Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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i
Novel heterocyclic NF-xB Inhibitors
Field of the invention
The present invention relates to compounds of the general formula (Ia), (Ib),
(Ic), (II), or
(III) or a stereoisomer thereof or possible pharmaceutically acceptable salts
thereof with an
acid or a base, or pharmaceutically acceptable prodrugs of these compounds,
for use as a
medicament. The compounds of the invention are exceptionally useful for the
treatment of
diseases associated with abnormal and hyperproliferation of cells in mammals,
especially
in humans. In particular, they are useful for the treatment of diseases
characterized by a
hyperproliferation of T-cells.
The present invention relates to compounds which are suitable for the therapy
of diseases
that can be treated by modulating cellular pathways in eukaryotes, e.g.
cancer,
immunological or inflammatory disorders, and viral infections, to fiuther
processes for the
preparation of these compounds, and to their use.
T-cell homeostasis is critical for the maintenance of immune tolerance.
Defects in T-cell
homeostasis can lead to autoiinmune pathology. Autoimmune diseases include a
large
spectrum of clinically distinct entities that share a common aetiology, a
misguided, self-
directed immune response.
This immune response can also be the consequence of an organ transplant.
Evidence suggests a prime role of T-cell reactivity in autoimmune diseases.
Measuring
proliferative responses in T-lymphocytes is a widely used assay to measure
immune
competence (Killestein, J. et al. J. NeuNoirnmunol. 133,217-24, 2002).
We used a nonradioactive technique for the measurement of in vitro T-cell
proliferation
(Messele, T. et al. Clinical and Diagnostic Laboratory Imnzunology 687-692,
2000).
Peripheral blood mononuclear cells (PBMCs) were isolated from human blood
obtained
from volunteer donators. PBMCs were isolated by centrifugation in ACCUSPIN
tubes
using HISTOPAQUE.
PBMCs were stimulated with PHA and cell proliferation was measured with a
Roche
colorimetric BromUridin incorporation ELISA kit.
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WO 2007/016979 PCT/EP2006/002396
2,
Regulation of the immune response is controlled by a variety of signalling
pathways such
as T-cell or TNF receptor signalling (Chen, G. et al. Science 296, 1634-1635,
2002). To
fiarther characterize targets of compounds which we found active in the T-cell
proliferation
assay, we tested the compounds on their ability to inhibit the human
proteasome.
The major neutral proteolytic activity in the cytosol and nucleus is the
proteasome, a 20S
(700 kDa) particle with multiple peptidase activities. The continual turnover
of cellular
proteins by the ubiquitin-proteasome pathway is used by the immune system to
screen for
the presence of abnormal intracellular proteins (Dantuma, N.P. et al. Nat.
Biotechnol.
2000, 18(5), 538-43; Goldberg, AL. et al. Nature 357, 375, 1993).
The ubiquitin-proteasome pathway plays an essential role in the regulation of
NF-xB
activity, being responsible for the degradation of the inhibitor IxB-a. In
order to be targeted
for degradation by the proteasome, IKB-a must first undergo selective
phosphorylation at
serine residues 32 and 36, followed by ubiquitinylation (Chen, ZI. et al.Cell
84, 853-862,
1996; Brown, K. et al. Science 267, 1485,1995):
NF-xB, a transcription factor, regulates the transcription of an important set
of genes,
involved in inflammatory responses (Baeuerle, PA. et al. Cell 87, 1, 13-20,
1996).
Proteasome inhibitors block IxB-a degradation and NF-icB activation (Traeckner
et al.
EMBO J. 13, 5433,1994).
Patents describing proteasome inhibitors have been described in reviews
(Adams, J. et al.
Ann. Rev. 1llea'. Chem. 31, 279-288, 1996) and in patents US 6117887, US
5834487, WO
00/004954, WO 00/04954, WO 00/170204, WO 00/33654, WO 00/64863, WO 00/114324,
WO 99/15183, WO 99/37666.
Here we describe novel chemical entities with proteasome inhibitory activity.
NF-xB (Nuclear Factor-icB) is an eucariotic transcription factor of the rel
family, which is
located in the cyctoplasm in an inactive complex, as a homo- or heterodimer.
Predominantly it exists as a heterodimer composed of p50 and p65 subunits,
bound to
inhibitory proteins of the IxB family, usually IxB-a (D. Thanos et al., Cell
80, 529, 1995).
NF-xB is activated in response to different stimuli, among which inflammatory
cytokines,
UV radiation, phorbol esters, bacterial and viral infections. Stimulation
triggers the release
of NF-icB from IxB in consequence of the phosphorylation and the following
degradation
of the IxB-a protein (P.A. Baeuerle et al., Annu. Rev. Immunol. 12, 141, 1995)
by the
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proteasome. Once it is set free, NF-xB translocates in the nucleus where it
binds to the
DNA at specific -ic.B-sites and induces the transcription of a variety of
genes encoding
proteins involved in controlling the immune and inflammatory responses,
amongst others
interleukins, TNF-a, the NO-synthase and the cyclooxigenase 2 (S. Grimm et
al., J.
Biochem. 290, 297, 1993). Accordingly, NF-xB is considered an early mediator
of the
immune and inflammatory responses and it is involved in the control of cell
proliferation
and in the pathogenesis of various human diseases, such as rheumatoid
arthritis (H. Beker
et al., Clin. Exp. Immunol. 99, 325, 1995), ischemia (A. Salminen et al.,
Biochem. Biophys.
Res. Comm. 212, 939, 1995), arteriosclerosis (A.S. Baldwin, Annals Rev.
Immunol. 212,
649, 1996), as well as in the pathogenesis of AIDS.
Inhibition of NF-xB mediated gene transcription can be accomplished through
inhibition
of phosphorylation of the inhibitory protein IxB, inhibition of IxB
degradation, inhibition
of NF-xB (p50/p65) nuclear translocation, the inhibition of NF-xB-DNA binding
or NF-
xB-mediated DNA transcription (J.C. Epinat et al., Oncogene 18, 6896, 1999).
The present invention relates to compounds of the general formula (Ia) or a
pharmaceutically acceptable salts thereof with an acid or a base, or
pharmaceutically
acceptable prodrugs or a stereoisomer thereof,
Y
N R2
RI N X N
R Z Rc (Ia)
wherein
R is independeiitly hydrogen, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl,
haloalkyloxy, aryl, or heteroaryl;
R' is independently alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy,
aryl, or
heteroaryl;
X is CO, CS or SOa;
Y is CO, CS or SO2;
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Z is NRZ', S, or 0;
R2' is H, alkyl, -C(O)NR7, -C(O)Re, cycloalkyl, haloalkyl, hydroxyalkyl,
hydroxyalkylamino, allcylamino, heteroaryl, or aryl;
R is independently H, OH, SH, NROR', NH2, alkylamino, hydroxyalkylamino,
halogen, CONRdRe, alkoxy, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl,
haloalkyloxy, aryl, or heteroaryl;
Rd is H, halogen, alkyl, -CW)NR7'R8, -(CHa)Paryl, -(CHa)pNR7RB, -C(O)NR7R8,
-N=CR7RB, -NR7C(O)R8, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino,
alkylamino, heteroaryl or aryl;
R7, RT independently represent H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl,
hydroxyalkylamino, alkylamino, heteroaryl or aryl;
R8 is H, NH2, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino,
alkylamino, heteroaryl or aryl;
Re independently represents H, -CN, -OH, -SH, -C02R4', -C(O)R4', -SO2NR4',
-NR4'RS', -C(O)NR7R8, -S02-alkyl, -S02R4', S03R4', -N=CR4'RS', NR4'C(O)R4",
-NR4'-CO-haloalkyl, -NOa, -NR4'-S02-haloalkyl, -NR4'-S02-alkyl, -NR4'-CO-
alkyl,
-NR4'(CHa)pheteroaryl, alkyl, hydroxyalkyl, cycloalkyl, alkylamino, aryl
hydroxyalkylamino, alkoxy, alkylthio, -O(CH2)p[O(CH2)p]qOCH3, -C(NR4")NR4'
-benzimidazolyl, -C(NR4")NR4'benzthiazolyl, -C(NR4")NR4'benz-oxazolyl, or
heteroaryl;
R4', R4", RS' independently represent H, alkyl, cycloalkyl, haloalkyl,
hydroxyalkyl,
hydroxyalkylamino, alkylamino, -C(NR7)NR7'R8, -(CH2)paryl, -CHa)pNR7R8, -
C(O)NRW, -N=CR7RB, -NR7C(O)R8, halogen, heteroaryl, or aryl
p is l to 6;
q islto6;
Ra is independently
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- -N R 5 -N ~ N R 5
, or - ~--/
R5 is independently H, COR6, C02R6, SOR6, S02R6, S03R6, alkyl, cycloalkyl,
alkoxy,
-NH2, alkylamine, -NR7COR6, halogen, -OH, -SH, alkylthio, hydroxyalkyl,
haloalkyl, haloalkyloxy, aryl or heteroaryl;
5 R6 is independently H, alkyl, cycloalkyl, amino, haloalkyl, hydroxyalkyl,
hydroxyalkylamino, alkylamino, aryl or heteroaryl;
an alkyl group, if not stated otherwise, denotes a linear or branched Cl-C6-
alkyl, preferably
a linear or branched chain of one to five carbon atoms, a linear or branched
C2-C6-alkenyl
or a linear or branched C2-C6-allcinyl group, which can optionally be
substituted by one or
more substituents R';
the Cl-C6-alkyl, C2-C6-alkenyl and C2-C6-alkinyl residue may be selected fiom
the group
comprising -CH3, -C2H5, -CH=CH2, -C=CH, -C3H7, -CH(CH3)2, -CH2-CH=CH2,
-C(CH3)=CH2, -CH=CH-CH3, -C=C-CH3, -CH2-C=CH, -C4H9, -CH2-CH(CH3)2,
-CH(CH3)-C2H5, -C(CH3)3, -CsHii, -C6H13, -C(IV )3, -C2(W)5, -CHa-C(R')3, -
C3K)7,
-C2H4-C(R')3, -C2H4-CH=CH2, -CH=CH-C2H5, -CH=C(CH3)2, -CHa-CH=CH-CH3,
-CH=CH-CH=CH2, -CaH4-C=CH, -C=C-C2H5, -CHa-C C-CH3, -C=C-CH=CH2,
-CH=CH-C=CH, -C=C-C CH, -CaH4-CH(CH3)a, -CH(CH3)-C3H7, -CH2-CH(CH3)-
C2H5, -CH(CH3)-CH(CH3)2, -C(CH3)2-CaH5, -CH2-C(CH3)3, -C3H6-CH=CH2,
-CH=CH-C3H7, -C2H4.-CH=CH-CH3, -CHa-CH=CH-C2H5, -CH2-CH=CH-CH=CH2,
-CH=CH-CH=CH-CH3, -CH=CH-CH2-CH=CH2, -C(CH3)=CH-CH=CHa,
-CH=C(CH3)-CH=CHa, -CH=CH-C(CH3)=CH2, -CH2-CH=C(CH3)2, C(CH3)=C(CH3)2,
-C3H6-C=CH, -C=C-C3H7, -C2H4-C=C-CH3, -CH2-C=C-C2H5, -CH2-C=C-CH=CH2,
-CH2-CH=CH-C=CH, -CH2-C=C-C=CH, -C=C-CH=CH-CH3, -CH=CH-C=C-CH3,
-C=C-C=C-CH3, -C=C-CH2-CH=CH2, -CH=CH-CHa-C=CH, -C=C-CH2-C=CH,
-C(CH3)=CH-CH=CH2, -CH=C(CH3)-CH=CH2, -CH=CH-C(CH3)=CH2, -C(CH3)=CH-
C=CH, -CH=C(CH3)-C=CH, -C=C-C(CH3)=CH2, -C3H6-CH(CH3)2, -C2H4-CH(CH3)-
C2H5, -CH(CH3)-C4H9, -CH2-CH(CH3)-C3H7, -CH(CH3)-CH2-CH(CH3)2, -CH(CH3)-
CH(CH3)-C2H5, -CH2-CH(CH3)-CH(CH3)2, -CHa-C(CH3)a-C2H5, -C(CH3)2-C3H7, -
C(CH3)2-CH(CH3)2, -C2H4-C(CH3)3, -CH(CH3)-C(CH3)3, -C4H8-CH=CH2, -CH=CH-
C4H9, -C3H6---CH=CH-CH3a -CH2-CH=CH-C3H7, -C2H4-CH=CH-C2H5, -CHa-
C(CH3)=C(CH3)2, -C2H4-CH=C(CH3)2, -C4H8-C=CH, -C=C-C4H9, -C3H6-C=C-CH3i
-CHa-C=C-C3H7, -C2H4-C=C-C2H5;
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R' is independently H, -COaR", -CONHR", -CR"O, -SO2NR", -NR"-CO-haloalkyl,
-NO2, NNR"-S02-haloalkyl, -NR"-S02-alkyl, -S02-alkyl, -NR"-CO-alkyl, -CN,
alkyl,
cycloalkyl, alkylamino, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl,
hydroxyalkylamino,
halogen, haloalkyl, haloalkyloxy, aryl, or heteroaryl;
R" is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, or
heteroaryl;
a cycloalkyl group denotes a non-aromatic ring system containing three to
eight carbon
atoms, preferably four to eight carbon atoms, wherein one or more of the
carbon atoms in
the ring can be substituted by a group E, E being 0, S, SO, SO2, N, or NR", R"
being as
defined above; the C3-C$-cycloalkyl residue may be selected from the group
comprising
-cyclo-C3H5, -cyclo-C4H~, -cyclo-C5H9, -cyclo-C6H11, -cyclo-C7H13, -cyclo-
C8H15,
morpholine-4-yl, piperazinyl, 1-alkylpiperazine-4-yl;
an alkoxy group denotes an 0-alkyl group, the alkyl group being as defined
above; the
alkoxy group is preferably a methoxy, ethoxy, isopropoxy, t-butoxy or pentoxy
group;
an alkylthio group denotes an S-alkyl group, the alkyl group being as defmed
above;
an haloalkyl group denotes an alkyl group which is substituted by one to five
halogen
atoms, the alkyl group being as defined above; the haloalkyl group is
preferably a-C(R10)3,
-CR10(Rl0 )2, -CR10(R10 )R10 ', -C2(R10)5, -CHa-C(R10)3, -CH2-CR1 (Ri0 )2, -
CH2-
CRI0(R10')R10 , -C3(Rio),, or -C2H4-C(R10)3, wherein Rlo, Rl , Rlo
represent F, Cl, Br or
I, preferably F;
a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being as
defined above;
an haloalkyloxy group denotes an alkoxy group which is substituted by one to
five halogen
atoms, the alkyl group being as defined above; the haloalkyloxy group is
preferably a
-OC(R10)3, -OCR10(Ri0 )2, -OCR10(R10 )R10 ', -OC2(Rlo)s, -OCH2-C(R10)3, -OCH2-
CR10(Rl0')a, -OCH2-CRI0(Ri0')R10", -OC3(Rl )7 or -OCaH4-C(R1 )3, wherein R10,
Rl0,
R101, represent F, Cl, Br or I, preferably F;
a hydroxyalkylamino group denotes an (HO-alkyl)a-N- group or HO-alkyl-NH-
group, the
alkyl group being as defined above;
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an alkylamino group denotes an HN-alkyl or N-dialkyl group, the alkyl group
being as
defmed above;
a halogen group. is chlorine, bromine, fluorine or iodine;
an aryl group denotes an aromatic group having five to fifteen carbon atoms,
which can
optionally be substituted by one or more substituents R', where R' is as
defined above; the
aryl group is preferably a benzyl group, a phenyl group, -o-C6H4- R', -m-C6H4-
R', -p-
C6H4- R', 1-naphthyl, 2-naphthyl, 1-anthracenyl or 2-anthracenyl;
a heteroaryl group denotes a 5- or 6-membered heterocyclic group which
contains at least
one heteroatom selected from 0, N, and S. This heterocyclic group can be fused
to another
aromatic ring. For example, this group can be selected from a thiadiazole,
thiazol-2-yl,
thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl,
oxazol-2-y1,
oxazol-4-yl, oxazol-5-yl, isooxazol-3-yl, isooxazol-4-yl, isooxazol-5-yl,
benzooxazol-2-yl,
benzooxazol-4-yl, benzooxazol-5-yl, benzoisooxazol-3-yl, benzoisooxazol-4-yl,
benzoisooxazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-
oxadiazol-3-yl,
1,2,5-oxadiazol-4-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, isothiazol-
3-yl,
isothiazol-4-y1, isothi.azol-5-yl, benzoisothiazol-3-yl, benzoisothiazol-4-yl,
benzoisothiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl, 1,2,5-
thiadiazol-4-
yl, 4-imidazolyl, benzoimidazol-4-yl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-
furanyl, 3-
furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyranyl, 3-
pyranyl, 4-
pyranyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrirnidinyl, 2,4-
d'unethoxy-6-
pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-
pyrazolyl, 4-
pyrazolyl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol73-yl, 1,2,4-
triazol-5-yl., 1.,3,5-
triazol-6-yl, 2,4-dimethoxy-1,3,5-triazol-6-yl, 1H-tetrazol-2-yl, 1H-tetrazol-
3-yl, tetrazolyl,
acridyl, furazane, indazolyl, pllenazinyl, carbazolyl, phenoxazinyl,
indolizine, 2-indolyl, 3-
indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 1-isoindolyl, 3-
isoindolyl, 4-isoindolyl,
5-isoindolyl, 6-isoindolyl, 7-isoindolyl, 2-indolinyl, 3-indolinyl, 4-
indolinyl, 5-indolinyl, 6-
indolinyl, 7-indolinyl, benzo[b]furanyl, benzofurazane, benzothiofiuazane,
benzotriazol-l-
y1, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl, benzotriazol-7-
yl, benzotriazine,
benzo[b]thiophenyl, benzimidazol-2-yl, 1H-benzinlidazolyl, benzimidazol-4-yl,
benzimidazol-5-yl, benzimidazol-6-yl, bel3zimidazol-7-yl, benzothiazolyl,
quinazolinyl,
quinoxazolinyl, cinnoline, quinolinyl, tetrahydroquinolinyl, isoquinolinyl,
tetrahydro-
isoquinolinyl,pu.rixie, phthalazixie, pteridine, thiatetraazaindene,
thiatriazaindene,
isothiazolopyrazine, isothiazolopyrimidine, pyrazolotriazine,
pyrazolopyrimidine, tetra-
hydrothieno[3,4-d]imidazol-2-one, pyrazolo[5,1-c][1,2,4]triazine, 2,3-
dihydrobenzo[1,4]-
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dioxiii-2-yl, 2,3-dihydrobenzo[1,4]-dioxin-3-yl, 2,3-dihydrobenzo[1,4]-dioxin-
5-yl, 2,3-
dihydrobenzo[1,4]-dioxin-6-yl, 2,6-dimethoxypyrimidin-3-yl, 2,6-dh-
nethoxypyrimidin-4-
yl, imidazopyridazine, imidazopyrirnid.ine, imidazopyridine,
imidazolotriazine,
triazolotriazine, triazolopyridine, triazolopyrazine, triazolopyrimidine, or 4-
[1,2,4]triazolo[4,3-a]pyridin-3-yl, 1-furo[2,3-c]pyridin-4-yl, 1-furo[2,3-
c]pyridin-5-yl, 1-
furo[2,3-c]pyridin-3-yl, and triazolopyridazine group. This heterocyclic group
can be
substituted by one or more substituents R', wherein R' is as defined above.
The present invention relates to compounds of the general formula (Ib) or
pharmaceutically
acceptable salts thereof with an acid or a base, or pharmaceutically
acceptable prodrugs or
a stereoisomer thereof,
Ra Rb
R2
RI N
/ Y
s"
R4
Z Rc (ro)
wherein
R' is -C(O)R7, -C(O)CHICRB, -C(O)NR7RB, -C(O)OR7, -R7C(O)R8, or -C(S)R7;
R9 independently represents H, -CN, -OH, -SH, -CO2R4', -C(O)R4', -SO2NR4',
-NR4'RS', -C(O)NR7Rg, -S02-alkyl, -S02R4', S03R4', -N=CR4'RS', -NR4'C(O)R4",
-NR4'-CO-haloalkyl, -NO2, -NR4'-S02-haloalkyl, -NR4'-SO2-alkyl, -NR4'-CO-
alkyl,
-NR4'(CH2)pheteroaryl, alkyl, hydroxyalkyl, cycloalkyl, alkylamino, aryl
hydroxyalkylamino, alkoxy, alkylthio, -O(CH2)p[O(CH2)P]qOCH3, -C(NR4")NR4'-
benzimidazolyl, -C(NR4")NR4'benzthiazolyl, -C(NR4")NR4'benzoxazolyl,
-(CH2)pNIeCORB, or heteroaryl;
R4 is H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino,
alkylamino,
heteroaryl, aryl ,
or Rl and R4 together with the X to which they are attached form a 3 to 8
membered
saturated or at least partially unsaturated monocyclic or polycyclic ring
system,
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9
wherein at least one ring atom is a heteroatom selected from 0, N, and S, and
the
ring optionally has one or more substituents R9;
X is N, or CR2';
Y is CO, CS or SO2;
Z is NR2", S, or 0;
R2" is H, alkyl, -C(O)NR7, -C(O)Re, cycloalkyl, haloalkyl, hydroxyalkyl,
hydroxyalkylamino, alkylamino, heteroaryl, or aryl;
Ra' is H, alkyl, -C(O)N R4', -C(O) R4', cycloalkyl, haloalkyl, hydroxyalkyl,
hydroxy-
alkylamino, alkylamino, heteroaryl, or aryl;
R4 , R4", RS' independently represent H, alkyl, cycloalkyl, haloalkyl,
hydroxyalkyl,
hydroxyalkylamino, alkylamino, -C(NR7)NR7'R8, -(CHa)Paryl, -CHa)pNR7R8,
-C(O)NR7R8, -N=CR7RB, -NR7C(O)R8, halogen, heteroaryl, or aryl
p is l to 6;
q is l to 6;
Ra is, independently H, OH, SH, NH2, allcyl, cycloalkyl, hydroxyalkyl,
haloalkyl,
haloalkyloxy, alkoxy, alkylamino, hydroxyalkylamino, halogen, aryl, or
heteroaryl;
Rb is independently H, OH, SH, NH2, alkyl, cycloalkyl, hydroxyalkyl,
haloalkyl,
haloalkyloxy, alkoxy, alkylamino, hydroxyalkylamino, halogen, aryl, or
heteroaryl;
R is independently H, OH, SH, NR4'OR5', NH2, alkylamino, hydroxyalkylamino,
halogen, CONRdRe, alkoxy, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl,
haloalkyloxy, aryl, or heteroaryl;
Rd is H, halogen, alkyl, -C(NR7)NIft8, -(CH2)paryl, -(CHa)pNR7RB, -C(O)NR7RB,
-N=CR'R8, -NWC(O)Rg, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino,
alkylamino, heteroaryl or aryl;
R7, RT independently represent H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl,
liydroxyalkylamino, alkylamino, heteroaryl or aryl;
R8 is H, NH2, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino,
alkylamino, heteroaryl or aryl;
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,
Re independently represents H, -CN, -OH, -SH, -C02R4', -C(O)R4', -SO2 4'
-NR4'RS', -C(O)NR7R8, -S02-alkyl, -SO2R4', S03R4', -N=CR4'RS', -NR4'C(O)R4",
NR4'-CO-haloalkyl, -NOa, -NR4'-S02-haloalkyl, -NR4'-S02-alkyl, -NR4'-CO-alkyl,
-NR4'(CH2)pheteroaryl, alkyl, hydroxyalkyl, cycloalkyl, alkylamino, hydroxy-
5 alkylamino, alkoxy, alkylthio, -O(CH2)p[O(CH2)p]qOCH3, -C(NR4")NR4'benz-
imidazolyl, -C(NR4")NR4'benzthiazolyl, -C(NR4")NR4'benzoxazolyl, aryl or
heteroaryl;
R2 is independently
- -N A R5
~1
10 n
A isN, 0, or CR2';
RS is independently H, SOR7, S02R7, S03R7, -C(O)R~, -C(O)CHR7RB, -C(O)NR7RB, -
C(O)OR7, -R7C(O)R8, -C(S)R7, -C(NR7)NR7'R8, -(CH2)paryl, -(CH2)pNWRB, -
C(O)NR7R8, -N=CR7RB, -NR7C(O)R7', alkyl, cycloalkyl, alkoxy, -NH2, alkylamino,
hydroxyalkylamino, halogen, -OH, -SH, alkylthio, hydroxyalkyl, haloalkyl,
haloalkyloxy, aryl or heteroaryl;
n is 0 to2;
wherein
an alkyl group, if not stated otherwise, denotes a linear or branched C1-C6-
alkyl, preferably
a linear or branched chain of one to five carbon atoms, a linear or branched
C2-C6--alkenyl
or a linear or branched Ca-C6--allcinyl group, which can optionally be
substituted by one or
more substituents R';
the Cl-C6-alkyl, C2-C6-alkenyl and C2-C6--alkinyl residue may be selected from
the group
comprising -CH3, -C2H5, -CH=CH2, -C=CH, -C3H7, -CH(CH3)2, -CH2-CH=CH2,
-C(CH3)=CHa, -CH=CH-CH3, -C=C-CH3, -CH2-C=CH, -C4H9, -CHa-CH(CH3)2,
-CH(CH3)-C2H5, -C(CH3)3, -C5Hii, -C6H13, -C(W )3, -C2(R:)5, -CH2-C(R')3, -
C3(W)7a
-C2H4=C(R')3, -C2H4-CH=CH2, -CH=CH-C2H5, -CH=C(CH3)2, -CH2-CH=CH-CH3,
-CH=CH-CH=CH2, -C2H4-C CH, -C C-C2H5, -CH2-C=C-CH3, -C=C-CH=CH2,
-CH=CH-C=CH, -C=C-C=CH, -C2H4-CH(CH3)2, -CH(CH3)-C3H7, -CH2-CH(CH3)-
C2H5, -CH(CH3)-CH(CH3)2, -C(CH3)2-C2H5, -CH2-C(CH3)3, -C3H6-CH=CH2,
-CH=CH-C3H7, -CaH4-CH=CH-CH3, -CH2-CH=CH-CaH5, -CHa-CH=CH-CH=CH2,
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11
-CH=CH-CH=CH-CH3, -CH=CH-CH2-CH=CHa, -C(CH3)=CH-CH=CH2,
-CH=C(CH3)-CH=CH2, -CH=CH-C(CH3)=CH2, -CH2-CH=C(CH3)2, C(CH3)=C(CH3)2,
-C3H6-C=CH, -C=C-C3H7, -CZH4-C=C-CH3, -CHa-C=C-C2Hs, -CH2-C=C-CH=CHa,
-CH2-CH=CH, C=CH, -CH2-C=C-C=CH, -C=GCH=CH-CH3, -CH=CH-C=C-CH3,
-C=C-C=C-CH3, -C=C-CHZ-CH=CH2, -CH=CH-CH2-C=CH, -C=C-CH2-C=CH,
-C(CH3)=CH-CH=CH2, -CH=C(CH3)-CH=CH2, -CH=CH-C(CH3)=CH2, -C(CH3)=CH-
C=CH, -CH=C(CH3)-C=CH, -C=C-C(CH3)=CH2, -C3H6-CH(CH3)2, -C2H4-CH(CH3)-
C2H5, -CH(CH3)-C4Hg, -CHa-CH(CH3)-C3H7, -CH(CH3)-CH2-CH(CH3)2, -CH(CH3)-
CH(CH3)-C2H5, -CH2-CH(CH3)-CH(CH3)2, -CH2-C(CH3)2-CaHs, -C(CH3)2-C3H7, -
C(CH3)a-CH(CH3)2, -C2H4-C(CH3)3, -CH(CH3)-C(CH3)3, -C4H$-CH=CH2, -CH=CH-
C4H9, -C3H6-CH=CH-CH3, -CHZ-CH=CH-C3H7, -C2H4-CH=CH-C2H5, -CH2-
C(CH3)=C(CH3)2, -C2H4 CH=C(CH3)a, -C4H8-C=CH, -C=C-C4H9, -C3H6-C=C-CH3,
-CH2-C=C-C3H7, -C2H4-C=C-C2Hs;
R' is independently H, -COaR", -CONHR", -CR"O, -SOaNR", -NR"-CO-haloalkyl,
NO2, -NR"-S02-haloalkyl, -NR"-S02-alkyl, -SOZ-alkyl, NR"-CO-alkyl, -CN, alkyl,
cycloalkyl, alkylamino, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl,
hydroxyalkylamino,
halogen, haloalkyl, haloalkyloxy, aryl, or heteroaryl;
R" is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, or
heteroaryl;
a cycloalkyl group denotes a non-aromatic ring system containing three to
eight carbon
atoms, preferably four to eight carbon atoms, wherein one or more of the
carbon atoms in
the ring can be substituted by a group E, E being 0, S, SO, SOa, N, or NR", R"
being as
defined above; the C3-C$-cycloalkyl residue inay be selected from the group
comprising
-cyclo-C3Hs, -cyclo-C4H7, -cyclo-C5H9, -cyclo-C6H11, -cyclo-C7H13, -cyclo-
C$His,
morpholine-4-yl, piperazinyl, 1-alkylpiperazine-4-yl;
an alkoxy group denotes an 0-alkyl group, the alkyl group being as defined
above; the
alkoxy group is preferably a methoxy, ethoxy, isopropoxy, t-butoxy or pentoxy
group;
an allcylthio group denotes an S-allcyl group, the alkyl group being as
defined above;
an haloallcyl group denotes an alkyl group which is substituted by one to five
halogen
atoms, the alkyl group being as defined above; the haloalkyl group is
preferably a-C(R1 )3,
-CRio(Rio')2, -CR10(Rl0')R1o , -C2(Rio)sa -CH2-C(Rio)3, -CH2-CR10(Ri0')2, -
CHa-
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CRio(Rlo )Rio , -C3(R10)7, or -CaH4-C(Rl0)3, wherein Rlo, Rio , Rio
represent F, Cl, Br or
I, prefer,ably F;
a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being as
defined above;
an haloalkyloxy group denotes an alkoxy group which is substituted by one to
five halogen
atoms, the alkyl group being as defmed above; the haloalkyloxy group is
preferably a
-OC(R10)3, -OCRlO(Rl0 )2, -OCRio(Rio )Rio , -OC2(Rio)sa -OCH2-C(R10)3, -OCHI
CR10(R10')2, -OCH2-CRio(R1o )R1o ', -OC3(Ri )7 or -OC2H4-C(R10)3 wherein R10,
Rl0 ,
R10" represent F, Cl, Br or I, preferably F;
a hydroxyalkylamino group denotes an (HO-alkyl)2-N- group or HO-alkyl-NH-
group, the
alkyl group being as defined above;
an alkylamino group denotes an HN-alkyl or N-dialkyl group, the alkyl group
being as
defined above;
a halogen group is chlorine, bromine, fluorine or iodine;
an aryl group denotes an aromatic group having five to fifteen carbon atoms,
which can
optionally be substituted by one or more substituents R', where R' is as
defmed above; the
aryl group is preferably a benzyl group, a phenyl group, -o-C6H4- R', -m-C6H4-
R', p-
C6H4-R', 1-naphthyl, 2-naphthyl, 1-anthracenyl or 2-anthracenyl;
a heteroaryl group denotes a 5- or 6-membered heterocyclic group which
contains at least
one heteroatom selected from 0, N, and S. This heterocyclic group can be fused
to another
aromatic ring. For example, this group can be selected from a thiadiazole,
thiazol-2-yl,
thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl,
oxazol-2-yl,
oxazol-4-yl, oxazol-5-yl, isooxazol-3-yl, isooxazol-4-yl, isooxazol-5-yl,
beiizooxazol-2-yl,
benzooxazol-4-yl, benzooxazol-5-yl, benzoisooxazol-3-yl, benzoisooxazol-4-yl,
benzoisooxazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-
oxadiazol-3-yl,
1,2,5-oxadiazol-4-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, lsothiazol-
3-yl,
isothiazol-4-yl, isothiazol-5-yl, benzoisotliiazol-3-yl, benzoisotlziazol-4-
yl,
benzoisotliiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl,
1,2,5-thiadiazol-4-
yl, 4-imidazolyl, benzoimidazol-4-yl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-
furanyl, 3-
furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyranyl, 3-
pyranyl, 4-
pyranyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2,4-
dinlethoxy-6-
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pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-
pyrazolyl, 4-
pyrazolyl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-
triazol-5-yl, 1,3,5-
triazol-6-yl, 2,4-dimethoxy-1,3,5-triazol-6-yl, 1H-tetrazol-2-yl, 1H-tetrazol-
3-yl, tetrazolyl,
acridyl, furazane, indazolyl, phenazinyl, carbazolyl, phenoxazinyl,
usdolizine, 2-indolyl, 3-
indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 1-isoindolyl, 3-
lsolndolyl, 4-isoindolyl,
5-isoindolyl, 6-isoindolyl, 7-isoindolyl, 2-indolinyl, 3-indolinyl, 4-
indolinyl, 5-indolinyl, 6-
indolinyl, 7-indolinyl, benzo[b]furanyl, benzofiu=azane, benzothiofiirazane,
benzotriazol-l-
yl, benzotTiazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl, benzotriazol-7-
yl, benzotriazine,
benzo[b]thiophenyl, benzimidazol-2-yl, 1H-benzimidazolyl, benzimidazol-4-yl,
benz-
imidazol-5-yl, benzimidazol-6-yl, benzimidazol-7-yl, benzothiazolyl,
quinazolinyl,
quinoxazolinyl, cim.a.oline, quinolinyl, tetrahydroquinolinyl, isoquinolinyl,
tetrahydro-
isoquinolinyl,purine, phthalazine, pteridine, thiatetraazaindene,
thiatriazaindene, iso-
thiazolopyrazine, isothiazolopyrimidine, pyrazolotriazine, pyrazolopyrimidine,
tetrahydro-
thieno[3,4-d]imidazol-2-one, pyrazolo[5,1-c][1,2,4]triazine,
imidazopyridazine, imidazo-
pyrimidine, imidazopyridine, imidazolotriazine, triazolotriazine, 2,3-
dihydrobenzo[1,4]-
dioxin-2-yl, 2,3-dihydrobenzo[1,4]-dioxin-3-yl, 2,3-dihydrobenzo[1,4]-dioxin-5-
yl, 2,3-
dihydrobenzo[1,4]-dioxin-6-yl, 2,6-d'nnethoxypyrunidin-3-yl, 2,6-
dimethoxypyrimidin-4-
yl, triazolopyridine, triazolopyrazine, triazolopyrimidine, 4-
[1,2,4]triazolo[4,3-a]pyridin-3-
yl, 1-furo[2,3-c]pyridin-4-yl, 1-furo[2,3-c]pyridin-5-yl, 1-furo[2,3-c]pyridin-
3-yl, and
triazolopyridazine group. This heterocyclic group can be substituted by one or
more
substituents R', wherein R' is as defmed above.
The present invention relates to compounds of the general formula (Ic) or
pharmaceutically
acceptable salts thereof with an acid or a base, or pharmaceutically
acceptable prodrugs or
a stereoisomer thereof,
N YrN Y Rb
l
~ I Jm
Rg
N Z c
1 R
R 4 O X S (Ic)
wherein
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14
Rl independently represents H, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl,
haloalkyloxy, aryl, or heteroaryl;
X is CO, CS or SO2;
Y is CO, CS or SOa;
Z is NRa"5S, or 0;
R~" is H, alkyl, -C(O)NR7, -C(O)Re, cycloalkyl, haloalkyl, hydroxyalkyl,
hydroxy-
alkylamino, alkylamino, heteroaryl, or aryl;
R4', R4", RS' independently represent H, alkyl, cycloalkyl, haloalkyl,
hydroxyalkyl,
hydroxyallcylamino, alkylamino, -CW)NR7'R8, -(CH2)Paryl, -(CH2)pNR7R8,
-C(O)NR'R$, -N=CR7R8, -NR7C(O)R8, halogen, heteroaryl, or aryl
p is l to 6;
q is l to 6;
m is O to 4;
r is0,or1;
t is0,or1;
s is0,or1;
Rb is independently H, OH, SH, NR4'ORS', NH2, alkylamino, hydroxyalkylamino,
halogen, CONRdRe, alkoxy, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl,
haloallcyloxy, aryl, or heteroaryl;
R is independently H, OH, SH, NR4'ORS', NH2, alkylamino, hydroxyalkylamino,
halogen, CONRdRe, alkoxy, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl,
haloalkyloxy, aryl, or heteroaryl;
Rd is H, halogen, alkyl, -C(NR7)NICR8, -(CH2)paryl, -(CH2)pNWRB, -C(O)NR7R$,
-N=CR!R', -NR7C(O)R8, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino,
alkylamino, heteroaryl or aryl;
R7, RT independently represent H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl,
hydroxyalkylamino, alkylarnino, heteroaryl or aryl;
R8 is H, NH2, allcyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino,
alkylamin.o, heteroaryl or aryl;
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Re independently represents H, -CN, -OH, -SH, -CO2R4', -C(O)R4', -SO2NR4',
-NR4'RS', -C(O)NR7R8, -SOa-alkyl, -S02R4', S03R4', -N=CR4,R5', NR4'C(O)R4",
-Nl.Z4'-CO-haloalkyl, -NOa, NR4'-SOa-haloalkyl, -NR4'-S02-alkyl, -NR4'-C.'O-
alkyl,
5 -NR4'(CH2)pheteroaryl, alkyl, hydroxyalkyl, cycloalkyl, alkylamino,
hydroxyalkyl-
amino, alkoxy, alkylthio, -O(CH2)PLO(CHa)p1qOCH3a -C(NR4")NR4'benz-
imidazolyl, -C(NR4")NR4'benzthiazolyl, -C(NR4")NR4'benz-oxazolyl, aryl or
heteroaryl;
R3 is independently H, OH, SH, NR4'OR5', NHa, hydroxyalkylamino, alkylamino,
10 halogen, CONRdRe, alkoxy, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl,
haloalkyloxy, aryl, or heteroaryl;
an alkyl group, if not stated otherwise, denotes a linear or branched Cl-C6-
alkyl, preferably
a linear or branched chain of one to five carbon atoms, a linear or branched
Ca-C6-alkenyl
15 or a linear or branched C2-C6-allcinyl group, which can optionally be
substituted by one or
more substituents R';
the Cl-C6--alkyl, C2-C6-alkenyl and C2-C6-alkinyl residue may be selected from
the group
comprising -CH3, -C2H5, -CH=CH2, -C=CH, -C3H7, -CH(CH3)2, -CH2-CH=CH2,
-C(CH3)=CH2, -CH=CH-CH3, -C=C-CH3, -CHa-C=CH, -C4H9, -CH2-CH(CH3)2,
-CH(CH3)-C2H5, -C(CH3)3, -C5H11, -C6H13, -C(Fv )3, -C2(R')5, -CH2-C(R')3, -
C3(l'')7,
-C2H4-C(R')3, -C2H4-CH=CH2, -CH=CH-C2H5, -CH=C(CH3)2, -CHa-CH=CH-CH3,
-CH=CH-CH=CH2, -CaH4-C=CH, -C=C-CaH5, -CHa-C=C-CH3, -C=C-CH=CH2,
-CH=CH-C CH, -C=C-C=CH, -C2H4-CH(CH3)2, -CH(CH3)-C3H7, -CHa-CH(CH3)-
C2H5, -CH(CH3)-CH(CH3)2, -C(CH3)2-C2H5, -CH2-C(CH3)3, -C3H6-CH=CH2,
-CH=CH-C3H7, -C2H4-CH=CH-CH3, -CHa-CH=CH-C2H5, -CH2-CH=CH-CH=CHa,
-CH=CH-CH=CH-CH3, -CH=CH-CH2-CH=CH2, -C(CH3)=CH-CH=CH2,
-CH=C(CH3)-CH=CH2, -CH=CH-C(CH3)=CH2, -CH2-CH=C(CH3)2, C(CH3)=C(CH3)2,
-C3H6-C=CH, -C=C-C3H7, -C2H4-C=C-CH3, -CH2-C=C-CaH5, -CHa-C=C-CH=CH2,
-CHa-CH=CH-C=CH, -CH2-C=C-C=CH, -C=C-CH=CH-CH3, -CH=CH-C C-CH3,
-C=C-C=C-CH3, -C=C-CH2-CH=CHa, -CH=CH-CHa-C=CH, -C=C-CHa-C=CH,
-C(CH3)=CH-CH=CH2, -CH=C(CH3)-CH=CH2, -CH=CH-C(CH3)=CH2a -C(CH3)=CH-
C=CH, -CH=C(CH3)-C=CH, -C=C-C(CH3)=CHa, -C3H6-CH(CH3)2, -CaH4-CH(CH3)-
'C2H5, -CH(CH3)-C4H9, -CH2-CH(CH3)-C3H7, -CH(CH3)-CH2-CH(CH3)2, -CH(CH3)-
CH(CH3)-C2H5, -CH2-CH(CH3)-CH(CH3)2, -CHa-C(CH3)2-C2H5a -C(CH3)2-C3H7, -
C(CH3)2-CH(CH3)2, -C2H4-C(CH3)3, -CH(CH3)-C(CH3)3, -C4H8-CH=CH2, -CH=CH-
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C4H9, -C3H6-CH=CH-CH3, -CH2-CH=CH-C3H7, -C2H4-CH=CH-CZH5, -CHa-
C(CH3)=C(CH3)2, -CaH4-CH=C(CH3)2, -C4H8-C CH, -C=C-C4H9a -C3H~C C-CH3,
-CHa-C=C-C3H7, -C2HH4 C=C-CaH5a
R' is independently H, -CO2R", -CONHR", -CR"O, -SO2NR", -NR"-CO-haloalkyl,
-NO2, -NR"-SOa-haloallcyl, -NR"-S02-alkyl, -SOa-alkyl, NR"-CO-alkyl, -CN,
alkyl,
cycloalkyl, alkylamino, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl,
hydroxyalkylamino,
halogen, haloalkyl, haloalkyloxy, aryl, or heteroaryl;
R" is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, or
heteroaryl;
a cycloalkyl group denotes a non-aromatic ring system containing three to
eight carbon
atoms, preferably four to eight carbon atoms, wherein one or more of the
carbon atoms in
the ring can be substituted by a group E, E being 0, S, SO, SO2, N, or NR", R"
being as
defmed above; the C3-C8-cycloalkyl residue may be selected from the group
comprising
-cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -cyclo-C6H11, -cyclo-C7H13, -cyclo-
CsHis,
morpholine-4-yl, piperazinyl, 1 -alkylpiperazine-4-yl;
an alkoxy group denotes an 0-alkyl group, the alkyl group being as defined
above; the
alkoxy group is preferably a methoxy, ethoxy, isopropoxy, t-butoxy or pentoxy
group;
an alkylthio group denotes an S-alkyl group, the alkyl group being as defined
above;
an haloalkyl group denotes an alkyl group which is substituted by one to five
halogen
atoms, the alkyl group being as defmed above; the haloalkyl group is
preferably a-C(R10)3,
io io'io io io ro io io io
-CR (R )2, -CR (R )R , -C~(R )5, -CHZ-C(R )3, -CHa-CR (R )2, -CH2-
CRI0(R10')R10 , -C3(Ri0)7, or -C2H4-C(R10)3, wherein Rlo, Rio , Rio
represent F, Cl, Br or
I, preferably F;
a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being as
defined above;
an haloalkyloxy group denotes an alkoxy group which is substituted by one to
five halogen
atoms, the allcyl group being as defined above; the haloalkyloxy group is
preferably a
-OC(R10)3, -OCR10(Rl0')2, -OCRio(Rio')Rio", -OC2(R10)5,, -OCH2-C(Rio
)3a -OCH2-
CRIO(R. 1 ')a, -OCH2-CRI0(R10 )Ri0 , -OC3(Ri)7 or -0C2H4-C(Ri0)3, wherein
Rio, Rio',
R10" represent F, Cl, Br or I, preferably F;
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17 -
a hydroxyalkylamino group denotes an (HO-alkyl)2-N- group or HO-alkyl-NH-
group, the
alkyl group being as defined above;
an alkylamino group denotes an HN-alkyl or N-dialkyl group, the allcyl group
being as
defmed above;
a halogen group is chlorine, bromine, fluorine or iodine;
an aryl group denotes an aromatic group having five to fifteen carbon atoms,
which can
optionally be substituted by one or more substituents R', where R' is as
defmed above; the
aryl group is preferably a benzyl group, a phenyl group, -o-C6H4- R', -m-C6H4-
R', p-
C6114- R', 1-naphthyl, 2-naphthyl, 1-anthracenyl or 2-anthracenyl;
a heteroaryl group denotes a 5- or 6-membered heterocyclic group which
contains at least
one heteroatom selected from 0, N, and S. This heterocyclic group can be fused
to another
aromatic ring. For example, this group can be selected from a thiadiazole,
thiazol-2-yl,
thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl,
oxazol-2-yl,
oxazol-4-yl, oxazol-5-yl, isooxazol-3-yl, isooxazol-4-yl, isooxazol-5-yl,
benzooxazol-2-yl,
benzooxazol-4-yl; benzooxazol-5-yl, benzoisooxazol-3-yl, benzoisooxazol-4-yl,
benzoisooxazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-
oxadiazol-3-yl,
1,2,5-oxadiazol-4-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl,
isothi.azol-3-yl,
isothiazol-4-yl, isothiazol-5-yl, benzoisothiazol-3-yl, benzoisothiazol-4-yl,
benzoisothiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl, 1,2,5-
thiadiazol-4-
yl, 4-imidazolyl, benzoimidazol-4-yl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-
furanyl, 3-
furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyranyl, 3-
pyranyl, 4-
pyranyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2,4-
dimethoxy-6-
pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-
pyrazolyl, 4-
pyrazolyl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-
triazol-5-yl, 1,3,5-
triazol-6-yl, 2,4-dimethoxy-1,3,5-triazol-6-yl, 1H-tetrazol-2-yl, 1H-tetrazol-
3-yl, tetrazolyl,
acridyl, furazane, indazolyl, phenazinyl, carbazolyl, phenoxazinyl,
indolizine, 2-indolyl, 3-
indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 1-isouidolyl, 3-
isoindolyl, 4-isoindolyl,
5-isoindolyl, 6-isoindolyl, 7-isoindolyl, 2-indolinyl, 3-indolinyl, 4-
indolinyl, 5-indolinyl, 6-
indolinyl, 7-indolinyl, benzo[b]furanyl, ben.zofurazane, benzothiofiu-azane,
benzotriazol-l-
yl, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl, benzotr iazol-7-
yl, benzotriazine,
benzo[b]thiophenyl, benzimidazol-2-yl, 1H-benziinidazolyl, benziYnidazol-4-yl,
benzimidazol-5-yl, benzimidazol-6-yl, benzimidazol-7-yl, benzothiazolyl,
quinazolinyl,
quinoxazolinyl, cinnoli.ne, quinolinyl, tetrahydroquinolinyl, isoquinolinyl,
tetrahydro-
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18
thieno[3,4-d]imidazol-2-one, pyrazolo[5, 1 -c] [1,2,4]triazine,
tetrahydroisoquinolinyl,
purine, phtlialazine, pteridiiie, thiatetraazaindene, thiatriazaindene,
isothiazolopyrazine,
isothiazolopyrimidine, pyrazolotriazine, pyrazolopyrimidine,
imidazopyridazine, imidazo-
pyrimidine, imidazopyridine, imidazolotriazine, triazolotriazine,
triazolopyridine, triazolo-
pyrazine, triazolopyrimidine, 2,3-dihydrobenzo[1,4]-dioxin-2-yl, 2,3-
dihydrobenzo[1,4]-
dioxin-3-yl, 2,3-dihydrobenzo[1,4]-dioxin-5-yl, .2,3-dihydrobenzo[1,4]-dioxin-
6-yl, 2,6-
dimethoxypyrimidin-3-yl, 2,6-dimethoxypyrimidin-4-yl, 4-[1,2,4]triazolo[4,3-
a]pyridin-3-
yl, 1-fUro[2,3-c]pyridin-4-yl, 1-furo[2,3-c]pyridin-5-yl, 1-fiuo[2,3-c]pyridin-
3-yl, and
triazolopyridazine group. This heterocyclic group can be substituted by one or
more
substituents R', wherein R' is as defined above.
The present invention also relates to compounds of the general formula (III)
or
pharmaceutically acceptable salts thereof with an acid or a base, or
pharmaceutically
acceptable prodrugs or a stereoisomer thereof,
R4
~
A-N
N ' R5
I R3
Rl
R1 2 III
( )
wherein
Rl is -C(O)R7a, -C(O)CHR7RB, -C(O)NR7RB, -C(O)OR7, -WC(O)R8, or -C(S)R7b;
R2 is H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl,
hydroxyalkylamino, alkylamino, heteroaryl,
or R' and Ra together with the N-atom or the C-atom to which they are attached
form a 3 to
8 membered saturated or at least partially unsaturated monocyclic or polycylic
ring
system, wherein at least one or more of the carbon atoms in the ring is a
heteroatom
selected from 0, N, and S, and the ring can be substituted by one or more R9
R4a is H, Cl-C6-alkyl, Ca-C6-alkenyl, cycloalkyl, haloalkyl, hydroxyalkyl,
hydroxyalkylamino, alkylaniino, -C(NR7)NR7'R8, -(CHa)Paryl, -(CHa)PNR7Rg,
-C(O)NR!RB, -N=CR7RB, -NWC(O)R8, halogen, heteroaryl, or aryl;
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19
R3 is H, -C(O)NRaRb, halogen, alkyl, haloallkyl, aryl, heteroaryl, OH, SH,
NR4'ORS',
NH2, hydroxyalkylamino, alkylamino, alkoxy, cycloalkyl, heterocycloalkyl,
hydroxyalkyl, or haloalkyloxy;
R4 is H, OH, SH, NH2, alkoxy, haloalkyloxy, halogen, alkyl, -C(NR7)NR7'R8, -
(CH2)paryl, -(CHa)pNR7R8, -C(O)NR7R8, N=CR7RB, -NR7C(O)R$, cycloalkyl,
heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino,
heteroaryl, or aryl;
RS is halogeii, alkyl, -C(NR7)NR7'R8, -(CH2)paryl, -(CH2)pNR7RB, -C(O)NR7R$,
-N=CWRg, -NR7C(O)R8, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl,
hydroxyallcylamino, alkylamino, heteroaryl, or aryl;
Ra is H, halogen, alkyl, -CW)NR7'R8, -(CH2)paryl, -(CH2)pNR7R$, -C(O)NR7R8,
-N=CR7RB, -NR7C(O)R8, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl,
hydroxyalkylamino, allcylamino, heteroaryl, or aryl;
Rb independently represents H, -CN, -OH, -SH, -CO2R4', -C(O)R4', -SO2NR4',
-NR4'RS, -C(O)NICR8, -SOa-alkyl, -SO2R4', S03R4', -N=CR4'RS', NR4,C(O)R4",
-NR4'-CO-haloalkyl, -NOa, -NR4'-SOa-haloalkyl, -NR4'-SO2-alkyl, -NR4'-CO-
alkyl,
-NR4'(CH2)pheteroaryl, alkyl, cycloalkyl, alkylamino, alkoxy, alkylthio,
halogen,
haloalkyl, haloalkyloxy, -O(CH2)p[O(CH2)p1qOCH3, -C(NR4")NR4'benzimidazolyl,
-C(NR4")NR4'benzthiazolyl, -C(NR4")NR4'benzoxazolyl, hydroxyalkyl, hydroxy-
cycloalkyl, hydroxyalkylarnino, heterocycloalkyl, aryl or heteroaryl;
R4', R4", RS' independently are H, halogen, alkyl, -CW)NR7'R8, -(CHa)paryl,
haloalkyl,
-CH2)pNR7RB, -C(O)NR7RB, -N=CR7RB, -NR7C(O)R8, cycloalkyl, heterocycloalkyl,
hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl;
W, RT, R8 independently are H, halogen, allcyl, cycloalkyl, heterocycloallcyl,
haloalkyl,
hydroxyalkyl, hydroxyalkylamino, alkylamino, arylamino heteroaryl, or aryl;
R7a is cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, heteroaryl, or
aryl;
R7b is H, halogen, alkyl, cycloallcyl, heterocycloalkyl, haloalkyl,
hydroxyalkyl,
hydroxyallcylamino, heteroaryl, or aryl;
A is CO or SO2;
X is NR2', 0, or S;
Z isNorCR2';
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R2' is H, alkyl, -C(O)NR', -C(O)Rb, cycloalkyl, heterocycloalkyl, haloalkyl,
hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl;
p islto6;
q is l to 6;
5
R9 independently represents H, -CN, -OH, -SH, alkoxy, alkylthio, -C02R4', -
C(O)R4a,
-C(O)NR7R8, -SO2NR4', -NR4'RS', -SO2-alkyl, -SO2R4', S03R4', -N=CR4'RS',
-NR4'C(O)R4", -NR4'-CO-haloallcyl, -NO2, -NR4'-S02-haloallcyl, NR4'-SO2-alkyl,
-NR4'-CO-alkyl, -NR4'(CH2,)pheteroaryl, alkyl, hydroxyalkyl, cycloalkyl,
halogen,
10 haloalkyl, alkylamino, -O(CH2)P[O(CH2)p]qOCH3, -C(NR4")NR4'benzimidazolyl,
-C(NR4")NR4'benzthiazolyl, -C(NR4")NR4'benzoxazolyl, hydroxycycloalkyl,
hydroxyalkylamino, haloalkyloxy, heterocycloalkyl, -(CH2)pNR7COR8, aryl, or
heteroaryl;
15 wherein
an Cl-C6-alkyl group, if not stated otherwise, denotes a linear or branched C1-
C6-alkyl,
preferably a linear or branched chain of one to five carbon atoms, which can
optionally be
substituted by one or more substituents R';
20 an C2-C6-alkenyl group, if not stated otherwise, denotes a linear or
branched C2-C6
alkenyl, preferably a linear or branched chain of two to six carbon atoms,
which can
optionally be substituted by one or more substituents R';
an alkyl group, if not stated otherwise, denotes a linear or branched Cl-C6-
alkyl, preferably
a linear or branched chain of one to six carbon atoms, a linear or branched C2-
C6-alkenyl or
a linear or branched C2-C6-alkynyl group, which can be substituted by one or
more
substituents R';
R' is independently H, -CO2R", -CONHR", -CR"O, -SOaNR", -NR"-CO-haloalkyl,
NO2, -NR"-SO2-haloalkyl, -NR"-SOa-alkyl, -SO2-allcyl, -NR"-CO-alkyl, -CN,
a1ky1,
cycloalkyl, alkylamino, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl,
hydroxyalkylamino,
halogen, haloalkyl, haloalkyloxy, aryl, or heteroaryl;
R" is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, or
heteroaryl;
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21
a cycloalkyl group denotes a non-aromatic ring system containing three to
eight carbon
atoms, preferably four to eight carbon atoms, wherein one or more of the
carbon atoms in
the ring can be substituted by a group R' being as defined above; the C3-C8-
cycloalkyl
residue may be selected from the group comprising -cyclo-C3Hs, -cyclo-C4H7, -
cyclo-C5H9,
-cyclo-C6H11, -cyclo-C7H13, -cyclo-C8H15;
a heterocycloalkyl group denotes a non-aromatic ring system containing two to
ten carbon
atoms and at least one heteroatom selected from 0, N, and S, wherein one or
more of the
carbon atoms in the ring can be substituted by R' being as defmed above;
preferred
heterocycloalkyl groups are morpholine-4-yl, piperazinyl, 1-alkylpiperazine-4-
yl,
piperidinyl, pyrrolidinyl, azepane-l-yl;
an alkoxy group denotes an O-alk.yl group, the alkyl group being as defined
above; the
alkoxy group is preferably a methoxy, ethoxy, isopropoxy, t-butoxy or pentoxy
group;
an alkylthio group denotes an S-alkyl group, the alkyl group being as defined
above;
an haloalkyl group denotes an alkyl group which is substituted by one to five
halogen
atoms, the alkyl group being as defined above; the haloalkyl group is
preferably a-C(R10)3,
-CRlo(Rlo')a, -CRlo(Rlo')R1o", -C2(R10)s, -CH2C(R10)3, -CHaCRIO lo'
(R )a,
-CH2CR1o(R1o )R1o , -C3(R10)7, or -C2H4C(Rl0)3, wherein Rlo, Rlo', R1o
represent F, Cl, Br
or I, preferably F;
a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being as
defined above;
an haloalkyloxy group denotes an alkoxy group which is substituted by one to
five halogen
atoms, the alkyl group being as defmed above; the haloalkyloxy group is
preferably a
-OC(R10)3, -OCR1o(Rlo')2, -OCR1o(Rlo )R1o , -OC2(Rlo)5, -OCHaC(R.10)3,
-OCH2CR10(Rl0')2, -OCH2CR1o(R1o')R1o a -OC3(R1o)7a or -OC2H4C(R10)3, wherein
R10,
Rlo', Rlo" represent F, Cl, Br or I, preferably F;
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a hydroxyalkylamino group denotes an (HO-alkyl)2-N- group or HO-alkyl-NH-
group, the
alkyl group being as defined above;
an alkylamino group denotes an HN-alkyl or N-dialkyl group, the alkyl group
being as
defined above;
a halogen group is fluorine, chlorine, bromine, or iodine;
an aryl group denotes an aromatic group having five to fifteen carbon atoms,
which can be
substituted by one or more substituents R', where R' is as defined above; the
aryl group is
preferably a benzyl group, a phenyl group, -o-C6H4- R', -m-C6H4- R', -p-C6H4-
R', 1-
naphthyl, 2-naphthyl, 1-anthracenyl or 2-anthracenyl, R' being as defmed
above;
an arylamino group denotes an HN-aryl or N-diaryl group, the aryl group being
as defined
above;
a heteroaryl group denotes a 5- or 6-membered heterocyclic group which
contains at least
one heteroatom selected from O. N, and S. This heterocyclic group can be fused
to another
aromatic ring. For example, this group can be selected from a thiadiazole,
thiazol-2-yl,
thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl,
oxazol-2-yl,
oxazol-4-yl, oxazol-5-yl, isooxazol-3-yl, isooxazol-4-yl, isooxazol-5-yl,
benzooxazol-2-yl,
benzooxazol-4-yl, benzooxazol-5-yl, benzoisooxazol-3-yl, benzoisooxazol-4-yl,
benzoisooxazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-
oxadiazol-3-yl,
1,2,5-oxadiazol-4-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, isothiazol-
3-yl,
isothiazol-4-yl, isothiazol-5-yl, benzoisothiazol-3-yl, benzoisotlliazol-4-yl,
benzoisothiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl, 1,2,5-
thiadiazol-4-
yl, 4-imidazolyl, benzoimidazol-4-yl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-
furanyl, 3-
furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyranyl, 3-
pyranyl, 4-
pyranyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2,4-
dimethoxy-6-
pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-
pyrazolyl, 4-
pyrazolyl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-
triazol-5-yl, 1,3,5-
triazol-6-yl, 2,4-dimethoxy-1,3,5-tI'la7-ol-6-yl, 1H-tetrazol-2-yl, 1H-
tetrazol-3-yl, tetrazolyl,
acridyl, furazane, indazolyl, pllenazinyl, carbazolyl, phenoxazinyl,
indolizitle, 2-indolyl, 3-
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indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 1-isoixldolyl, 3-
isoindolyl, 4-isoindolyl,
5-isoindolyl, 6-isoindolyl, 7-isoindolyl, 2-indolinyl, 3-indolinyl, 4-
indolinyl, 5-indolinyl, 6-
indolinyl, 7-indolinyl, benzo[b]furanyl, benzofurazane, benzothiafiirazane,
benzotriazol-l-
yl, benzotriazol-4-yl, benzotriazol-5-yl, belizotriazol-6-yl, benzotriazol-7-
yl, benzotriazine,
benzo[b]thiophenyl, benzimidazol-2-yl, 1H-benzimidazolyl, benzimidazol-4-yl,
benzimidazol-5-yl, benzimidazol-6-yl, benzimidazol-7-yl, benzothiazolyl,
quinazolinyl,
quinoxazolinyl, cinnolaxa.e, quinolinyl, tetrahydroquinolinyl, isoquinolinyl,
tetrahydro-
thieno[3,4-d]imidazol-2-one, pyrazolo[5,1-e] [1,2,4]triazine, 2,3-
dihydrobenzo[1,4]-dioxin-
2-yl, 2,3-dihydrobenzo[1,4]-dioxin-3-yl, 2,3-dihydrobenzo[1,4]-dioxin-5-yl,
2,3-
dihydrobenzo[1,4]-dioxin-6-yl, 2,6-dimethoxypyrimidin-3-yl, 2,6-
dimethoxypyrimidin-4-
yl, tetrahydroisoquinolinyl, purine, pllthalazine, pteridine,
thiatetraazaindene,
thiatriazaindene, isothiazolopyrazine, isothiazolopyrimidine,
pyrazolotriazine,
pyrazolopyrimidine, imidazopyridazine, imidazo-pyrimidine, imidazopyridine,
imidazolotriazine, triazolotriazine, triazolopyridine, triazolopyrazine,
triazolopyrimidine,
4-[1,2,4]triazolo[4,3-a]pyridin-3-yl, 1-furo[2,3-c]pyridin-4-yl, 1-furo[2,3-
c]pyridin-5-yl, 1-
furo[2,3-c]pyridin-3-yl, and triazolopyridazine group. This heterocyclic group
can be
substituted by one or more substituents R', wherein R' is as defmed above;
with the proviso that the following compounds are excluded:
0
N R2
R140 -}---~-X-N / I
q
s (I)
wherein
R' independently represents hydrogen, alkyl, cycloalkyl, hydroxyalkyl,
haloalkyl,
haloalkyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
arylalkyl or
substituted arylalkyl;
Ra independently represents -NR3R4,
N R5 --\
N R5
- -
, or - N
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Rs independently represents alkyl, cycloalkyl, alkoxy, alkylamine, -OH, -SH,
allcylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl,
R4 independently represents alkyl, cycloalkyl, alkoxy, alkylamine, alkylthio,
hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl;
RS independently represents H, COR6, C02R6, SOR6, SO2R6, SO3R6, alkyl,
cycloalkyl,
alkoxy, -NH2, alkylamine, -NWCOR6, halogen, -OH, -SH, alkylthio, hydroxyalkyl,
haloalkyl, haloalkyloxy, aryl or heteroaryl;
R6 independently represents H, alkyl, cycloalkyl, -NH2, alkylamine, aryl or
heteroaryl;
R7 independently represents H, alkyl, cycloalkyl, alkoxy, -OH, -SH, alkylthio,
hydroxyalkyl, aryl, or heteroaryl;
p is0,or1;
q is0,or1;
X is CO or SOa.
The present invention, relates also to compounds of the general formula (Ih)
or
pharmaceutically acceptable salts thereof with an acid or a base, or
pharmaceutically
acceptable prodrugs or a stereoisomer thereof,
0 A R d It
R1 N NR3a R2a
T--
Z X/ N
/ D
R2 X R3 0 r (m)
wherein
A is NR2', S or O;
t is0to4;
r is 0, or1;
R2a is independently H, OH, SH, NH2, alkyl, cycloalkyl, hydroxyalkyl,
haloalkyl,
haloallcyloxy, alkoxy, allcylamino, hydroxyalkylamino, halogen, aryl, or
heteroaryl;
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R3a is independently H, OH, SH, NH2, -C(NR7)NW'R8, -(CH2)Paryl, -(CH2)pNR7R8, -
C(O)NR7R8, -N=CR7R8, -NR7C(O)R$, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl,
haloalkyloxy, alkoxy, alkylamino, hydroxyalkylamino, halogen, aryl, or
heteroaryl;
Rd is H, halogen, alkyl, -C(NR7)NRTR8, -(CH2)Paryl, -(CH2)PNR7R8, -C(O)NR7R8,
5 N=CR7RB, NR7C(O)R8, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino,
alkylamino, heteroaryl or aryl;
R' is -C(O)R7a, -C(O)CHR7RB, -C(O)NR7RB, -C(O)OR7, -R7C(O)R8, or -C(S)R7";
R2 is H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl,
10 hydroxyalkylamino, alkylamino, heteroaryl,
or R' and R2 together with the N-atom or the C-atom to which they are attached
form a 3 to
8 membered saturated or at least partially unsaturated monocyclic or polycylic
ring
system, wherein at least one or more of the carbon atoms in the ring is a
heteroatom
selected from 0, N, and S, and the ring can be substituted by one or more R9
15 R4a is H, C1-C6-alkyl, C2-C6 alkenyl, cycloalkyl, haloalkyl, hydroxyalkyl,
hydroxyalkylamino, alkylamino, -C(NW)NR7'R8, -(CH2)paryl, -(CH2)pNR7Rg,
-C(O)NR7RB, -N=CR7R8, -NR7C(O)R8, halogen, heteroaryl, or aryl;
R3 is H, -C(O)NRaRb, halogen, alkyl, haloalkyl, aryl, heteroaryl, OH, SH,
NR4'OR5',
20 NH2, hydroxyalkylamino, alkylamino, alkoxy, cycloalkyl, heterocycloalkyl,
hydroxyalkyl, or haloalkyloxy;
Ra is H, halogen, alkyl, -C(NR7)NR7'R8, -(CH2)Paryl, -(CH2)pNR7R8, -C(O)NR7R8,
-N=CR7R8, -NWC(O)R8, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl,
hydroxyalkylamino, alkylamino, heteroaryl, or aryl;
25 Rb independently represents H, -CN, -OH, -SH, -C02R4', -C(O)R4', -SO2NR4',
NR4'RS', -C(O)NR7R8, -S02-alkyl, -S02R4', S03R4', -N=CR4'RS', NR4'C(O)R4",
-NR4'-CO-haloalkyl, NO2, -NR4'-S02-haloalkyl, -NR4'-S02-alkyl, -NR4'-CO-
allcyl,
-NR4'(CH2)pheteroaryl, alkyl, cycloalkyl, alkylamino, alkoxy, alkylthio,
halogen,
haloalkyl, haloalkyloxy, -0(CH2)pLO(CH2)p]qOCH3, -C(NR4")NR4'benzimidazolyl,
-C(NR4 )NR4'benztliiazolyl, -C(NR4")NR4'benzoxazolyl, hydroxyalkyl, hydroxy-
cycloalkyl, hydroxyalkylamino, heterocycloalkyl, aryl or heteroaryl;
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26
R4', R4", R5' independently are H, halogen, alkyl, -C(NR7 )NR7' R8, -
(CHa)paryl, haloalkyl,
-CH2)pNR7R8, -C(O)NR7RB, -N=CR7R$, -NR7C(O)Rg, cycloalkyl, heterocycloalkyl,
hydroxyalkyl, hydroxyalkylarnino, alkylamino, heteroaryl, or aryl;
R7, W', R8 independently are H, halogen, allcyl, cycloalkyl, heterocycloalkyl,
haloalkyl,
hydroxyalkyl, hydroxyalkylamino, alkylamino, arylanlino heteroaryl, or aryl;
R7a is cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, heteroaryl, or
aryl;
R7b is H, halogen, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl,
hydroxyallcyl,
hydroxyalkylamino, heteroaryl, or aryl;
X isNRa' ,O,orS;
Z is N or CRa';
Ra' is H, alkyl, -C(O)NR7, -C(O)Rb, cycloalkyl, heterocycloalkyl, haloallcyl,
hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl;
p is l to 6;
q is l to 6;
R9 independently represents H, -CN, -OH, -SH, alkoxy, alkylthio, -CO2R4', -
C(O)R4a,
-C(O)WR8, -SO2NR4', -NR4'R5', -S02-alkyl, -S02R4', SO3R4', -N=CR4'RS',
-NR4'C(O)R4", --NR4'-CO-haloalkyl, NO2, NR4'-SO2-haloalkyl, -NR>-SO2-alkyl,
-NR4'-CO-alkyl, -NR4'(CHa)pheteroaryl, alkyl, hydroxyalkyl, cycloalkyl,
halogen,
haloalkyl, alkylamino, -O(CH2)p[O(CHa)p]qOCH3, -C(NR4")NR4'benzimidazolyl,
-C(NR4")NR4'benzthiazolyl, -C(NR4")NR4'benzoxazolyl, hydroxycycloalkyl,
hydroxyalkylamino, haloallcyloxy, heterocycloalkyl, -(CH2)PNR7COR8, aryl, or
heteroaryl;
wherein
an Cl-C6-alkyl group, if not stated otherwise, denotes a linear or branched C1-
C6-alkyl,
preferably a linear or branched chain of one to five carbon atoms, which can
optionally be
substituted by one or more substituents R';
an C2-C6--alkenyl group, if not stated otherwise, denotes a linear or branched
Ca-Cg-
alkenyl, preferably a linear or branched chain of two to six carbon atoms,
which can
optionally be substituted by one or more substituents R';
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27
an alkyl group, if not stated otherwise, denotes a linear or branched Cl-C6-
alkyl, preferably
a linear or branched chain of one to six carbon atoms, a linear or branched C2-
C6-alkenyl or
a linear or branched Ca-C6-allcynyl group, which can be substituted by one or
more
substituents R';
R' is independently H, -COaR", -CONHR", -CR"O, -SO2NR", -NR"-CO-haloalkyl,
-NOa, -NR"-S02-haloalkyl, -NR"-SOa-alkyl, -S02-alkyl, NR"-CO-alkyl, -CN,
alkyl,
cycloalkyl, alkylamino, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl,
hydroxyalkylamino,
halogen, haloalkyl, haloalkyloxy, aryl, or heteroaryl;
R" is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, or
heteroaryl;
a cycloalkyl group denotes a non-aromatic ring system containing three to
eight carbon
atoms, preferably four to eight carbon atoms, wherein one or more of the
carbon atoms in
the ring can be substituted by a group R' being as defined above; the C3-C8-
cycloalkyl
residue may be selected from the group comprising -cyclo-C3H5, -cyclo-C4H7, -
cyclo-C5H9,
-cyclo-C6H11, -cyclo-C7H13, -cyclo-C8H15;
a heterocycloalkyl group denotes a non-aromatic ring system containing two to
ten carbon
atoms and at least one heteroatom selected from 0, N, and S, wherein one or
more of the
carbon atoms in the ring can be substituted by R' being as defined above;
preferred
heterocycloalkyl groups are morpholine-4-yl, piperazinyl, 1-alkylpiperazine-4-
yl,
piperidinyl, pyrrolidinyl, azepane-l-yl;
an alkoxy group denotes an 0-alkyl group, the alkyl group being as defined
above; the
alkoxy group is preferably a methoxy, ethoxy, isopropoxy, t-butoxy or pentoxy
group;
an alkylthio group denotes an S-allcyl group, the alkyl group being as defmed
above;
an haloalkyl group denotes an alkyl group which is substituted by one to five
halogen
atoms, the alkyl group being as defined above; the haloalkyl group is
preferably a-C(R10)3,
-CRio(Rio')2a -CRio(Rio )Rio , -C2(Ri )5, -CH2C(Rio)3, -CHaCRio(Rio')2,
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28
-CH2CRlo(R1o )Rio , -C3(R10),, or -C2HC(Rl0)3, wherein R10, Rlo', Rlo"
represent F, Cl, Br
or I, preferably F;
a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being as
defined above;
an haloallcyloxy group denotes an alkoxy group which is substituted by one to
five halogen
atoms, the alkyl group being as defined above; the haloalkyloxy group is
preferably a
-OC(R10)3, -OCRio(Rio')2, -OCRio(Ri )Rio , -OC2(Ri )5, -OCHaC(Rio)3,
-OCH2CR10(R1o')2, -OCH2CR1o(R1o')Rio , -OC300)7, or -OCaH4C(Rl0)3, wherein
R10,
Rlo', Rio" represent F, Cl, Br or I, preferably F;
a hydroxyalkylamino group denotes an (HO-alkyl)2-N- group or HO-alkyl-NH-
group, the
alkyl group being as defined above;
an alkylamino group denotes an HN-alkyl or N-dialkyl group, the alkyl group
being as
defmed above;
a halogen group is fluorine, chlorine, bromine, or iodine;
an aryl group denotes an aromatic group having five to fifteen carbon atoms,
which can be
substituted by one or more substituents R', where R' is as defined above; the
aryl group is
preferably a benzyl group, a phenyl group, -o-C6H4- R', -m-C6H4- R', -p-C6H4-
R', 1-
naphthyl, 2-naphthyl, l-anthracenyl or 2-anthracenyl, R' being as defined
above;
an arylamino group denotes an HN-aryl or N-diaryl group, the aryl group being
as defined
above;
a heteroaryl group denotes a 5- or 6-membered heterocyclic group which
contains at least
one heteroatom selected from 0, N, and S. This heterocyclic group can be fused
to another
aromatic ring. For example, this group can be selected from a thiadiazole,
thiazol-2-yl,
thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl,
oxazol-2-yl,
oxazol-4-yl, oxazol-5-yl, isooxazol-3-yl, isooxazol-4-yl, isooxazol-5-yl,
bexizooxazol-2-yl,
benzooxazol-4-yl, benzooxazol-5-yl, benzoisooxazol-3-yl, benzoisooxazol-4-yl,
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29
benzoisooxazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-
oxadiazol-3-yl,
1,2,5-oxadiazol-4-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl,
isothia.zol-3-yl,
isothi.azoi-4-yl, isothiazol-5-yl, benzoisothiazol-3-yl, benzoisothiazol-4-yl,
benzoisothiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl, 1,2,5-
thiadiazol-4-
yl, 4-imidazolyl, benzoimidazol-4-yl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-
furanyl, 3-
furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyranyl, 3-
pyranyl, 4-
pyranyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2,4-
dimethoxy-6-
pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-
pyrazolyl, 4-
pyrazolyl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-firiazol-3-yl, 1,2,4-
tiiazol-5-yl., 1,3,5-
triazol-6-yl, 2,4-dirnethoxy-1,3,5-triazol-6-yl, 1H-tetrazol-2-yl, 1H-tetrazol-
3-yl, tetrazolyl,
acridyl, fiuazane, indazolyl, phenazinyl, carbazolyl, phenoxazinyl,
indolizine, 2-indolyl, 3-
indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 1-isoindolyl, 3-
isoindolyl, 4-isoindolyl,
5-isoi.ndolyl, 6-isoindolyl, 7-isoindolyl, 2-indolinyl, 3-indolinyl, 4-
indolinyl, 5-indolinyl, 6-
indolinyl, 7-indolinyl, benzo[b]furanyl, benzo"furazane, benzotluofiirazane,
benzotriazol-l-
yl, benzotriazol-4-yl, benzotriazol-5-yl, be7izotriazol-6-yl, benzotriazol-7-
yl, benzotriazine,
benzo[b]thiophenyl, benzimidazol-2-yl, 1H-benzimidazolyl, benzimidazol-4-yl,
benzimidazol-5-yl, benzimidazol-6-yl, benzimidazol-7-yl, benzothiazolyl,
quinazolinyl,
quinoxazolinyl, cinnoline, quinolinyl, tetrahydroquinolinyl, isoquinolinyl,
tetrahydro-
thieno[3,4-d]imidazol-2-one, pyrazolo[5,1-c][1,2,4]triazine, 2,3-dihydrobenzo
[ 1,4] -dioxin-
2-yl, 2,3-dihydrobenzo[1,4]-dioxin-3-yl, 2,3-dihydrobenzo[1,4]-dioxin-5-yl,
2,3-
dihydrobenzo[1,4]-dioxin-6-yl, 2,6-dimethoxypyrimidin 3-yl, 2,6-
dimethoxypyrimidin-4-
yl, tetrahydroisoquinolinyl, purine, phthalazine, pteridine,
thiatetraazaindene,
thiatriazaindene, isothiazolopyrazine, isothiazolopyrimidine,
pyrazolotriazine,
pyrazolopyrimidine, imidazopyridazine, imidazo-pyrimidine, imidazopyridine,
imidazolotriazine, triazolotriazine, triazolopyridine, triazolopyrazine,
triazolopyrimidine,
4-[1,2,4]triazolo[4,3-a]pyridin-3-yl, 1-furo[2,3-c]pyridin-4-yl, 1-furo[2,3-
c]pyridin-5-yl, 1-
furo[2,3-c]pyridin-3-yl, and triazolopyridazine group. This heterocyclic group
can be
substituted by one or more substituents R', wherein R' is as defined above;
with the proviso that the following compounds are excluded:
CA 02617225 2008-01-29
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O
N 2
R14O~ ~
S (I)
wherein
R' independently represents hydrogen, alkyl, cycloalkyl, hydroxyalkyl,
haloalkyl,
haloalkyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
arylalkyl or
5 substituted arylalkyl;
R2 independently represents -NR3R4,
. / ~
- -N R5 - -N N R5
or \--~
R3 independently represents alkyl, cycloalkyl, alkoxy, alkylamine, -OH, -SH,
10 alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl,
R4 independently represents alkyl, cycloalkyl, alkoxy, alkylamine, alkylthio,
hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl;
RS independently represents H, COR6, C02R6, SOR6, S02R6, S03R6, alkyl,
cycloalkyl,
alkoxy, -NH2, alkylamine, NR7COR6, halogen, -OH, -SH, alkylthio, hydroxyalkyl,
15 haloalkyl, haloalkyloxy, aryl or heteroaryl;
R6 independently represents H, alkyl, cycloalkyl, -NH2, alkylamine, aryl or
heteroaryl;
R7 independently represents H, alkyl, cycloalkyl, alkoxy, -OH, -SH, alkylthio,
hydroxyalkyl, aryl, or heteroaryl;
p is 0, or 1;
20 q is 0, or 1;
X is CO or SOa.
The present invention relates also to compounds of the general formula (II) or
pharmaceutically acceptable salts thereof with an acid or a base, or
phaYmaceutically
25 acceptable prodrugs, or a stereoisomer thereof,
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31
A N 6
Y R
N ~n
Ri R3
~Z X
R2 II
()
wherein
Rl is -C(O)R7, -C(O)CHR7R8, -C(O)NR~RB, -C(O)OR7, -R7C(O)R8, -C(S)R7;
R2 is H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl,
alkylamino,
hydroxyalkylamino, heteroaryl,
or R' and R2 together with the N-atom or the C-atom to which they are attached
form a 3 to
8 membered saturated or at least partially unsaturated monocyclic or
polycyclic
ring system, wherein at least one or more of the carbon atoms in the ring is a
heteroatom selected from 0, N, and S, and the ring can be substituted by one
or
more R9;
R3 is H, -C(O)NRaRb, halogen, alkyl, haloalkyl, aryl, heteroaryl, OH, SH,
NR4'ORS',
NH2, hydroxyalkylamino, alkylarnino, alkoxy, cycloalkyl, heterocycloalkyl,
hydroxyalkyl, or haloallcyloxy;
Ra is H, halogen, alkyl, -CW)NR7'R8, -(CHZ)Paryl, -(CH2)pNR7RB, -C(O)NR7R8,
-N=CR7R8, -NR7C(O)R8, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl,
hydroxyalkylamino, alkylamino, heteroaryl, or aryl;
Rb independently represents H, -CN, -OH, -SH, -C02R4', -C(O)R4', -SO2NR4',
NR4'RS', -C(O)WR8, -SO2-alkyl, -S02R4', SO3R4', -N=CR4'RS', -NR4'C(O)R4",
-NR4'-CO-haloalkyl, -NOa, -NR4'-SO2-haloallcyl, -NR4'-SO2-alkyl, -NR4'-CO-
alkyl,
-NR4'(CH2)pheterocycle, alkyl, cycloalkyl, alkylamino, alkoxy, alkylthio,
halogen,
haloallcyl, haloalkyloxy, -O(CHa)P[O(CH2)p]qOCH3, -C(NR4")NR4'benzimidazolyl,
-C(NR4")NR4'benzthiazolyl, -C(NR4")W'benzoxazolyl, hydroxyalkyl, hydroxy-
alkylamino, aryl, heterocycloalkyl, or heteroaryl;
R6 is halogen, -C(O)R7, -C(O)CHR7RB, -C(O)NR~RB, -C(O)OR~, -R7C(O)R8, -C(S)R7,
-CW)NRTR$, -(CH2)paryl, -(CH2)pNR7RB, -C(O)NR!RB, -N=CR7R8, -
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32
WC(O)R7', alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl,
hydroxyalkylamino, alkylamino, heteroaryl, or aryl;
R7, RT, Rg independently are H, halogen, alkyl, cycloalkyl, heterocycloalkyl,
haloalkyl,
hydroxyalkyl, hydroxyallcylamino, alkylamino, -NHaryl, heteroaryl, or aryl;
A isCOorSO2;
X is NR2', O, or S;
Y is N, CRa' or if Y is 0 then R6 is absent;
Z is N or CR2'; if Z is CH then X is O or NRa'
Ra' is H, alkyl, -C(O)NR2, -C(O)Rb, cycloalkyl, heterocycloalkyl, haloalkyl,
hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl;
n is 0 to 2;
p is l to 6;
q is l to 6;
R9 independently represents H, -CN, -OH, -SH, -COZR4', -C(O)R4a, -C(O)NR7RB, -
SO2NR4', -NR4'RS', -SOZ-alkyl, -S02R4', SO3R4', N=CR4Y, -NR4'C(O)R4", -
NR4'-CO-haloalkyl, -NOa, -NR4'-S02-haloalkyl, -NR4'-SO2-alkyl, -NR4'-CO-alkyl,
-NR4'(CH2)pheteroaryl, alkyl, cycloalkyl, heterocycloalkyl, alkylamino,
alkoxy,
alkylthio, halogen, haloalkyl, haloalkyloxy, hydroxyalkylamino, hydroxyalkyl,
hydroxycycloalkyl, aryl, -O(CH2)p[O(CH2)p]qOCH3, -C(NR4")NR4'benzimidazolyl,
-C(NR4")NR4'benztlliazolyl, -C(NR4")NR4'benzoxazolyl, -(CH2)PNR7CORB, or
heteroaryl;
R4' R4"> R" independently are H, halogen, alkyl, -CW)NR7'R8, -(CH2)paryl,
>
-(CHa)pNR7R$, -C(O)NR7RB, -N=CR7RB, -NR7C(O)R8, cycloalkyl,
heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino,
heteroaryl, or aryl;
R4a is H, C1-C6-alkyl, Ca-C6-allcenyl, cycloalkyl, haloallcyl, hydroxyalkyl,
hydroxyalkylamino, alkylamino, -CWW'R8, -(CH2)paryl, -CH2)pNR7R8,
-C(OWRB, -N=CWR8, -NR7C(O)R8, halogen, heteroaryl, or aryl
wherein
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33
an Ci-C6-alkyl group, if not stated otherwise, denotes a linear or branched Cl-
C6-allcyl,
preferably a linear or branched chain of one to five carbon atoms, which can
optionally be
substituted by one or more substituents R';
an Cr-C6-alkenyl group, if not stated otherwise, denotes a linear or branched
Ca-C6-
alkenyl, preferably a linear or branched chain of two to six carbon atoms,
which can
optionally be substituted by one or more substituents R';
an alkyl group, if not stated otherwise, denotes a linear or branched Cl-C6-
allcyl, preferably
a linear or branched chain of one to six carbon atoms, a linear or branched Ca-
C6-alkenyl or
a linear or branched C2-C6-alkynyl group, which can be substituted by one or
more
substituents R';
R' is independently H, -CO2R", -CONHR", -CR"O, -SO2NR", -NR"-CO-haloalkyl,
-NO2, -NR"-S02-haloalkyl, -NR"-S02-alkyl, -S02-alkyl, NR"-CO-alkyl, -CN,
a1ky1,
cycloalkyl, alkylamino, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl,
hydroxyalkylamino,
halogen, haloalkyl, haloalkyloxy, aryl, or heteroaryl;
R" is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, or
heteroaryl;
a heterocycle denotes a heterocycloalkyl group or a heteroaryl group;
a cycloalkyl group denotes a non-aromatic ring system containing three to
eight carbon
atoms, preferably four to eight carbon atoms, wherein one or more of the
carbon atoms in
the ring can be substituted by a group R' being as defined above; the C3-C8-
cycloalkyl
residue may be selected from the group comprising -cyclo-C3H5, -cyclo-C4H7, -
cyclo-C5H9,
-cyclo-C6H11, -cyclo-C7H13a -cyclo-C8H15;
a heterocycloalkyl group denotes a non-aromatic ring system containing two to
ten carbon
atoms and at least one heteroatom selected from 0, N, and S, wherein one or
more of the
carbon atoms in the ring can be substituted by R' being as defined above;
preferred
heterocycloalkyl groups are morpholine-4-yl, piperazinyl, 1-alkylpiperazine-4-
yl,
piperidinyl, pyrrolidinyl, azocane-1-yl;
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34
an alkoxy group denotes an 0-alkyl group, the alkyl group being as defined
above; the
alkoxy group is preferably a methoxy, ethoxy, isopropoxy, t-butoxy or pentoxy
group;
an alkylthio group denotes an S-alkyl group, the alkyl group being as defined
above;
an haloalkyl group denotes an alkyl group which is substituted by one to five
halogen
atoms, the alkyl group being as defined above; the haloalkyl group is
preferably a-C(R10)3,
-CR10(Rl0')2, -CRio(Rio )Rio , -C2(Ri)5, -CHaC(R10)3, -CH2CR1o(R1o )a, -
CH2CRlo(Rio )R1o' , -C3(R10)7, or -C2H4C(R10)3, wherein Rlo, Rlo , Rio
represent F, Cl, Br
or I, preferably F;
a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being as
defined above;
an haloalkyloxy group denotes an alkoxy group which is substituted by one to
five halogen
atoms, the alkyl group being as defmed above; the haloalkyloxy group is
preferably a
-OC(R10)3, -OCR10(Rl0 )2, -OCRio(Rio )Rio , -OC2(Rio)5, -OCHaC(R10)3,
-OCH2CR10(R10')2, -OCHaCRi (R1 ')Rl0", -OC3(Rl )7, or -OC2H4C(R) io io
3, wherein R ,
Rio , Rio ' represent F, Cl, Br or I, preferably F;
a hydroxyalkylamino group denotes an (HO-alkyl)2-N- group or HO-alkyl-NH-
group, the
alkyl group being as defined above;
an alkylamino group denotes an HN-alkyl or N-dialkyl group, the alkyl group
being as
defmed above;
a halogen group is fluorine, chlorine, bromine, or iodine;
an aryl group denotes an aromatic group having five to fifteen carbon atoms,
which can be
substituted by one or more substituents R', where R' is as defined above; the
aryl group is
preferably a benzyl group, a phenyl group, -o-C6H4- R', -m-C6H4- R', -p-C6H4-
R', 1-
naphthyl, 2-naphthyl, 1-anthracenyl or 2-anthracenyl, R' being as defined
above;
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a heteroaryl group denotes a 5- or 6-membered heterocyclic group which
contains at least
one heteroatom selected from 0, N, and S. This heterocyclic group can be fused
to another
aromatic ring. For example, this group can be selected from a thiadiazole,
thiazol-2-yl,
thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl,
oxazol-2-yl,
5 oxazol-4-yl, oxazol-5-yl, isooxazol-3-yl, isooxazol-4-yl, isooxazol-5-yl,
benzooxazol-2-yl,
benzooxazol-4-yl, benzooxazol-5-yl, benzoisooxazol-3-yl, beiizoisooxazol-4-yl,
benzoisooxazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-
oxadiazol-3-yl,
1,2,5-oxadiazol-4-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, isothiazol-
3-yl,
isoth.iazol-4-yl, isothiazol-5-yl, benzoisothiazol-3-yl, benzoisothi.azol-4-
yl,
10 benzoisothiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl,
1,2,5-thiadiazol-4-
yl, 4-imidazolyl, benzoimidazol-4-yl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-
furanyl, 3-
furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyranyl, 3-
pyranyl, 4-
pyranyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2,4-
dimethoxy-6-
pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-
pyrazolyl, 4-
15 pyrazolyl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-3-yl,
1,2,4-triazol-5-yl, 1,3,5-
triazol-6-yl, 2,4-dixnethoxy-1,3,5-triazol-6-yl, 1H-tetrazol-2-yl, 1H-tetrazol-
3-yl, tetrazolyl,
acridyl, furazane, indazolyl, phenazinyl, carbazolyl, pheiioxazinyl,
indolizine, 2-indolyl, 3-
indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 1-isoindolyl, 3-
isoindolyl, 4-isoindolyl,
5-isoindolyl, 6-isoindolyl, 7-isoindolyl, 2-indolinyl, 3-indolinyl, 4-
indolinyl, 5-indolinyl, 6-
20 indolinyl, 7-indolinyl, benzo[b]furanyl, benzofurazane,
benzothio:Curazalie, benzotri.azol-l-
yl, benzotriazol-4-yl, benzotriazol-5-yl, benzol,Tiazok-6-yl, benzotriazol-7-
yl, benzotriazine,
benzo[b]thiophenyl, benzimidazol-2-yl, 1H-benzimidazolyl, benzimidazol-4-yl,
benzimidazol-5-yl, benzin-iidazol-6-yl, benzzi.midazol-7-yl, benzothiazolyl,
quinazolinyl,
quinoxazolinyl, cinnoline, quinolinyl, tetrahydroquinolinyl, isoquinolinyl,
tetrahydro-
25 thieno[3,4-d]imidazol-2-one, pyrazolo[5,1-c][1,2,4]triazine, 2,3 -
dihydrobenzo [1,4] -dioxin-
2-yl, 2,3-dihydrobenzo[1,4]-dioxin-3-yl, 2,3-dihydrobenzo[1,4]-dioxin-5-yl,
2,3-
dihydrobenzo[1,4]-dioxin-6-yl, 2,6-d:imethoxypyrimidin-3-yl, 2,6-
dimethoxypyrimidin-4-
yl, tetrahydroisoquinolinyl, purine, phthalazine, pteridine,
thiatetraazaindene,
thiatriazaindene, isothiazolopyrazine, isothiazolopyrimidine,
pyrazolotriazine,
30 pyrazolopyrimidine, imidazopyridazine, imidazopyrimidine, imidazopyridine,
imidazolotriazine, triazolotriazine, triazolopyridine, triazolopyrazine,
triazolopyrimidine,
4-[1,2,4]triazolo[4,3-a]pyridin-3-yl, 1-furo[2,3-c]pyridin-4-yl, 1-furo[2,3-
c]pyridin-5-yl, 1-
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36
furo[2,3-c]pyrid'ui-3-yl, and triazolopyridazine group. This heterocyclic
group can be
substituted by one or more substituents R', wherein R' is as defined above.
In a preferred embodiment of the invention, in the compounds of formula (Ia),
Z is S, Y is
CO, X is CO, R is H, R~ is H, and R' is aryl, benzyl, or heteroaryl, Ra is
--N N R5
---/ , and RS is optionally substituted aryl, benzyl or heteroaryl.
In a preferred embodiment of the invention, in the compounds of formula (Ia),
Z is 0, Y is
CO, X is CO, R is H, R is H, and R' is aryl, benzyl, or heteroaryl, R2 is
-N ~ N R5
-
and RS is optionally substituted aryl, benzyl or heteroaryl.
In a preferred embodiment of the invention, in the compounds of formula (Ib),
Z is S, Y is
CO, X forms a piperidine ring together with R' and R4, Ra and Rb is H, W is H
or methyl,
- -N N R5
R2 is and RS is optionally substituted aryl, benzyl or heteroaryl.
In a preferred embodiment of the invention, in the compounds of fonnula (lb),
Z is 0, Y is
CO, X forms a piperidine ring together with R' and R4, Ra and Rb is H, R is H
or methyl,
N -\ N R5
- -
R2 is and R5 is optionally substituted aryl, benzyl or heteroaryl.
In another preferred embodiment, in the compounds of formula (Ic), r is 1,Y is
CO, Z is 0,
t is 0, s is 1, X is CO, R is H, methyl, ethyl, methoxy, alkylamino,
morpholino, N-
- -N N R5
methylpiperazine, CF3, or OCF, Ra is and RS is optionally
substituted aryl, benzyl or heteroaryl.
In another preferred embodiment, in the compounds of forrnula (Ic), r is 1,Y
is CO, Z is S,
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37
t is 0, s is 0, R is H, methyl, ethyl, methoxy, alkylamino, morpholino, N-
methylpiperazine,
N --\ N R5
- -
CF3, or OCF, Ra is and RS is optionally substituted aryl, benzyl
or heteroaryl.
In another preferred embodiment, in the compounds of formula (Ic), r is 1,Y is
CO, Z is S,
t is 0, s is 1, X is CO, R is H, methyl, ethyl, methoxy, allcylamino,
morpholino, N-
- -N /--\ N R5
methylpiperazine, CF3, or OCF, R2 is and RS is optionally
substituted aryl, benzyl or heteroaryl.
In another preferred embodiment, in the compounds of formula (Ic), r is 1,Y is
CO, Z is 0,
t is 0, s is 0, R is H, methyl, ethyl, methoxy, alkylamino, morpholino, N-
methylpiperazine,
5
- -
CF3, or OCF, R2 is N \-/ N R
, and RS is optionally substituted aryl, benzyl
or heteroaryl.
A preferred embodiment of the invention, in the compounds of formula (III),
are compounds of the formula (IIIa),
0 R4
N
0 N \ R5
i
R3
R7a Z X
I (IIIa
)
wherein
R3 is H, methyl, methoxy, CF3, or OCF3;
R4, R5, R7a are defined as above; X is NRZ', 0 or S; and Z is as defined as
above.
Another preferred embodiment of the invention, in the compounds of fonnula
(III),
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38
are compounds of the formula (IIIa), with R7a = NH-aryl.
Another preferred embodiment of the invention, in the compounds of formula
(III),
are compounds of the formula (IIIb),
O
NHR5
N
1 R3
Z X
Y'
(IIIb)
wherein
R3 is H, methyl, methoxy, CF3, or OCF3; RS is defmed as above; X is NR2', 0 or
S;
if Z is N then X is NR2', 0 or S, or if Z is CRZ', X is 0;
Y' is 0 or NR2, Ra' is as defined above;
Another preferred embodiment of the invention, in the compounds of fonnula
(TII),
are compounds of the formula (IIIc),
R7N R7'
~
O N
N N
0 N R4 Yti R12'
3 Ri ,'
N X R
H
X~'/ (IIIc)
R12 R11
wherein
R", R 12 independently represent H, -CN, -OH, -SH, -C02R4', -C(O)R4', -
SO2NR4',
-NR4'RS', -S02-alkyl, -SO2R4', S03R4', N=CR4'RS', -NR4'C(O)R4", -NR4'-CO-
haloalkyl,
-NOa, NR4'-SO2-haloalkyl, -NR4'-SOa-alkyl, -NR4'-CO-alkyl, -NR4'
(CH2)pheteroaryl,
alkyl, cycloalkyl, alkylamino, alkoxy, alkylthio, -O(CHa)P[O(CH2)P]qOCH3a -
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C(NR4")NR4'benzimidazolyl, -C(NR4" )NR4'benzthiazolyl, -
C(NR4")NR4'benzoxazolyl
hydroxyalkyl, hydroxycycloalkyl, hydroxyalkylamino, halogen, haloalkyl,
haloalkyloxy,
aryl, arylalkyl or a heterocycle; and R4', R4", RS' are defined as above;
R3 is H, methyl, methoxy, CF3, or OCF3; X is NR2', 0 or S, R4 is defined as
above,
R7 and R7' are defined as above,
Rll', R12~ independently represents H, -CN, -OH, -SH, -C02R4', -C(O)R4' > -
SO2NR4',
NR4'RS', -SO2-alkyl, -SO2R4', S03R4', N=CR4'RS', -NR4'C(O)R4", -NR4'-CO-
haloalkyl,
NO2, NR4'-SOa-haloalkyl, -NR4'-SO2-alkyl, -NR4'-CO-alkyl, -NR4'
(CHa)pheteroaryl,
alkyl, cycloalkyl, alkylamino, alkoxy, alkylthio, -O(CHa)P[O(CH2)P]qOCH3,
-C(NR4")NR4'benzimidazolyl, -C(NR4")NR4'benzthiazolyl, -
C(NR4")NR4'benzoxazolyl
hydroxyalkyl, hydroxycycloalkyl, hydroxyalkyl-amino, halogen, haloalkyl,
haloalkyloxy,
aryl, arylalkyl or a heterocycle; and R4', R4", R$' are defined as above;
A more preferred embodiment of the invention, in the compounds of formula
(III),
are compounds of the formula (IIId),
R7N R7,
~
O N
N -_N
N R4 Ylv R12'
11'
N R3 R
X
Y (IIId)
wherein
R3 is H, methyl, methoxy, CF3, or OCF3; X is NR2', 0 or S, R4 is defined as
above,
R7 and RT are defined as above, Y" and Rll', R12' are defined as above under
formula
(IIIc), Y' is 0 or NR2'and R2' is as defined above.
Another more preferred embodiment of the invention, in the compounds of
formula (III),
are compounds of the formula (IIIe),
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0 R4
/
N
R5
R12
R11 R3
Z X
N (IIIe)
wherein
R3, R4 and RS are defmed as above, X is 0 or S,
Rll and R12 are defined as above under formula (IIIc), and
5 ifZisN,XisNR2',OorS,ifZisCH,XisO.
Another more preferred embodiment of the invention, in the compounds of
formula (III),
are compounds of the formula (IIIf),
R7N R7'
0 N
N N
" Ra Yll R12'
Z R3 R11'
(/
x N
' R12 (IIIf)
J
R11
10 wherein
Z isN or CH, and R3 is H, methyl, methoxy, CF3, or OCF3; X is NR2', 0 or S,
R4 is defined as above, W and W' are defmed as above, R2' is as defined above;
Y" and R", Rl l', R12, Rl2' are defined as above under forrnula (IIIc).
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41
A preferred embodiment of the invention, are compounds of the fonnula (Iha),
0 A R d it
R' N NR3a R2a
Z /
I N
R2 X R3 r(Iha)
wherein
R' is COR7a ; R2 and R3a are H; A is NH; R7 is as defined above; Z is N;
X is NRa', 0 or S; R3 is H, methyl, ethyl, methoxy, amine, alkylamine,
morpholino, N-
methylpiperazine, CF3, or OCF3; t is 0; r is 1; and Wa is optionally
substituted aryl, benzyl
or heteroaryl.
Another preferred embodiment of the invention, in the compounds of formula
(Ih),
are compounds of the formula (Iha), with R7a is optionally substituted aryl,
benzyl or
heteroaryl.
Another preferred embodiment of the invention, in the compounds of formula
(Ih),
are compounds of the formula (Ihb),
0 A Rd It
N N R3a R2a
Z I N
O
Y' X R3 r
--_j 15 (Ihb)
whereiii
R3a is H; A is NH; X is NRZ', O or S; Y' is O or NR2';
R2' is as defined above; R3 is H, methyl, ethyl, methoxy, ainine, alkylamine,
morpholino,
N-methylpiperazine, CF3, or OCF3; t is 0; r is 1; and Raa is optionally
substituted aryl,
benzyl or heteroaryl.
Another more preferred embodiment of the invention, in the compounds of
formula (Ih),
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42
are compounds of the formula (Ihe),
O A --- Ra it
R12
\UIl. R' 1 N NR3a R2a
Z I N r---~ X g 0
N R (Ihe) r
wherein
R3a is H; A is NH ; X 1s NR2', O or S;
R" and R12 independently represent H, -CN, -OH, -SH, -C02R4', -C(O)R4', -
SO2NR4',
-NR4'RS', -S02-allcyl, -S02R4', SO3R4', -N=CR4'RS', -NR4'C(O)R4", -NR4'-CO-
haloalkyl,
-NOa, -NR4'-SOa-haloalkyl, NR4'-SOa-alkyl, -NR4'-CO-alkyl, -NR4'
(CHZ)Pheteroaryl,
alkyl, cycloalkyl, alkylamino, alkoxy, allcylthio, -O(CHa)p[O(CH2)p]qOCH3, -
C(NR4")NR4'benzimidazolyl, -C(NR4")NR4'benzthiazolyl, -C(NR4")NR4'benzoxazolyl
hydroxyalkyl, hydroxycycloalkyl, hydroxyalkylamino, halogen, haloalkyl,
haloalkyloxy,
aryl, arylalkyl or a heterocycle; and R4', R4", R5' are defined as above;
R2' is as defined above; R3 is H, methyl, ethyl, methoxy, amine, alkylamine,
morpholino,
N-methylpiperazine, CF3, or OCF3; t is 0; r is 1; and R2a is optionally
substituted aryl,
benzyl or heteroaryl.
A preferred embodiment of the invention, in the compounds of formula (II),
are compounds of the formula (IIa),
0 SRll
IN
R~2
N\-j
N \
R3
Rl X
X
I 2 (TIa)
wherein
Rl and Ra are defmed as above, Z is defined as above; X is 0 or S;
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43
R3 is H, methyl, methoxy, CF3, or OCF3;
Rll and R 12 are defined as above under fonnula (IIIc).
A more preferred embodiment of the invention, in the compounds of formula
(II),
are compounds of the formula (IIb),
CF3
O
N N ' /
Rl R3 (IIb)
Z X
1 2
R
wherein
Rl and Ra are defined as above, Z is defmed as above; X is 0 or S,
R3 is H, meth.yl, methoxy, CF3, or OCF3.
Another more preferred embodiment of the invention, in the compounds of
formula (II),
are compounds of the formula (IIc),
CF3
O
N N
-/
I R3
Z X
(IIc)
wherein
X is 0 or S; R3 is H, methyl, methoxy, CF3, or OCF3; Y' is NRa'.
Another more preferred embodiment of the invention, in the compounds of
formula (II),
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44
are compounds of the formula (IId),
O ~
~
N \j)R12
N N RII
~ R3
Z X
N
RI 2'
' \J (IId)
Rill
wherein
Z is defined as above; R3 is H, methyl, methoxy, CF3, or OCF3;
R11, Rll' and R12, R12' are defined as above.
In addition, the present invention provides methods for preparing the
compounds of the
invention such as compounds of formula (Ia), (Ib), (Ic), (II), or (III).
The compounds of formula (Ia), (Ib), (Ic), (JI), or (III) may be obtained via
various
methods.
Piperidin-4yl-thiazole-4-carboxamide can be prepared by various methodes
described in
the literature. One such example is the oxidation of the appropriate 2,5-
dihydrothiazoles as
described in Houben-Weyl, 2002, 730. The dihydrothiazoles can also synthesised
by
methodes described in the same reference or described in You, S., Razavi, H.,
Kelly, J.W.
Angew. Chem. 2003, 115, 87 or Katritzky, AR., Cai, C., Suzuki, K., Singh, SK.
J. Org.
Chem. 2004, 69, 811-814 and references in both papers. Alternative methods
were
decribed by Yasuchika, S. et. al. Heterocycles, Vol. 57, No. 5, 2002.
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The compounds of formula (II), (Ic), and (III) canying a further substituent
on the
heterocycle can be obtained via various methods described in Organic
Syntheses, Coll.
Vol.9, p.155; and Vol.74, p.229; J. Org. Chem., 1975, Vol.40, No.10, page
1521, J.
Am. Chem. Soc.96:19/September 18,1974; J. Org. Chem., 1990, 55, 4484-4487;
Chemische
5 Berichte 1968, 101 (1), 302-307; Agricultural Chemistfy and Biotechnology,
2002, 45 (1),
page 37-42.
One possibility for the synthesis of substituted benzimindazole-substituent of
formula (III)
is described in Synthesis, 2006, 4, 597-602.
10 One possibility for the synthesis of compounds of formula (IIIa, c and IIa,
b) (see scheme
1) comprises a step of reacting a compound of formula (V) with a compound of
formula
(VI) under classical amide coupling conditions, like e.g. HBTU, iPr2NEt, DMF,
0 C to r.t.
to obtain intermediate (VII). Another alternative for this step might be the
reaction of (V)
with the corresponding acid chloride of (VI) to yield (VII). In a second step,
compound
15 (VII) is saponified with a 1 M NaOH solution, obtaining the expected acid
(VIII) in almost
quantitative yield. This step could be realized under acidic conditions as
well. Finally,
another amide coupling step (with primary or secundary amines), which works
sixnilarily
to step 1 described above, completes the synthesis for compounds of type
(IIIa, c and IIa,
and b).
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46
O
OEt
O
OEt 0 O N \
R" ~J
H X
Rti
N + ___k OH
\ "2N X R12 R12
(V) (VI) (~n
R4
O O
N OH
\
R5
O i O i \
RN X N X
Rb"H bl,
"
R12 R12
(IIIa, c, IIa, b) (VIII)
Scheme 1 Synthesis of derivatives of type (IIIa, c) and (IIa, b)
Compounds dealing with structure (IIIb, d, e, f) and (IIc, d) can be
synthesized according
to the procedure displayed in scheme 2. Herein, a heterocycle (IX) is reacted
with a
bromocompound (X), by means of a nucleophilic substitution reaction, to gain a
bicyclic
ester (XI), which is then saponified under standard and well-known conditions
to acid
(XII), completing the synthesis with another coupling step as described in
scheme 1 above.
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47
0
OEt
O
OEt N
Z + i \ Z X
Y'~ Y \ /
Br X
(DC) m c~)
R3
O O
N OH
\ R2
I \ E IX
X Z
ri Y
(IIIb, d, e, f, IIc, d) (XR)
Scheme 2 Synthesis of derivatives of type (IIIb, d, e, f) and (IIc, d), with
Z= N
In case of Z = CH, structure (IIIb, d, e, f) and (IIc, d) type compounds can
easily be
synthesized following a protocol outlined in scheme 3, wherein a heterocycle
(XIII) is
converted to compound (XV) by a cyclokondensation step. After saponification,
(XVI) is
coupled with an amine to yield the desired product (IIIb, d, e, f) or (IIc,
d).
ti
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48
0
OEt
X
O O
Z NHZ + ~Z X
Y ."i Br >-- OEt Y ~
Xm (Mv) (XV)
R3
O O
N\ OH
R~
' ~
X Z X
ri Y'"j
(Illb, d, e, f, IIc, d) (XVI)
Scheme 3 Synthesis of derivatives of type (IIIb, d, e, f) and (IIc, d), with
Z= CH
For the compounds of the formula (Ia), (Ib), (Ic), (II), or (III) above, the
term
"stereoisomer" means cis/trans or E/Z isomerism. More particularly, the
possible double
bond(s) present in the various substituent of the compounds of the present
invention can be
E or Z configuration. These pure or impure geometrical isomers, alone or as a
mixture,
form an integral part of the compounds of the formula (Ia), (Ib), (Ic), (II),
or (III).
The term "stereoisomer" includes also all the isomeric forms, alone or as
mixture, resulting
from the presence of one or more axes and/ or centres of symmetry in the
molecules, and
resulting in the rotation of a beam of polarized light. More particularly, it
includes
enatiomers and diastereomers, in pure form or as a mixture.
The compounds of the formula (Ia), (Ib), (Ic), (II), or (III) to be used
according to the
invention can form salts with inorgani.c or organic acids or bases. Examples
of
pharmaceutically acceptable salts comprise without limitation non-toxic
inorganic or
organic salts such as acetate derived from acetic acid, aconitate derived from
aconitic acid,
ascorbate derived from ascorbic acid, benzoate derived from benzoic acid,
cinnamate
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49
derived from cinnamic ,acid, citrate derived from citric acid, embonate
derived from
embonic acid, enantate derived from heptanoic acid, forrniate derived from
formic acid,
fumarate derived from fumaric acid, glutamate derived from glutamic acid,
glycolate
derived from glycolic acid, chloride derived from hydrochloric acid, bromide
derived from
hydrobromic acid, lactate derived from lactic acid, maleate derived from
maleic acid,
malonate derived from malonic acid, mandelate derived from mandelic acid,
methanesulfonate derived from methanesulfonic acid, naphtaline-2-sulfonate
derived from
naphtaline-2-sulfonic acid, nitrate derived from nitric acid, perchlorate
derived from
perchloric acid, phosphate derived from phosphoric acid, phthalate derived
from phthalic
acid, salicylate derived from salicylic acid, sorbate derived from sorbic
acid, stearate
derived from stearic acid, succinate derived from succinic acid, sulphate
derived from
sulphuric acid, tartrate derived from tartaric acid, toluene-p-sulfate derived
from p-toluene-
sulfonic acid and others. Such salts can be produced by methods known to
someone of skill
in the art and described in the prior art.
Other salts like oxalate derived from oxalic acid, which is not considered as
pharmaceutically acceptable can be appropriate as intermediates for the
production of
compounds of the formula (Ia), (Ib), (Ic), (II), or (III) or a
pharmaceutically acceptable salt
thereof or pharmaceutically acceptable prodrugs, or a stereoisomer thereof.
The invention covers the pharmaceutically acceptable salts, as indicated
above, but also
salts allowing a suitable seperation or crystallization of the compoimds of
the formula (Ia),
(lb), (Ic), (II), or (III), such as the salts obtained with chiral arnines.
The compounds of the fonnula (Ia), (Ib), (Ic), (II), or (III) above also
comprise the
prodrugs of these compounds.
The term "prodrLig" as used llerein refers to compounds which once
administered to the
patient are not pharmaceutically active themselves ('prodrugs') but which are
cheinically
and/ or biologically transformed into their pharmaceutical active form
(compounds of
formula (Ia), (Ib), (Ic), (II), or (III)) in vivo, i.e. in the subject to
which the compoiuld is
administered.
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The compounds according to the invention and medicaments prepared therewith
are
generally useful for the treatment of cell proliferation disorders, for the
treatment, or
prophylaxis of immunological diseases and conditions (as for instance
inflammatory
diseases, neuroimmunological diseases, autoimmune diseases or other).
5 The compounds of the present invention are useful for the treatment of
diseases which are
caused by malignant cell proliferation, such as all forms of solid tumors,
leukemias and
lymphomas. Therefore the compounds according to the invention and medicaments
prepared therewith are generally useful for regulating cell activation, cell
proliferation, cell
survival, cell differentiation, cell cycle, cell maturation and cell death or
to induce systemic
10 changes in metabolism such as changes in sugar, lipid or protein
metabolism. They can
also be used to support cell generation poiesis, including blood cell growth
and generation
(prohematopoietic effect) after depletion or destruction of cells, as caused
by, for example,
toxic agents, radiation, immunotherapy, growth defects, malnutrition,
malabsorption,
immune dysregulation, anemia and the like or to provide a therapeutic control
of tissue
15 generation and degradation, and therapeutic modification of cell and tissue
maintenance
and blood cell homeostasis.
These diseases and conditions include but are not limited to cancer as
hematological (e.g.
leukemia, lymphoma, myeloma) or solid tumors (for example breast, prostate,
liver,
20 bladder, lung, esophageal, stomach, colorectal, genitourinary,
gastrointestinal, skin,
pancreatic, brain, uterine, colon, head and neck, cervical, and ovarian,
melanoma,
astrocytoma, small cell lung cancer, glioma, basal and squameous cell
carcinoma,
sarcomas as Kaposi's sarcoma and osteosarcoma) or for the treatment of
diseases which
are cured or relieved by the inhibition of one or several kinases and/or
phosphatases.
"Treatment" according to the present invention is intended to mean complete or
partial
healing of a disease, or alleviation of a disease or stop of progression of a
given disease.
Thus, in one embodiment, the invention relates to the use of the compounds of
the formula
(Ia), (Ib), (Ic), (II), or (III) or a pharmaceutically acceptable salt or
pharmaceutically
acceptable prodrugs, or a stereoisomer thereof if desired with appropriate
adjuvants and
additives for the production of a medicament for the treatment or prevention
of a disease
characterized by hyperproliferation of keratinocytes and/or T cells,
especially
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51
inflammatory disorders and immune disorders, preferably selected from the
group
consisting of Addison's disease, alopecia areata, Ankylosing spondylitis,
haemolytic
anemia (anemia haemolytica), pernicious anemia (anemia pemiciosa), aphthae,
aphthous
stomatitis, arthritis, arteriosclerotic disorders, osteoarthritis, rheumatoid
arthritis,
aspermiogenese, asthma bronchiale, auto-immune asthma, auto-immune hemolysis,
Bechet's disease, Boeck's disease, inflammatory bowel disease, Burkitt's
lymphoma,
Crohn's disease, chorioiditis, colitis uIcerosa; Coeliac disease,
cryoglobulinemia, dermatitis
herpetiformis, dermatomyositis, insulin-dependent type I diabetes, juvenile
diabetes,
idiopathic diabetes insipidus, insulin-dependent diabetes mellisis, autoimmune
demyelinating diseases, Dupuytren's contracture, encephalomyelitis,
encephalomyelitis
allergica, endoplithalmia phacoanaphylactica, enteritis allergica, autoimmune
enteropathy
syndrome, erythema nodosum leprosum, idiopathic facial paralysis, chronic
fatigue
syndrome, febris rheumatica, glomerulo nephritis, Goodpasture's syndrome,
Graves'
disease, Harnman-Rich's disease, Hashimoto's disease, Hashimoto's thyroiditis,
sudden
hearing loss, sensoneural hearing loss, hepatitis chronica, Hodgkin's disease,
haemoglobinuria paroxysmatica, hypogonadism, ileitis regionalis, iritis,
leucopenia,
leucemia, lupus erythematosus disseminatus, systemic lupus erythematosus,
cutaneous
lupus erythematosus, lymphogranuloma malignum, mononucleosis infectiosa,
myasthenia
gravis, traverse myelitis, primary idiopathic myxedema, nephrosis, ophthalmia
symphatica,
orchitis granulomatosa, pancreatitis, pemphigus, pemphigus vulgaris,
polyarteritis nodosa,
polyarthritis chronica primaria, polymyositis, polyradiculitis acuta,
psoriasis, purpura,
pyoderma gangrenosum, Quervain's thyreoiditis, Reiter's syndrome, sarcoidosis,
ataxic
sclerosis, progressive systemic sclerosis, scleritis, sclerodermia, multiple
sclerosis,
sclerosis disseminata, acquired spenic atrophy, infertility due to
antispermatozoan
antibodies, thrombocytopenia, idiopathic thrombocytopenia purpura, thymoma,
acute
anterior uveitis, vitiligo, AIDS, HIV, SCID and Epstein Barr virus associated
diseases such
as Sjorgren's syndrome, virus (AIDS or EBV) associated B cell lymphoma,
parasitic
diseases such as Leishmania, and immunesuppressed disease states such as viral
infections
following allograft transplantations, AIDS, cancer, chronic active hepatitis
diabetes, toxic
chock syndrome and food poisoning.
Furthermore, the invention relates to a method of treatment or prevention of
diseases which
comprises the administration of an effective amount of compounds of the (Ia),
(Ib), (Ic),
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52
(II), or (III) or a pharmaceutically acceptable salt or pharmaceutically
acceptable
prodrugs,or a stereoisomer thereof.
The invention also provides a pharmaceutical composition comprising a compound
of
formula (Ia), (Ib), (Ic), (II), or (III), in free - form or in the form of
pharmaceutically
acceptable salts and pharmaceutically acceptable prodrugs, together with a
pharmaceutically acceptable diluent or carrier therefore.
In a preferred embodiment, the invention relates to the use of compounds of
the formula
(Ia), (Ib), (Ic), (II), or (III), or a pharmaceutically acceptable salt or
pharmaceutically
acceptable prodrugs or a stereoisomer thereof if desired with appropriate
adjuvants and
additives for the production of a medicament for the treatment or prevention
of skin
diseases in which T cells play a role; especially preferably the skin diseases
are selected
from the group consisting of psoriasis, atopic dermatitis, alopecia areata,
alopecia totalis,
alopecia subtotalis, alopecia universalis, alopecia diffusa, lupus
erythematodes of the skin,
lichen planus, dermatomyostis of the skin, atopic eczema, morphea,
sklerodermia, psoriasis
vulgaris, psoriasis capitis, psoriasis guttata, psoriasis inversa, alopecia
areata ophiasis-type,
androgenetic alopecia, allergic contact eczema, irritative contact eczema,
contact eczema,
pemphigus vulgaris, pemphigus foliaceus, pemphigus vegetans, scarring mucosal
pemphigoid, bullous pemphgoid, mucous pemphigoid, dermatitis, dermatitis
herpetiformis
duhring, urticaria, necrobiosis lipoidica, erythema nodosum, lichen vidal,
prurigo simplex,
prurigo nodularis, prurigo acuta, linear IgA dermatosis, polymorphic light
dermatoses,
erythema solaris, lichen sclerosus et atrophicans, exanthema of the skin, drug
exanthema,
purpura chronica progressiva, dihidrotic eczema, Eczema, fixed drug exanthema,
photoallergic skin reaction, lichen simplex eriorale, dermatitis and "Graft
versus Host-
Disease", acne, rosacea, scarring, keloids and vitiligo.
Moreover, the compounds of the present invention can be used for the treatment
of
diseases resulting from ischemia and/or reperfusion injury of organs and/or of
parts of the
body selected from the group comprising heart, brain, peripheral limb, kidney,
liver, spleen
and lung, and/or wherein the endothelial dysfunction is associated with
diseases selected
from a group comprising infarctions such as myocardial infarction and critical
limb
ischemia,and/or wherein the endothelial dysfunction is associated with
diseases selected
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53
from the group comprising ischemic diseases such as peripheral arterial
occlusive disease,
e. g. critical leg ischemia, myocardial infarction and ischemic diseases of
organs, e. g. of
the kidney, spleen, brain and lung.
The compounds of this invention also can be applied for the prevention and the
treatment
of neurological diseases or disorders (diseases or disorders associated with
the brain and
nervous system), including but not limited to, Alzheimer's disease,
Parkinson's disease,
Creutzfeld-Jacob Disease, Lewy Body Dementia, amyotrophic lateral sclerosis,
stroke,
epilepsy, multiple sclerosis, myasthenia gravis, Huntington's Disease, Down's
Syndrome,
nerve deafiiess, and Meniere's disease.). Other neurological diseases and
disorders will be
apparent to those of skill in the art and are encompassed by the definition as
used in this
invention.
The compounds of the present invention can further be used for diseases that
are caused by
protozoal infestations in humans and animals. Such veterinary and human
pathogenic
protozoas are preferably intracellular active parasites of the phylum
Apicomplexa or
Sarcomastigophora, especially Trypanosoma, Plasmodia, Leishmania, Babesia and
Theileria, Cryptosporidia, Sacrocystida, Amoebia, Coccidia and Trichomonadia.
These
active substances or corresponding drugs are especially suitable for the
treatment of
Malaria tropica, caused by Plas zodium falciparum, Malaria tertiana, caused by
Plasmodium vivax or Plasmodium ovale and for the treatment of Malaria
quartana, caused
by- Plasmodium malariae. They are also suitable for the treatment of
Toxoplasmosis,
caused by Toxoplasma gondii, Coccidiosis, caused for instance by Isospora
belli, intestinal
Sarcosporidiosis, caused by Sarcocystis suihominis, dysentery caused by
Entamoeba
histolytica, Cryptosporidiosis, caused by Cryptosporidium parvum, Chargas'
disease,
caused by Trypanosoma cruzi,. sleeping sickness, caused by Trypanosoma brucei
rhodesiense or gambiense, the cutaneous and visceral as well as other forms of
Leishmaniosis. They are also suitable for the treatment of animals infected by
veterinary
pathogenic protozoa, like Theileria parva, the pathogen causing bovine East
coast fever,
Tfypanosoma congolense congolense or Trypanosoma vivax vivax, Trypanosoma
brucei
brucei, pathogens causing Nagana cattle disease in Africa, Trypanosoma brucei
evansi
causing Surra, Babesia bigemina, the pathogen causing Texas fever in cattle
and buffalos,
Babesia bovis, the pathogen causing European bovine Babesiosis as well as
Babesiosis in
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54
dogs, cats and sheep, Sarcocystis ovicanis and ovifelis pathogens causing
Sarcocystiosis in
sheep, cattle and pigs, Cryptosporidia, pathogens causing Cryptosporidioses in
cattle and
birds, Eimeria and Isospora species, pathogens causing Coccidiosis in rabbits,
cattle, sheep,
goats, pigs and birds, especially in chickens and turkeys. The use of the
compounds of the
present invention is preferred in particular for the treatment of Coccidiosis
or Malaria
infections, or for the preparation of a drug or feed stuff for the treatment
of these diseases.
This treatment can be prophylactic or curative. In the treatment of malaria,
the compounds
of the present invention may be combined with other anti-malaria agents.
The compounds of the present invention can fiutlier be used for the
propliylaxis and/or
treatment of infectious diseases caused among others by bacteria and viruses,
including
opportunistic infections in a mammal, including a human. Said method comprises
administering to the mammal an amount of at least one compound of the general
formula (Ia),
(Ib), (Ic), (II), or (III) and/or pharmaceutically acceptable salts thereof,
effective to prevent
and/or treat said infectious disease and/or opportunistic infection.
The infectious disease can be selected from the group comprising AIDS,
Alveolar Hydatid,
Disease (AHD, Echinococcosis), Amebiasis (Entamoeba histolytica Infection),
Angiostrongylus Infection, Anisakiasis, Anthrax, Babesiosis (Babesia
Infection),
Balantidium Infection (Balantidiasis), Baylisascaris Infection (Raccoon
Roundworm),
Bilharzia (Schistosomiasis), Blastocystis hominis i Infection (Blastomycosis),
Boreliosis,
Botulism, Brainerd Diarrhea, Brucellosis, BSE (Bovine Spongiform
Encephalopathy),
Candidiasis, Capillariasis (Capillaria Infection), CFS (Chronic Fatigue
Syndrome), Chagas
Disease (American Trypanosomiasis), Chiclcenpox (Varicella-Zoster virus),
Chlamydia
pneumoniae Infection, Cholera, Chronic Fatigue Syndrome, CJD (Creutzfeldt-
Jakob
Disease), Clonorchiasis (Clonorchis Infection), CLM (Cutaneous Larva Migrans,
Hookworm Infection), Coccidioidomycosis, Conjunctivitis, Coxsackievirus A16
(Hand,
Foot and Mouth Disease), Cryptococcosis, Cryptosporidium Infection
(Cryptosporidiosis),
Culex mosquito (Vector of West Nile Virus), Cutaneous Larva Migrans (CLM),
Cyclosporiasis (Cyclospora Infection), Cysticercosis (Neurocysticercosis),
Cytomegalovirus Infection (CMV), Dengue / Dengue Fever, Dipylidium Infection
(Dog
and Cat Flea Tapeworm), Ebola Virus Hemorrhagic Fever, Echinococcosis
(Alveolar
Hydatid Disease), Encephalitis, Entomoeba coli Infection, Entomoeba dispar
Infection,
Entomoeba hartmanni Infection, Entomoeba histolytica Infection (Amebiasis),
Entomoeba
polecki Infection, Enterobiasis (Pinworm Infection), Enterovirus Infection
(Non-Polio),
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Epstein-Barr Virus Infection, Escherichia coli Infection, Foodborne Infection,
Foot and
mouth Disease, Fungal Dermatitis, Gastroenteritis, Group A streptococcal
Disease, Group
B streptococcal Disease, diseases caused by staphylococcal infections
(Staphylococcus
aureus and other stapliylococcus species), diseases caused by infections with
pseudomonas
5 aeruginosa and other pseudomonas species, Burkholderia cepacia infections,
Hansen's
Disease (Leprosy), Hantavirus Pulmonary Syndrome, Head Lice Infestation
(Pediculosis),
Helicobacter pylori Infection, Hematologic Disease, Hendra Virus Infection,
Hepatitis,
Herpes Zoster (Shingles), HIV Infection, Human Ehrlichiosis, Human
Parainfluenza Virus
Infection, Influenza, Isosporiasis (Isospora Infection), Lassa Fever,
Leishmaniasis, Kala-
10 azar (Kala-azar, Leishmania Infection), Leprosy, Lice (Body lice, Head
lice, Pubic lice),
Lyme Disease, Marburg Hemorrhagic Fever, Measles, Meningitis, Mosquito-borne
Diseases, Mycobacterium avium Complex (MAC) Infection, Naegleria Infection,
Nosocomial Infections, Nonpathogenic Intestinal Amebae Infection,
Onchocerciasis (River
Blindness), Opisthorciasis (Opisthorcis Infection), Parvovirus Infection,
Plague, PCP
15 (Pneumocystis carinii Pneumonia), Polio, Q Fever, Rabies, Respiratory
Syncytial Virus
(RSV) Infection, Rheumatic Fever, Rift Valley Fever, River Blindness
(Onchocerciasis),
Rotavirus Infection, Roundworms Infection, Salmonellosis, Salmonella
Enteritidis,
Scabies, Shigellosis, Shingles, Sleeping Sickness, Smallpox, Streptococcal
Infection,
Tapeworm Infection (Taenia Infection), Tetanus, Toxic Shock Syndrome,
Tuberculosis,
20 Ulcers (Peptic Ulcer Disease), Valley Fever, Vibrio parahaemolyticus
Infection, Vibrio
vulnificus Infection, Viral Hemorrhagic Fever, Warts, Waterborne infectious
Diseases,
West Nile Virus Infection (West Nile Encephalitis), Whooping Cough, Yellow
Fever.
The compounds of formula (Ia), (Ib), (Ic), (II), or (III) and their
pharmacologically
25 acceptable salts can be administered to aniinals, preferably to mammals,
and in particular
to humans, dogs and chickens as therapeutics per se, as mixtures with one
another or in the
form of pharmaceutical preparations which allow enteral or parenteral use and
which as
active constituent contain an effective dose of at least one compound of the
formula (Ia),
(Ib), (Ic), (II), or (III) or a salt thereof, in addition to customary
pharmaceutically
30 innocuous excipients and additives. The compounds of formula (Ia), (Ib),
(Ic), (II), or (III)
can also be administered in form of their salts, which are obtainable by
reacting the
respective compounds with physiologically acceptable acids and bases.
The production of medicaments containing the compounds of fonnula (Ia), (Ib),
(Ic), (II),
35 or (III) according to the invention and their application can be performed
according to
well-known pharmaceutical methods.
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While the compounds of fonnula (Ia), (Ib), (Ic), (II), or (III) according to
the invention for
use in therapy may be administered in the form of the raw chemical compound,
it is
preferred to introduce the active ingredient, optionally in the form of a
physiologically
acceptable salt in a pharmaceutical composition together with one or more
adjuvants,
excipients, carriers, buffers, -diluents, and/or other customary
pharmaceutical auxiliaries.
Such salts of the compounds may be anhydrous or solvated.
In a preferred embodiment, the invention provides medicaments comprising
compounds of
formula (Ia), (Ib), (Ic), (II), or (III) according to the invention, or a
pharmaceutically
acceptable salt or pharmaceutically acceptable prodrugs or a stereoisomer
thereof, together
with one or more pharmaceutically acceptable carriers thereof, and,
optionally, other
therapeutic and/or prophylactic ingredients. The carrier(s) must be
"acceptable" in the
sense of being compatible with the other ingredients of the formulation and
not harmful to
the recipient thereof.
A medicament of the invention may be those suitable for oral, rectal,
bronchial, nasal,
topical, buccal, sub-lingual, transdermal, vaginal or parenteral (including
cutaneous,
subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial,
intracerebral,
intraocular injection or infusion) administration, or those in a form suitable
for
administration by inhalation or insufflation, including powders and liquid
aerosol
administration, or by sustained release systems. Suitable examples of
sustained release
systems include semipermeable matrices of solid hydrophobic polymers
containing the
compound of the invention, which matrices may be in form of shaped articles,
e.g. films or
microcapsules.
The compounds according to the invention, together with a conventional
adjuvant, carrier,
or diluent, may thus be placed into the form of inedicament and unit dosages
thereof. Such
forms include solids, and in particular tablets, filled capsules, powder and
pellet forms, and
liquids, in particular aqueous or non-aqueous solutions, suspensions,
emulsions, elixirs,
and capsules filled with the same, all for oral use, suppositories for rectal
administration,
and sterile injectable solutions for parenteral use. Such Medicament and unit
dosage forms
thereof may comprise conventional ingredients in conventional proportions,
with or
without additional active compounds or principles, and such unit dosage forms
may
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57
contain any suitable effective amount of the active ingredient commensurate
with the
intended daily dosage range to be employed.
The compound useable according to the invention can be administered in a wide
variety of
oral and parenteral dosage forms. It will be obvious to those skilled in the
art that the
following dosage forms may comprise, as the active component, either a
compound of
foznzula (Ia), (Ib), (Ic), (II), or (III) according to the invention or a
pharmaceutically
acceptable salt or stereosomer thereof.
For preparing a medicament from a compounds of forinula (Ia), (Ib), (Ic),
(II), or (III)
pharmaceutically acceptable carriers can be either solid or liquid. Solid form
preparations
include powders, tablets, pills, capsules, cachets, suppositories, and
dispersible granules. A
solid carrier can be one or more substances which may also act as diluents,
flavouring
agents, solubilizers, lubricants, suspending agents, binders, preservatives,
tablet
disintegrating agents, or an encapsulating material.
In powders, the carrier is a finely divided solid which is in a mixture with
the finely
divided active component. In tablets, the active component is mixed with the
carrier having
the necessary binding capacity in suitable proportions and compacted in the
shape and size
desired. Suitable carriers are magnesium carbonate, magnesium stearate, talc,
sugar,
lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium
carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The
term
"preparation" is intended to include the formulation of the active compound
with
encapsulating material as carrier providing a capsule in which the active
component, with
or without carriers, is surrounded by a carrier, which is thus in association
with it.
Similarly, cachets and lozenges are included. Tablets, powders, capsules,
pills, cachets, and
lozenges can be used as solid forms suitable for oral administration.
For preparing suppositories, a low melting wax, such as a mixture of fatty
acid glyceride or
cocoa butter, is first melted and the active component is dispersed
homogeneously therein,
as by stirring. The molten homogenous mixture is then poured into convenient
sized
moulds, allowed to cool, and thereby to solidify. Compositions suitable for
vaginal
administration may be presented as pessaries, tampons, creams, gels, pastes,
foams or
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58
sprays containing in addition to the active ingredient such carriers as are
known in the art
to be appropriate. Liquid preparations include solutions, suspensions, and
emulsions, for
example, water or water-propylene glycol solutions. For example, parenteral
injection
liquid preparations can be formulated as solutions in aqueous polyethylene
glycol solution.
The compounds of formula (Ia), (Ib), (Ic), (II), or (III) according to the
present invention
may thus be formulated for parenteral administration (e.g. by injection, for
example bolus
injection or continuous infusion) and may be presented in unit dose form in
ampoules, pre-
filled syringes, small volume infusion or in multi-dose containers with an
added
preservative. The compositions may take such forms as suspensions, solutions,
or
emulsions in oily or aqueous vehicles, and may contain formulation agents such
as
suspending, stabilising and/or dispersing agents. Alternatively, the active
ingredient may
be in powder form, obtained by aseptic isolation of sterile solid or by
lyophilization from
solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free
water, before
use.
Aqueous solutions suitable for oral use can be prepared by dissolving the
active component
in water and adding suitable colorants, flavours, stabilising and thickening
agents, as
desired. Aqueous suspensions suitable for oral use can be made by dispersing
the finely
divided active component in water with viscous material, such as natural or
synthetic
gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well
known
suspending agents.
Also included are solid form preparations which are intended to be converted,
shortly
before use, to liquid form preparations for oral administration. Such liquid
forms include
solutions, suspensions, and emulsions. These preparations may contain, in
addition to the
active component, colorants, flavours, stabilisers, buffers, artificial and
natural sweeteners,
dispersants, thickeners, solubilizing agents, and the like.
In one embodiment of the present invention, the medicament is applied
topically or
systemically or via a combination of the two routes.
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In an especially preferred embodiment of the present invention the medicament
is applied
topically. This reduces possible side effects and limits the necessary
treatment to those
areas affected.
Preferably the medicament is prepared in form of an ointment, a gel, a
plaster, an
emulsion, a lotion, a foam, a cream of a mixed phase or am.phiphilic emulsion
system
(oil/water-water/oil mixed phase), a liposome, a transfersome, a paste or a
powder.
Ointments and creams may, for example, be forrnulated with an aqueous or oily
base with
the addition of suitable thickening and/or gelling agents. Lotions may be
formulated with
an aqueous or oily base and will in general also contain one or more
emulsifying agents,
stabilising agents, dispersing agents, suspending agents, thickening agents,
or colouring
agents.
Compositions suitable for topical administration in the mouth include lozenges
comprising
the active agent in a flavoured base, usually sucrose and acacia or
tragacanth; pastilles
comprising the active ingredient in an inert base such as gelatin and
glycerine or sucrose
and acacia; and mouthwashes comprising the active ingredient in a suitable
liquid carrier.
Solutions or suspensions are applied directly to the nasal cavity by
conventional means, for
example with a dropper, pipette or spray. The compositions may be provided in
single or
multi-dose form. In the latter case of a dropper or pipette, this may be
achieved by the
patient administering an appropriate, predetermined volume of the solution or
suspension.
In the case of a spray, this may be achieved for example by means of a
metering atomising
spray pump.
Administration to the respiratory tract may also be achieved by means of an
aerosol
formulation in which the active ingredient is provided in a pressurised pack
with a suitable
propellant such as a chlorofluorocarbon (CFC) for example
dichlorodifluoromethane,
trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other
suitable gas.
The aerosol may conveniently also contain a surfactant such as lecithin. The
dose of drug
may be controlled by provision of a metered valve.
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Alternatively the active ingredients may be provided in the form of a dry
powder, for
example a powder mix of the compound in a suitable powder base such as
lactose, starch,
starch derivatives such as hydroxypropylmethyl cellulose and
polyvinylpyrrolidone (PVP).
Conveniently the powder carrier will form a gel in the nasal cavity The powder
5 composition may be presented in unit dose form for example in capsules or
cartridges of,
e.g., gelatin, or blister packs from which the powder may be administered by
means of an
inhaler.
In compositions intended for administration to the respiratory tract,
including intranasal
10 compositions, the compound will generally have a small particle size for
example of the
order of 5 microns or less. Such a particle size may be obtained by means
known in the art,
for example by micronization.
When desired, compositions adapted to give sustained release of the active
ingredient may
15 be employed.
The phannaceutical preparations are preferably in unit dosage forms. In such
form, the
preparation is subdivided into unit doses containing appropriate quantities of
the active
component. The unit dosage form can be a packaged preparation, the package
containing
20 discrete quantities of preparation, such as packaged tablets, capsules, and
powders in vials
or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or
lozenge itself,
or it can be the appropriate number of any of these in packaged form. Tablets
or capsules
for oral administration and liquids for intravenous administration and
continuous infusion
are preferred compositions.
Further details on techniques for formulation and administration may be found
in the latest
edition of Remington's Pharmaceutical Sciences (Maack Publishing Co. Easton,
Pa.).
Pharmaceutical compositions can also contain two or more compounds of the
formula (Ia),
(Ib), (Ic), (II), or (III) or their pharmacologically acceptable salts and
also other
therapeutically active substances.
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Thus, the compounds of the present invention can be used in the form of one
compound
alone or in combination with other active compounds - for example with
medicaments
already known for the treatment of the aforementioned diseases, whereby in the
latter case
a favorable additive, amplifying effect is noticed. Suitable amounts to be
administered to
humans may range from 5 to 500 mg.
To prepare the pharmaceutical preparations, pharmaceutically inert inorganic
or organic
excipients can be used. To prepare pills, tablets, coated tablets and hard
gelatin capsules,
for example, lactose, corn starch or derivatives thereof, talc, stearic acid
or its salts, etc.
can be used. Excipients for soft gelatin capsules and suppositories are, for
example, fats,
waxes, semi-solid and liquid polyols, natural or hardened oils etc. Suitable
excipients for
the production of solutions and syrups are, for example, water, sucrose,
invert sugar,
glucose, polyols etc. Suitable excipients for the production of injection
solutions are, for
example, water, alcohols, glycerol, polyols or vegetable oils.
The dose can vary within wide limits and is to be suited to the individual
conditions in
each individual case. For the above uses the appropriate dosage will vary
depending on the
mode of administration, the particular condition to be treated and the effect
desired. In
general, however, satisfactory results are achieved at dosage rates of about 1
to 100 mg/kg
animal body weight preferably 1 to 50 mg/kg. In general, suitable dosage rates
for larger
manimals, for example humans, may be of the order of from about 10 mg to 3
g/day,
conveniently administered once, in divided doses 2 to 4 times a day, or in
sustained release
form.
In general, a daily dose of approximately 10 mg to 5000 mg, preferably 50 to
500 mg, per
human individual is appropriate in the case of the oral administration. In the
case of 'other
administration forms too, the daily dose is in similar ranges. For topical
delivery,
depending on the permeability of the skin, the type and the severity of the
.disease and
dependent on the type of formulation and frequency of application, different
concentrations
of active compounds within the medicament can be sufficient to elicit a
therapeutic effect
by topical application. Preferably the concentration of an active compound or
a
pharmaceutically acceptable salt thereof or a physiologically functional
derivative or a
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62
stereoisomer thereof within a medicament according to the invention is in the
range of
between 1 mol/1 and 100 mmol/l.
The following examples and figures are included to demonstrate preferred
embodiments of
the invention. It should be appreciated by those of skill in the art that the
techniques
disclosed in the examples that follow represent techniques discovered by the
inventors to
function well in the practice of the invention, and thus can be considered
preferred modes
for its practice. However, those of skill in the art should, in light of the
present disclosure,
appreciate that many changes can be made in the specific embodiments that are
disclosed
without departing from the spirit and scope of the invention as set out in the
appended
claims. All references cited are incorporated herein by reference.
Examples
Abbreviations: min, minute(s); h, hour(s); r.t., room temperature; t-, tert-.
NMR spectra: Bruker Avance 300 MHz. The spectra were recorded at 300 MHz ('H-
NMR), respectively, using the residual solvent peak as an internal standard
(DMSO-d6, SH
= 2.49; CD3OD, SH = 3.31; CDC13, SH = 7.26; CD3CN, SH =1.93; (CD3)2C0, SH =
2.05).
Analytical LC/ESI-MS: 2 x Waters 600 Multisolvent Delivery System. 50 l
sample loop.
Column, Chromolith Speed ROD RP18e (Merck, Darmstadt), 50 x 4.6 mm, witll 2 m
prefilter (Merck). Eluent A, H20 + 0.1 % HCOaH; eluent B, MeCN. Gradient, 5 %
B to 100
% B within 5 min; flow, 3 ml/min. Waters LCZ single quadrupol mass
spectrometer with
electrospray source. MS metliod, MS8minPM-80-800-20V; positive/negative ion
mode
scanning, m/z 80 - 800 in 1 s; capillary, 3.5 kV; cone voltage, 20 V;
multiplier voltage, 400
V; probe and desolvation gas temperature, 120 C and 350 C, respectively.
Waters 2487
Dual aAbsorbance Detector, set to 254 nm.
Preparative HPLC-MS: Waters 600 Multisolvent Delivery System with peparative
pump
heads. 2000 l or 5000 l sample loop. Column, Waters X-Terra RP18, 7 m, 19 x
150
mm with X-Terra RP18 guard cartridge 7 m, 19 x 10 mm; used at flow rate 20
ml/min or
YMC ODS-A, 120 A, 40 x 150 mm with X-Terra RP18 guard cartridge 7 m, 19 x 10
mm;
used at flow rate 50 ml/min. Make-up solvent: MeCN - H2O - HCO2H 80 : 20 :
0.05
(v:v:v). Eluent A, H20 + 0.1 % HCO2H; eluent B, MeCN. Different linear
gradients from 5
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63
- 100% eluent B, adapted to sample. Injection volume: 500 l - 2000 l
depending on
sample. Waters ZQ single quadrupol mass spectrometer with electrospray source.
Positive
or negative ion mode scanning m/z 80 - 800 in 1 s; capillary, 3.5 kV or 3.0
kV; cone
voltage, 20 V; multiplier voltage, 400 V; probe and desolvation gas
temperature, 120 C
and 350 C, respectively. Waters Fraction Collector II with mass-triggered
fraction
collection. Waters 996 photo diode array detector.
Synthesis of 4-(Methogy-methyl-carbamoyl)-piperidine-l-carboxylic acid t-butyl
ester
Piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.0 eq, 21.8 mmol) was
dissolved
under inert conditions in 35 ml dry N, N- dimethylformamide. O,N-dimethyl-
hydroxylamine hydrochloride (1.03 eq, 22.5 mmol), benzotriazol-l-ol
monohydrate (1.03
eq, 22.5 mmol) and triethylamine (1.5 eq, 32.7 mmol) were added. The reaction
mixture
was cooled to 0 C, N-(3-Dimethylaminopropyl)-N-ethylcarbodiimid hydrochloride
(1.0 eq,
21.8 mmol) was added over a period of 10 minutes and the mixture was stirred
vigorously
at 0 C for 1 h and at r.t. for 18 h.
The solvent was removed under vaccum and the residue was suspended in 400 ml
ethylacetate. The organic layer was extracted 3 times with 100 ml of 1 M
citric acid,
aqueous sodium carbonate and twice with 100 ml brine, dried over MgSO4 and
filtered.
The solvent was removed and the residue was purified by distillation resulting
in a yield of
80%.
Synthesis of 4-Formyl-piperidine-l-carboxylic acid t-butyl ester
4-(methoxy-methyl-carbamoyl)-piperidine-l-carboxylic acid tert-butyl ester
(1.0 eq, 16.4
mmol) was dissolved in 100 ml dry tetrahydrofurane under inert atmosphere.
This soli.ution
was added dropwise over a period of 1 h to a suspension of lithiumalanate (3.0
eq, 49.6
mmol) in 70 ml dry tetrahydrofurane at -50 C. During the adding of the
mixture, the
temperature was held at - 50 C and then allowed to warm to 0 C within 3 h.
The mixture was cooled to -78 C and quenched carefully with 100 ml 1 M citric
acid. The
mixture was warmed up to r.t. and diluted with 400 ml ethylacetate. The phases
were
separated and the aqueous phase was extracted 3 times with 70 ml ethylacetate.
The
combined organic layers were extracted 3 times with'100 ml 1 M citric acid,
aqueous
sodium carbonate and 2 times with 100 ml brine, dried over MgSO4 and
filtrated. The
solvent was removed and the residue was purified by distillation resulting in
a yield of
85%
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64
Synthesis of 4-(4-Ethoxycarbonyl-4,5-dihydro-thiazol-2-yl)-piperidine-l-
carboxylic
acid t-butyl ester
4-formyl-piperidine-l-carboxylic acid tert-butyl ester (1.0 eq, 13 mmol) was
dissolved
under inert conditions in 40 ml toluene. To this solution L-cystein ethylester
hydrochloride
(1.6 eq, 21 mmol) and triethylamine (1.6 eq, 21 mmol) were added. The mixture
was
refluxed for 14 h. The generated water was removed with a Dean & Stark trap.
The solvent was removed and the residue was dissolved in 100 ml ethylacetate.
The
organic layer was extracted 3 times with 50 ml 1 M citric acid, aqueous
potassium
hydrogen carbonate and 2 times with 50 ml brine, dried over MgSO4 and
filtrated. The
solvent was removed and the residue was purified by silica gel chromatography
using a
PE/ EA 4:1 gradient. Yield: 75%
Synthesis of 4-(4-Ethogycarbonyl-thiazol-2-yl)-piperidine-l-carbogylic acid t-
butyl
ester
4-(4-Ethoxycarbonyl-4,5-dihydro-thiazol-2-yl)-piperidine-l-carboxylic acid
tert-butyl ester
(1.0 eq, 8.7 mmol) was solved in 160 ml toluene under inert conditions. To
this solution
Mn02 (15.0 eq, 130 mmol) was added. The reaction was heated to 70 C under
stirring for
5 h. The mixture was filtered over celite and the filtration agent was washed
3 times with
30 ml toluene and ethylacetate. The combined organic layers were distilled in
vacuo. The
residue was purified by silica gel chromatography using a DCM/MeOH 95:5
gradient.
Yield: 30%
C-terminal functionalisation
4-(4-Ethoxycarbonyl-thiazol-2-yl)-piperidine-l-carboxylic acid tert-butyl
ester (1.0 eq, 2.9
mmol) was dissolved under inert gas in 40 ml dioxane. Under stirring 1.5 ml
aqueous 2 N
NaOH was added dropwise over a period of 10 min. Afterwards the mixture was
stirred for
2 h at r.t.
The reaction was neutralized with 2 N HCl and the 'solvent was evaporated in
vacuo. The
residue was dissolved in 50 ml ethylacetate. The organic layer was extracted 3
times with
10 ml of 1 M citric acid and water, dried over MgSO4 and filtered. The solvent
was
removed and the residue was dried in vacuo. Yield 95%
4-(4-Carboxy-thiazol-2-yl)-piperidine-l-carboxylic acid tert-butyl ester (1
eq) was
dissolved under inert conditions in dry dimethylacetamide (0,03 mmol/ml). To
this
solution aryl- or alkylamine (1 eq), diisopropylethylamine (2 eq) and O-
benzotriazol-1-yl-
N,N,N',N'-tetramethyluronium hexafluorophosphate (2 eq) was added. The
reaction
mixture was stirred for 12 h at r.t.
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The solvent was removed in vacuo and the residue was dissolved in
ethylacetate. The
organic layer was extracted 3 times with 1 M citric acid, aqueous potassium
hydrogen
carbonate and 2 times with brine, dried over MgSO4 and filtred. The solvent
was removed
and the residue was purified by silica gel chromatography using. a DCM/MeOH
5 95:5gradient. Yield: 40-80%
N-terminal functionalisation
The N-protected substrate was treated under inert condition with 4 M
HC1/dioxane (conc.
0,03 mmol substrate in 1 mL HC1/dioxane) and was stirred for 2 h at r.t.
10 The solvent was removed in vacuo to yield the HC1 salt of the free amine
without further
purification.
The free amino compound (1 eq) was dissolved under inert conditions in dry
dimethylacetamide (0,03 mmol/ml). To this solution aryl- or alkylcarboxylic
acid (1 eq),
15 diisopropylethylamine (2 eq) and O-benzotriazol-1-yl-N,N,N',N'-
tetramethyluronium
hexafluorophosphate (2 eq) was added in this sequence and the reaction mixture
was
stirred for 12 h at r.t.
The solvent was removed in vacuo and the residue was dissolved in
ethylacetate. The
organic layer was extracted 3 times with 1 M citric acid, aqueous potassium
hydrogen
20 carbonate and 2 times with brine, dried over MgSO4 and filtred. The solvent
was removed
and the residue was purified by silica gel chromatography using a DCM/MeOH
95:5
gradient. Yield: 40-80%
General synthesis for compounds of type (fII) and (II)
25 ProceduNe fof= the synthesis of compounds of type (IIIa), (IIIc), (IIa) and
(Ilb)
7,3x10'4 mol of the benzoic acid derivative (VI) was dissolved in 5 ml DMF and
1 eq. of
Hunig's base was added, stirring the reaction mixture for a few minutes,
followed by the
addition of 1 eq. of HBTU and further stirring at r.t. for 2 min. Afterwards 1
eq. 2-Amino-
thiazole-4-carboxylic acid ethyl ester was added, stirring the mixture
overnight at the same
30 temperature. Subsequently, the solvent was removed by filtration and the
residue
redissolved in 5 ml dioxane and treated with 0,5 ml of a 1M NaOH solution.
After the
reaction was complete, the pH was decreased to 1-2 with a 1M HCl solution and
the
precipitated product (VII) filtered and dried in vacuo. For the next step,
intermediate (VII)
was dissolved in 3 ml DMF and 1 eq. of Hunig's base was added, stirring the
reaction
35 mixture for a few minutes, followed by the addition of 1 eq. of HBTU and
further stirring
at r.t. for 2 min. Afterwards 1 eq. the amino component was added, stirring
the mixture
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66
overnight at the same temperature. Subsequently, the solvent was removed by
filtration and
the crude product redissolved in 10 ml ethyl acetate, washed twice with 10 ml
citric acid
(1M solution), 10 ml sat. NaHCO3 solution and 10 ml water. The organic phase
was then
evaporated and the residue dried over MgSO4. The solvent was removed and-
final
purification was realised by preparative HPLC as described above.
As a second variante for the first step, the corresponding acid chloride
derivative of (VI)
could be reacted.with the 2-Amino-thiazole-4-carboxylic acid ethyl ester (1:1)
using 1,1
eq. of Hiinig's base.
Procedure fot~ the synthesis of cofnpounds of type (IZIb, d, e, ) and (IIc, d)
6,3x10"4 mol of 2-Bromo-thiazole-4-carboxylic acid ethyl ester (X) was
dissolved in 10 ml
THF together with 2,2 eq. of the respective piperazine (IX), allowing to
reflux overnight.
Afterwards the solvent was removed in vacuo and the residue purified by pTLC
(PE/EE
2/1).
The second and the third step of the reaction were accomplished as described
above under
the procedure for the synthesis of compounds of type (IIIa) and (IIIc).
For as synthesis-protocol of type (Illb, d, e, f and IIc, d) compounds with Z=
CH, see WO
2004/058750.
Examplary compounds of formula (Ia) of the present invention include, but are
not limited
to, the followings:
Cp. Name Mass LC/(+)-ESI- Biological
MS: activi 1)
74 4-{4-[4-(3-Trifluoromethyl-phenyl)- 619 620 ++
piperazine-l-carbonyl]-thiazol-2-yl}- [M+H]+
piperidine-l-carboxylic acid (7-fluoro-2,3-
dihydro-benzo 1,4]dioxin-5-yl)-amide
75 4-{4-[4-(3-Trifluoromethyl-phenyl)- 601 602 ++
piperazine-l-carbonyl]-thiazol-2-yl}- [M+H]+
piperidine-l-carboxylic acid (2,3-dihydro-
benzo 1,4 dioxin-6-yl -axnide
76 4-{4-[4-(3-Trifluoromethyl-phenyl)- 615 616 ++
piperazine-l-carbonyl]-thiazol-2-yl}- [M+H]+
i eridine-l-carboxylic acid (5-methyl-2-
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trifluoromethyl-furan-3-yl)-amide
77 4-{4-[4-(3-Trifluoromethyl-phenyl)- 577 578 +++
piperazine-l-carbonyl]-thiazol-2-yl} - [M+H]+
piperidine-l-carboxylic acid (2-thiophen-2-
yl-ethyl)-amide
78 4-{4-[4-(3-Trifluoromethyl-phenyl)- 509 510 +
piperazine-l-carbonyl]-thiazol-2-yl}- [M+H] +
piperidine-l-carboxylic acid
isopropylamide
79 4-{4-[4-(3-Trifluoromethyl-phenyl)- 627 628 +++
piperazine-l-carbonyl]-thiazol-2-yl}- [M+H]+
piperidine-1-carboxylic acid (2-
trifluoromethoxy- henyl)-amide
80 4-{4-[4-(3-Trifluoromethyl-phenyl)- 573 574 +
piperazine-l-carbonyl]-thiazol-2-yl}- [M+H]+
piperidine-l-carboxylic acid (3 -methoxy-
henyl)-amide
81 4-{4-[4-(3-Trifluoromethyl-phenyl)- 633 634 ++
piperazine-l-carbonyl]-thiazol-2-yl}- [M+H]+
piperidine-l-carboxylic acid (3,4,5-
trimethoxy-phenyl -amide
114 4-(4-{4-[4-(3-Trifluoromethyl-phenyl)- 568 569 +
piperazine-l-carbonyl]-thiazol-2-yl}- [M+H]+
i eridine-l-carbonyl)-benzonitrile
134 4-{4-[4-(3-Trifluoromethyl-phenyl)- 543 544 +
piperazine-l-carbonyl] -thiazol-2-yl} - [M+H]+
piperidine- 1-carboxylic acid henylamide
142 4-{4-[4-(3-Trifluoromethyl-phenyl)- 561 562 -----
piperazine-l-carbonyl]-thiazol-2-yl}- [M+H]+
piperidine-l-carboxylic acid (3-fluoro-
henyl)-amide
143 4-{4-[4-(3-Trifluoromethyl-phenyl)- 561 562 +
piperazine-l-carbonyl]-thiazol-2-yl}- [M+H]+
piperidine-l-carboxylic acid (4-fluoro-
henyl -axnide
1) The biological data refer to results obtained from the NF-xB inflammation
assay.
[ '+" stands for 50-80% inhibition, "++" means 80-90% and "-f-F+" stands for
90-100% inhibition]
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Examplary compounds of formula (Ib) of the present invention include, but are
not limited
to, the followings:
Cp. Name Mass LC/(+)-ESI- Biological
MS: activi 1)
103 2-{5-Methyl-2-[1-(2-trifluoromethoxy- 640 641 ++
benzoyl)-piperidin-4-yl]-thiazol-4-yl}-1-[4- [M+H]+
(3-trifluoromethyl-phenyl)-piperazin-1-yl]-
ethanone
128 1-[4-(3-Chloro-phenyl)-piperazin-l-yl]-2- 606 607 +++
{5-methyl-2-[1-(2-trifluoromethoxy- [M+H]+
benzoyl)-piperidin-4-yl]-thiazol-4-yl} -
ethanone
1) The biological data refer to results obtained from the NF-xB inflammation
assay.
["+" stands for 50-80% inhibition, "++" means 80-90% and "+++" stands for 90-
100% inhibition]
Exatnplary compounds of formula (Ic) of the present invention include, but are
not limited
to, the followings:
Cp. Name Mass LC/(+)-ESI- Biological
MS: activi 1)
150 [1-(5-Chloro-2-methylamino-phenyl)-3,4- 654 655 ++
dihydro-lH-isoquinolin-2-yl]-{2-[1-(2- [M+H]+
trifluoromethoxy-benzoyl)-piperidin-4-yl] -
thiazol-4-yl}-methanone
160 1-{4-[4-(6,7-Dihydroxy-3,4-dihydro-lH- 495 496 +
isoquinoline-2-carbonyl)-thiazol-2-yl]- [M+H]+
piperidin-l-yl}-2-(4-fluoro-phenyl)-
ethanone
161 1-{4-[4-(6,7-Dimethoxy-3,4-dihydro-lH- 523 524 +
isoquinoline-2-carbonyl)-thiazol-2-yl]- [M+H]+
piperidin-l-yl } -2-(4-fluoro-phenyl)-
ethanone
163 1-{4-[4-(3,4-Dihydro-lH-isoquinoline-2- 463 464 +
carbonyl)-thiazol-2-yl]-piperidin-1-yl}-2- [M+H]+
4-fluoro- henyl)-ethanone
232 1-{4-[4-(6,7-Dimethoxy-3-methyl-3,4- 537 538 +
dihydro-lH-iso uinoline-2-carbonyl)- +H +
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thiazol-2-yl]-piperidin-1-yl}-2-(4-fluoro-
henyl)-ethanone
233 1-{4-j4-(6,7-Dihydroxy-l-methyl-3,4- 509 510 +
dihydro-lH-isoquinoline-2-carbonyl)- [M+H]+
thiazol-2-yl]-piperidin-1-yl}-2-(4-fluoro-
henyl)-ethanone
234 1-{4-[4-(6,7-Dimethoxy-l-methyl-3,4- 537 538 +
dihydro-l H-isoquinoline-2-carbonyl)- [M+H]+
thiazol-2-yl]-piperidin-1-yl}-2-(4-fluoro-
henyl)-ethanone
235 1-(4-{4-[1-(5-Chloro-2-methylamino- 602 603 +
phenyl)-3,4-dihydro-lH-isoquinoline-2- [M+H]+
carbonyl] -thiazol-2-yl } -pip eridin-1-yl)-2-
(4-fluoro- henyl)-ethanone
The biological data refer to results obtained from the NF-KB inflammation
assay.
["+" stands for 50-80% inhibition, "++" means 80-90% and "+++" stands for 90-
100% inhibition]
Examplary compounds of formula (II) of the present invention include, but are
not limited
to, the followings:
Cp. Naine Mass LC/(+)-ESI- Biological
MS: activi 1)
3 N-{4-[4-(4-Fluoro-phenyl)-piperazine-1- 494 495 ++
carbonyl]-thiazol-2-yl}-2-trifluoromethoxy- [M+H]+
benzamide
5 N-[5-(4-Pyrimidin-2-yl-piperazine-l- 478 479 +
carbonyl)-thiazol-2-yl]-2-trifluorometlioxy- [M+H]+
benzami.de
2-Methoxy-N-{4-[4-(3-trifluoromethyl- 490 491 +++
phenyl)-piperazine-l-carbonyl]-thiazol-2- [M+H]+
yl}-benzamide
16 3-Fluoro-4-trifluoromethyl-N-(1-{4-[4-(3- 643 644 ++
trifluoromethyl-phenyl)-piperazine-l- [M+H]+
carbonyl]-thiazol-2-yl}piperidin-4-
ylmethyl -benzamide
17 3-Cyclopentyl-N-(1-{4-[4-(3- 577 578 ++
trifluoromethyl-phenyl)-piperazine-l- [M+H]+
carbonyl -thiazol-2-yl - i eridin-
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4ylmethyl)- ro ionamide
18 2-Trifluoromethoxy-N-(1-{4-[4-(3- 641 642 ++
trifluoromethyl-phenyl)-piperazine-l- [M+H]+
carbonyl]-thiazol-2-yl} -piperidin-
4ylmethyl)-benzamide .
19 4-Cyano-N-(1-{4-[4-(3-trifluoromethyl- 582 583 ++
phenyl)-piperazine-l-carbonyl]-thiazol-2- [M+H]+
yl}- iperidin-4-ylmethyl)-benzamide
20 [4-(3-Trifluoromethyl-phenyl)-piperazin-l- 569 570 ++
yl]-{2-[4-(4-trifluoromethyl-phenyl)- [M+H]+
i erazin-1-yl]-thiazol-4-yl}-methanone
21 {2-[4-(4-Trifluoromethoxy-phenyl)- 585 586 +
piperazin-1-yl]-thiazol-4-yl}-[4-(3- [M+H]+
trifluoromethyl-phenyl) -piperazin-1-yl] -
methanone
22 {2-[4-(2-Trifluoromethoxy-benzyl)- 599 600 +++
piperazin-l-yl]-thiazol-4-yl}-[4-(3- [M+H]+
trifluoromethyl-phenyl)-piperazin-1-yl]-
methanone
23 {2-[4-(4-Bromo-benzyl)-piperazin-1-yl]- 593 594 +++
thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)- [M+H]+
i erazin-1-yl]-methanone
24 {2-[4-(3-Trifluoromethoxy-benzyl)- 599 600 +++
piperazin-1-yl]-thiazol-4-yl}-[4-(3- [M+H]+
trifluoromethyl-phenyl)-piperazin-l-yl] -
metlianone
32 2-Trifluoromethoxy-N-{4-[4-(3- 544 545 +++
trifluoromethyl-phenyl)-piperazine-l- [M+H]+
carbonyl]-thiazol-2-yl} -benzamide
33 3-Cyclopentyl-N-{4-[4-(3-trifluoromethyl- 480 481 +++
phenyl)-piperazine-l-carbonyl]-thiazol-2- [M+H]+
yl - ro ionamide
34 3-Fluoro-4-trifluoromethyl-N-{4-[4-(3- 546 547 +++
trifluoromethyl-phenyl)-piperazine-l- [M+H]+
carbonyl -thiazol-2-yl -benzamide
37 3-Cyclopentyl-l-(4-{4-[4-(3- 549 550 +++
trifluoromethyl-phenyl)- i erazine-l- M+H +
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71
carbonyl]-thiazol-2-yl}-piperazin-1-yl)-
ro an-l-one
38 {2-[4-(2-Methoxy-benzoyl)-piperazin-l- 559 560 +++
yl]-thiazol-4-yl}-[4-(3-trifluoromethyl- [M+H]+
henyl)- i erazin-1-yl]-methanone
39 {2-[4-(2-Trifluoromethoxy-benzoyl)- 613 614 +++
piperazin-1-yl]-thiazol-4-yl}-[4-(3- [M+H]+
trifluoromethyl-phenyl) -p ip erazin-l-yl] -
methanone
41 N-{4-[4-(3,4-Dichloro-phenyl)-piperazine- 544 545 -----+
1-carbonyl]-thiazol-2-yl} -2- [M+H]+
trifluoromethoxy-benzamide
44 N-{4-[4-(2-Methoxy-phenyl)-piperazine-l- 506 507 ++
carbonyl]-thiazol-2-yl}-2-trifluoromethoxy- [M+H]+
benzamide
55 1-(2-Trifluoromethoxy-phenyl)-3-{4-[4-(3- 559 560 +++
trifluoromethyl-phenyl)-piperazine-l- [M+H]+
c arbonyl] -thiazol-2-yl } -urea
58 N-[4-(4-Benzhydryl-piperazine-l- 566 567 ++
carbonyl)-thiazol-2-yl]-2-trifluoromethoxy- [M+H]+
benzamide
59 {2-[4-(3,5-Bis-trifluoromethyl-benzoyl)- 665 666 +
piperazin-1-yl]-thiazol-4-yl}-[4-(3- [M+H]+
trifluoromethyl-phenyl)-piperazin-1-yl]-
methanone
60 {2-[4-(3-Fluoro-4-trifluoromethyl- 615 616 +++
benzoyl)-piperazin-1-yl]-thiazol-4-yl}-[4- [M+H]+
(3 -trifluoromethyl-phenyl)-pip erazin-l-yl] -
methanone
61 4-(4-{4-[4-(3-Trifluoromethyl-phenyl)- 554 555 +++
piperazine-l-carbonyl]-thiazol-2-yl}- [M+H] +
i erazine-1-carbonyl -benzonitrile
62 4-(4-{4-[4-(3-Trifluoromethyl-phenyl)- 540 541 +++
piperazine-l-carbonyl]-thiazol-2-yl} - [M+H] +
i erazine-l-ylmethyl -benzonitrile
63 4-{4-[4-(3-Trifluoromethyl-phenyl)- 525 526 ++
iperazine-l-carbonyl]-thiazol-2-yl - + +
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i erazine-1-carboxylic acid tert-butyl ester
64 (2-Piperazin-1-yl-thiazol-4-yl)-[4-(3- 425 426 +
trifluoromethyl-phenyl)-piperazin-1-yl]- [1VI+H]+
methanone
65 {2-[4-(2-Methoxy-phenyl)-piperazin-1-yl]- 531 532 ++
thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)- [M+H] +
piperazin-1-yl]-methanone
66 1-[4-(4-{4-[4-(3-Trifluoromethyl-phenyl)- 543 544 ++
piperazine-l-carbonyl]-thiazol-2-yl}- [M+H]+
pi erazin-1-yl - henyl -ethanone
67 [4-(3-Trifluoromethyl-phenyl)-piperazin-l- 569 570 +
yl]- {2-[4-(3-trifluoromethyl-phenyl)- [M+H]+
i erazin-1-yl]-thiazol-4-yl}-methanone
68 [2-(4-Phenyl-piperazin-1-yl)-thiazol-4-yl]- 501 502 +
[4-(3-trifluoromethyl-phenyl)-piperazin-l- [M+H]+
yl]-methanone
69 {2-[4-(4-Fluoro-phenyl)-piperazin-l-yl]- 519 520 ++
thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)- [M+H]+
i erazin-l-yl -methanone
71 (4-Benzhydryl-piperazin-l-yl)-[2-(4- 537 538 +++
benzyl-piperazin-1-yl)-thiazol-4-yl]- [M+H]+
methanone
72 [2-(4-Benzyl-piperazin-l-yl)-thiazol-4-yl]- 515 516 -+-+-+
[4-(3-trifluoromethyl-phenyl)-piperazin-l- [M+H]+
yl]-methanone
99 3-Fluoro-4-trifluoromethyl-N-(1-{4-[4-(3- 642 643 +
trifluoromethyl-phenyl)-piperazine-l- [M+H]+
carbonyl]-thiazol-2-yl} -piperidin-4-
ylmethyl)-benzamide
100 3-Cyclopentyl-N-(1-{4-[4-(3- 576 577 +
trifluoromethyl-phenyl)-piperazine-l- [M+H]+
carbonyl] -thiazol-2-yl } -piperidin-4-
ylmethyl - ro ionamide
101 2-Trifluoromethoxy-N-(1-{4-[4-(3- 640 641 +
trifluoromethyl-phenyl)-piperazine-l- [M+H]+
carbonyl]-thiazol-2-yl} -piperidin-4-
ylmethyl -benzamide
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102 4-Cyano N-(1-{4-[4-(3-trifluoromethyl- 581 582 +
phenyl)-piperazine-l-carbonyl]-thiazol-2- [M+H]+
yl - i eridin-4-ylmethyl)-benzamide
241 {2-[1-(2,6-Dimethoxy-pyrimidin-4-yl)- 576 577 [M+H+] -+-
piperidin-4-yl]-5-methoxy-oxazol-4-yl} - [4-
(3 -trifluoromethyl-phenyl)-piperazin-l-yl] -
methanone
242 {2-[1-(4,6-Dimethoxy-[1,3,5]triazin-2-yl)- 577 578 [M+H+] ++
piperidin-4-yl]-5-methoxy-oxazol-4-yl} - [4-
(3 -trifluoromethyl-phenyl)-piperazin-1-yl] -
methanone
243 {2-[1-(2,6-Dimethoxy-pyrimidin-4-yl)- 616 617 [M+H] -H-
piperidin-4-yl]-5-methoxy-oxazol-4-yl} -[4-
(5-trifluoromethyl-benzotriazol-l-yl)-
pi eridin-1-yl]-methanone
244 {2-[1-(4,6-Dimethoxy-[1,3,5]triazin-2-yl)- 617 618 [M+H ++
piperidin-4-yl]-5-methoxy-oxazol-4-yl} - [4-
(5-trifluoromethyl-benzotriazol-l-yl)-
i eridin-1-yl -methanone
245 4-(4-{4-[4-(5-Trifluoromethyl-benzotriazol- 580 581 ++
1-yl)-piperidine-l-carbonyl]-thiazol-2-yl}- [M+H]+
piperazin-1-yl-methyl)-benzonitrile
246 (2-Morpholin-4-yl-oxazol-4-yl)-[4-(3- 410 411 +
trifluoromethyl-phenyl)-piperazin-1-yl]- [M+H]+
methanone
The biological data refer to results obtained from the NF-icB inflammation
assay.
["+" stands for 50-80% inhibition, "++" means 80-90% and "+++" stands for 90-
100% inhibition]
Examplary compounds of formula (III) of the present invention include, but are
not limited
to, the followings:
Cp. Name Mass LC/(+)-ESI- Biological
MS: activity 1 2-Morpholin-4-yl-thiazole-4-carboxylic 357 358 +
acid (5,6-dimethyl-1 H-benzoimidazol-2- [M+H]+
yl)-amide
2 2-[3-(2-Trifluoromethoxy-phenyl)-ureido]- 462 463 +
thiazole-4-carboxylic acid (1H- [M+ +
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benzoimidazol-2-yl)-alnide
4 2-(2-Fluoro-benzoylamino)-thiazole-4- 409 410 +
carboxylic acid (5,6-dimethyl-lH- [M+H]+
benzoimidazol-2-yl)=amide
6 N-{4-[N'-(1H-Benzoimidazol-2-y1)- 441 442 ++
guanidinocarbonyl]-thiazol-2-yl}-3,4- [M+H]+
difluoro-benzamide
7 N-{4-[N'-(1H-Benzoimidazol-2-yl)- 423 424 ++
guanidinocarbonyl]-thiazol-2-yl}-4-fluoro- [M+H] +
benzamide
8 N-{4-[N'-(1H-Benzoimidazol-2-yl)- 473 474 +-F+
guanidinocarbonyl]-oxazol-2-yl}-2- [M+H]+
trifluoromethoxy-benzamide
9 2-(2-Trifluoromethoxy-benzoylamino)- 453 454 +
thiazole-4-carboxylic acid (4- [M+H]+
dimethylamino-[1,3,5]triazin-2-yl -amide
N-{4-[N'-(1H-Benzoimidazol-2-yl)- 483 484 ++
guanidinocarbonyl]-thiazol-2-yl}-4-bromo- [M+H]+
benzamide
11 N-{4-[N'-(1H-Benzoimidazol-2-yl)- 435 436 ++
guanidinocarbonyl]-thiazol-2-yl}-2- [M+H]+
methoxy-benzamide
12 N-{4-[N'-(1H-Benzoimidazol-2-yl)- 489 490 +++
guanidinocarbonyl]-thiazol-2-yl}-2- [M+H]+
trifluoromethoxy-benzamide
13 N-(1H-Benzoimidazol-2-yl)-N'-{2-[4-(2- 558 559 +
trifluoromethoxy-benzoyl)-piperazin-l-yl]- [M+H]+
thiazole-4-carbonyl}- anidine
14 N-(1H-Benzoimidazol-2-yl)-N'-[2-(2,3- 420 421 +
dihydro-benzo[1,4]dioxin-2-yl)-thiazole-4- [M+H]+
carbonyl]-guanidine
25 2-(2-Trifluoromethoxy-benzoylamino)- 475 476 ++
thiazole-4-carboxylic acid (5,6-dimethyl- [M+H]+
1H-benzoimidazol-2-yl)-amide
26 2-(3-Fluoro-4-trifluoromethyl- 536 537 ++
benzoylamino)-oxazole-4-carboxylic acid [M+H]+
ethyl ester
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27 N-{4-[N'-(1H-Benzoimidazol-2-yl)- 475 476 ------E-
guanidinocarbonyl]-oxazol-2-yl}-3-fluoro- [M+H] +
4-trifluoromethyl-benzamide
30 N-(1H-Benzoimidazol-2-yl)-N'-[2-(4- 460 461 +++
benzyl-piperazin-1-yl)-thiazole-4- [M+H]+
carbonyl -guanidine
31 2-(2-Trifluoromethoxy-benzoylamino)- 447 448 +++
thiazole-4-carboxylic acid (1H- [M+H]+
benzoimidazol-2-yl)-amide
36 N-(1H-Benzoimidazol-2-yl)-N'-{2-[1-(2- 557 558 +++
trifluoromethoxy-benzoyl)-piperidin-4-yl]- [M+H] +
thiazole-4-carbonyl} -guanidine
40 2-(2-Trifluoromethoxy-benzoylamino)- 459 460 +++
oxazole-4-carboxylic acid (5,6-dimethyl- [M+H]+
1 H-benzoimidazol-2-yl)-amide
42 2-(2-Trifluoromethoxy-benzoylamino)- 562 563 +++
thiazole-4-carboxylic acid [6-(4-methyl- [M+H]+
piperazin-1-yl)-benzothiazol-2-yl]-amide
43 2-(2-Trifluoromethoxy-benzoylamino)- 492 493 +++
thiazole-4-carboxylic acid (5-nitro-lH- [M+H]+
benzoimidazol-2-yl)-amide
45 N-{4-[N'-(1H-Benzoimidazol-2-yl)- 487 488 -~-----
guanidinocarbonyl]-thiazol-2-yl}-2- [M+H]+
cyclohexyl-benzamide
46 2-(2-Trifluoromethoxy-benzoylamino)- 461 462 ++
thiazole-4-carboxylic acid (1-methyl-lH- [M+H]+
benzoimidazol-2-yl)-amide
47 2-(2-Trifluoromethoxy-benzoylamino)- 553 554 +++
thiazole-4-carboxylic acid [5-(propane-l- [M+H]+
sulfonyl -1H-benzoimidazol-2-yl -amide
49 N-(1H-Benzoimidazol-2-yl)-N'-(2- 371 372 +++
morpholin-4-yl-thiazole-4-carbonyl)- [M+H] +
anidine
51 N-{4-[N'-(1H-Benzoimidazol-2-yl)- 473 474 -I-I4
guanidinocarbonyl]-thiazol-2-yl}-4- [M+H]+
trifluoromethyl-b enzamide
52 2- 1-(2-Trifluoromethoxy-benzoyl)- 621 622 -H4
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76
piperidin-4-yl]-thiazole-4-carboxylic acid [M+H]+
[5-(propane-l-sulfonyl)-1 H-benzoimidazol-
2-yl -amide
53 N-{4-[N'-(1H-Benzoimidazol-2-yl)- 491 492 +++
guanidinocarbonyl]-thiazol-2-yl}-2-fluoro- [M+H]+
4-trifluoromethyl-benzamide
54 1-{4-[N'-(1H-Benzoimidazol-2-yl)- 504 505 +++
guanidinocarbonyl]-thiazol-2-yl}-3-(2- [M+H]+
trifluoromethoxy-phenyl)-urea
56 N-{4-[N'-(1H-Benzoimidazol-2-yl)- 491 492 +++
guanidinocarbonyl]-thiazol-2-yl}-3-fluoro- [M+H]+
4-trifluoromethyl-benzamide
57 N-{4-[N'-(1H-Benzoimidazol-2-yl)- 441 442 ++
guanidinocarbonyl]-thiazol-2-yl}-2,6- [M+H]+
difluoro-benzamide
91 N-(1H-Benzoimidazol-2-yl)-N'-(2- 371 372 +
morpholin-4-yl-thiazole-4-carbonyl)- [M+H]+
anidine
250 N-(1H-Benzoimidazol-2-yl)-N'-{2-[1-(4- 484 485 ++
cyano-benzyl)-piperidin-4-yl]-thiazole-4- [M+H]+
carbonyl}- anidine
251 N-Benzothiazol-2-yl-N'-{2-[1-(4-cyano- 501 502 ++
benzyl)-piperidin-4-yl]-thiazole-4- [M+H]+
carbonyl}-guanidine
252 N-(1H-Benzoimidazol-2-yl)-N'-{2-[4-(4- 485 485 ++---
cyano-benzyl)-piperazin-1-yl]-thiazole-4- [M+H]+
carbonyl}-guanidine
253 N-{2-[4-(4-Cyano-benzyl)-piperazin-1-yl]- 466 467 ++
thiazole-4-carbonyl}-N'-(4-methyl-thiazol- [M+H]+
2-yl)-guanidine
254 N-(4-Methyl-thiazol-2-yl)-N'-(2-morpholin- 352 353 +
4-yl-thiazole-4-carbon 1 - anidine +H +
255 N-(1H-Benzoimidazol-2-yl)-N'-(2- 371 372 -E.+
morpholin-4-yl-thiazole-4-carbonyl)- [M+H]+
guanidine
256 N-Benzothiazol-2-yl-N'-(2-morpholin-4-yl- 388 389 H-+
thiazole-4-carbonyl)-guanidine M+H +
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257 N-(1H-Benzoimidazol-2-yl) N'-(2- 355 356 ++
morpholin-4-yl-oxazole-4-carbonyl)- [M+H]+
guanidine
258 N-Benzooxazol-2-yl-N'-(2-morpholin-4-yl- 372 373 ++
thiazole-4-carbonyl)-guanidine M+ +
259 N-(2-Morpholin-4-yl-thiazole-4-carbonyl)- 417 418 ++
N'-(5-nitro-benzooxazol-2-yl)-guanidine [M+H]+
260 N-(5-Methyl-benzooxazol-2-yl)-N'-(2- 386 387 +
morpholin-4-yl-thiazole-4-carbonyl)- [M+H]+
guanidine
261 N-(5-Chloro-benzooxazol-2-yl)-N'-(2- 406 407 ++
morpholin-4-yl-thiazole-4-carbonyl)- [M+H]+
guanidine
262 N-{2-[1-(4-Cyano-benzyl)-piperidin-4-yl]- 465 466 +
thiazole-4-carbonyl}-N'-(4-rnethyl-thiazol- [M+H]+
2-yl)-guanidine
263 N-(6-Chloro-lH-benzoimidazol-2-yl)-N'- 591 592 +++
{2-[1-(2-trifluoromethoxy-benzoyl)- [M+H]+
piperidin-4-yl] -thiazole-4-carbonyl } -
guanidine
264 N-(5,6-Dichloro-lH-benzoimidazol-2-yl)- 625 626 ++
N'-{2-[1-(2-trifluoromethoxy-benzoyl)- [M+H]+
piperidin-4-yl]-thiazole-4-carbonyl} -
anidine
265 2-Morpholin-4-yl-thiazole-4-carboxylic 490 491
acid [4-(5-trifluoromethyl-benzothiazol-2- [M+H]+
yl)-phenyl]-amide
266 2-Morpholin-4-yl-thiazole-4-carboxylic 423 424
acid (5-benzothiazol-2-yl-pyridin-2-yl)- [M+H]+
amide
267 2-Morpholin-4-yl-thiazole-4-carboxylic 440 441
acid (4-benzothiazol-2-yl-2-fluoro-phenyl)- [M+H]+
amide
268 2-Morpholin-4-yl-thiazole-4-carboxylic 506 507
acid (4-benzothiazol-2-yl-2-trifluorometh- [M+H]+
oxy- henyl)-amide
269 2-(1-Furo 2,3-c yridin-4-yl- iperidin-4- 548 549
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7 1 H yl)-thiazole-4-carboxylic acid (5-benzoyl- [M+H]+
-benzoimidazol-2-y1)-amide
270 2-[1-(4,6-Dimethoxy-[1,3,5]triazin-2-yl)- 570 571
piperidin-4-yl]-thiazole-4-carboxylic acid [IVI+H]+
(5-benzoyl-1 H-benzoimidazol-2=y1)-amide
271 2-[1-(4,6-Dimethoxy-[1,3,5]triazin-2-yl)- 501 502
piperidin-4-yl]-thiazole-4-carboxylic acid [M+H]+
(5-fluoro-benzothiazol-2-yl)-amide
272 2-[1-(4-Cyano-benzyl)-piperidin-4-yl]- 546 547 [M+H+] -t-i-
thiazole-4-carboxylic acid (5-benzoyl-lH-
benzoimidazol-2-yl) -amide
273 2-(1-Thieno[3,2-d]pyrimidin-4-yl- 565 566 [M+H+] ++
piperidin-4-yl)-thiazole-4-carboxylic acid
(5-benzoyl-1 H-benzoimidazol-2-yl)-amide
274 2-[1-(4,6-Dimethoxy-[1,3,5]triazin-2-yl)- 570 571 [M+H'"] +++
piperidin-4-yl]-thiazole-4-carboxylic acid
5-benzoyl-1 H-benzoimidazol-2-yl)-amide
275 2-[1-(6-Trifluoromethyl-pyrimidin-4-yl)- 577 578 [M+W]
piperidin-4-yl]-thiazole-4-carboxylic acid ++
5-benzoyl-1 H-benzoimidazol-2-yl)-amide
276 2-[1-(4-Cyano-benzyl)-piperidin-4-yl]- 486 487 [M+H]+ +
thiazole-4-carboxylic acid (5-ethoxy-lH-
benzoimidazol-2-yl -amide
277 2-[1-(4-Cyano-benzyl)-piperidin-4-yl]- 476 477 [M+H]+ ++
thiazole-4-carboxylic acid (5-chloro-lH-
benzoimidazol-2-yl)-amide
278 2-[1-(4-Cyano-benzyl)-piperidin-4-yl]- 510 511 [M+H]+ -++
thiazole-4-carboxylic acid (5,6-dichloro-
1H-benzoimidazol-2-yl -amide
1) The biological data refer to results obtained from the NF-xB inflammation
assay.
["+" stands for 50-80% inhibition, "++" means 80-90% and "+++" stands for 90-
100% inhibition]
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Proteasome assay:
The chymotryptic activity of the 20S proteasome (Immatics, Tubingen) was
determined
using a Tecan Ultra plate reader and Suc-LLVT-AMC as substrate (Bachem). In
the wells
of a black 96 well polypropylene plate, 2 l of the respective inhibitor
dissolved in DMSO
were mixed with 50 l substrate solution (25 mM HEPES pH 7.5 at 20 C, 0.5 mM
EDTA
and Suc-LLVT-AMC (in the appropriate concentration) and the reaction was
initiated by
adding 150 l proteasome solution (1.3 g/ml 20S proteasome in 25 mM HEPES pH
7.5 at
20 C, 0.5 mM EDTA, 0.033% (w/v) SDS). Substrate hydrolysis was followed by
fluorescence spectroscopy (excitation wavelength: 360 nm; emission wavelength:
465 nm)
for 20 min at 30 C and initial velocities were calculated and expressed as
change in
relative fluorescence units (RFU) per second.
For the detennination of the IC50 values (concentration of inhibitor required
for 50%
inhibition) at least four different inhibitor concentrations were applied.
Each data point was
recorded in triplicates. Curves were fitted with the a suitable program.
The Compounds have average activities between 1 and 30 M
T-Lymphocyte Proliferation Assay:
Inhibition of stimulated peripheral blood monocytes (PBMC).
PBMCs were isolated from the blood of healthy volunteers with the help of
ACCUSPINTM
System Histopaquee-1077 tubes, washed and resuspended with 106 cells/ml in
Dulbecco's
modified eagles medium, containing 10 % fetal calf serum and 2 mM Glutamine.
The cells were stimulated with 2 g/ml phytohemoagglutinin in the presence of
test
compound or blank vehicle for 72 h. 4 h prior to the end of the incubation
period, 5-bromo-
2'-desoxyuridine (BrdU) was added to label the proliferating cells. After the
incubation,
the cells were separated by centrifugation and the culture supematant removed.
Incorporated BrdU was quantified with the help of an enzyme-linlced
immunosorbent
assay.
For the determination of the IC50 values (concentration of inhibitor required
for 50%
inhibition) at least four different inhibitor concentrations were applied.
Each data point was
recorded in triplicates. Curves were fitted with the a suitable program.
Influence of compounds according to the invention on proliferation of T-cells
Compounds according to Examples 1-24 resulted in an inhibition of more than
50%
compared to control experiments.
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The average EC50 of the compounds were between 3 and 40 M.
Thus, the compounds of formula I are suitable for treating inflammatory
diseases or
diseases associated with Tcells.
5 Inhibition of NF-xB-induced inflammation:
For the determination of anti-inflammatory activity of the compounds the
PRINCESS
NINA Instant Assay from Cell Culture Service GmBH was used. This assay is
based on
recombinant A549 NF-xB-SEAP reporter cells preseeded in 96-well flat bottom
plates. As
the transfected reportergen for SEAP (secreted embryonic alkaline phosphatase)
is under
10 transcriptional control of a NF-xB-responsive element, the expression of
this reporter is
activated upon stimulation with TNF-a. SEAP secretion into the culture
supernatant can be
detected by the chemiluminescent substrate CSPD . Test compounds that inhibit
the NF-
-KB activation show reduced SEAP activity and reduced luminescent readout.
Following 18 h of reactivation at 37 C, 5 % CO2 and 90 % relative humidity,
the cells
15 were incubated with 0.01 up to 100 M of test compound for 4.5 h before
stimulation with
2ng/ml TNF-a. After stimulation with TNF-a for 22 h endogenous phosphatases
were
inactivated and CSPD substrate was supplied for 40 min. SEAP activity then
was
quantified by measuring luminescence as relative light units (RLU) using a
Tecan Ultra
reader. Each data point was, recorded in quadruplicates and EC50 values were
calculated
20 via fitting function and the Microsoft Excel Solver.
