AU2007224659A1 - Novel heterocyclic NF-KB inhibitors - Google Patents

Novel heterocyclic NF-KB inhibitors Download PDF

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Publication number
AU2007224659A1
AU2007224659A1 AU2007224659A AU2007224659A AU2007224659A1 AU 2007224659 A1 AU2007224659 A1 AU 2007224659A1 AU 2007224659 A AU2007224659 A AU 2007224659A AU 2007224659 A AU2007224659 A AU 2007224659A AU 2007224659 A1 AU2007224659 A1 AU 2007224659A1
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Australia
Prior art keywords
alkyl
group
haloalkyl
aryl
heteroaryl
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AU2007224659A
Inventor
Rolf Krauss
Johann Leban
Stefano Pegoraro
Harald Schmitt
Kristina Wolf
Andreas Wuzik
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4SC AG
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4SC AG
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Priority claimed from US11/375,259 external-priority patent/US7601745B2/en
Priority claimed from PCT/EP2006/002396 external-priority patent/WO2007016979A2/en
Application filed by 4SC AG filed Critical 4SC AG
Priority claimed from PCT/EP2007/002265 external-priority patent/WO2007104557A2/en
Publication of AU2007224659A1 publication Critical patent/AU2007224659A1/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/48—Nitrogen atoms not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Description

WO 2007/104557 PCT/EP2007/002265 5 Novel heterocyclic NF-icB Inhibitors The present invention relates to compounds of the general formula (Ia), (Ib), (Ic), (Ih), (II), 10 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. The compounds of the invention can be used as a medicament and 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 15 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 processes for the preparation of these compounds, and to their use. 20 T-cell homeostasis is critical for the maintenance of immune tolerance. Defects in T-cell homeostasis can lead to autoimmune 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. 25 Measuring proliferative responses in T-lymphocytes is a widely used assay to measure immune competence (Killestein, J. et al. J Neuroimmunol. 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 Immunology 687-692, 2000). 30 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.
WO 2007/104557 PCT/EP2007/002265 2 Regulation of the immune response is controlled by a variety of signalling pathways sih as T-cell or TNF receptor signalling (Chen, G. et al. Science 296, 1634-1635, 2002). To further characterize targets of compounds which we found active in the T-cell proliferation 5 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 10 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-KB activity, being responsible for the degradation of the inhibitor IKB-a. In order to be targeted for degradation by the proteasome, IKB-a must first undergo selective phosphorylation at 15 serine residues 32 and 36, followed by ubiquitinylation (Chen, Z. et al. Cell 84, 853-862, 1996; Brown, K. et al. Science 267, 1485, 1995). NF-KB, 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 IcB-a degradation and NF-KB activation (Traeckner et al. EMBO J. 13, 5433, 1994). 20 Literature describing proteasome inhibitors has been described in reviews (Adams, J. et al. Ann. Rev. Med. 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. 25 Here we describe novel chemical entities with proteasome inhibitory activity. NF-KB (Nuclear Factor-KB) is a eukaryotic transcription factor of the rel family, which is located in the cytoplasm in an inactive complex, as a homo- or heterodimer. Predominantly 30 it exists as a heterodimer composed of p50 and p65 subunits, bound to inhibitory proteins of the IKB family, usually IKB-ox (D. Thanos et al., Cell 80, 529, 1995). NF-KB is activated in response to different stimuli, among which inflammatory cytokines, UV radiation, WO 2007/104557 PCT/EP2007/002265 3 phorbol esters, bacterial and viral infections. Stimulation triggers the release of NF-KB from licB in consequence of the nhosnhorylation and the following degradation of the TIB a protein (P.A. Baeuerle et al., Annu. Rev. Immunol. 12, 141, 1995) by the proteasome. Once it is set free, NF-iB translocates in the nucleus where it binds to the DNA at specific 5 KB-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 cyclooxygenase 2 (S. Grimm et al., J. Biochem. 290, 297, 1993). Accordingly, NF-B 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 10 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-rB mediated gene transcription can be accomplished through inhibition of phosphorylation of the inhibitory protein IrB, 15 inhibition of IKB degradation, inhibition of NF-KB (p50/p65) nuclear translocation, the inhibition of NF-icB-DNA binding or NF-icB-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 20 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 RZ (a) 25 wherein R is independently hydrogen, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, or heteroaryl;
R
1 is independently alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, or heteroaryl; WO 2007/104557 PCT/EP2007/002265 4 X is CO, CS or S02; Y is CO, CS or SO 2 ; z is NR2', S, or 0; R2' is H, alkyl, -C(O)NR 7 , -C(O)R*, cycloalkyl, haloalkyl, hydroxyalkyl, 5 hydroxyalkylamino, alkylamino, heteroaryl, or aryl; Re is independently H, OH, SH, NROR', NH 2 , alkylamino, hydroxyalkylamino, halogen, CONRdRe, alkoxy, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, or heteroaryl; Rd is H, halogen, alkyl, -C(NR 7
)NR
7 'R, -(CH 2 )paryl, -(CH 2 )pNR 7 R', -C(O)NR 7 R, 10 -N=CR 7 R', -NR 7
C(O)R
8 , cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;
R
7 , R 7 ' independently represent H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;
R
8 is H, NH 2 , alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, 15 alkylamino, heteroaryl or aryl; Re independently represents H, -CN, -OH, -SH, -C0 2
R
4 , -C(O)R 4 ', -SO 2
NR
4 , -NR4'R', -C(O)NR 7 R8, -S0 2 -alkyl, -S0 2
R
4 ', SO 3
R
4 ', -N=CR 4 'R", -NR 4
'C(O)R
4 ,
-NR
4 '-CO-haloalkyl, -NO 2 , -NR 4
'-SO
2 -haloalkyl, -NR 4'-S0 2 -alkyl, -NR4' -CO-alkyl,
-NR
4
'(CH
2 )pheteroaryl, alkyl, hydroxyalkyl, cycloalkyl, alkylamino, aryl 20 hydroxyalkylamino, alkoxy, alkylthio, -O(CH 2 )p[O(CH 2 )p]qOCH 3 , -C(NR 4 ")NR4' -benzimidazolyl, -C(NR 4
")NR
4 'benzthiazolyl, -C(NR 4
")NR
4 'benz-oxazolyl, or heteroaryl;
R
4 ', R 4 ", Rs' independently represent H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, -C(NR 7
)NR
7 'R, -(CH 2 )paryl, -(CH 2 )pNR7 R, 25 C(O)NR 7 R', -N=CR 7
R
8 , -NR 7
C(O)R
8 , halogen, heteroaryl, or aryl p is I to 6; q is 1 to 6; R2 is independently -N R 5 N N-R 5 or WO 2007/104557 PCT/EP2007/002265 5 is independently H, COR , CO 2
R
6 , SOR 6 , SO 2
R
6 , SO 3 R , alkyl, cycloalkyl, alkoxy,
-NH
2 , alkylamine, -NR 7
COR
6 , halogen, -OH, -SH, alkylthio, hydroxyAkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl; R6 is independently H, alkyl, cycloalkyl, amino, haloalkyl, hydroxyalkyl, 5 hydroxyalkylamino, alkylamino, aryl or heteroaryl; wherein an alkyl group, if not stated otherwise, denotes a linear or branched Ci-C 6 -alkyl, preferably a linear or branched chain of one to five carbon atoms, a linear or branched C 2
-C
6 -alkenyl 10 or a linear or branched C 2
-C
6 -alkinyl group, which can optionally be substituted by one or more substituents R'; the Ci-C 6 -alkyl, C 2
-C
6 -alkenyl and C 2
-C
6 -alkinyl residue may be selected from the group comprising -CH 3 , -C 2
H
5 , -CH=CH 2 , -C=CH, -C 3
H
7 , -CH(CH 3
)
2 , -CH 2
-CH=CH
2 ,
-C(CH
3
)=CH
2 , -CH=CH-CH 3 , -C=C-CH 3 , -CH 2 -C=CH, -C 4
H
9 , -CH 2
-CH(CH
3
)
2 , 15 -CH(CH 3
)-C
2
H
5 , -C(CH 3
)
3 , -C 5
H
1 , -C 6
H
13 , -C(R') 3 , -C 2
(R')
5 , -CH 2
-C(R')
3 , -C 3
(R')
7 ,
-C
2
H
4
-C(R')
3 , -C 2
H
4
-CH=CH
2 , -CH=CH-C 2
H
5 , -CH=C(CH 3
)
2 , -CH 2
-CH=CH-CH
3 ,
-CH=CH-CH=CH
2 , -C 2
H
4 -C=CH, -C=C-C 2
H
5 , -CH 2
-C=C-CH
3 , -C=C-CH=CH 2 , -CH=CH-C=CH, -C=C-CECH, -C 2
H
4
-CH(CH
3
)
2 , -CH(CH 3
)-C
3
H
7 , -CH 2
-CH(CH
3
)
C
2
H
5 , -CH(CH 3
)-CH(CH
3
)
2 , -C(CH 3
)
2
-C
2
H
5 , -CH 2
-C(CH
3
)
3 , -C 3
H
6
-CH=CH
2 , 20 -CH=CH-C 3
H
7 , -C 2
H
4
-CH=CH-CH
3 , -CH 2
-CH=CH-C
2
H
5 , -CH 2
-CH=CH-CH=CH
2 ,
-CH=CH-CH=CH-CH
3 , -CH=CH-CH 2
-CH=CH
2 , -C(CH 3
)=CH-CH=CH
2 ,
-CH=C(CH
3
)-CH=CH
2 , -CH=CH-C(CH 3
)=CH
2 , -CH 2
-CH=C(CH
3
)
2 , C(CH 3
)=C(CH
3
)
2 ,
-C
3
H
6 -C=CH, -CEC-C 3
H
7 , -C 2
H
4
-C=C-CH
3 , -CH 2
-C=C-C
2
H
5 , -CH 2
-C=C-CH=CH
2 ,
-CH
2 -CH=CH-C=CH, -CH 2 -C=C-C=CH, -C=C-CH=CH-CH 3 , -CH=CH-C=C-CH 3 , 25 -C=C-C=C-CH 3 , -C=C-CH 2
-CH=CH
2 , -CH=CH-CH 2 -C=CH, -C=C-CH 2 -C=CH,
-C(CH
3
)=CH-CH=CH
2 , -CH=C(CH 3
)-CH=CH
2 , -CH=CH-C(CH 3
)=CH
2 , -C(CH 3
)=CH
C=CH, -CH=C(CH 3 )-C=CH, -C=C-C(CH 3
)=CH
2 , -C 3
H
6
-CH(CH
3
)
2 , -C 2
H
4
-CH(CH
3
)
C
2
H
5 , -CH(CH 3
)-C
4
H
9 , -CH 2
-CH(CH
3
)-C
3
H
7 , -CH(CH 3
)-CH
2
-CH(CH
3
)
2 , -CH(CH 3
)
CH(CH
3
)-C
2
H
5 , -CH 2
-CH(CH
3
)-CH(CH
3
)
2 , -CH 2
-C(CH
3
)
2
-C
2
H
5 , -C(CH 3
)
2
-C
3
H
7 , 30 C(CH 3
)
2
-CH(CH
3
)
2 , -C 2
H
4
-C(CH
3
)
3 , -CH(CH 3
)-C(CH
3
)
3 , -C 4
H
8
-CH=CH
2 , -CH=CH
C
4
H
9 , -C 3
H
6
-CH=CH-CH
3 , -CH 2
-CH=CH-C
3
H
7 , -C 2
H
4
-CH=CH-C
2
H
5 , -CH 2 C(CH 3
)=C(CH
3
)
2 , -C 2
H
4
-CH=C(CH
3
)
2 , -C 4
H
8 -C=CH, -C=C-C 4
H
9 , -C 3
H
6
-C=C-CH
3 ,
-CH
2
-C=C-C
3
H
7 , -C 2
H
4
-C=C-C
2
H
5 ; R'. is independently H, -CO2R", -CONHR', -CR''0, -SO 2 NR", -NR''-CO-haloalkyl, 35 -NO 2 , -NR''-S0 2 -haloalkyl, -NR''-S0 2 -alkyl, -S0 2 -alkyl, -NR''-CO-alkyl, -CN, alkyl, WO 2007/104557 PCT/EP2007/002265 6 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 5 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, SO 2 , N, or NR", R" being as defined above; the C 3
-C
8 -- cycloalkyl residue may be selected from the group comprising -cyclo-C 3 Hs, -cyclo-C 4
H
7 , -cyclo-CsH 9 , -cyclo-C 6 Hu, -cyclo-C 7 Hi 3 , -cyclo-CsHis, morpholine-4-yl, piperazinyl, 1 -alkylpiperazine-4-yl; 10 an alkoxy group denotes an O-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; a 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(R'0)3, 15 -CR"(R'0')2, -CR' 0 (R'0')R10", -C 2
(R'
0
)
5 , -CH 2
-C(R'
0
)
3 , -CH 2
-CR'
0
(R'
0
)
2 , -CH 2 CR' 0
(R'
0 )R10", -C 3
(R'
0
)
7 , or -C 2
H
4
-C(R
0
)
3 , wherein R 10 , R10', R10" represent F, Cl, Br or I, preferably F; a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being as defined above; a haloalkyloxy group denotes an alkoxy group which is substituted by one to five halogen 20 atoms, the alkyl group being as defined above; the haloalkyloxy group is preferably a
-OC(R
1 0)3, -OCR' (R'0')2, -OCR 10 (R10')R 10 ", -OC 2 (R'0)5, -OCH 2
-C(RI)
3 , -OCH 2 CR' 0 (R0') 2 , -OCH 2
-CR
1 0 (R10')R'0", -OC 3
(R'
0
)
7 or -OC 2
H
4
-C(R
0
)
3 , wherein R1 0 , R' 0 , R'0" represent F, Cl, Br or I, preferably F; a hydroxyalkylamino group denotes an (HO-alkyl) 2 -N- group or HO-alkyl-NH- group, the 25 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 30 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-C 6
H
4 - R', -m-C 6
H
4 - R', -p
C
6
H
4 - R', l-naphthyl, 2-naphthyl, 1-anthracenyl or 2-anthracenyl; WO 2007/104557 PCT/EP2007/002265 7 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, 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, benzoisothiazol-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-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-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, benzothiofurazane, benzotriazol-1 yl, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-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 25 isoquinolinyl,purine, phthalazine, 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] 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-dimethoxypyimidin-3-yl, 2,6-dimethoxypyrimidin-4 30 yl, imidazopyridazine, imidazopyrimidine, 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- WO 2007/104557 PCT/EP2007/002265 8 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 5 acceptable salts thereof with an acid or a base, or pharmaceutically acceptable prodrugs or a stereoisomer thereof, Ra Rb R2 R1 N R4 Z Rc (Ib) 10 wherein
R
1 is -C(O)R 7 , -C(O)CHR 7
R
8 , -C(O)NR 7
R
8 , -C(O)OR 7 , -R 7 C(O)R', or -C(S)R7;
R
9 independently represents H, -CN, -OH, -SH, -C0 2
R
4 ', -C(O)R 4 ', -SO 2
NR
4 '
-NR
4 Rs, -C(O)NR 7
R
8 , -S0 2 -alkyl, -S0 2
R
4 ', SO 3
R
4 ', -N=CR 4 'R, -NR 4
'C(O)R
4 ",
-NR
4 '-CO-haloalkyl, -NO 2 , -NR 4 '-S0 2 -haloalkyl, -NR 4 '-S0 2 -alkyl, -NR 4 '-CO-alkyl, 15 -NR 4
'(CH
2 )pheteroaryl, alkyl, hydroxyalkyl, cycloalkyl, alkylamino, aryl hydroxyalkylamino, alkoxy, alkylthio, -O(CH 2 )p[O(CH 2 )p]qOCH 3 , -C(NR 4 ")NR4' benzimidazolyl, -C(NR 4
")NR
4 'benzthiazolyl, -C(NR 4
")NR
4 'benzoxazolyl,
-(CH
2 )pNR7COR', or heteroaryl;
R
4 is H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, 20 heteroaryl, or aryl; or R' and R 4 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, wherein at least one ring atom is a heteroatom selected from 0, N, and S, and the ring optionally has one or more substituents R 9 ; 25 X is N, or CR2'; Y is CO, CS or SO 2 ; Z is NR 2 ", S, or 0; WO 2007/104557 PCT/EP2007/002265 9 R 2" is H, alkyl, -C(O)NR 7 , -C(O)R*, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl; R2' is H, alkyl, -C(O)N R 4 ', -C(O) R 4 ', cycloalkyl, haloalkyl, hydroxyalkyl, hydroxy alkylamino, alkylamino, heteroaryl, or aryl; 5 R 4 ', R 4 ", R" independently represent H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, -C(NR 7
)NR
7 'R, -(CH 2 )paryl, -(CH 2 )pNR 7
R
8 ,
-C(O)NR
7 R', -N=CR 7R, -NR7C(O)R 8 , halogen, heteroaryl, or aryl; p is I to 6; q is I to 6; 10 Ra is independently H, OH, SH, NH 2 , alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, alkoxy, alkylamino, hydroxyalkylamino, halogen, aryl, or heteroaryl; Rb is independently H, OH, SH, NH 2 , alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, alkoxy, alkylamino, hydroxyalkylamino, halogen, aryl, or heteroaryl; Rc is independently H, OH, SH, NR 4
'OR
5 ', NH 2 , alkylamino, hydroxyalkylamino, 15 halogen, CONRdR*, alkoxy, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, or heteroaryl; Rd is H, halogen, alkyl, -C(NR7)NR7'R", -(CH 2 )paryl, -(CH2)p-7R8, -C(O)NR7 R,
-N=CR
7 R', -NR 7
C(O)R
8 , cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl; 20 R 7 , R 7 ' independently represent H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl; R is H, NH 2 , alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl; Re independently represents H, -CN, -OH, -SH, -C0 2
R
4 ', -C(O)R 4 ', -SO 2
NR
4 ', 25 -NR 4
R
5 , -C(O)NR 7
R
8 , -S0 2 -alkyl, -S0 2
R
4 ', S0 3
R
4 ', -N=CR 4
'R
5 ', -NR 4
'C(O)R
4 ",
-NR
4 '-CO-haloalkyl, -NO 2 , -NR 4 '-S0 2 -haloalkyl, -NR 4 '-S0 2 -alkyl, -NR 4 '-CO-alkyl,
-NR
4
'(CH
2 )pheteroaryl, alkyl, hydroxyalkyl, cycloalkyl, alkylamino, hydroxy alkylamino, alkoxy, alkylthio, -O(CH2)p[O(CH2)p]qOCH3, -C(NR 4
")NR
4 benz imidazolyl, -C(NR4")NR 4 'benzthiazolyl, -C(NR 4
")NR
4 'benzoxazolyl, aryl or 30 heteroaryl; R2 is independently WO 2007/104557 PCT/EP2007/002265 10 -4-N. F
.A-R
5 n A is N, O, or CR2;
R
5 is independently H, SOR 7 , S0 2
R
7 , S0 3
R
7 , -C(O)R 7 , -C(O)CHR 7 R', -C(O)NR 7 R', C(O)OR 7 , -R 7 C(O)R', -C(S)R 7 , -C(NR )NR' RI, -(CH 2 )paryl, -(CH 2 )pNR 7
R
8 , 5 C(O)NR 7 R', -N=CR R , -NR7C(O)R , alkyl, cycloalkyl, alkoxy, -NH 2 , alkylamino, hydroxyalkylamino, halogen, -OH, -SH, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl; n is0to2; 10 wherein an alkyl group, if not stated otherwise, denotes a linear or branched C -C 6 -alkyl, preferably a linear or branched chain of one to five carbon atoms, a linear or branched C 2
-C
6 -alkenyl or a linear or branched C 2
-C
6 -alkinyl group, which can optionally be substituted by one or more substituents R'; 15 the CI-C 6 -alkyl, C 2
-C
6 -alkenyl and C 2
-C
6 -alkinyl residue may be selected from the group comprising -CH 3 , -C 2
H
5 , -CH=CH 2 , -C=CH, -C 3
H
7 , -CH(CH 3
)
2 , -CH 2
-CH=CH
2 ,
-C(CH
3
)=CH
2 , -CH=CH-CH 3 , -C=C-CH 3 , -CH 2 -C=CH, -C 4
H
9 , -CH 2
-CH(CH
3
)
2 ,
-CH(CH
3
)-C
2 H5, -C(CH 3
)
3 , -C 5 Hu, -C 6
HI
3 , -C(R' ) 3 , -C 2
(R')
5 , -CH 2
-C(R')
3 , -C 3
(R')
7 ,
-C
2
H
4
-C(R')
3 , -C 2
H
4
-CH=CH
2 , -CH=CH-C 2
H
5 , -CH=C(CH 3
)
2 , -CH 2
-CH=CH-CH
3 , 20 -CH=CH-CH=CH 2 , -C 2
H
4 -C=CH, -C=C-C 2
H
5 , -CH 2 7-C=C-CH 3 , -C=C-CH=CH 2 , -CH=CH-C=CH, -C=C-C=CH, -C 2
H
4
-CH(CH
3
)
2 , -CH(CH 3
)-C
3
H
7 , -CH 2
-CH(CH
3
)
C
2
H
5 , -CH(CH 3
)-CH(CH
3
)
2 , -C(CH 3
)
2
-C
2
H
5 , -CH 2
-C(CH
3
)
3 , -C 3
H
6
-CH=CH
2 ,
-CH=CH-C
3
H
7 , -C 2
H
4 -- CH=CH-CH 3 , -CH 2
-CH=CH-C
2
H
5 , -CH 2
-CH=CH-CH=CH
2 ,
-CH=CH-CH=CH-CH
3 , -CH=CH-CH 2
-CH=CH
2 , -C(CH 3
)=CH-CH=CH
2 , 25 -CH=C(CH 3
)-CH=CH
2 , -CH=CH-C(CH 3
)=CH
2 , -CH 2
-CH=C(CH
3
)
2 , C(CH 3
)=C(CH
3
)
2 ,
-C
3
H
6 -CECH, -CEC-C 3
H
7 , -C 2
H
4
-C=C-CH
3 , -CH 2
-C=C-C
2
H
5 , -CH 2
-C=C-CH=CH
2 ,
-CH
2 -CH=CH-C=CH, -CH 2 -C=C-C=CH, -C=C-CH=CH-CH 3 , -CH=CH-CEC-CH 3 ,
-C=C-C=C-CH
3 , -C=C-CH 2
-CH=CH
2 , -CH=CH-CH 2 -C=CH, -CEC-CH 2 -- C=CH,
-C(CH
3
)=CH-CH=CH
2 , -CH=C(CH 3
)-CH=CH
2 , -CH=CH-C(CH 3
)=CH
2 , -C(CH 3
)=CH
30 C=CH, -CH=C(CH 3 )-C=CH, -C=C-C(CH 3
)=CH
2 , -C 3
H
6
-CH(CH
3
)
2 , -C 2
H
4
-CH(CH
3
)
C
2
H
5 , -CH(CH 3
)-C
4
H
9 , -CH 2
-CH(CH
3
)-C
3
H
7 , -CH(CH 3
)-CH
2
-CH(CH
3
)
2 , -CH(CH 3
)
CH(CH
3
)-C
2
H
5 , -CH 2
-CH(CH
3
)-CH(CH
3
)
2 , -CH 2
-C(CH
3
)
2
-C
2
H
5 , -C(CH 3
)
2
-C
3
H
7 , - WO 2007/104557 PCT/EP2007/002265 11
C(CH
3
)
2
-CH(CH
3
)
2 , -C 2
H
4
-C(CH
3
)
3 , -CH(CH 3
)-C(CH
3
)
3 , -C 4 Hs-CH=CH 2 , -CH=CH
C
4
H
9 , -C 3
H
6
-CH=CH-CH
3 . -CH,-CH=CH-C 3 H7, -C 2
H
4 -CH=CH-C2Hs, -C4H 2 C(CH 3
)=C(CH
3
)
2 , -C 2
H
4
-CH=C(CH
3
)
2 , -C 4 Hs-C=CH, -C=C-C 4
H
9 , -C 3
H
6
-C=C-CH
3 ,
-CH
2
-CC-C
3
H
7 , -C 2
H
4
-C=C-C
2
H
5 ; 5 R' is independently H, -CO 2 R", -CONHR", -CR''O, -SO 2 NR", -NR''-CO-haloalkyl,
-NO
2 , -NR''-S0 2 -haloalkyl, -NR''-S0 2 -alkyl, -S0 2 -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; 10 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, SO 2 , N, or NR', R" being as defined above; the C 3 -Cs-cycloalkyl residue may be selected from the group comprising -cyclo-C 3
H
5 , -cyclo-C 4
H
7 , -cyclo-C 5
H
9 , -cyclo-C 6 HI, -cyclo-C 7
H
13 , -cyclo-CsHi 5 , 15 morpholine-4-yl, piperazinyl, 1 -alkylpiperazine-4-yl; an alkoxy group denotes an O-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; a haloalkyl group denotes an alkyl group which is substituted by one to five halogen atoms, 20 the alkyl group being as defined above; the haloalkyl group is preferably a -C(R'0)3,
-CR
10 (Rl0') 2 , -CR' 0
(R
1 0 ')R'0", -C 2
(R'
0 )s, -CH 2
-C(R'
0
)
3 , -CH 2
-CR'
0 (R10') 2 , -CH 2 CR' 0 (R10')R 1 0 ", -C 3
(R'
0
)
7 , or -C 2
H
4
-C(R'
0
)
3 , wherein R1 0 , R10', R10" represent F, Cl, Br or I, preferably F; a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being as defied above; 25 a 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(R
0
)
3 , -OCR" 0
(R'
0
)
2 , -OCR' 0 (R10')R10", -OC 2
(R'
0 )s, -OCH 2
-C(R'
0
)
3 , -OCH 2 CR' 0
(R
1 O')2, -OCH 2
-CR'
0 (R10')R'0", -OC 3
(R'
0
)
7 or -OC 2
H
4
-C(R'
0
)
3 , wherein R' 0 , R'0
'
, R10" represent F, Cl, Br or I, preferably F; 30 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; WO 2007/104557 PCT/EP2007/002265 12 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-C 6
H
4 - R', -m-C 6
H
4 - R', -p 5 C 6
H
4 - 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, 10 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, benzoisothiazol-4-yl, 15 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 20 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-isoindolyl, 3-isoindolyl, 4-isoindolyl, 5-isoindolyl, 6-isoindolyl, 7-isoindolyl, 2-indolinyl, 3-indolinyl, 4-indolinyl, 5-indolinyl, 6 25 indolinyl, 7-indolinyl, benzo[b]furanyl, benzofurazane, benzothiofurazane, benzotriazol-l yl, benzotriazol-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, cinnoline, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydro 30 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]- WO 2007/104557 PCT/EP2007/002265 13 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-dimethoxypvrimidin-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 5 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 (Ic) or pharmaceutically acceptable salts thereof with an acid or a base, or pharmaceutically acceptable prodrugs or 10 a stereoisomer thereof, N Y N R1 O XJ N Z Rc R3(Ic) wherein 15 R' independently represents H, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, or heteroaryl; X is CO, CS or S02; Y is CO, CS or S02; Z is NR 2 ", S, or 0; 20 R 2 " is H, alkyl, -C(O)NR 7 , -C(O)Re, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxy alkylamino, alkylamino, heteroaryl, or aryl;
R
4 ', R 4 ", R" independently represent H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, -C(NR )NR'R', -(CH 2 )paryl, -(CH 2 )pNR R,
-C(O)NR
7
R
8 , -N=CR7 R, -NR 7
C(O)R
8 , halogen, heteroaryl, or aryl; 25 p is I to 6; q is I to 6; m is 0 to 4; WO 2007/104557 PCT/EP2007/002265 14 r is 0, or 1; t is 0, or 1; s is 0, or 1; Rb is independently H, OH, SH, NR 4 'ORs', NH 2 , alkylamino, hydroxyalkylamino, 5 halogen, CONRdR', alkoxy, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, or heteroaryl; Rc is independently H, OH, SH, NR 4 'OR", NH 2 , alkylamino, hydroxyalkylamino, halogen, CONRdR*, alkoxy, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, or heteroaryl; 10 Rd is H, halogen, alkyl, -C(NR7)N7'R, -(CH 2 )paryl, -(CH 2 )pNR 7 R', -C(O)NR7 R, -N=CR7R', -NR 7 C(O)R', cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl; R , R7' independently represent H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl; 15 R' is H, NH 2 , alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl; Re independently represents H, -CN, -OH, -SH, -C0 2
R
4 ', -C(O)R 4 , -SO 2
NR
4 ',
-NR
4
R
5 , -C(O)NR 7 R', -S0 2 -alkyl, -SO 2
R
4 ', SO 3
R
4 , -N=CR 4 R, -NR 4
'C(O)R
4 ",
-NR
4 '-CO-haloalkyl, -NO 2 , -NR 4 '-S0 2 -haloalkyl, -NR 4 '-S0 2 -alkyl, -NR 4 -CO-alkyl, 20 -NR 4
'(CH
2 )pheteroaryl, alkyl, hydroxyalkyl, cycloalkyl, alkylamino, hydroxyalkyl amino, alkoxy, alkylthio, -O(CH 2 )p[O(CH 2 )p]qOCH 3 , -C(NR 4
")NR
4 'benz imidazolyl, -C(NR 4
")NR
4 'benzthiazolyl, -C(NR 4
")NR
4 'benz-oxazolyl, aryl or heteroaryl; R 3 is independently H, OH, SH, NR 4 'OR 5 , NH 2 , hydroxyalkylamino, alkylamino, 25 halogen, CONRdR, alkoxy, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, or heteroaryl; an alkyl group, if not stated otherwise, denotes a linear or branched CI-C 6 -alkyl, preferably a linear or branched chain of one to five carbon atoms, a linear or branched C 2
-C
6 -alkenyl 30 or a linear or branched C 2
-C
6 -alkinyl group, which can optionally be substituted by one or more substituents R'; the C 1
-C
6 -alkyl, C 2
-C
6 -alkenyl and C 2
-C
6 -alkinyl residue may be selected from the group comprising -CH 3 , -C 2
H
5 , -CH=CH 2 , -C-CH, -C 3
H
7 , -CH(CH 3
)
2 , -CH 2
-CH=CH
2
,
WO 2007/104557 PCT/EP2007/002265 15
-C(CH
3
)=CH
2 , -CH=CH-CH 3 , -C=C-CH 3 , -CH 2 -C=CH, -C 4
H
9 , -CH 2
-CH(CH
3
)
2 ,
-CH(CH
3
)-C
2
H
5 , -C(CH 3
)
3 , -C 5 Hu, -C 6
H
1 3 , -- C(R') 3 , -C 2 (R')s, -CH 2 -C(R') -C(R')7,
-C
2
H
4
-C(R')
3 , -C 2
H
4
-CH=CH
2 , -CH=CH-C 2
H
5 , -CH=C(CH 3
)
2 , -CH 2
-CH=CH-CH
3 ,
-CH=CH-CH=CH
2 , -C 2
H
4 -C=CH, -C=C-C 2
H
5 , -CH 2
-C=C-CH
3 , -C=C-CH=CH 2 , 5 -CH=CH-C=CH, -C=C-C=CH, -C 2
H
4
-CH(CH
3
)
2 , -CH(CH 3
)-C
3
H
7 , -CH 2
-CH(CH
3
)
C
2
H
5 , -CH(CH 3
)-CH(CH
3
)
2 , -C(CH 3
)
2
-C
2
H
5 , -CH 2
-C(CH
3
)
3 , -C 3
H
6
-CH=CH
2 ,
-CH=CH-C
3
H
7 , -C 2
H
4
-CH=CH-CH
3 , -CH 2
-CH=CH-C
2
H
5 , -CH 2
-CH=CH-CH=CH
2 ,
-CH=CH-CH=CH-CH
3 , -CH=CH-CH 2
-CH=CH
2 , -C(CH 3
)=CH-CH=CH
2 ,
-CH=C(CH
3
)-CH=CH
2 , -CH=CH-C(CH 3
)=CH
2 , -CH 2
-CH=C(CH
3
)
2 , C(CH 3
)=C(CH
3
)
2 , 10 -C 3
H
6 -C=CH, -C=C-C 3
H
7 , -C 2
H
4
-C=C-CH
3 , -CH 2
-C=C-C
2
H
5 , -CH 2
-C=C-CH=CH
2 ,
-CH
2 -CH=CH-C=CH, -CH 2 -C=C-C=CH, -C=C-CH=CH-CH 3 , -CH=CH-C=C-CH 3 ,
-C=C-C=C-CH
3 , -C=C-CH 2
-CH=CH
2 , -CH=CH-CH 2 -C=CH, -C=C-CH 2 -C=CH,
-C(CH
3
)=CH-CH=CH
2 , -CH=C(CH 3
)-CH=CH
2 , -CH=CH-C(CH 3
)=CH
2 , -C(CH 3
)=CH
C=CH, -CH=C(CH 3 )-C=CH, -C=C-C(CH 3
)=CH
2 , -C 3
H
6
-CH(CH
3
)
2 , -C 2
H
4
-CH(CH
3
)
15 C 2
H
5 , -CH(CH 3
)-C
4
H
9 , -CH 2
-CH(CH
3
)-C
3
H
7 , -CH(CH 3
)-CH
2
-CH(CH
3
)
2 , -CH(CH 3
)
CH(CH
3
)-C
2
H
5 , -CH 2
-CH(CH
3
)-CH(CH
3
)
2 , -CH 2
-C(CH
3
)
2
-C
2
H
5 , -C(CH 3
)
2
-C
3
H
7 , C(CH 3
)
2
-CH(CH
3
)
2 , -C 2
H
4
-C(CH
3
)
3 , -CH(CH 3
)-C(CH
3
)
3 , -C 4
H-CH=CH
2 , -CH=CH
C
4
H
9 , -C 3
H
6
-CH=CH-CH
3 , -CH 2 rCH=CH-C 3
H
7 , -C 2
H
4
-CH=CH-C
2 Hs, -CH 2 C(CH 3
)=C(CH
3
)
2 , -C 2
H
4
-CH=C(CH
3
)
2 , -C 4 H=-CECH, -CEC-C 4
H
9 , -C 3
H
6
-C=C-CH
3 , 20 -CH 2
-C=C-C
3
H
7 , -C 2
H
4
-C=C-C
2
H
5 ; R' is independently H, -CO 2 R", -CONHR", -CR''O, -SO 2 NR", -NR''-CO-haloalkyl,
-NO
2 , -NR''-S0 2 -haloalkyl, -NR''-S0 2 -alkyl, -S0 2 -alkyl, -NR''-CO-alkyl, -CN, alkyl, cycloalkyl, alkylamino, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl, or heteroaryl; 25 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, SO 2 , N, or NR", R" being as defined above; the C 3
-C
8 -cycloalkyl residue may be selected from the group comprising 30 -cyclo-C 3 Hs, -cyclo-C 4
H
7 , -cyclo-C 5
H
9 , -cyclo-C 6 Hui, -cyclo-C 7
H
1 3 , -cyclo-CsHi 5 , morpholine-4-yl, piperazinyl, 1 -alkylpiperazine-4-yl; an alkoxy group denotes an O-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; WO 2007/104557 PCT/EP2007/002265 16 a 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(R'O)-,
-CR'
0 (R10') 2 , -CR' 0
(R'
0
)R'
0 ", -C 2
(R
10
)
5 , -CH 2
-C(R
0
)
3 , -CH 2
-CR'
0 (Rlo') 2 , -CH 2 CR1 0
(R
10 ')R1 0 ", -C 3
(R'
0
)
7 , or -C 2
H
4
-C(R
0
)
3 , wherein R' 0 , R' 0 , R10" represent F, Cl, Br or 5 I, preferably F; a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being as defined above; a 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(R'0)3, -OCR' 0
(R'
0
)
2 , -OCR1 0
(R
10
')R'
0 ", -OC 2
(R
0 )s, -OCH 2
-C(R
0
)
3 , -OCH 2 10 CR' 0 (Rlo') 2 , -OCH 2
-CR
10 (R1O')R 1 0 ", -OC 3
(R
0
)
7 or -OC 2
H
4
-C(R
0
)
3 , wherein R 10 , R' 0 ',
R
1 0 " 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 15 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 defined above; the aryl group is preferably a benzyl group, a phenyl group, -o-C 6
H
4 - R', -m-C 6 H- R', -p 20 C 6
H
4 - 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, 25 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, benzoisothiazol-4-yl, 30 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- WO 2007/104557 PCT/EP2007/002265 17 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 5 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, benzothiofurazane, benzotriazol-1 yl, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl, benzotriazol-7-yl, benzotriazine, benzo[b]thiophenyl, benzimidazol-2-yl, 1H-benzimidazolyl, benzimidazol-4-yl, 10 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, tetrahydroisoquinolinyl, purine, plithalazine, pteridine, thiatetraazaindene, thiatriazaindene, isothiazolopyrazine, isothiazolopyrimidine, pyrazolotriazine, pyrazolopyrimidine, imidazopyridazine, imidazo 15 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-furo[2,3-c]pyridin-3-yl, and 20 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 25 acceptable prodrugs or a stereoisomer thereof, R4 A-N RR R2(III) WO 2007/104557 PCT/EP2007/002265 18 wherein RI is -C(O)R 7 a, -C(O)CHR 7
R
8 , -C(O)NR 7 R', -C(O)OR 7 , -R 7
C(O)R
8 , or -C(S)R 7; R2 is H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, 5 or R' and R 2 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, C 1
-C
6 -alkyl, C 2
-C
6 -alkenyl, cycloalkyl, haloalkyl, hydroxyalkyl, 10 hydroxyalkylamino, alkylamino, -C(NR 7
)NR
7
'R
8 , -(CH 2 )paryl, -(CH 2 )pNR 7 R,
-C(O)NR
7 R', -N=CR 7 R', -NR 7 C(O)R', halogen, heteroaryl, or aryl; R' is H, -C(O)NRaRb, halogen, alkyl, haloalkyl, aryl, heteroaryl, OH, SH, NR 4'OR ,
NH
2 , hydroxyalkylamino, alkylamino, alkoxy, cycloalkyl, heterocycloalkyl, hydroxyalkyl, or haloalkyloxy; 15 R4 is H, OH, SH, NH 2 , alkoxy, haloalkyloxy, halogen, alkyl, -C(NR 7
)NR
7 'R, (CH 2 )paryl, -(CH 2 )pNR7 R, -C(O)NR 7
R
8 , -N=CR R, -NR 7
C(O)R
8 , cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl; R is halogen, alkyl, -C(NR7)NR7'R8, -(CH 2 )paryl, -(CH 2 )pNR RI, -C(O)NR R8, 20 -N=CR 7 R, -NR 7
C(O)R
8 , cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl; Ra is H, halogen, alkyl, -C(NR7)NR'R, -(CH 2 )paryl, -(CH 2 )pNR7 R, -C(O)NR7R8, -N=CRR8, NR7 C(O)R 8 , cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl; 25 Rb independently represents H, -CN, -OH, -SH, -C0 2
R
4 , -C(O)R 4 ', -SO 2
NR
4 , -NR'R', -C(O)NR7 R, -S0 2 -alkyl, -SO 2 R', SO 3 R4', -N=CR R , -NR4'C(O)R",
-NR
4 '-CO-haloalkyl, -NO 2 , -NR 4
'-SO
2 -haloalkyl, -NR 4 '-S0 2 -alkyl, -NR 4 '-CO-alkyl,
-NR
4
'(CH
2 )pheteroaryl, alkyl, cycloalkyl, alkylamino, alkoxy, alkylthio, halogen, haloalkyl, haloalkyloxy, -O(CH 2 )p[O(CH 2 )p]qOCH 3 , -C(NR 4
")NR
4 'benzimidazolyl, 30 -C(NR 4
")NR
4 'benzthiazolyl, -C(NR 4
")NR
4 'benzoxazolyl, hydroxyalkyl, hydroxy cycloalkyl, hydroxyalkylamino, heterocycloalkyl, aryl or heteroaryl; R , R", R independently are H, halogen, alkyl, -C(NR )NR'R8, -(CH 2 )paryl, haloalkyl,
-(CH
2 )pNRR8, -C(O)NR 7
R
8 , -N=CR7 R, -NR7C(O)R', cycloalkyl, WO 2007/104557 PCT/EP2007/002265 19 heterocycloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl;
R
7 , R 7 , R 8 independently are H, halogen, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, arylamino heteroaryl, or aryl; 5 R 7 a is cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, heteroaryl, or aryl; R~b is H, halogen, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, heteroaryl, or aryl; A is CO or SO 2 ; X is NR 2 , O, or S; 10 Z isNor CR ; R2 is H, alkyl, -C(O)NR 7 , -C(O)Rb, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl; p is I to 6; q is lto6; 15 R 9 independently represents H, -CN, -OH, -SH, alkoxy, alkylthio, -CO 2 R', -C(O)R~a
-C(O)NR
7 R', -SO 2
NR
4 ', -NR 4 'R 5 , -S0 2 -alkyl, -S0 2
R
4 ', S0 3
R
4 ', -N=CR 4 R",
-NR
4
'C(O)R
4 ", -NR'-CO-haloalkyl, -NO 2 , -NR 4 '-S0 2 -haloalkyl, -NR 4 '-S0 2 -alkyl,
-NR
4 '-CO-alkyl, -NR 4
'(CH
2 )pheteroaryl, alkyl, hydroxyalkyl, cycloalkyl, halogen, haloalkyl, alkylamino, -O(CH 2 )p[O(CH 2 )p]qOCH 3 , -C(NR 4
)NR
4 'benzimidazolyl, 20 -C(NR 4
")NR
4 'benzthiazolyl, -C(NR 4
")NR
4 'benzoxazolyl, hydroxycycloalkyl, hydroxyalkylamino, haloalkyloxy, heterocycloalkyl, -(CH 2 )pNR 7 COR', aryl, or heteroaryl; wherein 25 a Ci-C 6 -alkyl group, if not stated otherwise, denotes a linear or branched Ci-C 6 -alkyl, preferably a linear or branched chain of one to five carbon atoms, which can optionally be substituted by one or more substituents R'; a C 2
-C
6 -alkenyl group, if not stated otherwise, denotes a linear or branched C 2
-C
6 -alkenyl, preferably a linear or branched chain of two to six carbon atoms, which can optionally be 30 substituted by one or more substituents R'; an alkyl group, if not stated otherwise, denotes a linear or branched Ci-C 6 -alkyl, preferably a linear or branched chain of one to six carbon atoms, a linear or branched C 2
-C
6 -alkenyl or WO 2007/104557 PCT/EP2007/002265 20 a linear or branched C 2
-C
6 -alkynyl group, which can be substituted by one or more substituents R'; R' is independently H, -CO 2 R", -CONHR", -CR''0, -SO 2 NR'', -NR''-CO-haloalkyl,
-NO
2 , -NR'-S0 2 -haloalkyl, -NR''-S0 2 -alkyl, -S0 2 -alkyl, -NR''-CO-alkyl, -CN, alkyl, 5 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 10 the ring can be substituted by a group R' being as defined above; the C 3 -Cs-cycloalkyl residue may be selected from the group comprising -cyclo-C 3 H5, -cyclo-C 4
H
7 , -cyclo-C5H 9 , -cyclo-C 6 H i, -cyclo-C 7
H
13 , -cyclo-CsHis; 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 15 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-1-yl; an alkoxy group denotes an O-alkyl group, the alkyl group being as defined above; the alkoxy group is preferably a methoxy, ethoxy, isopropoxy, t-butoxy or pentoxy group; 20 an alkylthio group denotes an S-alkyl group, the alkyl group being as defined above; a 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(R'0)3, -CR10(R10)2, -CR1O(R1O')R1O", -C 2
(R
0
)
5 , -CH 2
C(R
0
)
3 , -CH 2
CR
1
(R"')
2 ,
-CH
2
CR'
0
(R
10
)R
10 ", -C 3
(R'
0
)
7 , or -C 2
H
4
C(R
0
)
3 , wherein R'O, R'0', R10" represent F, Cl, Br 25 or I, preferably F; a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being as defined above; a 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(RI")3, -OCRI'(Rlo') 2 , -OCR 10
(R
1 0
')R'
0 ", -OC 2
(R'
0
)
5 , -OCH 2
C(R
0
)
3 , 30 -OCH 2
CR'
0
(R'
0
)
2 , -OCH 2
CR
1 (R1O')R 1 "", -OC 3
(R
0
)
7 , or -OC 2
H
4
C(R
1 0
)
3 , wherein R 10 , R10', R 10 " 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; WO 2007/104557 PCT/EP2007/002265 21 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 5 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-C 6
H
4 -R', -m-C 6 H4-R', -p-C6H4-R', 1 naphthyl, 2-naphthyl, 1 -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; 10 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, 15 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, benzoisothiazol-4-yl, benzoisothiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl, 1,2,5-thiadiazol-4 20 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 25 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-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, benzothiofurazane, benzotriazol-1 30 yl, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-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- WO 2007/104557 PCT/EP2007/002265 22 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, 5 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 10 substituted by one or more substituents R', wherein R' is as defined above. The following compounds are excluded from formula (III): 0 R1 XN R2 R1~f4 X]= S (I) wherein 15 RI independently represents hydrogen, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl or substituted arylalkyl; R2 independently represents -NR3 R4, NaR 5 N N-R 5 or 20 R 3 independently represents alkyl, cycloalkyl, alkoxy, alkylamine, -OH, -SH, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl, R4 independently represents alkyl, cycloalkyl, alkoxy, alkylamine, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl; 25 R' independently represents H, COR, C0 2
R
6 , SOR 6 , S0 2
R
6 , S0 3
R
6 , alkyl, cycloalkyl, alkoxy, -NH 2 , alkylamine, -NR 7
COR
6 , halogen, -OH, -SH, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl; WO 2007/104557 PCT/EP2007/002265 23 R6 independently represents H, alkyl, cycloalkyl, -NH 2 , alkylamine, aryl or heteroaryl;
R
7 independently represents H, alkyl, cycloalkyl, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl, aryl, or heteroaryl; p is 0, or 1; 5 q is 0, or 1; X is CO or SO 2 . 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 10 acceptable prodrugs or a stereoisomer thereof, R Z N 0 N R3a N d R 2a R2 0 z N X R 3 - - r (Ih) wherein 15 A is NR 2 ', S or 0; t is 0 to 4; r is 0, or 1; R2a is independently H, OH, SH, NH 2 , alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, alkoxy, alkylamino, hydroxyalkylamino, halogen, aryl, or heteroaryl; 20 R3a is H, OH, SH, NH 2 , -C(NR7)NR7'R', -(CH 2 )paryl, -(CH 2 )pNR 7 R', -C(O)NR7 R,
-N=CR
7 R', -NRC(O)R 8 , alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, alkoxy, alkylamino, hydroxyalkylamino, halogen, aryl, or heteroaryl; Rd is H, halogen, alkyl, -C(NR7)NR'R, -(CH 2 )paryl, -(CH 2 )pNR 7 R', -C(O)NR R',
-N=CR
7 R', -NR 7
C(O)R
8 , cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, 25 alkylamino, heteroaryl or aryl; R 1 is -C(O)R 7 a, -C(O)CHR 7 R', -C(O)NR 7 R, -C(O)OR 7 , -R 7 C(O)R', or -C(S)REb; R2 is H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, or heteroaryl; WO 2007/104557 PCT/EP2007/002265 24 or RI 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' 5 R 4 a is H, CI-C-alkyl, C 2
-C
6 -alkenyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, -C(NR)NR'R', -(CH 2 )paryl, -(CH 2 )pNRR',
-C(O)NR
7 R', -N=CR7 R, NR7 C(O)R', halogen, heteroaryl, or aryl; R is H, -C(O)NRaRb, halogen, alkyl, haloalkyl, aryl, heteroaryl, OH, SH, NR 4'OR",
NH
2 , hydroxyalkylamino, alkylamino, alkoxy, cycloalkyl, heterocycloalkyl, 10 hydroxyalkyl, or haloalkyloxy; Ra is H, halogen, alkyl, -C(NR7W
R
7'R, -(CH 2 )paryl, -(CH 2 )pNR7R', -C(O)NR7R',
-N=CR
7 R', -NR 7 C(O)R , cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl; Rb independently represents H, -CN, -OH, -SH, -C0 2
R
4 ', -C(O)R 4 , -SO 2
NR
4 , 15 -NR 4 'R", -C(O)NR 7
R
8 , -S0 2 -alkyl, -S0 2
R
4 ', SO 3
R
4 , -N=CR4'R, -NR4'C(O)R 4 ,
-NR
4 '-CO-haloalkyl, -NO 2 , -NR 4 '-S0 2 -haloalkyl, -NR 4 '-S0 2 -alkyl, -NR 4 '-CO-alkyl,
-NR
4
'(CH
2 )pheteroaryl, alkyl, cycloalkyl, alkylamino, alkoxy, alkylthio, halogen, haloalkyl, haloalkyloxy, -O(CH 2 )p[O(CH2)p]qOCH3, -C(NR 4
")NR
4 'benzimidazolyl,
-C(NR
4
")NR
4 'benzthiazolyl, -C(NR 4
")NR
4 'benzoxazolyl, hydroxyalkyl, hydroxy 20 cycloalkyl, hydroxyalkylamino, heterocycloalkyl, aryl or heteroaryl; R , R", R 5 ' independently are H, halogen, alkyl, -C(NR 7)NR 'RI, -(CH 2 )paryl, haloalkyl,
-(CH
2 )pNR7 R, -C(O)NR 7 R', -N=CR7 R8, NR 7 C(O)R', cycloalkyl, heterocycloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl; 25 R 7 , R 7 , R independently are H, halogen, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, arylamino heteroaryl, or aryl;
R
7 a is cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, heteroaryl, or aryl; R 7 is H, halogen, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, heteroaryl, or aryl; 30 X is NR, O, or S; Z is N or CR2; R is H, alkyl, -C(O)NR', -C(O)R , cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl; WO 2007/104557 PCT/EP2007/002265 25 p is 1 to 6; q is I to 6; R 9 independently represents H, -CN, -OH, -SH, alkoxy, alkylthio, -CO 2
R
4 ', -C(O)R 4 a,
-C(O)NR
7 R', -SO 2
NR
4 ', -NR 4 'R", -S0 2 -alkyl, -SO 2
R
4 ', S0 3 R4', -N=CR4'R", 5 -NR 4
'C(O)R
4 ", -NR 4 '-CO-haloalkyl, -NO 2 , -NR 4 '-S0 2 -haloalkyl, -NR 4 '-S0 2 -alkyl,
-NR
4 '-CO-alkyl, -NR 4
'(CH
2 )pheteroaryl, alkyl, hydroxyalkyl, cycloalkyl, halogen, haloalkyl, alkylamino, -O(CH 2 )p[O(CH 2 )p]qOCH 3 , -C(NR 4
")NR
4 'benzimidazolyl,
-C(NR
4 ")NR4'benzthiazolyl, -C(NR 4
")NR
4 'benzoxazolyl, hydroxycycloalkyl, hydroxyalkylamino, haloalkyloxy, heterocycloalkyl, -(CH 2 )pNR 7 COR, aryl, or 10 heteroaryl; wherein a Ci-C 6 -alkyl group, if not stated otherwise, denotes a linear or branched C1-C 6 -alkyl, preferably a linear or branched chain of one to five carbon atoms, which can optionally be 15 substituted by one or more substituents R'; a C 2
-C
6 -alkenyl group, if not stated otherwise, denotes a linear or branched C 2
-C
6 -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 C 1
-C
6 -alkyl, preferably 20 a linear or branched chain of one to six carbon atoms, a linear or branched C 2
-C
6 -alkenyl or a linear or branched C 2
-C
6 -alkynyl group, which can be substituted by one or more substituents R'; R' is independently H, -CO 2 R", -CONHR'', -CR"0, -SO 2 NR", -NR''-CO-haloalkyl,
-NO
2 , -NR''-S0 2 -haloalkyl, -NR''-S0 2 -alkyl, -S0 2 -alkyl, -NR''-CO-alkyl, -CN, alkyl, 25 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 30 the ring can be substituted by a group R' being as defined above; the C 3 -Cs-cycloalkyl residue may be selected from the group comprising -cyclo-C 3 Hs, -cyclo-C 4
H
7 , -cyclo-CsH 9 , -cyclo-C 6 HiI, -cyclo-C 7
H
13 , -cyclo-CsHis; WO 2007/104557 PCT/EP2007/002265 26 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, 5 piperidinyl, pyrrolidinyl, azepane- 1-yl; an alkoxy group denotes an O-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; a haloalkyl group denotes an alkyl group which is substituted by one to five halogen atoms, 10 the alkyl group being as defined above; the haloalkyl group is preferably a -C(R"), -CRO(R10')2, -CR'O(R1O')R1O", -C2(R'0)s, -CH2C(R10)', -CH2CR10(R0'')2,
-CH
2 CR'O(R1O')R1O", -C 3 (R 0)7, or -C 2
H
4 C(R )3, wherein R", R ', R10" represent F, Cl, Br or I, preferably F; a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being as defined above; 15 a 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(R'
0
)
3 , -OCR' 0
(R'
0
)
2 , -OCR 10
(R
10 ')R1 0 ", -OC 2
(R
0
)
5 , -OCH 2
C(R
0
)
3 ,
-OCH
2
CR
10
(R'
0
)
2 , -OCH 2
CR
1 (R1O')R 10 ", -OC 3
(R'
0 )7, or -OC 2
H
4
C(R'
0
)
3 , wherein R1 0 ,
R'
0 ', R' 0 represent F, Cl, Br or I, preferably F; 20 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; 25 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-C 6
H
4 -R', -m-C 6
H
4 -R', -p-C 6
H
4 -R', 1 naphthyl, 2-naphthyl, 1 -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 30 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, WO 2007/104557 PCT/EP2007/002265 27 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-vl, isooxazol-5-yl. benzooxazol-2-vl, 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, 5 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, 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 10 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 15 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, benzothiofurazane, benzotriazol-1 yl, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl, benzotriazol-7-yl, benzotriazine, benzo[b]thiophenyl, benzimidazol-2-yl, 1H-benzimidazolyl, benzimidazol-4-yl, 20 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 25 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 30 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 following compounds are excluded from formula (Ih): WO 2007/104557 PCT/EP2007/002265 28 0 R4O4 4X N R2 S (I) wherein Rt independently represents hydrogen, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl or 5 substituted arylalkyl; R2 independently represents -NRR4, - -NaR 5 -- N N-R 5 \ or \ / R 3 independently represents alkyl, cycloalkyl, alkoxy, alkylamine, -OH, -SH, 10 alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl; independently represents alkyl, cycloalkyl, alkoxy, alkylamine, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl; R independently represents H, COR , CO 2 R', SOR6, S0 2
R
6 , SO 3
R
6 , alkyl, cycloalkyl, alkoxy, -NH 2 , alkylamine, -NR 7
COR
6 , halogen, -OH, -SH, alkylthio, hydroxyalkyl, 15 haloalkyl, haloalkyloxy, aryl or heteroaryl; R 6 independently represents H, alkyl, cycloalkyl, -NH 2 , alkylamine, aryl or heteroaryl; R 7 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 SO 2 . In formula (Ih), the following substituents are preferred, alone or in combination: 25 X is preferably S or 0, more preferably S. R3a is preferably H.
WO 2007/104557 PCT/EP2007/002265 29 In a preferred embodiment, Z is CR and R' and R 2 together with the C-atom to which they are attached form a 6 membered saturated ring. In another preferred embodiment, Z is N and R' and R2 together with the N-atom to which they are attached form a 6 membered 5 saturated ring.
R
9 is preferably heteroaryl, aryl or benzyl, more preferably heteroaryl. R 9 is even more preferably thienopyrimidine, quinazoline, purine, pyrazolopyrimidine or triazolpyrimidine. Even more preferably, R 9 is thienopyrimidine. 10 t is preferably 0. r is preferably 1. 15 R 2 a is preferably OH, alkyl, aryl or heteroaryl, more preferably alkyl, especially methyl. The present invention relates also to compounds of the general formula (II) or pharmaceutically acceptable salts thereof with an acid or a base, or pharmaceutically acceptable prodrugs, or a stereoisomer thereof, A-N Y-R 6 N n 20 R2 (II) wherein RI is -C(O)R 7 , -C(O)CHR 7 R', -C(O)NR 7 R', -C(O)OR', -R 7 C(O)Rg, or -C(S)R7; R2 is H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, alkylamino, hydroxyalkylamino, or heteroaryl; 25 or R 1 and R 2 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 WO 2007/104557 PCT/EP2007/002265 30 heteroatom selected from 0, N, and S, and the ring can be substituted by one or more R 9 ; R is H, -C(O)NRaRb, halogen, alkyl, haloalkyl, aryl, heteroaryl, OH, SH, NR 4 OR',
NH
2 , hydroxyalkylamino, alkylamino, alkoxy, cycloalkyl, heterocycloalkyl, 5 hydroxyalkyl, or haloalkyloxy; Ra is H, halogen, alkyl, -C(NR7)NR7'RI, -(CH 2 )paryl, -(CH 2 )pNR 7 R', -C(O)NR7 R,
-N=CR
7 R', -NR 7
C(O)R
8 , cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl; Rb independently represents H, -CN, -OH, -SH, -C0 2
R
4 ', -C(O)R 4 ', -SO 2 NR', 10 -NR 4 'R', -C(O)NR 7 R, -S0 2 -alkyl, -S0 2
R
4 , SO 3
R
4 ', -N=CR 4 'R", -NR 4'C(O)R4",
-NR
4 '-CO-haloalkyl, -NO 2 , -NR 4 '-S0 2 -haloalkyl, -NR 4 '-S0 2 -alkyl, -NR 4 '-CO-alkyl,
-NR
4
'(CH
2 )pheterocycle, alkyl, cycloalkyl, alkylamino, alkoxy, alkylthio, halogen, haloalkyl, haloalkyloxy, -O(CH 2 )p[O(CH 2 )p]qOCH 3 , -C(NR 4
")NR
4 'benzimidazolyl,
-C(NR
4
")N
4 'benzthiazolyl, -C(NR 4
")NR
4 'benzoxazolyl, hydroxyalkyl, hydroxy 15 alkylamino, aryl, heterocycloalkyl, or heteroaryl; 6 78 787 R is halogen, -C(O)R 7 , -C(O)CHR R', -C(O)NR'R', -C(O)OR 7 , -R C(O)R', -C(S)R,
-C(NR
7 )NR"R8, -(CH 2 )paryl, -(CH 2 )pNR 7
R
8 , -C(O)NR R', -N=CR7R, NR 7
C(O)R
7 ', alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl; 20 R 7 , R , RI independently are H, halogen, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, -NHaryl, heteroaryl, or aryl; A is CO or SO 2 ; X is NR 2 ', 0, or S; Y is N, CR2 or if Y is 0 then R6 is absent; 25 Z is N or CR 2 ; if Z is CH then X is O or NR R" 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 I to 6; 30 q is I to 6; R 9 independently represents H, -CN, -OH, -SH, -C0 2
R
4 ', -C(O)R 4 a, -C(O)NR 7 R, SO 2
NR
4 , -NR 4
'R
5 , -S0 2 -alkyl, -S0 2
R
4 ', S0 3
R
4 ', -N=CR 4 'R", -NR 4
'C(O)R
4 , NR 4 '-CO-haloalkyl, -NO 2 , -NR 4 '-S0 2 -haloalkyl, -NR 4 '-S0 2 -alkyl, -NR 4 '-CO-alkyl, WO 2007/104557 PCT/EP2007/002265 31
-NR
4
'(CH
2 )pheteroaryl, alkyl, cycloalkyl, heterocycloalkyl, alkylamino, alkoxy, alkylthio, halogen, haloalkyl, haloalkyloxy, hydroxyalkylamino, hvdroxvlkvl hydroxycycloalkyl, aryl, -O(CH 2 )p[O(CH 2 )p]qOCH 3 , -C(NR4" )NR4'benzimidazolyl,
-C(NR
4
")NR
4 'benzthiazolyl, -C(NR 4
")NR
4 'benzoxazolyl, -(CH 2 )pNR 7 COR', or 5 heteroaryl; R4', R4", R independently are H, halogen, alkyl, -C(NR7)NR7'R8, -(CH 2 )paryl,
-(CH
2 )pNR 7 R', -C(O)NR 7 R', -N=CR 7
R
8 , -NR 7
C(O)R
8 , cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl; 10 Ra is H, C 1
-C
6 -alkyl, C 2
-C
6 -alkenyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, -C(NR 7
)NR
7
'R
8 , -(CH 2 )paryl, -(CH 2 )pNR 7
R
8 ,
-C(O)NR
7 R', -N=CRR 8, NR7 C(O)R', halogen, heteroaryl, or aryl; wherein 15 a Ci-C 6 -alkyl group, if not stated otherwise, denotes a linear or branched CI-C 6 -alkyl, preferably a linear or branched chain of one to five carbon atoms, which can optionally be substituted by one or more substituents R'; a C 2
-C
6 -alkenyl group, if not stated otherwise, denotes a linear or branched C2-C 6 -alkenyl, preferably a linear or branched chain of two to six carbon atoms, which can optionally be 20 substituted by one or more substituents R'; an alkyl group, if not stated otherwise, denotes a linear or branched CI-C 6 -alkyl, preferably a linear or branched chain of one to six carbon atoms, a linear or branched C 2
-C
6 -alkenyl or a linear or branched C 2
-C
6 -alkynyl group, which can be substituted by one or more substituents R'; 25 R' is independently H, -CO 2 R', -CONHR", -CR''0, -SO 2 NR', -NR''-CO-haloalkyl, -NO2, -NR''-S0 2 -haloalkyl, -NR''-S0 2 -alkyl, -S0 2 -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; 30 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 C 3 -Cs-cycloalkyl WO 2007/104557 PCT/EP2007/002265 32 residue may be selected from the group comprising -cyclo-C 3 H5, -cyclo-C 4
H
7 , -cyclo-C 5
H
9 , -cyclo-C6Hu, -cyclo-C 7
H
13 , -cyclo-C8His; 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 5 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; an alkoxy group denotes an O-alkyl group, the alkyl group being as defined above; the alkoxy group is preferably a methoxy, ethoxy, isopropoxy, t-butoxy or pentoxy group; 10 an alkylthio group denotes an S-alkyl group, the alkyl group being as defined above; a 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(R'0)3,
-CR
0
(R'
0
)
2 , -CR 1 0 (R10)R10", -C 2
(R'
0
)
5 , -CH 2
C(R
0
)
3 , -CH 2
CR'
0 (Rlo')2, CH 2
CR'(R
10
')R'
0 ", -C 3
(R'
0
)
7 , or -C 2 H4C(R' 0
)
3 , wherein R1 0 , R 10 ', R10" represent F, Cl, Br 15 or I, preferably F; a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being as defined above; a 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(R"
0
)
3 , -OCR' 0
(R
10
')
2 , -OCR' 0 (R10')R 10 ", -OC 2
(R'
0
)
5 , -OCH 2
C(R'
0
)
3 , 20 -OCH 2
CR
10
(R
10
')
2 , -OCH 2
CR'(R')R'
0 ", -OC 3
(R'
0
)
7 , or -OC 2
H
4
C(R
0
)
3 , wherein R1 0 , R1 0 ', R1 0 " 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 25 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-C 6
H
4 -R', -m-C 6
H
4 -R', -p-C 6
H
4 -R', 1 30 naphthyl, 2-naphthyl, 1-anthracenyl or 2-anthracenyl, R' 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, WO 2007/104557 PCT/EP2007/002265 33 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-Vl. 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, 5 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, 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 10 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 15 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, benzothiofurazane, benzotriazol-1 yl, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl, benzotriazol-7-yl, benzotriazine, benzo[b]thiophenyl, benzimidazol-2-yl, 1H-benzimidazolyl, benzimidazol-4-yl, 20 benzimidazol-5-yl, benzimidazol-6-yl, benzimidazol-7-yl, benzothiazolyl, quinazolinyl, qumoxazolinyl, 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 25 yl, tetrahydroisoquinolinyl, purine, phthalazine, pteridine, thiatetraazaindene, thiatriazaindene, isothiazolopyrazine, isothiazolopyrimidine, pyrazolotriazine, 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 30 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.
WO 2007/104557 PCT/EP2007/002265 34 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, R 2 is - -N N- R 5 and R 5 is optionally substituted aryl, benzyl or heteroaryl. 5 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, RC is H, and Ri is aryl, benzyl, or heteroaryl, R 2 is - N-R 5 and R 5 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 10 CO, X forms a piperidine ring together with R' and R 4 , Ra and Rb is H, Rc is H or methyl, -N \ N--R 5
R
2 is , and R 5 is optionally substituted aryl, benzyl or heteroaryl. In a preferred embodiment of the invention, in the compounds of formula (Ib), Z is 0, Y is CO, X forms a piperidine ring together with R' and R4, Ra and R is H, Rc is H or methyl, - -N / \N-R 5 15 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, RC is H, methyl, ethyl, methoxy, alkylamino, morpholino, N - -N / \N- R 5 methylpiperazine, CF 3 , or OCF, R2 is , and R 5 is optionally 20 substituted aryl, benzyl or heteroaryl.
WO 2007/104557 PCT/EP2007/002265 35 In another preferred embodiment, in the compounds of formula (Ic), r is 1,Y is CO, Z is S, t is 0, s is 0, R' is H, methyl, ethyl, methoxy, alkylamino, morpholino, N-methylpiperazine, - -N / \N-R 5
CF
3 , or OCF, R 2 is , and R 5 is optionally substituted aryl, benzyl or heteroaryl. 5 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, Rc is H, methyl, ethyl, methoxy, alkylamino, morpholino, N - -N \N -R 5 methylpiperazine, CF 3 , or OCF R2 is , and R5 is optionally substituted aryl, benzyl or heteroaryl. 10 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, Rc is H, methyl, ethyl, methoxy, alkylamino, morpholino, N-methylpiperazine, - -N N-R 5
CF
3 , or OCF, R 2 is , and R5 is optionally substituted aryl, benzyl or heteroaryl. 15 A preferred embodiment of the invention, in the compounds of formula (III), are compounds of the formula (Ila), 0 R4 N 0 N \R5 O N R3 R7a)" Z :X (1I1a) 20 R 3 , R 4 , R', Ra and Z are defined as above.
WO 2007/104557 PCT/EP2007/002265 36 Preferably, R 3 is H, Me, OMe, CF 3 , OCF 3 , Cl, OH or SH, more preferably H, Me, OMe,
CF
3 , OCF 3 , even more preferably H. 5 Preferably, Z is N. Preferably, RW is H. Preferably, R 7 a is aryl or heteroaryl, more preferably aryl, even more preferably phenyl. 10 Further preferably, R7a is substituted by one or two substituents R', more preferably by one substituent R'. In a particularly preferred embodiment, R 7 a is 2-trifluormethoxyphenyl. In another particularly preferred embodiment, R 7 a is 2-methoxyphenyl. In another particularly preferred embodiment, R7a is 2-chlorophenyl. And in yet another particularly preferred embodiment, R 7 a is 2-methylphenyl. 15 Preferably, R 5 is aryl or heteroaryl, more preferably heteroaryl. The heteroaryl contains preferably 2 nitrogen atoms and is particularly preferably 2-imidazolyl or 2 benzoimidazolyl, even more preferably 2-benzoimidazolyl. In another preferred embodiment, the heteroaryl contains 1 nitrogen atom and 1 sulfur atom and is particularly 20 preferably 2-thiazolyl or 2-benzothiazolyl, even more preferably 2-benzothiazolyl. The heteroaryl further preferably is substituted by one to four substituents R', more preferably by one or two substituents R'. In a particularly preferred embodiment, R 5 is 5,6-dimethyl 1H-benzoimidazol-2-yl. In another particularly preferred embodiment, R 5 is 5,6-dimethyl 1H-benzothiazol-2-yl. 25 Preferably, R is -S0 2 -alkyl, -NO 2 , halogen, -CO 2 H, -OH, haloalkyloxy, alkoxy or alkyl. Particularly preferred for R' are the following: methanesulfonyl, nitro, fluorine, chlorine, bromine, carboxyl group, hydroxyl, trifluormethoxy, methoxy, ethoxy, methyl, ethyl or trifluoroethyl. 30 In one preferred embodiment X is 0. In another preferred embodiment X is S. In yet another preferred embodiment X is NR 2
.
WO 2007/104557 PCT/EP2007/002265 37 In a preferred embodiment of the compound of formula (1I1a), R 3 is H, methyl, methoxy,
CF
3 , or OCF 3 ; R 4 , R 5 , R 7 a are defined as above; X is NR2, 0 or S; and Z is as defined as above. 5 Another preferred embodiment of the invention, in the compounds of formula (III) are compounds of the formula (IIIa), with R 7 a = -NH-aryl. Another preferred embodiment of the invention, in the compounds of formula (III), are compounds of the formula (IIb), 0
NHR
5 :R3 Z X 10 (IIlb) wherein
R
3 is H, methyl, methoxy, CF 3 , or OCF 3 ; R is defined as above; X is NR , 0 or S; if Z is N then X is NR2, O or S; if Z is CR2 then X is 0; Y' is 0 or NR2, R 2 is as defined above. 15 Another preferred embodiment of the invention, in the compounds of formula (III), are compounds of the formula (I1Ic),
R
7 N R' \\/ 0 N O N \ R4 y', R1 3 R lN X R // H (IIc)
R
1 2
R
11 wherein WO 2007/104557 PCT/EP2007/002265 38 R", R1 2 independently represent H, -CN, -OH, -SH, -C0 2
R
4 ', -C(O)R4', -SO 2
NR
4 ',
-NR
4 'R", -S0 2 -alkyl, -S0 2
R
4 ', S0 3
R
4 , -N=CR 4 'R", -NR 4 'C(O)R4", -NR 4 '-CO-haloalkyl,
-NO
2 , -NR4'-S0 2 -haloalkyl, -NR 4 '-S0 2 -alkyl, -NR 4 '-CO-alkyl, -NR 4 ' (CH 2 )pheteroaryl, alkyl, cycloalkyl, alkylamino, alkoxy, alkylthio, -O(CH 2 )p[O(CH 2 )p]qOCH 3 , 5 C(NR 4
")NR
4 'benzimidazolyl, -C(NR 4
")NR
4 'benzthiazolyl, -C(NR 4
")NR
4 'benzoxazolyl hydroxyalkyl, hydroxycycloalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl, arylalkyl or a heterocycle; R4', R 4 ", R 5 are defined as above; R 3 is H, methyl, methoxy, CF 3 , or OCF 3 ; X is NR 2 ', 0 or S; R 4 is defined as above;
R
7 and R 7 are defined as above; R"', R' independently represents H, -CN, -OH, -SH, 10 C0 2
R
4 ', -C(O)R 4 ', -SO 2
NR
4 ', -NR 4
R
5 , -S0 2 -alkyl, -S0 2
R
4 ', S0 3
R
4 ', -N=CR 4
'R
5 , NR4'C(O)R4", -NR4'-CO-haloalkyl, -NO 2 , -NR4' -S0 2 -haloalkyl, -NR4'-SO 2 -alkyl, -NR' CO-alkyl, -NR 4 ' (CH 2 )pheteroaryl, alkyl, cycloalkyl, alkylamino, alkoxy, alkylthio, O(CH 2 )p[O(CH 2 )p]qOCH 3 , -C(NR 4
")NR
4 'benzimidazolyl, -C(NR 4 ")NR4'benzthiazolyl, C(NR 4 ")NR4'benzoxazolyl hydroxyalkyl, hydroxycycloalkyl, hydroxyalkyl-amino, 15 halogen, haloalkyl, haloalkyloxy, aryl, arylalkyl or a heterocycle; and R 4 ', R4", R 5 are defined as above. A more preferred embodiment of the invention, in the compounds of formula (III), are compounds of the formula (IIld),
R
7 N R' \/ 0 N N
R
4 y. R12' N3 R11' 20Y (Id) wherein R3 is H, methyl, methoxy, CF 3 , or OCF 3 ; X is NR 2 ', 0 or S; R is defined as above; R7 and R7' are defined as above; Y" and R"', RI' are defined as above under formula (II1c); Y' is 0 or NR2' and R 2 ' is as defined above. 25 WO 2007/104557 PCT/EP2007/002265 39 Another more preferred embodiment of the invention, in the compounds of formula (III), are compounds of the formula (IIIe), O R4 R5 NN N. N (IIle) wherein 5 R 3 , R 4 and R 5 are defined as above; X is 0 or S; R" and R1 2 are defined as above under formula (IlIc); and if Z is N, X is NR , 0 or S; if Z is CH, X is 0. Another more preferred embodiment of the invention, in the compounds of formula (III), are compounds of the formula (Ilf),
R
7 N R' 0 N N N R12' N 10 R11 wherein WO 2007/104557 PCT/EP2007/002265 40 3 2'4 Z is N or CH; R3 is H, methyl, methoxy, CF 3 , or OCF 3 ; X is NR , 0 or S; R4 is defined as 2'7 11 11' 12 12 above; R 7 and R 7 ' are defined as above; R is as defined above; Y" and R , R , R R are defined as above under formula (IIIc). 5 A preferred embodiment of the invention, are compounds of the formula (Iha), 0 R ORA R Z N NR 3a NR2a /t x .. . r (Iha) wherein R' is COR 7a
R
2 and R 3 a are H; 10 A is NH; R7 is as defined above; ZisN; X is NR2, O or S;
R
3 is H, methyl, ethyl, methoxy, amine, alkylamine, morpholino, N-methylpiperazine, CF 3 , 15 or OCF 3 ; t is 0; r is 1; and R2a is optionally substituted aryl, benzyl or heteroaryl. 20 Another preferred embodiment of the invention, in the compounds of formula (Ih), are compounds of the formula (Iha), wherein R 7 a is optionally substituted aryl, benzyl or heteroaryl. Another preferred embodiment of the invention, in the compounds of formula (Ih), are 25 compounds of the formula (Ihb), WO 2007/104557 PCT/EP2007/002265 41 0A R dI Z N NR 3a N R2a NR~N 3 0 (Ihb) wherein R3a is H; R is NH; 5 X is NR 2 , O or S; Y' is 0 or NR 2 ; R2 is as defined above; R3 is H, methyl, ethyl, methoxy, amine, alkylamine, morpholino, N-methylpiperazine, CF 3 , or OCF 3 ; 10 t is 0; r is 1; and R2a is optionally substituted aryl, benzyl or heteroaryl. In formula (Ihb), the following substituents are preferred, alone or in combination: 15 Z is preferably CR 2 . Y' is preferably NR2'. In a preferred embodiment, the R2 in the NR 2 of Y' is preferably substituted or unsubstituted heteroaryl. In another preferred embodiment, the R 2 in the 20 NR 2 of Y' is aryl. In yet another preferred embodiment, the R2 in the NR2 of Y' is benzyl. In a more prefered embodiment, the R 2 in the NR 2 of Y' is pyrimidine or triazine. In another more preferred embodiment, the R2 in the NR 2 of Y' is a substituted or unsubstituted bicyclic heteroaryl. more preferably thienopyrimidine, quinazoline, purine, pyrazolopyrimidine or triazolpyrimidine, even more preferably thienopyrimidine. 25 In a preferred embodiment, X is S. In another preferred embodiment, X is 0. In yet another preferred embodiment, X is NR 2
.
WO 2007/104557 PCT/EP2007/002265 42
R
3 is preferably H. R2a is preferably aryl or heteroaryl, more preferably phenyl. 5 Another more preferred embodiment of the invention, in the compounds of formula (Ih), are compounds of the formula (Ihe), O Rd A~ Jt 00 N N(RIhe) 10 wherein R3a is H; A is NH; X is NR2', O or S; R" and R1 2 independently represent H, -CN, -OH, -SH, -CO 2
R
4 ', -C(O)R 4 , -SO 2
NR
4 ',
-NR
4
R
5 , -S0 2 -alkyl, -SO 2
R
4 , S0 3
R
4 ', -N=CR 4
R
5 , -NR 4
C(O)R
4 ", -NR 4'-CO-haloalkyl,
-NO
2 , -NR 4 '-S0 2 -haloalkyl, -NR 4 '-S0 2 -alkyl, -NR 4 '-CO-alkyl, -NR 4 ' (CH 2 )pheteroaryl, 15 alkyl, cycloalkyl, alkylamino, alkoxy, alkylthio, -O(CH2)p[O(CH2)p]qOCH 3 , C(NR 4 ")NR4'benzimidazolyl, -C(NR 4
")NR
4 'benzthiazolyl, -C(NR 4
")NR
4 'benzoxazolyl hydroxyalkyl, hydroxycycloalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl, arylalkyl or a heterocycle;
R
4 ', Ri", R5' are defined as above; 20 R2' is as defined above; R3 is H, methyl, ethyl, methoxy, amine, alkylamine, morpholino, N-methylpiperazine, CF 3 , or OCF 3 ; t is 0; r is 1; and 25 R2a is optionally substituted aryl, benzyl or heteroaryl. In formula (The), the following substituents are preferred, alone or in combination: WO 2007/104557 PCT/EP2007/002265 43 Z is preferably CR 2 . In a preferred embodiment, X is S. In another preferred embodiment, X is 0. In yet another preferred embodiment, X is NRr 5
R
1 is preferably -H, -CN, -OH, halogen, haloalkyl, haloalkyloxy, more preferably -CN. R is preferably H. 10 Ra is preferably aryl or heteroaryl, more preferably phenyl. A preferred embodiment of the invention, in the compounds of formula (II), are compounds of the formula (IIa), 0R N N N R12 N, N (IIa) R2 15 wherein R' and R 2 are defined as above; Z is defined as above; X is 0 or S; R 3 is H, methyl, methoxy, CF 3 , or OCF 3 ; R 1 and R1 2 are defined as above under formula (IIc). A more preferred embodiment of the invention, in the compounds of formula (I), are 20 compounds of the formula (Ib), WO 2007/104557 PCT/EP2007/002265 44
CF
3 0 /- \__ N N N RX R3 (11b) R2 wherein R' and R 2 are defined as above; Z is defined as above; X is 0 or S; R 3 is H, methyl, methoxy, CF 3 , or OCF 3 . 5 Another more preferred embodiment of the invention, in the compounds of formula (II), are compounds of the formula (Ilc),
CF
3 0 __ N \ /N NN R3 z x (Ic) wherein 10 X is 0 or S; R 3 is H, methyl, methoxy, CF 3 , or OCF 3 ; Y' is NR 2 '. Another more preferred embodiment of the invention, in the compounds of formula (II), are compounds of the formula (Ild), WO 2007/104557 PCT/EP2007/002265 45 0 N\\ R12 N R3 N 6 (112) R (lId) wherein Z is defined as above; R3 is H, methyl, methoxy, CF 3 , or OCF 3 ; R", R"' and R, 12 R 1 2 ' are defined as above. 5 In addition, the present invention provides methods for preparing the compounds of the invention such as compounds of formula (Ia), (Ib), (Ic), (Ih), (II), or (III). The compounds of formula (Ia), (Ib), (Ic), (Ih), (II), or (III) may be obtained via various 10 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 be synthesised by 15 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 described by Yasuchika, S. et. al. Heterocycles, Vol. 57, No. 5, 2002.
WO 2007/104557 PCT/EP2007/002265 46 The compounds of formula (II), (Ic), and (III) carrying 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 Chemistry 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 (Ila, c and Ila, 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, iPr 2 NEt, DMF, OC to r.t. to obtain intermediate (VII). Another alternative for this step might be the reaction of (V) 15 with the corresponding acid chloride of (VI) to yield (VII). In a second step, compound (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 secondary amines), which works similarily to step 1 described above, completes the synthesis for compounds of type (IIa, c and Ha, 20 and b).
WO 2007/104557 PCT/EP2007/002265 47 0 OEt OEt 0 O N Ri" N OH X N X H
H
2 N XR12 (V) (VI) (VI) N OH R11 R1 N X N X H H R12 R12 (Ia, c, Ha, b) (VI) Scheme 1 Synthesis of derivatives of type (Ila, c) and (Ila, b) 5 Compounds dealing with structure (IIb, d, e, f) and (Ic, 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.
WO 2007/104557 PCT/EP2007/002265 48 0 o -OEt 0 OEt N Z N Z X Br X (IX) (XI) R3 0 0 H N 0oH R2 z z (IIMb, d, e, f, I1c, d) (XII) Scheme 2 Synthesis of derivatives of type (IIIb, d, e, f) and (IIc, d), with Z = N In case of Z = CH, structure (11b, d, e, f) and (Ilc, d) type compounds can easily be 5 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 (11b, d, e, f) or (IIc, d).
WO 2007/104557 PCT/EP2007/002265 49 0 o - OEt x 0 0 Z NH 2 + ----- z X Br OEt (XII) (XIV) (XV)
R
3 0 / 0 N OH ~R2 z Xz (IIIb, d, e, f, Ic, d) (XVI) Scheme 3 Synthesis of derivatives of type (11b, d, e, f) and (Ic, d), with Z = CH Compounds of the present invention carrying a piperidin-4-yl substituent in the 2-position 5 of the thiazole ring can, for example, be prepared as shown in the following scheme. This synthetic route is partially described in WO 2004/058750.
WO 2007/104557 PCT/EP2007/002265 50 S Br 0 BocNDNH B O Boc-N 0O 0 Boc-N IOH H 2
N-R
1 f 0 H Boc--ND ' N NR S H HCI HN IN .R O O RNCO 0 SHOH N R 1 RHN N N .N 1 R N N' 0 1-0 0 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)thiazole-4-carboxylic acid can be converted to the appropriate R' amide by coupling with HBTU, DIPEA in DMF. The different Rl-amines 5 are either commercially available or can be readily synthesized. The Boc-protection group can be removed under standard conditions, such as treatment with TFA for 2 to 3 hours at 00 or with 4 N HCl in dioxane for 2 to 3 hours. The deprotected piperidinoderivative HC1 salt can then be converted to the corresponding amides, ureas and N-heterocyclic analogs as follows. 10 Urea substituted piperidino compounds can be synthesized by coupling with commercially available isocyanates in the presence of DIPEA. Piperidino compounds substituted with heterocycles can be synthesized by standard procedures, such as coupling with the corresponding chloroheterocycle in the presence of a base. Alternatively, piperidino 15 compounds substituted with heterocycles can be obtained by palladium-mediated cross coupling. As a further alternative, hydroxypyridine derivatives can be coupled to the piperidino compound by the HBTU coupling method.
WO 2007/104557 PCT/EP2007/002265 51 An alternative route to compounds of the present invention carrying a piperidin-4-yl substituent in the 2-position of the thiazole ring is shown in the following scheme. Boc-N HCIH x OH N~ CN O H N xN OH\ 0 0 N N NH.R1 5 0 The Boc-protection group can be removed under standard conditions, such as treatment with TFA for 2 to 3 hours at 0* or with 4 N HCl in dioxane for 2 to 3 hours. The deprotected piperidinoderivative HCl salt can then be converted to the corresponding N 10 heterocyclic analog by various methods as described as described above. For the compounds of the formula (Ia), (Ib), (Ic), (Ih), (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 15 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), (Ih), (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 20 enatiomers and diastereomers, in pure form or as a mixture. The compounds of the formula (Ia), (Ib), (Ic), (Ih), (II), or (III) to be used according to the invention can form salts with inorganic or organic acids or bases. Examples of pharmaceutically acceptable salts comprise without limitation non-toxic inorganic or 25 organic salts such as acetate derived from acetic acid, aconitate derived from aconitic acid, WO 2007/104557 PCT/EP2007/002265 52 ascorbate derived from ascorbic acid, benzoate derived from benzoic acid, cinnamate derived from cinnamic acid, citrate derived from citric acid, embonate derived from embonic acid, enantate derived from heptanoic acid, formiate derived from formic acid, fumarate derived from fumaric acid, glutamate derived from glutamic acid, glycolate 5 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 10 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 15 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), (Ih), (II), or (III) or a pharmaceutically 20 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 compounds of the formula (Ia), (Ib), (Ic), (Ih), (II), or (III), such as the salts obtained with chiral amines. 25 The compounds of the formula (Ia), (Ib), (Ic), (Ih), (II), or (III) above also comprise the prodrugs of these compounds.The term "prodrug" as used herein refers to compounds which once administered to the patient are not pharmaceutically active themselves ('prodrugs') but which are chemically and/or biologically transformed into their 30 pharmaceutical active form (compounds of formula (Ia), (Ib), (Ic), (Ih), (II), or (III)) in vivo, i.e. in the subject to which the compound is administered. Prodrugs include, for example, compounds of the invention wherein hydroxy, amine or sulfhydryl groups are bonded to any group that, when administered to a patient, cleaves to form the hydroxy, WO 2007/104557 PCT/EP2007/002265 53 amine or sulfhydryl groups. Thus, representative examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol, sulfihydryl and amine functional groups of the compounds of the present invention. Further, in the case of carboxylic acid (-COOH), esters may be employed, such as methyl esters, ethyl esters, 5 double esters and the like. Esters may be active in their own right and/or be hydrolysable under in vivo conditions in the human body. The compounds according to the invention and medicaments prepared therewith are generally useful for the treatment of cell proliferation disorders, for the treatment or 10 prophylaxis of immunological diseases and conditions (as for instance inflammatory diseases, neuroimmunological diseases, autoimmune diseases or other). 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 15 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 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 20 (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 generation and degradation, and therapeutic modification of cell and tissue maintenance and blood cell homeostasis. 25 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, bladder, lung, esophageal, stomach, colorectal, genitourinary, gastrointestinal, skin, pancreatic, brain, uterine, colon, head and neck, cervical, and ovarian, melanoma, 30 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. The compounds according to the invention and medicaments prepared therewith are WO 2007/104557 PCT/EP2007/002265 54 particularly useful for the treatment of prostate cancer, melanoma, ovarial cancer and multiple myeloma. "Treatment" according to the present invention is intended to mean complete or partial 5 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), (lh), (II), or (III) or a pharmaceutically acceptable salt or pharmaceutically acceptable prodrugs, or a stereoisomer thereof if desired with appropriate adjuvants and 10 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 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 perniciosa), aphthae, aphthous 15 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 ulcerosa, Coeliac disease, cryoglobulinemia, dermatitis herpetiformis, dermatomyositis, insulin-dependent type I diabetes, juvenile diabetes, 20 idiopathic diabetes insipidus, insulin-dependent diabetes mellisis, autoimmune demyelinating diseases, Dupuytren's contracture, encephalomyelitis, encephalomyelitis allergica, endophthalmia phacoanaphylactica, enteritis allergica, autoimmune enteropathy syndrome, erythema nodosum leprosum, idiopathic facial paralysis, chronic fatigue syndrome, febris rheumatica, glomerulo nephritis, Goodpasture's syndrome, Graves' 25 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 30 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 WO 2007/104557 PCT/EP2007/002265 55 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 5 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. 10 The compounds according to the invention and medicaments prepared therewith are particularly useful for the treatment of autoimmune diseases and inflammatory diseases, such as rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease (in particular colitis and morbus crohn), inflammatory skin diseases (in particular neurodermitis and psoriasis) and lupus erythematosus. 15 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), (Ih), (II), or (III) or a pharmaceutically acceptable salt or pharmaceutically acceptable prodrugs, or a stereoisomer thereof. 20 The invention also provides a pharmaceutical composition comprising a compound of formula (Ia), (Ib), (Ic), (Ih), (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. 25 In a preferred embodiment, the invention relates to the use of compounds of the formula (Ia), (Ib), (Ic), (Ih), (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 30 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 WO 2007/104557 PCT/EP2007/002265 56 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 5 during, 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 10 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 15 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 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 20 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, 25 Creutzfeld-Jacob Disease, Lewy Body Dementia, amyotrophic lateral sclerosis, stroke, epilepsy, multiple sclerosis, myasthenia gravis, Huntington's Disease, Down's Syndrome, nerve deafness, 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 according to the invention and medicaments prepared therewith 30 are particularly useful for the treatment of stroke, reperfusion injury and Alzheimer's disease.
WO 2007/104557 PCT/EP2007/002265 57 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 nathocenic protozoas are preferably intracellular active parasites of the phylum Apicomplexa or Sarcomastigophora, especially Trypanosoma, Plasmodia, Leishmania, Babesia and 5 Theileria, Cryptosporidia, Sacrocystida, Amoebia, Coccidia and Trichomonadia. These active substances or corresponding drugs are especially suitable for the treatment of Malaria tropica, caused by Plasmodium 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, 10 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 15 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, Trypanosoma 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, 20 Babesia bovis, the pathogen causing European bovine Babesiosis as well as Babesiosis in 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 25 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. 30 The compounds of the present invention can further be used for the prophylaxis 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), WO 2007/104557 PCT/EP2007/002265 58 (Ib), (Ic), (Ih), (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 5 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 Infection (Blastomycosis), Boreliosis, Botulism, Brainerd Diarrhea, Brucellosis, BSE (Bovine Spongiform Encephalopathy), 10 Candidiasis, Capillariasis (Capillaria Infection), CFS (Chronic Fatigue Syndrome), Chagas Disease (American Trypanosomiasis), Chickenpox (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, 15 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 20 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), Epstein-Barr Virus Infection, Escherichia coli Infection, Foodborne Infection, Foot and mouth Disease, Fungal Dermatitis, Gastroenteritis, Group A streptococcal Disease, Group 25 B streptococcal Disease, diseases caused by staphylococcal infections (Staphylococcus aureus and other staphylococcus species), diseases caused by infections with pseudomonas 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, 30 Herpes Zoster (Shingles), HIV Infection, Human Ehrlichiosis, Human Parainfluenza Virus Infection, Influenza, Isosporiasis (Isospora Infection), Lassa Fever, Leishmaniasis, Kala azar (Kala-azar, Leishmania Infection), Leprosy, Lice (Body lice, Head lice, Pubic lice), Lyme Disease, Marburg Hemorrhagic Fever, Measles, Meningitis, Mosquito-borne WO 2007/104557 PCT/EP2007/002265 59 Diseases, Mycobacterium avium Complex (MAC) Infection, Naegleria Infection, Nosocomial Infections, Nonpathogenic Intestinal Amebae Infection. Onchocerciasis (River Blindness), Opisthorciasis (Opisthorcis Infection), Parvovirus Infection, Plague, PCP (Pneumocystis carinii Pneumonia), Polio, Q Fever, Rabies, Respiratory Syncytial Virus 5 (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, Ulcers (Peptic Ulcer Disease), Valley Fever, Vibrio parahaemolyticus Infection, Vibrio 10 vulnificus Infection, Viral Hemorrhagic Fever, Warts, Waterborne infectious Diseases, West Nile Virus Infection (West Nile Encephalitis), Whooping Cough, Yellow Fever. The compounds according to the invention and medicaments prepared therewith are particularly useful for the treatment of viral diseases, such as hepatits B, hepatitis C, influenza virus infections (in particular influenza A virus infections), AIDS (HIV 15 infections) and human papilloma virus infections. The compounds according to the invention and medicaments prepared therewith are also particularly useful for the treatment of artheriosclerosis. 20 The compounds according to the invention and medicaments prepared therewith are further particularly useful for the treatment of osteoporosis. In one embodiment, the present invention relates to the use of a compound or a composition of the present invention for the preparation of a medicament for the treatment 25 or prevention of a disease characterized by hyperproliferation of cells. In one embodiment, the present invention relates to the use of a compound or a composition of the present invention for the preparation of a medicament for the treatment or prevention of a disease resulting from ischemia and/or reperfusion injury of organs 30 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 WO 2007/104557 PCT/EP2007/002265 60 associated with diseases selected from the group comprising ischemic diseases, myocardial infarction and ischemic diseases of organs. In one embodiment, the present invention relates to the use of a compound or a 5 composition of the present invention for the preparation of a medicament for the treatment or prevention of a neurological diseases or disorders selected from the group comprising 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 deafness, and Meniere's disease. 10 The compounds of formula (Ia), (Ib), (Ic), (Ih), (II), or (III) and their pharmacologically acceptable salts can be administered to animals, 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 15 active constituent contain an effective dose of at least one compound of the formula (Ia), (Ib), (Ic), (Ih), (II), or (III) or a salt thereof, in addition to customary pharmaceutically innocuous excipients and additives. The compounds of formula (Ia), (Ib), (Ic), (Ih), (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. 20 The production of medicaments containing the compounds of formula (Ia), (Tb), (Ic), (Ih), (II), or (III) according to the invention and their application can be performed according to well-known pharmaceutical methods. 25 While the compounds of formula (Ia), (Tb), (Ic), (Ih), (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 30 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), (Ih), (II), or (III) according to the invention, or a pharmaceutically WO 2007/104557 PCT/EP2007/002265 61 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 5 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, 10 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 15 microcapsules. The compounds according to the invention, together with a conventional adjuvant, carrier, or diluent, may thus be placed into the form of medicament and unit dosages thereof. Such forms include solids, and in particular tablets, filled capsules, powder and pellet forms, and 20 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 25 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 30 following dosage forms may comprise, as the active component, either a compound of formula (Ia), (Tb), (Ic), (Ih), (II), or (III) according to the invention or a pharmaceutically acceptable salt or stereosomer thereof.
WO 2007/104557 PCT/EP2007/002265 62 For preparing a medicament from a compounds of formula (Ia), (Ib), (Ic), (Ih), (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 5 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 10 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 15 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. 20 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 25 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. 30 The compounds of formula (Ia), (Ib), (Ic), (Ih), (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 WO 2007/104557 PCT/EP2007/002265 63 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 5 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 10 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. 15 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. 20 In one embodiment of the present invention, the medicament is applied topically or systemically or via a combination of the two routes. In an especially preferred embodiment of the present invention the medicament is applied 25 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 amphiphilic emulsion system 30 (oil/water-water/oil mixed phase), a liposome, a transfersome, a paste or a powder. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with WO 2007/104557 PCT/EP2007/002265 64 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. 5 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. 10 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 15 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, 20 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. Alternatively the active ingredients may be provided in the form of a dry powder, for 25 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 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 30 inhaler. In compositions intended for administration to the respiratory tract, including intranasal compositions, the compound will generally have a small particle size for example of the WO 2007/104557 PCT/EP2007/002265 65 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 5 be employed. The pharmaceutical 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 10 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. 15 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), 20 (Ib), (Ic), (Ih), (II), or (III) or their pharmacologically acceptable salts and also other therapeutically active substances. 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 25 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 30 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 WO 2007/104557 PCT/EP2007/002265 66 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. 5 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 10 mammals, 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 15 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 20 by topical application. Preferably the concentration of an active compound or a pharmaceutically acceptable salt thereof or a physiologically functional derivative or a stereoisomer thereof within a medicament according to the invention is in the range of between 1 pmol/l and 100 mmol/l. 25 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, 30 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.
WO 2007/104557 PCT/EP2007/002265 67 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-d, 5H 5 = 2.49; CD 3 0D, 8 H = 3.31; CDCl 3 , 8H 7.26; CD 3 CN, 8H = 1.93; (CD 3
)
2 CO, 8 H = 2.05). Analytical LC/ESI-MS: 2 x Waters 600 Multisolvent Delivery System. 50 p1 sample loop. Column, Chromolith Speed ROD RP18e (Merck, Darmstadt), 50 x 4.6 mm, with 2 pm prefilter (Merck). Eluent A, H 2 0 + 0.1% HCO 2 H; eluent B, MeCN. Gradient, 5 % B to 100 % B within 5 min; flow, 3 ml/min. Waters LCZ single quadrupol mass spectrometer with 10 electrospray source. MS method, 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 X Absorbance Detector, set to 254 nm. Preparative HPLC-MS: Waters 600 -Multisolvent Delivery System with peparative pump 15 heads. 2000 pl or 5000 pl sample loop. Column, Waters X-Terra RP18, 7 pm, 19 x 150 mm with X-Terra RP18 guard cartridge 7 pm, 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 pm, 19 x 10 mm; used at flow rate 50 ml/min. Make-up solvent: MeCN - H 2 0 - HCO 2 H 80 : 20 : 0.05 (v:v:v). Eluent A, H 2 0 + 0.1% HCO 2 H; eluent B, MeCN. Different linear gradients from 5 20 - 100% eluent B, adapted to sample. Injection volume: 500 p 1 - 2000 pl 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 25 collection. Waters 996 photo diode array detector. Synthesis of 4-(Methoxy-methyl-carbamoyl)-piperidine-1-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 30 hydroxylamine hydrochloride (1.03 eq, 22.5 mmol), benzotriazol-1-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 0 C, N-(3-Dimethylaminopropyl)-N-ethylcarbodiimid hydrochloride (1.0 eq, WO 2007/104557 PCT/EP2007/002265 68 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, 5 aqueous sodium carbonate and twice with 100 ml brine, dried over MgSO 4 and filtered. The solvent was removed and the residue was purified by distillation resulting in a yield of 80%. Synthesis of 4-Formyl-piperidine-1-carboxylic acid t-butyl ester 10 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (1.0 eq, 16.4 mmol) was dissolved in 100 ml dry tetrahydrofurane under inert atmosphere. This solution 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. 15 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 MgSO 4 and filtrated. The 20 solvent was removed and the residue was purified by distillation resulting in a yield of 85% Synthesis of 4-(4-Ethoxycarbonyl-4,5-dihydro-thiazol-2-yl)-piperidine-1-carboxylic acid t-butyl ester 25 4-formyl-piperidine-1-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 30 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 MgSO 4 and filtrated. The solvent was removed and the residue was purified by silica gel chromatography using a PE/ EA 4:1 gradient. Yield: 75% WO 2007/104557 PCT/EP2007/002265 69 Synthesis of 4-(4-Ethoxycarbonyl-thiazol-2-yl)-piperidine-1-carboxylic acid t-butyl ester 4-(4-Ethoxycarbonyl-4,5-dihydro-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester 5 (1.0 eq, 8.7 mmol) was solved in 160 ml toluene under inert conditions. To this solution MnO 2 (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. 10 Yield: 30% C-terminal functionalisation 4-(4-Ethoxycarbonyl-thiazol-2-yl)-piperidine-1-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 15 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 MgSO 4 and filtered. The solvent was 20 removed and the residue was dried in vacuo. Yield 95% 4-(4-Carboxy-thiazol-2-yl)-piperidine-1-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 25 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 carbonate and 2 times with brine, dried over MgSO 4 and filtred. The solvent was removed and the residue was purified by silica gel chromatography using a DCM/MeOH 30 95:5gradient. Yield: 40-80% N-terminal functionalisation WO 2007/104557 PCT/EP2007/002265 70 The N-protected substrate was treated under inert condition with 4 M HCl/dioxane (conc. 0,03 mmol substrate in 1 mL HCl/dioxane) and was stirred for 2 h at r.t. The solvent was removed in vacuo to yield the HCl salt of the free amine without further purification. 5 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), diisopropylethylamine (2 eq) and 0-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. 10 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 MgSO 4 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% 15 General synthesis for compounds of type (III) and (II) Procedure for the synthesis of compounds of type (IIIa), (Ic), (IHa) and (IIb) 7
,
3 xlO-4 mol of the benzoic acid derivative (VI) was dissolved in 5 ml DMF and 1 eq. of Hilnig's base was added, stirring the reaction mixture for a few minutes, followed by the 20 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 temperature. Subsequently, the solvent was removed by filtration and the residue redissolved in 5 ml dioxane and treated with 0,5 ml of a IM NaOH solution. After the reaction was complete, the pH was decreased to 1-2 with a IM HCl solution and the 25 precipitated product (VII) filtered and dried in vacuo. For the next step, intermediate (VII) was dissolved in 3 ml DMF and 1 eq. of Hilnig'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. the amino component was added, stirring the mixture overnight at the same temperature. Subsequently, the solvent was removed by filtration and 30 the crude product redissolved in 10 ml ethyl acetate, washed twice with 10 ml citric acid (lM solution), 10 ml sat. NaHCO 3 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.
WO 2007/104557 PCT/EP2007/002265 71 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 Hfinig's base. Procedure for the synthesis of compounds of type (IIb, d, e, J) and (H7c, d) 5 6,3x 10 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 10 the procedure for the synthesis of compounds of type (IIIa) and (IIc). For a synthesis-protocol of type (IIIb, d, e, f and lIc, d) compounds with Z = CH, see WO 2004/058750. 15 Exemplary compounds of formula (Ia) of the present invention include, but are not limited to, the following: Cp. Name Mass LC/(+)-ESI- Biological MS: activity') 74 4-{4-[4-(3-Trifluoromethyl-phenyl)- 619 620 ++ piperazine-1 -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- 1 -carbonyl]-thiazol-2-yl} - [M+H]* piperidine-1-carboxylic acid (2,3-dihydro benzo[1,4]dioxin-6-yl)-amide 76 4- {4-[4-(3-Trifluoromethyl-phenyl)- 615 616 ++ piperazine- 1 -carbonyl]-thiazol-2-yl} - [M+H]+ piperidine-1-carboxylic acid (5-methyl-2 trifluoromethyl-furan-3-yl)-amide 77 4-{4-[4-(3-Trifluoromethyl-phenyl)- 577 578 piperazine-l-carbonyl]-thiazol-2-yl}- [M+H]* piperidine-1-carboxylic acid (2-thiophen-2 yl-ethyl)-amide 78 4-{4-[4-(3-Trifluoromethyl-phenyl)- 509 510 + WO 2007/104557 PCT/EP2007/002265 72 piperazine- 1 -carbonyl]-thiazol-2-yl} - [M+H] 1 piperidine- 1 -carboxylic acid isopropylamide 79 4- {4-[4-(3-Trifluoromethyl-phenyl)- 627 628 piperazine-1 -carbonyl]-thiazol-2-yl}- [M+H]+ piperidine-1-carboxylic acid (2 trifluoromethoxy-phenyl)-amide 80 4- {4-[4-(3-Trifluoromethyl-phenyl)- 573 574 + piperazine- 1 -carbonyl]-thiazol-2-yl} - [M+H]+ piperidine-1-carboxylic acid (3-methoxy phenyl)-amide 81 4- {4-[4-(3-Trifluoromethyl-phenyl)- 633 634 ++ piperazine-1 -carbonyl]-thiazol-2-yl} - [M+H]+ piperidine-1-carboxylic acid (3,4,5 trimethoxy-phenyl)-amide 114 4-(4-{4-[4-(3-Trifluoromethyl-phenyl)- 568 569 + piperazine- 1 -carbonyl]-thiazol-2-yl} - [M+H]+ piperidine- 1 -carbonyl)-benzonitrile 134 4- {4-[4-(3-Trifluoromethyl-phenyl)- 543 544 + piperazine- 1 -carbonyl]-thiazol-2-yl} - [M+H]+ piperidine- 1 -carboxylic acid phenylamide 142 4- {4-[4-(3-Trifluoromethyl-phenyl)- 561 562 ++ piperazine-1 -carbonyl]-thiazol-2-yl}- [M+H]+ piperidine- 1 -carboxylic acid (3-fluoro phenyl)-amide 143 4-{4-[4-(3-Trifluoromethyl-phenyl)- 561 562 + piperazine- 1 -carbonyl]-thiazol-2-yl} - [M±H]+ piperidine- 1 -carboxylic acid (4-fluoro ___phenyl)-amide_______________ 1) The biological data refer to results obtained from the NF-KB inflammation assay. ["+" stands for 50-80% inhibition, "++" means 80-90% and "+!-!i-" stands for 90-100% inhibition] Exemplary compounds of formula (Tb) of the present invention include, but are not limited 5 to, the following: Cp. NaeMass LC/(+)-ESI- Biological 103 2- {5-Methyl-2-[1 -(2-trifluoromethoxy- 640 641 + WO 2007/104557 PCT/EP2007/002265 73 benzoyl)-piperidin-4-yl]-thiazol-4-yV}-1-[4- [M+H] (3-trifluoromethyl-phenyl)-piperazin-1I-yl] ethanone 128 1-[4-(3-Chloro-phenyl)-piperazin-1-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-icB inflammation assay. ["+" stands for 50-80% inhibition, "++" means 80-90% and "+++" stands for 90-100% inhibition] Exemplary compounds of formula (Ic) of the present invention include, but are not limited 5 to, the following: Cp. Name Mass LC/(+)-ESI- Biological MS: activity') 150 [1-(5-Chloro-2-methylamino-phenyl)-3,4- 654 655 ++ dihydro-1H-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- 1 H- 495 496 + isoquinoline-2-carbonyl)-thiazol-2-yl]- [M+H]+ piperidin- 1-yl } -2-(4-fluoro-phenyl) ethanone 161 1-{4-[4-(6,7-Dimethoxy-3,4-dihydro-1H- 523 524 + isoquinoline-2-carbonyl)-thiazol-2-yl]- [M+H]+ piperidin- 1-yl} -2-(4-fluoro-phenyl) ethanone 163 1-{4-[4-(3,4-Dihydro-1H-isoquinoline-2- 463 464 + carbonyl)-thiazol-2-yl]-piperidin-1-yl}-2- [M+H]+ (4-fluoro-phenyl)-ethanone 232 1-{4-[4-(6,7-Dimethoxy-3-methyl-3,4- 537 538 + dihydro- 1 H-isoquinoline-2-carbonyl)- [M+H]* thiazol-2-yl]-piperidin-1-yl}-2-(4-fluoro phenyl)-ethanone 233 1-{4-[4-(6,7-Dihydroxy-1-methyl-3,4- 509 510 + dihydro- 1 H-isoquinoline-2-carbonyl)- [M+H]* thiazol-2-yl]-piperidin- 1-yl} -2-(4-fluoro phenyl)-ethanone WO 2007/104557 PCT/EP2007/002265 74 234 1-4-[4-(6,7-Dimethoxy-I-methyl-3,4- 537 538 + dihydro-1H-isoquinoline-2-carbonyl)- 5 M+7 5 4] thiazol-2-yl]-piperidin- 1-yl} -2-(4-fluoro phenyl)-ethanone 235 1-(4-{4-[1-(5-Chloro-2-methylamino- 602 603 + phenyl)-3,4-dihydro- 1 H-isoquinoline-2- [M+H]* carbonyl]-thiazol-2-yl} -piperidin-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] Exemplary compounds of formula (II) of the present invention include, but are not limited 5 to, the following: Cp. Name Mass LC/(+)-ESI- Biological MS: activity') 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-1- 478 479 + carbonyl)-thiazol-2-yl]-2-trifluoromethoxy- [M+H]+ benzamide 15 2-Methoxy-N-{4-[4-(3-trifluoromethyl- 490 491 ++ phenyl)-piperazine-1-carbonyl]-thiazol-2- [M+H] yl } -benzamide 16 3-Fluoro-4-trifluoromethyl-N-(1-{4-[4-(3- 643 644 ++ trifluoromethyl-phenyl)-piperazine- 1- [M+H]+ carbonyl]-thiazol-2-yl } piperidin-4 ylmethyl)-benzamide 17 3-Cyclopentyl-N-(l-{4-[4-(3- 577 578 ++ trifluoromethyl-phenyl)-piperazine- 1- [M+H]+ carbonyl]-thiazol-2-yl} -piperidin 4ylmethyl)-propionamide 18 2-Trifluoromethoxy-N-(1-{4-[4-(3- 641 642 ++ trifluoromethyl-phenyl)-piperazine- 1- [M+H]+ carbonyl]-thiazol-2-yl } -piperidin 4ylmethyl)-benzamide 19 4-Cyano-N-(1-{4-[4-(3-trifluoromethyl- 582 583 ++ WO 2007/104557 PCT/EP2007/002265 75 phenyl)-piperazine- 1 -carbonyl] -thiazol-2- [M+H] + __yI } -pipefidin-4-ylmethyl)-benzamide I 29 [4-(3-Trifluoromethyl-phenyl)-piperazi-n-1- 569 570 ++ yl] - {2-[4-(4-trifluoromethyl-phenyl)- [M+H] + piperazin- I -yl]-thiazol-4-yl}I -methanone ___ 21 f{2-[4-(4-Trifluoromethoxy-phenyl)- 585 586 + piperazin- 1 -yl]-thiazol-4-yl} -[4-(3- [M+H] + trifluoromethyl-phenyl)-piperazin- 1l-yl] methanone _______________ 22 {2-[4-(2-Trifluoromethoxy-benzyl)- 599 600 trifluoromethyl-phenyl)-piperazin- l-yl] methanone 23 {2-[4-(4-Bromo-benzyl)-piperazin-1I-yl]- 593 594 thiazol-4-yl }-[4-(3 -trifluoromethyl-phenyl)- [M+H] + piperazin- Il-yl] -methanone ______ 24 {2-[4-(3-Trifluoromethoxy-benzyl)- 599 600 trifluoromethyl-phenyl)-piperazin- Il-yl] methanone 32 2-Trifluoromethoxy-N-{14-[4-(3 - 544 545 trifluoromethyl-phenyl)-piperazine- 1 - [M+H] + ___carbonyl]-thiazol-2-yl I -benzamnide ______ 33 3-Cyclopentyl-N-{4-[4-(3-trifluoromethyl- 480 481 phenyl)-piperazine-l1-carbonyl] -thiazol-2- [M+H] + yl } -propionamide 34 3-Fluoro-4-trifluoromethyl-N- {4-[4-(3- 546 547 trifluoromethyl-phenyl)-piperazine- 1 - [M+H] + carbonyl]-thiazol-2-yl}I -benzamide 37 3-Cyclopentyl- 1-(4-14- [4-(3 - 549 550 trifluoromethyl-phenyl)-piperazine- 1 - tM+H] + carbonyl]-thiazol-2-yl I -piperazin- 1 -yl).' propan- 1 -one____________ 38 {2-[4-(2-Methoxy-benzoyl)-piperazin- 1 - 559 560 yl] -thiazol-4-yl}I -[4-(3-tnifluoromethyl- [M±H]+ phenyl)-piperazin- 1 -yl]-methanone 39 { 2-[4-(2-Trifluoromethoxy-benzoyl)- 613 614______ WO 2007/104557 PCT/EP2007/002265 76 piperazin-1-yl]-thiazol-4-yl}-[4-(3- [M+H]* trifluoromethyl-phenyl)-piperazin-1-~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- 1- 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-1- [M+H]+ carbonyl]-thiazol-2-yl}-urea 58 N-[4-(4-Benzhydryl-piperazine-1- 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)-piperazin- 1-yl] methanone 61 4-(4-{4-[4-(3-Trifluoromethyl-phenyl)- 554 555 piperazine-1 -carbonyl]-thiazol-2-yl}- [M+H]* piperazine- 1 -carbonyl)-benzonitrile 62 4-(4-{4-[4-(3-Trifluoromethyl-phenyl)- 540 541 piperazine-1-carbonyl]-thiazol-2-yl}- [M+H]+ piperazine- 1 -ylmethyl)-benzonitrile 63 4- {4-[4-(3-Trifluoromethyl-phenyl)- 525 526 ++ piperazine- 1 -carbonyl] -thiazol-2-yl } - [M+H]* piperazine-1-carboxylic acid tert-butyl ester 64 (2-Piperazin- 1 -yl-thiazol-4-yl)-[4-(3 - 425 426 + trifluoromethyl-phenyl)-piperazin- 1-yl]- [M+H]+ methanone I_1_1 65 {2-[4-(2-Methoxy-phenyl)-piperazin-1 -yl]- 531 532 ++ thiazol-4-yl} -[4-(3-trifluoromethyl-phenyl)- [M+H]+ WO 2007/104557 PCT/EP2007/002265 77 piperazin- 1 -yl]-methanone 66 -[4-4-4-4- uor mthyl-pheny- 5 544 piperazine-1-carbonyl]-thiazol-2-yl}- [M+H]* piperazin- 1 -yl)-phenyl]-ethanone 67 [4-(3-Trifluoromethyl-phenyl)-piperazin-1- 569 570 + yl]-{2-[4-(3-trifluoromethyl-phenyl)- [M+H]+ piperazin-1 -yl]-thiazol-4-yl}-methanone 68 [2-(4-Phenyl-piperazin-1-yl)-thiazol-4-yl]- 501 502 + [4-(3-trifluoromethyl-phenyl)-piperazin- 1- [M+H]+ yl]-methanone 69 {2-[4-(4-Fluoro-phenyl)-piperazin-1-yl]- 519 520 ++ thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)- [M+H]+ piperazin- 1-yl] -methanone 71 (4-Benzhydryl-piperazin-1-yl)-[2-(4- 537 538 benzyl-piperazin- 1 -yl)-thiazol-4-yl] - [M+H]* methanone 72 [2-(4-Benzyl-piperazin-1-yl)-thiazol-4-yl]- 515 516 [4-(3-trifluoromethyl-phenyl)-piperazin- 1- [M+H]+ yl]-methanone 99 3-Fluoro-4-trifluoromethyl-N-(1-{4-[4-(3- 642 643 + trifluoromethyl-phenyl)-piperazine- 1- [M+H]* carbonyl]-thiazol-2-yl} -piperidin-4 ylmethyl)-benzamide 100 3-Cyclopentyl-N-(1-{4-[4-(3- 576 577 + trifluoromethyl-phenyl)-piperazine- 1- [M+H]+ carbonyl]-thiazol-2-yl } -piperidin-4 ylmethyl)-propionamide 101 2-Trifluoromethoxy-N-(1-{4-[4-(3- 640 641 + trifluoromethyl-phenyl)-piperazine- 1- [M+H]+ carbonyl]-thiazol-2-yl} -piperidin-4 ylmethyl)-benzamide 102 4-Cyano-N-(1-{4-[4-(3-trifluoromethyl- 581 582 + phenyl)-piperazine-1-carbonyl]-thiazol-2- [M+H]+ yl } -piperidin-4-ylmethyl)-benzamide 241 {2-[1-(2,6-Dimethoxy-pyrimidin-4-yl)- 576 577 [M+H*] +4 piperidin-4-yl]-5-methoxy-oxazol-4-yl}-[4 1 (3-trifluoromethyl-phenyl)-piperazin-1 -yl] - I WO 2007/104557 PCT/EP2007/002265 78 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+] ++ piperidin-4-yl]-5-methoxy-oxazol-4-yl}-[4 (5-trifluoromethyl-benzotriazol- 1-yl) piperidin-1-yl]-methanone 244 {2-[1-(4,6-Dimethoxy-[1,3,5]triazin-2-y)- 617 618 [M+H*] ++ piperidin-4-yl]-5-methoxy-oxazol-4-yl}-[4 (5-trifluoromethyl-benzotriazol- 1-yl) piperidin-1-yl]-methanone 245 4-(4-{4-[4-(5-Trifluoromethyl-benzotriazol- 580 581 ++ 1-yl)-piperidine-1-carbonyl]-thiazol-2-yl}- [M+H]+ I 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 1) The biological data refer to results obtained from the NF-cB inflammation assay. ["+" stands for 50-80% inhibition, "++" means 80-90% and "+++" stands for 90-100% inhibition] Exemplary compounds of formula (III) of the present invention include, but are not limited 5 to, the following: Cp. Name Mass LC/(+)-ESI- Biological MS: activity 1 2-Morpholin-4-yl-thiazole-4-carboxylic 357 358 + acid (5,6-dimethyl-1H-benzoimidazol-2- [M+H]+ yl)-amide 2 2-[3-(2-Trifluoromethoxy-phenyl)-ureido]- 462 463 + thiazole-4-carboxylic acid (1H- [M+H] benzoimidazol-2-yl)-amide 4 2-(2-Fluoro-benzoylamino)-thiazole-4- 409 410 + carboxylic acid (5,6-dimethyl-1H- [M+H] benzoimidazol-2-yl)-amide 6 N-{4-[N'-(1H-Benzoimidazol-2-yl)- 441 ,442 ++ WO 2007/104557 PCT/EP2007/002265 79 guanidinocarbonyl]-thiazol-2-yl}-3,4- [M+H]* difluoro-benzamideI 7 N- {4-[N'-(l H-Benzoimidazol-2-yl)- 423 424 ++ guanidinocarbonyl]-thiazol-2-yl} -4-fluoro- [M+H]+ benzamide 8 N-{4-[N'-(lH-Benzoimidazol-2-yl)- 473 474 ++ 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 10 N-{4-[N'-(lH-Benzoimidazol-2-yl)- 483 484 ++ guanidinocarbonyl]-thiazol-2-yl} -4-bromo- [M+H]+ benzamide 11 N-{4-[N'-(lH-Benzoimidazol-2-yl)- 435 436 ++ guanidinocarbonyl]-thiazol-2-yl}-2- [M+H)* methoxy-benzamide 12 N- {4-[N'-(l H-Benzoimidazol-2-yl)- 489 490 guanidinocarbonyl]-thiazol-2-yl} -2- [M+H]+ trifluoromethoxy-benzamide 13 N-(lH-Benzoimidazol-2-yl)-N'-{2-[4-(2- 558 559 + trifluoromethoxy-benzoyl)-piperazin- 1-yl]- [M+H]+ thiazole-4-carbonyl} -guanidine 14 N-(lH-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]+ 1 IH-benzoimidazol-2-yl)-amide 26 2-(3-Fluoro-4-trifluoromethyl- 536 537 benzoylamino)-oxazole-4-carboxylic acid [M+H]* ethyl ester 27 N- {4-[N'-(lH-Benzoimidazol-2-yl)- 475 476 guanidinocarbonyl]-oxazol-2-yl}-3-fluoro- [M+H]+ 4-trifluoromethyl-benzamide 30 N-(lH-Benzoimidazol-2-yl)-N'-[2-(4- 460 461 benzyl-piperazin- 1 -yl)-thiazole-4- [M+H]+ WO 2007/104557 PCT/EP2007/002265 80 carbonyl]-guani dine _________ 31 2 2-(2-Tri flIuorom ethoxv- ben-7nvlamino)- 447 AAQ thiazole-4-carboxylic acid .(1H- [M+H] + benzoimidazol-2.-yl)-amide___ 36 N-(1 H-Benzoimidazol-2-yl)-N'-{12-[1-(2- 557 558trifluoromethoxy-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- 1H- [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-1H- [M+H] + benzoimidazol-2-yl)-amide.II 47 2-(2-Trifluoromethoxy-benzoylamino)- 553 554 thiazole-4-carboxylic acid [5-(propane- 1- [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] + guanidine 51 N- {4-[N'-(1H-Benzoimidazol-2-yl)- 473 474 guanidinocarbonyl]-thiazol-2-yl} -4- [M+H] + trifluoromethyl-benzamide___ 52 2-[1-(2-Trifluoromethoxy-benzoyl)- 621 622 piperidin-4-yl]-thiazole-4-carboxylic acid [M+H] + [5-(propane- I -sulfonyl)- 1H-benzoimidazol 2-yl]-amide 53 N- {4-[N'-(1 H-Benzoimidazol-2-yl)- 491 492 __guanidinocarbonyl]-thiazol-2-yl} -2-fluoro- __ [M±H]+ WO 2007/104557 PCT/EP2007/002265 81 4-trifluoromethyl-benzamide 54 1- {4-[N'-(l H-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]+ guanidine 250 N-(1H-Benzoimidazol-2-yl)-N'-{2-[1-(4- 484 485 ++ cyano-benzyl)-piperidin-4-yl]-thiazole-4- [M+H]+ carbonyl}-guanidine 251 N-Benzothiazol-2-yl-N'- {2-[1-(4-cyano- 501 502 ++ benzyl)-piperidin-4-yl]-thiazole-4- [M+H]+ carbonyl}-guanidine 252 N-(1 H-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-carbonyl)-guanidine [M+H]+ 255 N-(1H-Benzoimidazol-2-yl)-N'-(2- 371 372 morpholin-4-yl-thiazole-4-carbonyl)- [M+H]+ I guanidine 256 N-Benzothiazol-2-yl-N'-(2-morpholin-4-yl- 388 389 thiazole-4-carbonyl)-guanidine [M+H]+ 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+H]+ WO 2007/104557 PCT/EP2007/002265 82 259 N-(2-Morpholin-4-yl-thiazole-4-carbonyl)- 417 418 ++ N'-(5-nitro-benzooxazol-2-y)-guanidmie [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-methyl-thiazol- [M+H]+ 2-yl)-guanidine 263 N-(6-Chloro-1H-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-1H-benzoimidazol-2-yl)- 625 626 N'- {2-[1-(2-trifluoromethoxy-benzoyl)- [M+H]+ piperidin-4-yl]-thiazole-4-carbonyl} guanidine 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-phenyl)-amide 269 2-(1-Furo[2,3-c]pyridin-4-yl-piperidin-4- 548 549 yl)-thiazole-4-carboxylic acid (5-benzoyl- [M+H]+ 1H-benzoimidazol-2-yl)-amide 270 2-[1-(4,6-Dimethoxy-[1,3,5]triazin-2-yl)- 570 571 piperidin-4-yl]-thiazole-4-carboxylic acid [M+H]+ I__ 1(5-benzoyl-1H-benzoimidazol-2-yl)-amide I I I _I WO 2007/104557 PCT/EP2007/002265 83 271 2-[1-(4,6-Dimethoxy-[1,3,5]triazin-2-yl)- 501 502 piperidin-4-yl]-thiazole-4-carboxylic acid [M+H]+ I (5-fluoro-benzothiazol-2-yl)-amide 272 2-[1-(4-Cyano-benzyl)-piperidin-4-yl]- 546 547 [M+H+] ++ thiazole-4-carboxylic acid (5-benzoyl-1H 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+H*] piperidin-4-yl]-thiazole-4-carboxylic acid ++ (5-benzoyl-1H-benzoimidazol-2-yl)-amide 276 2-[1-(4-Cyano-benzyl)-piperidin-4-yl]- 486 487 [M+H]+ + thiazole-4-carboxylic acid (5-ethoxy-1H benzoimidazol-2-yl)-amide 277 2-[1-(4-Cyano-benzyl)-piperidin-4-yl]- 476 477 [M+H]+ ++ thiazole-4-carboxylic acid (5-chloro-1H benzoimidazol-2-yl)-amide 278 2-[1-(4-Cyano-benzyl)-piperidin-4-yl]- 510 511 [M+H]+ ++ thiazole-4-carboxylic acid (5,6-dichloro I 1H-benzoimidazol-2-yl)-amide 1) 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] Exemplary compounds of formula (Ih) of the present invention include, but are not limited 5 to, the following: LC/(+)-ESI- Biological MS: [M+H]+ activity 2-(1-(2,6-dimethoxypyrimidin-4 279 yl)piperidin-4-yl)-N-(6-(thiophene-3- 575 576 + carbonyl)-1H-benzo[d]imidazol-2 yl)thiazole-4-carboxamide 280 2-(1-(thieno[3,2-d]pyrimidin-4- 571 572 +++ WO 2007/104557 PCT/EP2007/002265 84 carbonyl)- IH-benzo~dlimidazol-2-1 yl)thiazole-4-carboxamide 2-(1-(4,6-dimethoxy- 1,3,5-triazin-2 21yl)piperidin-4-yl)-N-(6-(thiophene-3-5757 carbonyl)- 1 H-benzo[d]imidazol-2 yl)thiazole-4-carboxamide___ N-(6-benzoyl- 1H-benzo[d]imidazol-2-yl) 282 2-(1-(2,6-dimethoxypyrimidin-4- 569 570 yl)piperidin-4-yl)thiazole-4-carboxamide N-(5-acetylbenzo[d]thiazol-2-yl)-2-(1 283 (thieno[3 ,2-d]pyrimidin-4-yl)piperidin-4- 520 521 yl)thiazole-4-carboxamide N-(5-(3-fluoro-4 24methoxybenzoyl)benzo[d]thiazol-2-yl)-2- 6361+ (1 -(thieno[3 ,2-d]pyrimidin-4-yl)piperidin 4-yl)thiazole-4-carboxamide N-(5-(4-hydroxy-3 25methoxybenzoyl)benzo[d]thiazol-2-yl)-2- 6269+ (1 -(thieno [3 ,2-d]pyrimidin-4-yl)piperi din 4-yl)thiazole-4-carboxamide _________ N-(6-benzoyl- 1 H-benzo [d] imidazol-2-yl) 286 2-(l1 -(thiophen-2-ylsulfonyl)piperidin-4- 577 578 -H yl)thiazole-4-carboxamide N-(5-benzoyl- 1 H-benzo[d] imidazol-2-yl) 287 2-(1-(6,7-dimethoxyquinazolin-4- 619 620 . yl)piperidin-4-yl)thiazole-4-carboxamide_______ N-(5-(3 -methoxybenzoyl)benzo[d]thiazol 288 2-yl)-2-(1 -(thieno[3 ,2-d]pyrimidin-4- 612 613 + yl)piperidin-4-yl)thiazole-4-carboxamide 2-( 1-(7H-purin-6-yl)piperidin-4-yl)-N-(6 289 benzoyl-1H-benzo[d]imidazol-2- 549 550 yl)thiazole-4-carboxamide N-(6-benzoyl- 1H-benzo[d]imidazol-2-yl) 202-( 1-(2 ,6-dichloropyridin-4-6162 ylcarbamoyl)piperidin-4-yl)thiazole-4 carboxamide WO 2007/104557 PCT/EP2007/002265 85 N-(6-benzoyl-1H-benzo[d]imidazol-2-yl) 291 2-(1-(4-cyanopyridin-2-yl)piperidin-4- 533 534 + yl)thiazole-4-carboxamide N-(5-benzoyl-1H-benzo[d]imidazol-2-yl) 292 2-(1-(4,6-dimethoxy-1,3,5-triazin-2- 570 571 yl)piperidin-4-yl)thiazole-4-carboxamide N-(6-benzoyl-1 H-benzo[d]imidazol-2-yl) 293 2-(1-(thieno[3,2-d]pyrimidin-4- 565 566 ++ yl)piperidin-4-yl)thiazole-4-carboxamide N-(6-benzoyl- 1 H-benzo[d]imidazol-2-yl) 294 2-(1-(6-(trifluoromethyl)pyrimidin-4- 577 578 ++ yl)piperidin-4-yl)thiazole-4-carboxamide N-(5-benzoyl-1H-benzo[d]imidazol-2-yl) 295 2-(1-(4-cyanobenzyl)piperidin-4- 546 547 ++ yl)thiazole-4-carboxamide 2-(1-([1,2,4]triazolo[1,5-a]pyrimidin-7 296 yl)piperidin-4-yl)-N-(5-benzoyl-1H- 549 550 benzo[d]imidazol-2-yl)thiazole-4 carboxamide N-(5-benzoyl- 1H-benzo[d]imidazol-2-yl) 297 2-(1-(2-methylpyrazolo[1,5-a]pyrimidin-7- 562 563 yl)piperidin-4-yl)thiazole-4-carboxamide 4- {4-[4-(5-Benzoyl- 1 H-benzoimidazol-2 298 ylcarbamoyl)-thiazol-2-yl]-piperidin-1 -yl}- 620 621 + 5-methyl-pyrrolo[2,1-f][1,2,4]triazine-6 carboxylic acid methyl ester methyl 7-(4-(4-(5-benzoyl-1H 299 benzo[d]imidazol-2-ylcarbamoyl)thiazol-2- 607 608 ++ yl)piperidin-1-yl)-[1,2,4]triazolo[1,5 a]pyrimidine-2-carboxylate 1) The biological data refer to results obtained from the NF-KB inflammation assay. ["+" stands for an EC50 of 30-100 gM, "++" stands for an EC50 of 10-30 gM and "+++" stands for an EC50 of smaller than 10 gM.] 5 Exemplary compounds of formula (1I1a) of the present invention include, but are not limited to, the following: WO 2007/104557 PCT/EP2007/002265 86 Cp. 1 % Biological Name Mass [M+H] + activity') ____ ___ ___ ___ ___ ___([M-H]-) 300 2-(isonicotinamido)-N-(6 (methylsulfonyl)benzo[d]thiazol-2- 459 460 yl)thiazole-4-carboxamide + 301 2-cinnamamido-N-(6 (methylsulfonyl)benzo[d]thiazol-2- 484 485 ___yl)thiazole-4-carboxamide + 302 2-(furan-2-carboxamido)-N-(6 (methylsulfonyl)benzo[d]thiazol-2- 448 449 ___yl)thiazole-4-carboxamide ______+ 303 N-(5 ,6-dimethyl- 1H-benzo[d]imidazol-2 yl)-2-(ftiran-2-carboxamido)thiazole-4- 381 382 carboxamide + 304 N-(5,6-dimethyl- 1H-benzo[d]imidazol-2 yl)-2-(isonicotinamido)thiazole-4- 392 393 carboxamide + 305 2-cinnamamido-N-(5,6-dimethyl- 1H benzo[d]imidazol-2-yl)thiazole-4- .417 418 carboxamide + 306 ethyl 2-(2-(2 (trifluoromethoxy)benzarm'do)thiazole-4- 519 518 carboxamido)- 1H-benzo[d]imidazole-6- [M-H] carboxylate 307 ethyl 2-(2-(2 (trifluoromethoxy)benzamido)thiazole-4- 536 [535 carboxamido)benzo[d]thiazole-6- [-] carboxylate ++ 308 2-(2-chlorobenzamido)-N-(6-(phenylthio)- 505 1 H-benzo[d]imidazol-2-yl)thiazole-4- 506 [M-HY+ carboxamide+ 309 N-(5-benzoyl-l1H-benzo[d]imidazol-2-yl)- 500 2-(2-chlorobenzamido)thiazole-4- 501 [M-H] carboxamide + 310 ethyl 2-(2-(2-chlorobenzamido)thiazole-4- 485 carboxamido)benzo[d]thiazole-6- 48 [M-H] carboxylate+ 311 2-(2-chlorobenzamido)-N-(6-48 (trifluoromethyl)benzo[d]thiazol-2- 482 481H] I___ yl)thiazole-4-carboxamide ___ MHY++ 312 2-(2-chlorobenzamido)-N-(4- 443 methoxybenzo[d]thiazol-2-yl)thiazole-4- 444 [M-H]- _ ___carboxamideLJ _ WO 2007/104557 PCT/EP2007/002265 87 313 2-(2-chlorobenzamido)-N-(6- 427 methylbenzo[d]thiazol-2-yl)thiazole-4- 428 ru r carboxamide 428 [ JL +++ 314 2-(2-chlorobenzamido)-N-(6- 458 nitrobenzo[d]thiazol-2-yl)thiazole-4- 459 [M-H] carboxamide ++ 315 2-(2-chlorobenzamido)-N-(6- 457 ethoxybenzo[d]thiazol-2-yl)thiazole-4- 458 [M-H]~ carboxamide 316 2-(2-chlorobenzamido)-N-(6- 429 hydroxybenzo[d]thiazol-2-yl)thiazole-4- 430 [M-H]~ carboxamide ++ 317 2-(2-chlorobenzamido)-N-(6- 443 methoxybenzo[d]thiazol-2-yl)thiazole-4- 444 [M-H]~ carboxamide ++ 318 2-(2-chlorobenzamido)-N-(4- 427 methylbenzo[d]thiazol-2-yl)thiazole-4- 428 [M-H]~ carboxamide 319 2-(2-chlorobenzamido)-N-(6- 431 fluorobenzo[d]thiazol-2-yl)thiazole-4- 432 [M-H] carboxamide +++ 320 2-(2-chlorobenzamido)-N-(6- 447 chlorobenzo[d]thiazol-2-yl)thiazole-4- 448 [M-H]~ carboxamide 321 N-(6-bromobenzo[d]thiazol-2-yl)-2-(2- 492 chlorobenzamido)thiazole-4-carboxamide [M-H~ + 322 2-(2-chlorobenzamido)-N-(4- 447 chlorobenzo[d]thiazol-2-yl)thiazole-4- 448 [M-H] carboxamide +++ 323 2-(2-chlorobenzamido)-N-(5,6 dimethylbenzo[d]thiazol-2-yl)thiazole-4- 442 441 carboxamide EM-Hr 324 2-(2-chlorobenzamido)-N-(6- 497 (trifluoromethoxy)benzo[d]thiazol-2- 498 [M-H]~ yl)thiazole-4-carboxamide +++ 325 2-(2-chlorobenzamido)-N-(6 (methylsulfonyl)benzo[d]thiazol-2- 492 [M-H] yl)thiazole-4-carboxamide + 326 N-(5,6-dimethyl-1 H-benzo[d]imidazol-2 yl)-2-(l -(thiophen-2- 479 478 yl)cyclohexanecarboxamido)thiazole-4-
[M-H]
carboxamide + 327 N-(5,6-dimethyl-1H-benzo[d]imidazol-2 yl)-2-(1- 431 430 phenylcyclopropanecarboxamido)thiazole- [M-H]r _ 4-carboxamide I I + 328 N-(5,6-dimethyl-1H-benzo[d]imidazol-2- 425 424 + WO 2007/104557 PCT/EP2007/002265 88 yl)-2-(2,5-dimethylthiophene-3 - r[M-H] carboxamido)thiazole-4-carboxamide t JI______ 329 N-(5 ,6-dimethyi- 1 H-benzojd] imidazol-2 yl)-2-(tetrahydrofiiran-3- 385 386 carboxamido)thiazole-4-carboxamide ______+ 330 N-(5 ,6-dimethyl- 1 H-benzo[d] imidazol-2-46 yl)-2-(5-methyl-2-(trifluoromethyl)furan-3- 463 462H] carboxamido)thiazole-4-carboxamide [HY + 331 N-(5 ,6-dimethyl- 1 H-benzo [d]imidazol-2 (dimethylamino)acetamido)thiazole-4-3733 carboxamide + 332 N-(5 ,6-dimethyl- 1H-benzo[d] imidazol-2-47 yl)-2-(5-(morpholinomethyl)furan-2- 480 [-] carboxamido)thiazole-4-carboxamide MHf + 333 2-(2-(2-methoxybenzamido)thiazole-4-45 carboxamido)benzo[d]thiazole-6-carboxylic 454 [-] acid MH 334 2-(2-methoxybenzamido)-N-(6 (phenylthio)-l1H-benzo [d] imidazol-2- 501 502 yl)thiazole-4-carboxamide ++ 335 N-(4-(5 ,6-dimethyl- 1H-benzo[d]imidazol-48 2-ylcarbamoyl)thiazol-2-yl)thieno[2,3 - 448[MH] b~pyazin-6-carboxarm'de[MH ±± 336 N-(5 ,6-dimethyl-l1H-benzo[d] imidazol-2 yl)--(2-477 476 morpholinoisonicotinamido)thiazole-4- [M-H] carboxamide + 337 ethyl 2-(2-(2-methoxybenzamido)thiazole-48 4-carboxamido)benzo[d]thiazole-6- 482 481H] carboxylate E-H + 338 N-(5-benzoyl- 1H-benzo[d]imidazol-2-yl)- 495 2-(2-methoxybenzamido)thiazole-4- 496 [M-HY carboxamide _________ 339 2-(2-methoxybenzamido)-N-(6-49 (trifluoromethoxy)benzo[d]thiazol-2- 494 [-] yl)thiazole-4-carboxamide[MH + 340 2-(2-methoxybenzamido)-N-(6-47 (trifluoromethyl)benzo[d]thiazol-2- 478 I-] yl)thiazole-4-carboxamide___ MH + 341 2-(2-methoxybenzamido)-N-(4 methoxybenzo[d]thiazol-2-yl)thiazole-4- 440 441 ___carboxamide________ 342 2-(2-methoxybenzamido)-N-(6-42 methylbenzo[d]thiazol-2-yl)thiazole-4- 424 423H] carboxamide MH + 343 2-(2-methoxybenzamido)-N-(6- 45 454 ____nitrobenzo [d]thiazol-2-yl)thiazole-4- ____ M-Hf + WO 2007/104557 PCT/EP2007/002265 89 Imethoxyzm" 'liz'i--atoail A[- M-HY + 345 tert-butyl 4-(5 ,6-dimethyl-l1H benzo[d] imidazol-2-ylcarbamoyl)thiazol-2- 387 388 ylcarbamate + 346 N-(6-methyl- 1H-benzo[d] imidazol-2-yl)-2 (2-(trifluoromethoxy)benzamido)thiazole-4- 461 462 carboxamide ________________ 347 N-(5-ethoxy- 1H-benzo[d] imidazol-2-yl)-2 (2-(trifluoromethoxy)benzamido)thiazole-4- 491 492 carboxamide 348 N-(6-fluoro- 1H-benzo[d]imidazol-2-yl)-2 (2-(trifluoromethoxy)benzamido)thiazole-4- 465 466 carboxamide 349 N-( 1-ethyl- I H-benzo[d]imidazol-2-yl)-2 (2-(trifluoromethoxy)benzamido)thiazole-4- 475 476 carboxamide 350 N-(5 -nitro- 1 H-benzo [d] imi dazol-2-yl)-2-(2 (trifluoromethoxy)benzamido)thiazole-4- 492 493 carboxamide________ 351 N-(5-methyl-7-(trifluoromethyl) [ 1,2,4]triazolo[ 1 ,5-a]pyrimidin-2-yl)-2-(2- 531 532 (trifluoromethoxy)benzamido)thiazole-4 carboxamide+ 352 N-(6-benzoyl-1H-benzo[d]imidazol-2-yl) 2-(2-(trifluoromethoxy)benzamido)thiazole- 551 552 4-carboxamide+ 353 N-( 1-methyl-i H-benzo[d] imidazol-2-yl>-2 (2-(trifluoromethoxy)benzamido)thiazole-4- 461 462 carboxamide _______ 354 N-(6-hydroxybenzo[d]thiiazol-2-yl)-2-(2- 426 425 methoxybenzamido)thiazole-4-carboxamide [M-H] ++ 355 2-(2-methoxybenzamido)-N-(4 methylbenzo[d]thiazol-2-yl)thiazole-4- 424 425 carboxamide _______ 356 N-(6-fluorobenzo[d]thiazol-2-yl)-2-(2- 4249 methoxybenzamido)thiazole-4-carboxamide4249 357 N-(6-bromobenzo[d]thiazol-2-yl)-2-(2- 488 487 ___methoxybenzamido)thiazole-4-carboxamide [M-H] ±+ 38 N-(6-chlorobenzo[d]thiazol-2-yl)-2-(2- 4 4 359 N-(4-chlorobenzo [d]thiazol-2-yl)-2-(2-1 ___methoxybenzamido)thiazole-4-carboxamide 444 45 360 N-(5,6-dimethylbenzo[d]thiazol-2-yl)-2-(2- 438 439 _______ WO 2007/104557 PCT/EP2007/002265 90 methoxybenzamido)thiazole-4-carboxamide 361 2-(2-methoxybenzamido)-N-(6 (trifluoromethoxy)benzo[d]thiazoi-2- 494 495 yl)thiazole-4-carboxamide +++ 362 2-(2-methoxybenzamido)-N-(6 (methylsulfonyl)benzo[d]thiazol-2- 488 489 yl)thiazole-4-carboxamide 363 2-{[2-(2-Trifluoromethoxy-benzoylamino) thiazole-4-carbonyl]-amino } -benzothiazole- 536 537 6-carboxylic acid ethyl ester ++ 364 N-(6-hydroxybenzo[d]thiazol-2-yl)-2-(2 (trifluoromethoxy)benzamido)thiazole-4- 480 481 carboxamide ++ 365 N-(6-chlorobenzo[d]thiazol-2-yl)-2-(2 (trifluoromethoxy)benzamido)thiazole-4- 498 499 carboxamide ++ 366 N-(6-fluorobenzo[d]thiazol-2-yl)-2-(2 (trifluoromethoxy)benzamido)thiazole-4- 482 483 carboxamide +++ 367 N-(6-bromobenzo[d]thiazol-2-yl)-2-(2 (trifluoromethoxy)benzamido)thiazole-4- 542 543 carboxamide ++ 368 N-(7-chlorobenzo[d]thiazol-2-yl)-2-(2 (trifluoromethoxy)benzamido)thiazole-4- 498 499 carboxamide + 369 N-(6-(methylsulfonyl)benzo[d]thiazol-2 yl)-2-(2- 542 541 (trifluoromethoxy)benzamido)thiazole-4- [M-H]~ carboxamide ++ 370 N-(6-nitrobenzo[d]thiazol-2-yl)-2-(2 (trifluoromethoxy)benzamido)thiazole-4- 509 510 carboxamide + 371 N-(5-nitrobenzo[d]thiazol-2-yl)-2-(2 (trifluoromethoxy)benzamido)thiazole-4- 509 510 carboxamide + 372 N-(5-methoxybenzo[d]thiazol-2-yl)-2-(2 (trifluoromethoxy)benzamido)thiazole-4- 494 495 carboxamide + 373 N-(7-methoxybenzo[d]thiazol-2-yl)-2-(2 (trifluoromethoxy)benzamido)thiazole-4- 494 495 carboxamide + 374 N-(5-ethoxybenzo[d]thiazol-2-yl)-2-(2 (trifluoromethoxy)benzamido)thiazole-4- 508 509 carboxamide + 375 2-(2-(trifluoromethoxy)benzamido)-N-(5 (trifluoromethyl)benzo[d]thiazol-2- 532 533 yl)thiazole-4-carboxamide
+
WO 2007/104557 PCT/EP2007/002265 91 376 2-(2-(trifluoromethoxy)benzamido)-N-(5 (trifluoromethoxy)benzo[d]thiazol-2- 548 549 -1%U 1 A_1 yl)Ihiazole-4-tcarlboxamide 377 N-(5-fluorobenzo[d]thiazol-2-yl)-2-(2- 481 (trifluoromethoxy)benzamido)thiazole-4- 482 MH]~ carboxamide ____ + The biological data refer to results obtained from the NF-B inflammation assay. ["+" stands for an EC50 of 30-100 .tM, "++" stands for an EC50 of 10-30 pM and "+++" stands for an EC50 of smaller than 10 gM.] 5 Proteasome assay: The chymotryptic activity of the 20S proteasome (Immatics, Tiibingen) 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 pl of the respective inhibitor dissolved in DMSO were mixed with 50 pl substrate solution (25 mM HEPES pH 7.5 at 20*C, 0.5 mM EDTA 10 and Suc-LLVT-AMC (in the appropriate concentration) and the reaction was initiated by adding 150 pl proteasome solution (1.3 pg/mi 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 15 relative fluorescence units (RFU) per second. For the determination of the IC 50 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. 20 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 Histopaque*-1077 tubes, washed and resuspended with 106 cells/ml in Dulbecco's 25 modified eagles medium, containing 10 % fetal calf serum and 2 mM glutamine. The cells were stimulated with 2 pg/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 supernatant removed. Incorporated WO 2007/104557 PCT/EP2007/002265 92 BrdU was quantified with the help of an enzyme-linked immunosorbent assay. For the determination of the IC 50 values (concentration of inhibitor required for 50%1 inhibition)at least four different inhibitor concentrations were applied. Each data point was recorded in triplicates. Curves were fitted with the a suitable program. 5 Based on results obtained in the T-lymphocyte proliferation assay, the compounds of the present invention are suitable for treating inflammatory diseases or diseases associated with T-cells. Inhibition of NF-icB-induced inflammation: 10 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-icB-SEAP reporter cells preseeded in 96-well flat bottom plates. As the transfected reporter gene for SEAP (secreted embryonic alkaline phosphatase) is under transcriptional control of a NF-iB-responsive element, the expression of this reporter is 15 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 % CO 2 and 90 % relative humidity, the cells were incubated with 0.01 up to 100 pM of test compound for 4.5 h before stimulation with 20 2ng/ml TNF-ct. After stimulation with TNF-ax 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 via fitting function and the Microsoft Excel Solver. 25

Claims (19)

1. A compound of the general formula (Lh) or pharmaceutically acceptable salts thereof with an acid or a base, or pharmaceutically acceptable prodrugs or a 5 stereoisomer thereof, 0 Rd Z N NR 3 a R2a X3 RR3 - .. r (Ih) wherein A is NR , S or 0; 10 t is 0 to 4; r is 0, or 1; R2a is independently H, OH, SH, NH 2 , alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, alkoxy, alkylamino, hydroxyalkylamino, halogen, aryl, or heteroaryl; 15 Ra is H, OH, SH, NH 2 , -C(NR')NR"', -(CH 2 )paryl, -(CH 2 )pNR7 R, -C(O)NR7 R, -N=CR7 R, -NRC(O)R', alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, alkoxy, alkylamino, hydroxyalkylamino, halogen, aryl, or heteroaryl; Rd is H, halogen, alkyl, -C(NR 7)NR 'R', -(CH 2 )paryl, -(CH 2 )pNR 7 R', 20 C(O)NR 7 R 8 , -N=CR 7 R 8 , -NR 7 C(O)R', cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl; R' is -C(O)R a, -C(O)CHR7 R, -C(O)NR7R', -C(O)OR', -R 7 C(O)R', or -C(S)R 7 R 2 is H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, 25 hydroxyalkylamino, alkylamino, or heteroaryl, or R' and R 2 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 monocycloc or polycyclic ring system, wherein at least one or more of the WO 2007/104557 PCT/EP2007/002265 94 carbon atoms in the ring is a heteroatom selected from 0, N, and S and the ring can be substituted by one or more R Ra 3 is H, -C(O)NRaRb, halogen, alkyl, haloalkyl, aryl, heteroaryl, OH, SH, NR 4 'OR 5 ', NH 2 , hydroxyalkylamino, alkylamino, alkoxy, cycloalkyl, hetero 5 cycloalkyl, hydroxyalkyl, or haloalkyloxy; Ra is H, halogen, alkyl, -C(NR 7 )NR'R8, -(CH 2 )paryl, -(CH2)pNR7R', aryl, -C(O)NR 7R, -N=CR 7 R', -NR C(O)R8, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, or heteroaryl; Rb independently represents H, -CN, -OH, -SH, -C0 2 R 4 ', -C(O)R 4 , -SO 2 NR 4 ', 10 -NR 4 'R , -C(O)NR 7 R 8 , -S0 2 -alkyl, -S0 2 R 4 ', S0 3 R 4 ', -N=CR 4 R", NR 4 'C(O)R 4 ", -NR 4 '-CO-haloalkyl, -NO 2 , -NR 4 '-S0 2 -haloalkyl, -NR4'-SO2 alkyl, -NR 4 '-CO-alkyl, -NR 4 '(CH 2 )pheteroaryl, alkyl, cycloalkyl, alkylamino, alkoxy, alkylthio, halogen, haloalkyl, haloalkyloxy, -O(CH 2 )p[O(CH 2 )p]qOCH 3 , -C(NR 4 ")NR 4 'benzimidazolyl, -C(NR 4 ")NR 4 ' 15 benzthiazolyl, -C(NR 4 ")NR4'benzoxazolyl, hydroxyalkyl, hydroxy cycloalkyl, hydroxyalkylamino, heterocycloalkyl, aryl or heteroaryl; R4', R", R' independently are H, halogen, alkyl, -C(NR )NR7R', -(CH 2 )paryl, haloalkyl, -(CH 2 )pNR R', -C(O)NR 7 R, -N=CR R', -NR C(O)R', cycloalkyl, heterocycloalkyl, hydroxyalkyl, hydroxyalkylamino, 20 alkylamino, heteroaryl, or aryl; R 7 , R 7 ', R 8 independently are H, halogen, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, arylamino heteroaryl, or aryl; R7a is cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, heteroaryl, or 25 aryl; R 7 is H, halogen, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, heteroaryl, or aryl; X is NR , O, or S; Z is N or CR 2 '; 30 R 2 is H, alkyl, -C(O)NR 7 , -C(0)R , cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl; p is I to 6; q is I to 6; WO 2007/104557 PCT/EP2007/002265 95 R 9 independently represents H, -CN, -OH, -SH, alkoxy, alkylthio, -C0 2 R 4 ', -C(O)R 4 a, -C(O)NR 7 R 8 , -SO 2 NR 4 , -NR 4 R'. -SO 2 -alkvl, -SO 2 R4, S0 3 R 4 ', -N=CR4'R", -NR 4 'C(O)R 4 ", -NR 4 '-CO-haloalkyl, -NO 2 , -NR 4 '-SO 2 haloalkyl, -NR 4 '-SO 2 -alkyl, -NR 4 '-CO-alkyl, -NR 4 '(CH 2 )pheteroaryl, alkyl, 5 hydroxyalkyl, cycloalkyl, halogen, haloalkyl, alkylamino, -O(CH 2 )p[O(CH 2 )p]qOCH 3 , -C(NR4")NR4'benzimidazolyl, -C(NR 4 ")NR4' benzthiazolyl, -C(NR4" )NR 4 'benzoxazolyl, hydroxycycloalkyl, hydroxy alkylamino, haloalkyloxy, heterocycloalkyl, -(CH 2 )pNR 7 COR', aryl, or heteroaryl; 10 R 4 a is H, Ci-C 6 -alkyl, C 2 -C 6 -alkenyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, -C(NR 7 )NR 7 R', -(CH 2 )paryl, (CH 2 )pNR 7 R', -C(O)NR R', -N=CR R', -NR 7 C(O)R 8 , halogen, heteroaryl, or aryl; 15 wherein a CI-C 6 -alkyl group, if not stated otherwise, denotes a linear or branched C 1 -C 6 alkyl, which can optionally be substituted by one or more substituents R'; R' is independently H, -CO 2 R", -CONHR", -CR'O, -SO 2 NR', -NR"-CO haloalkyl, -NO 2 , -NR'-S0 2 -haloalkyl, -NR'-S0 2 -alkyl, -S0 2 -alkyl, -NR''-CO 20 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; 25 a C 2 -C 6 -alkenyl group, if not stated otherwise, denotes a linear or branched C 2 -C 6 - alkenyl, which can optionally be substituted by one or more substituents R'; an alkyl group, if not stated otherwise, denotes a linear or branched CI-C 6 -alkyl, a linear or branched C 2 -C 6 -alkenyl or a linear or branched C 2 -C 6 -alkynyl group, which can be substituted by one or more substituents R; R being defined as above. 30 a cycloalkyl group denotes a non-aromatic ring system containing three to eight carbon atoms, wherein one or more of the carbon atoms in the ring can be substituted by one or more substituents R'; R being defined as above; WO 2007/104557 PCT/EP2007/002265 96 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; 5 an alkoxy group denotes an O-alkyl group, the alkyl group being as defined above; an alkylthio group denotes an S-alkyl group, the alkyl group being as defined above; a haloalkyl group denotes an alkyl group which is substituted by one to five halogen atoms, the alkyl group being as defined above; 10 a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being as defined above; a haloalkyloxy group denotes an alkoxy group which is substituted by one to five halogen atoms, the alkyl group being as defined above; a hydroxyalkylamino group denotes an (HO-alkyl) 2 -N- group or HO-alkyl-NH 15 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 20 can be substituted by one or more substituents R, where R is 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- to 10-membered aromatic heterocyclic group which contains at least one heteroatom selected from 0, N, and S, wherein the 25 heterocyclic group may be fused to another ring and the heterocyclic group or the fused ring can both be substituted independently by one or more substituents R, wherein R is as defined above; with the proviso that the following compounds are excluded 0 R R2 s() WO 2007/104557 PCT/EP2007/002265 97 wherein R 1 independently represents hydrogen, alkyl. cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl or substituted arylalkyl; 5 R 2 independently represents -NR 3 R 4 , R 5 -N N--R 5 or R 3 independently represents alkyl, cycloalkyl, alkoxy, alkylamine, -OH, -SH, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl; 10 R 4 independently represents alkyl, cycloalkyl, alkoxy, alkylamine, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl; R 5 independently represents H, COR 6 , C0 2 R', SOR 6 , S0 2 R 6 , SO 3 R 6 , alkyl, cycloalkyl, alkoxy, -NH 2 , alkylamine, -NR 7 COR 6 , halogen, -OH, -SH, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl; 15 R 6 independently represents H, alkyl, cycloalkyl, -NH 2 , alkylamine, aryl or heteroaryl; R 7 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 SO 2 .
2. A compound of the general formula (Ia) or a pharmaceutically acceptable salts 25 thereof with an acid or a base, or pharmaceutically acceptable prodrugs or a stereoisomer thereof, Y N R2 RI- -X-N R Z Rc (la) WO 2007/104557 PCT/EP2007/002265 98 R is independently hydrogen, akyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, or heteroaryl; R1 is independently alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, 5 aryl, or heteroaryl; X is CO, CS or SO 2 ; Y is CO, CS or SO 2 ; Z is NR 2 , S, or 0; R2 is H, alkyl, -C(O)NR 7 , -C(O)Re, cycloalkyl, haloalkyl, hydroxyalkyl, 10 hydroxyalkylamino, alkylamino, heteroaryl, or aryl; Rc is independently H, OH, SH, NROR', NH 2 , alkylamino, hydroxyalkylamino, halogen, CONRdR, alkoxy, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, or heteroaryl; Rd is H, halogen, alkyl, -C(NR 7 )NR 7 'R', -(CH 2 )paryl, -(CH 2 )pNR 7 R', 15 C(O)NR 7 R', -N=CR 7 R', -NR 7 C(O)R', cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl; R , R 7 ' independently represent H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl; R 8 is H, NH 2 , alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, 20 alkylamino, heteroaryl or aryl; Re independently represents H, -CN, -OH, -SH, -CO 2 R 4 , -C(O)R 4 ', -SO 2 NR 4 , -NR 4 R , -C(O)NR 7 R 8 , -SO 2 -alkyl, -S0 2 R 4 ', S0 3 R 4 , -N=CR 4 R 5 , NR4'C(O)R 4 ", -NR 4 '-CO-haloalkyl, -NO 2 , -NR 4 '-S0 2 -haloalkyl, -NR4'-SO 2 alkyl, -NR4'-CO-alkyl, -NR 4 '(CH 2 )pheteroaryl, alkyl, hydroxyalkyl, 25 cycloalkyl, alkylamino, aryl hydroxyalkylamino, alkoxy, alkylthio, -O(CH2)p[O(CH2)p]qOCH3, -C(NR 4 ")NR 4 ' benzimidazolyl, -C(NR 4 ")NR4' benzthiazolyl, -C(NR4")NR 4 'benz-oxazolyl, or heteroaryl; R 4 ', R 4 ", R 5 independently represent H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, -C(NR 7 )NR 7 R', -(CH 2 )paryl, 30 (CH 2 )pNR 7 R', -C(O)NR 7 R', -N=CR 7 R', -NR 7 C(O)R 8 , halogen, heteroaryl, or aryl p is I to 6; q is I to 6; WO 2007/104557 PCT/EP2007/002265 99 R2 is independently R 5 - -N N- R 5 or R5 is independently H, COR 6 , CO 2 R 6 , SOR 6 , SO 2 R 6 , SO 3 R 6 , alkyl, cycloalkyl, alkoxy, -NH 2 , alkylamine, -NR 7 COR 6 , halogen, -OH, -SH, alkylthio, 5 hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl; R6 is independently H, alkyl, cycloalkyl, amino, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, aryl or heteroaryl; wherein 10 an alkyl group, if not stated otherwise, denotes a linear or branched C 1 -C 6 -alkyl, a linear or branched C 2 -C 6 -alkenyl or a linear or branched C 2 -C 6 -alkynyl group, which can be substituted by one or more substituents R', R', being defined as above. R' is independently H, -CO 2 R", -CONHR", -CR''O, -SO 2 NR", -NR''-CO haloalkyl, -NO 2 , -NR''-S0 2 -haloalkyl, -NR''-S0 2 -alkyl, -S0 2 -alkyl, -NR''-CO 15 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; 20 a cycloalkyl group denotes a non-aromatic ring system containing three 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, SO 2 , N, or NR", R" being as defined above; an alkoxy group denotes an O-alkyl group, the alkyl group being as defined above; 25 an alkylthio group denotes an S-alkyl group, the alkyl group being as defined above; a haloalkyl group denotes an alkyl group which is substituted by one to five halogen atoms, the alkyl group being as defined above; a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being as defined 30 above; WO 2007/104557 PCT/EP2007/002265 100 a haloalkyloxy group denotes an alkoxy group which is substituted by one to five halogen atoms, the alkyl group being as defined above; a hydroxyalkylamino group denotes an (HO-alkyl) 2 -N- group or HO-alkyl-NH group, the alkyl group being as defined above; 5 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; 10 a heteroaryl group denotes a 5- to 10-membered aromatic heterocyclic group which contains at least one heteroatom selected from 0, N, and S, wherein the heterocyclic group may be fused to another ring and the heterocyclic group or the fused ring can both be substituted independently by one or more substituents R', wherein R' is as defined above. 15
3. A compound 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 R N X R z 20 Rc (Ib) wherein RI is -C(O)R 7 , -C(O)CHR 7 R 8 , -C(O)NRR', -C(O)OR 7 , -R 7 C(O)R 8 , or -C(S)R'; 25 R 9 independently represents H, -CN, -OH, -SH, -CO 2 R 4 , -C(O)R 4 , -SO 2 NR4' -NR 4 R , -C(O)NR 7 R , -S0 2 -alkyl, -SO 2 R 4 ', SO 3 R 4 ', -N=CR 4 R 5 , NR4'C(O)R4", -NR4'-CO-haloalkyl, -NO 2 , -NR4'-SO 2 -haloalkyl, -NR 4 '-SO 2 alkyl, -NR 4 '-CO-alkyl, -NR4'(CH 2 )pheteroaryl, heteroaryl, hydroxyalkyl, WO 2007/104557 PCT/EP2007/002265 101 cycloalkyl, alkylamino, aryl hydroxyalkylamino, alkoxy, alkylthio, -O(CH 2 )p[O(CH 2 )p]qOCH 3 , -C(NR4")NR4'benzimidazoly 4")NR4' benzthiazolyl, -C(NR 4 ")NR 4 'benzoxazolyl, -(CH 2 )pNR 7 COR', or alkyl R4 is H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, 5 alkylamino, heteroaryl, or aryl; or R' and R 4 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, wherein at least one ring atom is a heteroatom selected from 0, N, and S, and the ring optionally has one or more 10 substituents R; X is N, or CR2; Y is CO, CS or SO 2 ; Z is NR2", S, or 0; R 2 " is H, alkyl, -C(O)NR 7 , -C(O)R*, cycloalkyl, haloalkyl, hydroxyalkyl, 15 hydroxyalkylamino, alkylamino, heteroaryl, or aryl; R2 is H, alkyl, -C(O)N R4', -C(O) R4', cycloalkyl, haloalkyl, hydroxyalkyl, hydroxy-alkylamino, alkylamino, heteroaryl, or aryl; R 4 ', R 4 ", R 5 independently represent H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, -C(NR 7 )NR 7 'R', -(CH 2 )paryl, 20 (CH 2 )pNRR', -C(O)NR R', -N=CR R8, -NR 7 C(O)R 8 , halogen, heteroaryl, or aryl; p is I to 6; q is 1 to 6; R a is independently H, OH, SH, NH 2 , alkyl, cycloalkyl, hydroxyalkyl, 25 haloalkyl, haloalkyloxy, alkoxy, alkylamino, hydroxyalkylamino, halogen, aryl, or heteroaryl; R is independently H, OH, SH, NH 2 , alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, alkoxy, alkylamino, hydroxyalkylamino, halogen, aryl, or heteroaryl; 30 Rc is independently H, OH, SH, NR 4 'OR 5 , NH 2 , alkylamino, hydroxyalkylamino, halogen, CONRd R, alkoxy, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, or heteroaryl; WO 2007/104557 PCT/EP2007/002265 102 Rd is H, halogen, alkyl, -C(NR7 )NR 'R', -(CH 2 )paryl, -(CH 2 )pNR 7 R', C(O)NR R', -N=CR7 R, -NR 7 C(O)R'. cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl; R, R7' independently represent H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, 5 hydroxyalkylamino, alkylamino, heteroaryl or aryl; R is H, NH 2 , alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl; Re independently represents H, -CN, -OH, -SH, -CO 2 R 4 ', -C(O)R 4 , -SO 2 NR 4 , -NR 4 R", -C(O)NR 7 R', -S0 2 -alkyl, -SO 2 R 4 ', SO 3 R 4 , -N=CR 4 R", 10 NR 4 'C(O)R 4 ", -NR 4 '-CO-haloalkyl, -NO 2 , -NR 4 '-S0 2 -haloalkyl, -NR 4 '-SO 2 alkyl, -NR 4 '-CO-alkyl, -NR 4 '(CH 2 )pheteroaryl, alkyl, hydroxyalkyl, cycloalkyl, alkylamino, hydroxy-alkylamino, alkoxy, alkylthio, -O(CH 2 )p[O(CH 2 )p]qOCH3, -C(NR 4 ")NR 4 'benz-imidazolyl, -C(NR 4 ")NR 4 ' benzthiazolyl, -C(NR 4 ")NR 4 benzoxazolyl, aryl or heteroaryl; 15 R2 is independently N A-R 5 In A is N, O, or CR; R 5 is independently H, SOR 7 , S0 2 R 7 , S0 3 R 7 , -C(O)R, -C(O)CHR 7 R', C(O)NR R8, -C(O)OR', -R 7 C(O)R', -C(S)R', -C(NR )NR'R', -(CH 2 )paryl, 20 -(CH 2 )pNR 7 R 8 , -C(O)NR7R', -N=CR R, -NR 7 C(O)R', alkyl, cycloalkyl, alkoxy, -NH 2 , alkylamino, hydroxyalkylamino, halogen, -OH, -SH, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl; n is 0 to 2; 25 wherein an alkyl group, if not stated otherwise, denotes a linear or branched Ci-C 6 -alkyl, a linear or branched C 2 -C 6 -alkenyl or a linear or branched C 2 -C 6 -alkynyl group, which can be substituted by one or more substituents R'; R' being defined as above; R' is independently H, -CO 2 R", -CONHR", -CR''O, -SO 2 NR', -NR''-CO 30 haloalkyl, -NO 2 , -NR''-S0 2 -haloalkyl, -NR''-S0 2 -alkyl, -SO 2 -alkyl, -NR''-CO- WO 2007/104557 PCT/EP2007/002265 103 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 5 heteroaryl; a cycloalkyl group denotes a non-aromatic ring system containing three 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, SO 2 , N, or NR', R" being as defined above; 10 an alkoxy group denotes an O-alkyl group, the alkyl group being as defined above; an alkylthio group denotes an S-alkyl group, the alkyl group being as defined above; a haloalkyl group denotes an alkyl group which is substituted by one to five halogen atoms, the alkyl group being as defined above; 15 a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being as defined above; a haloalkyloxy group denotes an alkoxy group which is substituted by one to five halogen atoms, the alkyl group being as defined above; a hydroxyalkylamino group denotes an (HO-alkyl) 2 -N- group or HO-alkyl-NH 20 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 25 can be substituted by one or more substituents R', where R' is as defined above; a heteroaryl group denotes a 5- to 10-membered aromatic heterocyclic group which contains at least one heteroatom selected from 0, N, and S, wherein the heterocyclic group may be fused to another ring and the heterocyclic group or the fused ring can both be substituted independently by one or more substituents R', 30 wherein R' is as defined above. WO 2007/104557 PCT/EP2007/002265 104
4. A compound of the general formula (Ic) or pharmaceutically acceptable salts thereof with an acid or a base, or pharmaceutically acceptable prodnis or a stereoisomer thereof, N Y N R1[ 0 X N Z RcR3 (Ic) 5 wherein R 1 independently represents H, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, halo alkyloxy, aryl, or heteroaryl; X is CO, CS or S02; 10 Y is CO, CS or SO 2 ; Z is NR 2 ", S, or 0; R 2 " is H, alkyl, -C(O)NR 7 , -C(O)Re, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl; R 4 , R 4 ", R" independently represent H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, 15 hydroxyalkylamino, alkylamino, -C(NR 7 )NR 7 R', -(CH 2 )paryl, (CH 2 )pNR 7 R', -C(O)NR 7 R', -N=CR 7 R, -NR 7 C(O)R 8 , halogen, heteroaryl, or aryl; p is 1 to 6; q is 1 to 6; 20 m is 0 to 4; r is 0, or 1; t is 0, or 1; s is 0, or 1; Rb is independently H, OH, SH, NR 4 'OR', NH 2 , alkylamino, 25 hydroxyalkylamino, halogen, CONRd R, alkoxy, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, or heteroaryl; WO 2007/104557 PCT/EP2007/002265 105 R is independently H, OH, SH, NR 4 'OR", NH 2 , alkylamino, hydroxyalkylamino, halogen, CONRdR, alkoxv, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, or heteroaryl; Rd is H, halogen, alkyl, -C(NR )NR 'R', -(CH 2 )paryl, -(CH 2 )pNR R', 5 -C(O)NR R', -N=CR R', -NR 7 C(O)R , cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl; R , R7' independently represent H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl; R 8 is H, NH 2 , alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, 10 alkylamino, heteroaryl or aryl; Re independently represents H, -CN, -OH, -SH, -C0 2 R 4 ', -C(O)R 4 ', -SO 2 NR 4 ', -NR 4 R 5 ', -C(O)NR 7 R , -S0 2 -alkyl, -S0 2 R 4 , SO 3 R 4 ', -N=CR 4 R 5 , NR 4 'C(O)R 4 ", -NR 4 '-CO-haloalkyl, -NO 2 , -NR 4 '-S0 2 -haloalkyl, -NR4'-SO 2 alkyl, -NR 4'-CO-alkyl, -NR 4 (CH 2 )pheteroaryl, alkyl, hydroxyalkyl, 15 cycloalkyl, alkylamino, . hydroxyalkyl-amino, alkoxy, alkylthio, -O(CH 2 )p[O(CH2)p]qOCH3, -C(NR 4 ")NR 4 'benzimidazolyl, -C(NR 4 ")NR 4 ' benzthiazolyl, -C(NR 4 ")NR4'benz-oxazolyl, aryl or heteroaryl; R 3 is independently H, OH, SH, NR 4 'OR 5 , NH 2 , hydroxyalkylamino, d e alkylamino, halogen, CONR Re, alkoxy, alkyl, cycloalkyl, hydroxyalkyl, 20 haloalkyl, haloalkyloxy, aryl, or heteroaryl; wherein an alkyl group, if not stated otherwise, denotes a linear or branched Ci-C 6 -alkyl, a linear or branched C 2 -C 6 -alkenyl or a linear or branched C 2 -C 6 -alkynyl group, which 25 can be substituted by one or more substituents R'; R' being defined as above; R' is independently H, -CO 2 R', -CONHR", -CR''0, -SO 2 NR", -NR''-CO haloalkyl, -NO 2 , -NR''-S0 2 -haloalkyl, -NR''-SO 2 -alkyl, -S0 2 -alkyl, -NR''-CO alkyl, -CN, alkyl, cycloalkyl, alkylamino, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl, or 30 heteroaryl; R' is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, or heteroaryl; WO 2007/104557 PCT/EP2007/002265 106 a cycloalkyl group denotes a non-aromatic ring system containing three 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, S02, N, or NR', R" being as defined above; 5 an alkoxy group denotes an O-alkyl group, the alkyl group being as defined above; an alkylthio group denotes an S-alkyl group, the alkyl group being as defined above; a haloalkyl group denotes an alkyl group which is substituted by one to five halogen atoms, the alkyl group being as defined above; 10 a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being as defined above; a haloalkyloxy group denotes an alkoxy group which is substituted by one to five halogen atoms, the alkyl group being as defined above; a hydroxyalkylamino group denotes an (HO-alkyl) 2 -N- group or HO-alkyl-NH 15 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 20 can be substituted by one or more substituents R', where R' is as defined above; a heteroaryl group denotes a 5- to 10-membered aromatic heterocyclic group which contains at least one heteroatom selected from 0, N, and S, wherein the heterocyclic group may be fused to another ring and the heterocyclic group or the fused ring can both be substituted independently by one or more substituents R', 25 wherein R' is as defined above.
5. The compound according to any one of claims I to 4 for the use as a medicament.
6. A composition containing a compound according to any one of claims 1 to 4 and a 30 pharmaceutically acceptable carrier or diluent. WO 2007/104557 PCT/EP2007/002265 107
7. The compound according to any one of claims 1 to 4 or the composition of claim 6 for the treatment or prevention of a disease characterized by hyperproliferation of cells. 5
8. The compound according to any of claims 1 to 4 or the composition of claim 6 for the treatment or prevention of a disease 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 10 comprising infarctions such as myocardial infarction and critical limb ischemia, and/or wherein the endothelial dysfunction is associated with diseases selected from the group comprising ischemic diseases, myocardial infarction and ischemic diseases of organs. 15
9. The compound according to any of claims 1 to 4 or the composition of claim 6 for the treatment or prevention of a neurological diseases or disorders selected from the group comprising 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, 20 nerve deafness, and Meniere's disease.
10. The compound or composition according to claim 7, wherein the disease is selected from the group consisting of psoriasis, atopic dermatitis, alopecia areata, alopecia totalis, alopecia subtotalis, alopecia universalis, alopecia diffusa, lupus 25 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, 30 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 WO 2007/104557 PCT/EP2007/002265 108 skin, drug exanthema, purpura chronica progressiva, dihidrotic ekzema, Ekzema, fixed drug exanthema, photoallergic skin reaction, lichen simplex eriorale, dermatitis and "Graft versus Host-Disease", acne, rosacea, scarring, keloids, vitiligo, actinic keratoses, hyperkeratoses like epidermolytic hyperkeratosis, 5 Hyperkeratosis Lenticularis Perstans, Keratosis pilaris and Ichthyoses.
11. The compound or composition according to claim 7, wherein the disease is selected from the group consisting of hematological or solid tumors. 10
12. The compound or composition according to claim 11, wherein the disease is selected from the group consisting of prostate cancer, melanoma, ovarial cancer and multiple myeloma.
13. The compound according to any of claims 1 to 4 or the composition according to 15 claim 6 for the treatment or prevention of an autoimmune disease or an inflammatory disease.
14. The compound or composition according to claim 13, wherein the disease is rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, inflammatory 20 skin diseases or lupus erythematosus.
15. The compound according to any of claims 1 to 4 or the composition according to claim 6 for the treatment or prevention of stroke, reperfusion injury and Alzheimer's disease. 25
16. The compound according to any of claims 1 to 4 or the composition according to claim 6 for the treatment or prevention of a viral disease.
17. The compound or composition according to claim 16, wherein the viral disease is 30 hepatits B, hepatitis C, influenza virus infections, AIDS (HIV infections) and human papilloma virus infections. WO 2007/104557 PCT/EP2007/002265 109
18. The compound according to any of claims 1 to 4 or the composition according to claim 6 for the treatment or prevention of artheriosclerosis.
19. The compound according to any of claims 1 to 4 or the composition according to 5 claim 6 for the treatment or prevention of osteoporosis.
AU2007224659A 2006-03-15 2007-03-14 Novel heterocyclic NF-KB inhibitors Abandoned AU2007224659A1 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US11/375,259 2006-03-15
US11/375,259 US7601745B2 (en) 2004-09-27 2006-03-15 Heterocyclic NF-kB inhibitors
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