.sub.1-C.sub.4alkyl).sub.2,
SO.sub.2NH(C.sub.1-C.sub.4alkyl), (C.dbd.O)NH(C.sub.1-4alkyl),
(C.dbd.S)NH(C.sub.1-4alkyl), C.sub.1-C.sub.4alkyl and
C.sub.1-C.sub.4alkyl substituted with one hydroxy; or [0118]
Het.sup.1 represents a 4 to 6 membered saturated ring containing
one O atom, substituted with one or more substituents each
independently selected from the group consisting of halo,
C.sub.1-C.sub.4alkyloxy, CF.sub.3, NH(C.dbd.O)(C.sub.1-4alkyl),
(C.dbd.O)NH(C.sub.1-4alkyl) and C.sub.1-C.sub.4alkyl; or [0119]
Het.sup.1 represents a bicyclic 7 to 11 membered non-aromatic
heterocycle containing one or two heteroatoms each independently
selected from the group consisting of O, S and N, optionally
substituted with one or more substituents each independently
selected from the group consisting of halo,
C.sub.1-C.sub.4alkyloxy, SO.sub.2R.sup.8,
C.sub.1-C.sub.4alkylcarbonyl, CO(aryl), COHet.sup.2,
C.sub.1-C.sub.4alkyloxycarbonyl, pyridinyl, CF.sub.3,
SO.sub.2N(C.sub.1-C.sub.4alkyl).sub.2,
SO.sub.2NH(C.sub.1-C.sub.4alkyl), (C.dbd.O)NH(C.sub.1-4alkyl),
(C.dbd.S)NH(C.sub.1-4alkyl), C.sub.1-C.sub.4alkyl and
C.sub.1-C.sub.4alkyl substituted with one hydroxy; [0120] Het.sup.2
represents a monocyclic 5 to 6 membered aromatic heterocycle
containing one or more heteroatoms each independently selected from
the group consisting of O, S and N; or a bicyclic 8 to 12 membered
aromatic heterocycle containing one or more heteroatoms each
independently selected from the group consisting of O, S and N;
said Het.sup.2 optionally being substituted with one or more
substituents each independently selected from the group consisting
of halo, C.sub.1-C.sub.4alkyloxy, C.sub.1-C.sub.4alkyl, OH, CN,
CF.sub.2H, CF.sub.3, CONR.sup.8R.sup.9, COOR.sup.8,
CON(R.sup.8)SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sup.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8,
OCONR.sup.8R.sup.9, OCONR.sup.8R.sup.12,
N(R.sup.8)CON(R.sup.8R.sup.9), N(R.sup.8)COOR.sup.12; [0121] Z is C
or N; R.sup.5 is present where Z is C, whereby R.sup.5 is selected
form the group consisting of hydrogen, CF.sub.3 and halogen;
R.sup.5 is absent where Z is N; and the pharmaceutically acceptable
addition salts, and the solvates thereof.
[0122] In an embodiment, the present invention concerns novel
compounds of Formula (I) and stereoisomeric forms thereof, wherein
Het is a heterocycle having formula (b), (c), (d) or (e); [0123]
each X independently is C or N; provided that at least one X is N;
[0124] R.sup.1b is present when Het has formula (b) and X is C;
each R.sup.1b is selected independently from the group consisting
of H, halogen, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, N(R.sup.6).sub.2, CO(R.sup.7),
CH.sub.2NH.sub.2, CH.sub.2OH, CN, C(.dbd.NOH)NH.sub.2,
C(.dbd.NOCH.sub.3)NH.sub.2, C(.dbd.NH)NH.sub.2, CF.sub.3,
OCF.sub.3, B(OH).sub.2 and B(O--C.sub.1-C.sub.6alkyl).sub.2;
R.sup.1b is absent when the X to which it is bound is N; [0125]
R.sup.2b is --(CR.sup.8R.sup.9).sub.m--R.sup.10b; [0126] each
R.sup.6 is independently selected from the group consisting of H,
C.sub.1-C.sub.6alkyl, COOCH.sub.3 and CONHSO.sub.2CH.sub.3; [0127]
each R.sup.7 is independently selected from the group consisting of
OH, C.sub.1-C.sub.6alkyloxy, NH.sub.2,
NHSO.sub.2N(C.sub.1-C.sub.6alkyl).sub.2, NHSO.sub.2NHCH.sub.3,
NHSO.sub.2(C.sub.1-C.sub.6alkyl);
NHSO.sub.2(C.sub.3-C.sub.7cycloalkyl) and
N(C.sub.1-C.sub.6-alkyl).sub.2; [0128] each R.sup.8 and R.sup.9 are
independently chosen from the group consisting of H,
C.sub.1-C.sub.10alkyl and C.sub.3-C.sub.7cycloalkyl; or R.sup.8 and
R.sup.9 taken together form a 4 to 6 membered aliphatic ring that
optionally contains one or more heteroatoms selected from the group
consisting of N, S and O; [0129] R.sup.10b is selected from the
group consisting of H, R.sup.11, OH, CN, F, CF.sub.2H, CF.sub.3,
CONR.sup.8R.sup.9, COOR.sup.8, CON(R.sup.8)SO.sub.2R.sup.9,
CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9), NR.sup.8R.sup.9,
NR.sup.8COOR.sup.9, OCOR.sup.8, O-Benzyl, NR.sup.8SO.sub.2R.sup.9,
SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8, OCONR.sup.8R.sup.9,
OCONR.sup.8R.sup.12, N(R.sup.8)CON(R.sup.8R.sup.9),
N(R.sup.8)COOR.sup.12, and a 4 to 6 membered saturated ring
containing one oxygen atom; [0130] m is an integer from 2 to 6;
[0131] R.sup.11 is selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7cycloalkyl, phenyl, pyridinyl
and pyrazolyl; each optionally substituted with one or more
substituents each independently selected from the group consisting
of CF.sub.3, CH.sub.3, OCH.sub.3, OCF.sub.3 and halogen; [0132]
R.sup.12 is selected from the group consisting of phenyl, pyridinyl
and pyrazolyl; each optionally substituted with one or more
substituents each independently selected from the group consisting
of CF.sub.3, CH.sub.3, OCH.sub.3, OCF.sub.3 and halogen; [0133] or
R.sup.12 is C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.7cycloalkyl;
each substituted with one or more substituents each independently
selected from the group consisting of CF.sub.3, CH.sub.3,
OCH.sub.3, OCF.sub.3 and halogen; [0134] R.sup.1c is present when
Het has formula (c); [0135] each R.sup.1c is selected independently
from the group consisting of H, halogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkyloxy,
N(R.sup.6).sub.2, CO(R.sup.7c), CH.sub.2NH.sub.2, CH.sub.2OH, CN,
C(.dbd.NOH)NH.sub.2, C(.dbd.NOCH.sub.3)NH.sub.2,
C(.dbd.NH)NH.sub.2, CF.sub.3, OCF.sub.3, B(OH).sub.2 and
B(O--C.sub.1-C.sub.6alkyl).sub.2; [0136] R.sup.3c is selected from
the group consisting of H, halogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkyloxy and
CO(R.sup.7c); [0137] R.sup.2c is
--(CR.sup.8R.sup.9).sub.m--R.sup.10c; [0138] R.sup.7 is selected
from the group consisting of OH, O(C.sub.1-C.sub.6alkyl), NH.sub.2,
NHSO.sub.2N(C.sub.1-C.sub.6alkyl).sub.2, NHSO.sub.2NHCH.sub.3,
NHSO.sub.2(C.sub.1-C.sub.6alkyl),
NHSO.sub.2(C.sub.3-C.sub.7cycloalkyl),
N(C.sub.1-C.sub.6-alkyl).sub.2, NR.sup.8R.sup.9 and
NR.sup.9R.sup.10c; [0139] R.sup.10c is selected from the group
consisting of H, C.sub.1-C.sub.6alkyl, OH, CN, F, CF.sub.2H,
CF.sub.3, C(.dbd.NOH)NH.sub.2, CONR.sup.8R.sup.9, COOR.sup.8,
CONR.sup.8SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sup.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8
and a 4 to 6 membered saturated ring containing one oxygen atom;
[0140] R.sup.1d is present when Het has formula (d) and X is C;
each R.sup.1d is selected independently from the group consisting
of H, OH, halogen, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, N(R.sup.6).sub.2, CO(R.sup.7),
CH.sub.2NH.sub.2, CH.sub.2OH, CN, C(.dbd.NOH)NH.sub.2,
C(.dbd.NOCH.sub.3)NH.sub.2, C(.dbd.NH)NH.sub.2, CF.sub.3,
OCF.sub.3, B(OH).sub.2 and B(O--C.sub.1-C.sub.6alkyl).sub.2;
R.sup.1d is absent when the X to which it is bound is N; [0141]
R.sup.3d is selected from the group consisting of H, halogen,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, and CO(R.sup.7); [0142] R.sup.2d is
--(CR.sup.8R.sup.9).sub.m--R.sup.10d; [0143] R.sup.10d is selected
from the group consisting of H, C.sub.1-C.sub.6alkyl, OH, CN, F,
CF.sub.2H, CF.sub.3, CONR.sup.8R.sup.9, COOR.sup.8,
CONR.sup.8SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sub.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8
and a 4 to 6 membered saturated ring containing one oxygen atom;
[0144] each Y independently is C or N; [0145] R.sup.1e is present
when Het has formula (e) and Y is C; each R.sup.1e is selected
independently from the group consisting of H, halogen,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, N(R.sup.6).sub.2, CO(R.sup.7),
CH.sub.2NH.sub.2, CH.sub.2OH, CN, C(.dbd.NOH)NH.sub.2,
C(.dbd.NOCH.sub.3)NH.sub.2, C(.dbd.NH)NH.sub.2, CF.sub.3,
OCF.sub.3, B(OH).sub.2 and B(O--C.sub.1-C.sub.6alkyl).sub.2;
R.sup.1e is absent when the Y to which it is bound is N; [0146]
R.sup.3e is selected from the group consisting of H, halogen,
--(CR.sup.8R.sup.9).sub.m--R.sup.10e,
C.ident.C--CH.sub.2--R.sup.10e, C.ident.C--R.sup.10e and
C.dbd.C--R.sup.10e; [0147] R.sup.10e is selected from the group
consisting of H, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy,
C.sub.3-C.sub.7cycloalkyl, OH, CN, F, CF.sub.2H, CF.sub.3,
CONR.sup.8R.sup.9, COOR.sup.8, CON(R.sup.8)SO.sub.2R.sup.9,
CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9), NR.sup.8R.sup.9,
NR.sup.8COOR.sup.9, OCOR.sup.8, NR.sup.8SO.sub.2R.sup.9,
SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8 and a 4 to 6 membered
saturated ring containing one oxygen atom; [0148] R.sup.4 is
selected from the group consisting of tert-butyl, Het.sup.1, aryl,
Het.sup.2, CH(CH.sub.3)(CF.sub.3), and C.sub.3-C.sub.7cycloalkyl
substituted with one or more substituents selected from the group
consisting of halo and C.sub.1-C.sub.4alkyl; [0149] aryl represents
phenyl or naphthalenyl; said aryl optionally being substituted with
one or more substituents each independently selected from the group
consisting of halo, C.sub.1-C.sub.4alkyloxy, C.sub.1-C.sub.4alkyl,
OH, CN, CF.sub.2H, CF.sub.3, CONR.sup.8R.sup.9, COOR.sup.8,
CON(R.sup.8)SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sup.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8,
OCONR.sup.8R.sup.9, OCONR.sup.8R.sup.12,
N(R.sup.8)CON(R.sup.8R.sup.9), N(R.sup.8)COOR.sup.12; [0150]
Het.sup.1 represents a 4 to 6 membered saturated ring containing
one N atom, optionally being substituted with one or more
substituents each independently selected from the group consisting
of halo, C.sub.1-C.sub.4alkyloxy, SO.sub.2R.sup.8,
C.sub.1-C.sub.4alkylcarbonyl, CO(aryl), COHet.sup.2,
C.sub.1-C.sub.4alkyloxycarbonyl, pyridinyl, CF.sub.3,
SO.sub.2N(C.sub.1-C.sub.4alkyl).sub.2,
SO.sub.2NH(C.sub.1-C.sub.4alkyl), (C.dbd.O)NH(C.sub.1-4alkyl),
(C.dbd.S)NH(C.sub.1-4alkyl), C.sub.1-C.sub.4alkyl and
C.sub.1-C.sub.4alkyl substituted with one hydroxy; or [0151]
Het.sup.1 represents a 4 to 6 membered saturated ring containing
one O atom, substituted with one or more substituents each
independently selected from the group consisting of halo,
C.sub.1-C.sub.4alkyloxy, CF.sub.3, NH(C.dbd.O)(C.sub.1-4alkyl),
(C.dbd.O)NH(C.sub.1-4alkyl) and C.sub.1-C.sub.4alkyl; [0152]
Het.sup.2 represents a monocyclic 5 to 6 membered aromatic
heterocycle containing one or more heteroatoms each independently
selected from the group consisting of O, S and N; or a bicyclic 8
to 12 membered aromatic heterocycle containing one or more
heteroatoms each independently selected from the group consisting
of O, S and N; said Het.sup.2 optionally being substituted with one
or more substituents each independently selected from the group
consisting of halo, C.sub.1-C.sub.4alkyloxy, C.sub.1-C.sub.4alkyl,
OH, CN, CF.sub.2H, CF.sub.3, CONR.sup.8R.sup.9, COOR.sup.8,
CON(R.sup.8)SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sup.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8,
OCONR.sup.8R.sup.9, OCONR.sup.8R.sup.12,
N(R.sup.8)CON(R.sup.8R.sup.9), N(R.sup.8)COOR.sup.12; [0153] Z is C
or N; R.sup.5 is present where Z is C, whereby R.sup.5 is selected
form the group consisting of hydrogen, CF.sub.3 and halogen;
R.sup.5 is absent where Z is N; and the pharmaceutically acceptable
addition salts, and the solvates thereof.
[0154] In an embodiment, the present invention concerns novel
compounds of Formula (I) and stereoisomeric forms thereof, wherein
Het is a heterocycle having formula (b), (c), (d) or (e); [0155]
each X independently is C or N; provided that at least one X is N;
[0156] R.sup.1b is present when Het has formula (b) and X is C;
each R.sup.1b is selected independently from the group consisting
of H, halogen, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, N(R.sup.6).sub.2, CO(R.sup.7),
CH.sub.2NH.sub.2, CH.sub.2OH, CN, C(.dbd.NOH)NH.sub.2,
C(.dbd.NOCH.sub.3)NH.sub.2, C(.dbd.NH)NH.sub.2, CF.sub.3,
OCF.sub.3, B(OH).sub.2 and B(O--C.sub.1-C.sub.6alkyl).sub.2;
R.sup.1b is absent when the X to which it is bound is N; [0157]
R.sup.2b is --(CR.sup.8R.sup.9).sub.m--R.sup.10b; [0158] each
R.sup.6 is independently selected from the group consisting of H,
C.sub.1-C.sub.6alkyl, COOCH.sub.3 and CONHSO.sub.2CH.sub.3; [0159]
each R.sup.7 is independently selected from the group consisting of
OH, C.sub.1-C.sub.6alkyloxy, NH.sub.2,
NHSO.sub.2N(C.sub.1-C.sub.6alkyl).sub.2, NHSO.sub.2NHCH.sub.3,
NHSO.sub.2(C.sub.1-C.sub.6alkyl),
NHSO.sub.2(C.sub.3-C.sub.7cycloalkyl) and
N(C.sub.1-C.sub.6-alkyl).sub.2; [0160] each R.sup.8 and R.sup.9 are
independently chosen from the group consisting of H,
C.sub.1-C.sub.10alkyl and C.sub.3-C.sub.7cycloalkyl; or R.sup.8 and
R.sup.9 taken together form a 4 to 6 membered aliphatic ring that
optionally contains one or more heteroatoms selected from the group
consisting of N, S and O; [0161] R.sup.10b is selected from the
group consisting of H, R.sup.11, OH, CN, F, CF.sub.2H, CF.sub.3,
CONR.sup.8R.sup.9, COOR.sup.8, CON(R.sup.8)SO.sub.2R.sup.9,
CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9), NR.sup.8R.sup.9,
NR.sup.8COOR.sup.9, OCOR.sup.8, O-Benzyl, NR.sup.8SO.sub.2R.sup.9,
SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8, OCONR.sup.8R.sup.9,
OCONR.sup.8R.sup.12, N(R.sup.8)CON(R.sup.8R.sup.9),
N(R.sup.8)COOR.sup.12, and a 4 to 6 membered saturated ring
containing one oxygen atom; [0162] m is an integer from 2 to 6;
[0163] R.sup.11 is selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7cycloalkyl, phenyl, pyridinyl
and pyrazolyl; each optionally substituted with one or more
substituents each independently selected from the group consisting
of CF.sub.3, CH.sub.3, OCH.sub.3, OCF.sub.3 and halogen; [0164]
R.sup.12 is selected from the group consisting of phenyl, pyridinyl
and pyrazolyl; each optionally substituted with one or more
substituents each independently selected from the group consisting
of CF.sub.3, CH.sub.3, OCH.sub.3, OCF.sub.3 and halogen; [0165] or
R.sup.12 is C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.7cycloalkyl;
each substituted with one or more substituents each independently
selected from the group consisting of CF.sub.3, CH.sub.3,
OCH.sub.3, OCF.sub.3 and halogen; [0166] R.sup.1c is present when
Het has formula (c); [0167] each R.sup.1c is selected independently
from the group consisting of H, halogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkyloxy,
N(R.sup.6).sub.2, CO(R.sup.7c), CH.sub.2NH.sub.2, CH.sub.2OH, CN,
C(.dbd.NOH)NH.sub.2, C(.dbd.NOCH.sub.3)NH.sub.2,
C(.dbd.NH)NH.sub.2, CF.sub.3, OCF.sub.3, B(OH).sub.2 and
B(O--C.sub.1-C.sub.6alkyl).sub.2; [0168] R.sup.3c is selected from
the group consisting of H, halogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.7cycloalkyl,
[0169] C.sub.1-C.sub.6alkyloxy and CO(R.sup.7c); [0170] R.sup.2c is
--(CR.sup.8R.sup.9).sub.m--R.sup.10c; [0171] R.sup.7c is selected
from the group consisting of OH, O(C.sub.1-C.sub.6alkyl), NH.sub.2,
NHSO.sub.2N(C.sub.1-C.sub.6alkyl).sub.2, NHSO.sub.2NHCH.sub.3,
NHSO.sub.2(C.sub.1-C.sub.6alkyl),
NHSO.sub.2(C.sub.3-C.sub.7cycloalkyl),
N(C.sub.1-C.sub.6-alkyl).sub.2, NR.sup.8R.sup.9 and
NR.sup.9R.sup.10c; R.sup.10c is selected from the group consisting
of H, C.sub.1-C.sub.6alkyl, OH, CN, F, CF.sub.2H, CF.sub.3,
C(.dbd.NOH)NH.sub.2, CONR.sup.8R.sup.9, COOR.sup.8,
CONR.sup.8SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sup.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8
and a 4 to 6 membered saturated ring containing one oxygen atom;
[0172] R.sup.1d is present when Het has formula (d) and X is C;
each R.sup.1d is selected independently from the group consisting
of H, OH, halogen, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, N(R.sup.6).sub.2, CO(R.sup.7),
CH.sub.2NH.sub.2, CH.sub.2OH, CN, C(.dbd.NOH)NH.sub.2,
C(.dbd.NOCH.sub.3)NH.sub.2, C(.dbd.NH)NH.sub.2, CF.sub.3,
OCF.sub.3, B(OH).sub.2 and B(O--C.sub.1-C.sub.6alkyl).sub.2;
R.sup.1d is absent when the X to which it is bound is N; [0173]
R.sup.3d is selected from the group consisting of H, halogen,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, and CO(R.sup.7); [0174] R.sup.2d is
--(CR.sup.8R.sup.9).sub.m--R.sup.10d; [0175] R.sup.10d is selected
from the group consisting of H, C.sub.1-C.sub.6alkyl, OH, CN, F,
CF.sub.2H, CF.sub.3, CONR.sup.8R.sup.9, COOR.sup.8,
CONR.sup.8SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sub.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8
and a 4 to 6 membered saturated ring containing one oxygen atom;
[0176] each Y independently is C or N; [0177] R.sup.1e is present
when Het has formula (e) and Y is C; each R.sup.1e is selected
independently from the group consisting of H, halogen,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, N(R.sup.6).sub.2, CO(R.sup.7),
CH.sub.2NH.sub.2, CH.sub.2OH, CN, C(.dbd.NOH)NH.sub.2,
C(.dbd.NOCH.sub.3)NH.sub.2, C(.dbd.NH)NH.sub.2, CF.sub.3,
OCF.sub.3, B(OH).sub.2 and B(O--C.sub.1-C.sub.6alkyl).sub.2;
R.sup.1e is absent when the Y to which it is bound is N; [0178]
R.sup.3e is selected from the group consisting of H, halogen,
--(CR.sup.8R.sup.9).sub.m--R.sup.10e,
C.ident.C--CH.sub.2--R.sup.10e, C.ident.C--R.sup.10e and
C.dbd.C--R.sup.10e; [0179] R.sup.10e is selected from the group
consisting of H, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy,
C.sub.3-C.sub.7cycloalkyl, OH, CN, F, CF.sub.2H, CF.sub.3,
CONR.sup.8R.sup.9, COOR.sup.8, CON(R.sup.8)SO.sub.2R.sup.9,
CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9), NR.sup.8R.sup.9,
NR.sup.8COOR.sup.9, OCOR.sup.8, NR.sup.8SO.sub.2R.sup.9,
SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8 and a 4 to 6 membered
saturated ring containing one oxygen atom; [0180] R.sup.4 is
selected from the group consisting of tert-butyl, Het.sup.1, aryl,
Het.sup.2, CH(CH.sub.3)(CF.sub.3), and C.sub.3-C.sub.7cycloalkyl
substituted with one or more substituents selected from the group
consisting of halo and C.sub.1-C.sub.4alkyl; [0181] aryl represents
phenyl or naphthalenyl; said aryl optionally being substituted with
one or more substituents each independently selected from the group
consisting of halo, C.sub.1-C.sub.4alkyloxy, C.sub.1-C.sub.4alkyl,
OH, CN, CF.sub.2H, CF.sub.3, CONR.sup.8R.sup.9, COOR.sup.8,
CON(R.sup.8)SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sup.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8,
OCONR.sup.8R.sup.9, OCONR.sup.8R.sup.12,
N(R.sup.8)CON(R.sup.8R.sup.9), N(R.sup.8)COOR.sup.12; [0182]
Het.sup.1 represents a 4 to 6 membered saturated ring containing
one N atom, optionally being substituted with one or more
substituents each independently selected from the group consisting
of halo, C.sub.1-C.sub.4alkyloxy, SO.sub.2R.sup.8,
C.sub.1-C.sub.4alkylcarbonyl, CO(aryl), COHet.sup.2,
C.sub.1-C.sub.4alkyloxycarbonyl, pyridinyl, CF.sub.3,
SO.sub.2N(C.sub.1-C.sub.4alkyl).sub.2,
SO.sub.2NH(C.sub.1-C.sub.4alkyl), (C.dbd.O)NH(C.sub.1-4alkyl),
(C.dbd.S)NH(C.sub.1-4alkyl), C.sub.1-C.sub.4alkyl and
C.sub.1-C.sub.4alkyl substituted with one hydroxy; or [0183]
Het.sup.1 represents a 4 to 6 membered saturated ring containing
one O atom, substituted with one or more substituents each
independently selected from the group consisting of halo,
C.sub.1-C.sub.4alkyloxy, CF.sub.3, NH(C.dbd.O)(C.sub.1-4alkyl),
(C.dbd.O)NH(C.sub.1-4alkyl) and C.sub.1-C.sub.4alkyl; [0184]
Het.sup.2 represents a monocyclic 5 to 6 membered aromatic
heterocycle containing one or more heteroatoms each independently
selected from the group consisting of O, S and N; or a bicyclic 8
to 12 membered aromatic heterocycle containing one or more
heteroatoms each independently selected from the group consisting
of O, S and N; said Het.sup.2 optionally being substituted with one
or more substituents each independently selected from the group
consisting of halo, C.sub.1-C.sub.4alkyloxy, C.sub.1-C.sub.4alkyl,
OH, CN, CF.sub.2H, CF.sub.3, CONR.sup.8R.sup.9, COOR.sup.8,
CON(R.sup.8)SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sup.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8,
OCONR.sup.8R.sup.9, OCONR.sup.8R.sup.12,
N(R.sup.8)CON(R.sup.8R.sup.9), N(R.sup.8)COOR.sup.12; [0185] Z is C
or N; R.sup.5 is present where Z is C, whereby R.sup.5 is selected
form the group consisting of CF.sub.3 and halogen; R.sup.5 is
absent where Z is N; and the pharmaceutically acceptable addition
salts, and the solvates thereof.
[0186] In an embodiment, the present invention concerns novel
compounds of Formula (I) and stereoisomeric forms thereof, wherein
Het is a heterocycle having formula (b), (c), (d) or (e); [0187]
each X independently is C or N; provided that at least one X is N;
[0188] R.sup.1b is present when Het has formula (b) and X is C;
each R.sup.1b is selected independently from the group consisting
of H, halogen, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, N(R.sup.6).sub.2, CO(R.sup.7),
CH.sub.2NH.sub.2, CH.sub.2OH, CN, C(.dbd.NOH)NH.sub.2,
C(.dbd.NOCH.sub.3)NH.sub.2, C(.dbd.NH)NH.sub.2, CF.sub.3,
OCF.sub.3, B(OH).sub.2 and B(O--C.sub.1-C.sub.6alkyl).sub.2;
R.sup.1b is absent when the X to which it is bound is N; [0189]
R.sup.2b is --(CR.sup.8R.sup.9).sub.m--R.sup.10b; [0190] each
R.sup.6 is independently selected from the group consisting of H,
C.sub.1-C.sub.6alkyl, COOCH.sub.3 and CONHSO.sub.2CH.sub.3; [0191]
each R.sup.7 is independently selected from the group consisting of
OH, C.sub.1-C.sub.6alkyloxy, NH.sub.2,
NHSO.sub.2N(C.sub.1-C.sub.6alkyl).sub.2, NHSO.sub.2NHCH.sub.3,
NHSO.sub.2(C.sub.1-C.sub.6alkyl),
NHSO.sub.2(C.sub.3-C.sub.7cycloalkyl) and
N(C.sub.1-C.sub.6-alkyl).sub.2; [0192] each R.sup.8 and R.sup.9 are
independently chosen from the group consisting of H,
C.sub.1-C.sub.10alkyl and C.sub.3-C.sub.7cycloalkyl; or R.sup.8 and
R.sup.9 taken together form a 4 to 6 membered aliphatic ring that
optionally contains one or more heteroatoms selected from the group
consisting of N, S and O; [0193] R.sup.10b is selected from the
group consisting of H, R.sup.11, OH, CN, F, CF.sub.2H, CF.sub.3,
CONR.sup.8R.sup.9, COOR.sup.8, CON(R.sup.8)SO.sub.2R.sup.9,
CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9), NR.sup.8R.sup.9,
NR.sup.8COOR.sup.9, OCOR.sup.8, O-Benzyl, NR.sup.8SO.sub.2R.sup.9,
SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8, OCONR.sup.8R.sup.9,
OCONR.sup.8R.sup.12, N(R.sup.8)CON(R.sup.8R.sup.9),
N(R.sup.8)COOR.sup.12, and a 4 to 6 membered saturated ring
containing one oxygen atom; [0194] m is an integer from 2 to 6;
[0195] R.sup.11 is selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7cycloalkyl, phenyl, pyridinyl
and pyrazolyl; each optionally substituted with one or more
substituents each independently selected from the group consisting
of CF.sub.3, CH.sub.3, OCH.sub.3, OCF.sub.3 and halogen; [0196]
R.sup.12 is selected from the group consisting of phenyl, pyridinyl
and pyrazolyl; each optionally substituted with one or more
substituents each independently selected from the group consisting
of CF.sub.3, CH.sub.3, OCH.sub.3, OCF.sub.3 and halogen; [0197] or
R.sup.12 is C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.7cycloalkyl;
each substituted with one or more substituents each independently
selected from the group consisting of CF.sub.3, CH.sub.3,
OCH.sub.3, OCF.sub.3 and halogen; [0198] R.sup.1c is present when
Het has formula (c); [0199] each R.sup.1c is selected independently
from the group consisting of H, halogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkyloxy,
N(R.sup.6).sub.2, CO(R.sup.7c), CH.sub.2NH.sub.2, CH.sub.2OH, CN,
C(.dbd.NOH)NH.sub.2, C(.dbd.NOCH.sub.3)NH.sub.2,
C(.dbd.NH)NH.sub.2, CF.sub.3, OCF.sub.3, B(OH).sub.2 and
B(O--C.sub.1-C.sub.6alkyl).sub.2; [0200] R.sup.3c is selected from
the group consisting of H, halogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkyloxy and
CO(R.sup.7c); [0201] R.sup.2c is
--(CR.sup.8R.sup.9).sub.m--R.sup.10c; [0202] R.sup.7c is selected
from the group consisting of OH, O(C.sub.1-C.sub.6alkyl), NH.sub.2,
NHSO.sub.2N(C.sub.1-C.sub.6alkyl).sub.2, NHSO.sub.2NHCH.sub.3,
NHSO.sub.2(C.sub.1-C.sub.6alkyl),
NHSO.sub.2(C.sub.3-C.sub.7cycloalkyl),
N(C.sub.1-C.sub.6-alkyl).sub.2, NR.sup.8R.sup.9 and
NR.sup.9R.sup.10e; R.sup.10e is selected from the group consisting
of H, C.sub.1-C.sub.6alkyl, OH, CN, F, CF.sub.2H, CF.sub.3,
C(.dbd.NOH)NH.sub.2, CONR.sup.8R.sup.9, COOR.sup.8,
CONR.sup.8SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, [0203] NR.sup.8COOR.sup.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8
and a 4 to 6 membered saturated ring containing one oxygen atom;
[0204] R.sup.1d is present when Het has formula (d) and X is C;
each R.sup.1d is selected independently from the group consisting
of H, OH, halogen, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, N(R.sup.6).sub.2, CO(R.sup.7),
CH.sub.2NH.sub.2, CH.sub.2OH, CN, C(.dbd.NOH)NH.sub.2,
C(.dbd.NOCH.sub.3)NH.sub.2, C(.dbd.NH)NH.sub.2, CF.sub.3,
OCF.sub.3, B(OH).sub.2 and B(O--C.sub.1-C.sub.6alkyl).sub.2;
R.sup.1d is absent when the X to which it is bound is N; [0205]
R.sup.3d is selected from the group consisting of H, halogen,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, and CO(R.sup.7); [0206] R.sup.2d is
--(CR.sup.8R.sup.9).sub.m--R.sup.10d; [0207] R.sup.10d is selected
from the group consisting of H, C.sub.1-C.sub.6alkyl, OH, CN, F,
CF.sub.2H, CF.sub.3, CONR.sup.8R.sup.9, COOR.sup.8,
CONR.sup.8SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sub.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8
and a 4 to 6 membered saturated ring containing one oxygen atom;
[0208] each Y independently is C or N; [0209] R.sup.1e is present
when Het has formula (e) and Y is C; each R.sup.1e is selected
independently from the group consisting of H, halogen,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, N(R.sup.6).sub.2, CO(R.sup.7),
CH.sub.2NH.sub.2, CH.sub.2OH, CN, C(.dbd.NOH)NH.sub.2,
C(.dbd.NOCH.sub.3)NH.sub.2, C(.dbd.NH)NH.sub.2, CF.sub.3,
OCF.sub.3, B(OH).sub.2 and B(O--C.sub.1-C.sub.6alkyl).sub.2;
R.sup.1e is absent when the Y to which it is bound is N; [0210]
R.sup.3e is selected from the group consisting of H, halogen,
--(CR.sup.8R.sup.9).sub.m--R.sup.10e,
C.ident.C--CH.sub.2--R.sup.10e, C.ident.C--R.sup.10e and
C.dbd.C--R.sup.10e; [0211] R.sup.10e is selected from the group
consisting of H, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy,
C.sub.3-C.sub.7cycloalkyl, OH, CN, F, CF.sub.2H, CF.sub.3,
CONR.sup.8R.sup.9, COOR.sup.8, CON(R.sup.8)SO.sub.2R.sup.9,
CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9), NR.sup.8R.sup.9,
NR.sup.8COOR.sup.9, OCOR.sup.8, NR.sup.8SO.sub.2R.sup.9,
SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8 and a 4 to 6 membered
saturated ring containing one oxygen atom; [0212] R.sup.4 is
Het.sup.1; [0213] aryl represents phenyl or naphthalenyl; said aryl
optionally being substituted with one or more substituents each
independently selected from the group consisting of halo,
C.sub.1-C.sub.4alkyloxy, C.sub.1-C.sub.4alkyl, OH, CN, CF.sub.2H,
CF.sub.3, CONR.sup.8R.sup.9, COOR.sup.8,
CON(R.sup.8)SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sup.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8,
OCONR.sup.8R.sup.9, OCONR.sup.8R.sup.12,
N(R.sup.8)CON(R.sup.8R.sup.9), N(R.sup.8)COOR.sup.12; [0214]
Het.sup.1 represents a 4 to 6 membered saturated ring containing
one N atom, optionally being substituted with one or more
substituents each independently selected from the group consisting
of halo, C.sub.1-C.sub.4alkyloxy, SO.sub.2R.sup.8,
C.sub.1-C.sub.4alkylcarbonyl, CO(aryl), COHet.sup.2,
C.sub.1-C.sub.4alkyloxycarbonyl, pyridinyl, CF.sub.3,
SO.sub.2N(C.sub.1-C.sub.4alkyl).sub.2,
SO.sub.2NH(C.sub.1-C.sub.4alkyl), (C.dbd.O)NH(C.sub.1-4alkyl),
(C.dbd.S)NH(C.sub.1-4alkyl), C.sub.1-C.sub.4alkyl and
C.sub.1-C.sub.4alkyl substituted with one hydroxy; or [0215]
Het.sup.1 represents a 4 to 6 membered saturated ring containing
one O atom, substituted with one or more substituents each
independently selected from the group consisting of halo,
C.sub.1-C.sub.4alkyloxy, CF.sub.3, NH(C.dbd.O)(C.sub.1-4alkyl),
(C.dbd.O)NH(C.sub.1-4alkyl) and C.sub.1-C.sub.4alkyl; [0216]
Het.sup.2 represents a monocyclic 5 to 6 membered aromatic
heterocycle containing one or more heteroatoms each independently
selected from the group consisting of O, S and N; or a bicyclic 8
to 12 membered aromatic heterocycle containing one or more
heteroatoms each independently selected from the group consisting
of O, S and N; said Het.sup.2 optionally being substituted with one
or more substituents each independently selected from the group
consisting of halo, C.sub.1-C.sub.4alkyloxy, C.sub.1-C.sub.4alkyl,
OH, CN, CF.sub.2H, CF.sub.3, CONR.sup.8R.sup.9, COOR.sup.8,
CON(R.sup.8)SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sup.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8,
OCONR.sup.8R.sup.9, OCONR.sup.8R.sup.12,
N(R.sup.8)CON(R.sup.8R.sup.9), N(R.sup.8)COOR.sup.12; [0217] Z is C
or N; R.sup.5 is present where Z is C, whereby R.sup.5 is selected
form the group consisting of hydrogen, CF.sub.3 and halogen;
R.sup.5 is absent where Z is N; and the pharmaceutically acceptable
addition salts, and the solvates thereof.
[0218] In an embodiment, the present invention concerns novel
compounds of Formula (I) and stereoisomeric forms thereof, wherein
Het is a heterocycle having formula (b), (c), (d) or (e); [0219]
each X independently is C or N; provided that at least one X is N;
[0220] R.sup.1b is present when Het has formula (b) and X is C;
each R.sup.1b is selected independently from the group consisting
of H, halogen, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, N(R.sup.6).sub.2, CO(R.sup.7),
CH.sub.2NH.sub.2, CH.sub.2OH, CN, C(.dbd.NOH)NH.sub.2,
C(.dbd.NOCH.sub.3)NH.sub.2, C(.dbd.NH)NH.sub.2, CF.sub.3,
OCF.sub.3, B(OH).sub.2 and B(O--C.sub.1-C.sub.6alkyl).sub.2;
R.sup.1b is absent when the X to which it is bound is N; [0221]
R.sup.2b is --(CR.sup.8R.sup.9).sub.m--R.sup.10b; [0222] each
R.sup.6 is independently selected from the group consisting of H,
C.sub.1-C.sub.6alkyl, COOCH.sub.3 and CONHSO.sub.2CH.sub.3; [0223]
each R.sup.7 is independently selected from the group consisting of
OH, C.sub.1-C.sub.6alkyloxy, NH.sub.2,
NHSO.sub.2N(C.sub.1-C.sub.6alkyl).sub.2, NHSO.sub.2NHCH.sub.3,
NHSO.sub.2(C.sub.1-C.sub.6alkyl),
NHSO.sub.2(C.sub.3-C.sub.7cycloalkyl) and
N(C.sub.1-C.sub.6-alkyl).sub.2; [0224] each R.sup.8 and R.sup.9 are
independently chosen from the group consisting of H,
C.sub.1-C.sub.10alkyl and C.sub.3-C.sub.7cycloalkyl; or R.sup.8 and
R.sup.9 taken together form a 4 to 6 membered aliphatic ring that
optionally contains one or more heteroatoms selected from the group
consisting of N, S and O; [0225] R.sup.10b is selected from the
group consisting of H, R.sup.11, OH, CN, F, CF.sub.2H, CF.sub.3,
CONR.sup.8R.sup.9, COOR.sup.8, CON(R.sup.8)SO.sub.2R.sup.9,
CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9), NR.sup.8R.sup.9,
NR.sup.8COOR.sup.9, OCOR.sup.8, O-Benzyl, NR.sup.8SO.sub.2R.sup.9,
SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8, OCONR.sup.8R.sup.9,
OCONR.sup.8R.sup.12, N(R.sup.8)CON(R.sup.8R.sup.9),
N(R.sup.8)COOR.sup.12, and a 4 to 6 membered saturated ring
containing one oxygen atom; [0226] m is an integer from 2 to 6;
[0227] R.sup.11 is selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7cycloalkyl, phenyl, pyridinyl
and pyrazolyl; each optionally substituted with one or more
substituents each independently selected from the group consisting
of CF.sub.3, CH.sub.3, OCH.sub.3, OCF.sub.3 and halogen; [0228]
R.sup.12 is selected from the group consisting of phenyl, pyridinyl
and pyrazolyl; each optionally substituted with one or more
substituents each independently selected from the group consisting
of CF.sub.3, CH.sub.3, OCH.sub.3, OCF.sub.3 and halogen; [0229] or
R.sup.12 is C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.7cycloalkyl;
each substituted with one or more substituents each independently
selected from the group consisting of CF.sub.3, CH.sub.3,
OCH.sub.3, OCF.sub.3 and halogen; [0230] R.sup.1c is present when
Het has formula (c); [0231] each R.sup.1c is selected independently
from the group consisting of H, halogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkyloxy,
N(R.sup.6).sub.2, CO(R.sup.7c), CH.sub.2NH.sub.2, CH.sub.2OH, CN,
C(.dbd.NOH)NH.sub.2, C(.dbd.NOCH.sub.3)NH.sub.2,
C(.dbd.NH)NH.sub.2, CF.sub.3, OCF.sub.3, B(OH).sub.2 and
B(O--C.sub.1-C.sub.6alkyl).sub.2; [0232] R.sup.3c is selected from
the group consisting of H, halogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkyloxy and
CO(R.sup.7c); [0233] R.sup.2c is
--(CR.sup.8R.sup.9).sub.m--R.sup.10c; [0234] R.sup.7c is selected
from the group consisting of OH, O(C.sub.1-C.sub.6alkyl), NH.sub.2,
NHSO.sub.2N(C.sub.1-C.sub.6alkyl).sub.2, NHSO.sub.2NHCH.sub.3,
NHSO.sub.2(C.sub.1-C.sub.6alkyl),
NHSO.sub.2(C.sub.3-C.sub.7cycloalkyl),
N(C.sub.1-C.sub.6-alkyl).sub.2, NR.sup.8R.sup.9 and
NR.sup.9R.sup.10c; [0235] R.sup.10c is selected from the group
consisting of H, C.sub.1-C.sub.6alkyl, OH, CN, F, CF.sub.2H,
CF.sub.3, C(.dbd.NOH)NH.sub.2, CONR.sup.8R.sup.9, COOR.sup.8,
CONR.sup.8SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sup.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8
and a 4 to 6 membered saturated ring containing one oxygen atom;
[0236] R.sup.1d is present when Het has formula (d) and X is C;
each R.sup.1d is selected independently from the group consisting
of H, OH, halogen, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, N(R.sup.6).sub.2, CO(R.sup.7),
CH.sub.2NH.sub.2, CH.sub.2OH, CN, C(.dbd.NOH)NH.sub.2,
C(.dbd.NOCH.sub.3)NH.sub.2, C(.dbd.NH)NH.sub.2, CF.sub.3,
OCF.sub.3, B(OH).sub.2 and B(O--C.sub.1-C.sub.6alkyl).sub.2;
R.sup.1d is absent when the X to which it is bound is N; [0237]
R.sup.3d is selected from the group consisting of H, halogen,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, and CO(R.sup.7); [0238] R.sup.2d is
--(CR.sup.8R.sup.9).sub.m--R.sup.10d; [0239] R.sup.10d is selected
from the group consisting of H, C.sub.1-C.sub.6alkyl, OH, CN, F,
CF.sub.2H, CF.sub.3, CONR.sup.8R.sup.9, COOR.sup.8,
CONR.sup.8SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sub.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8
and a 4 to 6 membered saturated ring containing one oxygen atom;
[0240] each Y independently is C or N; [0241] R.sup.1e is present
when Het has formula (e) and Y is C; each R.sup.1e is selected
independently from the group consisting of H, halogen,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, N(R.sup.6).sub.2, CO(R.sup.7),
CH.sub.2NH.sub.2, CH.sub.2OH, CN, C(.dbd.NOH)NH.sub.2,
C(.dbd.NOCH.sub.3)NH.sub.2, C(.dbd.NH)NH.sub.2, CF.sub.3,
OCF.sub.3, B(OH).sub.2 and B(O--C.sub.1-C.sub.6alkyl).sub.2;
R.sup.1e is absent when the Y to which it is bound is N; [0242]
R.sup.3e is selected from the group consisting of H, halogen,
--(CR.sup.8R.sup.9).sub.m--R.sup.10e,
C.ident.C--CH.sub.2--R.sup.10e, C.ident.C--R.sup.10e and
C.dbd.C--R.sup.10e; [0243] R.sup.10e is selected from the group
consisting of H, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy,
C.sub.3-C.sub.7cycloalkyl, OH, CN, F, CF.sub.2H, CF.sub.3,
CONR.sup.8R.sup.9, COOR.sup.8, CON(R.sup.8)SO.sub.2R.sup.9,
CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9), NR.sup.8R.sup.9,
NR.sup.8COOR.sup.9, OCOR.sup.8, NR.sup.8SO.sub.2R.sup.9,
SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8 and a 4 to 6 membered
saturated ring containing one oxygen atom; [0244] R.sup.4 is
Het.sup.1; [0245] Het.sup.1 represents a 4 to 6 membered saturated
ring containing one N atom, optionally being substituted with one
or more substituents each independently selected from the group
consisting of halo, C.sub.1-C.sub.4alkyloxy, SO.sub.2R.sup.8,
C.sub.1-C.sub.4alkylcarbonyl, C.sub.1-C.sub.4alkyloxycarbonyl,
pyridinyl, CF.sub.3, SO.sub.2N(C.sub.1-C.sub.4alkyl).sub.2,
SO.sub.2NH(C.sub.1-C.sub.4alkyl), (C.dbd.O)NH(C.sub.1-4alkyl),
(C.dbd.S)NH(C.sub.1-4alkyl), C.sub.1-C.sub.4alkyl and
C.sub.1-C.sub.4alkyl substituted with one hydroxy; or [0246]
Het.sup.1 represents a 4 to 6 membered saturated ring containing
one O atom, substituted with one or more substituents each
independently selected from the group consisting of halo,
C.sub.1-C.sub.4alkyloxy, CF.sub.3, NH(C.dbd.O)(C.sub.1-4alkyl),
(C.dbd.O)NH(C.sub.1-4alkyl) and C.sub.1-C.sub.4alkyl; [0247] Z is C
or N; R.sup.5 is present where Z is C, whereby R.sup.5 is selected
form the group consisting of hydrogen, CF.sub.3 and halogen;
R.sup.5 is absent where Z is N; and the pharmaceutically acceptable
addition salts, and the solvates thereof.
[0248] In an embodiment, the present invention concerns novel
compounds of Formula (I) and stereoisomeric forms thereof, wherein
Het is a heterocycle having formula (b), (c), (d) or (e); [0249]
each X independently is C or N; provided that at least one X is N;
[0250] R.sup.1b is present when Het has formula (b) and X is C;
each R.sup.1b is selected independently from the group consisting
of H, halogen, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, N(R.sup.6).sub.2, CO(R.sup.7),
CH.sub.2NH.sub.2, CH.sub.2OH, CN, C(.dbd.NOH)NH.sub.2,
C(.dbd.NOCH.sub.3)NH.sub.2, C(.dbd.NH)NH.sub.2, CF.sub.3,
OCF.sub.3, B(OH).sub.2 and B(O--C.sub.1-C.sub.6alkyl).sub.2;
R.sup.1b is absent when the X to which it is bound is N; [0251]
R.sup.2b is --(CR.sup.8R.sup.9).sub.m--R.sup.10b; [0252] each
R.sup.6 is independently selected from the group consisting of H,
C.sub.1-C.sub.6alkyl, COOCH.sub.3 and CONHSO.sub.2CH.sub.3; [0253]
each R.sup.7 is independently selected from the group consisting of
OH, C.sub.1-C.sub.6alkyloxy, NH.sub.2,
NHSO.sub.2N(C.sub.1-C.sub.6alkyl).sub.2, NHSO.sub.2NHCH.sub.3,
NHSO.sub.2(C.sub.1-C.sub.6alkyl);
NHSO.sub.2(C.sub.3-C.sub.7cycloalkyl) and
N(C.sub.1-C.sub.6-alkyl).sub.2; [0254] each R.sup.8 and R.sup.9 are
independently chosen from the group consisting of H,
C.sub.1-C.sub.10alkyl and C.sub.3-C.sub.7cycloalkyl; or R.sup.8 and
R.sup.9 taken together form a 4 to 6 membered aliphatic ring that
optionally contains one or more heteroatoms selected from the group
consisting of N, S and O; [0255] R.sup.10b is selected from the
group consisting of H, R.sup.11, OH, CN, F, CF.sub.2H, CF.sub.3,
CONR.sup.8R.sup.9, COOR.sup.8, CON(R.sup.8)SO.sub.2R.sup.9,
CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9), NR.sup.8R.sup.9,
NR.sup.8COOR.sup.9, OCOR.sup.8, O-Benzyl, NR.sup.8SO.sub.2R.sup.9,
SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8, OCONR.sup.8R.sup.9,
OCONR.sup.8R.sup.12, N(R.sup.8)CON(R.sup.8R.sup.9),
N(R.sup.8)COOR.sup.12, and a 4 to 6 membered saturated ring
containing one oxygen atom; [0256] m is an integer from 2 to 6;
[0257] R.sup.11 is selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7cycloalkyl, phenyl, pyridinyl
and pyrazolyl; each optionally substituted with one or more
substituents each independently selected from the group consisting
of CF.sub.3, CH.sub.3, OCH.sub.3, OCF.sub.3 and halogen; [0258]
R.sup.12 is selected from the group consisting of phenyl, pyridinyl
and pyrazolyl; each optionally substituted with one or more
substituents each independently selected from the group consisting
of CF.sub.3, CH.sub.3, OCH.sub.3, OCF.sub.3 and halogen; [0259] or
R.sup.12 is C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.7cycloalkyl;
each substituted with one or more substituents each independently
selected from the group consisting of CF.sub.3, CH.sub.3,
OCH.sub.3, OCF.sub.3 and halogen; [0260] R.sup.1c is present when
Het has formula (c); [0261] each R.sup.1c is selected independently
from the group consisting of H, halogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkyloxy,
N(R.sup.6).sub.2, CO(R.sup.7c), CH.sub.2NH.sub.2, CH.sub.2OH, CN,
C(.dbd.NOH)NH.sub.2, C(.dbd.NOCH.sub.3)NH.sub.2,
C(.dbd.NH)NH.sub.2, CF.sub.3, OCF.sub.3, B(OH).sub.2 and
B(O--C.sub.1-C.sub.6alkyl).sub.2; [0262] R.sup.3c is selected from
the group consisting of H, halogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkyloxy and
CO(R.sup.7c); [0263] R.sup.2c is
--(CR.sup.8R.sup.9).sub.m--R.sup.10c; [0264] R.sup.7c is selected
from the group consisting of OH, O(C.sub.1-C.sub.6alkyl), NH.sub.2,
NHSO.sub.2N(C.sub.1-C.sub.6alkyl).sub.2, NHSO.sub.2NHCH.sub.3,
NHSO.sub.2(C.sub.1-C.sub.6alkyl),
NHSO.sub.2(C.sub.3-C.sub.7cycloalkyl),
N(C.sub.1-C.sub.6-alkyl).sub.2, NR.sup.8R.sup.9 and
NR.sup.9R.sup.10c; [0265] R.sup.10c is selected from the group
consisting of H, C.sub.1-C.sub.6alkyl, OH, CN, F, CF.sub.2H,
CF.sub.3, C(.dbd.NOH)NH.sub.2, CONR.sup.8R.sup.9, COOR.sup.8,
CONR.sup.8SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sup.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8
and a 4 to 6 membered saturated ring containing one oxygen atom;
[0266] R.sup.1d is present when Het has formula (d) and X is C;
each R.sup.1d is selected independently from the group consisting
of H, OH, halogen, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, N(R.sup.6).sub.2, CO(R.sup.7),
CH.sub.2NH.sub.2, CH.sub.2OH, CN, C(.dbd.NOH)NH.sub.2,
C(.dbd.NOCH.sub.3)NH.sub.2, C(.dbd.NH)NH.sub.2, CF.sub.3,
OCF.sub.3, B(OH).sub.2 and B(O--C.sub.1-C.sub.6alkyl).sub.2;
R.sup.1d is absent when the X to which it is bound is N; [0267]
R.sup.3d is selected from the group consisting of H, halogen,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, and CO(R.sup.7); [0268] R.sup.2d is
--(CR.sup.8R.sup.9).sub.m--R.sup.10d; [0269] R.sup.10d is selected
from the group consisting of H, C.sub.1-C.sub.6alkyl, OH, CN, F,
CF.sub.2H, CF.sub.3, CONR.sup.8R.sup.9, COOR.sup.8,
CONR.sup.8SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sub.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8
and a 4 to 6 membered saturated ring containing one oxygen atom;
[0270] each Y independently is C or N; [0271] R.sup.1e is present
when Het has formula (e) and Y is C; each R.sup.1e is selected
independently from the group consisting of H, halogen,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, N(R.sup.6).sub.2, CO(R.sup.7),
CH.sub.2NH.sub.2, CH.sub.2OH, CN, C(.dbd.NOH)NH.sub.2,
C(.dbd.NOCH.sub.3)NH.sub.2, C(.dbd.NH)NH.sub.2, CF.sub.3,
OCF.sub.3, B(OH).sub.2 and B(O--C.sub.1-C.sub.6alkyl).sub.2;
R.sup.1e is absent when the Y to which it is bound is N; [0272]
R.sup.3e is selected from the group consisting of H, halogen,
--(CR.sup.8R.sup.9).sub.m--R.sup.10e,
C.ident.C--CH.sub.2--R.sup.10e, C.ident.C--R.sup.10e and
C.dbd.C--R.sup.10e; [0273] R.sup.10e is selected from the group
consisting of H, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy,
C.sub.3-C.sub.7cycloalkyl, OH, CN, F, CF.sub.2H, CF.sub.3,
CONR.sup.8R.sup.9, COOR.sup.8, CON(R.sup.8)SO.sub.2R.sup.9,
CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9), NR.sup.8R.sup.9,
NR.sup.8COOR.sup.9, OCOR.sup.8, NR.sup.8SO.sub.2R.sup.9,
SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8 and a 4 to 6 membered
saturated ring containing one oxygen atom; [0274] R.sup.4 is
selected from the group consisting of aryl and Het.sup.2; in
particular Het.sup.2; [0275] aryl represents phenyl or
naphthalenyl; said aryl optionally being substituted with one or
more substituents each independently selected from the group
consisting of halo, C.sub.1-C.sub.4alkyloxy, C.sub.1-C.sub.4alkyl,
OH, CN, CF.sub.2H, CF.sub.3, CONR.sup.8R.sup.9, COOR.sup.8,
CON(R.sup.8)SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sup.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8,
OCONR.sup.8R.sup.9, OCONR.sup.8R.sup.12,
N(R.sup.8)CON(R.sup.8R.sup.9), N(R.sup.8)COOR.sup.12; [0276]
Het.sup.2 represents a monocyclic 5 to 6 membered aromatic
heterocycle containing one or more heteroatoms each independently
selected from the group consisting of O, S and N; or a bicyclic 8
to 12 membered aromatic heterocycle containing one or more
heteroatoms each independently selected from the group consisting
of O, S and N; said Het.sup.2 optionally being substituted with one
or more substituents each independently selected from the group
consisting of halo, C.sub.1-C.sub.4alkyloxy, C.sub.1-C.sub.4alkyl,
OH, CN, CF.sub.2H, CF.sub.3, CONR.sup.8R.sup.9, COOR.sup.8,
CON(R.sup.8)SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sup.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8,
OCONR.sup.8R.sup.9, OCONR.sup.8R.sup.12,
N(R.sup.8)CON(R.sup.8R.sup.9), N(R.sup.8)COOR.sup.12; [0277] Z is C
or N; R.sup.5 is present where Z is C, whereby R.sup.5 is selected
form the group consisting of hydrogen, CF.sub.3 and halogen;
R.sup.5 is absent where Z is N; and the pharmaceutically acceptable
addition salts, and the solvates thereof.
[0278] In an embodiment, the present invention concerns novel
compounds of Formula (I) and stereoisomeric forms thereof, wherein
Het is a heterocycle having formula (b), (c), (d) or (e); [0279]
each X independently is C or N; provided that at least one X is N;
[0280] R.sup.1b is present when Het has formula (b) and X is C;
each R.sup.1b is selected independently from the group consisting
of H, halogen, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, N(R.sup.6).sub.2, CO(R.sup.7),
CH.sub.2NH.sub.2, CH.sub.2OH, CN, C(.dbd.NOH)NH.sub.2,
C(.dbd.NOCH.sub.3)NH.sub.2, C(.dbd.NH)NH.sub.2, CF.sub.3,
OCF.sub.3, B(OH).sub.2 and B(O--C.sub.1-C.sub.6alkyl).sub.2;
R.sup.1b is absent when the X to which it is bound is N; [0281]
R.sup.2b is --(CR.sup.8R.sup.9).sub.m--R.sup.10b; [0282] each
R.sup.6 is independently selected from the group consisting of H,
C.sub.1-C.sub.6alkyl, COOCH.sub.3 and CONHSO.sub.2CH.sub.3; [0283]
each R.sup.7 is independently selected from the group consisting of
OH, C.sub.1-C.sub.6alkyloxy, NH.sub.2,
NHSO.sub.2N(C.sub.1-C.sub.6alkyl).sub.2, NHSO.sub.2NHCH.sub.3,
NHSO.sub.2(C.sub.1-C.sub.6alkyl),
NHSO.sub.2(C.sub.3-C.sub.7cycloalkyl) and
N(C.sub.1-C.sub.6-alkyl).sub.2; [0284] each R.sup.8 and R.sup.9 are
independently chosen from the group consisting of H,
C.sub.1-C.sub.10alkyl and C.sub.3-C.sub.7cycloalkyl; [0285]
R.sup.10b is selected from the group consisting of H, R.sup.11, OH,
CN, F, CF.sub.2H, CF.sub.3, CONR.sup.8R.sup.9, COOR.sup.8,
CON(R.sup.8)SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sup.9, OCOR.sup.8, O-Benzyl,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8,
OCONR.sup.8R.sup.9, OCONR.sup.8R.sup.12,
N(R.sup.8)CON(R.sup.8R.sup.9), N(R.sup.8)COOR.sup.12, and a 4 to 6
membered saturated ring containing one oxygen atom; [0286] m is an
integer from 2 to 6; [0287] R.sup.11 is selected from the group
consisting of C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7cycloalkyl,
phenyl, pyridinyl and pyrazolyl; each optionally substituted with
one or more substituents each independently selected from the group
consisting of CF.sub.3, CH.sub.3, OCH.sub.3, OCF.sub.3 and halogen;
[0288] R.sup.12 is selected from the group consisting of phenyl,
pyridinyl and pyrazolyl; each optionally substituted with one or
more substituents each independently selected from the group
consisting of CF.sub.3, CH.sub.3, OCH.sub.3, OCF.sub.3 and halogen;
[0289] or R.sup.12 is C.sub.1-C.sub.6 alkyl or
C.sub.3-C.sub.7cycloalkyl; each substituted with one or more
substituents each independently selected from the group consisting
of CF.sub.3, CH.sub.3, OCH.sub.3, OCF.sub.3 and halogen; [0290]
R.sup.1c is present when Het has formula (c); [0291] each R.sup.1c
is selected independently from the group consisting of H, halogen,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, N(R.sup.6).sub.2, CO(R.sup.7c),
CH.sub.2NH.sub.2, CH.sub.2OH, CN, C(.dbd.NOH)NH.sub.2,
C(.dbd.NOCH.sub.3)NH.sub.2, C(.dbd.NH)NH.sub.2, CF.sub.3,
OCF.sub.3, B(OH).sub.2 and B(O--C.sub.1-C.sub.6alkyl).sub.2; [0292]
R.sup.3c is selected from the group consisting of H, halogen,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy and CO(R.sup.7c); [0293] R.sup.2c is
--(CR.sup.8R.sup.9).sub.m--R.sup.10c; [0294] R.sup.7c is selected
from the group consisting of OH, O(C.sub.1-C.sub.6alkyl), NH.sub.2,
NHSO.sub.2N(C.sub.1-C.sub.6alkyl).sub.2, NHSO.sub.2NHCH.sub.3,
NHSO.sub.2(C.sub.1-C.sub.6alkyl),
NHSO.sub.2(C.sub.3-C.sub.7cycloalkyl),
N(C.sub.1-C.sub.6-alkyl).sub.2, NR.sup.8R.sup.9 and
NR.sup.9R.sup.10c; [0295] R.sup.10c is selected from the group
consisting of H, C.sub.1-C.sub.6alkyl, OH, CN, F, CF.sub.2H,
CF.sub.3, C(.dbd.NOH)NH.sub.2, CONR.sup.8R.sup.9, COOR.sup.8,
CONR.sup.8SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sup.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8
and a 4 to 6 membered saturated ring containing one oxygen atom;
[0296] R.sup.1d is present when Het has formula (d) and X is C;
each R.sup.1d is selected independently from the group consisting
of H, OH, halogen, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, N(R.sup.6).sub.2, CO(R.sup.7),
CH.sub.2NH.sub.2, CH.sub.2OH, CN, C(.dbd.NOH)NH.sub.2,
C(.dbd.NOCH.sub.3)NH.sub.2, C(.dbd.NH)NH.sub.2, CF.sub.3,
OCF.sub.3, B(OH).sub.2 and B(O--C.sub.1-C.sub.6alkyl).sub.2;
R.sup.1d is absent when the X to which it is bound is N; [0297]
R.sup.3d is selected from the group consisting of H, halogen,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, and CO(R.sup.7); [0298] R.sup.2d is
--(CR.sup.8R.sup.9).sub.m--R.sup.10d; [0299] R.sup.10d is selected
from the group consisting of H, C.sub.1-C.sub.6alkyl, OH, CN, F,
CF.sub.2H, CF.sub.3, CONR.sup.8R.sup.9, COOR.sup.8,
CONR.sup.8SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sub.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8
and a 4 to 6 membered saturated ring containing one oxygen atom;
[0300] each Y independently is C or N; [0301] R.sup.1e is present
when Het has formula (e) and Y is C; each R.sup.1e is selected
independently from the group consisting of H, halogen,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, N(R.sup.6).sub.2, CO(R.sup.7),
CH.sub.2NH.sub.2, CH.sub.2OH, CN, C(.dbd.NOH)NH.sub.2,
C(.dbd.NOCH.sub.3)NH.sub.2, C(.dbd.NH)NH.sub.2, CF.sub.3,
OCF.sub.3, B(OH).sub.2 and B(O--C.sub.1-C.sub.6alkyl).sub.2;
R.sup.1e is absent when the Y to which it is bound is N; [0302]
R.sup.3e is selected from the group consisting of H, halogen,
--(CR.sup.8R.sup.9).sub.m--R.sup.10e,
C.ident.C--CH.sub.2--R.sup.10e, C.ident.C--R.sup.10e and
C.dbd.C--R.sup.10e; [0303] R.sup.10e is selected from the group
consisting of H, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy,
C.sub.3-C.sub.7cycloalkyl, OH, CN, F, CF.sub.2H, CF.sub.3,
CONR.sup.8R.sup.9, COOR.sup.8, CON(R.sup.8)SO.sub.2R.sup.9,
CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9), NR.sup.8R.sup.9,
NR.sup.8COOR.sup.9, OCOR.sup.8, NR.sup.8SO.sub.2R.sup.9,
SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8 and a 4 to 6 membered
saturated ring containing one oxygen atom; [0304] R.sup.4 is
selected from the group consisting of tert-butyl, Het.sup.1, aryl,
Het.sup.2, CH(CH.sub.3)(CF.sub.3), and C.sub.3-C.sub.7cycloalkyl
substituted with one or more substituents selected from the group
consisting of halo and C.sub.1-C.sub.4alkyl; [0305] aryl represents
phenyl or naphthalenyl; said aryl optionally being substituted with
one or more substituents each independently selected from the group
consisting of halo, C.sub.1-C.sub.4alkyloxy, C.sub.1-C.sub.4alkyl,
OH, CN, CF.sub.2H, CF.sub.3, CONR.sup.8R.sup.9, COOR.sup.8,
CON(R.sup.8)SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sup.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8,
OCONR.sup.8R.sup.9, OCONR.sup.8R.sup.12,
N(R.sup.8)CON(R.sup.8R.sup.9), N(R.sup.8)COOR.sup.12; [0306]
Het.sup.1 represents a 4 to 6 membered saturated ring containing
one N atom, optionally being substituted with one or more
substituents each independently selected from the group consisting
of halo, C.sub.1-C.sub.4alkyloxy, SO.sub.2R.sup.8,
C.sub.1-C.sub.4alkylcarbonyl, CO(aryl), COHet.sup.2,
C.sub.1-C.sub.4alkyloxycarbonyl, pyridinyl, CF.sub.3,
SO.sub.2N(C.sub.1-C.sub.4alkyl).sub.2,
SO.sub.2NH(C.sub.1-C.sub.4alkyl), (C.dbd.O)NH(C.sub.1-4alkyl),
(C.dbd.S)NH(C.sub.1-4alkyl), C.sub.1-C.sub.4alkyl and
C.sub.1-C.sub.4alkyl substituted with one hydroxy; or [0307]
Het.sup.1 represents a 4 to 6 membered saturated ring containing
one O atom, substituted with one or more substituents each
independently selected from the group consisting of halo,
C.sub.1-C.sub.4alkyloxy, CF.sub.3, NH(C.dbd.O)(C.sub.1-4alkyl),
(C.dbd.O)NH(C.sub.1-4alkyl) and C.sub.1-C.sub.4alkyl; [0308]
Het.sup.2 represents a monocyclic 5 to 6 membered aromatic
heterocycle containing one or more heteroatoms each independently
selected from the group consisting of O, S and N; or a bicyclic 8
to 12 membered aromatic heterocycle containing one or more
heteroatoms each independently selected from the group consisting
of O, S and N; said Het.sup.2 optionally being substituted with one
or more substituents each independently selected from the group
consisting of halo, C.sub.1-C.sub.4alkyloxy, C.sub.1-C.sub.4alkyl,
OH, CN, CF.sub.2H, CF.sub.3, CONR.sup.8R.sup.9, COOR.sup.8,
CON(R.sup.8)SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sup.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8,
OCONR.sup.8R.sup.9, OCONR.sup.8R.sup.12,
N(R.sup.8)CON(R.sup.8R.sup.9), N(R.sup.8)COOR.sup.12; [0309] Z is C
or N; R.sup.5 is present where Z is C, whereby R.sup.5 is selected
form the group consisting of hydrogen, CF.sub.3 and halogen;
R.sup.5 is absent where Z is N; and the pharmaceutically acceptable
addition salts, and the solvates thereof.
[0310] In an embodiment, the present invention concerns novel
compounds of Formula (I) and stereoisomeric forms thereof, wherein
Het is a heterocycle having formula (b), (c), (d) or (e); [0311]
each X independently is C or N; provided that at least one X is N;
[0312] R.sup.1b is present when Het has formula (b) and X is C;
each R.sup.1b is selected independently from the group consisting
of H, halogen, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, N(R.sup.6).sub.2, CO(R.sup.7),
CH.sub.2NH.sub.2, CH.sub.2OH, CN, C(.dbd.NOH)NH.sub.2,
C(.dbd.NOCH.sub.3)NH.sub.2, C(.dbd.NH)NH.sub.2, CF.sub.3,
OCF.sub.3, B(OH).sub.2 and B(O--C.sub.1-C.sub.6alkyl).sub.2;
R.sup.1b is absent when the X to which it is bound is N; [0313]
R.sup.2b is --(CR.sup.8R.sup.9).sub.m--R.sup.10b; [0314] each
R.sup.6 is independently selected from the group consisting of H,
C.sub.1-C.sub.6alkyl, COOCH.sub.3 and CONHSO.sub.2CH.sub.3; [0315]
each R.sup.7 is independently selected from the group consisting of
OH, C.sub.1-C.sub.6alkyloxy, NH.sub.2,
NHSO.sub.2N(C.sub.1-C.sub.6alkyl).sub.2, NHSO.sub.2NHCH.sub.3,
NHSO.sub.2(C.sub.1-C.sub.6alkyl),
NHSO.sub.2(C.sub.3-C.sub.7cycloalkyl) and
N(C.sub.1-C.sub.6-alkyl).sub.2; [0316] each R.sup.8 and R.sup.9 are
independently chosen from the group consisting of H; [0317]
R.sup.10b is selected from the group consisting of H, R.sup.11, OH,
CN, F, CF.sub.2H, CF.sub.3, CONR.sup.8R.sup.9, COOR.sup.8,
CON(R.sup.8)SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sup.9, OCOR.sup.8, O-Benzyl,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2CH.sub.3,
OCONR.sup.8R.sup.9, OCONR.sup.8R.sup.12,
N(R.sup.8)CON(R.sup.8R.sup.9), N(R.sup.8)COOR.sup.12, and a 4 to 6
membered saturated ring containing one oxygen atom; [0318] m is an
integer from 2 to 6; [0319] R.sup.11 is selected from the group
consisting of C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7cycloalkyl,
phenyl, pyridinyl and pyrazolyl; each optionally substituted with
one or more substituents each independently selected from the group
consisting of CF.sub.3, CH.sub.3, OCH.sub.3, OCF.sub.3 and halogen;
[0320] R.sup.12 is selected from the group consisting of phenyl,
pyridinyl and pyrazolyl; each optionally substituted with one or
more substituents each independently selected from the group
consisting of CF.sub.3, CH.sub.3, OCH.sub.3, OCF.sub.3 and halogen;
[0321] or R.sup.12 is C.sub.1-C.sub.6 alkyl or
C.sub.3-C.sub.7cycloalkyl; each substituted with one or more
substituents each independently selected from the group consisting
of CF.sub.3, CH.sub.3, OCH.sub.3, OCF.sub.3 and halogen; [0322]
R.sup.1c is present when Het has formula (c); [0323] each R.sup.1c
is selected independently from the group consisting of H, halogen,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, N(R.sup.6).sub.2, CO(R.sup.7c),
CH.sub.2NH.sub.2, CH.sub.2OH, CN, C(.dbd.NOH)NH.sub.2,
C(.dbd.NOCH.sub.3)NH.sub.2, C(.dbd.NH)NH.sub.2, CF.sub.3,
OCF.sub.3, B(OH).sub.2 and B(O--C.sub.1-C.sub.6alkyl).sub.2; [0324]
R.sup.3c is selected from the group consisting of H, halogen,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy and CO(R.sup.7c); [0325] R.sup.2c is
--(CR.sup.8R.sup.9).sub.m--R.sup.10c; [0326] R.sup.7c is selected
from the group consisting of OH, O(C.sub.1-C.sub.6alkyl), NH.sub.2,
NHSO.sub.2N(C.sub.1-C.sub.6alkyl).sub.2, NHSO.sub.2NHCH.sub.3,
NHSO.sub.2(C.sub.1-C.sub.6alkyl),
NHSO.sub.2(C.sub.3-C.sub.7cycloalkyl),
N(C.sub.1-C.sub.6-alkyl).sub.2, NR.sup.8R.sup.9 and
NR.sup.9R.sup.10c; [0327] R.sup.10c is selected from the group
consisting of H, C.sub.1-C.sub.6alkyl, OH, CN, F, CF.sub.2H,
CF.sub.3, C(.dbd.NOH)NH.sub.2, CONR.sup.8R.sup.9, COOR.sup.8,
CONR.sup.8SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sup.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2CH.sub.3
and a 4 to 6 membered saturated ring containing one oxygen atom;
[0328] R.sup.1d is present when Het has formula (d) and X is C;
each R.sup.1d is selected independently from the group consisting
of H, OH, halogen, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, N(R.sup.6).sub.2, CO(R.sup.7),
CH.sub.2NH.sub.2, CH.sub.2OH, CN, C(.dbd.NOH)NH.sub.2,
C(.dbd.NOCH.sub.3)NH.sub.2, C(.dbd.NH)NH.sub.2, CF.sub.3,
OCF.sub.3, B(OH).sub.2 and B(O--C.sub.1-C.sub.6alkyl).sub.2;
R.sup.1d is absent when the X to which it is bound is N; [0329]
R.sup.3d is selected from the group consisting of H, halogen,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, and CO(R.sup.7); [0330] R.sup.2d is
--(CR.sup.8R.sup.9).sub.m--R.sup.10d; [0331] R.sup.10d is selected
from the group consisting of H, C.sub.1-C.sub.6alkyl, OH, CN, F,
CF.sub.2H, CF.sub.3, CONR.sup.8R.sup.9, COOR.sup.8,
CONR.sup.8SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sub.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2CH.sub.3
and a 4 to 6 membered saturated ring containing one oxygen atom;
[0332] each Y independently is C or N; [0333] R.sup.1e is present
when Het has formula (e) and Y is C; each R.sup.1e is selected
independently from the group consisting of H, halogen,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, N(R.sup.6).sub.2, CO(R.sup.7),
CH.sub.2NH.sub.2, CH.sub.2OH, CN, C(.dbd.NOH)NH.sub.2,
C(.dbd.NOCH.sub.3)NH.sub.2, C(.dbd.NH)NH.sub.2, CF.sub.3,
OCF.sub.3, B(OH).sub.2 and B(O--C.sub.1-C.sub.6alkyl).sub.2;
R.sup.1e is absent when the Y to which it is bound is N; [0334]
R.sup.3e is selected from the group consisting of H, halogen,
--(CR.sup.8R.sup.9).sub.m--R.sup.10e,
C.ident.C--CH.sub.2--R.sup.10e, C.ident.C--R.sup.10e and
C.dbd.C--R.sup.10e; [0335] R.sup.10e is selected from the group
consisting of H, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy,
C.sub.3-C.sub.7cycloalkyl, OH, CN, F, CF.sub.2H, CF.sub.3,
CONR.sup.8R.sup.9, COOR.sup.8, CON(R.sup.8)SO.sub.2R.sup.9,
CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9), NR.sup.8R.sup.9,
NR.sup.8COOR.sup.9, OCOR.sup.8, NR.sup.8SO.sub.2R.sup.9,
SO.sub.2NR.sup.8R.sup.9, SO.sub.2CH.sub.3 and a 4 to 6 membered
saturated ring containing one oxygen atom; [0336] R.sup.4 is
selected from the group consisting of tert-butyl, Het.sup.1, aryl,
Het.sup.2, CH(CH.sub.3)(CF.sub.3), and C.sub.3-C.sub.7cycloalkyl
substituted with one or more substituents selected from the group
consisting of halo and C.sub.1-C.sub.4alkyl; [0337] aryl represents
phenyl or naphthalenyl; said aryl optionally being substituted with
one or more substituents each independently selected from the group
consisting of halo, C.sub.1-C.sub.4alkyloxy, C.sub.1-C.sub.4alkyl,
OH, CN, CF.sub.2H, CF.sub.3, CONR.sup.8R.sup.9, COOR.sup.8,
CON(R.sup.8)SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sup.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2CH.sub.3,
OCONR.sup.8R.sup.9, OCONR.sup.8R.sup.12,
N(R.sup.8)CON(R.sup.8R.sup.9), N(R.sup.8)COOR.sup.12; [0338]
Het.sup.1 represents a 4 to 6 membered saturated ring containing
one N atom, optionally being substituted with one or more
substituents each independently selected from the group consisting
of halo, C.sub.1-C.sub.4alkyloxy, SO.sub.2CH.sub.3,
C.sub.1-C.sub.4alkylcarbonyl, CO(aryl), COHet.sup.2,
C.sub.1-C.sub.4alkyloxycarbonyl, pyridinyl, CF.sub.3,
SO.sub.2N(C.sub.1-C.sub.4alkyl).sub.2,
SO.sub.2NH(C.sub.1-C.sub.4alkyl), (C.dbd.O)NH(C.sub.1-4alkyl),
(C.dbd.S)NH(C.sub.1-4alkyl), C.sub.1-C.sub.4alkyl and
C.sub.1-C.sub.4alkyl substituted with one hydroxy; or [0339]
Het.sup.1 represents a 4 to 6 membered saturated ring containing
one O atom, substituted with one or more substituents each
independently selected from the group consisting of halo,
C.sub.1-C.sub.4alkyloxy, CF.sub.3, NH(C.dbd.O)(C.sub.1-4alkyl),
(C.dbd.O)NH(C.sub.1-4alkyl) and C.sub.1-C.sub.4alkyl; [0340]
Het.sup.2 represents a monocyclic 5 to 6 membered aromatic
heterocycle containing one or more heteroatoms each independently
selected from the group consisting of O, S and N; or a bicyclic 8
to 12 membered aromatic heterocycle containing one or more
heteroatoms each independently selected from the group consisting
of O, S and N; said Het.sup.2 optionally being substituted with one
or more substituents each independently selected from the group
consisting of halo, C.sub.1-C.sub.4alkyloxy, C.sub.1-C.sub.4alkyl,
OH, CN, CF.sub.2H, CF.sub.3, CONR.sup.8R.sup.9, COOR.sup.8,
CON(R.sup.8)SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sup.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2CH.sub.3,
OCONR.sup.8R.sup.9, OCONR.sup.8R.sup.12,
N(R.sup.8)CON(R.sup.8R.sup.9), N(R.sup.8)COOR.sup.12; [0341] Z is C
or N; R.sup.5 is present where Z is C, whereby R.sup.5 is selected
form the group consisting of hydrogen, CF.sub.3 and halogen;
R.sup.5 is absent where Z is N; and the pharmaceutically acceptable
addition salts, and the solvates thereof.
[0342] In an embodiment, the present invention concerns novel
compounds of Formula (I) and stereoisomeric forms thereof, wherein
Het is a heterocycle having formula (b), (c), (d) or (e); in
particular (b) or (c); [0343] each X independently is C or N;
provided that at least one X is N; [0344] R.sup.1b is present when
Het has formula (b) and X is C; each R.sup.1b is selected
independently from the group consisting of H, halogen,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, CF.sub.3 and OCF.sub.3; R.sup.1b is absent
when the X to which it is bound is N; [0345] R.sup.2b is
--(CR.sup.8R.sup.9).sub.m--R.sup.10b; [0346] each R.sup.8 and
R.sup.9 are independently chosen from the group consisting of H and
C.sub.1-C.sub.10alkyl; [0347] R.sup.10b is selected from the group
consisting of H, R.sup.11, OH, CN, F, CF.sub.2H, CF.sub.3,
NR.sup.8R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8; [0348] m
is an integer from 2 to 6; [0349] R.sup.11 is selected from the
group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.7cycloalkyl, phenyl, pyridinyl and pyrazolyl; each
optionally substituted with one or more substituents each
independently selected from the group consisting of CF.sub.3,
CH.sub.3, OCH.sub.3, OCF.sub.3 and halogen; in particular
C.sub.1-C.sub.6 alkyl; [0350] R.sup.12 is selected from the group
consisting of phenyl, pyridinyl and pyrazolyl; each optionally
substituted with one or more substituents each independently
selected from the group consisting of CF.sub.3, CH.sub.3,
OCH.sub.3, OCF.sub.3 and halogen; [0351] or R.sup.12 is
C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.7cycloalkyl; each
substituted with one or more substituents each independently
selected from the group consisting of CF.sub.3, CH.sub.3,
OCH.sub.3, OCF.sub.3 and halogen; [0352] R.sup.1c is present when
Het has formula (c); [0353] each R.sup.1c is selected independently
from the group consisting of H, halogen, C.sub.1-C.sub.6alkyl,
[0354] C.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkyloxy, CF.sub.3
and OCF.sub.3; [0355] R.sup.3c is selected from the group
consisting of H, halogen, C.sub.1-C.sub.6alkyl; [0356] R.sup.2c is
--(CR.sup.8R.sup.9).sub.m--R.sup.10e; [0357] R.sup.10c is selected
from the group consisting of H, C.sub.1-C.sub.6alkyl, OH, CN, F,
CF.sub.2H, CF.sub.3, NR.sup.8R.sup.9, SO.sub.2NR.sup.8R.sup.9,
SO.sub.2R.sup.8; [0358] R.sup.1d is present when Het has formula
(d) and X is C; each R.sup.1d is selected independently from the
group consisting of H, halogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkyloxy, CF.sub.3 and
OCF.sub.3; R.sup.1d is absent when the X to which it is bound is N;
[0359] R.sup.3d is selected from the group consisting of H,
halogen, C.sub.1-C.sub.6alkyl; [0360] R.sup.2d is
--(CR.sup.8R.sup.9).sub.m--R.sup.10d; [0361] R.sup.10d is selected
from the group consisting of H, C.sub.1-C.sub.6alkyl, OH, CN, F,
CF.sub.2H, CF.sub.3, NR.sup.8R.sup.9, SO.sub.2NR.sup.8R.sup.9,
SO.sub.2R.sup.8; [0362] each Y independently is C or N; [0363]
R.sup.1e is present when Het has formula (e) and Y is C; each
R.sup.1e is selected independently from the group consisting of H,
halogen, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, CF.sub.3 and OCF.sub.3; R.sup.1e is absent
when the Y to which it is bound is N; [0364] R.sup.3e is selected
from the group consisting of H, halogen; [0365] R.sup.4 is selected
from the group consisting of tert-butyl, Het.sup.1, aryl,
Het.sup.2, CH(CH.sub.3)(CF.sub.3), and C.sub.3-C.sub.7cycloalkyl
substituted with one or more substituents selected from the group
consisting of halo and C.sub.1-C.sub.4alkyl; [0366] aryl represents
phenyl or naphthalenyl; said aryl optionally being substituted with
one or more substituents each independently selected from the group
consisting of halo, C.sub.1-C.sub.4alkyloxy, C.sub.1-C.sub.4alkyl,
OH, CN, CF.sub.2H, CF.sub.3, CONR.sup.8R.sup.9, NR.sup.8R.sup.9,
NR.sup.8COOR.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8,
OCONR.sup.8R.sup.9, OCONR.sup.8R.sup.12, N(R.sup.8)COOR.sup.12;
[0367] Het.sup.1 represents a 4 to 6 membered saturated ring
containing one N atom, optionally being substituted with one or
more substituents each independently selected from the group
consisting of halo, C.sub.1-C.sub.4alkyloxy, SO.sub.2R.sup.8,
C.sub.1-C.sub.4alkylcarbonyl, C.sub.1-C.sub.4alkyloxycarbonyl,
pyridinyl, CF.sub.3, SO.sub.2N(C.sub.1-C.sub.4alkyl).sub.2,
SO.sub.2NH(C.sub.1-C.sub.4alkyl), (C.dbd.O)NH(C.sub.1-4alkyl),
(C.dbd.S)NH(C.sub.1-4alkyl), C.sub.1-C.sub.4alkyl and
C.sub.1-C.sub.4alkyl substituted with one hydroxy; or [0368]
Het.sup.1 represents a 4 to 6 membered saturated ring containing
one O atom, substituted with one or more substituents each
independently selected from the group consisting of halo,
C.sub.1-C.sub.4alkyloxy, CF.sub.3, NH(C.dbd.O)(C.sub.1-4alkyl),
(C.dbd.O)NH(C.sub.1-4alkyl) and C.sub.1-C.sub.4alkyl; [0369]
Het.sup.2 represents a monocyclic 5 to 6 membered aromatic
heterocycle containing one or more heteroatoms each independently
selected from the group consisting of O, S and N; or a bicyclic 8
to 12 membered aromatic heterocycle containing one or more
heteroatoms each independently selected from the group consisting
of O, S and N; said Het.sup.2 optionally being substituted with one
or more substituents each independently selected from the group
consisting of halo, C.sub.1-C.sub.4alkyloxy, C.sub.1-C.sub.4alkyl,
OH, CN, CF.sub.2H, CF.sub.3, CONR.sup.8R.sup.9, NR.sup.8R.sup.9,
NR.sup.8COOR.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8,
OCONR.sup.8R.sup.9, OCONR.sup.8R.sup.12, N(R.sup.8)COOR.sup.12;
[0370] Z is C or N; R.sup.5 is present where Z is C, whereby
R.sup.5 is selected form the group consisting of hydrogen, CF.sub.3
and halogen; in particular R.sup.5 is selected form the group
consisting of CF.sub.3 and halogen; R.sup.5 is absent where Z is N;
and the pharmaceutically acceptable addition salts, and the
solvates thereof.
[0371] In an embodiment, the present invention concerns novel
compounds of Formula (I) and stereoisomeric forms thereof, wherein
Het is a heterocycle having formula (b), (c), (d) or (e); in
particular (b) or (c); [0372] each X independently is C or N;
provided that at least one X is N; [0373] R.sup.1b is present when
Het has formula (b) and X is C; each R.sup.1b is selected
independently from the group consisting of H, halogen,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, CF.sub.3 and OCF.sub.3; R.sup.1b is absent
when the X to which it is bound is N; [0374] R.sup.2b is
--(CR.sup.8R.sup.9).sub.m--R.sup.10b; [0375] each R.sup.8 and
R.sup.9 are independently chosen from the group consisting of H and
C.sub.1-C.sub.10alkyl; [0376] R.sup.10b is selected from the group
consisting of H, R.sup.11, OH, CN, F, CF.sub.2H, CF.sub.3,
NR.sup.8R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8; [0377] m
is an integer from 2 to 6; [0378] R.sup.11 is selected from the
group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.7cycloalkyl, phenyl, pyridinyl and pyrazolyl; each
optionally substituted with one or more substituents each
independently selected from the group consisting of CF.sub.3,
CH.sub.3, OCH.sub.3, OCF.sub.3 and halogen; in particular
C.sub.1-C.sub.6 alkyl; [0379] R.sup.1c is present when Het has
formula (c); [0380] each R.sup.1c is selected independently from
the group consisting of H, halogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkyloxy, CF.sub.3 and
OCF.sub.3; [0381] R.sup.3c is selected from the group consisting of
H, halogen, C.sub.1-C.sub.6alkyl; [0382] R.sup.2c is
--(CR.sup.8R.sup.9).sub.m--R.sup.10e; [0383] R.sup.10c is selected
from the group consisting of H, C.sub.1-C.sub.6alkyl, OH, CN, F,
CF.sub.2H, CF.sub.3, NR.sup.8R.sup.9, SO.sub.2NR.sup.8R.sup.9,
SO.sub.2R.sup.8; [0384] R.sup.1d is present when Het has formula
(d) and X is C; each R.sup.1d is selected independently from the
group consisting of H, halogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkyloxy, CF.sub.3 and
OCF.sub.3; R.sup.1d is absent when the X to which it is bound is N;
[0385] R.sup.3d is selected from the group consisting of H,
halogen, C.sub.1-C.sub.6alkyl; [0386] R.sup.2d is
--(CR.sup.8R.sup.9).sub.m--R.sup.10d; [0387] R.sup.10d is selected
from the group consisting of H, C.sub.1-C.sub.6alkyl, OH, CN, F,
CF.sub.2H, CF.sub.3, NR.sup.8R.sup.9, SO.sub.2NR.sup.8R.sup.9,
SO.sub.2R.sup.8; [0388] each Y independently is C or N; [0389]
R.sup.1e is present when Het has formula (e) and Y is C; each
R.sup.1e is selected independently from the group consisting of H,
halogen, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, CF.sub.3 and OCF.sub.3; R.sup.1e is absent
when the Y to which it is bound is N; [0390] R.sup.3e is selected
from the group consisting of H, halogen; [0391] R.sup.4 is selected
from the group consisting of tert-butyl, Het.sup.1, aryl,
Het.sup.2, CH(CH.sub.3)(CF.sub.3), and C.sub.3-C.sub.7cycloalkyl
substituted with one or more substituents selected from the group
consisting of halo and C.sub.1-C.sub.4alkyl; [0392] aryl represents
phenyl or naphthalenyl; said aryl optionally being substituted with
one or more substituents each independently selected from the group
consisting of halo, C.sub.1-C.sub.4alkyloxy, C.sub.1-C.sub.4alkyl;
[0393] Het.sup.1 represents a 4 to 6 membered saturated ring
containing one N atom, optionally being substituted with one or
more substituents each independently selected from the group
consisting of halo, C.sub.1-C.sub.4alkyloxy, SO.sub.2R.sup.8,
C.sub.1-C.sub.4alkylcarbonyl, C.sub.1-C.sub.4alkyloxycarbonyl,
pyridinyl, CF.sub.3, C.sub.1-C.sub.4alkyl and C.sub.1-C.sub.4alkyl
substituted with one hydroxy; or [0394] Het.sup.1 represents a 4 to
6 membered saturated ring containing one O atom, substituted with
one or more substituents each independently selected from the group
consisting of halo, C.sub.1-C.sub.4alkyloxy, CF.sub.3 and
C.sub.1-C.sub.4alkyl; [0395] Het.sup.2 represents a monocyclic 5 to
6 membered aromatic heterocycle containing one or more heteroatoms
each independently selected from the group consisting of O, S and
N; or a bicyclic 8 to 12 membered aromatic heterocycle containing
one or more heteroatoms each independently selected from the group
consisting of O, S and N; said Het.sup.2 optionally being
substituted with one or more substituents each independently
selected from the group consisting of halo,
C.sub.1-C.sub.4alkyloxy, C.sub.1-C.sub.4alkyl; [0396] Z is C or N;
R.sup.5 is present where Z is C, whereby R.sup.5 is selected form
the group consisting of hydrogen, CF.sub.3 and halogen; in
particular R.sup.5 is selected form the group consisting of
CF.sub.3 and halogen; R.sup.5 is absent where Z is N; and the
pharmaceutically acceptable addition salts, and the solvates
thereof.
[0397] In an embodiment, the present invention concerns novel
compounds of Formula (I) and stereoisomeric forms thereof, wherein
Het is a heterocycle having formula (b), (c), (d) or (e); [0398]
each X independently is C or N; provided that at least one X is N;
[0399] R.sup.1b is present when Het has formula (b) and X is C;
each R.sup.1b is selected independently from the group consisting
of H, halogen, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, N(R.sup.6).sub.2, CO(R.sup.7),
CH.sub.2NH.sub.2, CH.sub.2OH, CN, C(.dbd.NOH)NH.sub.2,
C(.dbd.NOCH.sub.3)NH.sub.2, C(.dbd.NH)NH.sub.2, CF.sub.3,
OCF.sub.3, B(OH).sub.2 and B(O--C.sub.1-C.sub.6alkyl).sub.2;
R.sup.1b is absent when the X to which it is bound is N; [0400]
R.sup.2b is --(CR.sup.8R.sup.9).sub.m--R.sup.10b; [0401] each
R.sup.6 is independently selected from the group consisting of H,
C.sub.1-C.sub.6alkyl, COOCH.sub.3 and CONHSO.sub.2CH.sub.3; [0402]
each R.sup.7 is independently selected from the group consisting of
OH, C.sub.1-C.sub.6alkyloxy, NH.sub.2,
NHSO.sub.2N(C.sub.1-C.sub.6alkyl).sub.2, NHSO.sub.2NHCH.sub.3,
NHSO.sub.2(C.sub.1-C.sub.6alkyl),
NHSO.sub.2(C.sub.3-C.sub.7cycloalkyl) and
N(C.sub.1-C.sub.6-alkyl).sub.2; [0403] each R.sup.8 and R.sup.9 are
independently chosen from the group consisting of H,
C.sub.1-C.sub.10alkyl and C.sub.3-C.sub.7cycloalkyl; or R.sup.8 and
R.sup.9 taken together form a 4 to 6 membered aliphatic ring that
optionally contains one or more heteroatoms selected from the group
consisting of N, S and O; [0404] R.sup.10b is selected from the
group consisting of H, R.sup.11, OH, CN, F, CF.sub.2H, CF.sub.3,
CONR.sup.8R.sup.9, COOR.sup.8, CON(R.sup.8)SO.sub.2R.sup.9,
CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9), NR.sup.8R.sup.9,
NR.sup.8COOR.sup.9, OCOR.sup.8, O-Benzyl, NR.sup.8SO.sub.2R.sup.9,
SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8, OCONR.sup.8R.sup.9,
OCONR.sup.8R.sup.12, N(R.sup.8)CON(R.sup.8R.sup.9),
N(R.sup.8)COOR.sup.12, and a 4 to 6 membered saturated ring
containing one oxygen atom; [0405] m is an integer from 2 to 6;
[0406] R.sup.11 is selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7cycloalkyl, phenyl, pyridinyl
and pyrazolyl; each optionally substituted with one or more
substituents each independently selected from the group consisting
of CF.sub.3, CH.sub.3, OCH.sub.3, OCF.sub.3 and halogen; [0407]
R.sup.12 is selected from the group consisting of phenyl, pyridinyl
and pyrazolyl; each optionally substituted with one or more
substituents each independently selected from the group consisting
of CF.sub.3, CH.sub.3, OCH.sub.3, OCF.sub.3 and halogen; [0408] or
R.sup.12 is C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.7cycloalkyl;
each substituted with one or more substituents each independently
selected from the group consisting of CF.sub.3, CH.sub.3,
OCH.sub.3, OCF.sub.3 and halogen; [0409] R.sup.1c is present when
Het has formula (c); [0410] each R.sup.1c is selected independently
from the group consisting of H, halogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkyloxy,
N(R.sup.6).sub.2, CO(R.sup.7c), CH.sub.2NH.sub.2, CH.sub.2OH, CN,
C(.dbd.NOH)NH.sub.2, C(.dbd.NOCH.sub.3)NH.sub.2,
C(.dbd.NH)NH.sub.2, CF.sub.3, OCF.sub.3, B(OH).sub.2 and
B(O--C.sub.1-C.sub.6alkyl).sub.2; [0411] R.sup.3c is selected from
the group consisting of H, halogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkyloxy and
CO(R.sup.7c); [0412] R.sup.2c is
--(CR.sup.8R.sup.9).sub.m--R.sup.10c; [0413] R.sup.7c is selected
from the group consisting of OH, O(C.sub.1-C.sub.6alkyl), NH.sub.2,
NHSO.sub.2N(C.sub.1-C.sub.6alkyl).sub.2, NHSO.sub.2NHCH.sub.3,
NHSO.sub.2(C.sub.1-C.sub.6alkyl),
NHSO.sub.2(C.sub.3-C.sub.7cycloalkyl),
N(C.sub.1-C.sub.6-alkyl).sub.2, NR.sup.8R.sup.9 and
NR.sup.9R.sup.10c; [0414] R.sup.10c is selected from the group
consisting of H, C.sub.1-C.sub.6alkyl, OH, CN, F, CF.sub.2H,
CF.sub.3, C(.dbd.NOH)NH.sub.2, CONR.sup.8R.sup.9, COOR.sup.8,
CONR.sup.8SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sup.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8
and a 4 to 6 membered saturated ring containing one oxygen atom;
[0415] R.sup.1d is present when Het has formula (d) and X is C;
each R.sup.1d is selected independently from the group consisting
of H, OH, halogen, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, N(R.sup.6).sub.2, CO(R.sup.7),
CH.sub.2NH.sub.2, CH.sub.2OH, CN, C(.dbd.NOH)NH.sub.2,
C(.dbd.NOCH.sub.3)NH.sub.2, C(.dbd.NH)NH.sub.2, CF.sub.3,
OCF.sub.3, B(OH).sub.2 and B(O--C.sub.1-C.sub.6alkyl).sub.2;
R.sup.1d is absent when the X to which it is bound is N; [0416]
R.sup.3d is selected from the group consisting of H, halogen,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, and CO(R.sup.7); [0417] R.sup.2d is
--(CR.sup.8R.sup.9).sub.m--R.sup.10d; [0418] R.sup.10d is selected
from the group consisting of H, C.sub.1-C.sub.6alkyl, OH, CN, F,
CF.sub.2H, CF.sub.3, CONR.sup.8R.sup.9, COOR.sup.8,
CONR.sup.8SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sub.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8
and a 4 to 6 membered saturated ring containing one oxygen atom;
[0419] each Y independently is C or N; [0420] R.sup.1e is present
when Het has formula (e) and Y is C; each R.sup.1e is selected
independently from the group consisting of H, halogen,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, N(R.sup.6).sub.2, CO(R.sup.7),
CH.sub.2NH.sub.2, CH.sub.2OH, CN, C(.dbd.NOH)NH.sub.2,
C(.dbd.NOCH.sub.3)NH.sub.2, C(.dbd.NH)NH.sub.2, CF.sub.3,
OCF.sub.3, B(OH).sub.2 and B(O--C.sub.1-C.sub.6alkyl).sub.2;
R.sup.1e is absent when the Y to which it is bound is N; [0421]
R.sup.3e is selected from the group consisting of H, halogen,
--(CR.sup.8R.sup.9).sub.m--R.sup.10e,
C.ident.C--CH.sub.2--R.sup.10e, C.ident.C--R.sup.10e and
C.dbd.C--R.sup.10e; [0422] R.sup.10e is selected from the group
consisting of H, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy,
C.sub.3-C.sub.7cycloalkyl, OH, CN, F, CF.sub.2H, CF.sub.3,
CONR.sup.8R.sup.9, COOR.sup.8, CON(R.sup.8)SO.sub.2R.sup.9,
CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9), NR.sup.8R.sup.9,
NR.sup.8COOR.sup.9, OCOR.sup.8, NR.sup.8SO.sub.2R.sup.9,
SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8 and a 4 to 6 membered
saturated ring containing one oxygen atom; [0423] R.sup.4 is
selected from the group consisting of Het.sup.1, aryl, Het.sup.2,
and C.sub.3-C.sub.7cycloalkyl substituted with one or more
substituents selected from the group consisting of halo and
C.sub.1-C.sub.4alkyl; in particular Het.sup.1, Het.sup.2, and
C.sub.3-C.sub.7cycloalkyl substituted with one or more substituents
selected from the group consisting of halo and
C.sub.1-C.sub.4alkyl; [0424] aryl represents phenyl or
naphthalenyl; said aryl optionally being substituted with one or
more substituents each independently selected from the group
consisting of halo, C.sub.1-C.sub.4alkyloxy, C.sub.1-C.sub.4alkyl,
OH, CN, CF.sub.2H, CF.sub.3, CONR.sup.8R.sup.9, COOR.sup.8,
CON(R.sup.8)SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sup.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8,
OCONR.sup.8R.sup.9, OCONR.sup.8R.sup.12,
N(R.sup.8)CON(R.sup.8R.sup.9), N(R.sup.8)COOR.sup.12; [0425]
Het.sup.1 represents a 4 to 6 membered saturated ring containing
one N atom, optionally being substituted with one or more
substituents each independently selected from the group consisting
of halo, C.sub.1-C.sub.4alkyloxy, SO.sub.2R.sup.8,
C.sub.1-C.sub.4alkylcarbonyl, CO(aryl), COHet.sup.2,
C.sub.1-C.sub.4alkyloxycarbonyl, pyridinyl, CF.sub.3,
SO.sub.2N(C.sub.1-C.sub.4alkyl).sub.2,
SO.sub.2NH(C.sub.1-C.sub.4alkyl), (C.dbd.O)NH(C.sub.1-4alkyl),
(C.dbd.S)NH(C.sub.1-4alkyl), C.sub.1-C.sub.4alkyl and
C.sub.1-C.sub.4alkyl substituted with one hydroxy; or [0426]
Het.sup.1 represents a 4 to 6 membered saturated ring containing
one O atom, substituted with one or more substituents each
independently selected from the group consisting of halo,
C.sub.1-C.sub.4alkyloxy, CF.sub.3, NH(C.dbd.O)(C.sub.1-4alkyl),
(C.dbd.O)NH(C.sub.1-4alkyl) and C.sub.1-C.sub.4alkyl; [0427]
Het.sup.2 represents a monocyclic 5 to 6 membered aromatic
heterocycle containing one or more heteroatoms each independently
selected from the group consisting of O, S and N; or a bicyclic 8
to 12 membered aromatic heterocycle containing one or more
heteroatoms each independently selected from the group consisting
of O, S and N; said Het.sup.2 optionally being substituted with one
or more substituents each independently selected from the group
consisting of halo, C.sub.1-C.sub.4alkyloxy, C.sub.1-C.sub.4alkyl,
OH, CN, CF.sub.2H, CF.sub.3, CONR.sup.8R.sup.9, COOR.sup.8,
CON(R.sup.8)SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sup.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8,
OCONR.sup.8R.sup.9, OCONR.sup.8R.sup.12,
N(R.sup.8)CON(R.sup.8R.sup.9), N(R.sup.8)COOR.sup.12; [0428] Z is C
or N; R.sup.5 is present where Z is C, whereby R.sup.5 is selected
form the group consisting of hydrogen, CF.sub.3 and halogen;
R.sup.5 is absent where Z is N; and the pharmaceutically acceptable
addition salts, and the solvates thereof.
[0429] In an embodiment, the present invention concerns novel
compounds of Formula (I) and stereoisomeric forms thereof, wherein
[0430] Het is a heterocycle having formula (b), (c), (d) or (e);
[0431] each X independently is C or N; provided that at least one X
is N; [0432] R.sup.1b is present when Het has formula (b) and X is
C; each R.sup.1b is selected independently from the group
consisting of H, halogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkyloxy,
N(R.sup.6).sub.2, CO(R.sup.7), CH.sub.2NH.sub.2, CH.sub.2OH, CN,
C(.dbd.NOH)NH.sub.2, C(.dbd.NOCH.sub.3)NH.sub.2,
C(.dbd.NH)NH.sub.2, CF.sub.3, OCF.sub.3, B(OH).sub.2 and
B(O--C.sub.1-C.sub.6alkyl).sub.2; R.sup.1b is absent when the X to
which it is bound is N; [0433] R.sup.2b is
--(CR.sup.8R.sup.9).sub.m--R.sup.10b; [0434] each R.sup.6 is
independently selected from the group consisting of H,
C.sub.1-C.sub.6alkyl, COOCH.sub.3 and CONHSO.sub.2CH.sub.3; [0435]
each R.sup.7 is independently selected from the group consisting of
OH, C.sub.1-C.sub.6alkyloxy, NH.sub.2,
NHSO.sub.2N(C.sub.1-C.sub.6alkyl).sub.2, NHSO.sub.2NHCH.sub.3,
NHSO.sub.2(C.sub.1-C.sub.6alkyl);
NHSO.sub.2(C.sub.3-C.sub.7cycloalkyl) and
N(C.sub.1-C.sub.6-alkyl).sub.2; [0436] each R.sup.8 and R.sup.9 are
independently chosen from the group consisting of H,
C.sub.1-C.sub.10alkyl and C.sub.3-C.sub.7cycloalkyl; or R.sup.8 and
R.sup.9 taken together form a 4 to 6 membered aliphatic ring that
optionally contains one or more heteroatoms selected from the group
consisting of N, S and O; [0437] R.sup.10b is selected from the
group consisting of H, R.sup.11, OH, CN, F, CF.sub.2H, CF.sub.3,
CONR.sup.8R.sup.9, COOR.sup.8, CON(R.sup.8)SO.sub.2R.sup.9,
CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9), NR.sup.8R.sup.9,
NR.sup.8COOR.sup.9, OCOR.sup.8, O-Benzyl, NR.sup.8SO.sub.2R.sup.9,
SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8, OCONR.sup.8R.sup.9,
OCONR.sup.8R.sup.12, N(R.sup.8)CON(R.sup.8R.sup.9),
N(R.sup.8)COOR.sup.12, and a 4 to 6 membered saturated ring
containing one oxygen atom; [0438] m is an integer from 2 to 6;
[0439] R.sup.11 is selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7cycloalkyl, phenyl, pyridinyl
and pyrazolyl; each optionally substituted with one or more
substituents each independently selected from the group consisting
of CF.sub.3, CH.sub.3, OCH.sub.3, OCF.sub.3 and halogen; [0440]
R.sup.12 is selected from the group consisting of phenyl, pyridinyl
and pyrazolyl; each optionally substituted with one or more
substituents each independently selected from the group consisting
of CF.sub.3, CH.sub.3, OCH.sub.3, OCF.sub.3 and halogen; [0441] or
R.sup.12 is C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.7cycloalkyl;
each substituted with one or more substituents each independently
selected from the group consisting of CF.sub.3, CH.sub.3,
OCH.sub.3, OCF.sub.3 and halogen; [0442] R.sup.1c is present when
Het has formula (c); [0443] each R.sup.1c is selected independently
from the group consisting of H, halogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkyloxy,
N(R.sup.6).sub.2, CO(R.sup.7c), CH.sub.2NH.sub.2, CH.sub.2OH, CN,
C(.dbd.NOH)NH.sub.2, C(.dbd.NOCH.sub.3)NH.sub.2,
C(.dbd.NH)NH.sub.2, CF.sub.3, OCF.sub.3, B(OH).sub.2 and
B(O--C.sub.1-C.sub.6alkyl).sub.2; [0444] R.sup.3c is selected from
the group consisting of H, halogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkyloxy and
CO(R.sup.7c); [0445] R.sup.2c is --(CR.sup.8R.sup.9)--R.sup.10c;
[0446] R.sup.7c is selected from the group consisting of OH,
O(C.sub.1-C.sub.6alkyl), NH.sub.2,
NHSO.sub.2N(C.sub.1-C.sub.6alkyl).sub.2, NHSO.sub.2NHCH.sub.3,
NHSO.sub.2(C.sub.1-C.sub.6alkyl),
NHSO.sub.2(C.sub.3-C.sub.7cycloalkyl),
N(C.sub.1-C.sub.6-alkyl).sub.2, NR.sup.8R.sup.9 and
NR.sup.9R.sup.10c; [0447] R.sup.10c is selected from the group
consisting of H, C.sub.1-C.sub.6alkyl, OH, CN, F, CF.sub.2H,
CF.sub.3, C(.dbd.NOH)NH.sub.2, CONR.sup.8R.sup.9, COOR.sup.8,
CONR.sup.8SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sup.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8
and a 4 to 6 membered saturated ring containing one oxygen atom;
[0448] R.sup.1d is present when Het has formula (d) and X is C;
each R.sup.1d is selected independently from the group consisting
of H, OH, halogen, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, N(R.sup.6).sub.2, CO(R.sup.7),
CH.sub.2NH.sub.2, CH.sub.2OH, CN, C(.dbd.NOH)NH.sub.2,
C(.dbd.NOCH.sub.3)NH.sub.2, C(.dbd.NH)NH.sub.2, CF.sub.3,
OCF.sub.3, B(OH).sub.2 and B(O--C.sub.1-C.sub.6alkyl).sub.2;
R.sup.1d is absent when the X to which it is bound is N; [0449]
R.sup.3d is selected from the group consisting of H, halogen,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, and CO(R.sup.7); [0450] R.sup.2d is
--(CR.sup.8R.sup.9).sub.m--R.sup.10d; [0451] R.sup.10d is selected
from the group consisting of H, C.sub.1-C.sub.6alkyl, OH, CN, F,
CF.sub.2H, CF.sub.3, CONR.sup.8R.sup.9, COOR.sup.8,
CONR.sup.8SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sub.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8
and a 4 to 6 membered saturated ring containing one oxygen atom;
[0452] each Y independently is C or N; [0453] R.sup.1e is present
when Het has formula (e) and Y is C; each R.sup.1e is selected
independently from the group consisting of H, halogen,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, N(R.sup.6).sub.2, CO(R.sup.7),
CH.sub.2NH.sub.2, CH.sub.2OH, CN, C(.dbd.NOH)NH.sub.2,
C(.dbd.NOCH.sub.3)NH.sub.2, C(.dbd.NH)NH.sub.2, CF.sub.3,
OCF.sub.3, B(OH).sub.2 and B(O--C.sub.1-C.sub.6alkyl).sub.2;
R.sup.1e is absent when the Y to which it is bound is N; [0454]
R.sup.3e is selected from the group consisting of H, halogen,
--(CR.sup.8R.sup.9).sub.m--R.sup.10e,
C.ident.C--CH.sub.2--R.sup.10e, C.ident.C--R.sup.10e and
C.dbd.C--R.sup.10e; [0455] R.sup.10e is selected from the group
consisting of H, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy,
C.sub.3-C.sub.7cycloalkyl, OH, CN, F, CF.sub.2H, CF.sub.3,
CONR.sup.8R.sup.9, COOR.sup.8, CON(R.sup.8)SO.sub.2R.sup.9,
CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9), NR.sup.8R.sup.9,
NR.sup.8COOR.sup.9, OCOR.sup.8, NR.sup.8SO.sub.2R.sup.9,
SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8 and a 4 to 6 membered
saturated ring containing one oxygen atom; [0456] R.sup.4 is
selected from the group consisting of tert-butyl, Het.sup.1, aryl,
Het.sup.2, CH(CH.sub.3)(CF.sub.3), and C.sub.3-C.sub.7cycloalkyl
substituted with one or more substituents selected from the group
consisting of halo and C.sub.1-C.sub.4alkyl; [0457] aryl represents
phenyl or naphthalenyl; said aryl optionally being substituted with
one or more substituents each independently selected from the group
consisting of halo, C.sub.1-C.sub.4alkyloxy, C.sub.1-C.sub.4alkyl,
SO.sub.2CH.sub.3, CF.sub.3, SO.sub.2N(C.sub.1-C.sub.4alkyl).sub.2,
SO.sub.2NH(C.sub.1-C.sub.4alkyl), CN,
(C.dbd.O)NH(C.sub.1-C.sub.4alkyl),
(C.dbd.O)N(C.sub.1-C.sub.4alkyl).sub.2,
NH(C.dbd.O)O(C.sub.1-4alkyl), O(C.dbd.O)NH(C.sub.1-C.sub.4alkyl)
and O(C.dbd.O)N(C.sub.1-C.sub.4alkyl).sub.2; [0458] Het.sup.1
represents a 4 to 6 membered saturated ring containing one N atom,
optionally being substituted with one or more substituents each
independently selected from the group consisting of halo,
C.sub.1-C.sub.4alkyloxy, SO.sub.2CH.sub.3,
C.sub.1-C.sub.4alkylcarbonyl, C.sub.1-C.sub.4alkyloxycarbonyl,
pyridinyl, CF.sub.3, SO.sub.2N(C.sub.1-C.sub.4alkyl).sub.2,
SO.sub.2NH(C.sub.1-C.sub.4alkyl), (C.dbd.O)NH(C.sub.1-4alkyl),
C.sub.1-C.sub.4alkyl and C.sub.1-C.sub.4alkyl substituted with one
hydroxy; or [0459] Het.sup.1 represents a 4 to 6 membered saturated
ring containing one O atom, substituted with one or more
substituents each independently selected from the group consisting
of halo, C.sub.1-C.sub.4alkyloxy, CF.sub.3,
NH(C.dbd.O)(C.sub.1-4alkyl), (C.dbd.O)NH(C.sub.1-4alkyl) and
C.sub.1-C.sub.4alkyl; [0460] Het.sup.2 represents a monocyclic 5 to
6 membered aromatic heterocycle containing one or more heteroatoms
each independently selected from the group consisting of O, S and
N; or a bicyclic 8 to 12 membered aromatic heterocycle containing
one or more heteroatoms each independently selected from the group
consisting of O, S and N; said Het.sup.2 optionally being
substituted with one or more substituents each independently
selected from the group consisting of halo,
C.sub.1-C.sub.4alkyloxy, C.sub.1-C.sub.4alkyl, SO.sub.2CH.sub.3,
CF.sub.3, SO.sub.2N(C.sub.1-C.sub.4alkyl).sub.2,
SO.sub.2NH(C.sub.1-C.sub.4alkyl), CN,
(C.dbd.O)NH(C.sub.1-C.sub.4alkyl),
(C.dbd.O)N(C.sub.1-C.sub.4alkyl).sub.2,
NH(C.dbd.O)O(C.sub.1-4alkyl), O(C.dbd.O)NH(C.sub.1-C.sub.4alkyl)
and O(C.dbd.O)N(C.sub.1-C.sub.4alkyl).sub.2; [0461] Z is C or N;
R.sup.5 is present where Z is C, whereby R.sup.5 is selected form
the group consisting of hydrogen, CF.sub.3 and halogen; R.sup.5 is
absent where Z is N; and the pharmaceutically acceptable addition
salts, and the solvates thereof.
[0462] In an embodiment, the present invention concerns novel
compounds of Formula (I) and stereoisomeric forms thereof, [0463]
Het is a heterocycle having formula (b), (c), (d) or (e); in
particular (b) or (c); [0464] each X independently is C or N;
provided that at least one X is N; [0465] R.sup.1b is present when
Het has formula (b) and X is C; each R.sup.1b is selected
independently from the group consisting of H, halogen,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, CH.sub.2NH.sub.2, CH.sub.2OH, CN,
CF.sub.3, OCF.sub.3; R.sup.1b is absent when the X to which it is
bound is N; [0466] R.sup.2b is
--(CR.sup.8R.sup.9).sub.m--R.sup.10b; [0467] each R.sup.8 and
R.sup.9 are independently chosen from the group consisting of H,
C.sub.1-C.sub.10alkyl and C.sub.3-C.sub.7cycloalkyl; [0468]
R.sup.10b is selected from the group consisting of H, R.sup.11, OH,
CN, F, CF.sub.2H, CF.sub.3, SO.sub.2R.sup.8; [0469] m is an integer
from 2 to 6; [0470] R.sup.11 is selected from the group consisting
of C.sub.1-C.sub.6 alkyl optionally substituted with one or more
substituents each independently selected from the group consisting
of CF.sub.3, CH.sub.3, OCH.sub.3, OCF.sub.3 and halogen; [0471]
R.sup.1c is present when Het has formula (c); [0472] each R.sup.1c
is selected independently from the group consisting of H, halogen,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, CH.sub.2NH.sub.2, CH.sub.2OH, CN,
CF.sub.3, OCF.sub.3; [0473] R.sup.3c is selected from the group
consisting of H; [0474] R.sup.2c is
--(CR.sup.8R.sup.9).sub.m--R.sup.10c; [0475] R.sup.10c is selected
from the group consisting of H, C.sub.1-C.sub.6alkyl, OH, CN, F,
CF.sub.2H, CF.sub.3, SO.sub.2R.sup.8; [0476] R.sup.1d is present
when Het has formula (d) and X is C; each R.sup.1d is selected
independently from the group consisting of H, OH, halogen,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, CH.sub.2NH.sub.2, CH.sub.2OH, CN,
CF.sub.3, OCF.sub.3; [0477] R.sup.1d is absent when the X to which
it is bound is N; [0478] R.sup.3d is selected from the group
consisting of H; [0479] R.sup.2d is
--(CR.sup.8R.sup.9).sub.m--R.sup.10d; [0480] R.sup.10d is selected
from the group consisting of H, C.sub.1-C.sub.6alkyl, OH, CN, F,
CF.sub.2H, CF.sub.3, SO.sub.2R.sup.8; [0481] each Y independently
is C or N; [0482] R.sup.1e is present when Het has formula (e) and
Y is C; each R.sup.1e is selected independently from the group
consisting of H, halogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkyloxy,
CH.sub.2NH.sub.2, CH.sub.2OH, CN, CF.sub.3, OCF.sub.3; [0483]
R.sup.1e is absent when the Y to which it is bound is N; [0484]
R.sup.3e is selected from the group consisting of
--(CR.sup.8R.sup.9).sub.m--R.sup.10e; [0485] R.sup.10e is selected
from the group consisting of H, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkyloxy, C.sub.3-C.sub.7cycloalkyl, OH, CN, F,
CF.sub.2H, CF.sub.3, SO.sub.2R.sup.8; [0486] R.sup.4 is selected
from the group consisting of tert-butyl, Het.sup.1, aryl,
Het.sup.2, CH(CH.sub.3)(CF.sub.3), and C.sub.3-C.sub.7cycloalkyl
substituted with one or more substituents selected from the group
consisting of halo and C.sub.1-C.sub.4alkyl; [0487] aryl represents
phenyl or naphthalenyl; said aryl optionally being substituted with
one or more substituents each independently selected from the group
consisting of halo, C.sub.1-C.sub.4alkyloxy, C.sub.1-C.sub.4alkyl,
SO.sub.2CH.sub.3, CF.sub.3, SO.sub.2N(C.sub.1-C.sub.4alkyl).sub.2,
SO.sub.2NH(C.sub.1-C.sub.4alkyl), CN,
(C.dbd.O)NH(C.sub.1-C.sub.4alkyl),
(C.dbd.O)N(C.sub.1-C.sub.4alkyl).sub.2,
NH(C.dbd.O)O(C.sub.1-4alkyl), O(C.dbd.O)NH(C.sub.1-C.sub.4alkyl)
and O(C.dbd.O)N(C.sub.1-C.sub.4alkyl).sub.2; [0488] Het.sup.1
represents a 4 to 6 membered saturated ring containing one N atom,
optionally being substituted with one or more substituents each
independently selected from the group consisting of halo,
C.sub.1-C.sub.4alkyloxy, SO.sub.2CH.sub.3,
C.sub.1-C.sub.4alkylcarbonyl, C.sub.1-C.sub.4alkyloxycarbonyl,
pyridinyl, CF.sub.3, SO.sub.2N(C.sub.1-C.sub.4alkyl).sub.2,
SO.sub.2NH(C.sub.1-C.sub.4alkyl), (C.dbd.O)NH(C.sub.1-4alkyl),
C.sub.1-C.sub.4alkyl and C.sub.1-C.sub.4alkyl substituted with one
hydroxy; or [0489] Het.sup.1 represents a 4 to 6 membered saturated
ring containing one O atom, substituted with one or more
substituents each independently selected from the group consisting
of halo, C.sub.1-C.sub.4alkyloxy, CF.sub.3,
NH(C.dbd.O)(C.sub.1-4alkyl), (C.dbd.O)NH(C.sub.1-4alkyl) and
C.sub.1-C.sub.4alkyl; [0490] Het.sup.2 represents a monocyclic 5 to
6 membered aromatic heterocycle containing one or more heteroatoms
each independently selected from the group consisting of O, S and
N; or a bicyclic 8 to 12 membered aromatic heterocycle containing
one or more heteroatoms each independently selected from the group
consisting of O, S and N; said Het.sup.2 optionally being
substituted with one or more substituents each independently
selected from the group consisting of halo,
C.sub.1-C.sub.4alkyloxy, C.sub.1-C.sub.4alkyl, SO.sub.2CH.sub.3,
CF.sub.3, SO.sub.2N(C.sub.1-C.sub.4alkyl).sub.2,
SO.sub.2NH(C.sub.1-C.sub.4alkyl), CN,
(C.dbd.O)NH(C.sub.1-C.sub.4alkyl),
(C.dbd.O)N(C.sub.1-C.sub.4alkyl).sub.2,
NH(C.dbd.O)O(C.sub.1-4alkyl), O(C.dbd.O)NH(C.sub.1-C.sub.4alkyl)
and O(C.dbd.O)N(C.sub.1-C.sub.4alkyl).sub.2; [0491] Z is C or N;
R.sup.5 is present where Z is C, whereby R.sup.5 is selected form
the group consisting of hydrogen, CF.sub.3 and halogen; R.sup.5 is
absent where Z is N; and the pharmaceutically acceptable addition
salts, and the solvates thereof.
[0492] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein each R.sup.8 and R.sup.9 are
independently chosen from the group consisting of H,
C.sub.1-C.sub.10alkyl and C.sub.3-C.sub.7cycloalkyl.
[0493] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein R.sup.4 is Het.sup.1.
[0494] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein R.sup.4 is aryl or Het.sup.2;
in particular Het.sup.2.
[0495] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, [0496] aryl represents phenyl or
naphthalenyl; said aryl optionally being substituted with one or
more substituents each independently selected from the group
consisting of halo, C.sub.1-C.sub.4alkyloxy, C.sub.1-C.sub.4alkyl;
[0497] Het.sup.1 represents a 4 to 6 membered saturated ring
containing one N atom, optionally being substituted with one or
more substituents each independently selected from the group
consisting of halo, C.sub.1-C.sub.4alkyloxy, SO.sub.2R.sup.8,
C.sub.1-C.sub.4alkylcarbonyl, C.sub.1-C.sub.4alkyloxycarbonyl,
pyridinyl, CF.sub.3, C.sub.1-C.sub.4alkyl and C.sub.1-C.sub.4alkyl
substituted with one hydroxy; or [0498] Het.sup.1 represents a 4 to
6 membered saturated ring containing one O atom, substituted with
one or more substituents each independently selected from the group
consisting of halo, C.sub.1-C.sub.4alkyloxy, CF.sub.3 and
C.sub.1-C.sub.4alkyl; [0499] Het.sup.2 represents a monocyclic 5 to
6 membered aromatic heterocycle containing one or more heteroatoms
each independently selected from the group consisting of O, S and
N; or a bicyclic 8 to 12 membered aromatic heterocycle containing
one or more heteroatoms each independently selected from the group
consisting of O, S and N; said Het.sup.2 optionally being
substituted with one or more substituents each independently
selected from the group consisting of halo,
C.sub.1-C.sub.4alkyloxy, C.sub.1-C.sub.4alkyl; [0500] Z is C or N;
R.sup.5 is present where Z is C, whereby R.sup.5 is selected form
the group consisting of hydrogen, CF.sub.3 and halogen; in
particular R.sup.5 is selected form the group consisting of
CF.sub.3 and halogen; R.sup.5 is absent where Z is N.
[0501] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein [0502] aryl represents phenyl
or naphthalenyl; said aryl optionally being substituted with one or
more substituents each independently selected from the group
consisting of halo,
[0503] C.sub.1-C.sub.4alkyloxy, C.sub.1-C.sub.4alkyl,
SO.sub.2CH.sub.3, CF.sub.3, SO.sub.2N(C.sub.1-C.sub.4alkyl).sub.2,
SO.sub.2NH(C.sub.1-C.sub.4alkyl), CN,
(C.dbd.O)NH(C.sub.1-C.sub.4alkyl),
(C.dbd.O)N(C.sub.1-C.sub.4alkyl).sub.2,
NH(C.dbd.O)O(C.sub.1-4alkyl); O(C.dbd.O)NH(C.sub.1-C.sub.4alkyl)
and O(C.dbd.O)N(C.sub.1-C.sub.4alkyl).sub.2; [0504] Het.sup.1
represents a 4 to 6 membered saturated ring containing one N atom,
optionally being substituted with one or more substituents each
independently selected from the group consisting of halo,
C.sub.1-C.sub.4alkyloxy, SO.sub.2CH.sub.3,
C.sub.1-C.sub.4alkylcarbonyl, C.sub.1-C.sub.4alkyloxycarbonyl,
pyridinyl, CF.sub.3, SO.sub.2N(C.sub.1-C.sub.4alkyl).sub.2,
SO.sub.2NH(C.sub.1-C.sub.4alkyl); (C.dbd.O)NH(C.sub.1-4alkyl),
C.sub.1-C.sub.4alkyl and C.sub.1-C.sub.4alkyl substituted with one
hydroxy; or [0505] Het.sup.1 represents a 4 to 6 membered saturated
ring containing one O atom, substituted with one or more
substituents each independently selected from the group consisting
of halo, C.sub.1-C.sub.4alkyloxy, CF.sub.3,
NH(C.dbd.O)(C.sub.1-4alkyl), (C.dbd.O)NH(C.sub.1-4alkyl) and
C.sub.1-C.sub.4alkyl; [0506] Het.sup.2 represents a monocyclic 5 to
6 membered aromatic heterocycle containing one or more heteroatoms
each independently selected from the group consisting of O, S and
N; or a bicyclic 8 to 12 membered aromatic heterocycle containing
one or more heteroatoms each independently selected from the group
consisting of O, S and N; said Het.sup.2 optionally being
substituted with one or more substituents each independently
selected from the group consisting of halo,
C.sub.1-C.sub.4alkyloxy, C.sub.1-C.sub.4alkyl, SO.sub.2CH.sub.3,
CF.sub.3, SO.sub.2N(C.sub.1-C.sub.4alkyl).sub.2,
SO.sub.2NH(C.sub.1-C.sub.4alkyl), CN,
(C.dbd.O)NH(C.sub.1-C.sub.4alkyl),
(C.dbd.O)N(C.sub.1-C.sub.4alkyl).sub.2,
NH(C.dbd.O)O(C.sub.1-4alkyl), O(C.dbd.O)NH(C.sub.1-C.sub.4alkyl)
and O(C.dbd.O)N(C.sub.1-C.sub.4alkyl).sub.2.
[0507] In an embodiment, the present invention concerns novel
compounds of Formula (I) and stereoisomeric forms thereof, wherein
[0508] Het is a heterocycle having formula (b), (c), (d) or (e);
[0509] each X independently is C or N; provided that at least one X
is N; [0510] R.sup.1b is present when Het has formula (b) and X is
C; each R.sup.1b is selected independently from the group
consisting of H, halogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkyloxy,
N(R.sup.6).sub.2, CO(R.sup.7), CH.sub.2NH.sub.2, CH.sub.2OH, CN,
C(.dbd.NOH)NH.sub.2, C(.dbd.NOCH.sub.3)NH.sub.2,
C(.dbd.NH)NH.sub.2, CF.sub.3, OCF.sub.3, B(OH).sub.2 and
B(O--C.sub.1-C.sub.6alkyl).sub.2; R.sup.1b is absent when the X to
which it is bound is N; [0511] R.sup.2b is
--(CR.sup.8R.sup.9).sub.m--R.sup.10b; [0512] each R.sup.6 is
independently selected from the group consisting of H,
C.sub.1-C.sub.6alkyl, COOCH.sub.3 and CONHSO.sub.2CH.sub.3; [0513]
each R.sup.7 is independently selected from the group consisting of
OH, C.sub.1-C.sub.6alkyloxy, NH.sub.2,
NHSO.sub.2N(C.sub.1-C.sub.6alkyl).sub.2, NHSO.sub.2NHCH.sub.3,
NHSO.sub.2(C.sub.1-C.sub.6alkyl),
NHSO.sub.2(C.sub.3-C.sub.7cycloalkyl) and
N(C.sub.1-C.sub.6-alkyl).sub.2; [0514] each R.sup.8 and R.sup.9 are
independently chosen from the group consisting of H,
C.sub.1-C.sub.10alkyl and C.sub.3-C.sub.7cycloalkyl; or R.sup.8 and
R.sup.9 taken together form a 4 to 6 membered aliphatic ring that
optionally contains one or more heteroatoms selected from the group
consisting of N, S and O; [0515] R.sup.10b is selected from the
group consisting of H, R.sup.11, OH, CN, F, CF.sub.2H, CF.sub.3,
CONR.sup.8R.sup.9, COOR.sup.8, CON(R.sup.8)SO.sub.2R.sup.9,
CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9), NR.sup.8R.sup.9,
NR.sup.8COOR.sup.9, OCOR.sup.8, O-Benzyl, NR.sup.8SO.sub.2R.sup.9,
SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8, OCONR.sup.8R.sup.9,
OCONR.sup.8R.sup.12, N(R.sup.8)CON(R.sup.8R.sup.9),
N(R.sup.8)COOR.sup.12, and a 4 to 6 membered saturated ring
containing one oxygen atom; [0516] m is an integer from 2 to 6;
[0517] R.sup.11 is selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7cycloalkyl, phenyl, pyridinyl
and pyrazolyl; each optionally substituted with one or more
substituents each independently selected from the group consisting
of CF.sub.3, CH.sub.3, OCH.sub.3, OCF.sub.3 and halogen; [0518]
R.sup.12 is selected from the group consisting of phenyl, pyridinyl
and pyrazolyl; each optionally substituted with one or more
substituents each independently selected from the group consisting
of CF.sub.3, CH.sub.3, OCH.sub.3, OCF.sub.3 and halogen; [0519] or
R.sup.12 is C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.7cycloalkyl;
each substituted with one or more substituents each independently
selected from the group consisting of CF.sub.3, CH.sub.3,
OCH.sub.3, OCF.sub.3 and halogen; [0520] R.sup.1c is present when
Het has formula (c); [0521] each R.sup.1c is selected independently
from the group consisting of H, halogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkyloxy,
N(R.sup.6).sub.2, CO(R.sup.7c), CH.sub.2NH.sub.2, CH.sub.2OH, CN,
C(.dbd.NOH)NH.sub.2, C(.dbd.NOCH.sub.3)NH.sub.2,
C(.dbd.NH)NH.sub.2, CF.sub.3, OCF.sub.3, B(OH).sub.2 and
B(O--C.sub.1-C.sub.6alkyl).sub.2; [0522] R.sup.3c is selected from
the group consisting of H, halogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkyloxy and
CO(R.sup.7c); [0523] R.sup.2c is
--(CR.sup.8R.sup.9).sub.m--R.sup.10c; [0524] R.sup.7c is selected
from the group consisting of OH, O(C.sub.1-C.sub.6alkyl), NH.sub.2,
NHSO.sub.2N(C.sub.1-C.sub.6alkyl).sub.2, NHSO.sub.2NHCH.sub.3,
NHSO.sub.2(C.sub.1-C.sub.6alkyl),
NHSO.sub.2(C.sub.3-C.sub.7cycloalkyl),
N(C.sub.1-C.sub.6-alkyl).sub.2, NR.sup.8R.sup.9 and
NR.sup.9R.sup.10c; [0525] R.sup.10c is selected from the group
consisting of H, C.sub.1-C.sub.6alkyl, OH, CN, F, CF.sub.2H,
CF.sub.3, C(.dbd.NOH)NH.sub.2, CONR.sup.8R.sup.9, COOR.sup.8,
CONR.sup.8SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sup.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8
and a 4 to 6 membered saturated ring containing one oxygen atom;
[0526] R.sup.1d is present when Het has formula (d) and X is C;
each R.sup.1d is selected independently from the group consisting
of H, OH, halogen, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, N(R.sup.6).sub.2, CO(R.sup.7),
CH.sub.2NH.sub.2, CH.sub.2OH, CN, C(.dbd.NOH)NH.sub.2,
C(.dbd.NOCH.sub.3)NH.sub.2, C(.dbd.NH)NH.sub.2, CF.sub.3,
OCF.sub.3, B(OH).sub.2 and B(O--C.sub.1-C.sub.6alkyl).sub.2;
R.sup.id is absent when the X to which it is bound is N; [0527]
R.sup.3d is selected from the group consisting of H, halogen,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, and CO(R.sup.7); [0528] R.sup.2d is
--(CR.sup.8R.sup.9).sub.m--R.sup.10d; [0529] R.sup.10d is selected
from the group consisting of H, C.sub.1-C.sub.6alkyl, OH, CN, F,
CF.sub.2H, CF.sub.3, CONR.sup.8R.sup.9, COOR.sup.8,
CONR.sup.8SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sub.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8
and a 4 to 6 membered saturated ring containing one oxygen atom;
[0530] each Y independently is C or N; [0531] R.sup.1e is present
when Het has formula (e) and Y is C; each R.sup.1e is selected
independently from the group consisting of H, halogen,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, N(R.sup.6).sub.2, CO(R.sup.7),
CH.sub.2NH.sub.2, CH.sub.2OH, CN, C(.dbd.NOH)NH.sub.2,
C(.dbd.NOCH.sub.3)NH.sub.2, C(.dbd.NH)NH.sub.2, CF.sub.3,
OCF.sub.3, B(OH).sub.2 and B(O--C.sub.1-C.sub.6alkyl).sub.2;
R.sup.1e is absent when the Y to which it is bound is N; [0532]
R.sup.3e is selected from the group consisting of H, halogen,
--(CR.sup.8R.sup.9).sub.m--R.sup.10e,
C.ident.C--CH.sub.2--R.sup.10e, C.ident.C--R.sup.10e and
C.dbd.C--R.sup.10e; [0533] R.sup.10e is selected from the group
consisting of H, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy,
C.sub.3-C.sub.7cycloalkyl, OH, CN, F, CF.sub.2H, CF.sub.3,
CONR.sup.8R.sup.9, COOR.sup.8, CON(R.sup.8)SO.sub.2R.sup.9,
CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9), NR.sup.8R.sup.9,
NR.sup.8COOR.sup.9, OCOR.sup.8, NR.sup.8SO.sub.2R.sup.9,
SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8 and a 4 to 6 membered
saturated ring containing one oxygen atom; [0534] R.sup.4 is
selected from the group consisting of Het.sup.1 and
C.sub.3-C.sub.7cycloalkyl substituted with one or more substituents
selected from the group consisting of halo and
C.sub.1-C.sub.4alkyl; in particular R.sup.4 is Het.sup.1; [0535]
Het.sup.1 represents a 4 to 6 membered saturated ring containing
one N atom, optionally being substituted with one or more
substituents each independently selected from the group consisting
of halo, C.sub.1-C.sub.4alkyloxy, SO.sub.2R.sup.8,
C.sub.1-C.sub.4alkylcarbonyl, CO(aryl), COHet.sup.2,
C.sub.1-C.sub.4alkyloxycarbonyl, pyridinyl, CF.sub.3,
SO.sub.2N(C.sub.1-C.sub.4alkyl).sub.2,
SO.sub.2NH(C.sub.1-C.sub.4alkyl), (C.dbd.O)NH(C.sub.1-4alkyl),
(C.dbd.S)NH(C.sub.1-4alkyl), C.sub.1-C.sub.4alkyl and
C.sub.1-C.sub.4alkyl substituted with one hydroxy; or [0536]
Het.sup.1 represents a 4 to 6 membered saturated ring containing
one O atom, substituted with one or more substituents each
independently selected from the group consisting of halo,
C.sub.1-C.sub.4alkyloxy, CF.sub.3, NH(C.dbd.O)(C.sub.1-4alkyl),
(C.dbd.O)NH(C.sub.1-4alkyl) and C.sub.1-C.sub.4alkyl; [0537] aryl
represents phenyl or naphthalenyl; said aryl optionally being
substituted with one or more substituents each independently
selected from the group consisting of halo,
C.sub.1-C.sub.4alkyloxy, C.sub.1-C.sub.4alkyl, OH, CN, CF.sub.2H,
CF.sub.3, CONR.sup.8R.sup.9, COOR.sup.8,
CON(R.sup.8)SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sup.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8,
OCONR.sup.8R.sup.9, OCONR.sup.8R.sup.12,
N(R.sup.8)CON(R.sup.8R.sup.9), N(R.sup.8)COOR.sup.12; [0538]
Het.sup.2 represents a monocyclic 5 to 6 membered aromatic
heterocycle containing one or more heteroatoms each independently
selected from the group consisting of O, S and N; or a bicyclic 8
to 12 membered aromatic heterocycle containing one or more
heteroatoms each independently selected from the group consisting
of O, S and N; said Het.sup.2 optionally being substituted with one
or more substituents each independently selected from the group
consisting of halo, C.sub.1-C.sub.4alkyloxy, C.sub.1-C.sub.4alkyl,
OH, CN, CF.sub.2H, CF.sub.3, CONR.sup.8R.sup.9, COOR.sup.8,
CON(R.sup.8)SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sup.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8,
OCONR.sup.8R.sup.9, OCONR.sup.8R.sup.12,
N(R.sup.8)CON(R.sup.8R.sup.9), N(R.sup.8)COOR.sup.12; [0539] Z is C
or N; R.sup.5 is present where Z is C, whereby R.sup.5 is selected
form the group consisting of hydrogen, CF.sub.3 and halogen;
R.sup.5 is absent where Z is N; and the pharmaceutically acceptable
addition salts, and the solvates thereof.
[0540] In an embodiment, the present invention concerns novel
compounds of Formula (I) and stereoisomeric forms thereof, wherein
[0541] Het is a heterocycle having formula (b), (c), (d) or (e);
[0542] each X independently is C or N; provided that at least one X
is N; [0543] R.sup.1b is present when Het has formula (b) and X is
C; each R.sup.1b is selected independently from the group
consisting of H, halogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkyloxy,
N(R.sup.6).sub.2, CO(R.sup.7), CH.sub.2NH.sub.2, CH.sub.2OH, CN,
C(.dbd.NOH)NH.sub.2, C(.dbd.NOCH.sub.3)NH.sub.2,
C(.dbd.NH)NH.sub.2, CF.sub.3, OCF.sub.3, B(OH).sub.2 and
B(O--C.sub.1-C.sub.6alkyl).sub.2; R.sup.1b is absent when the X to
which it is bound is N; [0544] R.sup.2b is
--(CR.sup.8R.sup.9).sub.m--R.sup.10b; [0545] each R.sup.6 is
independently selected from the group consisting of H,
C.sub.1-C.sub.6alkyl, COOCH.sub.3 and CONHSO.sub.2CH.sub.3; [0546]
each R.sup.7 is independently selected from the group consisting of
OH, C.sub.1-C.sub.6alkyloxy, NH.sub.2,
NHSO.sub.2N(C.sub.1-C.sub.6alkyl).sub.2, NHSO.sub.2NHCH.sub.3,
NHSO.sub.2(C.sub.1-C.sub.6alkyl),
NHSO.sub.2(C.sub.3-C.sub.7cycloalkyl) and
N(C.sub.1-C.sub.6-alkyl).sub.2; [0547] each R.sup.8 and R.sup.9 are
independently chosen from the group consisting of H,
C.sub.1-C.sub.10alkyl and C.sub.3-C.sub.7cycloalkyl; or R.sup.8 and
R.sup.9 taken together form a 4 to 6 membered aliphatic ring that
optionally contains one or more heteroatoms selected from the group
consisting of N, S and O; [0548] R.sup.10b is selected from the
group consisting of H, R.sup.11, OH, CN, F, CF.sub.2H, CF.sub.3,
CONR.sup.8R.sup.9, COOR.sup.8, CON(R.sup.8)SO.sub.2R.sup.9,
CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9), NR.sup.8R.sup.9,
NR.sup.8COOR.sup.9, OCOR.sup.8, O-Benzyl, NR.sup.8SO.sub.2R.sup.9,
SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8, OCONR.sup.8R.sup.9,
OCONR.sup.8R.sup.12, N(R.sup.8)CON(R.sup.8R.sup.9),
N(R.sup.8)COOR.sup.12, and a 4 to 6 membered saturated ring
containing one oxygen atom; [0549] m is an integer from 2 to 6;
[0550] R.sup.11 is selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7cycloalkyl, phenyl, pyridinyl
and pyrazolyl; each optionally substituted with one or more
substituents each independently selected from the group consisting
of CF.sub.3, CH.sub.3, OCH.sub.3, OCF.sub.3 and halogen; [0551]
R.sup.12 is selected from the group consisting of phenyl, pyridinyl
and pyrazolyl; each optionally substituted with one or more
substituents each independently selected from the group consisting
of CF.sub.3, CH.sub.3, OCH.sub.3, OCF.sub.3 and halogen; [0552] or
R.sup.12 is C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.7cycloalkyl;
each substituted with one or more substituents each independently
selected from the group consisting of CF.sub.3, CH.sub.3,
OCH.sub.3, OCF.sub.3 and halogen; [0553] R.sup.1c is present when
Het has formula (c); [0554] each R.sup.1c is selected independently
from the group consisting of H, halogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkyloxy,
N(R.sup.6).sub.2, CO(R.sup.7c), CH.sub.2NH.sub.2, CH.sub.2OH, CN,
C(.dbd.NOH)NH.sub.2, C(.dbd.NOCH.sub.3)NH.sub.2,
C(.dbd.NH)NH.sub.2, CF.sub.3, OCF.sub.3, B(OH).sub.2 and
B(O--C.sub.1-C.sub.6alkyl).sub.2; [0555] R.sup.3c is selected from
the group consisting of H, halogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkyloxy and
CO(R.sup.7c); [0556] R.sup.2e is
--(CR.sup.8R.sup.9).sub.m--R.sup.10c; [0557] R.sup.7c is selected
from the group consisting of OH, O(C.sub.1-C.sub.6alkyl), NH.sub.2,
NHSO.sub.2N(C.sub.1-C.sub.6alkyl).sub.2, NHSO.sub.2NHCH.sub.3,
NHSO.sub.2(C.sub.1-C.sub.6alkyl),
NHSO.sub.2(C.sub.3-C.sub.7cycloalkyl),
N(C.sub.1-C.sub.6-alkyl).sub.2, NR.sup.8R.sup.9 and
NR.sup.9R.sup.10c; [0558] R.sup.10c is selected from the group
consisting of H, C.sub.1-C.sub.6alkyl, OH, CN, F, CF.sub.2H,
CF.sub.3, C(.dbd.NOH)NH.sub.2, CONR.sup.8R.sup.9, COOR.sup.8,
CONR.sup.8SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sup.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8
and a 4 to 6 membered saturated ring containing one oxygen atom;
[0559] R.sup.1d is present when Het has formula (d) and X is C;
each R.sup.1d is selected independently from the group consisting
of H, OH, halogen, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, N(R.sup.6).sub.2, CO(R.sup.7),
CH.sub.2NH.sub.2, CH.sub.2OH, CN, C(.dbd.NOH)NH.sub.2,
C(.dbd.NOCH.sub.3)NH.sub.2, C(.dbd.NH)NH.sub.2, CF.sub.3,
OCF.sub.3, B(OH).sub.2 and B(O--C.sub.1-C.sub.6alkyl).sub.2;
R.sup.1d is absent when the X to which it is bound is N; [0560]
R.sup.3d is selected from the group consisting of H, halogen,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, and CO(R.sup.7); [0561] R.sup.2d is
--(CR.sup.8R.sup.9).sub.m--R.sup.10d; [0562] R.sup.10d is selected
from the group consisting of H, C.sub.1-C.sub.6alkyl, OH, CN, F,
CF.sub.2H, CF.sub.3, CONR.sup.8R.sup.9, COOR.sup.8,
CONR.sup.8SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sub.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8
and a 4 to 6 membered saturated ring containing one oxygen atom;
[0563] each Y independently is C or N; [0564] R.sup.1e is present
when Het has formula (e) and Y is C; each R.sup.1e is selected
independently from the group consisting of H, halogen,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, N(R.sup.6).sub.2, CO(R.sup.7),
CH.sub.2NH.sub.2, CH.sub.2OH, CN, C(.dbd.NOH)NH.sub.2,
C(.dbd.NOCH.sub.3)NH.sub.2, C(.dbd.NH)NH.sub.2, CF.sub.3,
OCF.sub.3, B(OH).sub.2 and B(O--C.sub.1-C.sub.6alkyl).sub.2;
R.sup.1e is absent when the Y to which it is bound is N; [0565]
R.sup.3e is selected from the group consisting of H, halogen,
--(CR.sup.8R.sup.9).sub.m--R.sup.10e,
C.ident.C--CH.sub.2--R.sup.10e, C.ident.C--R.sup.10e and
C.dbd.C--R.sup.10e; [0566] R.sup.10e is selected from the group
consisting of H, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy,
C.sub.3-C.sub.7cycloalkyl, OH, CN, F, CF.sub.2H, CF.sub.3,
CONR.sup.8R.sup.9, COOR.sup.8, CON(R.sup.8)SO.sub.2R.sup.9,
CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9), NR.sup.8R.sup.9,
NR.sup.8COOR.sup.9, OCOR.sup.8, NR.sup.8SO.sub.2R.sup.9,
SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8 and a 4 to 6 membered
saturated ring containing one oxygen atom; [0567] R.sup.4 is
selected from the group consisting of Het.sup.1 and
C.sub.3-C.sub.7cycloalkyl substituted with one or more substituents
selected from the group consisting of halo and
C.sub.1-C.sub.4alkyl; in particular R.sup.4 is Het.sup.1; [0568]
Het.sup.1 represents a 4 to 6 membered saturated ring containing
one N atom, optionally being substituted with one or more
substituents each independently selected from the group consisting
of halo, C.sub.1-C.sub.4alkyloxy, SO.sub.2R.sup.8,
C.sub.1-C.sub.4alkylcarbonyl, C.sub.1-C.sub.4alkyloxycarbonyl,
pyridinyl, CF.sub.3, SO.sub.2N(C.sub.1-C.sub.4alkyl).sub.2,
SO.sub.2NH(C.sub.1-C.sub.4alkyl), (C.dbd.O)NH(C.sub.1-4alkyl),
(C.dbd.S)NH(C.sub.1-4alkyl), C.sub.1-C.sub.4alkyl and
C.sub.1-C.sub.4alkyl substituted with one hydroxy; or [0569]
Het.sup.1 represents a 4 to 6 membered saturated ring containing
one O atom, substituted with one or more substituents each
independently selected from the group consisting of halo,
C.sub.1-C.sub.4alkyloxy, CF.sub.3, NH(C.dbd.O)(C.sub.1-4alkyl),
(C.dbd.O)NH(C.sub.1-4alkyl) and C.sub.1-C.sub.4alkyl; [0570] Z is C
or N; R.sup.5 is present where Z is C, whereby R.sup.5 is selected
form the group consisting of hydrogen, CF.sub.3 and halogen;
R.sup.5 is absent where Z is N; and the pharmaceutically acceptable
addition salts, and the solvates thereof.
[0571] In an embodiment, the present invention concerns novel
compounds of Formula (I) and stereoisomeric forms thereof, wherein
[0572] Het is a heterocycle having formula (b), (c), (d) or (e);
[0573] each X independently is C or N; provided that at least one X
is N; [0574] R.sup.1b is present when Het has formula (b) and X is
C; each R.sup.1b is selected independently from the group
consisting of H, halogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkyloxy,
N(R.sup.6).sub.2, CO(R.sup.7), CH.sub.2NH.sub.2, CH.sub.2OH, CN,
C(.dbd.NOH)NH.sub.2, C(.dbd.NOCH.sub.3)NH.sub.2,
C(.dbd.NH)NH.sub.2, CF.sub.3, OCF.sub.3, B(OH).sub.2 and
B(O--C.sub.1-C.sub.6alkyl).sub.2; R.sup.1b is absent when the X to
which it is bound is N; [0575] R.sup.2b is
--(CR.sup.8R.sup.9).sub.m--R.sup.10b; [0576] each R.sup.6 is
independently selected from the group consisting of H,
C.sub.1-C.sub.6alkyl, COOCH.sub.3 and CONHSO.sub.2CH.sub.3; [0577]
each R.sup.7 is independently selected from the group consisting of
OH, C.sub.1-C.sub.6alkyloxy, NH.sub.2,
NHSO.sub.2N(C.sub.1-C.sub.6alkyl).sub.2, NHSO.sub.2NHCH.sub.3,
NHSO.sub.2(C.sub.1-C.sub.6alkyl),
NHSO.sub.2(C.sub.3-C.sub.7cycloalkyl) and
N(C.sub.1-C.sub.6-alkyl).sub.2; [0578] each R.sup.8 and R.sup.9 are
independently chosen from the group consisting of H,
C.sub.1-C.sub.10alkyl and C.sub.3-C.sub.7cycloalkyl; or R.sup.8 and
R.sup.9 taken together form a 4 to 6 membered aliphatic ring that
optionally contains one or more heteroatoms selected from the group
consisting of N, S and O; [0579] R.sup.10b is selected from the
group consisting of H, R.sup.11, OH, CN, F, CF.sub.2H, CF.sub.3,
CONR.sup.8R.sup.9, COOR.sup.8, CON(R.sup.8)SO.sub.2R.sup.9,
CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9), NR.sup.8R.sup.9,
NR.sup.8COOR.sup.9, OCOR.sup.8, O-Benzyl, NR.sup.8SO.sub.2R.sup.9,
SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8, OCONR.sup.8R.sup.9,
OCONR.sup.8R.sup.12, N(R.sup.8)CON(R.sup.8R.sup.9),
N(R.sup.8)COOR.sup.12, and a 4 to 6 membered saturated ring
containing one oxygen atom; [0580] m is an integer from 2 to 6;
[0581] R.sup.11 is selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7cycloalkyl, phenyl, pyridinyl
and pyrazolyl; each optionally substituted with one or more
substituents each independently selected from the group consisting
of CF.sub.3, CH.sub.3, OCH.sub.3, OCF.sub.3 and halogen; [0582]
R.sup.12 is selected from the group consisting of phenyl, pyridinyl
and pyrazolyl; each optionally substituted with one or more
substituents each independently selected from the group consisting
of CF.sub.3, CH.sub.3, OCH.sub.3, OCF.sub.3 and halogen; or
R.sup.12 is C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.7cycloalkyl;
each substituted with one or more substituents each independently
selected from the group consisting of CF.sub.3, CH.sub.3,
OCH.sub.3, OCF.sub.3 and halogen; [0583] R.sup.1c is present when
Het has formula (c); [0584] each R.sup.1c is selected independently
from the group consisting of H, halogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkyloxy,
N(R.sup.6).sub.2, CO(R.sup.7c), CH.sub.2NH.sub.2, CH.sub.2OH, CN,
C(.dbd.NOH)NH.sub.2, C(.dbd.NOCH.sub.3)NH.sub.2,
C(.dbd.NH)NH.sub.2, CF.sub.3, OCF.sub.3, B(OH).sub.2 and
B(O--C.sub.1-C.sub.6alkyl).sub.2; [0585] R.sup.3c is selected from
the group consisting of H, halogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkyloxy and
CO(R.sup.7c); [0586] R.sup.2c is
--(CR.sup.8R.sup.9).sub.m--R.sup.10c; [0587] R.sup.7c is selected
from the group consisting of OH, O(C.sub.1-C.sub.6alkyl), NH.sub.2,
NHSO.sub.2N(C.sub.1-C.sub.6alkyl).sub.2, NHSO.sub.2NHCH.sub.3,
NHSO.sub.2(C.sub.1-C.sub.6alkyl),
NHSO.sub.2(C.sub.3-C.sub.7cycloalkyl),
N(C.sub.1-C.sub.6-alkyl).sub.2, NR.sup.8R.sup.9 and
NR.sup.9R.sup.10c; [0588] R.sup.10c is selected from the group
consisting of H, C.sub.1-C.sub.6alkyl, OH, CN, F, CF.sub.2H,
CF.sub.3, C(.dbd.NOH)NH.sub.2, CONR.sup.8R.sup.9, COOR.sup.8,
CONR.sup.8SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sup.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8
and a 4 to 6 membered saturated ring containing one oxygen atom;
[0589] R.sup.1d is present when Het has formula (d) and X is C;
each R.sup.1d is selected independently from the group consisting
of H, OH, halogen, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, N(R.sup.6).sub.2, CO(R.sup.7),
CH.sub.2NH.sub.2, CH.sub.2OH, CN, C(.dbd.NOH)NH.sub.2,
C(.dbd.NOCH.sub.3)NH.sub.2, C(.dbd.NH)NH.sub.2, CF.sub.3,
OCF.sub.3, B(OH).sub.2 and B(O--C.sub.1-C.sub.6alkyl).sub.2;
R.sup.1d is absent when the X to which it is bound is N; [0590]
R.sup.3d is selected from the group consisting of H, halogen,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, and CO(R.sup.7); [0591] R.sup.2d is
--(CR.sup.8R.sup.9).sub.m--R.sup.10d; [0592] R.sup.10d is selected
from the group consisting of H, C.sub.1-C.sub.6alkyl, OH, CN, F,
CF.sub.2H, CF.sub.3, CONR.sup.8R.sup.9, COOR.sup.8,
CONR.sup.8SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sub.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8
and a 4 to 6 membered saturated ring containing one oxygen atom;
[0593] each Y independently is C or N; [0594] R.sup.1e is present
when Het has formula (e) and Y is C; each R.sup.1e is selected
independently from the group consisting of H, halogen,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, N(R.sup.6).sub.2, CO(R.sup.7),
CH.sub.2NH.sub.2, CH.sub.2OH, CN, C(.dbd.NOH)NH.sub.2,
C(.dbd.NOCH.sub.3)NH.sub.2, C(.dbd.NH)NH.sub.2, CF.sub.3,
OCF.sub.3, B(OH).sub.2 and B(O--C.sub.1-C.sub.6alkyl).sub.2;
R.sup.1e is absent when the Y to which it is bound is N; [0595]
R.sup.3e is selected from the group consisting of H, halogen,
--(CR.sup.8R.sup.9).sub.m--R.sup.10e,
C.ident.C--CH.sub.2--R.sup.10e; C.ident.C--R.sup.10e and
C.dbd.C--R.sup.10e; [0596] R.sup.10e is selected from the group
consisting of H, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkyloxy,
C.sub.3-C.sub.7cycloalkyl, OH, CN, F, CF.sub.2H, CF.sub.3,
CONR.sup.8R.sup.9, COOR.sup.8, CON(R.sup.8)SO.sub.2R.sup.9,
CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9), NR.sup.8R.sup.9,
NR.sup.8COOR.sup.9, OCOR.sup.8, NR.sup.8SO.sub.2R.sup.9,
SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8 and a 4 to 6 membered
saturated ring containing one oxygen atom; [0597] R.sup.4 is
selected from the group consisting of Het.sup.1 and
C.sub.3-C.sub.7cycloalkyl substituted with one or more substituents
selected from the group consisting of halo and
C.sub.1-C.sub.4alkyl; in particular R.sup.4 is Het1; [0598]
Het.sup.1 represents a 4 to 6 membered saturated ring containing
one N atom, optionally being substituted on the nitrogen atom with
one substituent selected from the group consisting of halo,
C.sub.1-C.sub.4alkyloxy, SO.sub.2R.sup.8,
C.sub.1-C.sub.4alkylcarbonyl, C.sub.1-C.sub.4alkyloxycarbonyl,
pyridinyl, CF.sub.3, SO.sub.2N(C.sub.1-C.sub.4alkyl).sub.2,
SO.sub.2NH(C.sub.1-C.sub.4alkyl), (C.dbd.O)NH(C.sub.1-4alkyl),
(C.dbd.S)NH(C.sub.1-4alkyl), C.sub.1-C.sub.4alkyl and
C.sub.1-C.sub.4alkyl substituted with one hydroxy; or [0599]
Het.sup.1 represents a 4 to 6 membered saturated ring containing
one O atom, wherein the carbon atom attached to the remainder of
the molecule is substituted with one substituent selected from the
group consisting of halo, C.sub.1-C.sub.4alkyloxy, CF.sub.3,
NH(C.dbd.O)(C.sub.1-4alkyl), (C.dbd.O)NH(C.sub.1-4alkyl) and
C.sub.1-C.sub.4alkyl; in particular C.sub.1-C.sub.4alkyl; more in
particular methyl; [0600] Z is C or N; R.sup.5 is present where Z
is C, whereby R.sup.5 is selected form the group consisting of
hydrogen, CF.sub.3 and halogen; R.sup.5 is absent where Z is N; and
the pharmaceutically acceptable addition salts, and the solvates
thereof.
[0601] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein [0602] Het.sup.1 represents a
4 to 6 membered saturated ring containing one N atom, optionally
being substituted on the nitrogen atom with one substituent
selected from the group consisting of halo,
C.sub.1-C.sub.4alkyloxy, SO.sub.2R.sup.8,
C.sub.1-C.sub.4alkylcarbonyl, CO(aryl), COHet.sup.2,
C.sub.1-C.sub.4alkyloxycarbonyl, pyridinyl, CF.sub.3,
SO.sub.2N(C.sub.1-C.sub.4alkyl).sub.2,
SO.sub.2NH(C.sub.1-C.sub.4alkyl), (C.dbd.O)NH(C.sub.1-4alkyl),
(C.dbd.S)NH(C.sub.1-4alkyl), C.sub.1-C.sub.4alkyl and
C.sub.1-C.sub.4alkyl substituted with one hydroxy; or [0603]
Het.sup.1 represents a 4 to 6 membered saturated ring containing
one O atom, wherein the carbon atom attached to the remainder of
the molecule is substituted with one substituent selected from the
group consisting of halo, C.sub.1-C.sub.4alkyloxy, CF.sub.3,
NH(C.dbd.O)(C.sub.1-4alkyl), (C.dbd.O)NH(C.sub.1-4alkyl) and
C.sub.1-C.sub.4alkyl; in particular C.sub.1-C.sub.4alkyl; more in
particular
[0604] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein R.sup.4 is selected from the
group consisting of Het.sup.1 and C.sub.3-C.sub.7cycloalkyl
substituted with one or more substituents selected from the group
consisting of halo and C.sub.1-C.sub.4alkyl; in particular R.sup.4
is Het1.
[0605] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein [0606] R.sup.10b is selected
from the group consisting of H, R.sup.11, OH, CN, F, CF.sub.2H,
CF.sub.3, CONR.sup.8R.sup.9, COOR.sup.8,
CON(R.sup.8)SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sup.9, OCOR.sup.8, O-Benzyl,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2CH.sub.3,
OCONR.sup.8R.sup.9, OCONR.sup.8R.sup.12,
N(R.sup.8)CON(R.sup.8R.sup.9), N(R.sup.8)COOR.sup.12, and a 4 to 6
membered saturated ring containing one oxygen atom; [0607]
R.sup.10c is selected from the group consisting of H, R.sup.11, OH,
CN, F, CF.sub.2H, CF.sub.3, C(.dbd.NOH)NH.sub.2, CONR.sup.8R.sup.9,
COOR.sup.8, CONR.sup.8SO.sub.2R.sup.9,
CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9), NR.sup.8R.sup.9,
NR.sup.8COOR.sup.9, OCOR.sup.8, NR.sup.8SO.sub.2R.sup.9,
SO.sub.2NR.sup.8R.sup.9, SO.sub.2CH.sub.3 and a 4 to 6 membered
saturated ring containing one oxygen atom; [0608] R.sup.10d is
selected from the group consisting of H, R.sup.11, OH, CN, F,
CF.sub.2H, CF.sub.3, CONR.sup.8R.sup.9, COOR.sup.8,
CONR.sup.8SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sub.9, OCOR.sup.8,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2CH.sub.3
and a 4 to 6 membered saturated ring containing one oxygen atom;
[0609] R.sup.10e is selected from the group consisting of H,
R.sup.11, C.sub.1-C.sub.6alkyloxy, OH, CN, F, CF.sub.2H, CF.sub.3,
CONR.sup.8R.sup.9, COOR.sup.8, CON(R.sup.8)SO.sub.2R.sup.9,
CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9), NR.sup.8R.sup.9,
NR.sup.8COOR.sup.9, OCOR.sup.8, NR.sup.8SO.sub.2R.sup.9,
SO.sub.2NR.sup.8R.sup.9, SO.sub.2CH.sub.3 and a 4 to 6 membered
saturated ring containing one oxygen atom.
[0610] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein SO.sub.2R.sup.8 is restricted
to SO.sub.2CH.sup.3 or SO.sub.2C.sub.3-C.sub.7cycloalkyl; in
particular SO.sub.2CH.sup.3.
[0611] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein R.sup.4 is selected from the
group consisting of Het.sup.1, aryl, Het.sup.2, and
C.sub.3-C.sub.7cycloalkyl substituted with one or more substituents
selected from the group consisting of halo and
C.sub.1-C.sub.4alkyl; in particular Het.sup.1, Het.sup.2, and
C.sub.3-C.sub.7cycloalkyl substituted with one or more substituents
selected from the group consisting of halo and
C.sub.1-C.sub.4alkyl.
[0612] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein R.sup.4 is selected from the
group consisting of Het.sup.1 and C.sub.3-C.sub.7cycloalkyl
substituted with one or more substituents selected from the group
consisting of halo and C.sub.1-C.sub.4alkyl; in particular R.sup.4
is Het1; and wherein [0613] Het.sup.1 represents a 4 to 6 membered
saturated ring containing one N atom, optionally being substituted
on the nitrogen atom with one substituent selected from the group
consisting of halo, C.sub.1-C.sub.4alkyloxy, SO.sub.2R.sup.8,
C.sub.1-C.sub.4alkylcarbonyl, CO(aryl), COHet.sup.2,
C.sub.1-C.sub.4alkyloxycarbonyl, pyridinyl, CF.sub.3,
SO.sub.2N(C.sub.1-C.sub.4alkyl).sub.2,
SO.sub.2NH(C.sub.1-C.sub.4alkyl), (C.dbd.O)NH(C.sub.1-4alkyl),
(C.dbd.S)NH(C.sub.1-4alkyl), C.sub.1-C.sub.4alkyl and
C.sub.1-C.sub.4alkyl substituted with one hydroxy; or [0614]
Het.sup.1 represents a 4 to 6 membered saturated ring containing
one O atom, wherein the carbon atom attached to the remainder of
the molecule is substituted with one substituent selected from the
group consisting of halo, C.sub.1-C.sub.4alkyloxy, CF.sub.3,
NH(C.dbd.O)(C.sub.1-4alkyl), (C.dbd.O)NH(C.sub.1-4alkyl) and
C.sub.1-C.sub.4alkyl; in particular C.sub.1-C.sub.4alkyl; more in
particular methyl.
[0615] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein R.sup.4 is Het.sup.1, and
wherein [0616] Het.sup.1 represents a 4 to 6 membered saturated
ring containing one N atom, optionally being substituted on the
nitrogen atom with one substituent selected from the group
consisting of halo, C.sub.1-C.sub.4alkyloxy, SO.sub.2R.sup.8,
C.sub.1-C.sub.4alkylcarbonyl, CO(aryl), COHet.sup.2,
C.sub.1-C.sub.4alkyloxycarbonyl, pyridinyl, CF.sub.3,
SO.sub.2N(C.sub.1-C.sub.4alkyl).sub.2,
SO.sub.2NH(C.sub.1-C.sub.4alkyl), (C.dbd.O)NH(C.sub.1-4alkyl),
(C.dbd.S)NH(C.sub.1-4alkyl), C.sub.1-C.sub.4alkyl and
C.sub.1-C.sub.4alkyl substituted with one hydroxy; or [0617]
Het.sup.1 represents a 4 to 6 membered saturated ring containing
one O atom, wherein the carbon atom attached to the remainder of
the molecule is substituted with one substituent selected from the
group consisting of halo, C.sub.1-C.sub.4alkyloxy, CF.sub.3,
NH(C.dbd.O)(C.sub.1-4alkyl), (C.dbd.O)NH(C.sub.1-4alkyl) and
C.sub.1-C.sub.4alkyl; in particular C.sub.1-C.sub.4alkyl; more in
particular methyl.
[0618] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein R.sup.4 is Het.sup.1, and
wherein [0619] Het.sup.1 represents a 4 to 6 membered saturated
ring containing one O atom, wherein the carbon atom attached to the
remainder of the molecule is substituted with one substituent
selected from the group consisting of halo,
C.sub.1-C.sub.4alkyloxy, CF.sub.3, NH(C.dbd.O)(C.sub.1-4alkyl),
(C.dbd.O)NH(C.sub.1-4alkyl) and C.sub.1-C.sub.4alkyl; in particular
C.sub.1-C.sub.4alkyl; more in particular methyl.
[0620] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein R.sup.4 is Het.sup.1, and
wherein [0621] Het.sup.1 represents a 4 membered saturated ring
containing one O atom, wherein the carbon atom attached to the
remainder of the molecule is substituted with one methyl group.
[0622] In an embodiment, the present invention concerns novel
compounds of Formula (I) and stereoisomeric forms thereof, wherein
[0623] Het is a heterocycle having formula (b) or (c), [0624] each
X independently is C or N; provided that at least one X is N;
[0625] R.sup.1b is present when Het has formula (b) and X is C;
each R.sup.1b is selected independently from the group consisting
of H and halogen; R.sup.1b is absent when the X to which it is
bound is N; [0626] R.sup.2b is
--(CR.sup.8R.sup.9).sub.m--R.sup.10b; [0627] each R.sup.8 and
R.sup.9 are independently chosen from the group consisting of H
and
[0628] C.sub.1-C.sub.10alkyl; in particular H and C.sub.1-C.sub.6
alkyl; [0629] R.sup.10b is selected from the group consisting of F,
C.sub.1-C.sub.6 alkyl, CF.sub.3, SO.sub.2R.sub.8; m is an integer
from 2 to 4; [0630] R.sup.1c is present when Het has formula (c);
[0631] each R.sup.1c is selected independently from the group
consisting of H and halogen; [0632] R.sup.3c is H; [0633] R.sup.2c
is --(CR.sup.8R.sup.9).sub.m--R.sup.10c; [0634] R.sup.10c is
selected from the group consisting of F and SO.sub.2R.sup.8; [0635]
R.sup.4 is selected from the group consisting of tert-butyl,
Het.sup.1, Het.sup.2, and C.sub.3-C.sub.7cycloalkyl substituted
with one or more substituents selected from the group consisting of
halo and C.sub.1-C.sub.4alkyl; [0636] Het.sup.1 represents a 4
membered saturated ring containing one N atom, optionally being
substituted with one or more substituents each independently
selected from the group consisting of SO.sub.2R.sup.8,
C.sub.1-C.sub.4alkylcarbonyl, C.sub.1-C.sub.4alkyloxycarbonyl and
C.sub.1-C.sub.4alkyl substituted with one hydroxy; or [0637]
Het.sup.1 represents a 4 membered saturated ring containing one O
atom, substituted with one or more substituents each independently
selected from the group consisting of C.sub.1-C.sub.4alkyl; [0638]
Het.sup.2 represents a monocyclic 5 membered aromatic heterocycle
containing one or more heteroatoms each independently selected from
the group consisting of S and N; or a bicyclic 10-membered aromatic
heterocycle containing one N-atom; [0639] Z is C or N; R.sup.5 is
present where Z is C, whereby R.sup.5 is halogen; R.sup.5 is absent
where Z is N; and the pharmaceutically acceptable addition salts,
and the solvates thereof.
[0640] In an embodiment, the present invention concerns novel
compounds of Formula (I) and stereoisomeric forms thereof, wherein
[0641] Het is a heterocycle having formula (b) or (c), [0642] each
X independently is C or N; provided that at least one X is N;
[0643] R.sup.1b is present when Het has formula (b) and X is C;
each R.sup.1b is selected independently from the group consisting
of H and halogen; R.sup.1b is absent when the X to which it is
bound is N; [0644] R.sup.2b is
--(CR.sup.8R.sup.9).sub.m--R.sup.10b; [0645] each R.sup.8 and
R.sup.9 are independently chosen from the group consisting of H and
C.sub.1-C.sub.10alkyl; in particular H and C.sub.1-C.sub.6 alkyl;
[0646] R.sup.10b is selected from the group consisting of F,
C.sub.1-C.sub.6 alkyl, CF.sub.3, SO.sub.2R.sub.8; [0647] m is an
integer from 2 to 4; [0648] R.sup.1c is present when Het has
formula (c); [0649] each R.sup.1c is selected independently from
the group consisting of H and halogen; [0650] R.sup.3c is H; [0651]
R.sup.2c is --(CR.sup.8R.sup.9).sub.m--R.sup.10c; [0652] R.sup.10c
is selected from the group consisting of F and SO.sub.2R.sup.8;
[0653] R.sup.4 is selected from the group consisting of tert-butyl,
Het.sup.1, Het.sup.2, and C.sub.3-C.sub.7cycloalkyl substituted
with one or more substituents selected from the group consisting of
halo and C.sub.1-C.sub.4alkyl; [0654] Het.sup.1 represents a 4
membered saturated ring containing one N atom, optionally being
substituted with one or more substituents each independently
selected from the group consisting of SO.sub.2R.sup.8,
C.sub.1-C.sub.4alkylcarbonyl, C.sub.1-C.sub.4alkyloxycarbonyl and
C.sub.1-C.sub.4alkyl substituted with one hydroxy; [0655] Het.sup.2
represents a monocyclic 5 membered aromatic heterocycle containing
one or more heteroatoms each independently selected from the group
consisting of S and N; or a bicyclic 10-membered aromatic
heterocycle containing one N-atom; [0656] Z is C or N; R.sup.5 is
present where Z is C, whereby R.sup.5 is halogen; R.sup.5 is absent
where Z is
[0657] N;
and the pharmaceutically acceptable addition salts, and the
solvates thereof.
[0658] In an embodiment, the present invention concerns novel
compounds of Formula (I) and stereoisomeric forms thereof, wherein
[0659] Het is a heterocycle having formula (b) or (c), [0660] each
X independently is C or N; provided that at least one X is N;
[0661] R.sup.1b is present when Het has formula (b) and X is C;
each R.sup.1b is selected independently from the group consisting
of H and halogen; R.sup.1b is absent when the X to which it is
bound is N; [0662] R.sup.2b is
--(CR.sup.8R.sup.9).sub.m--R.sup.10b; [0663] each R.sup.8 and
R.sup.9 are H; [0664] R.sup.10b is selected from the group
consisting of F, C.sub.1-C.sub.6 alkyl, CF.sub.3, SO.sub.2CH.sub.3;
[0665] m is an integer from 2 to 4; [0666] R.sup.1c is present when
Het has formula (c); [0667] each R.sup.1c is selected independently
from the group consisting of H and halogen; [0668] R.sup.3c is H;
[0669] R.sup.2c is --(CR.sup.8R.sup.9).sub.m--R.sup.10c; [0670]
R.sup.10c is selected from the group consisting of F and
SO.sub.2CH.sub.3; [0671] R.sup.4 is selected from the group
consisting of tert-butyl, Het.sup.1, Het.sup.2, and
C.sub.3-C.sub.7cycloalkyl substituted with one or more substituents
selected from the group consisting of halo and
C.sub.1-C.sub.4alkyl; [0672] Het.sup.1 represents a 4 membered
saturated ring containing one N atom, optionally being substituted
with one or more substituents each independently selected from the
group consisting of SO.sub.2CH.sub.3, C.sub.1-C.sub.4alkylcarbonyl,
C.sub.1-C.sub.4alkyloxycarbonyl and C.sub.1-C.sub.4alkyl
substituted with one hydroxy; [0673] Het.sup.2 represents a
monocyclic 5 membered aromatic heterocycle containing one or more
heteroatoms each independently selected from the group consisting
of S and N; or a bicyclic 10-membered aromatic heterocycle
containing one N-atom; [0674] Z is C or N; R.sup.5 is present where
Z is C, whereby R.sup.5 is halogen; R.sup.5 is absent where Z is N;
and the pharmaceutically acceptable addition salts, and the
solvates thereof.
[0675] In an embodiment, the present invention concerns novel
compounds of Formula (I) and stereoisomeric forms thereof, wherein
[0676] Het is a heterocycle having formula (b-1a) or (c-1a),
[0676] ##STR00004## [0677] R.sup.2b is
--(CR.sup.8R.sup.9).sub.m--R.sup.10b; [0678] each R.sup.8 and
R.sup.9 are H; [0679] R.sup.10b is selected from the group
consisting of F, isopropyl, CF.sub.3, SO.sub.2CH.sub.3; [0680] m is
an integer from 2 to 4; [0681] R.sup.3c is H; [0682] R.sup.2c is
--(CR.sup.8R.sup.9).sub.m--R.sup.10c; [0683] R.sup.10c is selected
from the group consisting of F and SO.sub.2CH.sub.3; [0684] R.sup.4
is selected from the group consisting of tert-butyl, Het.sup.1,
Het.sup.2, and C.sub.3-C.sub.7cycloalkyl substituted with one or
more substituents selected from the group consisting of halo and
C.sub.1-C.sub.4alkyl; [0685] Het.sup.1 represents a 4 membered
saturated ring containing one N atom, optionally being substituted
on the nitrogen atom with one substituent selected from the group
consisting of SO.sub.2CH.sub.3, methylcarbonyl,
tert-butyloxycarbonyl and C.sub.1-C.sub.4alkyl substituted with one
hydroxy; [0686] Het.sup.2 represents a monocyclic 5 membered
aromatic heterocycle containing one or more heteroatoms each
independently selected from the group consisting of S and N; or a
bicyclic 10-membered aromatic heterocycle containing one N-atom;
[0687] Z is C or N; R.sup.5 is present where Z is C, whereby
R.sup.5 is fluoro; R.sup.5 is absent where Z is N; and the
pharmaceutically acceptable addition salts, and the solvates
thereof.
[0688] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein R.sup.5 is selected from the
group consisting of CF.sub.3 and halogen.
[0689] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein R.sup.3e is
--(CR.sup.8R.sup.9).sub.m--R.sup.10e.
[0690] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein Het has formula (b) or
(c).
[0691] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein Het has formula (b).
[0692] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein Het has formula (c).
[0693] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein Het has formula (d).
[0694] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein Het has formula (e).
[0695] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein Het is a heterocycle having
formula (bb), (cc), (dd) or (ee); in particular (bb) or (cc); more
in particular (bb); more in particular (cc); more in particular
(dd); more in particular (cc);
##STR00005##
wherein R.sup.1bb, R.sup.1cc, R1.sup.dd or R.sup.1ee are chloro or
bromo; in particular chloro; wherein R.sup.1b, R.sup.1c, R1.sup.d,
R.sup.1e and the other substituents are defined according to any of
the other embodiments; in a particular embodiment R.sup.1bb,
R.sup.1cc, R1.sup.dd or R.sup.1ee are chloro; R.sup.1b, R.sup.1c,
R1.sup.d, R.sup.1e if present are H; and the other substituents are
defined according to any of the other embodiments.
[0696] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein Het is a heterocycle having
formula (b-1) or (c-1); in particular (b-1); also in particular
(c-1);
##STR00006##
wherein R.sup.1b and R.sup.1c are chloro or bromo.
[0697] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein Het is a heterocycle having
formula (b-1a) or (c-1a); in particular (b-1a); also in particular
(c-1a);
##STR00007##
[0698] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein
R.sup.4 is selected from the group consisting of tert-butyl,
azetidinyl substituted on the N atom with one substituent selected
from the group consisting of C.sub.1-C.sub.4alkylcarbonyl and
C.sub.1-C.sub.4alkyloxycarbonyl, phenyl substituted with one
substituent selected from the group consisting of F and
C.sub.1-C.sub.4alkyloxy, and cyclopropyl substituted with one
substituent selected from the group consisting of
C.sub.1-C.sub.4alkyl and F; Z is C or N; R.sup.5 is present where Z
is C, whereby R.sup.5 is halogen; R.sup.5 is absent where Z is
N.
[0699] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein [0700] R.sup.4 is selected
from the group consisting of tert-butyl, Het.sup.1, Het.sup.2, and
C.sub.3-C.sub.7cycloalkyl substituted with one or more substituents
selected from the group consisting of halo and
C.sub.1-C.sub.4alkyl; [0701] Het.sup.1 represents a 4 membered
saturated ring containing one N atom, optionally being substituted
on the nitrogen atom with one substituent selected from the group
consisting of SO.sub.2CH.sub.3, C.sub.1-C.sub.4alkylcarbonyl,
C.sub.1-C.sub.4alkyloxycarbonyl and C.sub.1-C.sub.4alkyl
substituted with one hydroxy; [0702] Het.sup.2 represents a
monocyclic 5 membered aromatic heterocycle containing one or more
heteroatoms each independently selected from the group consisting
of S and N; or a bicyclic 10-membered aromatic heterocycle
containing one N-atom; [0703] Z is C or N; R.sup.5 is present where
Z is C, whereby R.sup.5 is halo; R.sup.5 is absent where Z is
N.
[0704] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein R.sup.4 is selected from the
group consisting of tert-butyl, Het.sup.1, aryl, Het.sup.2 and
C.sub.3-C.sub.7cycloalkyl substituted with one or more substituents
selected from the group consisting of halo and
C.sub.1-C.sub.4alkyl.
[0705] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein R.sup.4 is selected from the
group consisting of tert-butyl, Het.sup.1, CH(CH.sub.3)(CF.sub.3),
and C.sub.3-C.sub.7cycloalkyl substituted with one or more
substituents selected from the group consisting of halo and
C.sub.1-C.sub.4alkyl; in particular R.sup.4 is selected from the
group consisting of Het.sup.1 and C.sub.3-C.sub.7cycloalkyl
substituted with one or more substituents selected from the group
consisting of halo and C.sub.1-C.sub.4alkyl; more in particular
R.sup.4 is Het.sup.1.
[0706] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein R.sup.4 is selected from the
group consisting of tert-butyl, aryl, Het.sup.2 and
CH(CH.sub.3)(CF.sub.3); in particular R.sup.4 is aryl or Het.sup.2;
more in particular R.sup.4 is Het.sup.2.
[0707] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein Z is C or N; R.sup.5 is
present where Z is C, whereby R.sup.5 is selected form the group
consisting of CF.sub.3 and halogen; R.sup.5 is absent where Z is
N.
[0708] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein each R.sup.1c is selected
independently from the group consisting of H, halogen,
C.sub.1-C.sub.6alkyloxy, CF.sub.3, and OCF.sub.3.
[0709] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein Het has formula (c) wherein
each R.sup.1c is selected independently from the group consisting
of H, halogen, C.sub.1-C.sub.6alkyloxy, CF.sub.3, and
OCF.sub.3.
[0710] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein R.sup.1c in the para position
to N--R.sup.2.degree. is selected from the group consisting of H,
halogen and all other R.sup.1c are H. In preferred embodiment,
halogen is bromo or chloro.
[0711] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein Het has formula (c) wherein
R.sup.1c in the para position to N--R.sup.2.degree. is selected
from the group consisting of H, halogen and all other R.sup.1c are
H. In preferred embodiment, halogen is bromo or chloro.
[0712] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein Het has formula (c) wherein
R.sup.2c comprises a --(CR.sup.8R.sup.9).sub.m chain wherein
R.sup.8 and R.sup.9 are H and m is 2-4. Preferably R.sup.10c is
selected from the group consisting of OH, F, CF.sub.2H, CF.sub.3,
SO.sub.2R.sub.8, and CN. R.sup.8 preferably is methyl.
[0713] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein R.sup.2c comprises a
--(CR.sup.8R.sup.9) chain wherein R.sup.8 and R.sup.9 are H and m
is 2-4. Preferably R.sup.10c is selected from the group consisting
of OH, F, CF.sub.2H, CF.sub.3, SO.sub.2R.sub.8, and CN. R.sup.8
preferably is methyl.
[0714] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein R.sup.4 is
C.sub.3-C.sub.7cycloalkyl substituted with one or more substituents
selected from the group consisting of halo and
C.sub.1-C.sub.4alkyl; more preferably cyclopropyl substituted with
halo or C.sub.1-C.sub.4alkyl.
[0715] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein Z is N.
[0716] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein R.sup.5 is H.
[0717] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein R.sup.4 is selected from the
group consisting of tert-butyl, Het.sup.1, aryl, Het.sup.2 and
C.sub.3-C.sub.7cycloalkyl substituted with one or more substituents
selected from the group consisting of halo and
C.sub.1-C.sub.4alkyl;
R.sup.10b is selected from the group consisting of H,
C.sub.1-C.sub.6alkyl, OH, CN, F, CF.sub.2H, CF.sub.3,
CONR.sup.8R.sup.9, COOR.sup.8, CON(R.sup.8)SO.sub.2R.sup.9,
CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9), NR.sup.8R.sup.9,
NR.sup.8COOR.sup.9, OCOR.sup.8, O-Benzyl, NR.sup.8SO.sub.2R.sup.9,
SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8 and a 4 to 6 membered
saturated ring containing one oxygen atom; and m is an integer from
2 to 6.
[0718] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein R.sup.10b is selected from
the group consisting of H, C.sub.1-C.sub.6alkyl, OH, CN, F,
CF.sub.2H, CF.sub.3, CONR.sup.8R.sup.9, COOR.sup.8,
CON(R.sup.8)SO.sub.2R.sup.9, CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9),
NR.sup.8R.sup.9, NR.sup.8COOR.sup.9, OCOR.sup.8, O-Benzyl,
NR.sup.8SO.sub.2R.sup.9, SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8
and a 4 to 6 membered saturated ring containing one oxygen
atom.
[0719] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein Het has formula (b) wherein
R.sup.10b is selected from the group consisting of H,
C.sub.1-C.sub.6alkyl, OH, CN, F, CF.sub.2H, CF.sub.3,
CONR.sup.8R.sup.9, COOR.sup.8, CON(R.sup.8)SO.sub.2R.sup.9,
CON(R.sup.8)SO.sub.2N(R.sup.8R.sup.9), NR.sup.8R.sup.9,
NR.sup.8COOR.sup.9, OCOR.sup.8, O-Benzyl, NR.sup.8SO.sub.2R.sup.9,
SO.sub.2NR.sup.8R.sup.9, SO.sub.2R.sup.8 and a 4 to 6 membered
saturated ring containing one oxygen atom.
[0720] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein Het has formula (b) wherein
at most two X are N. In a preferred embodiment, one X is N. In a
more preferred embodiment, the one X that is N is located in meta
position to the N--R.sup.2b group of the imidazole ring.
[0721] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein Het having formula (b) has at
most two X being N. In a preferred embodiment, one X is N. In a
more preferred embodiment, the one X that is N is located in meta
position to the N--R.sup.2b group of the imidazole ring.
[0722] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein each R.sup.1b is selected
independently from the group consisting of H, halogen and
CH.sub.2--NH.sub.2. In a further preferred embodiment, R.sup.1b in
the para position to C--N--R.sup.2b is selected from the group
consisting of H, halogen and CH.sub.2--NH.sub.2, and all other
R.sup.1b are H. In a further preferred embodiment said halogen is
bromo or chloro. In a most preferred embodiment, at most one
R.sup.1b is chloro, and all other R.sup.1b are H. In yet an even
more preferred embodiment, R.sup.1b in the para position to
C--N--R.sup.2b is chloro.
[0723] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein Het has formula (b) wherein
each R.sup.1b is selected independently from the group consisting
of H, halogen and CH.sub.2--NH.sub.2. In a further preferred
embodiment, R.sup.1b in the para position to C--N--R.sup.2b is
selected from the group consisting of H, halogen and
CH.sub.2--NH.sub.2, and all other R.sup.1b are H. In a further
preferred embodiment said halogen is bromo or chloro. In a most
preferred embodiment, at most one R.sup.1b is chloro, and all other
R.sup.1b are H. In yet an even more preferred embodiment, R.sup.1b
in the para position to C--N--R.sup.2b is chloro. In an embodiment,
the present invention relates to those compounds of formula (I), or
any subgroup thereof as mentioned in any of the other embodiments,
wherein R.sup.11 is C.sub.1-C.sub.6alkyl or
C.sub.3-C.sub.7cycloalkyl; in particular C.sub.1-C.sub.6alkyl.
[0724] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein R.sup.2b comprises a
--(CR.sup.8R.sup.9).sub.m--R.sup.10b chain wherein R.sup.8 and
R.sup.9 are preferably H and m is 2-4. Preferably R.sup.10b is
selected from the group consisting of OH, C.sub.1-C.sub.6alkyl;
more preferably 2-propyl. Also preferably R.sup.10b is selected
from the group consisting of methoxy, SO.sub.2R.sup.8, with R.sup.8
preferably being methyl. Most preferably R.sup.10b is fluoro or
CF.sub.3.
[0725] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein Het has formula (b) wherein
R.sup.2b comprises a --(CR.sup.8R.sup.9).sub.m--R.sup.10b chain
wherein R.sup.8 and R.sup.9 are preferably H and m is 2-4.
Preferably R.sup.10b is selected from the group consisting of OH,
C.sub.1-C.sub.6alkyl; more preferably 2-propyl. Also preferably
R.sup.10b is selected from the group consisting of methoxy,
SO.sub.2R.sup.8, with R.sup.8 preferably being methyl. Most
preferably R.sup.10b is fluoro or CF.sub.3.
[0726] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein R.sup.4 is selected from
C.sub.3-C.sub.7cycloalkyl substituted with one or more substituents
selected from the group consisting of halo and
C.sub.1-C.sub.4alkyl.
[0727] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein R.sup.4 is selected from the
group consisting of Het.sup.1 and cyclopropyl substituted with halo
or C.sub.1-C.sub.4alkyl.
[0728] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein R.sup.5 is halogen, in
particular fluoro.
[0729] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein each R.sup.1d independently
is selected from the group of H, halogen, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkyloxy,
N(R.sup.6).sub.2, CO(R.sup.6), CH.sub.2NH.sub.2, CH.sub.2OH, CN,
C(.dbd.NOH)NH.sub.2, C(.dbd.NOCH.sub.3)NH.sub.2,
C(.dbd.NH)NH.sub.2, CF.sub.3, OCF.sub.3, B(OH).sub.2 and
B(O--C.sub.1-C.sub.6alkyl).sub.2.
[0730] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein Het has formula (d) wherein
each R.sup.1d independently is selected from the group of H,
halogen, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl,
C.sub.1-C.sub.6alkyloxy, N(R.sup.6).sub.2, CO(R.sup.6),
CH.sub.2NH.sub.2, CH.sub.2OH, CN, C(.dbd.NOH)NH.sub.2,
C(.dbd.NOCH.sub.3)NH.sub.2, C(.dbd.NH)NH.sub.2, CF.sub.3,
OCF.sub.3, B(OH).sub.2 and B(O--C.sub.1-C.sub.6alkyl).sub.2.
[0731] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein Het has formula (d) wherein
at most two X are N. In a preferred embodiment, one X is N. In a
more preferred embodiment, the one X that is N is located is in
meta or para position to the N--R.sup.2d. In a further preferred
embodiment, X is in the position para to N--R.sup.2d.
[0732] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein Het having formula (d) has at
most two X being N. In a preferred embodiment, one X is N. In a
more preferred embodiment, the one X that is N is located is in
meta or para position to the N--R.sup.2d. In a further preferred
embodiment, X is in the position para to N--R.sup.2d.
[0733] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein each R.sup.1d is selected
independently from the group consisting of H or halogen. In a
further preferred embodiment, R.sup.1d in the para position to
N--R.sup.2d is halogen, and all other R.sup.1d are H. In a further
preferred embodiment said halogen is bromo or chloro. In a most
preferred embodiment, said halogen is chloro.
[0734] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein Het has formula (d) wherein
each R.sup.1d is selected independently from the group consisting
of H or halogen. In a further preferred embodiment, R.sup.1d in the
para position to N--R.sup.2d is halogen, and all other R.sup.1d are
H. In a further preferred embodiment said halogen is bromo or
chloro. In a most preferred embodiment, said halogen is chloro.
[0735] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein R.sup.2d comprises a
--(CR.sup.8R.sup.9) chain wherein R.sup.8 and R.sup.9 are
preferably H and m is 2-4. Preferably R.sup.10d is selected from
the group consisting of OH, F, CF.sub.3, CF.sub.2H and
C.sub.1-C.sub.6alkyl; in particular 2-propyl.
[0736] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein Het has formula (d) wherein
R.sup.2d comprises a --(CR.sup.8R.sup.9).sub.m chain wherein
R.sup.8 and R.sup.9 are preferably H and m is 2-4. Preferably
R.sup.10d is selected from the group consisting of OH, F, CF.sub.3,
CF.sub.2H and C.sub.1-C.sub.6alkyl; in particular 2-propyl.
[0737] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein Het has formula (e) wherein
R.sup.3e is selected from the group consisting of H, halogen,
--(CR.sup.8R.sup.9).sub.m--R.sup.10e,
C.ident.C--CH.sub.2--R.sup.10e and C.ident.C--R.sup.10e.
[0738] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein R.sup.3e is selected from the
group consisting of H, halogen,
--(CR.sup.8R.sup.9).sub.m--R.sup.10e,
C.ident.C--CH.sub.2--R.sup.10e and C.ident.C--R.sup.10e.
[0739] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein Het has formula (e) wherein Y
is C.
[0740] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein Y is C.
[0741] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein Het having formula (e) is
limited to formula (e1)
##STR00008##
[0742] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein all substituents R.sup.1e are
H.
[0743] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein Het has formula (e) wherein
all substituents R.sup.1e are H.
[0744] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein at least one of R.sub.1e is
halogen, more preferably Cl or Br.
[0745] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein Het has formula (e) wherein
at least one of R.sup.1e is halogen, more preferably Cl or Br.
[0746] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein m comprises a carbon chain of
2-6 atoms, in particular 2-4 atoms, more in particular 3-5
atoms.
[0747] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein R.sup.10e is selected from
the group consisting of OH, C.sub.1-C.sub.6alkyloxy, secondary
C.sub.1-C.sub.6alkyl; in particular OH or 2-propyl. "Secondary
C.sub.1-C.sub.6alkyl" is intended to refer to an alkyl moiety that
is attached via a non-terminal carbon atom, e.g. 2-propyl,
3-pentyl, and the like.
[0748] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein Het has formula (e) wherein
R.sup.10e is selected from the group consisting of OH,
C.sub.1-C.sub.6alkyloxy, secondary C.sub.1-C.sub.6alkyl; in
particular OH or 2-propyl. "Secondary C.sub.1-C.sub.6alkyl" is
intended to refer to an alkyl moiety that is attached via a
non-terminal carbon atom, e.g. 2-propyl, 3-pentyl, and the
like.
[0749] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein R.sup.3e is
C.ident.C--CH.sub.2--R.sup.10e. Herein R.sup.10e preferably is
C.sub.1-C.sub.6alkyloxy, preferably methoxy, or
C.sub.1-C.sub.6alkyl, preferably branched alkyl.
[0750] In an embodiment, the present invention relates to those
compounds of formula (I), or any subgroup thereof as mentioned in
any of the other embodiments, wherein Het has formula (e) wherein
R.sup.3e is C.ident.C--CH.sub.2--R.sup.10e. Herein R.sup.10e
preferably is C.sub.1-C.sub.6alkyloxy, preferably methoxy, or
C.sub.1-C.sub.6alkyl, preferably branched alkyl.
[0751] Interesting compounds of formula (I) are those compounds of
formula (I) wherein one or more of the following restrictions
apply: [0752] a) Het is a heterocycle having formula (b), (d) or
(e); [0753] b) Het is a heterocycle having formula (b), [0754] c)
Het is a heterocycle having formula (c); [0755] d) Het is a
heterocycle having formula (d); [0756] e) Z is N and R.sup.5 is
absent; [0757] f) Z is C and R.sup.5 is halogen; [0758] g) R.sup.4
is selected from the group consisting of Het.sup.1, aryl,
Het.sup.2, and C.sub.3-C.sub.7cycloalkyl substituted with one or
more substituents selected from the group consisting of halo and
C.sub.1-C.sub.4alkyl; [0759] h) R.sup.4 is Het'; [0760] i) R.sup.4
is Het.sup.2; [0761] j) R.sup.4 is aryl; [0762] k) aryl is phenyl
optionally being substituted with one or more substituents each
independently selected from the group consisting of halo,
C.sub.1-C.sub.4alkyloxy, C.sub.1-C.sub.4alkyl, CN,
CONR.sup.8R.sup.9, COOR.sup.8, SO.sub.2R.sup.8,
polyhaloC.sub.1-4alkyloxy or C.sub.1-4alkyloxyC.sub.1-4alkyloxy;
[0763] l) aryl is phenyl optionally being substituted with one or
more substituents each independently selected from the group
consisting of halo, C.sub.1-C.sub.4alkyloxy, C.sub.1-C.sub.4alkyl,
CN, CONR.sup.8R.sup.9, COOR.sup.8, SO.sub.2R.sup.8; [0764] m) aryl
is phenyl substituted with two substituents each independently
selected from the group consisting of halo, C.sub.1-C.sub.4alkyloxy
or C.sub.1-C.sub.4alkyl; [0765] n) Het is a heterocycle having
formula (c-1a) wherein R.sup.3c is H and R.sup.2c is
--(CR.sup.8R.sup.9).sub.m--R.sup.10c wherein R.sup.8 and R.sup.9
are each H, m is 3 and R.sup.10c represents CN or
SO.sub.2CH.sub.3.
General Synthetic Schemes
[0766] The compounds of formula I may be prepared by the methods
described below, using synthetic methods known in the art of
organic chemistry, or modifications and derivatisations that are
familiar to those skilled in the art. The starting materials used
herein are commercially available or may be prepared by routine
methods known in the art such as those methods disclosed in
standard reference books. Preferred methods include, but are not
limited to, those described below.
[0767] During any of the following synthetic sequences it may be
necessary and/or desirable to protect sensitive or reactive groups
on any of the molecules concerned. This can be achieved by means of
conventional protecting groups, such as those described in T. W.
Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry,
John Wiley & Sons, 1999, which are hereby incorporated by
reference.
[0768] Compounds of formula I, or their pharmaceutically acceptable
salts, can be prepared according to the reaction schemes discussed
herein below. Unless otherwise indicated, the substituent in the
schemes are defined as above. Isolation and purification of the
products is accomplished by standard procedures, which are known to
a chemist of ordinary skill.
[0769] Scheme 1 illustrates a method for the preparation of
compounds of formula (I), wherein Het is a heterocycle of formula
(b), hereby named a compound of formula I-b where R.sup.1b,
R.sup.2b, R.sup.4, R.sup.5 and Z are defined as above.
[0770] Referring to scheme 1, a compound of formula I-b can be
synthesized by coupling 2-hydroxymethylene imidazopyridines of
formula II-a with a N.sup.3-substituted 2-oxo-imidazopyridine or
with a N.sup.3-substituted 2-oxo-imidazobenzene of formula III in a
known in the art method such as a Mitsunobu reaction which uses
azadiisopropyldicarboxylate and triphenyl phosphine in a suitable
solvent such as DMF (N,N-dimethylformamide) or THF
(tetrahydrofuran). Alternatively, a compound of formula I-b may be
prepared by displacement of Q, which is a halide, preferably
chlorine II-b, or a sulfonate such as mesylate II-c in the presence
of a base such as sodium hydride, potassium carbonate or cesium
carbonate in a suitable solvent such as DMF or THF.
##STR00009##
Preparation of Intermediates II-b and II-c
[0771] Treatment of the alcohol II-a with thionyl chloride provides
2-chloromethyl imidazopyridines II-b. Alternatively, alcohol II-a
may be transformed to the intermediate II-c by a reaction with
methane sulfonyl chloride in the presence of an organic base such
as triethyl amine or diisopropyl ethyl amine in a suitable solvent
such as dichloromethane (scheme 2).
##STR00010##
Preparation of Intermediate II-a
[0772] Intermediates of formula II-a are either commercially
available or can be prepared, but not limited to, by general
procedures illustrated by scheme 3, wherein R.sup.1b, R.sup.2b, X
are defined as above. Referring to scheme 3 below, haloheteroaryls
IV-b, where W is an halide preferably fluorine, can be treated with
primary amines of formula V-b in the presence of a suitable base
such as potassium carbonate and the like, in a suitable solvent
such as ethanol or dichloromethane at a reaction temperature
ranging from room temperature to 100.degree. C. to give
intermediates of formula VI-b. Hydrogenation of the nitro group
using well-precedented conditions such as Pd/C, or other catalyst,
under hydrogen or Fe/EtOH/CaCl.sub.2 can yield diamine of formula
VII-b. Alternatively, the hydrogenation of the nitro group of
intermediate VIII-b using well-precedented conditions such as Pd/C,
or other catalyst, under hydrogen or Fe/EtOH/CaCl.sub.2 yield
diamine of formula IX-b which can be treated with the aldehydes of
formula X-b in the presence of suitable reducing agents such as
NaBH(OAc).sub.3 (sodium triacetoxyborohydride), or Na(CN)BH.sub.3
in solvents such as methylene chloride, DMF or THF, at about room
temperature gives compounds of formula VII-b. The imidazole ring
can be formed by treating diamines VII-b with glycolic acid or an
ester like XIII-b under strong acidic conditions, such as aqueous
hydrochloric acid, at elevated temperature such as reflux to yield
the alcohols of formula II-a. Alternatively, diamines VII-b can be
condensed with dialkoxyacetate of formula XII-b, in the presence of
acetic acid, in a suitable solvent such as methanol gives the
acetal II-e. The acetal of compounds II-e can be removed with acids
such as hydrochloric acid to give the aldehydes of formula II-f.
The resulting aldehydes of formula II-f can be reduced to alcohols
using a suitable reducing agent such as NaBH.sub.4 or LiA1H.sub.4
in a suitable solvent such as ethanol or THF to yield the desired
alcohols of formula II-a. In addition, diamines VII-b can be
cyclize with dialkyl oxalate of formula XI-b in a suitable solvent
such as ethanol at elevated temperature with or without microwave
heating to produce imidazoles of formula II-d. Alternatively,
intermediates of formula II-d may be prepared in two steps
synthesis starting from diamines VII-b. Firstly diamine VII-b may
be reacted with an alkyl trihaloacetimidate, preferably methyl
2,2,2-trichloro-acetimidate, in an acidic media, preferably acetic
acid, at a temperature ranging between 25 and 50.degree. C. to
yield compound of formula II-g. Secondly a reaction of compounds of
formula II-g with metalcarbonate, preferably sodium carbonate in a
suitable solvent such as methanol, lead to intermediates of formula
II-d. Intermediates of formula II-d may subsequently be reduced to
the desired alcohols of formula II-a using a suitable reducing
agent such as NaBH.sub.4 or LiA1H.sub.4 in a suitable solvent such
as ethanol or THF.
##STR00011##
[0773] An alternative route for the preparation of intermediates of
type II-a is depicted in scheme 4. Diamine IX-b may be first
coupled to an alkyl glycolic acid or an ester like XIII-b under
strong acidic conditions, such as aqueous hydrochloric acid, at
elevated temperature such as reflux to yield the alcohols of
formula XIV-b. This alcohol may be protected by a PG, where PG is a
protecting group such as, but not limiting to, a trityl which
consequently results in intermediates of formula XV-b. A suitable
solvent for this type of reactions can be, but not limiting to,
dichloromethane. The treatment of intermediate XV-b with
intermediate XVI-b, wherein the LG is a leaving group, such as
halide, preferably bromine, or sulfonate, in the presence of a base
such as sodium hydride, potassium carbonate or cesium carbonate in
a suitable solvent such as DMF or THF, gives intermediate II-h. The
removal of the PG in intermediate II-h may be done in the presence
of an acid such as hydrochloric acid in the presence of a solvent,
not limited to, such as dioxane to yield an intermediate of formula
II-a.
##STR00012##
[0774] The Synthesis of a 2-oxo-imidazopyridine and a
2-oxo-imidazobenzene of formula III is shown in scheme 5.
Intermediates of formula III can be synthesized using the procedure
depicted in scheme 5. Displacement of W, which is a halide,
preferably fluorine, or an alkoxy group, preferably methoxy, of
nitro pyridine or of nitro aryl XVII with an amine, in a suitable
solvent such as THF or DMF, in the presence of an organic base such
as triethyl amine or diisopropyl ethyl amine, gives an intermediate
of formula XVIII. Reduction of the nitro group to the amine XIX can
be done in a catalytic way using hydrogen in the presence of a
catalyst such as palladium or platinum, in a suitable solvent such
as methanol, or in a stoichiometric way using iron in the presence
of ammonium chloride or tin chloride in the presence of
concentrated hydrochloric acid. The cyclisation of the resulting
diamine XIX using 1,1'-carbonyldiimidazole (CDI), phosgene or
triphosgene, in a solvent such as acetonitrile or THF, provides a
N.sup.3-substituted 2-oxo-imidazopyridine or a N.sup.3-substituted
2-oxo-imidazobenzene derivative of formula III. Alternatively, an
intermediate of type III may be prepared starting from commercially
available dianilines XX which can be cyclized by ring closure with
CDI, phosgene or triphosgene yields intermediates of type XXI.
Introduction of a R.sup.4 substituent (other than H) on an
intermediate of formula XXI can be accomplished by a Mitsunobu
reaction with commercially available alcohols, or by displacement
of the LG in the intermediates of formula XXII, where LG is a
leaving group such as halide, preferably bromine, or sulfonate, in
the presence of a base such as sodium hydride, potassium carbonate
or cesium carbonate in a suitable solvent such as DMF or THF. This
will finally yield intermediates of formula III.
##STR00013##
[0775] Scheme 6 illustrates a method for the preparation of
compounds of formula (I), wherein Het is a heterocycle of formula
(c), hereby named a compound of formula I-c, where R.sup.1c,
R.sup.2c, R.sup.3c, R.sup.4, R.sup.5 and Z are defined as
above.
[0776] Referring to scheme 6, a compound of formula I-c can be
synthesized by coupling a 2-hydroxymethylene indole of formula II-i
with a N.sup.3-substituted 2-oxo-imidazopyridine or with a
N.sup.3-substituted 2-oxo-imidazobenzene of formula III with a
method known in the art method such as a Mitsunobu reaction which
uses azadiisopropyldicarboxylate and triphenyl phosphine in a
suitable solvent such as DMF or THF. Alternatively, a compound of
formula I-c may be prepared by displacement of Y, which is a
halide, preferably chlorine II-j, or a sulfonate such as mesylate
II-k in the presence of a base such as sodium hydride, potassium
carbonate or cesium carbonate in a suitable solvent such as DMF or
THF.
##STR00014##
Preparation of Compound II-i
[0777] Starting materials IV-c used in this invention are
commercially available, or can be synthesized, but not limited to,
by methods known in the art such as Reissert synthesis or Fischer
synthesis. Reaction of such indoles with R.sup.2c-LG, where LG is a
leaving group such as halide, preferably bromine, or sulfonate, in
the presence of a base such as sodium hydride, potassium carbonate
or cesium carbonate in a suitable solvent such as DMF or THF, gives
intermediates V-c (scheme 7). The conversion of the alkyl ester of
an intermediate of formula V-c to the alcohol II-i may be carried
out with metal hydride such as lithium aluminum hydride or sodium
borohydride in a suitable solvent such as THF, methanol or
ethanol.
[0778] Alternatively, starting materials VI-c can be synthesized,
but not limited to, by methods known in the art such as Reissert
synthesis or Fischer synthesis. Reaction of such indoles with
R.sup.2c-LG, where LG is a leaving group such as halide, preferably
bromine, or sulfonate, in the presence of a base such as sodium
hydride, potassium carbonate or cesium carbonate in a suitable
solvent such as DMF or THF, gives intermediates of formula VII-c.
The oxidation of the methyl with selenium oxide or manganese
dioxide in a suitable solvent such as dichloromethane or heptane
leads to the aldehyde VIII-c. The conversion of the aldehyde VIII-c
to the alcohol II-i may be carried out with metal hydride such as
lithium aluminum hydride or sodium borohydride in a suitable
solvent such as THF, methanol or ethanol.
##STR00015##
[0779] Treatment of the alcohol II-i with thionyl chloride provides
2-chloromethyl indole II-j. Alternatively, alcohol II-i may be
transformed to the intermediate II-k by a reaction with methane
sulfonyl chloride in the presence of an organic base such as
triethyl amine or diisopropyl ethyl amine in a suitable solvent
such dichloromethane (scheme 8).
##STR00016##
##STR00017##
[0780] Scheme 9 illustrates a method for the preparation of
compounds of formula I-d, where R.sup.1d, R.sup.2d, R.sup.3d,
R.sup.4, R.sup.5 and Z are defined as above.
[0781] A compound of formula I-d can be synthesized by coupling
2-hydroxymethylene indole II-l with a benzimidazolone III in a
known in the art method such as Mitsunobu reaction which uses
azadiisopropyldicarboxylate (DIAD) and triphenylphosphine in a
suitable solvent such as DMF or THF. Alternatively, compounds of
formula I-d may be prepared by displacement of Q, which is a
halide, preferably chlorine II-m, or sulfonate such as mesylate
II-n in the presence of a base such as, but not limiting to, sodium
hydride, potassium carbonate or cesium carbonate in a suitable
solvent such as DMF or THF.
##STR00018##
[0782] An intermediate of formula II-l is prepared according to the
methods as depicted in scheme 10.
[0783] Starting materials IV-d used in this invention, according to
method 1, are commercially available, or can be synthesized, but
not limited to, by methods known in the art such as Reissert
synthesis or Fischer synthesis. Reaction of such an intermediate
with R.sup.2d-LG, where LG is a leaving group such as halide,
preferably bromine, or sulfonate, in the presence of a base such as
sodium hydride, potassium carbonate or cesium carbonate in a
suitable solvent such as DMF or THF, gives an intermediate of
formula V-d. The conversion of the alkyl ester of intermediate V-d
to the alcohol II-l can be done with a metal hydride such as
lithium aluminum hydride or sodium borohydride in a suitable
solvent such as THF or methanol.
[0784] Alternatively a II-l type intermediate can also be
synthesized as shown in scheme 10, method 2. The commercially
available starting material VI-d is protected by a PG, where PG is
a protecting group such as, but not limiting to, a tosyl, which
consequently results in an intermediate of formula VII-d. A
suitable solvent for this kind of reactions can be, but not
limiting to, toluene. The metallation of intermediate VII-d
followed by treatment with compound carbon dioxide, in a suitable
solvent such as, but not limited to, THF, yields intermediate IX-d.
The esterification of acid in the intermediate IX-d can be
performed with alcohols such methanol or ethanol in acidic
conditions to yield intermediate X-d. The removal of the PG in
intermediate X-d may be done in the presence of a base such as
potassium carbonate or cesium carbonate in a suitable solvent such
as THF and methanol to obtain indole XI-d. Reaction of indoles XI-d
with R.sup.2d-LG, where LG is a leaving group such as a halide,
preferably bromine, or sulfonate, in the presence of a base such as
sodium hydride, potassium carbonate or cesium carbonate in a
suitable solvent such as DMF or THF, gives intermediate XII-d. The
conversion of the alkyl ester of intermediate XII-d to the alcohol
II-l can be carried out with a metal hydride such as lithium
aluminium hydride or sodium borohydride in a suitable solvent such
as THF or ethanol.
##STR00019##
[0785] Treatment of the alcohol II-l with reagents like, but not
limiting to, SOCl.sub.2, PBr.sub.3, p-TsCl (4-toluenesulfonyl
chloride) or MsCl (methanesulfonyl chloride), provides
2-chloromethyl indole derivatives II-m or intermediates like
II-n.
##STR00020##
[0786] Scheme 12 illustrates a method for the preparation of
compounds of formula I-e, where R.sup.1e, R.sup.3e, R.sup.4,
R.sup.5, R.sup.10e, Q, Y and Z are defined as above.
[0787] A IV-e type compound can be made by coupling
2-hydroxymethylene imidazopyridine II-o with a N.sup.3-substituted
benzimidazolone III in a known in the art method such as Mitsunobu
reaction which use the azadiisopropyldicarboxylate and
triphenylphosphine in a suitable solvent such as, but not limiting
to, DMF or THF. Alternatively, compounds of formula I-e may be
prepared by displacement of Q, which is a halide, II-p, preferably
chlorine, or sulfonate, II-q, such as mesylate or tosylate, in the
presence of base such as, but not limiting to, sodium hydride,
potassium carbonate or cesium carbonate in a suitable solvent such
as DMF or THF. Halogenating reagents such as, but not limited to,
N-iodosuccinimide can be used to convert a IV-e type intermediate
to a V-e type intermediate and CH.sub.3CN can be a suitable solvent
for this reaction. By coupling an alkyn to a V-e type intermediate
in a known in the art method such as Sonogashira-type coupling
reaction, a VI-e type intermediate can be generated. Reduction of
the triple bond can be done in a catalytic way using hydrogen in
the presence of the catalyst such as palladium or platinum, in a
suitable solvent such as methanol, or in a stoichiometric way using
iron in the presence of ammoniumchloride or tin chloride in the
presence of concentrated hydrochloric acid to yield a compound of
formula I-e.
##STR00021##
[0788] The synthesis of II-o type intermediates can generally be
prepared as depicted in scheme 13. A IX-e type intermediate can be
synthesized by coupling a commercially available VII-e type
intermediate with a commercially available VIII-e type
intermediate, of which the halogen is preferably bromine, through a
base mediated coupling reaction. Possible bases to effect this
reaction, but not limiting to, are K.sub.2CO.sub.3,
Cs.sub.2CO.sub.3, triethylamine and sodium hydride. A suitable
solvent for this type of base mediated coupling is DME
(1,2-dimethoxyethane). After an intra molecular ring closure by
thermal heating, an intermediate of formula X-e can be generated.
The conversion of the alkyl ester of intermediate X-e to the
alcohol II-o was carried out with metal hydride such as lithium
aluminium hydride or sodium borohydride in a suitable solvent such
as THF or methanol.
##STR00022##
[0789] Scheme 14 shows the possibilities to synthesize II-p and
II-q type intermediates. Treatment of the alcohol II-o with
reagents like, but not limiting to, SOCl.sub.2, PBr.sub.3, p-TsCl
(4-toluenesulfonyl chloride), MsCl (methane sulfonyl chloride)
provides 2-chloromethyl indole II-p and to the intermediate II-q in
the presence of an organic base, such as triethylamine or
diisopropylethylamine in a suitable solvent such as
dichloromethane. This is illustrated by method 1.
[0790] Alternatively a II-p type compound can also be generated
through an inter molecular ring closure between a commercially
available XI-e type compound and an also commercially available
XII-e type compound. A suitable solvent for this reaction can be
ethanol. This is illustrated by method 2.
[0791] Pure stereochemically isomeric forms of the compounds of
formula (I) may be obtained by the application of art-known
procedures. Diastereomers may be separated by physical methods such
as selective crystallization and chromatographic techniques, e.g.,
counter-current distribution, liquid chromatography and the
like.
[0792] The compounds of formula (I) as prepared in the hereinabove
described processes are generally racemic mixtures of enantiomers
which can be separated from one another following art-known
resolution procedures. The racemic compounds of formula (I) which
are sufficiently basic or acidic may be converted into the
corresponding diastereomeric salt forms by reaction with a suitable
chiral acid, respectively chiral base. Said diastereomeric salt
forms are subsequently separated, for example, by selective or
fractional crystallization and the enantiomers are liberated
therefrom by alkali or acid. An alternative manner of separating
the enantiomeric forms of the compounds of formula (I) involves
liquid chromatography, in particular liquid chromatography using a
chiral stationary phase. Said pure stereochemically isomeric forms
may also be derived from the corresponding pure stereochemically
isomeric forms of the appropriate starting materials, provided that
the reaction occurs stereospecifically. Preferably if a specific
stereoisomer is desired, said compound will be synthesized by
stereospecific methods of preparation. These methods will
advantageously employ enantiomeric ally pure starting
materials.
[0793] In a further aspect, the present invention concerns a
pharmaceutical composition comprising a therapeutically effective
amount of a compound of formula (I) as specified herein, or a
compound of any of the embodiments of compounds of formula (I) as
specified herein, and a pharmaceutically acceptable carrier. A
therapeutically effective amount in this context is an amount
sufficient to prophylaxictically act against, to stabilize or to
reduce viral infection, and in particular RSV viral infection, in
infected subjects or subjects being at risk of being infected. In
still a further aspect, this invention relates to a process of
preparing a pharmaceutical composition as specified herein, which
comprises intimately mixing a pharmaceutically acceptable carrier
with a therapeutically effective amount of a compound of formula
(I), as specified herein, or of a compound of any of the
embodiments of compounds of formula (I) as specified herein.
[0794] Therefore, the compounds of the present invention or any
embodiment thereof may be formulated into various pharmaceutical
forms for administration purposes. As appropriate compositions
there may be cited all compositions usually employed for
systemically administering drugs. To prepare the pharmaceutical
compositions of this invention, an effective amount of the
particular compound, optionally in addition salt form, as the
active ingredient is combined in intimate admixture with a
pharmaceutically acceptable carrier, which carrier may take a wide
variety of forms depending on the form of preparation desired for
administration. These pharmaceutical compositions are desirable in
unitary dosage form suitable, particularly, for administration
orally, rectally, percutaneously, or by parenteral injection. For
example, in preparing the compositions in oral dosage form, any of
the usual pharmaceutical media may be employed such as, for
example, water, glycols, oils, alcohols and the like in the case of
oral liquid preparations such as suspensions, syrups, elixirs,
emulsions and solutions; or solid carriers such as starches,
sugars, kaolin, lubricants, binders, disintegrating agents and the
like in the case of powders, pills, capsules, and tablets. Because
of their ease in administration, tablets and capsules represent the
most advantageous oral dosage unit forms, in which case solid
pharmaceutical carriers are obviously employed. For parenteral
compositions, the carrier will usually comprise sterile water, at
least in large part, though other ingredients, for example, to aid
solubility, may be included. Injectable solutions, for example, may
be prepared in which the carrier comprises saline solution, glucose
solution or a mixture of saline and glucose solution. Injectable
suspensions may also be prepared in which case appropriate liquid
carriers, suspending agents and the like may be employed. Also
included are solid form preparations which are intended to be
converted, shortly before use, to liquid form preparations. In the
compositions suitable for percutaneous administration, the carrier
optionally comprises a penetration enhancing agent and/or a
suitable wetting agent, optionally combined with suitable additives
of any nature in minor proportions, which additives do not
introduce a significant deleterious effect on the skin.
[0795] The compounds of the present invention may also be
administered via oral inhalation or insufflation by means of
methods and formulations employed in the art for administration via
this way. Thus, in general the compounds of the present invention
may be administered to the lungs in the form of a solution, a
suspension or a dry powder, a solution being preferred. Any system
developed for the delivery of solutions, suspensions or dry powders
via oral inhalation or insufflation are suitable for the
administration of the present compounds.
[0796] Thus, the present invention also provides a pharmaceutical
composition adapted for administration by inhalation or
insufflation through the mouth comprising a compound of formula (I)
and a pharmaceutically acceptable carrier. Preferably, the
compounds of the present invention are administered via inhalation
of a solution in nebulized or aerosolized doses.
[0797] It is especially advantageous to formulate the
aforementioned pharmaceutical compositions in unit dosage form for
ease of administration and uniformity of dosage. Unit dosage form
as used herein refers to physically discrete units suitable as
unitary dosages, each unit containing a predetermined quantity of
active ingredient calculated to produce the desired therapeutic
effect in association with the required pharmaceutical carrier.
Examples of such unit dosage forms are tablets (including scored or
coated tablets), capsules, pills, suppositories, powder packets,
wafers, injectable solutions or suspensions and the like, and
segregated multiples thereof.
[0798] The compounds of formula (I) show antiviral properties.
Viral infections treatable using the compounds and methods of the
present invention include those infections brought on by ortho- and
paramyxoviruses and in particular by human and bovine respiratory
syncytial virus (RSV). A number of the compounds of this invention
moreover are active against mutated strains of RSV. Additionally,
many of the compounds of this invention show a favorable
pharmacokinetic profile and have attractive properties in terms of
bioavailabilty, including an acceptable half-life, AUC and peak
values and lacking unfavourable phenomena such as insufficient
quick onset and tissue retention.
[0799] The in vitro antiviral activity against RSV of the present
compounds was tested in a test as described in the experimental
part of the description, and may also be demonstrated in a virus
yield reduction assay. The in vivo antiviral activity against RSV
of the present compounds may be demonstrated in a test model using
cotton rats as described in Wyde et al. (Antiviral Research (1998),
38, 31-42).
[0800] Due to their antiviral properties, particularly their
anti-RSV properties, the compounds of formula (I) or any embodiment
thereof, and stereoisomeric forms thereof, and the pharmaceutically
acceptable addition salts, and the solvates thereof, are useful in
the treatment of individuals experiencing a viral infection,
particularly a RSV infection, and for the prophylaxis of these
infections. In general, the compounds of the present invention may
be useful in the treatment of warm-blooded animals infected with
viruses, in particular the respiratory syncytial virus.
[0801] The compounds of the present invention or any embodiment
thereof may therefore be used as medicines. Said use as a medicine
or method of treatment comprises the systemic administration to
viral infected subjects or to subjects susceptible to viral
infections of an amount effective to combat the conditions
associated with the viral infection, in particular the RSV
infection.
[0802] The present invention also relates to the use of the present
compounds or any embodiment thereof in the manufacture of a
medicament for the treatment or the prevention of viral infections,
particularly RSV infection.
[0803] The present invention furthermore relates to a method of
treating a warm-blooded animal infected by a virus, or being at
risk of infection by a virus, in particular by RSV, said method
comprising the administration of an anti-virally effective amount
of a compound of formula (I), as specified herein, or of a compound
of any of the embodiments of compounds of formula (I), as specified
herein.
[0804] In general it is contemplated that an antivirally effective
daily amount would be from 0.01 mg/kg to 500 mg/kg body weight,
more preferably from 0.1 mg/kg to 50 mg/kg body weight. It may be
appropriate to administer the required dose as two, three, four or
more sub-doses at appropriate intervals throughout the day. Said
sub-doses may be formulated as unit dosage forms, for example,
containing 1 to 1000 mg, and in particular 5 to 200 mg of active
ingredient per unit dosage form.
[0805] The exact dosage and frequency of administration depends on
the particular compound of formula (I) used, the particular
condition being treated, the severity of the condition being
treated, the age, weight, sex, extent of disorder and general
physical condition of the particular patient as well as other
medication the individual may be taking, as is well known to those
skilled in the art. Furthermore, it is evident that said effective
daily amount may be lowered or increased depending on the response
of the treated subject and/or depending on the evaluation of the
physician prescribing the compounds of the instant invention. The
effective daily amount ranges mentioned hereinabove are therefore
only guidelines.
[0806] Also, the combination of another antiviral agent and a
compound of formula (I) can be used as a medicine. Thus, the
present invention also relates to a product containing (a) a
compound of formula (I), and (b) another antiviral compound, as a
combined preparation for simultaneous, separate or sequential use
in antiviral treatment. The different drugs may be combined in a
single preparation together with pharmaceutically acceptable
carriers. For instance, the compounds of the present invention may
be combined with interferon-beta or tumor necrosis factor-alpha in
order to treat or prevent RSV infections.
[0807] The invention will hereinafter be illustrated with reference
to the following, non-limiting examples.
Experimental Part
[0808] Hereinafter, the term `eq.` means equivalent, `THF` means
tetrahydrofuran, `Psi` means pound-force per square inch, `DMF`
means N,N-dimethylformamide, `DMSO` means dimethyl sulfoxide,
`DIEA` means diisopropylethylamine, `DIAD` means diisopropyl
azodicarboxylate, `HOAc` or `AcOH` means acetic acid, `RP` means
reversed phase, `EtOAc` means ethyl acetate,
`Pd(dppf)Cl.sub.2CH.sub.2Cl.sub.2` means
[1,1'-bis(diphenylphosphino)ferrocene]palladium chloride complex
with dichloromethane, `TPP` means triphenylphosphine, `m-cPBA`
means 3-chlorobenzene-carboperoxoic acid, `Cu(OAc).sub.2` means
copper(II) acetate, `EtOH` means ethanol, `MeOH` means methanol,
`MeCN` means methyl cyanide, `CDT` means 1,1'-carbonyldiimidazole,
`KOEt` means potassium ethoxide, and `FIPLC` means High Performance
Liquid Chromatography.
LCMS (Liquid Chromatography/Mass Spectrometry)
[0809] LCMS was done using either of the following methods:
General Method A
[0810] The LC measurement was performed using an Acquity UPLC
(Waters) ('UPLC' means Ultra Performance Liquid Chromatography)
system comprising a binary pump, a sample organizer, a column
heater (set at 55.degree. C.), a diode-array detector (DAD) and a
column as specified in the respective methods below. Flow from the
column was split to a MS spectrometer. The MS detector was
configured with an electrospray ionization source. Mass spectra
were acquired by scanning from 100 to 1000 in 0.18 seconds using a
dwell time of 0.02 seconds. The capillary needle voltage was 3.5 kV
and the source temperature was maintained at 140.degree. C.
Nitrogen was used as the nebulizer gas. Data acquisition was
performed with a Waters-Micromass MassLynx-Openlynx data
system.
General Method B
[0811] The LC measurement was performed using an Acquity UPLC
(Waters) system comprising a binary pump, a sample organizer, a
column heater (set at 55.degree. C.), a diode-array detector (DAD)
and a column as specified in the respective methods below. All the
flow from the column went to a MS spectrometer. The MS detector was
configured with an electrospray ionization source. Mass spectra
were acquired by scanning from 120 to 1000 in 0.1 seconds. The
capillary needle voltage was 3.0 kV and the source temperature was
maintained at 150.degree. C. Nitrogen was used as the nebulizer
gas. Data acquisition was performed with a Waters-Micromass
MassLynx-Openlynx data system.
Method 1
[0812] In addition to the general method A: Reversed phase UPLC was
carried out on a bridged ethylsiloxane/silica hybrid (BEH) C18
column (1.7 .mu.m, 2.1.times.50 mm; Waters Acquity) with a flow
rate of 0.8 ml/min. Two mobile phases (10 mM ammonium acetate in
H.sub.2O/acetonitrile 95/5; mobile phase B: acetonitrile) were used
to run a gradient condition from 95% A and 5% B to 5% A and 95% B
in 1.3 minutes and hold for 0.3 minutes. An injection volume of 0.5
.mu.l was used. Cone voltage was 10 V for positive ionization mode
and 20 V for negative ionization mode.
Method 2
[0813] In addition to the general method B: Reversed phase UPLC
(Ultra Performance Liquid Chromatography) was carried out on a
Acquity UPLC HSS T3 column (1.8 .mu.m, 2.1.times.100 mm; Waters
Acquity) with a flow rate of 0.8 ml/min. Two mobile phases (A: 10
mM ammonium acetate in H.sub.2O/acetonitrile 95/5; mobile phase B:
acetonitrile) were used to run a gradient condition from 95% A and
5% B to 0% A and 100% B in 2.5 minutes and subsequently to 5% A and
95% B in 0.5 minutes. An injection volume of 1 .mu.l was used. Cone
voltage was 30 V for positive ionization mode and 30 V for negative
ionization mode.
NMR
[0814] For a number of compounds, .sup.1H NMR spectra were recorded
on a Bruker DPX-400 spectrometer operating at 400 MHz or on a
Bruker DPX-360 operating at 360 MHz using CHLOROFORM-d (deuterated
chloroform, CDCl.sub.3) or DMSO-d.sub.6 (deuterated DMSO,
dimethyl-d6 sulfoxide) as solvent. Chemical shifts (6) are reported
in parts per million (ppm) relative to tetramethylsilane (TMS),
which was used as internal standard.
Melting Points
[0815] For a number of compounds, melting points (m.p.) were
determined with a DSC823e (Mettler-Toledo). Melting points were
measured with a temperature gradient of 30.degree. C./minute.
Maximum temperature was 400.degree. C. Values are peak values.
Synthesis of Intermediates
[0816] All the intermediates needed for the synthesis of targeted
compounds of formula (I) are synthesized as described in the
following schemes 15 to 22.
##STR00023##
Step 1: Synthesis of tert-butyl
3-(2-nitrophenylamino)azetidine-1-carboxylate 15-d
[0817] To a mixture of 2-fluoro-2-nitrobenzene, 15-a (17.278 g,
122.45 mmol, 1 eq.), triethylamine (24.782 g, 244.91 mmol, 2.0 eq.)
in ethanol (170 mL) at 0.degree. C. tert-butyl
3-aminoazetidine-1-carboxylate (23.2 g, 134.708 mmol, 1.1 eq.) was
added dropwise. The resulting mixture was refluxed overnight. The
mixture was cooled to room temperature and filtrated. The cake was
washed with cooled ethanol and dried under vacuum. 22 g of
intermediate 15-b was obtained (61.5% yield).
Step 2: Synthesis of tert-butyl
3-(2-aminophenylamino)azetidine-1-carboxylate 15-c
[0818] Intermediate 15-b (21.0 g, 71.595 mmol, 1 eq.) in methanol
(70 mL), THF (70 mL) and ethyl acetate (70 mL) was hydrogenated (50
Psi) at 50.degree. C. with Pt/C (2.1 g) as a catalyst for 12 hours.
After uptake of H.sub.2 (3 eq.), the catalyst was filtered off and
the filtrate was evaporated to give intermediate 15-c (18 g, Yield
95.5%).
Step 3: Synthesis of
1-cyclopropyl-7-methyl-1H-benzo[d]imidazol-2(3H)-one 15-d
[0819] Carbonyldiimidazole (15.517 g, 95.696 mmol, 1.05 eq.) was
added to a solution of intermediate 15-c (24.0 g, 91.139 mmol, 1.0
eq.) in CH.sub.3CN (240 mL) at 0.degree. C. The reaction mixture
was allowed to warm to 25.degree. C. and stirred for 1 h. The solid
was collected by filtration and was washed with CH.sub.3CN (70 mL)
to afford the title intermediate 15-d as a white powder (19.35 g,
74%).
##STR00024##
[0820] Intermediate 16-d was prepared by an analogous reaction
protocol as intermediate 15-d using 1,4-difluoro-2-nitrobenzene
16-a as starting material.
##STR00025##
[0821] Intermediate 17-d was prepared by following an analogous
reaction protocol as described for intermediate 15-d using
4-chloro-3-nitropyridine 17-a as starting material.
##STR00026##
[0822] Intermediate 18-c was prepared by following an analogous
reaction protocol as described for intermediate 15-d using
4-chloro-3-nitropyridine 17-a and 1-methyl-cyclopropylamine as
starting material.
##STR00027##
[0823] Intermediate 19-c was prepared by following an analogous
reaction protocol as described for intermediate 15-d using
4-chloro-3-nitropyridine 17-a and 2-methyl-propane-2-amine as
starting material.
##STR00028##
[0824] Intermediate 20-c was prepared by following an analogous
reaction protocol as described for intermediate 15-d using
4-chloro-3-nitropyridine 17-a and quinolin-6-amine as starting
material.
##STR00029##
[0825] Intermediate 21-c was prepared by following an analogous
reaction protocol as described for intermediate 15-d using
4-chloro-3-nitropyridine 17-a and thiazol-2-amine as starting
material.
##STR00030##
[0826] Intermediate 22-c was prepared by following an analogous
reaction protocol as described for intermediate 15-d using
4-chloro-3-nitropyridine 17-a and 4-methoxyaniline as starting
material.
##STR00031##
Step 1: Synthesis of 3-(methylsulfonyl)propan-1-ol 23-b
[0827] The alcohol 23-a (200 g, 1900 mmol) was dissolved in
CH.sub.2Cl.sub.2 (2000 ml). The mixture was cooled to 0.degree. C.
The m-CPBA 85% in water (970 g, 5700 mmol) was added portion wise
keeping the temperature between 0 to 5.degree. C. After addition,
the mixture was allowed to warm to 25.degree. C. and stirred for 15
h. The mixture was filtered through a celite pad. The filtrate was
purified by flash column (Eluent: petroleum ether:ethyl acetate=3:1
and then ethyl acetate: methanol=10:1) to yield the intermediate
23-b (75 g, 29%).
Step 2: Synthesis of 1-bromo-3-(methylsulfonyl)propane 23-c
[0828] The intermediate 23-b (75 g, 543 mmol) was dissolved in
CH.sub.2Cl.sub.2 (750 ml). The mixture was cooled to 0.degree. C.
The phosphorus tribromide (53.6 ml, 570 mmol) was added drop wise
keeping the temperature between 0 to 5.degree. C. After addition,
the mixture was allowed to warm to 25.degree. C. and stirred for 15
h. The mixture was poured into ice-water. The separated organic
layer was washed with brine (2.times.1500 mL), dried over
Na.sub.2SO.sub.4, filtered and evaporated under vacuum to yield the
title intermediate 23-c (77 g, 71%).
[0829] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 2.25-2.40
(m, 2H) 2.91 (s, 3H) 3.1-3.2 (m, 2H) 3.5-3.6 (m, 2H).
##STR00032##
Step 1: Synthesis of ethyl
5-chloro-1-(3-(methylsulfonyl)propyl)-1H-indole-2-carboxylate
24-b
[0830] Ethyl 5-bromo-1H-indole-2-carboxylate 24-a (2.3 g, 8.6 mmol)
was dissolved in DMF (50 mL). The mixture was stirred at room
temperature, then sodium hydride 60% suspension in mineral oil
(0.52 g, 12.8 mmol) was added. The resulting mixture was stirred at
room temperature for 1 hour, then 1-bromo-3-(methylsulfonyl)propane
23-c (2.6 g, 12.8 mmol) was added. The resulting mixture was
stirred at room temperature overnight. The mixture was poured in
ice/water solution and extracted with ethyl acetate. The organic
layer was dried over MgSO.sub.4 and concentrated to yield a brown
crude oil. The crude was purified by column chromatography using
dichloromethane/methanol to yield the title compound 24-b (3.2 g,
96%) as a white solid.
[0831] m/z=344 (M+H).sup.+.
Step 2: Synthesis of
(5-chloro-1-(3-(methylsulfonyl)propyl)-1H-indol-2-yl)methanol
24-c
[0832] To a solution of intermediate 24-b (3.2 g, 8.24 mmol) in THF
(100 mL) was added at room temperature lithium aluminum hydride (2
M solution in THF, 5.2 mL, 10.4 mmol). The resulting mixture was
stirred at room temperature overnight. The reaction mixture was
quenched by addition of ethyl acetate and ethanol. The resulting
mixture was poured in ice/water solution then filtered on celite.
The aqueous layer was extracted with ethyl acetate (3.times.50 mL).
The combined organic extracts were washed with brine (100 mL),
dried over MgSO.sub.4, filtered and concentrated under reduced
pressure. The residue was purified by column chromatography using
dichloromethane/methanol as the eluent. The intermediate 24-c was
collected (2.5 g, 88%) as a white solid. m/z=302 (M+H).sup.+.
[0833] The following schemes described the synthesis of
intermediates needed for the synthesis of compounds of formula
I.
##STR00033##
[0834] Intermediate 32-c was prepared by following an analogous
reaction protocol as described for intermediate 15-d using
4-chloro-3-nitropyridine 17-a and 3,4-dimethoxyaniline as starting
material.
##STR00034##
[0835] Intermediate 33-c was prepared by following an analogous
reaction protocol as described for intermediate 15-d using
4-chloro-3-nitropyridine 17-a and 4-methoxy-2-methylaniline as
starting material.
##STR00035##
[0836] Intermediate 34-c was prepared by following an analogous
reaction protocol as described for intermediate 15-d using
4-chloro-3-nitropyridine 17-a and pyridin-4-amine as starting
material.
##STR00036##
[0837] Intermediate 35-c was prepared by following an analogous
reaction protocol as described for intermediate 15-d using
4-chloro-3-nitropyridine 17-a and pyrimidin-4-amine as starting
material.
##STR00037##
[0838] Intermediate 36-c was prepared by following an analogous
reaction protocol as described for intermediate 15-d using
4-chloro-3-nitropyridine 17-a and 3-fluoropyridin-4-amine as
starting material.
##STR00038##
[0839] Intermediate 37-c was prepared by following an analogous
reaction protocol as described for intermediate 16-d using
1,4-difluoro-2-nitrobenzene 16-a and thiazol-2-amine as starting
material.
##STR00039##
[0840] Intermediate 38-c was prepared by following an analogous
reaction protocol as described for intermediate 16-d using
1,4-difluoro-2-nitrobenzene 16-a and pyridin-4-amine as starting
material.
##STR00040##
[0841] Intermediate 39-c was prepared by following an analogous
reaction protocol as described for intermediate 15-d using
4-chloro-3-nitropyridine 17-a and 4-(2-methoxyethoxy)aniline as
starting material.
##STR00041##
[0842] Intermediate 40-c was prepared by following an analogous
reaction protocol as described for intermediate 15-d using
4-chloro-3-nitropyridine 17-a and 4-(trifluoromethoxy)aniline as
starting material.
##STR00042##
[0843] Intermediate 41-c was prepared by following an analogous
reaction protocol as described for intermediate 15-d using
4-chloro-3-nitropyridine 17-a, and 4-chloroaniline as starting
material.
##STR00043##
[0844] Intermediate 42-c was prepared by following an analogous
reaction protocol as described for intermediate 15-d using
4-chloro-3-nitropyridine 17-a, and 1-methyl-1H-imidazol-2-amine as
starting material.
##STR00044##
[0845] Intermediate 43-c was prepared by following an analogous
reaction protocol as described for intermediate 15-d using
4-chloro-3-nitropyridine 17-a, and oxazol-2-amine as starting
material.
##STR00045##
[0846] Intermediate 44-c was prepared by following an analogous
reaction protocol as described for intermediate 15-d using
4-chloro-3-nitropyridine 17-a, and 1-methyl-1H-pyrazol-3-amine as
starting material.
##STR00046##
[0847] Intermediate 45-c was prepared by following an analogous
reaction protocol as described for intermediate 15-d using
4-chloro-3-nitropyridine 17-a, and 3-fluoro-4-methoxyaniline as
starting material.
##STR00047##
[0848] Intermediate 46-c was prepared by following an analogous
reaction protocol as described for intermediate 15-d using
4-chloro-3-nitropyridine 17-a, and 2-fluoro-4-methoxyaniline as
starting material.
##STR00048##
[0849] Intermediate 47-c was prepared by following an analogous
reaction protocol as described for intermediate 15-d using
4-chloro-3-nitropyridine 17-a, and 4-aminobenzonitrile as starting
material.
##STR00049##
Step 1: synthesis of
4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)benzoic acid
48-a
[0850] A solution of
4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)benzonitrile
47-c (5 g, 21.2 mmol) in 50 mL isopropanol and 50 mL KOH solution
(1.5 M in water) was refluxed during 60 minutes. The solution was
poured into an ice bath and neutralized to pH=7. The precipitate
was filtered off and washed with water. Dried in the oven to afford
a white solid (5 g, 93%).
[0851] m/z=256 (M+1).sup.+
[0852] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.17 (d,
J=5.28 Hz, 1H) 7.71 (d, J=8.58 Hz, 2H) 8.12 (d, J=8.58 Hz, 2H) 8.22
(d, J=5.28 Hz, 1H) 8.32 (s, 1H)
Step 2: synthesis of methyl
4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)-benzoate
48-c
[0853] To a solution of
4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)benzoic acid
48-a (3 g, 12 mmol) in 100 mL DCM was added thionyl chloride (9 mL,
120 mmol, 10 eq.) at room temperature and the solution was refluxed
for 16 hours. After concentration to dryness, excess MeOH was added
at room temperature and stirred for 2 hours. The solution was
concentrated in vacuo and crystallized with water/MeOH. The solid
was filtered off and dried to give 3.1 g (98%) of title
intermediate 48-c.
[0854] LCMS m/z=270 (M+H).sup.+
[0855] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 3.89 (s, 3H)
7.06 (d, J=5.06 Hz, 1H) 7.76 (d, J=9.02 Hz, 2H) 8.01 (d, J=4.84 Hz,
1H) 8.10 (d, J=9.02 Hz, 2H) 8.18 (s, 1H)
##STR00050##
Step 1: synthesis of 2-bromo-6-chloropyridin-3-amine 49-a
[0856] Bromine (24.86 g, 155.57 mmol) was added to a solution of
6-chloropyridin-3-amine (20.00 g, 155.57 mmol) and sodium acetate
(25.52 g, 311.14 mmol) in acetic acid (383 ml). The reaction
mixture was stirred at room temperature for 1 hour. Acetic acid was
then evaporated. The residue was dissolved in EtOAc, washed with
saturated aqueous Na.sub.2CO.sub.3, water and brine. The organic
layer was dried over MgSO.sub.4, filtered and evaporated, yielding
32.20 g of the desired product 49-a (99.8%).
[0857] m/z=206.96 (M+1).sup.+
Step 2: synthesis of
5-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid 49-b
[0858] 2-oxopropanoic acid (36.22 g, 411.31 mmol),
palladium(II)acetate (7.74 g, 34.15 mmol) and Et.sub.3N (69.11 g,
682.94 mmol) were added to a solution of
2-bromo-6-chloropyridin-3-amine 49-a (32.20 g, 155.21 mmol) and TPP
(35.83 g, 136.59 mmol) in dry DMF (300 ml). The reaction mixture
was stirred at 100.degree. C. overnight. The solvent was then
evaporated, water was added and the water layer was washed with
EtOAc. The water layer was acidified with conc. HCl. The
precipitate was filtered off and dried, yielding 25.21 g of the
wanted product 49-b (82.6%).
[0859] m/z=197.1 (M+1).sup.+.
Step 3: synthesis of methyl
5-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylate 49-c
[0860] 5-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid 49-b
(25.20 g, 128.18 mmol) was added to a refluxing mixture of sulfuric
acid (20 ml) and methanol (400 ml). The mixture was refluxed
overnight. The mixture was then evaporated and a cold NaHCO.sub.3
solution was added until basic pH. The precipitate was filtered off
and dried, yielding 16.15 g of the desired product (59.8%).
[0861] m/z=211.17 (M+H).sup.+, Cl pattern.
Step 4: synthesis of methyl
5-chloro-1-(4,4,4-trifluorobutyl)-1H-pyrrolo[3,2-b]-pyridine-2-carboxylat-
e 49-d
[0862] To a solution of methyl
5-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylate 49-c (2.9 g, 12.2
mmol) in DMF (50 mL) were added successively cesium carbonate (4 g,
12.2 mmol) and 4-bromo-1,1,1-trifluorobutane (2.3 g, 12.2 mmol).
The resulting mixture was heated at 60.degree. C. overnight. The
reaction mixture was allowed to cool down to room temperature then
poured into iced water and the product was extracted 3 times with
DCM. The combined organic layers were dried over Na.sub.2SO.sub.4,
filtered and evaporated to give the targeted product 49-d as a
yellowish solid. The product was used as such in the next step.
[0863] m/z=320 (M+1).sup.+
Step 5: synthesis of
(5-chloro-1-(4,4,4-trifluorobutyl)-1H-pyrrolo[3,2-b]pyridin-2-yl)-methano-
l 49-e
[0864] To a solution of methyl
5-chloro-1-(4,4,4-trifluorobutyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylate
49-d (3.82 g, 10.8 mmol) in dry THF (100 mL) was added a 1M
solution of lithium aluminumhydride (11.96 mL, 11.96 mmol) at
-75.degree. C. The cooling bath was then removed and the reaction
mixture was kept at room temperature for 3 hours. EtOAc was added,
followed by a saturated NH.sub.4Cl solution. The mixture was
stirred for 30 min. The organic layer was dried over
Na.sub.2SO.sub.4, filtered and evaporated to give a residue, which
was purified by column chromatography to yield the targeted
intermediate as a white powder (2.8 g, 98%).
[0865] m/z=292 (M+1).sup.+
##STR00051##
[0866] Intermediate 50-c was prepared by following an analogous
reaction protocol as described for intermediate 15-d using
4-chloro-3-nitropyridine 17-a, and 4-(methylsulfonyl)aniline as
starting material.
##STR00052##
[0867] Intermediate 51-c was prepared by following an analogous
reaction protocol as described for intermediate 15-d using
4-chloro-3-nitropyridine 17-a, and p-toluidine as starting
material.
##STR00053##
[0868] Intermediate 52-c was prepared by following an analogous
reaction protocol as described for intermediate 15-d using
4-chloro-3-nitropyridine 17-a, and 2,4-dimethoxyaniline as starting
material
##STR00054##
[0869] Intermediate 53-c was prepared by following an analogous
reaction protocol as described for intermediate 15-d using
4-chloro-3-nitropyridine 17-a, and pyrimidin-2-amine as starting
material
Synthesis of Compounds
Example 1
[0870] A detailed description of the synthesis of
tert-butyl-3-(3-((5-chloro-1-(3-(methylsulfonyl)propyl)-1H-indol-2-yl)met-
hyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)azetidine-1-carboxyla-
te (P1), a representative example of the invention is given in
Scheme 25.
##STR00055##
[0871] In a 100 mL dry flask, intermediate 17-d (1.9 g, 6.6 mmol),
triphenylphosphine (2.08 g, 7.9 mmol, 1.2 eq) and intermediate 24-c
(2 g, 6.6 mmol) were dissolved in tetrahydrofuran (THF) (60 mL).
The solution was placed under N.sub.2 atmosphere and
diisopropylazodicarboxylate (DIAD) (1.9 mL, 9.9 mmol) was added via
syringe. The reaction mixture was stirred at room temperature under
nitrogen overnight. The mixture was evaporated to dryness and
purified by preparative HPLC on an RP Vydac Denali C18 column (10
nm, 250 g, 5 cm) using a 0.25% NH.sub.4HCO.sub.3 in
water/CH.sub.3CN solution as the eluent. After evaporation and
drying in vacuo, 963 mg (25%) of a white solid was obtained.
[0872] m/z=574 (M+H).sup.+ (LCMS method 1)
[0873] MP=195.degree. C.
[0874] .sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm 1.43 (s, 9H)
1.87-2.01 (m, 2H) 2.96 (s, 3H) 3.09-3.19 (m, 2H) 4.22-4.44 (m, 6H)
5.21-5.31 (m, 1H) 5.35 (s, 2H) 6.55 (s, 1H) 7.17 (dd, J=8.80, 1.98
Hz, 1H) 7.31 (d, J=5.28 Hz, 1H) 7.52-7.59 (m, 2H) 8.29 (d, J=5.28
Hz, 1H) 8.48 (s, 1H)
Example 2
Synthesis of tert-butyl
3-(3-((5-chloro-1-(3-(methylsulfonyl)propyl)-1H-indol-2-yl)methyl)-5-fluo-
ro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)azetidine-1-carboxylate
(P2)
##STR00056##
[0876] Compound P2 was prepared by following an analogous reaction
protocol as described for compound P1 using intermediate 24-c and
tert-butyl
3-(5-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)azetidine-1-carbox-
ylate 5-d as starting material.
[0877] m/z=591 (M+H).sup.+ (LCMS Method 1)
[0878] MP=185.degree. C.
[0879] .sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm 1.43 (s, 9H)
1.90-2.01 (m, 2H) 2.97 (s, 3H) 3.10-3.18 (m, 2H) 4.23-4.45 (m, 6H)
5.22-5.28 (m, 1H) 5.29 (s, 2H) 6.46 (s, 1H) 6.94-7.02 (m, 1H) 7.16
(dd, J=8.69, 2.09 Hz, 1H) 7.22-7.29 (m, 2H) 7.51-7.58 (m, 2H)
Example 3
Synthesis of
1-(azetidin-3-yl)-3-((5-chloro-1-(3-(methylsulfonyl)propyl)-1H-indol-2-yl-
)methyl)-5-fluoro-1H-benzo[d]imidazol-2(3H)-one (P3)
##STR00057##
[0881] To a solution of compound P2 (800 mg, 1.353 mmol) in
dichloromethane (10 mL) was added trifluoroacetic acid (1.036 ml,
13.534 mmol) at room temperature. The reaction mixture was stirred
for 16 h. The reaction mixture was quenched with some iced water
and the pH was basified with a saturated aqueous NaHCO.sub.3
solution. Then dichloromethane was evaporated and the pink solid in
water was stirred at room temperature for 12 hours then was
filtered off. The solid was washed with water and isopropyl ether
to give 536 mg of the desired compound (P3) as a beige solid
(yield=78%). P3 was obtained as a trifluoroacetate salt form
(0.0.17 CF.sub.3COOH).
[0882] m/z=491 (M+H).sup.+ (LCMS method 1)
[0883] .sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm 1.84-2.06 (m, 2H)
2.96 (s, 3H) 3.08-3.17 (m, 2H) 3.81-3.94 (m, 2H) 3.98-4.06 (m, 2H)
4.40 (t, J=7.59 Hz, 2H) 5.18-5.27 (m, 1H) 5.28 (s, 2H) 6.42 (s, 1H)
6.91-7.00 (m, 1H) 7.15 (dd, J=8.69, 2.09 Hz, 1H) 7.23 (dd, J=9.24,
2.42 Hz, 1H) 7.53 (d, J=8.80 Hz, 1H) 7.56 (d, J=1.98 Hz, 1H) 7.75
(dd, J=8.69, 4.51 Hz, 1H)
Example 4
Synthesis of
1-(azetidin-3-yl)-3-((5-chloro-1-(3-(methylsulfonyl)propyl)-1H-indol-2-yl-
)methyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (P4)
##STR00058##
[0885] Compound P4 was prepared by an analogous reaction protocol
as described for compound P3. P4 was obtained as a trifluoroacetate
salt (CF.sub.3COOH).
[0886] m/z=474 (M+H).sup.+ (LCMS Method 1)
[0887] .sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm 1.92-2.05 (m, 2H)
2.97 (s, 3H) 3.09-3.20 (m, 2H) 4.19-4.31 (m, 2H) 4.40 (t, J=7.70
Hz, 2H) 4.55-4.66 (m, 2H) 5.32-5.46 (m, 3H) 6.56 (s, 1H) 7.17 (dd,
J=9.02, 2.20 Hz, 1H) 7.52 (d, J=5.28 Hz, 1H) 7.54-7.58 (m, 2H) 8.30
(d, J=5.28 Hz, 1H) 8.49 (s, 1H) 8.73 (br. s, 1H)
Example 5
Synthesis of
3-((5-chloro-1-(3-(methylsulfonyl)propyl)-1H-indol-2-yl)methyl)-1-(1-(met-
hylsulfonyl)azetidin-3-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one
(P5)
##STR00059##
[0889] To a solution of P4 (350 mg, 0.6 mmol) in dichloromethane
(20 mL) triethyl amine (0.248 mL, 1.8 mmol) was added. The mixture
was stirred at RT then methanesulfonyl chloride (0.0485 mL, 0.625
mmol) was added at room temperature. The resulting mixture was
stirred at room temperature for 24 hours. A thick white precipitate
was seen in the flask. The reaction mixture was washed with
saturated NaHCO.sub.3. The organic layer was separated, dried on
MgSO.sub.4 and concentrated. The resulting solid was refluxed in
methanol. After cooling down to room temperature the precipitate
was filtered off and dried in vacuum for 2 hours to give compound
P5 (110 mg, 32%) as an off white solid.
[0890] m/z=552 (M+H).sup.+ (LCMS method 1)
[0891] MP=240.degree. C.
[0892] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.87-2.02
(m, 2H), 2.97 (s, 3H), 3.09-3.20 (m, 5H), 4.29 (t, J=8.80 Hz, 2H),
4.39 (t, J=7.59 Hz, 2H), 4.50 (dd, J=8.91, 6.49 Hz, 2H), 5.30-5.40
(m, 3H), 6.56 (s, 1H), 7.17 (dd, J=8.69, 2.09 Hz, 1H), 7.49-7.60
(m, 3H), 8.31 (d, J=5.28 Hz, 1H), 8.48 (s, 1H)
Example 6
Synthesis of
1-(1-acetylazetidin-3-yl)-3-((5-chloro-1-(3-(methylsulfonyl)propyl)-1H-in-
dol-2-yl)methyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (P6)
##STR00060##
[0894] Compound P6 was prepared by an analogous reaction protocol
as described for compound P5 using P4 and acetyl chloride as
starting material.
[0895] m/z=516 (M+H).sup.+ (LCMS method 1)
[0896] MP=252.degree. C.
[0897] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.86 (s,
3H), 1.94 (ddd, J=15.24, 8.03, 7.76 Hz, 2H), 2.97 (s, 3H),
3.11-3.19 (m, 2H), 4.22-4.35 (m, 2H), 4.39 (t, J=7.70 Hz, 2H),
4.50-4.58 (m, 1H), 4.59-4.66 (m, 1H), 5.30 (tt, J=8.39, 5.69 Hz,
1H), 5.35 (s, 2H), 6.56 (s, 1H), 7.17 (dd, J=8.80, 1.98 Hz, 1H),
7.33 (d, J=5.28 Hz, 1H), 7.52-7.59 (m, 2H), 8.29 (d, J=5.28 Hz,
1H), 8.48 (s, 1H)
Example 7
Synthesis of
3-((5-chloro-1-(3-(methylsulfonyl)propyl)-1H-indol-2-yl)methyl)-1-(1-meth-
ylcyclopropyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (P7)
##STR00061##
[0899] Compound P7 was prepared by an analogous reaction protocol
as described for compound P1 using intermediate 24-c and
1-(1-methylcyclopropyl)-1H-imidazo-[4,5-c]pyridin-2(3H)-one 18-c as
starting material.
[0900] m/z=473 (M+H).sup.+ (LCMS method 1)
[0901] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.97-1.02
(m, 2H), 1.06-1.12 (m, 2H), 1.43 (s, 3H), 1.92-2.04 (m, 2H), 2.97
(s, 3H), 3.10-3.18 (m, 2H), 4.39 (t, J=7.5 Hz, 2H), 5.31 (s, 2H),
6.49 (s, 1H), 7.16 (dd, J=8.7, 2.1 Hz, 1H), 7.31 (dd, J=5.3, 0.4
Hz, 1H), 7.54 (d, J=8.8 Hz, 1H), 7.57 (d, J=2.0 Hz, 1H), 8.26 (d,
J=5.1 Hz, 1H), 8.40 (s, 1H)
Example 8
Synthesis of
1-tert-butyl-3-((5-chloro-1-(3-(methylsulfonyl)propyl)-1H-indol-2-yl)meth-
yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (P8)
##STR00062##
[0903] Compound P8 was prepared by an analogous reaction protocol
as described for compound P1 using fragment A-c and
1-tert-butyl-1H-imidazo[4,5-c]pyridin-2(3H)-one 19-c as starting
material.
[0904] m/z=475 (M+H).sup.+ (LCMS method 2)
[0905] MP=226.degree. C.
[0906] 1H NMR (400 MHz, DMSO-d6) .delta. ppm 1.74 (s, 9H) 1.93-2.06
(m, 2H) 2.97 (s, 3H) 3.10-3.20 (m, 2H) 4.40 (t, J=7.48 Hz, 2H) 5.31
(s, 2H) 6.42 (s, 1H) 7.16 (dd, J=8.69, 2.09 Hz, 1H) 7.47-7.61 (m,
3H) 8.14 (d, J=5.72 Hz, 1H) 8.41 (s, 1H)
Example 9
Synthesis of
3-((5-chloro-1-(4,4,4-trifluorobutyl)-1H-imidazo[4,5-b]pyridin-2-yl)-meth-
yl)-1-(1-methylcyclopropyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (P9)
scheme 26
##STR00063##
[0907] Step 1: Synthesis of
6-chloro-N.sup.3-(4,4,4-trifluorobutyl)-pyridine-2,3-diamine
26-b
[0908] The intermediate 26-a (5 g, 34.82 mmol) was dissolved in
dichloromethane (200 mL), acetic acid (20 drops) and
4,4,4-trifluorobutanal (4.38 g, 34.8 mmol) were added. The
resulting mixture was stirred for 30 minutes and then sodium
triacetoxyhydroborate (22.14 g, 104.5 mmol) was added. The reaction
mixture was stirred at room temperature overnight and a solution of
50% Na.sub.2CO.sub.3 was added dropwise until gas evolution
stopped. The organic layer was separated, dried on MgSO.sub.4,
filtrated and evaporated to dryness. The residue was purified by
column chromatography using heptane/EtOAc 7/3 to pure EtOAc.
Intermediate 26-b was recovered as a white solid and dried in vacuo
overnight (6.16 g, 70%). m/z=254 (M+H).sup.+.
Step 2: Synthesis of
(5-chloro-1-(4,4,4-trifluorobutyl)-1H-imidazo[4,5-b]pyridin-2-yl)-methano-
l 26-c
[0909] A mixture of intermediate 26-b (5.68 g, 22.46 mmol) and
2-hydroxyacetic acid (4.27 g, 56.2 mmol) was stirred at 150.degree.
C. for 4 hours. The mixture was allowed to cool down to room
temperature and treated carefully with 3N hydrochloric acid. The
resulting mixture was made basic with aqueous ammonia and extracted
with CH.sub.2Cl.sub.2 (300 mL). The organic layer was dried over
MgSO.sub.4 and evaporated to dryness. The residue was purified by
column chromatography on silica using CH.sub.2Cl.sub.2 to EtOAc.
The intermediate 26-c was isolated as brown solid (4.27 g,
65%).
[0910] m/z=294 (M+H).sup.+.
[0911] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.00 (s,
2H), 1.12-1.23 (m, 2H), 1.83-1.99 (m, 2H), 2.12-2.31 (m, 2H), 2.91
(spt, J=3.50 Hz, 1H), 4.38-4.54 (m, 2H), 5.38 (s, 2H), 7.13 (dd,
J=5.27, 0.50 Hz, 1H), 7.27 (d, J=8.28 Hz, 1H), 7.61 (d, J=8.53 Hz,
1H), 8.36 (d, J=5.27 Hz, 1H), 8.77 (s, 1H)
Synthesis of
3-((5-chloro-1-(4,4,4-trifluorobutyl)-1H-imidazo[4,5-b]pyridin-2-yl)methy-
l)-1-(1-methylcyclopropyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one
(P9)
##STR00064##
[0913] Compound P9 was prepared by an analogous reaction protocol
as described for compound P1 using intermediate 26-c and
1-(1-methylcyclopropyl)-1H-imidazo-[4,5-c]pyridin-2(3H)-one 18-c as
starting material.
[0914] m/z=465 (M+H).sup.+ (LCMS method 2)
[0915] 1H NMR (400 MHz, DMSO-d6) .delta. ppm 0.94-1.09 (m, 4H) 1.42
(s, 3H) 1.89-2.01 (m, 2H) 2.30-2.45 (m, 2H) 4.48 (t, J=7.59 Hz, 2H)
5.47 (s, 2H) 7.33 (d, J=5.28 Hz, 1H) 7.38 (d, J=8.36 Hz, 1H) 8.22
(d, J=8.36 Hz, 1H) 8.28 (d, J=5.28 Hz, 1H) 8.45 (s, 1H)
Example 10
Synthesis of
3-((5-chloro-1-(4-fluorobutyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-1-(t-
hiazol-2-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (P10)
##STR00065##
[0917] Intermediate 27-a was prepared by an analogous reaction
protocol as described for intermediate 26-c using intermediate 26-a
and 4-fluorobutanal as starting material. Compound P10 was prepared
by an analogous reaction protocol as described for compound P1
using intermediate 27-a and
1-(thiazol-6-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 21-c as
starting material.
[0918] MP=238.degree. C.
[0919] m/z=458 (M+H).sup.+
[0920] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.71-1.93 (m,
2H), 4.39 (t, J=5.6 Hz, 1H), 4.42-4.48 (m, 1H), 4.51 (t, J=5.4 Hz,
1H), 5.53 (s, 1H), 7.23 (d, J=3.5 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H),
7.65 (d, J=8.4 Hz, 1H), 7.70 (d, J=3.5 Hz, 1H), 8.41 (dd, J=5.4,
0.6 Hz, 1H), 8.53 (d, J=5.3 Hz, 1H), 8.91 (s, 1H)
Example 11
Synthesis of
3-((5-chloro-1-(4-fluorobutyl)-1H-indol-2-yl)methyl)-1-(thiazol-2-yl)-1H--
imidazo[4,5-c]pyridin-2(3H)-one (P11)
##STR00066##
[0922] Intermediate 28-a was prepared by an analogous reaction
protocol as described for intermediate 24-c using intermediate 24-a
and 1-bromo-4-fluorobutane as starting material.
[0923] Compound P11 was prepared by an analogous reaction protocol
as described for compound P1 using intermediate 28-a and
1-(thiazol-6-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 21-c as
starting material.
[0924] MP=240.degree. C.
[0925] m/z=456 (M+H).sup.+
[0926] .sup.1H NMR (360 MHz, DMSO-d.sub.6) .delta. ppm 1.51-1.64
(m, 3H), 1.69 (m, J=5.5 Hz, 1H), 4.24-4.36 (m, 3H), 4.41 (t, J=6.0
Hz, 1H), 5.48 (s, 2H), 6.64 (s, 1H), 7.15 (dd, J=8.8, 2.2 Hz, 1H),
7.52 (d, J=8.8 Hz, 1H), 7.57 (d, J=2.2 Hz, 1H), 7.63 (d, J=3.7 Hz,
1H), 7.79 (d, J=3.3 Hz, 1H), 8.33 (d, J=5.1 Hz, 1H), 8.45 (d, J=5.5
Hz, 1H), 8.63 (s, 1H)
Example 12
Synthesis of 3-((5-chloro-1-(3
(methylsulfonyl)propyl)-1H-indol-2-yl)methyl)-5-fluoro-1-(1-(2-hydroxy-2--
methylpropyl)azetidin-3-yl)-1H-benzo[d]imidazol-2 (3H)-one
(P12)
##STR00067##
[0928] Compound P3 (150 mg, 0.3 mmol) was dissolved in ethanol (5
mL), triethylamine (133 .mu.L, 0.88 mmol) and 2,2-dimethyloxerane
(40 .mu.L, 0.45 mmol) were added. The resulting mixture was stirred
at 60.degree. C. overnight. The reaction mixture was allowed to
cool down to room temperature than evaporated to dryness. The
residue was purified by column chromatography using
CH.sub.2Cl.sub.2/MeOH:9/1. Compound P12 was recovered as a white
solid and dried in vacuo overnight (130 mg, 78%).
[0929] m/z=463 (M+H).sup.+
[0930] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.19 (s,
6H), 2.11 (quin, J=7.59 Hz, 2H), 2.63 (br. s, 3H), 2.85 (s, 3H),
2.96-3.03 (m, 2H), 3.87-3.96 (m, 4H), 4.37-4.44 (m, 2H), 5.08 (qd,
J=7.08, 6.93 Hz, 1H), 5.18 (s, 2H), 6.56 (s, 1H), 6.83 (td, J=9.13,
2.42 Hz, 1H), 6.92 (dd, J=8.36, 2.42 Hz, 1H), 7.14-7.19 (m, 1H),
7.20-7.25 (m, 1H), 7.51 (dd, J=8.58, 4.40 Hz, 1H), 7.55 (d, J=1.54
Hz, 1H)
Example 13
Synthesis of
3-((5-chloro-1-isopentyl-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-1-(quinoli-
n-6-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (P13)
##STR00068##
[0932] Intermediate 30-a was prepared by an analogous reaction
protocol as described for intermediate 26-c using intermediate 26-a
and 3-methylbutanal as starting material. Compound P13 was prepared
by an analogous reaction protocol as described for compound P1
using intermediate 30-a and
1-(quinolin-6-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 20-c as
starting material.
[0933] m/z=498 (M+H).sup.+
[0934] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.00 (d,
J=6.38 Hz, 6H), 1.58-1.66 (m, 2H), 1.67-1.79 (m, 1H), 4.37-4.48 (m,
2H), 5.52 (s, 2H), 7.09 (dd, J=5.50, 0.66 Hz, 1H), 7.23-7.28 (m,
1H), 7.51 (dd, J=8.36, 4.18 Hz, 1H), 7.64 (d, J=8.36 Hz, 1H), 7.84
(dd, J=9.02, 2.42 Hz, 1H), 8.01 (d, J=2.42 Hz, 1H), 8.23 (dd,
J=8.47, 0.99 Hz, 1H), 8.31 (d, J=8.80 Hz, 1H), 8.38 (d, J=5.28 Hz,
1H), 8.89 (s, 1H), 9.02 (dd, J=4.29, 1.65 Hz, 1H)
Example 14
Synthesis of
4-(5-chloro-2-((1-(4-methoxyphenyl)-2-oxo-1H-imidazo[4,5-c]pyridin-3
(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile (P14)
##STR00069##
[0935] Step 1: synthesis of ethyl
5-chloro-1-(3-cyanopropyl)-1H-indole-2-carboxylate 31-a
[0936] Ethyl-5-chloroindol-2-carboxylate 24-a (33.55 g, 150 mmol)
was dissolved in acetonitrile (600 mL) and stirred at room
temperature. Then cesiumcarbonate (73.31 g, 225 mmol) was added and
stirring was continued for 30 minutes. 4-Bromobutyronitrile (18.83
mL, 180 mmol) was added in small portions over a period of one hour
and stirring was done overnight at ambient temperature. The
reaction mixture was filtered and the filtrate was evaporated to
dryness. The residue was dissolved in dichloromethane and washed
with water. The organic layer was dried over MgSO4, filtered and
evaporated. The residue 43.5 g was used as such in the next step
99% yield.
[0937] m/z=290 (M+H).sup.+
Step 2: Synthesis of
5-Chloro-1-(3-cyanopropyl)-1H-indole-2-carboxylic acid 31-b
[0938] Ethyl 5-chloro-1-(3-cyanopropyl)indol-2-carboxylate 31-a
(43.61 g, 149.97 mmol) was dissolved in 1,4-dioxane (850 mL) and
stirred at room temperature. Then a solution of lithiumhydroxide
(10.78 g, 450 mmol) in distilled water (150 mL) was added the
stirring was continued overnight at ambient temperature. The
reaction mixture was evaporated to dryness. The residue was
dissolved in 500 mL water and neutralised with aqueous solution of
hydrochloric acid 1 N (450 mL). The white precipitate was filtered
off and dried in vacuo to yield 39.8 g of the intermediate 31-b
100%.
[0939] m/z=262 (M+H).sup.+
Step 3: Synthesis of
4-(5-chloro-2-(hydroxymethyl)-1H-indol-1-yl)butanenitrile 31-c
[0940] 5-chloro-1-(3-cyanopropyl)indol-2-carboxylic acid 31-b (39.4
g, 149.98 mmol) and Hunigs base (51.69 mL, 300 mmol) were dissolved
in tetrahydrofuran (550 mL) and stirred at -10.degree. C. under a
nitrogen atmosphere. Then a solution of isoButylchloroformate in
tetrahydrofuran (50 ml) was added dropwise the stirring was
continued for one hour at -10.degree. C. and one hour at ambient
temperature. Then sodiumborohydride (17.02 g, 450 mmol) was added
portionwise at -10.degree. C. and stirred for one hour, afterwards
distilled water (200 mL) was added cautiously to the reaction
mixture and stirring was continued for another hour at room
temperature under a nitrogen atmosphere. The mixture was
neutralised with 10% citric acid in water and then extracted with
ethyl acetate. The organic layer was dried over MgSO4, filtered and
evaporated. The residue was purified over silica with
Heptane/dichloromethane/methanol 50/50/0->0/100/0->0/99/1 as
gradient. The corresponding fractions were evaporated to yield the
intermediate 31-c 23.9 g as a white powder 64%.
[0941] m/z=248 (M+H).sup.+
Step 4: Synthesis of
4-(5-chloro-2-((1-(4-methoxyphenyl)-2-oxo-1H-imidazo[4,5-c]pyridin-3
(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile (P14)
##STR00070##
[0943] To a suspension of intermediate 31-c (3 g, 12.02 mmol),
intermediate 22-c (2.9 g, 12.02 mmol) and triphenylphosphine (3.78
g, 14.43 mmol) in dry THF (90 mL) diisopropylazodicarboxylate
(DIAD) (3.509 ml, 18.03 mmol) was added at room temperature
dropwise. The resulting mixture was stirred overnight. The solvent
was evaporated and the residue was triturated in ether. After
stirring for 1 hour, the solid was filtered off and then the beige
powder was crystallized in MeOH. The formed crystals were filtered
off and washed with some MeOH and ether to get the title product
P14 as a white powder (2.2 g, 40%).
[0944] m/z=472 (M+H).sup.+
[0945] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.95 (quin,
J=7.59 Hz, 2H) 2.54 (t, J=7.50 Hz, 2H) 3.84 (s, 3H) 4.35 (t, J=7.70
Hz, 2H) 5.42 (s, 2H) 6.55 (s, 1H) 7.02 (d, J=5.28 Hz, 1H) 7.11-7.19
(m, 3H) 7.47-7.52 (m, 2H) 7.54 (d, J=8.80 Hz, 1H) 7.57 (d, J=1.98
Hz, 1H) 8.23 (d, J=5.28 Hz, 1H) 8.51 (s, 1H)
Example 15
Synthesis of
4-(5-chloro-2-((1-(3-fluoro-4-methoxyphenyl)-2-oxo-1H-imidazo[4,5-c]pyrid-
in-3(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile (P15)
##STR00071##
[0947] Compound P15 was prepared by an analogous reaction protocol
as described for compound P1 using intermediate 31-c and
1-(3-fluoro-4-methoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one
45-c as starting material.
[0948] m/z=490 (M+1).sup.+
[0949] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 2.01 (qd,
J=7.37, 7.15 Hz, 2H), 2.36 (t, J=7.15 Hz, 2H), 3.97 (s, 3H),
4.34-4.45 (m, 2H), 5.31 (s, 2H), 6.69 (s, 1H), 6.99 (dd, J=5.28,
0.66 Hz, 1H), 7.09-7.16 (m, 1H), 7.16-7.30 (m, 4H), 7.56 (d, J=1.54
Hz, 1H), 8.32 (d, J=5.28 Hz, 1H), 8.51 (s, 1H)
Example 16
Synthesis of
3-((5-chloro-1-isopentyl-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-1-(4-metho-
xyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (P16)
##STR00072##
[0951] Compound P16 was prepared by an analogous reaction protocol
as described for compound P1 using intermediate 30-a and
1-(4-methoxyphenyl)-1H-imidazo-[4,5-c]pyridin-2(3H)-one 22-c as
starting material.
[0952] m/z=477 (M+1).sup.+
[0953] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.98 (d,
J=6.60 Hz, 6H), 1.52-1.63 (m, 2H), 1.68 (s, 1H), 3.88 (s, 3H),
4.34-4.46 (m, 2H), 5.48 (s, 2H), 6.93 (d, J=5.28 Hz, 1H), 7.02-7.09
(m, 2H), 7.24 (d, J=8.58 Hz, 1H), 7.33-7.41 (m, 2H), 7.62 (d,
J=8.36 Hz, 1H), 8.32 (d, J=5.50 Hz, 1H), 8.82 (s, 1H)
Example 17
Synthesis of
3-((5-chloro-1-(4,4,4-trifluorobutyl)-1H-pyrrolo[3,2-b]pyridin-2-yl)-meth-
yl)-1-(4-methoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one
(P17)
##STR00073##
[0955] Compound P17 was prepared by an analogous reaction protocol
as described for compound P1 using intermediate 49-e and
1-(4-methoxyphenyl)-1H-imidazo[4,5-c]-pyridin-2(3H)-one 22-c as
starting material.
[0956] m/z=516 (M+1).sup.+
[0957] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.80-1.92
(m, 2H), 2.04-2.21 (m, 2H), 3.88 (s, 3H), 4.32-4.42 (m, 2H), 5.36
(s, 2H), 6.90 (s, 1H), 6.95 (d, J=5.28 Hz, 1H), 7.05-7.11 (m, 2H),
7.16 (d, J=8.58 Hz, 1H), 7.34-7.41 (m, 2H), 7.54 (d, J=8.58 Hz,
1H), 8.31 (d, J=5.06 Hz, 1H), 8.49 (s, 1H)
Example 18
Synthesis of 3
#5-chloro-1-isopentyl-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-1-(1-methylcy-
clopropyl)-1H-imidazo[4,5-c]pyridin-2 (3H)-one (P18)
##STR00074##
[0959] Compound P18 was prepared by an analogous reaction protocol
as described for compound P1 using intermediate 30-a and
1-(1-methylcyclopropyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 18-c as
starting material.
[0960] m/z=425 (M+1).sup.+
[0961] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.99 (d,
J=6.60 Hz, 6H), 1.02-1.07 (m, 2H), 1.11-1.19 (m, 2H), 1.50 (s, 3H),
1.52-1.60 (m, 2H), 1.63-1.78 (m, 1H), 4.30-4.42 (m, 2H), 5.37 (s,
2H), 7.13 (d, J=5.06 Hz, 1H), 7.20 (d, J=8.36 Hz, 1H), 7.60 (d,
J=8.36 Hz, 1H), 8.34 (d, J=3.74 Hz, 1H), 8.71 (br. s., 1H)
Example 19
Synthesis of
4-(5-chloro-2-((1-(3,4-dimethoxyphenyl)-2-oxo-1H-imidazo[4,5-c]pyridin-3(-
2H)-yl)methyl)-1H-indol-1-yl)butanenitrile (P19)
##STR00075##
[0963] Compound P19 was prepared by an analogous reaction protocol
as described for compound P1 using intermediate 31-c and
1-(3,4-dimethoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 32-c as
starting material.
[0964] m/z=502 (M+1).sup.+
[0965] MP=176.51.degree. C.
[0966] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.94 (quin,
J=7.48 Hz, 2H) 2.52-2.58 (m, 2H) 3.79 (s, 3H) 3.84 (s, 3H)
4.32-4.40 (m, 2H) 5.42 (s, 2H) 6.56 (s, 1H) 7.05-7.20 (m, 5H) 7.55
(d, J=8.80 Hz, 1H) 7.57 (d, J=1.98 Hz, 1H) 8.23 (d, J=5.28 Hz, 1H)
8.51 (s, 1H)
Example 20
Synthesis of
4-(5-chloro-2-((1-(4-methoxy-2-methylphenyl)-2-oxo-1H-imidazo[4,5-c]pyrid-
in-3(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile (P20)
##STR00076##
[0968] Compound P20 was prepared by an analogous reaction protocol
as described for compound P1 using intermediate 31-c and
1-(4-methoxy-2-methylphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one
33-c as starting material.
[0969] m/z=486 (M+1).sup.+
[0970] MP=172.59.degree. C.
[0971] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.89-2.05
(m, 2H) 2.07 (s, 3H) 2.52-2.60 (m, 2H) 3.83 (s, 3H) 4.26-4.42 (m,
2H) 5.43 (s, 2H) 6.50 (s, 1H) 6.76 (d, J=5.06 Hz, 1H) 6.96 (dd,
J=8.69, 2.75 Hz, 1H) 7.06 (d, J=2.64 Hz, 1H) 7.17 (dd, J=8.69, 2.09
Hz, 1H) 7.34 (d, J=8.58 Hz, 1H) 7.55 (d, J=8.80 Hz, 1H) 7.58 (d,
J=1.98 Hz, 1H) 8.21 (d, J=5.28 Hz, 1H) 8.51 (s, 1H)
Example 21
Synthesis of
4-(5-chloro-2-((2-oxo-1-(pyrimidin-2-yl)-1H-imidazo[4,5-c]pyridin-3(2H)-y-
l)methyl)-1H-indol-1-yl)butanenitrile (P21)
##STR00077##
[0973] Compound P21 was prepared by an analogous reaction protocol
as described for compound P1 using intermediate 31-c and
1-(pyrimidin-2-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 53-c as
starting material.
[0974] m/z=445 (M+1).sup.+
[0975] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.91 (quin,
J=7.65 Hz, 2H) 2.54-2.63 (m, 2H) 4.28-4.43 (m, 2H) 5.45 (s, 2H)
6.52 (s, 1H) 7.16 (dd, J=8.69, 2.09 Hz, 1H) 7.54 (d, J=8.80 Hz, 1H)
7.57 (d, J=2.20 Hz, 1H) 7.61 (t, J=4.84 Hz, 1H) 7.77 (dd, J=5.39,
0.77 Hz, 1H) 8.33 (d, J=5.28 Hz, 1H) 8.58 (s, 1H) 9.02 (d, J=4.84
Hz, 2H)
Example 22
Synthesis of
3-((5-chloro-1-isopentyl-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-1-(thiazol-
-2-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (P22)
##STR00078##
[0977] Compound P22 was prepared by an analogous reaction protocol
as described for compound P1 using intermediate 30-a and
1-(thiazol-2-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 21-c as
starting material.
[0978] m/z=454 (M+1).sup.+
[0979] MP=231.23.degree. C. and 238.22.degree. C.
[0980] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.95 (d,
J=6.38 Hz, 6H) 1.56-1.77 (m, 3H) 4.35-4.50 (m, 2H) 5.67 (s, 2H)
7.37 (d, J=8.36 Hz, 1H) 7.63 (d, J=3.52 Hz, 1H) 7.81 (d, J=3.52 Hz,
1H) 8.16 (d, J=8.36 Hz, 1H) 8.35 (d, J=5.28 Hz, 1H) 8.49 (d, J=5.28
Hz, 1H) 8.68 (s, 1H)
Example 23
Synthesis of 3
#5-chloro-1-isopentyl-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-1-(pyridin-4--
yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (P23)
##STR00079##
[0982] Compound P23 was prepared by an analogous reaction protocol
as described for compound P1 using intermediate 30-a and
1-(pyridin-4-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 34-c as
starting material.
[0983] m/z=448 (M+1).sup.+
[0984] MP=210
[0985] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.95 (d,
J=6.16 Hz, 6H) 1.57-1.75 (m, 3H) 4.34-4.49 (m, 2H) 5.60 (s, 2H)
7.37 (d, J=8.58 Hz, 1H) 7.44 (d, J=5.28 Hz, 1H) 7.70-7.80 (m, 2H)
8.16 (d, J=8.58 Hz, 1H) 8.34 (d, J=5.50 Hz, 1H) 8.62 (s, 1H)
8.75-8.85 (m, 2H)
Example 24
Synthesis of
4-(5-chloro-2-((2-oxo-1-(pyrimidin-4-yl)-1H-imidazo[4,5-c]pyridin-3(2H)-y-
l)methyl)-1H-indol-1-yl)butanenitrile (P24)
##STR00080##
[0987] Compound P24 was prepared by an analogous reaction protocol
as described for compound P1 using intermediate 31-c and
1-(pyrimidin-4-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 35-c as
starting material.
[0988] m/z=444 (M+1).sup.+
[0989] MP=229.17.degree. C.
[0990] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.98 (quin,
J=7.32 Hz, 2H) 2.58 (t, J=7.37 Hz, 2H) 4.36 (t, J=7.59 Hz, 2H) 5.46
(s, 2H) 6.51 (s, 1H) 7.16 (dd, J=8.80, 1.76 Hz, 1H) 7.48-7.60 (m,
2H) 8.34 (d, J=5.28 Hz, 1H) 8.38-8.47 (m, 2H) 8.60 (s, 1H) 8.97 (d,
J=5.94 Hz, 1H) 9.24 (s, 1H)
Example 25
Synthesis of
3-((5-chloro-1-isopentyl-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-5-fluoro-1-
-(thiazol-2-yl)-1H-benzo[d]imidazol-2(3H)-one (P25)
##STR00081##
[0992] Compound P25 was prepared by an analogous reaction protocol
as described for compound P1 using intermediate 30-a and
5-fluoro-1-(thiazol-2-yl)-1H-benzo[d]imidazol-2(3H)-one 37-c as
starting material.
[0993] m/z=471 (M+1).sup.+
[0994] MP=264.42.degree. C.
[0995] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.94 (d,
J=6.38 Hz, 6H) 1.54-1.74 (m, 3H) 4.34-4.47 (m, 2H) 5.61 (s, 2H)
7.07-7.18 (m, 1H) 7.36 (d, J=8.36 Hz, 1H) 7.42 (dd, J=8.91, 2.53
Hz, 1H) 7.57 (d, J=3.52 Hz, 1H) 7.75 (d, J=3.52 Hz, 1H) 8.16 (d,
J=8.36 Hz, 1H) 8.46 (dd, J=8.80, 4.84 Hz, 1H)
Example 26
Synthesis of 3
#5-chloro-1-isopentyl-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-1-(3-fluoropy-
ridin-4-yl)-1H-imidazo[4,5-c]pyridin-2 (3H)-one (P26)
##STR00082##
[0997] Compound P26 was prepared by an analogous reaction protocol
as described for compound P1 using intermediate 30-a and
1-(3-fluoropyridin-4-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 36-c as
starting material.
[0998] m/z=466 (M+1).sup.+
[0999] MP=123.79.degree. C.
[1000] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.94 (d,
J=6.16 Hz, 6H) 1.57-1.74 (m, 3H) 4.35-4.48 (m, 2H) 5.62 (s, 2H)
7.20 (dd, J=5.06, 2.20 Hz, 1H) 7.37 (d, J=8.36 Hz, 1H) 7.83 (t,
J=5.83 Hz, 1H) 8.16 (d, J=8.36 Hz, 1H) 8.33 (d, J=5.28 Hz, 1H) 8.62
(s, 1H) 8.68 (d, J=5.06 Hz, 1H) 8.93 (d, J=1.98 Hz, 1H)
Example 27
Synthesis of
4-(5-chloro-2-((6-fluoro-2-oxo-3-(thiazol-2-yl)-2,3-dihydro-1H-benzo[d]im-
idazol-1-yl)methyl)-1H-indol-1-yl)butanenitrile (P27)
##STR00083##
[1002] Compound P27 was prepared by an analogous reaction protocol
as described for compound P1 using intermediate 31-c and
5-fluoro-1-(thiazol-2-yl)-1H-benzo[d]imidazol-2(3H)-one 37-c as
starting material.
[1003] m/z=466 (M+1).sup.+
[1004] MP=238.29.degree. C.
[1005] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.90-2.04
(m, 2H) 2.58 (t, J=7.37 Hz, 2H) 4.31-4.43 (m, 2H) 5.44 (s, 2H) 6.40
(s, 1H) 7.07-7.14 (m, 1H) 7.16 (dd, J=8.80, 1.98 Hz, 1H) 7.41 (dd,
J=8.91, 2.53 Hz, 1H) 7.49-7.60 (m, 3H) 7.75 (d, J=3.52 Hz, 1H) 8.46
(dd, J=8.91, 4.95 Hz, 1H)
Example 28
Synthesis of
4-(5-chloro-2-((1-(4-(2-methoxyethoxyl)phenyl)-2-oxo-1H-imidazo[4,5-c]pyr-
idin-3(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile (P28)
##STR00084##
[1007] Compound P28 was prepared by an analogous reaction protocol
as described for compound P1 using intermediate 31-c and
1-(4-(2-methoxyethoxyl)phenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one
39-c as starting material.
[1008] m/z=516 (M+1).sup.+
[1009] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.98 (quin,
J=7.5 Hz, 2H), 2.51-2.58 (m, 2H), 3.34 (s, 3H), 3.65-3.75 (m, 2H),
4.14-4.24 (m, 2H), 4.36 (t, J=7.7 Hz, 2H), 5.40 (s, 2H), 6.53 (s,
1H), 6.99 (d, J=5.2 Hz, 1H), 7.09-7.18 (m, 3H), 7.42-7.57 (m, 4H),
8.22 (d, J=5.2 Hz, 1H), 8.46 (s, 1H)
Example 29
Synthesis of 4-(5-chloro-2-((2-oxo-1-(4-(tri
fluoromethoxy)phenyl)-1H-imidazo[4,5-c]pyridin-3
(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile (P29)
##STR00085##
[1011] Compound P29 was prepared by an analogous reaction protocol
as described for compound P1 using intermediate 31-c and
1-(4-(trifluoromethoxy)phenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one
40-c as starting material.
[1012] m/z=526 (M+1).sup.+
[1013] .sup.1H NMR (360 MHz, DMSO-d.sub.6) .delta. ppm 1.97 (quin,
J=7.5 Hz, 2H), 2.56 (t, J=7.5 Hz, 2H), 4.36 (t, J=7.5 Hz, 2H), 5.44
(s, 2H), 6.56 (s, 1H), 7.09-7.25 (m, 2H), 7.50-7.69 (m, 4H),
7.73-7.83 (m, 2H), 8.27 (d, J=5.5 Hz, 1H), 8.56 (s, 1H)
Example 30
Synthesis of
3-((5-chloro-1-(3-(methylsulfonyl)propyl)-1H-indol-2-yl)methyl)-1-(4-chlo-
rophenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (P30)
##STR00086##
[1015] Compound P30 was prepared by an analogous reaction protocol
as described for compound P1 using intermediate 24-c and
1-(4-chlorophenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 41-c as
starting material.
[1016] m/z=529 (M+1).sup.+
[1017] .sup.1H NMR (360 MHz, DMSO-d.sub.6) .delta. ppm 2.03 (m,
J=7.7, 7.7 Hz, 2H), 2.94 (s, 3H), 3.15 (m, J=15.7 Hz, 2H), 4.43 (t,
J=7.5 Hz, 2H), 5.43 (s, 2H), 6.62 (s, 1H), 7.10-7.23 (m, 2H),
7.52-7.61 (m, 2H), 7.67 (s, 4H), 8.26 (d, J=5.1 Hz, 1H), 8.56 (s,
1H)
Example 31
Synthesis of
3-((5-chloro-1-(4-fluorobutyl)-1H-indol-2-yl)methyl)-1-(quinolin-6-yl)-1H-
-imidazo[4,5-c]pyridin-2(3H)-one (P31)
##STR00087##
[1019] Compound P31 was prepared by an analogous reaction protocol
as described for compound P1 using intermediate 28-a and
1-(quinolin-6-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 20-c as
starting material.
[1020] m/z=500 (M+1).sup.+
[1021] .sup.1H NMR (360 MHz, DMSO-d.sub.6) .delta. ppm 1.52-1.78
(m, 4H), 4.26-4.41 (m, 3H), 4.47 (t, J=5.5 Hz, 1H), 5.47 (s, 2H),
6.69 (s, 1H), 7.16 (dd, J=8.8, 2.2 Hz, 1H), 7.28 (d, J=5.5 Hz, 1H),
7.54 (d, J=8.8 Hz, 1H), 7.60 (d, J=2.2 Hz, 1H), 7.65 (dd, J=8.4,
4.4 Hz, 1H), 8.00 (dd, J=9.1, 2.2 Hz, 1H), 8.19-8.33 (m, 3H), 8.51
(d, J=7.3 Hz, 1H), 8.58 (s, 1H), 9.02 (dd, J=4.2, 1.6 Hz, 1H)
Example 32
Synthesis of
3-((5-chloro-1-(4-fluorobutyl)-1H-indol-2-yl)methyl)-1-(4-methoxyphenyl)--
1H-imidazo[4,5-c]pyridin-2(3H)-one (P32)
##STR00088##
[1023] Compound P32 was prepared by an analogous reaction protocol
as described for compound P1 using intermediate 28-a and
1-(4-methoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 22-c as
starting material.
[1024] m/z=479 (M+1).sup.+
[1025] MP=163.degree. C.
[1026] .sup.1H NMR (360 MHz, DMSO-d.sub.6) .delta. ppm 1.63 (m,
J=2.9, 2.9 Hz, 4H), 3.84 (s, 3H), 4.33 (m, J=5.5 Hz, 3H), 4.46 (t,
J=5.9 Hz, 1H), 5.41 (s, 2H), 6.66 (s, 1H), 6.99-7.04 (m, 1H),
7.10-7.19 (m, 3H), 7.44-7.55 (m, 3H), 7.59 (d, J=2.2 Hz, 1H), 8.22
(d, J=5.5 Hz, 1H), 8.47-8.53 (m, 1H)
Example 33
Synthesis of
4-(5-chloro-2-((1-(1-methyl-1H-imidazol-2-yl)-2-oxo-1H-imidazo[4,5-c]pyri-
din-3(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile (P33)
##STR00089##
[1028] Compound P33 was prepared by an analogous reaction protocol
as described for compound P1 using intermediate 31-c and
1-(1-methyl-1H-imidazol-2-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one
42-c as starting material.
[1029] m/z=446 (M+1).sup.+
Example 34
Synthesis of
3-((5-chloro-1-(4-fluorobutyl)-1H-indol-2-yl)methyl)-1-(4-chlorophenyl)-1-
H-imidazo[4,5-c]pyridin-2(3H)-one (P34)
##STR00090##
[1031] Compound P34 was prepared by an analogous reaction protocol
as described for compound P1 using intermediate 28-a and
1-(4-chlorophenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 41-c as
starting material.
[1032] m/z=483 (M+1).sup.+
[1033] MP=168.degree. C.
[1034] .sup.1H NMR (360 MHz, DMSO-d.sub.6) .delta. ppm 1.53-1.72
(m, 4H), 4.32 (m, J=4.4 Hz, 3H), 4.46 (t, J=5.5 Hz, 1H), 5.42 (s,
2H), 6.67 (s, 1H), 7.08-7.20 (m, 2H), 7.52 (d, J=8.8 Hz, 1H), 7.59
(d, J=1.8 Hz, 1H), 7.61-7.73 (m, 4H), 8.25 (d, J=5.5 Hz, 1H), 8.53
(s, 1H)
Example 35
Synthesis of
3-((5-chloro-1-(3-(methylsulfonyl)propyl)-1H-indol-2-yl)methyl)-1-(4-meth-
oxyphenyl)-1H-imidazo[4,5-c]pyridin-2 (3H)-one (P35)
##STR00091##
[1036] Compound P35 was prepared by an analogous reaction protocol
as described for compound P1 using intermediate 24-c and
1-(4-methoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 22-c as
starting material.
[1037] m/z=525 (M+1).sup.+
[1038] MP=215.degree. C.
[1039] .sup.1H NMR (360 MHz, DMSO-d.sub.6) .delta. ppm 1.94-2.10
(m, 2H), 2.95 (s, 3H), 3.15 (m, J=15.4 Hz, 2H), 3.84 (s, 3H), 4.43
(t, J=7.5 Hz, 2H), 5.43 (s, 2H), 6.61 (s, 1H), 7.02 (d, J=5.1 Hz,
1H), 7.10-7.21 (m, 3H), 7.48-7.62 (m, 4H), 8.23 (d, J=5.1 Hz, 1H),
8.53 (s, 1H)
Example 36
Synthesis of
4-(5-chloro-2-((1-(1-methyl-1H-pyrazol-3-yl)-2-oxo-1H-imidazo[4,5-c]pyrid-
in-3(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile (P36)
##STR00092##
[1041] Compound P36 was prepared by an analogous reaction protocol
as described for compound P1 using intermediate 31-c and
1-(1-methyl-1H-pyrazol-3-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one
44-c as starting material.
[1042] m/z=446 (M+1).sup.+
[1043] MP=244.degree. C.
[1044] .sup.1H NMR (360 MHz, DMSO-d.sub.6) .delta. ppm 1.92 (quin,
J=7.4 Hz, 2H), 2.56 (t, J=7.5 Hz, 2H), 3.93 (s, 3H), 4.35 (t, J=7.7
Hz, 2H), 5.44 (s, 2H), 6.46 (s, 1H), 6.71 (d, J=2.2 Hz, 1H), 7.16
(dd, J=8.8, 2.2 Hz, 1H), 7.48-7.60 (m, 2H), 7.78 (d, J=5.1 Hz, 1H),
7.88 (d, J=2.6 Hz, 1H), 8.34 (d, J=5.5 Hz, 1H), 8.54 (s, 1H)
Example 37
Synthesis of
4-(5-chloro-2-((1-(oxazol-2-yl)-2-oxo-1H-imidazo[4,5-c]pyridin-3(2H)-yl)m-
ethyl)-1H-indol-1-yl)butanenitrile (P37)
##STR00093##
[1046] Compound P37 was prepared by an analogous reaction protocol
as described for compound P1 using intermediate 31-c and
1-(oxazol-2-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 43-c as starting
material.
[1047] m/z=433 (M+1).sup.+
[1048] MP=234.degree. C.
[1049] .sup.1H NMR (360 MHz, DMSO-d.sub.6) .delta. ppm 1.89-2.07
(m, 2H), 2.58 (t, J=7.5 Hz, 2H), 4.35 (m, J=15.4 Hz, 2H), 5.44 (s,
2H), 6.50 (s, 1H), 7.10-7.22 (m, 1H), 7.47 (d, J=0.7 Hz, 1H),
7.51-7.60 (m, 2H), 7.74-7.82 (m, 1H), 8.26 (d, J=1.1 Hz, 1H), 8.40
(d, J=5.1 Hz, 1H), 8.58 (s, 1H)
Example 38
Synthesis of
3-((5-chloro-1-(4-fluorobutyl)-1H-indol-2-yl)methyl)-1-(1-methyl-1H-pyraz-
ol-3-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (P38)
##STR00094##
[1051] Compound P38 was prepared by an analogous reaction protocol
as described for compound P1 using intermediate 28-a and
1-(1-methyl-1H-pyrazol-3-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one
44-c as starting material.
[1052] m/z=453 (M+1).sup.+
[1053] MP=169.3.degree. C.
[1054] .sup.1H NMR (360 MHz, DMSO-d.sub.6) .delta. ppm 1.49-1.73
(m, 4H), 3.93 (s, 3H), 4.25-4.35 (m, 3H), 4.42 (t, J=6.0 Hz, 1H),
5.42 (s, 2H), 6.59 (s, 1H), 6.70 (d, J=2.2 Hz, 1H), 7.14 (dd,
J=8.8, 2.2 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.58 (d, J=1.8 Hz, 1H),
7.77 (d, J=5.5 Hz, 1H), 7.88 (d, J=2.2 Hz, 1H), 8.32 (d, J=5.5 Hz,
1H), 8.52 (s, 1H)
Example 39
Synthesis of
4-(5-chloro-2-((1-(4-chlorophenyl)-2-oxo-1H-imidazo[4,5-c]pyridin-3(2H)-y-
l)methyl)-1H-indol-1-yl)butanenitrile (P39)
##STR00095##
[1056] Compound P39 was prepared by an analogous reaction protocol
as described for compound P1 using intermediate 31-c and
1-(4-chlorophenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 41-c as
starting material.
[1057] m/z=476 (M+1).sup.+
[1058] MP=210.8.degree. C.
[1059] .sup.1H NMR (360 MHz, DMSO-d.sub.6) .delta. ppm 1.88-2.05
(m, 2H), 2.52-2.61 (m, 2H), 4.36 (t, J=7.9 Hz, 2H), 5.43 (s, 2H),
6.55 (s, 1H), 7.10-7.22 (m, 2H), 7.49-7.60 (m, 2H), 7.63-7.72 (m,
4H), 8.26 (d, J=5.5 Hz, 1H), 8.55 (s, 1H)
Example 40
Synthesis of
4-(5-chloro-2-((6-fluoro-2-oxo-3-(pyridin-4-yl)-2,3-dihydro-1H-benzo[d]im-
idazol-1-yl)methyl)-1H-indol-1-yl)butanenitrile (P40)
##STR00096##
[1061] Compound P40 was prepared by an analogous reaction protocol
as described for compound P1 using intermediate 31-c and
5-fluoro-1-(pyridin-4-yl)-1H-benzo[d]imidazol-2(3H)-one 38-c as
starting material.
[1062] m/z=461 (M+1).sup.+
[1063] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.97 (quin,
J=7.54 Hz, 2H) 2.56 (t, J=7.37 Hz, 2H) 4.20-4.41 (m, 2H) 5.39 (s,
2H) 6.44 (s, 1H) 6.91-7.01 (m, 1H) 7.16 (dd, J=8.80, 2.20 Hz, 1H)
7.33-7.40 (m, 2H) 7.51-7.57 (m, 2H) 7.68-7.77 (m, 2H) 8.67-8.83 (m,
2H)
Example 41
Synthesis of
4-(5-chloro-2-((1-(4-(methylsulfonyl)phenyl)-2-oxo-1H-imidazo[4,5-c]pyrid-
in-3(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile (P41)
##STR00097##
[1065] Compound P41 was prepared by an analogous reaction protocol
as described for compound P1 using intermediate 31-c and
1-(4-(methylsulfonyl)phenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one
50-c as starting material.
[1066] m/z=521 (M+1).sup.+
[1067] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.92-2.06
(m, 2H) 2.53-2.59 (m, 2H) 3.31 (s, 3H) 4.36 (t, J=7.90 Hz, 2H) 5.45
(s, 2H) 6.56 (s, 1H) 7.09-7.22 (m, 1H) 7.29 (d, J=5.28 Hz, 1H)
7.52-7.58 (m, 2H) 7.94 (d, J=8.58 Hz, 2H) 8.16 (d, J=8.58 Hz, 2H)
8.30 (d, J=5.50 Hz, 1H) 8.57 (s, 1H)
Example 42
Synthesis of
4-(5-chloro-2-((1-(3-fluoropyridin-4-yl)-2-oxo-1H-imidazo[4,5-c]pyridin-3-
(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile (P42)
##STR00098##
[1069] Compound P42 was prepared by an analogous reaction protocol
as described for compound P1 using intermediate 31-c and
1-(3-fluoropyridin-4-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 36-c as
starting material.
[1070] m/z=462 (M+1).sup.+
[1071] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.97 (quin,
J=7.59 Hz, 2H) 2.52-2.57 (m, 2H) 4.35 (t, J=7.59 Hz, 2H) 5.46 (s,
2H) 6.56 (s, 1H) 7.14-7.20 (m, 2H) 7.55 (d, J=8.80 Hz, 1H) 7.58 (d,
J=1.98 Hz, 1H) 7.81-7.88 (m, 1H) 8.31 (d, J=5.50 Hz, 1H) 8.59 (s,
1H) 8.69 (d, J=5.06 Hz, 1H) 8.92 (d, J=1.98 Hz, 1H)
Example 43
Synthesis of
4-(5-chloro-2-((2-oxo-1-(quinolin-6-yl)-1H-imidazo[4,5-c]pyridin-3
(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile (P43)
##STR00099##
[1073] Compound P43 was prepared by an analogous reaction protocol
as described for compound P1 using intermediate 31-c and
1-(quinolin-6-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 20-c as
starting material.
[1074] m/z=494 (M+1).sup.+
[1075] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.99 (quin,
J=7.54 Hz, 2H) 2.57 (t, J=7.37 Hz, 2H) 4.19-4.51 (m, 2H) 5.48 (s,
2H) 6.59 (s, 1H) 7.18 (dd, J=8.80, 2.20 Hz, 1H) 7.28 (d, J=5.28 Hz,
1H) 7.56 (d, J=8.80 Hz, 1H) 7.58 (d, J=1.98 Hz, 1H) 7.65 (dd,
J=8.36, 4.18 Hz, 1H) 8.00 (dd, J=8.91, 2.31 Hz, 1H) 8.24 (d, J=9.02
Hz, 1H) 8.27-8.31 (m, 2H) 8.50 (d, J=7.48 Hz, 1H) 8.59 (s, 1H) 9.01
(dd, J=4.18, 1.54 Hz, 1H)
Example 44
Synthesis of
3-((5-chloro-1-(4-fluorobutyl)-1H-indol-2-yl)methyl)-1-(pyridin-4-yl)-1H--
imidazo[4,5-c]pyridin-2(3H)-one (P44)
##STR00100##
[1077] Compound P44 was prepared by an analogous reaction protocol
as described for compound P1 using intermediate 28-a and
1-(pyridin-4-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 20-c as
starting material.
[1078] m/z=451 (M+1).sup.+
[1079] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.48-1.73
(m, 4H) 4.25-4.37 (m, 3H) 4.44 (t, J=5.61 Hz, 1H) 5.43 (s, 2H) 6.66
(s, 1H) 7.15 (dd, J=8.69, 2.09 Hz, 1H) 7.40 (dd, J=5.39, 0.55 Hz,
1H) 7.52 (d, J=8.80 Hz, 1H) 7.58 (d, J=1.98 Hz, 1H) 7.70-7.76 (m,
2H) 8.30 (d, J=5.28 Hz, 1H) 8.56 (s, 1H) 8.77-8.83 (m, 2H)
Example 45
Synthesis of
4-(5-chloro-2-((1-(2-fluoro-4-methoxyphenyl)-2-oxo-1H-imidazo[4,5-c]pyrid-
in-3(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile (P45)
##STR00101##
[1081] Compound P45 was prepared by an analogous reaction protocol
as described for compound P1 using intermediate 31-c and
1-(2-fluoro-4-methoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one
46-c as starting material.
[1082] m/z=491 (M+1).sup.+
[1083] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.79-2.03
(m, 2H) 2.52-2.56 (m, 2H) 3.87 (s, 3H) 4.22-4.45 (m, 2H) 5.41 (s,
2H) 6.51 (s, 1H) 6.91 (d, J=5.94 Hz, 1H) 6.97-7.05 (m, 1H)
7.11-7.21 (m, 2H) 7.54 (d, J=9.02 Hz, 1H) 7.57-7.63 (m, 2H) 8.23
(d, J=5.50 Hz, 1H) 8.53 (s, 1H)
Example 46
Synthesis of
4-(5-chloro-2-((2-oxo-1-p-tolyl-1H-imidazo[4,5-c]pyridin-3(2H)-yl)methyl)-
-1H-indol-1-yl)butanenitrile (P46)
##STR00102##
[1085] Compound P46 was prepared by an analogous reaction protocol
as described for compound P1 using intermediate 31-c and
1-p-tolyl-1H-imidazo[4,5-c]pyridin-2(3H)-one 51-c as starting
material.
[1086] m/z=457 (M+1).sup.+
[1087] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.94 (quin,
J=7.54 Hz, 2H) 2.41 (s, 3H) 2.52-2.58 (m, 2H) 4.23-4.45 (m, 2H)
5.43 (s, 2H) 6.55 (s, 1H) 7.07 (d, J=5.50 Hz, 1H) 7.16 (dd, J=8.69,
2.09 Hz, 1H) 7.37-7.50 (m, 4H) 7.54 (d, J=8.80 Hz, 1H) 7.57 (d,
J=1.98 Hz, 1H) 8.24 (d, J=5.50 Hz, 1H) 8.52 (s, 1H)
Example 47
Synthesis of
4-(5-chloro-2-((1-(2,4-dimethoxyphenyl)-2-oxo-1H-imidazo[4,5-c]pyridin-3(-
2H)-yl)methyl)-1H-indol-1-yl)butanenitrile (P47)
##STR00103##
[1089] Compound P47 was prepared by an analogous reaction protocol
as described for compound P1 using intermediate 31-c and
1-(2,4-dimethoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 52-c as
starting material.
[1090] m/z=503 (M+1).sup.+
[1091] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.74-2.06
(m, 2H) 3.35-3.42 (m, 2H) 3.73 (s, 3H) 3.86 (s, 3H) 4.19-4.47 (m,
2H) 5.40 (s, 2H) 6.54 (s, 1H) 6.70 (dd, J=8.80, 2.64 Hz, 1H) 6.73
(d, J=4.84 Hz, 1H) 6.82 (d, J=2.64 Hz, 1H) 7.16 (dd, J=8.80, 1.98
Hz, 1H) 7.39 (d, J=8.58 Hz, 1H) 7.53 (d, J=8.80 Hz, 1H) 7.59 (d,
J=2.20 Hz, 1H) 8.17 (d, J=5.28 Hz, 1H) 8.49 (s, 1H)
Example 48
Synthesis of
4-(5-chloro-2-((2-oxo-1-(pyridin-4-yl)-1H-imidazo[4,5-c]pyridin-3(2H)-yl)-
methyl)-1H-indol-1-yl)butanenitrile (P48)
##STR00104##
[1093] Compound P48 was prepared by an analogous reaction protocol
as described for compound P1 using intermediate 31-c and
1-(pyridin-4-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 34-c as
starting material.
[1094] m/z=444 (M+1).sup.+
[1095] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.98 (quin,
J=7.48 Hz, 2H) 2.56 (t, J=7.37 Hz, 2H) 4.27-4.42 (m, 2H) 5.45 (s,
2H) 6.54 (s, 1H) 7.17 (dd, J=8.69, 2.09 Hz, 1H) 7.41 (dd, J=5.39,
0.55 Hz, 1H) 7.51-7.59 (m, 2H) 7.71-7.77 (m, 2H) 8.32 (d, J=5.50
Hz, 1H) 8.57 (s, 1H) 8.74-8.85 (m, 2H)
Example 49
Synthesis of
4-(5-chloro-2-((2-oxo-1-(thiazol-2-yl)-1H-imidazo[4,5-c]pyridin-3(2H)-yl)-
methyl)-1H-indol-1-yl)butanenitrile (P49)
##STR00105##
[1097] Compound P49 was prepared by an analogous reaction protocol
as described for compound P1 using intermediate 31-c and
1-(thiazol-2-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 21-c as
starting material.
[1098] m/z=450 (M+1).sup.+
[1099] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.98 (quin,
J=7.59 Hz, 2H) 2.57 (t, J=7.37 Hz, 2H) 4.36 (t, J=7.59 Hz, 2H) 5.49
(s, 2H) 6.51 (s, 1H) 7.16 (dd, J=8.69, 2.09 Hz, 1H) 7.49-7.58 (m,
2H) 7.63 (d, J=3.52 Hz, 1H) 7.79 (d, J=3.52 Hz, 1H) 8.34 (d, J=5.28
Hz, 1H) 8.47 (d, J=5.28 Hz, 1H) 8.63 (s, 1H)
Example 50
Synthesis of
4-(3-((5-chloro-1-(3-cyanopropyl)-1H-indol-2-yl)methyl)-2-oxo-2,3-dihydro-
-1H-imidazo[4,5-c]pyridin-1-yl)benzonitrile (P50)
##STR00106##
[1101] Compound P50 was prepared by an analogous reaction protocol
as described for compound P1 using intermediate 31-c and
4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)benzonitrile
47-c as starting material.
[1102] m/z=468 (M+1).sup.+
[1103] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.88-2.07
(m, 2H) 2.53-2.61 (m, 2H) 4.36 (t, J=7.70 Hz, 2H) 5.44 (s, 2H) 6.56
(s, 1H) 7.17 (dd, J=8.80, 1.98 Hz, 1H) 7.27 (d, J=5.28 Hz, 1H)
7.49-7.59 (m, 2H) 7.88 (d, J=8.58 Hz, 2H) 8.09 (d, J=8.58 Hz, 2H)
8.29 (d, J=5.50 Hz, 1H) 8.56 (s, 1H)
Example 51
Synthesis of methyl
4-(3-((5-chloro-1-(3-cyanopropyl)-1H-indol-2-yl)methyl)-2-oxo-2,3-dihydro-
-1H-imidazo[4,5-c]pyridin-1-yl)benzoate (P51)
##STR00107##
[1105] Compound P51 was prepared by an analogous reaction protocol
as described for compound P1 using intermediate 31-c and methyl
4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)benzoate 48-c as
starting material.
[1106] m/z=501 (M+1).sup.+
[1107] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.89-2.13
(m, 2H) 2.58 (t, J=7.37 Hz, 2H) 3.92 (s, 3H) 4.26-4.43 (m, 2H) 5.50
(s, 2H) 6.58 (s, 1H) 7.18 (dd, J=8.69, 2.09 Hz, 1H) 7.50-7.60 (m,
3H) 7.78-7.87 (m, 2H) 8.17-8.25 (m, 2H) 8.50 (d, J=6.16 Hz, 1H)
8.79 (s, 1H)
Example 52
Synthesis of
4-(3-((5-chloro-1-(3-cyanopropyl)-1H-indol-2-yl)methyl)-2-oxo-2,3-dihydro-
-1H-imidazo[4,5-c]pyridin-1-yl)benzoic acid (P52)
##STR00108##
[1109] Compound P51 (650 mg, 1.17 mmol) was dissolved in 75 mL
THF/Water (3:1) and a excess LiOH (112 mg, 4.68 mmol, 4 eq.) was
added at room temperature. After two days stirring at room
temperature the solution was adjusted till pH=6 with HCl (6M in
water). The solid was filtered off and further crystallized in
MeOH/water to give the title compound P52 (335 mg, 60%).
[1110] m/z=487 (M+1).sup.+
[1111] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.87-2.04
(m, 2H) 2.53-2.59 (m, 2H) 4.21-4.50 (m, 2H) 5.43 (s, 2H) 6.50 (s,
1H) 7.17 (dd, J=8.58, 1.98 Hz, 1H) 7.25 (d, J=5.72 Hz, 1H)
7.44-7.62 (m, 2H) 7.77 (d, J=7.70 Hz, 2H) 8.08-8.20 (m, 2H) 8.28
(d, J=5.50 Hz, 1H) 8.55 (s, 1H)
Example 53
Synthesis of
4-(3-((5-chloro-1-(3-cyanopropyl)-1H-indol-2-yl)methyl)-2-oxo-2,3-dihydro-
-1H-imidazo[4,5-c]pyridin-1-yl)-N-cyclopropylbenzamide (P53)
##STR00109##
[1113] To a solution of compound P52 (220 mg, 0.439 mmol) in 40 mL
DMF, was added cyclopropylamine (0.092 mL, 1.32 mmol, 3 eq.),
triethylamine (0.183 mL, 1.32 mmol, 3 eq.) and diethyl
cyanophosphonate (0.2 mL, 1.32 mmol, 3 eq.) at room temperature.
After 16 hours the solution was concentrated in vacuo and taken up
in diethyl ether. The solid was filtered off and further
crystallized in Diisopropyl ether/acetonitrile to yield the title
compound P53 (160 mg, 68%) as a white solid.
[1114] m/z=526 (M+1).sup.+
[1115] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.49-0.66
(m, 2H) 0.69-0.77 (m, 2H) 1.80-2.10 (m, 2H) 2.53-2.63 (m, 2H)
2.75-3.01 (m, 1H) 4.14-4.50 (m, 2H) 5.44 (s, 2H) 6.55 (s, 1H)
7.12-7.20 (m, 2H) 7.55 (d, J=8.80 Hz, 1H) 7.57 (d, J=1.98 Hz, 1H)
7.70 (d, J=8.58 Hz, 2H) 8.03 (d, J=8.80 Hz, 2H) 8.28 (d, J=5.28 Hz,
1H) 8.55 (s, 1H) 8.58 (d, J=3.96 Hz, 1H)
Antiviral Activity
[1116] Black 96-well clear-bottom microtiter plates (Corning,
Amsterdam, The Netherlands) were filled in duplicate using a
customized robot system with serial 4-fold dilutions of compound in
a final volume of 50 .mu.l culture medium [RPMI medium without
phenol red, 10% FBS, 0.04% gentamycin (50 mg/ml) and 0.5% DMSO].
Then, 100 .mu.l of a HeLa cell suspension (5.times.10.sup.4
cells/ml) in culture medium was added to each well followed by the
addition of 50 .mu.l rgRSV224 (MOI=0.02) virus in culture medium
using a multidrop dispenser (Thermo Scientific, Erembodegem,
Belgium). rgRSV224 virus is an engineered virus that includes an
additional GFP gene (Hallak et al, 2000) and was in-licensed from
the NIH (Bethesda, Md., USA). Medium, virus- and mock-infected
controls were included in each test. Cells were incubated at
37.degree. C. in a 5% CO.sub.2 atmosphere. Three days post-virus
exposure, viral replication was quantified by measuring GFP
expression in the cells by a MSM laser microscope (Tibotec, Beerse,
Belgium). The EC.sub.50 was defined as the 50% inhibitory
concentration for GFP expression. In parallel, compounds were
incubated for three days in a set of white 96-well microtiter
plates (Corning) and the cytotoxicity of compounds in HeLa cells
was determined by measuring the ATP content of the cells using the
ATPlite kit (PerkinElmer, Zaventem, Belgium) according to the
manufacturer's instructions. The CC.sub.50 was defined as the 50%
concentration for cytotoxicity.
REFERENCES
[1117] Hallak L K, Spillmann D, Collins P L, Peeples M E.
Glycosaminoglycan sulfation requirements for respiratory syncytial
virus infection. J. Virol. 740, 10508-10513 (2000).
[1118] The following compounds were prepared according to the
working examples.
TABLE-US-00001 WT act- ivity Tox Structure pEC.sub.50 pCC.sub.50 P1
##STR00110## 8.3 4.3 P2 ##STR00111## 7.9 5.0 P3 ##STR00112##
.cndot.0.17 CF.sub.3COOH 7.0 4.9 P4 ##STR00113##
.cndot.CF.sub.3COOH 7.5 <4.0 P5 ##STR00114## 8.8 4.0 P6
##STR00115## 8.4 <4.6 P7 ##STR00116## 9.3 4.3 P8 ##STR00117##
8.6 4.4 P9 ##STR00118## 9.0 <4.0 P10 ##STR00119## n.d. n.d. P11
##STR00120## 7.9 <4.6 P12 ##STR00121## 7.4 4.9 P13 ##STR00122##
n.d. n.d. P14 ##STR00123## 9.4 4.9 P15 ##STR00124## 9 <4 P16
##STR00125## 9 <4.3 P17 ##STR00126## 8 <4 P18 ##STR00127##
8.7 <4 P19 ##STR00128## 9.9 <4 P20 ##STR00129## 9.4 <4 P21
##STR00130## 8.2 <4 P22 ##STR00131## 8.4 4.6 P23 ##STR00132##
8.1 <4 P24 ##STR00133## 8 <4.3 P25 ##STR00134## 7.8 <4.3
P26 ##STR00135## 7.6 <4 P27 ##STR00136## 7.5 <4 P28
##STR00137## 9.7 <4 P29 ##STR00138## 8.9 <4 P30 ##STR00139##
8.8 <4 P31 ##STR00140## 8.8 <4 P32 ##STR00141## 8.4 4.1 P33
##STR00142## 8 <4 P34 ##STR00143## 7.5 <4 P35 ##STR00144##
9.5 4.5 P36 ##STR00145## 8.8 4.2 P37 ##STR00146## 8.8 <4 P38
##STR00147## 8.8 <4 P39 ##STR00148## 8.4 4.6 P40 ##STR00149## --
<4 P41 ##STR00150## 9.7 <4 P42 ##STR00151## 9.5 <4 P43
##STR00152## 9.4 <4 P44 ##STR00153## 9 <4 P45 ##STR00154## 9
4.8 P46 ##STR00155## 8.9 <4 P47 ##STR00156## 8.8 <4 P48
##STR00157## 8.6 <4 P49 ##STR00158## 8.2 <4.6 P50
##STR00159## -- -- P51 ##STR00160## 9.1 4.4 P52 ##STR00161## 9.3
<4.6 P53 ##STR00162## 9.3 4.6
[1119] The following compounds can be prepared according to the
working examples:
##STR00163##
Composition Examples
[1120] "Active ingredient" (a.i.) as used throughout these examples
relates to a compound of Formula (I), including any stereoisomeric
form thereof, or a pharmaceutically acceptable addition salt or a
solvate thereof; in particular to any one of the exemplified
compounds.
[1121] Typical examples of recipes for the formulation of the
invention are as follows:
1. Tablets
TABLE-US-00002 [1122] Active ingredient 5 to 50 mg Di-calcium
phosphate 20 mg Lactose 30 mg Talcum 10 mg Magnesium stearate 5 mg
Potato starch ad 200 mg
2. Suspension
[1123] An aqueous suspension is prepared for oral administration so
that each milliliter contains 1 to 5 mg of active ingredient, 50 mg
of sodium carboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg
of sorbitol and water ad 1 ml.
3. Injectable
[1124] A parenteral composition is prepared by stirring 1.5%
(weight/volume) of active ingredient in 0.9% NaCl solution or in
10% by volume propylene glycol in water.
4. Ointment
TABLE-US-00003 [1125] Active ingredient 5 to 1000 mg Stearyl
alcohol 3 g Lanoline 5 g White petroleum 15 g Water ad 100 g
[1126] In this Example, active ingredient can be replaced with the
same amount of any of the compounds according to the present
invention, in particular by the same amount of any of the
exemplified compounds.
[1127] Reasonable variations are not to be regarded as a departure
from the scope of the invention. It will be obvious that the thus
described invention may be varied in many ways by those skilled in
the art.
* * * * *