NZ588971A

NZ588971A - Novel heterocyclic NF-kappaB inhibitors

Info

Publication number: NZ588971A
Application number: NZ588971A
Authority: NZ
Inventors: Johann Leban; Harald Schmitt; Kristina Wolf; Stefano Pegoraro; Andreas Wuzik
Original assignee: 4Sc Discovery Gmbh
Priority date: 2005-07-29
Filing date: 2006-03-15
Publication date: 2012-06-29
Also published as: KR20080031038A; WO2007016979A3; EA200800175A1; UA97348C2; EA016300B1; NZ565470A; SG172738A1; CA2617225A1; BRPI0614188A2; CN101233119A; WO2007016979A2; IL189112A0; NO20081056L; AU2006278998A1; JP2009502816A

Abstract

Disclosed is a carboxy amide substituted compound of formula (III) where the substituents are as disclosed it the specification. The compounds are useful as NF-kappaB inhibitors. Also disclosed is a composition comprising a compound of formula (III) and the use of a compound of formula (III) in the manufacture of a medicament for treating diseases characterized by hyperproliferation of cells such as epilepsy, stroke and Alzheimer's diseases. Examples of compounds are: 2-[3-(2-Trifluoromethoxy-phenyl)-ureido]-thiazole-4-carboxylic acid; 2-(2-Trifluoromethoxy-benzoylarnino)-thiazole-4-carboxylic acid (4-dimethylamino-[1,3,5]triazin-2-yl)-amide and 1-{ 4-[N'-(1H-Benzoimidazol-2-yl)-guanidinocarbonyl]-thiazol-2-yl} -3-(2-trifluoromethoxy-phenyl)-urea.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 588971 58 8 9 71 Patents Form No. 5 *10059251452* N.Z. No. Divided out of Application No. 565470 NEW ZEALAND Patents Act 1953 COMPLETE SPECIFICATION NOVEL HETEROCYCLIC NF-kB INHIBITORS We, 4SC AG, a German company of Am BGopferspitz 19a, 82152 Martinsried, GERMANY do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: - (Followed by 1A) 1A Novel heterocyclic NF-kB Inhibitors This is a divisional application of NZ 565470. Field of the invention The present invention relates to compounds of the general formula (la), (lb), (Ic), (II), or 5 (HI) or a stereoisomer thereof or possible pharmaceutically acceptable salts thereof with an acid or a base, or pharmaceutically acceptable prodrugs of these compounds, for use as a medicament. The compounds of the invention are exceptionally useful for the treatment of diseases associated with abnormal and hyperproliferation of cells in mammals, especially in humans. In particular, they are useful for the treatment of diseases characterized by a 10 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 further processes for the preparation of these compounds, and to their use. 15 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. 20 This immune response can also be the consequence of an organ transplant. Evidence suggests a prime role of T-cell reactivity in autoimmune diseases. Measuring proliferative responses in T-lymphocytes is a widely used assay to measure immune competence (Killestein, J. et al. J. Neuroimmunol. 133,217-24,2002). 25 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). Peripheral blood mononuclear cells (PBMCs) were isolated from human blood obtained from volunteer donators. PBMCs were isolated by centrifugation in ACCUSPIN tubes using HISTOPAQUE. 30 PBMCs were stimulated with PHA and cell proliferation was measured with a Roche colorimetric BromUridin incorporation ELISA kit. 2 Regulation of the immune response is controlled by a variety of signalling pathways such as T-cell or TNF receptor signalling (Chen, G. et al. Science 296, 1634-1635, 2002). To further characterize targets of compounds which we found active in the T-cell proliferation assay, we tested the compounds on their ability to inhibit the human proteasome. 5 The major neutral proteolytic activity in the cytosol and nucleus is the proteasome, a 20S (700 kDa) particle with multiple peptidase activities. The continual turnover of cellular proteins by the ubiquitin-proteasome pathway is used by the immune system to screen for the presence of abnormal intracellular proteins (Dantuma, N.P. et al. Nat. Biotechnol. 10 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 hcB-a. In order to be targeted for degradation by the proteasome, IKB-a must first undergo selective phosphorylation at serine residues 32 and 36, followed by ubiquitinylation (Chen, ZJ. et al.Cell 84, 853-862, 15 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 IxB-a degradation and NF-kB activation (Traeckner et al. EMBOJ. 13, 5433,1994). 20 Patents describing proteasome inhibitors have 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 an eucariotic transcription factor of the rel family, which is located in the cyctoplasm in an inactive complex, as a homo- or heterodimer. Predominantly it exists as a heterodimer composed of p50 and p65 subunits, bound to inhibitory proteins of the IkB family, usually IkB-cc (D. Thanos et al, Cell 80, 529,1995). 30 NF-kB is activated in response to different stimuli, among which inflammatory cytokines, UV radiation, phorbol esters, bacterial and viral infections. Stimulation triggers the release of NF-kB from IkB in consequence of the phosphorylation and the following degradation of the IicB-a protein (P.A. Baeuerle et al., Annu. Rev. Immunol. 12, 141, 1995) by the proteasome. Once it is set free, NF-kB translocates in the nucleus where it binds to the DNA at specific 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 cyclooxigenase 2 (S. Grimm et al., J Biochem 290, 297, 1993). Accordingly, NF-kB is considered an early mediator of the immune and inflammatory responses and it is involved in the control of cell proliferation and in the pathogenesis of various human diseases, such as rheumatoid arthritis (H. Beker et al., Clin. Exp. Immunol. 99,325,1995), ischemia (A. Salminen et al., Biochem. Biophys. Res. Comm. 212, 939, 1995), arteriosclerosis (A.S. Baldwin, Annals Rev. Immunol 212, 649,1996), as well as in the pathogenesis of AIDS. Inhibition of NF-kB mediated gene transcription can be accomplished through inhibition of phosphorylation of the inhibitory protein IkB, inhibition of IkB degradation, inhibition of NF-kB (p50/p65) nuclear translocation, the inhibition of NF-kB-DNA binding or NF-kb-mediated DNA transcription (J.C. Epinat et al., Oncogene 18,6896,1999). The present invention relates to compounds of the general formula (la) or a pharmaceutically acceptable salts thereof with an acid or a base, or pharmaceutically acceptable prodrugs or a stereoisomer thereof, wherein R is independently hydrogen, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, or heteroaryl; R1 is independently alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, or heteroaryl; X is CO, CS or SO2; Y is CO, CS or S02; z is NR2, S, or 0; 4 R2 is H, alkyl, -C(0)NR7, -C(0)Re, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl; 5 Rc is independently H, OH, SH, NROR1, NH2, alkylamino, hydroxyalkylamino, halogen, CONRdRe, alkoxy, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, or heteroaryl; 10 Rd is H, halogen, alkyl, -C(NR7)NRrR8, -(CH2)paryl, -(CH2)PNR7R8, -C(0)NR7R8, -N=CR7R8, -NR7C(0)R8, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl; R7, R7 independently represent H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl; A 15 R is H, NH2, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl; Re independently represents H, -CN, -OH, -SH, -CO2R4, -C(0)R4, -SO2NR4, -NR4'R5', -C(0)NR7R8, -S02-alkyl, -S02R4', SO3R4', -N=CR4R5', -NR4 C(0)R4 , 20 -NR4 -CO-haloalkyl, -N02, -NR4'-S02-haloalkyl, -NR4'-S02-alkyl, -NR4'-CO-alkyl, -NR4 (CH2)pheteroaryl, alkyl, hydroxyalkyl, cycloalkyl, alkylamino, aryl hydroxyalkylamino, alkoxy, alkylthio, -0(CH2)p[0(CH2)p]q0CH3, -C(NR4 )NR4 -benzimidazolyl, -C(NR4 )NR4 benzthiazolyl, -C(NR4 )NR4 benz-oxazolyl, or heteroaryl; 25 R4,R4 ,R5 independently represent H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, -C(NR7)NR7 R8, -(CH2)paryl, -CH2)PNR7R8, -C(0)NR7R8, -N=CR7R8, -NR7C(0)R8, halogen, heteroaryl, or aryl p is 1 to 6; q is 1 to 6; 30 R2 is independently R5 5 R6 an alkyl group, if not stated otherwise, denotes a linear or branched Ci-Cs-alkyl, preferably a linear or branched chain of one to five carbon atoms, a linear or branched C2-C6-alkenyl 10 or a linear or branched C2-C6—alkinyl group, which can optionally be substituted by one or more substituents R"; the Ci-Cs-alkyl, C2-C6-alkenyl and C2-C$-alkinyl residue may be selected from the group comprising -CH3, -C2H5, -CH=CH2, -C=CH, -C3H7, -CH(CH3)2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -C=C-CH3, -CH2-C=CH, -C4H9, -CH2-CH(CH3>2, 15 -CH(CH3)-C2H5, -C(CH3)3, -C5H„, -C6H13, -C(R' )3, -c2(r:)5, -CH2-C(R^)3, -C3(R>, -C2H4-C(R^)3, -C2tl4-CH=CH2, -CH=CH-C2H5, -CH=C(CH3)2, -CH2-CH=CH-CH3, -CH=CH-CH=CH2, -C2H4-C=CH, -OC-C2H5, -CH2-C=C-CH3, -C=C-CH=CH2, -CH=CH-C=CH, -C=C-C=CH, -C2H4-CH(CH3)2, -CH(CH3)-C3H7, -CH2-CH(CH3)-C2H5, -CH(CH3)-CH(CH3)2, -C(CH3)2-C2H55 -CH2-C(CH3)3, -C3H6-CH=CH2, 20 -CH-CH-C3H7, -C2H4-CH=CH-CH3, -CH2-CH=CH-C2H5, -CH2-CH=CH-CH=CH2, -CH=CH-CH=CH-CH3j -CH=CH-CH2-CH=CH2, -C(CH3)=CH-CH=CH2} -CH=C(CH3)-CH=CH2, -CH=CH-C(CH3)=CH2, -CH2-CH=C(CH3)2, C(CH3)=C(CH3)2, -C3H6-CsCH5 -C=C-C3H7, -C2H4-C=C-CH3, -CH2-C=C-C2H5, -CH2-C=C-CH=CH2, -CH2-CH=CH-C=CH, -CH2-C=C-C=CH5 -C=C-CH=CH-CH3, -CH=CH-OC-CH3, 25 -C=C-OC-CH3, -OC-CH2-CH=CH2, -CH=CH-CH2-C=CH, -OC-CH2-OCH, -C(CH3)=CH-CH=CH2, -CH=C(CH3)-CH=CH2, -CH=CH-C(CH3)=CH2, -C(CH3)=CH-OCH, -CH=C(CH3)-OCH, -C=C-C(CH3)=CH2, -C3H6-CH(CH3)2, -C2H4-CH(CH3)-C2H5, -CH(CH3)-C4H9, -CH2-CH(CH3)-C3H7, -CH(CH3)-CH2-CH(CH3)2, -CH(CH3)-CH(CH3)-C2H5, -CH2-CH(CH3)-CH(CH3)2, -CH2-C(CH3)2-C2H5, -C(CH3)2-C3H7, -30 C(CH3)2-CH(CH3)2, -C2H4-C(CH3)3, -CH(CH3)-C(CH3)3, -C4H8-CENCH2, -CH=CH-C4H9, -C3H6-CH=CH-CH3, -CH2-CH=CH-C3H7, -C2H4-CH-CH-C2H5, -CH2-C(CH3)=C(CH3)2, -C2H4-CH=C(CH3)2, -C4H8-OCH, -OC-C4H9, -C3H6-OC-CH3, -CH2-C=C-C3H7, -C2H4-C=C-C2H5; I . s /-\ . —n ) r5 -l-n n r5 is independently H, COR6, C02R6, SOR6, S02R6, S03R6, alkyl, cycloalkyl, alkoxy, -NH2, alkylamine, -NR7COR6, halogen, -OH, -SH, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl; is independently H, alkyl, cycloalkyl, amino, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, aryl or heteroaryl; 6 IT is independently H, -C02R", -CONHR", -CR"0, -S02NR", -NR"-CO-haloalkyl, -N02, -NR"-S02-haloalkyl, -NR"-S02-alkyl, -S02-alkyl, -NR"-CO-alkyl, -CN, alkyl, cycloalkyl, alkylamino, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl, or heteroaryl; 5 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 E, E being O, S, SO, S02, N, or NR", R" being as defined above; the Cj-Cg-cycloalkyl residue may be selected from the group comprising -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -cyclo-C6Hn, -cyclo-C7Hi3, -cyclo-CgHis, morpholine-4-yl, piperazinyl, l-alkylpiperazine-4-yl; 15 an alkoxy group denotes an O-alkyl group, the alkyl group being as defined above; the alkoxy group is preferably a methoxy, ethoxy, isopropoxy, f-butoxy or pentoxy group; an alkylthio group denotes an S-alkyl group, the alkyl group being as defined above; 20 an haloalkyl group denotes an alkyl group which is substituted by one to five halogen atoms, the alkyl group being as defined above; the haloalkyl group is preferably a -C(R10)3, -CRI0(Rl0)2, -CRI0(R10')R10", -C2(R10)5, -CH2-C(R10)3, —CH2—CR10(Ri0')2, -CH2-CR10(R10')R10", -C3(R10)7, or -C2H4-C(R10)3, wherein R10, R10', R10" represent F, CI, Br or I, preferably F; 25 ' a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being as defined above; an haloalkyloxy group denotes an alkoxy group which is substituted by one to five halogen atoms, the alkyl group being as defined above; the haloalkyloxy group is preferably a 30 -OC(R10)3, -OCR10(R10')2, -OCR10(R10,)R10", -OC2(R10)5, -OCH2-C(R10)3, -OCH2-CR10(R10')2, -OCH2-CRI0(R10')R10", -OC3(R10)7 or -OC2H4-C(R10)3, wherein R10, R10', R10 represent F, CI, Br or I, preferably F; 35 a hydroxyalkylamino group denotes an (HO-alkyl)2-N- group or HO-alkyl-NH- group, the alkyl group being as defined above; > 7 " 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; 5 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-QHU— R\ -m-CeHU— R\ —p-C6H4-R", 1-naphthyl, 2-naphthyl, 1-anthracenyl or 2-anthracenyl; 10 a heteroaryl group denotes a 5- or 6-membered heterocyclic group which contains at least one heteroatom selected from O, N, and S. This heterocyclic group can be fused to another aromatic ring. For example, this group can be selected from a thiadiazole, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, oxazol-2-yl, 15 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, l,2,4-oxadiazol-3-yl, l,2,4-oxadiazol-5-yl, l,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl, l,2,4-thiadiazol-3-yl, l,2,4-thiadiazol-5-yl, isotliiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, benzoisothiazol-3-yl, benzoisothiazol-4-yl, 20 benzoisothiazol-5-yl, l,2,5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl, l,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-pyriniidinyl, 4-pyriinidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2,4-dimethoxy-6-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl, 4-25 pyrazolyl, l,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, l,2,4-triazol73-yl, l,2,4-triazol-5-yl, 1,3,5-triazol-6-yl, 2,4-dimethoxy-l,3,5-triazol-6-yl, l/f-tetrazol-2-yl, li7-tetrazol-3-yl, tetrazolyl, acridyl, furazane, indazolyl, phenazinyl, carbazolyl, phenoxazinyl, indolizine, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, l-isoindolyl, 3-isoindolyl, 4-isoindolyl, 5-isoindolyl, 6-isoindolyl, 7-isoindolyl, 2-indolinyl, 3-indolinyl, 4-indolinyl, 5-indolinyl, 6-30 indolinyl, 7-indolinyl, benzo[b]furanyl, benzofurazane, benzothiofiirazane, benzotriazol-1-yl, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl, benzotriazol-7-yl, benzotriazine, benzo[b]thiophenyl, benzimidazol-2-yl, lH-benzimidazolyl, benzimidazol-4-yl, benzamidazol-5-yl, benzimidazol-6-yl, benzimidazol-7-yl, benzothiazolyl, quinazolinyl, quinoxazolinyl, cinnoline, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydro-35 isoquinolinyl,purine, phtlialazine, pteridine, thiatetraazaindene, thiatriazaindene, isothiazolopyrazine, isothiazolopyriinidine, pyrazolotriazihe, pyrazolopyrimidine, tetra-hydrothieno[3,4-d]imidazol-2-one, pyrazolo[5,1-c][1,2,4]triazine, 2,3-dihydrobenzo[l,4]- 8 dioxin-2-yl, 2,3-dihydrobenzo[ 1,4]-dioxin-3-yl, 2,3-dihydrobenzo[1,4]-dioxin-5-yl, 2,3-dihydrobenzo[l,4]-dioxin-6-yl, 2,6-dimethoxypyriirudin-3-yl, 2,6-dimethoxypyiimidiii-4-yl, imidazopyridazine, imidazopyrimidine, imidazopyridine, imidazolotriazine, triazolotriazine, triazolopyridine, triazolopyrazine, triazolopyrimidine, or 4-[1,2,4]triazolo[4,3-a]pyridin-3-yl, l-furo[2,3-c]pyridin-4-yl, l-furo[2,3-c]pyridiii-5-yl, 1-furo[2,3-c]pyridin-3-yl, and triazolopyridazine group. This heterocyclic group can be substituted by one or more substituents R\ wherein R" is as defined above. The present invention relates to compounds of the general formula (lb) or pharmaceutically acceptable salts thereof with an acid or a base, or pharmaceutically acceptable prodrugs or a stereoisomer thereof, R1 is -C(0)R7, -C(0)CHR7R8, -C(0)NR7R8, -C(0)0R7, -R7C(0)R8, or -C(S)R7; R9 independently represents H, -CN, -OH, -SH, -CO2R4, -C(0)R4, -SO2NR4, -NR4'R5', -C(0)NR7R8, -S02-alkyl, -S02R4', S03R4', -N=CR4R5>, -NR4C(0)R4", -NR4-CO-haloalkyl, -NOa, -NR4'-S02-haloalkyl, -NR4>-S02-all<yl, -NR4'-CO-alkyl, -NR4 (CH2)pheteroaryl, alkyl, hydroxyalkyl, cycloalkyl, alkylamino, aryl hydroxyalkylamino, alkoxy, alkylthio, -0(CH2)p[0(CH2)p]q0CH3, -C(NR4")NR4'-benzimidazolyl, -C(NR4 )NR4 benzthiazolyl, -C(NR4 )NR4 benzoxazolyl, -(CH2)pNR7COR8, or heteroaryl; R4 is H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, aryl, or R1 and R4 together with the X to which they are attached form a 3 to 8 membered saturated or at least partially unsaturated monocyclic or polycyclic ring system, wherein 9 wherein at least one ring atom is a heteroatom selected from O, N, and S, and the ring optionally has one or more substituents R9; X is N, or CR2; 5 Y is CO, CS or S02; Z is NR2 , S, or O; R2 is H, alkyl, -C(0)NR7, -C(0)Re, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl; 10 R2' is H, alkyl, -C(0)N R4, -C(O) R4, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl; R4, R4 , R5 independently represent H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, -C(NR7)NRrR8, -(CH2)paryl, -CH2)PNR7R8, -C(0)NR7R8, -N=CR7R8, -NR7C(0)R8, halogen, heteroaryl, or aryl is 1 to 6; is 1 to 6; is independently H, OH, SH, NH2, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, alkoxy, alkylamino, hydroxyalkylamino, halogen, aryl, or heteroaryl; is independently H, OH, SH, NH2, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, alkoxy, alkylamino, hydroxyalkylamino, halogen, aryl, or heteroaryl; is independently H, OH, SH, NR4 OR5, NH2, alkylamino, hydroxyalkylamino, halogen, CONRdRe, alkoxy, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, or heteroaryl; is H, halogen, alkyl, -C(NR7)NR7 R8, -(CH2)paryl, -(CH2)PNR7R8, -C(0)NR7R8, -N=CR7R8, -NR7C(0)R8, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl; R7, R7 independently represent H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, 30 hydroxyalkylamino, alkylamino, heteroaryl or aryl; R8 is H, NH2, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl; 15 p q Ra 20 Rb Rc 25 Rd 10 10 Re independently represents H, -CN, -OH, -SH, -C02R4', -C(0)R4', -S02NR4', -NR4'R5', -C(0)NR7R8, -S02-alkyl, -S02R4', S03R4', -N=CR4R5', -NR4C(0)R4", -NR4-CO-haloalkyl, -N02, -NR4-S02-haloalkyl, -NR4'-S02-alkyl, -NR4'-CO-alkyl, -NR4 (CH2)pheteroaryl, alkyl, hydroxyalkyl, cycloalkyl, alkylaxnino, hydroxyalkylamino, alkoxy, alkylthio, -0(CH2)p[0(CH2)p]q0CH3, -C(NR4")NR4'benz-imidazolyl, -C(NR4 )NR4 benzthiazolyl, -C(NR4 )NR4 benzoxazolyl, aryl or heteroaryl; R2 is independently /"A a -n a r5 w t J n A isN, O, or CR2'; R5 is independently H, SOR7, S02R7, SO3R7, -C(0)R7, -C(0)CHR7R8, -C(0)NR7R8, -C(0)0R7, -R7C(0)R8, -C(S)R7, -C(NR7)NR7'R8, -(CH2)paryl, -(CH2)pNR7R8, -C(0)NR7R8, -N=CR7R8, -NR7C(0)R7', alkyl, cycloalkyl, alkoxy, -NH2, alkylamino, 15 hydroxyalkylamino, halogen, -OH, -SH, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl; n is 0 to2; wherein 20 an alkyl group, if not stated otherwise, denotes a linear or branched Ci-C6-alkyl, preferably a linear or branched chain of one to five carbon atoms, a linear or branched C^-Ce-alkenyl or a linear or branched C2-C6-alkinyl group, which can optionally be substituted by one or more substituents R"; the Ci-C6-alkyl, Cz-Q-alkenyl and C2-Ce~alkinyl residue may be selected from the group 25 comprising -CH3, -C2H5, -CH=CH2, -C=CH, -C3H7, -CH(CH3)2, -CHr-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -C=C-CH3, -CH2-CsCH, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -C5HH, -C6H13, -C(R^)3, -C2(R>, -CH2-C(R% -C3(R% -C2H4-C(R^)3, -C2H4-CH=CH2, -CH=CH-C2H5, -CH=C(CH3)2, -CH2-CH=CH-CH3, -CH=CH-CH=CH2, -C2H4-C=CH, -OC-C2H5, -CH2-C=C-CH3, -OC-CH=CH2, 30 -CH=CH-C=CH, -C=C-C=CH, -C2H4-CH(CH3)2, -CH(CH3)-C3H7, -CH2-CH(CH3>-C2H5, -CH(CH3)-CH(CH3)2, -C(CH3)2-C2H5, -CH2-C(CH3)3, -C3H6-CH=CH2, -CH=CH-C3H7, -C2H4-CH=CH-CH3, -CH2-CH=CH-C2H5, -CHr-CH=CH-CH=CH2, 11 -ch=ch-ch=ch-ch3, -ch=ch-ch2-ch=ch2, -c(CH3)=ch-ch=ch2, -ch=c(ch3>-ch=ch2, -ch=ch-c(ch3)=ch2, -ch2-ch=c(ch3)2, c(ch3)=c(ch3)2, -c3h6-c=ch, -c=c-c3h7, -c2H4-c=c-ch3, -ch2-OC-C2H5j -ch2-oc-ch=ch2, -ch2-ch=ch-och, -ch2-oc-och, -c=c-ch=ch-ch3, -ch=ch-oc-ch3, 5 -C=C-0=C-CH3, -OC-CH2-CH=CH2, -CH=CH-CH2-OCH, -OC-CH2-OCH, -C(CH3)=CH-CH=CH2> -CH=C(CH3)-CH=CH2, -CH=CH-C(CH3)=CH25 -C(CH3)=CH-C=CH, -CH=C(CH3)-C=CH, -OC-C(CH3)=CH2, -C3H6-CH(CH3)2, -C2H4-CH(CH3>-C2Hs, -CH(CH3)-C4H9> -CH2-CH(CH3)-C3H7, -CH(CH3)-CH2-CH(CH3)2, -CH(CH3)-CH(CH3)-C2H5, -CH2~CH(CH3)-CH(CH3)2, -CHr-C(CH3)2-C2H5, -C(CH3)2-C3H7, -10 C(CH3)2-CH(CH3)2, -C2H4-C(CH3)3, -€H(CH3)-C(CH3)3, -C4Hg-CH=CH2, -CH=CH-C4H9, -C3H6-CH=CH-CH3, -CH2-CH=CH-C3H7, -C2H4-CH=CH-C2H5, -CH2-C(CH3)=C(CH3)2, -C2H4-CH=C(CH3)2, -C4Hr-CsCH, -OC-C4H9, -C3H6-C=C-CH3, -CHz-C=C-C3H7, -C2H4-OC-C2H5; 15 IT is independently H, -C02R", -CONHR", -CR"0, -S02NR", -NR"-CO-haloalkyl, -N02, -NR"-S02-haloalkyl, -NR"-S02-alkyl, -S02-alkyl, -NR"-CO-alkyl, -CN, alkyl, cycloalkyl, alkylamino, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl, or heteroaryl; 20 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 ling can be substituted by a group E, E being O, S, SO, S02, N, or NR", R" being as 25 defined above; the Cs-Cs-cycloalkyl residue may be selected from the group comprising -cyclo-CsHs, -cyclo-C4H7, -cyclo-CsHp, -cyclo-CeHn, -cyclo-C7Hi3, -cyclo-CgHis, morpholine-4-yl, piperazinyl, l-alkylpiperazine-4-yl; an alkoxy group denotes an O-alkyl group, the alkyl group being as defined above; the 30 alkoxy group is preferably a methoxy, ethoxy, isopropoxy, £-butoxy or pentoxy group; an alkylthio group denotes an S-alkyl group, the alkyl group being as defined above; an haloalkyl group denotes an alkyl group which is substituted by one to five halogen 35 atoms, the alkyl group being as defined above; the haloalkyl group is preferably a -C(R10)3, -CR10(R10')2, -CR10(R10)R10", -C2(R10)5, -CH2-C(R10)3, -CH2-CR10(R10')2, -CH2- 12 CR10(R10')R10", -C3(R10)7> or -C2H4~C(R10)3, wherein R10, R10>, R10" represent F, CI, Br or I, preferably F; ; a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being as defined above; 5 an haloalkyloxy group denotes an alkoxy group which is substituted by one to five halogen atoms, the alkyl group being as defined above; the haloalkyloxy group is preferably a -OC(R10)3, -OCR10(R10')2, -OCR10(R10')Rlf)", -OC2(R10)5, -OCH2-C(Ri0)3, -OCH2-cr10(r1°')25 _ocH2-CR10(R10 )R10 , -OC3(R10)7 or -OC2H4-C(R10)3, wherein R10, R10', 10 R10 represent F, CI, 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; 15 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; 20 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, -0-C6H4- R\ -m-CeHU- R\ —p-CgJLj— R\ 1-naphthyl, 2-naphthyl, 1-anthracenyl or 2-anthracenyl; 25 a heteroaryl group denotes a 5- or 6-membered heterocyclic group which contains at least one heteroatom selected from O, N, and S. This heterocyclic group can be fused to another aromatic ring. For example, this group can be selected from a thiadiazole, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isooxazol-3-yl, isooxazol-4-yl, isooxazol-5-yl, benzooxazol-2-yl, 30 benzooxazol-4-yl, benzooxazol-5-yl, benzoisooxazol-3-yl, benzoisooxazol-4-yl, benzoisooxazol-5-yl, l,2,4-oxadiazol-3-yl, l,2,4-oxadiazol-5-yl, l,2,5-oxadiazol-3-yl, l,2,5-oxadiazol-4-yl, l,2,4-thiadiazol-3-yl, l,2,4-thiadiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, benzoisothiazol-3-yl, benzoisothiazol-4-yl, benzoisothiazol-5-yl, l,2,5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl, l,2,5-thiadiazol-4-35 yl, 4-imidazolyl, benzoimidazol-4-yl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3-fiiranyl, 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- I 13 pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, l,2,3-triazol-4-yl, l,2,3-triazol-5-yl, l,2,4-triazol-3-yl, l,2,4-triazol-5-yl, 1,3,5-triazol-6-yl, 2,4-dimethoxy-l,3,5-triazol-6-yl, lif-tetrazol-2-yl, l/f-tetrazol-3-yl, tetrazolyl, acridyl, forazane, 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[b3furany^ benzofurazane, benzothiofurazane, benzotriazol-1-yl, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl, benzotriazol-7-yl, benzotriazine, benzo[b]thiophenyl, benzimidazol-2-yl, lH-benzimidazolyl, benzimidazol-4-yl, benz-imidazol-5-yl, benzimidazol-6-yl, benzimidazol-7-yl, benzothiazolyl, quinazolinyl, quinoxazolinyl, cinnoline, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydro-isoquinolinyl,purine, phthalazine, pteridine, thiatetraazaindene, thiatriazaindene, iso-thiazolopyrazine, isothiazolopyrimidine, pyrazolotriazine, pyrazolopyrimidine, tetrahydro-thieno[3,4-d]imidazol-2-one, pyrazolo[5,1-c][1,2,4]triazine, imidazopyridazine, imidazo-pyrimidine, imidazopyridine, imidazolotriazine, triazolotriazine, 2,3-dihydrobenzo[l,4]-dioxin-2-yl, 2,3-dihydrobenzo[l,4]-dioxin-3-yl, 2,3-dihydrobenzo[l,4]-dioxin-5-yl, 2,3-dihydrobenzo[l,4]-dioxin-6-yl, 2,6-dimethoxypyrimidin-3-yl, 2,6-dimethoxypyrimidin-4-yl, triazolopyridine, triazolopyrazine, triazolopyrimidine, 4-[l,2,4]triazolo[4,3-a]pyridin-3-yl, l-furo[2,3-c]pyridin-4-yl, l-furo[2,3-c]pyridin-5-yl, l-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 (Ic) or pharmaceutically acceptable salts thereof with an acid or a base, or pharmaceutically acceptable prodrugs or a stereoisomer thereof, do) m wherein 14 independently represents H, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, or heteroaryl; X isCO,CSorS02; 5 Y is CO, CS or S02; Z is NR2 , S, or O; R2 is H, alkyl, -C(0)NR7, -C(0)Re, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl; 10 R4, R4 , R5 independently represent H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, -C(NR7)NRrR8, -(CH2)paryl, -(CH2)PNR7R8, -C(0)NR7R8, -N=CR7R8, -NR7C(0)R8, halogen, heteroaryl, or aryl p is 1 to 6; 15 q is 1 to 6; m is 0 to 4; r is 0, or 1; t isO, orl; s is 0, or 1; 20 Rb is independently H, OH, SH, NR4 OR5, NH2, alkylamino, hydroxyalkylamino, halogen, CONRdRe, alkoxy, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, or heteroaryl; R° is independently H, OH, SH, NR4OR5', NH2, alkylamino, hydroxyalkylamino, 25 halogen, CONRdRe, alkoxy, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, or heteroaryl; Rd is H, halogen, alkyl, -C(NR7)NR7R8, -(CH2)paiyl, -(CH2)PNR7R8, -C(0)NR7R8, -N=CR7R8, -NR7C(0)R8, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl; 30 R7, R7 independently represent H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl; R8 is H, NH2, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl; 15 Re independently represents H, -CN, -OH, -SH, -C02R4', -C(0)R4', -S02NR4', -NR4R5', -C(0)NR7R8, -S02-alkyl, -S02R4', S03R4>, -N=CR4R5, -NR4'C(0)R4", -NR4-CO-haloalkyl, -N02, -NR4'-S02-haloalkyl, -NR4'-S02-alkyl, -NR4'-CO-alkyl, 5 -NR4 (CH2)plieteroaryl, alkyl, hydroxyalkyl, cycloalkyl, alkylamino, hydroxyalkyl amino, alkoxy, alkylthio, -0(CH2)p[0(CH2)p]q0CH3, -C(NR4")NR4benz-imidazolyl, -C(NR4 )NR4 benzthiazolyl, -C(NR4 )NR4 benz-oxazolyl, aryl or heteroaryl; R3 is independently H, OH, SH, NR4 OR5, NH2, hydroxyalkylamino, alkylamino, 10 halogen, CONRdRe, alkoxy, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, or heteroaryl; an alkyl group, if not stated otherwise, denotes a linear or branched Ci-Cg-alkyl, preferably a linear or branched chain of one to five carbon atoms, a linear or branched Qr-Cg-alkenyl 15 or a linear or branched C2-C6-alkinyl group, which can optionally be substituted by one or more substituents R"; the Ci-Cg-alkyl, Cr-Ce-alkenyl and C2-<V-alkinyl residue may be selected from the group comprising -CH3, -C2H5, -CH=CH2, -C^CH, -C3H7, -CH(CH3)2, -CH2-CH==CH2, -C(CH3)=CH2, -CH=CH-CH3, -C=C-CH3, -CH2-C=CH, -C4H9, -CH2-CH(CH3)2, 20 -CH(CH3)-C2H5, -C(CH3)3, -C5Hu, -C6H13, -C(RX )3, -C2(R)5, -CH2-C(R")3, -C3(R>, -C2H4-C(R^)3, -C2H4-CH=CH2, -CH=CH-C2Hs, -CH=C(CH3)2, -CH2-CH=CH-CH3, -CH=CH-CH=CH2, -C2H4~C=CH, -OC-C2H5, -CH2-C=C-CH3, -OC-CH=CH2, —CH=CH-C=CH, ~C=C-C^CH, -C2H4-CH(CH3)2, -CH(CH3)-C3H7, -CH2-CH(CH3>-C2Hs, -CH(CH3)-CH(CH3)2, -C(CH3)2-C2H5j -CH2-C(CH3)3, -C3H6-CH=CH2, 25 -ch=ch-c3h7, -c2H4-ch=ch-ch3, -ch^-ch=ch-c2h5, -ch2-ch=ch-ch=ch2, -CH=CH-CH=CH-CH3, -CH=CH-CH2-CH=CH2, -C(CH3)=CH-CH=CH2, -CH=C(CH3)-CH=CH2, -CH=CH-C(CH3)==CH2, -CH2-CH=C(CH3)2, C(CH3)=C(CH3)2, -C3H6-C^CH, -C=C-C3H7, -C2H4-C^C-CH3, -CH2-C^C-C2H5, -CH2-OC-CH=CH2, -CH2-CH=CH-OCH, -CH2-C=C-C=CH, -OC-CH=CH-CH3, -CH=CH-OC-CH3, 30 -C^C-OC-CH3, -C=C-CH2-CH=CH2, -CH=CH-CH2-CsCH, -C^C-CHz-C^CH, -C(CH3)=CH-CH=CH2, -CH=C(CH3)-CH=CH2, -CH=CH-C(CH3)=CH2, -C(CH3)=CH-OCH, -CH=C(CH3)-CsCH, -OC-C(CH3)=CH2, -C3Hr-CH(CH3)2, -C2H4-CH(CH3>-C2H5, -CH(CH3)-C4H9, -CH2-CH(CH3)-C3H7, -CH(CH3)-CH2-CH(CH3)2, -CH(CH3)-CH(CH3)-C2H5, -CH2-CH(CH3)-CH(CH3)2, -CH2-C(CH3)2-C2H5, -C(CH3)x-C3H7, -35 C(CH3)2-CH(CH3)2, -C2H4-C(CH3)3, -CH(CH3)-C(CH3)3, -C4HH3H=CH2> -CH=CH- 16 C4H9, -C3H6-CH=CH-CH3, -€H2-CH=CH-C3H7, -C2H4-CH=CH-C2H5, -CH2-C(CH3)=C(CH3)2, -C2H4-CH=C(CH3)2, -C4H8-OCH, -CHO-C4H9, -CsEfe-OC-CHs, -CH2-C=C-C3H7, -C2Hr-OC-C2H5; 5 R" is independently H, -C02R", -CONHR", -CR"0, -S02NR", -NR"-CO-haloalkyl, -N02, -NR"-S02-haloalkyl, -NR"-S02-alkyl, -S02-alkyl, -NR"-CO-alkyl, -CN, alkyl, cycloalkyl, alkylamino, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl, or heteroaryl; 10 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 O, S, SO, S02, N, or NR", R" being as 15 defined above; the C3-C&-cycloalkyl residue may be selected from the group comprising -cyclo-C3H5, -cyclo-C4H7, -cyclo-CsHg, -cyclo-CgHn, -cyclo-C7Hi3, -cyclo-CgH^, morpholine-4-yl, piperazinyl, l-alkylpiperazine-4-yl; an alkoxy group denotes an O-alkyl group, the alkyl group being as defined above; the 20 alkoxy group is preferably a methoxy, ethoxy, isopropoxy, f-butoxy or pentoxy group; an alkylthio group denotes an S-alkyl group, the alkyl group being as defined above; an haloalkyl group denotes an alkyl group which is substituted by one to five halogen 25 atoms, the alkyl group being as defined above; the haloalkyl group is preferably a -C(R10)3, -CR10(R10')2, -CR10(R10')R10", -C2(R10)5, -CH2-C(R10)3, -CH2-CR10(Ri0')2, -CH2-CR10(R10 )R10 , -C3(R10)7, or -C2H4-C(R10)3, wherein R10, R10', R10" represent F, CI, Br or I, preferably F; 30 a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being as defined above; an haloalkyloxy group denotes an alkoxy group which is substituted by one to five halogen atoms, the alkyl group being as defined above; the haloalkyloxy group is preferably a -OC(R10)3, -OCR10(R10')2, -OCR10(R10,)R10", -OC2(R10)5, -OCH2-C(R10)3, -OCH2-35 CR10(R10,)2, -OCH2-CR10(R10,)R10", -OC3(Rio)7 or -OC2H4-C(R10)3) wherein R10, R10', R10 represent F, CI, Br or I, preferably F; 17 a hydroxyalkylamino group denotes an (HO-alkyl)2-N- group or HO-alkyl-NH- group, the alkyl group being as defined above; an alkylamino group denotes an HN-alkyl or N-dialkyl group, the alkyl group being as 5 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 10 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, -0-C6H4- R\ -m-C&HLr- R\ -p-CgH4-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 15 one heteroatom selected from O, N, and S. This heterocyclic group can be fused to another aromatic ring. For example, this group can be selected from a thiadiazole, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isotbiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isooxazol-3-yl, isooxazol-4-yl, isooxazol-5-yl. benzooxazol-2-yl, benzooxazol-4-yl, benzooxazol-5-yl, benzoisooxazol-3-yl, benzoisooxazol-4-yl, 20 benzoisooxazol-5-yl, l,2,4-oxadiazol-3-yI, l,2,4-oxadiazol-5-yl, l,2,5-oxadiazol-3-yl, l,2,5-oxadiazol-4-yl, l,2,4-thiadiazol-3-yl, l,2,4-thiadiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, benzoisothiazol-3-yl, benzoisothiazol-4-yl, benzoisothiazol-5-yl, l,2,5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl, l,2,5-thiadiazol-4~ yl, 4-imidazolyl, benzoimidazol-4-yl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3-25 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, l,2,3-triazol-4-yl, l,2,3-triazol-5-yl, l,2.4-triazol-3-yl, l,2,4-triazol-5-yl, 1,3,5-triazol-6-yl, 2,4-dimethoxy-l,3,5-triazol-6-yl, lif-tetrazol-2-yl, l/7-tetrazol-3-yl, tetrazolyl, 30 acridyl, furazane, indazolyl, phenazinyl, carbazolyl, phenoxazinyl, indolizine, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 1-isoindolyl, 3-isomdolyl, 4-isoindolyl, 5-isoindolyl, 6-isoindolyl, 7-isoindolyl, 2-indolinyl, 3-indolinyl, 4-indolinyl, 5-indolinyl, 6-indolinyl, 7-indolinyl, benzo[b]furanyl, benzofiirazane, benzothiofurazane, benzotiiazol-1-yl, beiizotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl. benzotriazol-7-yl, benzotriazine, 35 benzo[b]thiophenyl, benzimidazol-2-yl, lH-benzimidazolyl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl, benzimidazol-7-yl, benzothiazolyl, quinazolinyl, quinoxazolinyl, cinnoline, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydro- RECEIVED at IPONZ on 30 January 2012 18 thieno[3,4-d]imidazol-2-one, pyrazolo [5,1 -c] [ 1,2,4]triazine, tetrahydroisoquinolinyl, purine, phthalazine, pteridine, thiatetraazaindene, thiatriazaindene, isothiazolopyrazine, isothiazolopyrimidine, pyrazolotriazine, pyrazolopyrimidine, iroidazopyridazine, imidazo-pyrimidine, imidazopyridine, imidazolotriazine, triazolotriazine, triazolopyridine, triazolo-5 pyrazine, triazolopyrimidine, 2,3-dihydrobenzo[l,4]-dioxin-2-yl, 2,3-dihydrobenzo[l,4J-dioxin-3-yl, 2,3-dihydrobenzo[l,4]-dioxin-5-yl, 2,3-dihydrobenzo[l,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, l-furo[2,3-c]pyridin-4-yl, 1 -faro[2,3-cjpyridin-5-y 1, l-furo[2,3-c]pyridin-3-yl, and triazolopyridazine group. This heterocyclic group can be substituted by one or more 10 substituents R\ wherein R" is as defined above. The compounds of formulae (Ia)-(Ic) are described herein for completeness. However the present invention specifically relates to compounds of the general formula (III) or pharmaceutically acceptable salts thereof with an acid or a base, or pharmaceutically acceptable prodrugs or a stereoisomer thereof, 15 r2 (III) wherein R1 is -C(0)R7a, -C(0)CHR7R8, -C(0)NR7R8, -C(0)0R7, -R7C(0)R8, or -C(S)R7b; R is H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, 1 o 20 or R and R 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 O, N, and S, and the ring can be substituted by one or more R9' R4a is H, Ci-C6-alkyl, C2-C<s-aIkenyl, cycloalkyl, haloalkyl, hydroxyalkyl, 25 hydroxyalkylamino, alkylamino, -C(NR7)NR7 R8, -(CH2)paryl, -(CH2)pNR7R8, -C(0)NR7R8, -N=CR7R8, -NR7C(0)R8, halogen, heteroaryl, or aryl; 19 R3 is H, -C(0)NRaRb, halogen, alkyl, haloalkyl, aryl, heteroaryl, OH, SH, NR4'OR5', NH2, hydroxyaJOkylamino, alkylamino, alkoxy, cycloalkyl, heterocycloalkyl, hydroxyalkyl, or haloalkyloxy; R4 is H, OH, SH, NH2, alkoxy, haloalkyloxy, halogen, alkyl, -C(NR7)NRrR8, -(CH2)paryl, -(CH2)pNR7R8, -C(0)NR7R8, -N=CR7R8, -NR7C(0)R8, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaiyl, or aryl; R5 is halogen, alkyl, -C(NR7)NRrR8, -(CH2)paryl, -(CH2)PNR7R8, -C(0)NR7R8, -N-CR7R8, -NR7C(0)R8, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl; Ra is H, halogen, alkyl, -C(NR7)NR7R8, -(CH2)Paryl, -(CH2)PNR7R8, -C(0)NR7R8, -N=CR7R8, -NR7C(0)R8, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylaxnino, alkylamino, heteroaryl, or aryl; Rb independently represents H, -CN, -OH, -SH, -C02R4', -C(0)R4', -S02NR4', -NR4R5', -C(0)NR7R8, -S02-aIkyl, -S02R4', SO3R4', -N=CR4R5>, -NR4C(0)R4", -NR4-CO-haloalkyl, -N02, -NR4'-S02-haloalkyl, -NR4'-S02-alkyl, -NR4'-CO-alkyl, -NR4'(CH2)pheteroaryl, alkyl, cycloalkyl, alkylamino, alkoxy, alkylthio, halogen, haloalkyl, haloalkyloxy, -0(CH2)p[0(CH2)p]q0CH3, -C(NR4 )NR4 benzimidazolyl, -C(NR4 )NR4 benzthiazolyl, -C(NR4 )NR4 benzoxazolyl, hydroxyalkyl, hydroxy-cycloalkyl, hydroxyalkylamino, heterocycloalkyl, aryl or heteroaryl; R4, R4 , R5 independently are H, halogen, alkyl, -C(NR7)NR7 R8, -(CH2)paryl, haloalkyl, -CH2)pNR7R8, -C(0)NR7R8, -N=CR7R8, -NR7C(0)R8, cycloalkyl, heterocycloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl; R7, R7, R8 independently are H, halogen, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, arylamino heteroaryl, or aryl; R7a is cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, heteroaryl, or aryl; R7b is H, halogen, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, heteroaryl, or aryl; A X Z is CO or S02; is NR2', O, or S; is N or CR2; 20 R2 is H, alkyl, -C(0)NR7, -C(0)Rb, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aiyl; p is 1 to 6; q is 1 to 6; 5 R9 independently represents H, -CN, -OH, -SH, alkoxy, alkylthio, -CO2R4, -C(0)R4a, -C(0)NR7R8, -S02NR4', -NR4>R5', -S02-alkyl, -S02R4', S03R4', -N=CR4R5', -NR4'C(0)R4", -NR4 -CO-haloalkyl, -NO* -NR4'-S02-haloalkyl, -NR4'-S02-alkyl, -NR4-CO-alkyl, -NR4 (CH2)pheteroatyl, alkyl, hydroxyalkyl, cycloalkyl, halogen, 10 haloalkyl, alkylamino, -0(CH2)p[0(CH2)p]q0CH3, -C(NR4")NR4'benzimidazolyl, -C(NR4 )NR4 benzthiazolyl, -C(NR4 )NR4 benzoxazolyl, hydroxycycloalkyl, hydroxyalkylamino, haloalkyloxy, heterocycloalkyl, -(CH2)pNR7COR8, aryl, or heteroaryl; 15 wherein an Cj-Ce-alkyl group, if not stated otherwise, denotes a linear or branched Ci-Cg-alkyl, preferably a linear or branched chain of one to five carbon atoms, which can optionally be substituted by one or more substituents Rx; 20 an Cj-Cg-alkenyl group, if not stated otherwise, denotes a linear or branched C2-C6— alkenyl, preferably a linear or branched chain of two to six carbon atoms, which can optionally be substituted by one or more substituents R"; an alkyl group, if not stated otherwise, denotes a linear or branched Ci-C6-alkyl, preferably 25 a linear or branched chain of one to six carbon atoms, a linear or branched C2-C6-alkenyl or a linear or branched C2-C6-alkynyl group, which can be substituted by one or more substituents R"; R' is independently H, -C02R", -CONHR", -CR"0, -S02NR", -NR"-CO-haloalkyl, 30 -N02, -NR"-S02-haloalkyl, -NR"-S02-alkyl, -S02-alkyl, -NR"-CO-alkyl, -CN, alkyl, cycloalkyl, alkylamino, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl, or heteroaryl; R" is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, or heteroaryl; 21 a cycloalkyl group denotes a non-aromatic ring system containing three to eight carbon atoms, preferably four to eight carbon atoms, wherein one or more of the carbon atoms in the ring can be substituted by a group IT being as defined above; the C3-Cs-cycloalkyl 5 residue may be selected from the group comprising -cyclo-C3H5, -cyclo-GiH7, -cyclo-CsHk, -cyclo-C6Hn, -cyclo-C7Hi3, -cyclo-C8Hi5; a heterocycloalkyl group denotes a non-aromatic ring system containing two to ten carbon atoms and at least one heteroatom selected from O, N, and S, wherein one or more of the 10 carbon atoms in the ring can be substituted by R% being as defined above; preferred heterocycloalkyl groups are morpholine-4-yl, piperazinyl, l-alkylpiperazine-4-yl, piperidinyl, pyrrolidinyl, azepane-l-yl; an alkoxy group denotes an O-alkyl group, the alkyl group being as defined above; the 15 alkoxy group is preferably a methoxy, ethoxy, isopropoxy, f-butoxy or pentoxy group; an alkylthio group denotes an S-alkyl group, the alkyl group being as defined above; an haloalkyl group denotes an alkyl group which is substituted by one to five halogen 20 atoms, the alkyl group being as defined above; the haloalkyl group is preferably a -C(R10)3, -CR10(R10')23 -CR10(R10')R10", -C2(R10)5, -CH2C(R10)3, -CH2CRl0(R10')2, -CH2CR10(R10')R10", -C3(R10)7, or -C2H4C(R10)3) wherein R10, R10', R10" represent F, CI, Br or I, preferably F; 25 a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being as defined above; an haloalkyloxy group denotes an alkoxy group which is substituted by one to five halogen atoms, the alkyl group being as defined above; the haloalkyloxy group is preferably a -OC(R10>3, -OCR10(R10,)2, -OCRl0(R10)R10, -OC2(R10)5, -OCH2CCR.10)3, 30 -OCH2CR10(RI0')2, -OCH2CR10(R10')R10", -OC3(R10)7, or -OC2H4C(R10)3, wherein R10, R10', R10" represent F, CI, Br or I, preferably F; 22 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 5 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 10 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-QFLr R\ -m-QHU- R\ -p-CgHU- 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 15 above; a heteroaryl group denotes a 5- or 6-membered heterocyclic group which contains at least one heteroatom selected from O, N, and S. This heterocyclic group can be fused to another aromatic ring. For example, this group can be selected from a thiadiazole, thiazol-2-yl, 20 thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isooxazol-3-yl, isooxazol-4-yl, isooxazol-5-yl, benzooxazol-2-yl, benzooxazol-4-yl, benzooxazoI-5-yl, benzoisooxazol-3-yl, benzoisooxazol-4-yl, benzoisooxazol-5-yl, l,2,4-oxadiazol-3-yl, l,2,4-oxadiazol-5-yl, l,2,5-oxadiazol-3-yl, l,2,5-oxadiazol-4-yl, l,2,4-thiadiazol-3-yl, l,2,4-thiadiazol-5-yl, isothiazol-3-yl, 25 isothiazol-4-yl, isothiazol-5-yl, benzoisothiazol-3-yl, benzoisothiazol-4-yl, benzoisothiazol-5-yl, l,2,5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl, l,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-6-30 pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, l,2,3-triazol-4-yl, l,2,3-triazol-5-yl, l,2,4-triazol-3-yl, l,2,4-triazol-5-yl, 1,3,5-triazol-6-yl, 2,4-dimethoxy-l,3,5-triazol-6-yl, 1 //-tetrazol-2-y 1, l//-tetrazol-3-yl, tetrazolyl, acridyl, furazane, indazolyl, phenazinyl, carbazolyl, phenoxazinyl, indolizine, 2-indolyl, 3- 23 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, 5 benzo[b]thiophenyl, benzimidazol-2-yl, lH-benzimidazolyl, benzimidazol-4-yl, beozimidazol-5-yl, beiizimidazol-6-yl, benzimidazol-7-yl, benzothiazolyl, quinazolinyl, quinoxazolinyl, cinnoline, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydro-thieno[3,4-d]imidazol-2-one, pyrazolo[5,l-c][l,2,4]triazine, 2,3-dihydrobenzo[l,4]-dioxin-2-yl, 2,3-dihydrobenzo[l ,4]-dioxin-3-yl, 2,3-dihydrobenzo[l ,4]-dioxin-5-yl, 2,3-10 dihydrobenzo[l,4]-dioxin-6-yl, 2,6-dimethoxypyrimidin-3-yl, 2,6-dimethoxypyrimidin-4-yl, tetrahydroisoquinolinyl, purine, phthalazine, pteridine, thiatetraazaindene, thiatriazaindene, isothiazolopyrazine, isothiazolopyrimidine, pyrazolotriazine, pyrazolopyrixnidine, imidazopyridazine, imidazo-pyrimidine, imidazopyridine, iinidazolotriazine, triazolotriazine, triazolopyridine, triazolopyrazine, triazolopyrixnidine, 15 4-[l,2,4]triazolo[4,3-a]pyridin-3-yl, l-furo[2,3-c]pyridin-4-yl, l-furo[2,3-c]pyridin-5-yl, 1-furo[2,3-c]pyridin-3-yl, and triazolopyridazine group. This heterocyclic group can be substituted by one or more substituents R\ wherein R" is as defined above; with the proviso that the following compounds are excluded: wherein R1 independently represents hydrogen, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl or substituted arylalkyl; 25 R2 independently represents -NR3R4, O '4°VHrY^—( 20 (I) RECEIVED at IPONZ on 30 January 2012 24 R3 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; 5 R5 independently represents H, COR6, C02R6, SOR6, S02R6, S03R6, alkyl, cycloalkyl, alkoxy, -NH2, alkylamine, -NR?COR6, halogen, -OH, -SH, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl; R6 independently represents H, alkyl, cycloalkyl, -NH2, alkylamine, aryl or heteroaryl; R7 independently represents H, alkyl, cycloalkyl, alkoxy, -OH, -SH, alkylthio, 10 hydroxyalkyl, aryl, or heteroaryl; p isO, or 1; q is 0, or 1; X is CO or S02. 15 The subject matter of the parent application NZ 565470, also described herein for completeness, relates to compounds of the general formula (Ih) or pharmaceutically acceptable salts thereof with an acid or a base, or pharmaceutically acceptable prodrugs or a stereoisomer thereof, 20 25 r1 \ IN \_/ / r2 wherein A is NR2, S or O; t is 0 to 4; r is 0, orl; >2a o nr3a r3 (Ih) R is independently H, OH, SH, NH2, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, alkoxy, alkylamino, hydroxyalkylamino, halogen, aryl, or heteroaryl; 25 R3a is independently H, OH, SH, NH2, -C(NR7)NR7R8, -(CH2)paryl, -(CH2)PNR7R8, -C(0)NR7R8, -N=CR7R8, -NR7C(0)R8, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, alkoxy, alkylamino, hydroxyalkylamino, halogen, aryl, or heteroaryl; Rd isH, halogen, alkyl, -C(NR7)NRrR8,-(CH2)paryl, -(CH2)PNR7R8, -C(0)NR7R8, -N=CR7R8, -NR7C(0)R8, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl; R1 is -C(0)R7a, -C(0)CHR7R8, -C(0)NR7R8, -C(0)0R7, -R7C(0)R8, or -C(S)R7b; R2 is H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or R1 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 O, N, and S, and the ring can be substituted by one or more R9; R4a is H, Ci-C6-alkyl, Qr-Cs-alkenyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, -C(NR7)NRrR8, -(CH2)paryl, -(CH2)PNR7R8, -C(0)NR7R8, -N=CR7R8, -NR7C(0)R8, halogen, heteroaryl, or aryl; R3 isH, -C(0)NRaRb,halogen,alkyl,haloalkyl, aryl, heteroaryl, OH, SH,NR4OR5', NH2, hydroxyalkylamino, alkylamino, alkoxy, cycloalkyl, heterocycloalkyl, hydroxyalkyl, or haloalkyloxy; Ra is H, halogen, alkyl, -C(NR7)NRrR8, -(CH2)paryl, -(CH2)PNR7R8, -C(0)NR7R8, -N=CR7R8, -NR7C(0)R8, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl; Rb independently represents H, -CN, -OH, -SH, -C02R4', -C(0)R4', -S02NR4', -NR4'R5', -C(0)NR7R8, -S02-alkyl, -S02R4', S03R4', -N=CR4R5', -NR4C(0)R4", -NR4-CO-haloalkyl, -N02, -NR4'-S02-haloalkyl, -NR4'-S02-alkyl, -NR4-CO-alkyl, -NR4 (CH2)pheteroaryl, alkyl, cycloalkyl, alkylamino, alkoxy, alkylthio, halogen, haloalkyl, haloalkyloxy, -0(CH2)p[0(CH2)p]q0CH3, -C(NR4 )NR4 benzimidazolyl, -C(NR4 )NR4 benzthiazolyl, -C(NR4 )NR4 benzoxazolyl, hydroxyalkyl, hydroxy-cycloalkyl, hydroxyalkylamino, heterocycloalkyl, aiyl or heteroaryl; 26 R4, R4 , R5 independently are H, halogen, alkyl, -C(NR7)NR7 R8, -(CH2)paryl, haloalkyl, -CH2)pNR7R8, -C(0)NR7R8, -N=CR7R8, -NR7C(0)R8, cycloalkyl, heterocycloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl; R7, R7, R8 independently are H, halogen, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, arylamino heteroaryl, or aryl; R7a is cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, heteroaryl, or aryl; *71% R is H, halogen, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, heteroaryl, or aryl; X is NR2,0, or S; Z is N or CR2; R2 is H, alkyl, -C(0)NR7, -C(0)Rb, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl; p is 1 to 6; q is 1 to 6; R9 independently represents H, -CN, -OH, -SH, alkoxy, alkylthio, -CO2R4, -C(0)R4a, -C(0)NR7R8, -SO2NR4', -NR4R5>, -S02-alkyl, -SOzR4', SO3R4', -N=CR4R5', -NR4 C(0)R4 , -NR4 -CO-haloalkyl, -N02, -NR4'-S02-haloalkyl, -NR4'-S02-alkyl, -NR4-CO-alkyl, -NR4 (CH2)pheteroaryl, alkyl, hydroxyalkyl, cycloalikyl, halogen, haloalkyl, alkylamino, -0(CH2)p[0(CH2)p]q0CH3, -C(NR4")NR4'benzimidazolyl, -C(NR4 )NR4 benzthiazolyl, -C(NR4 )NR4 benzoxazolyl, hydroxycycloalkyl, hydroxyalkylamino, haloalkyloxy, heterocycloalkyl, -(CH2)pNR7COR8, aryl, or heteroaryl; wherein an Ci-C6-alkyl group, if not stated otherwise, denotes a linear or branched Ci-C6-alkyl, preferably a linear or branched chain of one to five carbon atoms, which can optionally be substituted by one or more substituents R"; an Qr-Ce-alkenyl group, if not stated otherwise, denotes a linear or branched C2-C6-alkenyl, preferably a linear or branched chain of two to six carbon atoms, which can optionally be substituted by one or more substituents R"; 27 an alkyl group, if not stated otherwise, denotes a linear or branched Ci-C6-alkyl, preferably a linear or branched chain of one to six carbon atoms, a linear or branched QrQ-alkenyl or a linear or branched C2-C6-alkynyl group, which can be substituted by one or more 5 substituents R^; R' is independently H, -C02R", -CONHR", -CR"0, -S02NR", -NR"-CO-haloalkyl, -N02, -NR"-S02-haloalkyl, -NR"-S02-alkyl, -S02-alkyl, -NR"-CO-alkyl, -CN, alkyl, cycloalkyl, alkylamino, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl, hydroxyalkylamino, 10 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 15 atoms, preferably four to eight carbon atoms, wherein one or more of the carbon atoms in the ring can be substituted by a group R* being as defined above; the C3-Cg-cycloalkyl residue may be selected from the group comprising -cyclo-CsHs, -cyclo-C+H?, -cyclo-CsH9, -cyclo-CgHn, -cyclo-C7Hi3, -cyclo-C8Hi5; 20 a heterocycloalkyl group denotes a non-aromatic ring system containing two to ten carbon atoms and at least one heteroatom selected from O, 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, l-alkylpiperazine-4-yl, piperidinyl, pyrrolidinyl, azepane-l-yl; 25 an alkoxy group denotes an O-alkyl group, the alkyl group being as defined above; the alkoxy group is preferably a methoxy, ethoxy, isopropoxy, f-butoxy or pentoxy group; an alkylthio group denotes an S-alkyl group, the alkyl group being as defined above; 30 an haloalkyl group denotes an alkyl group which is substituted by one to five halogen atoms, the alkyl group being as defined above; the haloalkyl group is preferably a -C(RI0)3, -CR10(R10)2, -CR10(R10)R10", -C2(R10)5, -CH2C(R10)3, -CH2CR10(R10)2, 28 -CH2CR10(R10')R10", -C3(R10)7, or -C2H4C(R10)3> wherein R10, R10', R10" represent F, CI, Br or I, preferably F; a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being as defined above; 5 an haloalkyloxy group denotes an alkoxy group which is substituted by one to five halogen atoms, the alkyl group being as defined above; the haloalkyloxy group is preferably a -OC(R10)3, -OCR10(R10')2, -OCR10(R10,)R10", -OC2(R10)5, -OCH2C(R10)3, -OCH2CR10(R10')2, -OCH2CR10(R10)R10", -OC3(R10)7, or -OC2H4C(R10)3> wherein R10, 10 R10,R10 represent F, CI, 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; 15 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; 20 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, -0-C6H4- R\ -m-QHU- R\ -p-CgEU- R\ 1-naphthyl, 2-naphthyl, 1-anthracenyl or 2-anthracenyI, R" being as defined above; 25 an arylamino group denotes an HN-aryl or N-diaryl group, the aryl group being as defined above; a heteroaryl group denotes a 5- or 6-membered heterocyclic group which contains at least one heteroatom selected from O, N, and S. This heterocyclic group can be fused to another 30 aromatic ring. For example, this group can be selected from a thiadiazole, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isooxazol-3-yl, isooxazol-4-yl, isooxazol-5-yl, benzooxazol-2-yl, benzooxazol-4-yl, benzooxazol-5-yl, benzoisooxazol-3-yl, benzoisooxazol-4-yl, 29 benzoisooxazol-5-yl, 1,2,4-oxadiazol-3 -yl, l,2,4-oxadiazol-5-yl, l,2,5-oxadiazol-3-yl, l,2,5-oxadiazol-4-yl, 1,2,4-thiadiazol-3-yl3 l,2,4-thiadiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, benzoisotMazol-3-yl, benzoisothiazol-4-yI, benzoisothiazol-5-yI, l,2,5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl, l,2,5-thiadiazol-4-5 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-pyrbnidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, l,2,3-triazol-4-yl, l,2,3-triazol~5-yl, l,2,4-triazol-3-yl, l,2,4-triazol-5-yl, 1,3,5-10 triazol-6-yl, 2,4-dimethoxy-l,3,5-triazol-6-yl, lff-tetrazol-2-yl, l#-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]furany 1, benzo furazane, benzothiofurazane, benzotriazol-1-15 yl, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl, benzotriazol-7-yl, benzotriazine, benzo[b]thiophenyl, benzimidazol-2-yl, lH-benzimidazolyl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl, benzimidazol-7-yl, benzothiazolyl, quinazolinyl, quinoxazolinyl, cinnoline, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydro-thieno[3,4-d]imidazol-2-one, pyrazolo[5,1 -c][ 1,2,4]triazine, 2,3-dihydrobenzo[l,4]-dioxin-20 2-yl, 2,3-dihydrobenzo[l,4]-dioxin-3-yl, 2,3-diliydrobenzo[l,4]-dioxin-5-yl, 2,3-dihydrobenzo[l ,4]-dioxin-6-yl, 2,6-dimethoxypyrimidin-3-yl, 2,6-dimethoxypyrimidin-4-yl, tetrahydroisoquinolinyl, purine, phthalazine, pteridine, thiatetraazaindene, tMatriazaindene, isothiazolopyrazine, isothiazolopyrimidine, pyrazolotriazine, pyrazolopyrimidine, imidazopyridazine, imidazo-pyrimidine, imidazopyridine, 25 iinidazolotriazine, triazolotriazine, triazolopyridine, triazolopyrazine, triazolopyiimidine, 4-[l,2,4]triazolo[4,3-a]pyridin-3-yl, l-furo[2,3-c]pyiidin-4-yl, l-furo[2,3-c]pyridin-5-yl, 1-furo[2,3-c]pyridin-3-yl, and triazolopyridazine group. This heterocyclic group can be substituted by one or more substituents R\ wherein R" is as defined above; 3 0 with the proviso that the following compounds are excluded: 30 R,4°-k44r -n V / ^ ^ 0) wherein R1 independently represents hydrogen, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, substituted aiyl, heteroaryl, substituted heteroaryl, arylalkyl or substituted arylalkyl; R2 independently represents -NR3R4, Z-\_s I / \ . -n ) r5 -§-n n r5 v_y ? v_/ ,or R3 independently represents alkyl, cycloalkyl, alkoxy, alkylamine, -OH, -SH, 10 alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl, R4 independently represents alkyl, cycloalkyl, alkoxy, alkylamine, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl; R5 independently represents H, COR6, COaR6, SOR6, S02R6, SO3R6, alkyl, cycloalkyl, alkoxy, -NH2, alkylamine, -NR7COR6, halogen, -OH, -SH, alkylthio, hydroxyalkyl, 15 haloalkyl, haloalkyloxy, aryl or heteroaryl; R6 independently represents H, alkyl, cycloalkyl, -NH2, alkylamine, aryl or heteroaryl; R7 independently represents H, alkyl, cycloalkyl, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl, aryl, or heteroaryl; p is 0, or 1; 20 q isO, orl; X is CO or S02. 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 25 acceptable prodrugs, or a stereoisomer thereof, (n) wherein R1 is -C(0)R7, -C(0)CHR7R8, -C(0)NR7R8, -C(0)0R7, -R7C(0)R8, -C(S)R7; R2 is H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, alkylamino, 5 hydroxyalkylamino, heteroaryl, or R1 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 polycyplic ring system, wherein at least one or more of the carbon atoms in the ring is a heteroatom selected from O, N, and S, and the ring can be substituted by one or 10 moreR9; R3 is H, -C(0)NRaRb, halogen, alkyl, haloalkyl, aryl, heteroaryl, OH, SH, NR4 OR5, NH2, hydroxyalkylamino, alkylamino, alkoxy, cycloalkyl, heterocycloalkyl, hydroxyalkyl, or haloalkyloxy; Ra isH,halogen, alkyl, -C(NR7)NR7R8, -(CH2)paryl, -(CH2)pNR7R8, -C(0)NR7R8, 15 -N=CR7R8, -NR7C(0)R8, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl; Rb independently represents H, -CN, -OH, -SH, -C02R4, -C(0)R4, -S02NR4, -NR4R5', -C(0)NR7R8, -S02-alkyl, -S02R4', S03R4', ~N=CR4R5', -NR4 C(0)R4", -NR4-CO-haloalkyl, -N02, -NR4'-S02-haloalkyl, -NR4'-S02-alkyl, -NR4'-CO-alkyl, 20 -NR4(CH2)pheterocycle, alkyl, cycloalkyl, alkylamino, alkoxy, alkylthio, halogen, haloalkyl, haloalkyloxy, -0(CH2)p[0(CH2)p]q0CH3, -C(NR4")NR4 benzimidazolyl, -C(NR4")NR4 benzthiazolyl, -C(NR4 )NR4 benzoxazolyl, hydroxyalkyl, hydroxyalkylamino, aryl, heterocycloalkyl, or heteroaryl; 25 R6 is halogen, -C(0)R7, -C(0)CHR7R8, -C(0)NR7R8, -C(0)0R7, -R7C(0)R8, -C(S)R7, -C(NR7)NR7'R8, -(CH2)paryl, -(CH2)PNR7R8, -C(0)NR7R8, -N=CR7R8, - 32 NR7C(0)R7, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl; R7, R7, R8 independently are H, halogen, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, -NHaryl, heteroaryl, or aryl; 5 A is CO or S02; X isNR2,0, orS; Y is N, CR2 or if Y is 0 then R6 is absent; Z is N or CR2'; if Z is CH then X is 0 or NR2' R2' is H, alkyl, -C(0)NR2, -C(0)Rb, cycloalkyl, heterocycloalkyl, haloalkyl, 10 hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl; n is 0 to 2 P is 1 to 6 q is 1 to 6 15 R9 independently represents H, -CN, -OH, -SH, -C02R4', -C(0)R4a, -C(0)NR7R8, -S02NR4', -NR4R5', -S02-alkyl, -S02R4', SO3R4', -NCR4^, -NR4'C(0)R4", -NR4'-CO-haloalkyl, -N02, -NR4'-S02-haloalkyl, -NR4'-S02-alkyl, -NR4'-CO-alkyl, -NR4 (CH2)pheteroaryl, alkyl, cycloalkyl, heterocycloalkyl, alkylamino, alkoxy, alkylthio, halogen, haloalkyl, haloalkyloxy, hydroxyalkylamino, hydroxyalkyl, 20 hydroxycycloalkyl, aryl, -0(CH2)p[0(CH2)p]q0CH3, -C(NR4")NR4'benzimidazolyl, -C(NR4 )NR4 benzthiazolyl, -C(NR4")NR4'benzoxazolyl, -(CH2)pNR7COR8, or heteroaryl; R4', R4", R5' independently are H, halogen, alkyl, -C(NR7)NRrR8, -(CH2)paryl, -(CH2)PNR7R8, -C(0)NR7R8, -N=CR7Rs, -NR7C(0)R8, cycloalkyl, 25 heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl; R4a is H, Ci-Cg-alkyl, Cr-Ce-alkenyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, -C(NR7)NRrR8, -(CH2)paryl, -CH2)pNR7R8, -C(0)NR7R8, -N=CR7R8, -NR7C(0)R8, halogen, heteroaryl, or aryl 30 wherein 33 an Ci-C6-alkyl group, if not stated otherwise, denotes a linear or branched Ci-Ce-alkyl, preferably a linear or branched chain of one to five carbon atoms, which can optionally be substituted by one or more substituents IT; 5 an Cr-Cs-alkenyl group, if not stated otherwise, denotes a linear or branched Cr-Cg-alkenyl, preferably a linear or branched chain of two to six carbon atoms, which can optionally be substituted by one or more substituents R"; an alkyl group, if not stated otherwise, denotes a linear or branched Ci-C6-alkyl, preferably 10 a linear or branched chain of one to six carbon atoms, a linear or branched C2-C6-alkenyl or a linear or branched C2-C6-alkynyl group, which can be substituted by one or more substituents R"; R" is independently H, -C02R", -CONHR", -CR"0, -S02NR", -NR"-CO-haloalkyl, -N02, -NR"-S02-haloalkyl, -NR"-S02-alkyl, -S02~alkyl, -NR"-CO-alkyl, -CN, alkyl, 15 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 heterocycle denotes a heterocycloalkyl group or a heteroaryl group; a cycloalkyl group denotes a non-aromatic ring system containing three to eight carbon atoms, preferably four to eight carbon atoms, wherein one or more of the carbon atoms in the ring can be substituted by a group R" being as defined above; the C3-Cg-cycloalkyl 25 residue may be selected from the group comprising -cyclo-CaHs, -cyclo-C4H7, -cyclo-CsHp, -cyclo-CeHu, -cyclo-C7Hi3, -cyclo-C8Hi5; a heterocycloalkyl group denotes a non-aromatic ring system containing two to ten carbon atoms and at least one heteroatom selected from O, N, and S, wherein one or more of the 30 carbon atoms in the ring can be substituted by R" being as defined above; preferred heterocycloalkyl groups are morpholine-4-yI, piperazinyl, l-aIkylpiperazine-4-yl, piperidinyl, pyrrolidinyl, azocane-l-yl; 34 an alkoxy group denotes an O-alkyl group, the alkyl group being as defined above; the . alkoxy group is preferably a methoxy, ethoxy, isopropoxy, /-butoxy or pentoxy group; an alkylthio group denotes an S-alkyl group, the alkyl group being as defined above; 5 an haloalkyl group denotes an alkyl group which is substituted by one to five halogen atoms, the alkyl group being as defined above; the haloalkyl group is preferably a -C(R10)3, -CR10(R10')2, -CR10(R10')R10", -C2(R10)5, -CH2C(R10)3, -CH2CR10(R10')2, -CH2CR10(R10')R10", -C3(R10)7, or -C2H4C(R10)3, wherein R10, R10', R10" represent F, CI, Br 10 or I, preferably F; a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being as defined above; an haloalkyloxy group denotes an alkoxy group which is substituted by one to five halogen 15 atoms, the alkyl group being as defined above; the haloalkyloxy group is preferably a -OC(R10)3, -OCR10(R10')2, -OCR10(R10,)R10", -OC2(R10)5, -OCH2C(R10)3, -OCH2CR10(R10')2, -OCHjCR^CR10')^0", -OC3(R10)73 or -OC2H4C(R10)3, wherein R10, R10, R10 represent F, CI, 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; 25 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 30 preferably a benzyl group, a phenyl group, -0-C6H4- R\ -m-CeH*- R\ -p-CeHLt- R\ 1-naphthyl, 2-naphthyl, 1-anthracenyl or 2-anthracenyl, R" being as defined above; I 35 a heteroaryl group denotes a 5- or 6-membered heterocyclic group which contains at least one heteroatom selected from O, N, and S. This heterocyclic group can be fused to another aromatic ring. For example, this group can be selected from a thiadiazole, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, oxazol-2-yl, 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, benzoi sooxazol-3-yl, benzoisooxazol-4-yl, benzoisooxazol-5 -yl, l,2,4-oxadiazol-3-yl, l,2,4-oxadiazol-5-yl, l,2,5-oxadiazol-3-yl, l,2,5-oxadiazol-4-yl, l,2,4-thiadiazol-3-yl, l,2,4-thiadiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, benzoisothiazol-3-yl, benzoisothiazol-4-yl, 10 benzoisothiazol-5-yl, l,2,5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl, l,2,5-thiadiazol-4-yl, 4-imidazolyl, benzoimidazol-4-yl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-fiiranyl, 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, l,2,3-triazol-4-yl, l,2,3-triazol-5-yl, 1,2,4-triazol-3-yl, l,2,4-triazol-5-yl, 1,3,5-triazol-6-yl, 2,4-dimethoxy-l,3,5-triazol-6-yl, lH-tetrazol-2-yl, l£T-tetrazol-3-yl, tetrazolyl, acridyl, furazane, indazolyl, phenazinyl, carbazolyl, phenoxazinyl, indolizine, 2-indolyl, 3-indolyl, 4-indoIyl, 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, benzotriazo 1-1-yl, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl, benzotriazol-7-yl, benzotriazine, benzo[b]thiophenyl, benzimidazol-2-yl, lH-benzimidazolyl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl, benzimidazol-7-yl, benzothiazolyl, quinazolinyl, quinoxazolinyl, cinnoline, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydro-25 thieno[3,4-d]imidazol-2-one, pyrazolo[5,l-c][l,2,4]triazine, 2,3-dihydrobenzo[l,4]-dioxin-2-yl, 2,3-dihydrobenzo[l,4]-dioxin-3-yl, 2,3-dihydrobenz9[l,4]-dioxin-5-yl, 2,3-dihydrobenzo[l,4]-dioxin-6-yl, 2,6-dimethoxypyrimidin-3-yl, 2,6-dimethoxypyrimidin-4-yl, tetrahydroisoquinolinyl, purine, phthalazine, pteridine, thiatetraazaindene, thiatriazaindene, isothiazolopyrazine, isothiazolopyrimidine, pyrazolotriazine, 30 pyrazolopyrimidine, imidazopyridazine, imidazopyrimidine, imidazopyridine, iinidazolotriazine, triazolotriazine, triazolopyridine, triazolopyrazine, triazolopyrimidine, 4-[l,2,4]triazolo[4,3-a]pyridin-3-yl, l-furo[2,3-c]pyridin-4-yl, 1 -furo[2,3-c3pyridin-5-yl, 1- 36 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. In a preferred embodiment of the invention, in the compounds of formula (la), Z is S, Y is 5 CO, X is CO, R is H, R° is H, and R1 is aryl, benzyl, or heteroaryl, R2 is s ^ . —n n r5 < \ / , and R5 is optionally substituted aryl, benzyl or heteroaryl. In a preferred embodiment of the invention, in the compounds of formula (la), Z is O, Y is CO, X is CO, R is H, Rc is H, and R1 is aryl, benzyl, or heteroaryl, R2 is I . —e—n n r5 ? \ / 10 and R is optionally substituted aryl, benzyl or heteroaryl. In a preferred embodiment of the invention, in the compounds of formula (lb), Z is S, Y is CO, X forms a piperidine ring together with R1 and R4, Ra and Rb is H, R° is H or methyl, / \ —e—n n r 5 2 \ / 5 R is \ ' , and R is optionally substituted aryl, benzyl or heteroaryl. In a preferred embodiment of the invention, in the compounds of formula (lb), Z is O, Y is 15 CO, X forms a piperidine ring together with R1 and R4, Ra and Rb is H, R° is H or methyl, % . n n r5 2 \ / R is \ f , and R 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 O, t is 0, s is 1, X is CO, Rc is H, methyl, ethyl, methoxy, alkylamino, morpholino, N- i . —n n r5 20 methylpiperazine, CF3, or OCF; R2 is ? v_y , 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 S, 37 t is 0, s is 0, Rc is H, methyl, ethyl, methoxy, alkylamino, morpholino, N-methylpiperazine, -n CF3, or OCF, R2 is or heteroaryl. In another preferred embodiment, in the compounds of formula (Ic), r is 1,Y is CO, Z is S, 5 t is 0, s is 1, X is CO, R° is H, methyl, ethyl, methoxy, alkylamino, morpholino, N- I AA . —n n r5 methylpiperazine, CF3, or OCF, 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 O, t is 0, s is 0, Rc is H, methyl, ethyl, methoxy, alkylamino, morpholino, N-methylpiperazine, /~~\ 4 Is 10 CF3, or OCF R2 is v_/ or heteroaryl. / \ . i n r5 v_/ J r>5 , and R is optionally substituted aryl, benzyl !—N n r5 , and R5 is optionally substituted aryl, benzyl 15 A preferred embodiment of the invention, in the compounds of formula (III), are compounds of the formula (Ilia), (ma) wherein R3 is H, methyl, methoxy, CF3, or OCF3; R4, R5, R7a are defined as above; X is NR2, O or S; and Z is as defined as above, 20 Another preferred embodiment of the invention, in the compounds of formula (III), 38 are compounds of the formula (Ilia), with R7a = -NH-aryl. Another preferred embodiment of the invention, in the compounds of formula (HI), wherein R3 is H, methyl, methoxy, CF3, or OCF3; R5 is defined as above; X is NR2,0 or S; if Z is N then X is NR2', O or S, or if Z is CR2', X is O; Y' is O or NR2, R2 is as defined above; Another preferred embodiment of the invention, in the compounds of formula (III), are compounds of the formula (IIIc), 15 R11, R12 independently represent H, -CN, -OH, -SH, -C02R4', -C(0)R4', -S02NR4', -NR4'R5', -S02-alkyl, -SO2R4', SO3R4', -N=CR4R5', -NR4'C(0)R4", -NR4'-CO-haloalkyl, -N02, -NR4'-S02-haloalkyI, -NR4'-S02-alkyl, -NR4'-CO-alkyl, -NR4' (CH2)pheteroaryl, alkyl, cycloalkyl, alkylamino, alkoxy, alkylthio, -0(CH2)p[0(CH2)p]q0CH3, - 39 C(NR4")NR4>benzimidazolyl, -C(NR4 )NR4 benzthiazolyl, -C(NR4 )NR4 benzoxazolyl hydroxyalkyl, hydroxycycloalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl, arylalkyl or a heterocycle; andR4 , R4 , R5 are defined as above; R3 is H, methyl, methoxy, CF3, or OCF3; X is NR2,0 or S, R4 is defined as above, 5 R7 and R7 are defined as above, R11', R12; independently represents H, -CN, -OH, -SH, -C02R4', -C(0)R4', -S02NR4', -NR4R5', -S02-alkyl, -SOaR4', SO3R4', -N=CR4R5', -NR4C(0)R4", -NR4'-CO-haloalkyl, -N02, -NR4-S02-haloalkyl, -NR4,-S02-alkyl, -NR4'-CO-alkyl, -NR4' (CH2)pheteroaryl, alkyl, cycloalkyl, alkylamino, alkoxy, alkylthio, -0(CH2)p[0(CH2)p]q0CH3, 10 -C(NR4' )NR4'benzimidazolyl, -C(NR4 ")NR4'benzthiazolyl, -C(NR4 )NR4 benzoxazolyl hydroxyalkyl, hydroxycycloalkyl, hydroxyalkyl-amino, halogen, haloalkyl, haloalkyloxy, aryl, arylalkyl or a heterocycle; andR4,R4 ,R5 are defined as above; A more preferred embodiment of the invention, in the compounds of formula (III), 15 are compounds of the formula (Hid), wherein R3 is H, methyl, methoxy, CF3, or OCF3; X is NR2, O or S, R4 is defined as above, R7 and R7 are defined as above, Y" and R11, R12' are defined as above under formula 20 (Die), Y' is O or NR2 and R2 is as defined above. y Another more preferred embodiment of the invention, in the compounds of formula (III), are compounds of the formula (DOfe), 40 wherein R3, R4 and R5 are defined as above, X is O or S, R11 and R12 are defined as above under formula (Hie), and 5 if Z is N, X is NR2', O or S, if Z is CH, X is O. Another more preferred embodiment of the invention, in the compounds of formula (III), are compounds of the formula (IUf), r7n r7' Y_/ 10 wherein Z is N or CH, and R3 is H, methyl, methoxy, CF3, or OCF3; X is NR2,0 or S, R4 is defined as above, R7 and R7 are defined as above, R2 is as defined above; Y" and R11, R11', R12, R12' are defined as above under formula (IHc). 41 A preferred embodiment of the invention, are compounds of the formula (Iha), r1 \ z < n n r2a r2 x r3 O r (Iha) wherein R1 is COR7a; R2 and R3a are H; A is NH; R7 is as defined above; Z is N; 5 X is NR2, O or S; R3 is H, methyl, ethyl, methoxy, amine, alkylamine, morpholino, N-methylpiperazine, CF3, or OCF3; t is 0; r is 1; and R2a is optionally substituted aryl, benzyl or heteroaryl. Another preferred embodiment of the invention, in the compounds of formula (Ih), 10 are compounds of the formula (Iha), with R7a is optionally substituted aryl, benzyl or heteroaryl. Another preferred embodiment of the invention, in the compounds of formula (Ih), are compounds of the formula (Ihb), R3a is H; A is NH; X is NR2,0 or S; Y' isOorNR2'; R2 is as defined above; R3 is H, methyl, ethyl, methoxy, amine, alkylamine, morpholino, N-methylpiperazine, CF3, or OCF3; t is 0; r is 1; and R2a is optionally substituted aryl, 20 benzyl or heteroaryl. 15 r (Ihb) wherein Another more preferred embodiment of the invention, in the compounds of formula (Ih), 42 are compounds of the formula (Ihe), R2a r wherein 5 R3a is H; A is NH; X isNR2,0 or S; R11 and R12 independently represent H, -CN, -OH, -SH, -C02R4', -C(0)R4', -S02NR4', -NR4'R5',-S02-alkyl, -S02R4', SO3R4',-N=CR4R5', -NR4C(0)R4",-NR4'-CO-haloalkyl, -N02, -NR4-S02-haloalkyl, -NR4'-S02-alkyl, -NR4'-CO-alkyl, -NR4' (CH2)pheteroaryl, alkyl, cycloalkyl, alkylamino, alkoxy, alkylthio, -0(CH2)p[0(CH2)p]q0CH3, -10 C(NR4")NR4'benzimidazolyl, -C(NR4")NR4'benzthiazolyl, -C(NR4")NR4'benzoxazolyl hydroxyalkyl, hydroxycycloalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl, arylalkyl or a heterocycle; and R4, R4 , R5 are defined as above; R2' is as defined above; R3 is H, methyl, ethyl, methoxy, amine, alkylamine, morpholino, N-methylpiperazine, CF3, or OCF3; t is 0; r is 1; and R2a is optionally substituted aryl, 15 benzyl or heteroaryl. A preferred embodiment of the invention, in the compounds of formula (II), are compounds of the formula (Ila), Z 43 R3 is H, methyl, methoxy, CF3, or OCF3; R11 and R12 are defined as above under formula (IIIc). 10 A more preferred embodiment of the invention, in the compounds of formula (D), are compounds of the formula (lib), CF3 \ / m wherein 1 0 R and R are defined as above, Z is defined as above; X is O or S, R3 is H, methyl, methoxy, CF3, or OCF3. Another more preferred embodiment of the invention, in the compounds of formula (II), are compounds of the formula (He), cf3 wherein \ / (He) 15 X is O or S; R" is H, methyl, methoxy, CF3, or OCF3; Y* is NR2'. Another more preferred embodiment of the invention, in the compounds of formula (II), 44 are compounds of the formula (Hd), wherein Z is defined as above; R3 is H, methyl, methoxy, CF3, or OCF3; R11, R11 andR12, R12 are defined as above. In addition, the present invention provides methods for preparing the compounds of the invention such as compounds of formula (la), (lb), (Ic), (II), or (III). 10 The compounds of formula (la), (lb), (Ic), (II), or (III) may be obtained via various methods. Piperidin-4yl-thiazole-4-carboxamide can be prepared by various methodes described in the literature. One such example is the oxidation of the appropriate 2,5-dihydrothiazoles as described in Houben-Weyl, 2002, 730. The dihydrothiazoles can also synthesised by 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 decribed by Yasuchika, S. et al. Heterocycles, Vol. 57, No. 5,2002. 45 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 VoL74,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 (IH) is described in Synthesis, 2006,4, 597-602. 10 One possibility for the synthesis of compounds of formula (Hla, c and Ha, 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, iP^NEt, DMF, 0°C to r.t. to obtain intermediate (VII). Another alternative for this step might be the reaction of (V) with the corresponding acid chloride of (VI) to yield (VII). In a second step, compound 15 (VH) is saponified with a 1 M NaOH solution, obtaining the expected acid (VIH) in almost quantitative yield. This step could be realized under acidic conditions as well. Finally, another amide coupling step (with primary or secundary amines), which works similarily to step 1 described above, completes the synthesis for compounds of type (Hla, c and Ha, and b). 46 7^ R12 (Ilia, c, Ha, b) R12 OEt (vm) Scheme 1 Synthesis of derivatives of type (Hla, c) and (Ha, b) Compounds dealing with structure (IIIb, d, e, f) and (lie, 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 (XT), 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. 47 r- (IX) OEt R2 (XI) OEt (nib, d, e, f, He, d) (XII) Scheme 2 Synthesis of derivatives of type (HIb, d, e, f) and (lie, d), with Z = N In case of Z = CH, structure (LUb, d, e, f) and (lie, d) type compounds can easily be synthesized following a protocol outlined in scheme 3, wherein a heterocycle (XIII) is converted to compound (XV) by a cyclokondensation step. After saponification, (XVI) is coupled with an amine to yield the desired product (Illb, d, e, f) or (lie, d). 48 z nh2 (xm) C w OEt (XIV) (xv) OEt (inb, d, e, f, He, d) (XVI) Scheme 3 Synthesis of derivatives of type (Illb, d, e, f) and (lie, d), with Z = CH 10 For the compounds of the formula (la), (lb), (Ic), (II), or (III) above, the term "stereoisomer" means cis/trans or E/Z isomerism. More particularly, the possible double bond(s) present in the various substituent of the compounds of the present invention can be E or Z configuration. These pure or impure geometrical isomers, alone or as a mixture, form an integral part of the compounds of the formula (la), (lb), (Ic), (II), or (III). The term "stereoisomer" includes also all the isomeric forms, alone or as mixture, resulting from the presence of one or more axes and/ or centres of symmetry in the molecules, and resulting in the rotation of a beam of polarized light. More particularly, it includes enatiomers and diastereomers, in pure form or as a mixture. The compounds of the formula (la), (lb), (Ic), (II), or (III) to be used according to the 15 invention can form salts with inorganic or organic acids or bases. Examples of pharmaceutically acceptable salts comprise without limitation non-toxic inorganic or organic salts such as acetate derived from acetic acid, aconitate derived from aconitic acid, ascorbate derived from ascorbic acid, benzoate derived from benzoic acid, cinnamate 49 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 fiimaric acid, glutamate derived from glutamic acid, glycolate * derived from glycolic acid, chloride derived from hydrochloric acid, bromide derived from 5 hydrobromic acid, lactate derived from lactic acid, maleate derived from maleic acid, malonate derived from malonic acid, mandelate derived from mandelic acid, methanesulfonate derived from methanesulfonic acid, naphtaline-2-sulfonate derived from naphtaline-2-sulfonic acid, nitrate derived from nitric acid, perchlorate derived from perchloric acid, phosphate derived from phosphoric acid, phthalate derived from phthalic 10 acid, salicylate derived from salicylic acid, sorbate derived from sorbic acid, stearate derived from stearic acid, succinate derived from succinic acid, sulphate derived from sulphuric acid, tartrate derived from tartaric acid, toluene-p-sulfate derived from p-toluene-sulfonic acid and others. Such salts can be produced by methods known to someone of skill in the art and described in the prior art. 15 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 (la), (lb), (Ic), (II), or (HI) or a pharmaceutically acceptable salt thereof or pharmaceutically acceptable prodrugs, or a stereoisomer thereof. 20 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 (la), (lb), (Ic), (IT), or (III), such as the salts obtained with chiral amines. 25 The compounds of the formula (la), (lb), (Ic), (II), or (IH) 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 pharmaceutical active form (compounds of 30 formula (la), (lb), (Ic), (n), or (HI)) in vivo, i.e. in the subject to which the compound is administered. 50 The compounds according to the invention and medicaments prepared therewith are generally useful for the treatment of cell proliferation disorders, for the treatment, or prophylaxis of immunological diseases and conditions (as for instance inflammatory diseases, neuroimmunological diseases, autoimmune diseases or other). 5 The compounds of the present invention are useful for the treatment of diseases which are caused by malignant cell proliferation, such as all forms of solid tumors, leukemias and lymphomas. Therefore the compounds according to the invention and medicaments prepared therewith are generally useful for regulating cell activation, cell proliferation, cell survival, cell differentiation, cell cycle, cell maturation and cell death or to induce systemic 10 changes in metabolism such as changes in sugar, lipid or protein metabolism. They can also be used to support cell generation poiesis, including blood cell growth and generation (prohematopoietic effect) after depletion or destruction of cells, as caused by, for example, toxic agents, radiation, immunotherapy, growth defects, malnutrition, malabsorption, immune dysregulation, anemia and the like or to provide a therapeutic control of tissue 15 generation and degradation, and therapeutic modification of cell and tissue maintenance and blood cell homeostasis. These diseases and conditions include but are not limited to cancer as hematological (e.g. leukemia, lymphoma, myeloma) or solid tumors (for example breast, prostate, liver, 20 bladder, lung, esophageal, stomach, colorectal, genitourinary, gastrointestinal, skin, pancreatic, brain, uterine, colon, head and neck, cervical, and ovarian, melanoma, astrocytoma, small cell lung cancer, glioma, basal and squameous cell carcinoma, sarcomas as Kaposi's sarcoma and osteosarcoma) or for the treatment of diseases which are cured or relieved by the inhibition of one or several kinases and/or phosphatases. 25 "Treatment" according to the present invention is intended to mean complete or partial healing of a disease, or alleviation of a disease or stop of progression of a given disease. Thus, in one embodiment, the invention relates to the use of the compounds of the formula 30 (la), (lb), (Ic), (H), or (III) or a pharmaceutically acceptable salt or pharmaceutically acceptable prodrugs, or a stereoisomer thereof if desired with appropriate adjuvants and additives for the production of a medicament for the treatment or prevention of a disease characterized by hyperproliferation of keratinocytes and/or T cells, especially 51 inflammatory disorders and immune disorders, preferably selected from the group consisting of Addison's disease, alopecia areata, Ankylosing spondylitis, haemolytic anemia (anemia haemolytica), pernicious anemia (anemia perniciosa), aphthae, aphthous stomatitis, arthritis, arteriosclerotic disorders, osteoarthritis, rheumatoid arthritis, 5 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, idiopathic diabetes insipidus, insulin-dependent diabetes mellisis, autoimmune 10 demyelinating diseases, Dupuytren's contracture, encephalomyelitis, encephalomyelitis allergica, endophthaimia phacoanaphylactica, enteritis allergica, autoimmune enteropathy syndrome, erythema nodosum leprosum, idiopathic facial paralysis, chronic fatigue syndrome, febris rheumatica, glomerulo nephritis, Goodpasture's syndrome, Graves' disease, Harnman-Rich's disease, Hashimoto's disease, Hashimoto's thyroiditis, sudden 15 hearing loss, sensoneural hearing loss, hepatitis chronica, Hodgkin's disease, haemoglobinuria paroxysmatica, hypogonadism, ileitis regionalis, iritis, leucopenia, leucemia, lupus erythematosus disseminatus, systemic lupus erythematosus, cutaneous lupus erythematosus, lymphogranuloma malignum, mononucleosis infectiosa, myasthenia gravis, traverse myelitis, primary idiopathic myxedema, nephrosis, ophthalmia symphatica, 20 orchitis granulomatosa, pancreatitis, pemphigus, pemphigus vulgaris, polyarteritis nodosa, polyarthritis chronica primaria, polymyositis, polyradiculitis acuta, psoriasis, purpura, pyoderma gangrenosum, Quervain's thyreoiditis, Reiter's syndrome, sarcoidosis, ataxic sclerosis, progressive systemic sclerosis, scleritis, sclerodermia, multiple sclerosis, sclerosis disseminata, acquired spenic atrophy, infertility due to antispermatozoan 25 antibodies, thrombocytopenia, idiopathic thrombocytopenia purpura, thymoma, acute anterior uveitis, vitiligo, AIDS, HIV, SCID and Epstein Barr virus associated diseases such as Sjorgren's syndrome, virus (AIDS or EBV) associated B cell lymphoma, parasitic diseases such as Leishmania, and immunesuppressed disease states such as viral infections following allograft transplantations, AIDS, cancer, chronic active hepatitis diabetes, toxic 3 0 chock syndrome and food poisoning. Furthermore, the invention relates to a method of treatment or prevention of diseases which comprises the administration of an effective amount of compounds of the (la), (lb), (Ic), 52 (II), or (EI) or a pharmaceutically acceptable salt or pharmaceutically acceptable prodrugs,or a stereoisomer thereof. The invention also provides a pharmaceutical composition comprising a compound of 5 formula (la), (lb), (Ic), (D), or (HI), in free form or in the form of pharmaceutically acceptable salts and pharmaceutically acceptable prodrugs, together with a pharmaceutically acceptable diluent or carrier therefore. In a preferred embodiment, the invention relates to the use of compounds of the formula 10 (la), (lb), (Ic), (II), or (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable prodrugs or a stereoisomer thereof if desired with appropriate adjuvants and additives for the production of a medicament for the treatment or prevention of skin diseases in which T cells play a role; especially preferably the skin diseases are selected from the group consisting of psoriasis, atopic dermatitis, alopecia areata, alopecia totalis, 15 alopecia subtotalis, alopecia universalis, alopecia diffusa, lupus erythematodes of the skin, lichen planus, dermatomyostis of the skin, atopic eczema, morphea, sklerodermia, psoriasis vulgaris, psoriasis capitis, psoriasis guttata, psoriasis inversa, alopecia areata ophiasis-type, androgenetic alopecia, allergic contact eczema, irritative contact eczema, contact eczema, pemphigus vulgaris, pemphigus foliaceus, pemphigus vegetans, scarring mucosal 20 pemphigoid, bullous pemphgoid, mucous pemphigoid, dermatitis, dermatitis herpetiformis duhring, urticaria, necrobiosis lipoidica, erythema nodosum, lichen vidal, prurigo simplex, prurigo nodularis, prurigo acuta, linear IgA dermatosis, polymorphic light dermatoses, erythema solaris, lichen sclerosus et atrophicans, exanthema of the skin, drug exanthema, purpura chronica progressiva, dihidrotic eczema, Eczema, fixed drug exanthema, 25 photoallergic skin reaction, lichen simplex eriorale, dermatitis and "Graft versus Host-Disease", acne, rosacea, scarring, keloids and vitiligo. Moreover, the compounds of the present invention can be used for the treatment of diseases resulting from ischemia and/or reperfusion injury of organs and/or of parts of the 30 body selected from the group comprising heart, brain, peripheral limb, kidney, liver, spleen and lung, and/or wherein the endothelial dysfunction is associated with diseases selected from a group comprising infarctions such as myocardial infarction and critical limb ischemia,and/or wherein the endothelial dysfunction is associated with diseases selected 53 from the group comprising ischemic diseases such as peripheral arterial occlusive disease, e. g. critical leg ischemia, myocardial infarction and ischemic diseases of organs, e. g. of the kidney, spleen, brain and lung. 5 The compounds of this invention also can be applied for the prevention and the treatment of neurological diseases or disorders (diseases or disorders associated with the brain and nervous system), including but not limited to, Alzheimer's disease, Parkinson's disease, Creutzfeld-Jacob Disease, Lewy Body Dementia, amyotrophic lateral sclerosis, stroke, epilepsy, multiple sclerosis, myasthenia gravis, Huntington's Disease, Down's Syndrome, 10 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 of the present invention can further be used for diseases that are caused by 15 protozoal infestations in humans and animals. Such veterinary and human pathogenic protozoas are preferably intracellular active parasites of the phylum Apicomplexa or Sarcomastigophora, especially Trypanosoma, Plasmodia, Leishmania, Babesia and Theileria, Cryptosporidia, Sacrocystida, Amoebia, Coccidia and Trichomonadia. These active substances or corresponding drugs are especially suitable for the treatment of 20 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, caused by Toxoplasma gondii, Coccidiosis, caused for instance by Isospora belli, intestinal Sarcosporidiosis, caused by Sarcocystis suihominis, dysentery caused by Entamoeba 25 histolytica, Cryptosporidiosis, caused by Cryptosporidium parvum, Chargas" disease, caused by Trypanosoma cruzi,. sleeping sickness, caused by Trypanosoma brucei rhodesiense or gambiense, the cutaneous and visceral as well as other forms of Leishmaniosis. They are also suitable for the treatment of animals infected by veterinary pathogenic protozoa, like Theileria parva, the pathogen causing bovine East coast fever, 30 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, Babesia bovis, the pathogen causing European bovine Babesiosis as well as Babesiosis in 54 dogs, cats and sheep, Sarcocystis ovicanis and ovifelis pathogens causing Sarcocystiosis in sheep, cattle and pigs, Cryptosporidia, pathogens causing Cryptosporidioses in cattle and birds, Eimeria and Isospora species, pathogens causing Coccidiosis in rabbits, cattle, sheep, goats, pigs and birds, especially in chickens and turkeys. The use of the compounds of the 5 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. 10 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 (la), (lb), (Ic), (II), or (III) and/or pharmaceutically acceptable salts thereof, effective to prevent 15 and/or treat said infectious disease and/or opportunistic infection. The infectious disease can be selected from the group comprising AIDS, Alveolar Hydatid Disease (AHD, Echinococcosis), Amebiasis (Entamoeba histolytica Infection), Angiostrongylus Infection, Anisakiasis, Anthrax, Babesiosis (Babesia Infection), 20 Balantidium Infection (Balantidiasis), Baylisascaris Infection (Raccoon Roundworm), Bilharzia (Schistosomiasis), Blastocystis hominisi Infection (Blastomycosis), Boreliosis, Botulism, Brainerd Diarrhea, Brucellosis, BSE (Bovine Spongiform Encephalopathy), Candidiasis, Capillariasis (Capillaria Infection), CFS (Chronic Fatigue Syndrome), Chagas Disease (American Trypanosomiasis), Chickenpox (Varicella-Zoster virus), Chlamydia 25 pneumoniae Infection, Cholera, Chronic Fatigue Syndrome, CJD (Creutzfeldt-Jakob Disease), Clonorchiasis (Clonorchis Infection), CLM (Cutaneous Larva Migrans, Hookworm Infection), Coccidioidomycosis, Conjunctivitis, Coxsackievirus A16 (Hand, Foot and Mouth Disease), Cryptococcosis, Cryptosporidium Infection (Cryptosporidiosis), Culex mosquito (Vector of West Nile Virus), Cutaneous Larva Migrans (CLM), 30 Cyclosporiasis (Cyclospora Infection), Cysticercosis (Neurocysticercosis), Cytomegalovirus Infection (CMV), Dengue / Dengue Fever, Dipylidium Infection (Dog and Cat Flea Tapeworm), Ebola Virus Hemorrhagic Fever, Echinococcosis (Alveolar Hydatid Disease), Encephalitis, Entomoeba coli Infection, Entomoeba dispar Infection, Entomoeba hartmanni Infection, Entomoeba histolytica Infection (Amebiasis), Entomoeba 35 polecki Infection, Enterobiasis (Pinworm Infection), Enterovirus Infection (Non-Polio), 55 Epstein-Barr Virus Infection, Escherichia coli Infection, Foodborne Infection, Foot and mouth Disease, Fungal Dermatitis, Gastroenteritis, Group A streptococcal Disease, Group B streptococcal Disease, diseases caused by staphylococcal infections (Staphylococcus aureus and other staphylococcus species), diseases caused by infections with pseudomonas 5 aeruginosa and other pseudomonas species, Burkholderia cepacia infections, Hansen's Disease (Leprosy), Hantavirus Pulmonary Syndrome, Head Lice Infestation (Pediculosis), Helicobacter pylori Infection, Hematologic Disease, Hendra Virus Infection, Hepatitis, Herpes Zoster (Shingles), HIV Infection, Human Ehrlichiosis, Human Parainfluenza Virus Infection, Influenza, Isosporiasis (Isospora Infection), Lassa Fever, Leishmaniasis, Kala-10 azar (Kala-azar, Leishmania Infection), Leprosy, Lice (Body lice, Head lice, Pubic lice), Lyme Disease, Marburg Hemorrhagic Fever, Measles, Meningitis, Mosquito-borne Diseases, Mycobacterium avium Complex (MAC) Infection, Naegleria Infection, Nosocomial Infections, Nonpathogenic Intestinal Amebae Infection, Onchocerciasis (River Blindness), Opisthorciasis (Opisthorcis Infection), Parvovirus Infection, Plague, PCP 15 (Pneumocystis carinii Pneumonia), Polio, Q Fever, Rabies, Respiratory Syncytial Virus (RSV) Infection, Rheumatic Fever, Rift Valley Fever, River Blindness (Onchocerciasis), Rotavirus Infection, Roundworms Infection, Salmonellosis, Salmonella Enteritidis, Scabies, Shigellosis, Shingles, Sleeping Sickness, Smallpox, Streptococcal Infection, Tapeworm Infection (Taenia Infection), Tetanus, Toxic Shock Syndrome, Tuberculosis, 20 Ulcers (Peptic Ulcer Disease), Valley Fever, Vibrio parahaemolyticus Infection, Vibrio vulnificus Infection, Viral Hemorrhagic Fever, Warts, Waterborne infectious Diseases, West Nile Virus Infection (West Nile Encephalitis), Whooping Cough, Yellow Fever. The compounds of formula (la), (lb), (Ic), (II), or (III) and their pharmacologically 25 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 active constituent contain an effective dose of at least one compound of the formula (la), (lb), (Ic), (II), or (III) or a salt thereof, in addition to customary pharmaceutically 30 innocuous excipients and additives. The compounds of formula (la), (lb), (Ic), (II), or (IH) can also be administered in form of their salts, which are obtainable by reacting the respective compounds with physiologically acceptable acids and bases. The production of medicaments containing the compounds of formula (la), (lb), (Ic), (II), 35 or (HI) according to the invention and their application can be performed according to well-known pharmaceutical methods. 56 While the compounds of formula (la), (lb), (Ic), (II), or (HI) 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 5 acceptable salt in a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents, and/or other customary pharmaceutical auxiliaries. Such salts of the compounds may be anhydrous or solvated. In a preferred embodiment, the invention provides medicaments comprising compounds of 10 formula (la), (lb), (Ic), (II), or (III) according to the invention, or a pharmaceutically acceptable salt or pharmaceutically acceptable prodrugs or a stereoisomer thereof, together with one or more pharmaceutically acceptable carriers thereof, and, optionally, other therapeutic and/or prophylactic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to 15 the recipient thereof. A medicament of the invention may be those suitable for oral, rectal, bronchial, nasal, topical, buccal, sub-lingual, transdermal, vaginal or parenteral (including cutaneous, subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial, intracerebral, intraocular injection or infusion) administration, or those in a form suitable for 20 administration by inhalation or insufflation, including powders and liquid aerosol administration, or by sustained release systems. Suitable examples of sustained release systems include semipermeable matrices of solid hydrophobic polymers containing the compound of the invention, which matrices may be in form of shaped articles, e.g. films or microcapsules. 25 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 liquids, in particular aqueous or non-aqueous solutions, suspensions, emulsions, elixirs, 30 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 57 contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. The compound useable according to the invention can be administered in a wide variety of 5 oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as the active component, either a compound of formula (la), (lb), (Ic), (II), or (IH) according to the invention or a pharmaceutically acceptable salt or stereosomer thereof. 10 For preparing a medicament from a compounds of formula (la), (lb), (Ic), (II), or (HI) pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet 15 disintegrating agents, or an encapsulating material. In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size 20 desired. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with 25 or without carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration. For preparing suppositories, a low melting wax, such as a mixture of fatty acid glyceride or 30 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 58 sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate. Liquid preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions. For example, parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution. 5 The compounds of formula (la), (lb), (Ic), (13), or (HI) according to the present invention may thus be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added 10 preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulation agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before 15 use. Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilising and thickening agents, as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic 20 gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include 25 solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavours, stabilisers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like. In one embodiment of the present invention, the medicament is applied topically or 30 systemically or via a combination of the two routes. 59 In an especially preferred embodiment of the present invention the medicament is applied topically. This reduces possible side effects and limits the necessary treatment to those areas affected. 5 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 (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 10 the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents. 15 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. 20 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 25 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, 30 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. 60 Alternatively the active ingredients may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP). Conveniently the powder carrier will form a gel in the nasal cavity The powder 5 composition may be presented in unit dose form for example in capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler. In compositions intended for administration to the respiratory tract, including intranasal 10 compositions, the compound will generally have a small particle size for example of the order of 5 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization. When desired, compositions adapted to give sustained release of the active ingredient may 15 be employed. The 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 20 discrete quantities of preparation, such as packaged tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are preferred compositions. 25 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 (la), 30 (lb), (Ic), (II), or (IH) or their pharmacologically acceptable salts and also other therapeutically active substances. 61 Thus, the compounds of the present invention can be used in the form of one compound alone or in combination with other active compounds - for example with medicaments already known for the treatment of the aforementioned diseases, whereby in the latter case a favorable additive, amplifying effect is noticed. Suitable amounts to be administered to 5 humans may range from 5 to 500 mg. To prepare the pharmaceutical preparations, pharmaceutically inert inorganic or organic excipients can be used. To prepare pills, tablets, coated tablets and hard gelatin capsules, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts, etc. 10 . can be used. Excipients for soft gelatin capsules and suppositories are, for example, fats, waxes, semi-solid and liquid polyols, natural or hardened oils etc. Suitable excipients for the production of solutions and syrups are, for example, water, sucrose, invert sugar, glucose, polyols etc. Suitable excipients for the production of injection solutions are, for example, water, alcohols, glycerol, polyols or vegetable oils. 15 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 20 animal body weight preferably 1 to 50 mg/kg. In general, suitable dosage rates for larger 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. 25 In general, a daily dose of approximately 10 mg to 5000 mg, preferably 50 to 500 mg, per human individual is appropriate in the case of the oral administration. In the case of other administration forms too, the daily dose is in similar ranges. For topical delivery, depending on the permeability of the skin, the type and the severity of the disease and dependent on the type of formulation and frequency of application, different concentrations 30 of active compounds within the medicament can be sufficient to elicit a therapeutic effect by topical application. Preferably the concentration of an active compound or a pharmaceutically acceptable salt thereof or a physiologically functional derivative or a 62 stereoisomer thereof within a medicament according to the invention is in the range of between 1 jj.mol/1 and 100 mmol/1. The following examples and figures are included to demonstrate preferred embodiments of 5 the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples that follow represent techniques discovered by the inventors to function well in the practice of the invention, and thus can be considered preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments that are disclosed 10 without departing from the spirit and scope of the invention as set out in the appended claims. All references cited are incorporated herein by reference. Examples Abbreviations: min, minute(s); h, hour(s); r.t., room temperature; t-, tert-. 15 NMR spectra: Bruker Avance 300 MHz. The spectra were recorded at 300 MHz (1H-NMR), respectively, using the residual solvent peak as an internal standard (DMSO-de, 8h = 2.49; CD3OD, 5h = 3.31; CDCI3,8H = 7.26; CD3CN, 8H = 1.93; (CD3)2CO, 5H = 2.05). Analytical LC/ESI-MS: 2 x Waters 600 Multisolvent Delivery System. 50 [xl sample loop. Column, Chromolith Speed ROD RP18e (Merck, Darmstadt), 50 x 4.6 mm, with 2 jam 20 prefilter (Merck). Eluent A, H2O + 0.1% HCO2H; eluent B, MeCN. Gradient, 5 % B to 100 % B within 5 min; flow, 3 ml/min. Waters LCZ single quadrupol mass spectrometer with electrospray source. MS 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 25 Dual XAbsorbance Detector, set to 254 nm. Preparative HPLC-MS: Waters 600 Multisolvent Delivery System with peparative pump heads. 2000 jil or 5000 fil sample loop. Column, Waters X-Terra RP18, 7 \im, 19 x 150 mm with X-Terra RP18 guard cartridge 7 |im, 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 jim, 19x10 mm; 30 used at flow rate 50 ml/min. Make-up solvent: MeCN — H2O — HCO2H 80 : 20 : 0.05 (v:v:v). Eluent A, H2O + 0.1% HC02H; eluent B, MeCN. Different linear gradients from 5 63 - 100% eluent B, adapted to sample. Injection volume: 500 pi - 2000 pi 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 5 and 350° C, respectively. Waters Fraction Collector II with mass-triggered fraction collection. Waters 996 photo diode array detector. Synthesis of 4-(Methoxy-methyl-carbamoyl)-piperidine-l-carboxylic acid t-butyl ester Piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.0 eq, 21.8 mmol) was dissolved 10 under inert conditions in 35 ml dry N, N- dimethylformamide. 0,N-dimethyl-hydroxylamine hydrochloride (1.03 eq, 22.5 mmol), benzotriazol-l-ol monohydrate (1.03 eq, 22.5 mmol) and triethylamine (1.5 eq, 32.7 mmol) were added. The reaction mixture was cooled to 0°C, N-(3-Dimethylaminopropyl)-N-ethylcarbodiimid hydrochloride (1.0 eq, 21.8 mmol) was added over a period of 10 minutes and the mixture was stirred vigorously 15 at 0°C for 1 h and at r.t. for 18 h. The solvent was removed under vaccum and the residue was suspended in 400 ml ethylacetate. The organic layer was extracted 3 times with 100 ml of 1 M citric acid, aqueous sodium carbonate and twice with 100 ml brine, dried over MgSC>4 and filtered. The solvent was removed and the residue was purified by distillation resulting in a yield of 20 80%. Synthesis of 4-Formy 1-piperidine-l-carboxylic acid t-butyl ester 4-(methoxy-methyl-carbamoyl)-piperidine-l-carboxylic acid tert-butyl ester (1.0 eq, 16.4 mmol) was dissolved in 100 ml dry tetrahydrofurane under inert atmosphere. This solution 25 was added dropwise over a period of 1 h to a suspension of lithiumalanate (3.0 eq, 49.6 mmol) in 70 ml dry tetrahydrofurane at -50°C. During the adding of the mixture, the temperature was held at — 50°C and then allowed to warm to 0°C within 3 h. The mixture was cooled to -78 °C and quenched carefully with 100 ml 1 M citric acid. The mixture was warmed up to r.t. and diluted with 400 ml ethylacetate. The phases were 30 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 MgSC>4 and filtrated. The solvent was removed and the residue was purified by distillation resulting in a yield of 85% 35 64 Synthesis of 4-(4-Ethoxycarbonyl-4,5-dihydro-thiazoI-2-yl)-piperidine-l-carboxylic acid t-butyl ester 4-formyl-piperidine-l-carboxylic acid tert-butyl ester (1.0 eq, 13 mmol) was dissolved under inert conditions in 40 ml toluene. To this solution L-cystein ethylester hydrochloride 5 (1.6 eq, 21 mmol) and triethylamine (1.6 eq, 21 mmol) were added. The mixture was refluxed for 14 h. The generated water was removed with a Dean & Stark trap. The solvent was removed and the residue was dissolved in 100 ml ethylacetate. The organic layer was extracted 3 times with 50 ml 1 M citric acid, aqueous potassium hydrogen carbonate and 2 times with 50 ml brine, dried over MgSC>4 and filtrated. The 10 solvent was removed and the residue was purified by silica gel chromatography using a PE/EA 4:1 gradient. Yield: 75% Synthesis of 4-(4-Ethoxycarbonyl-thiazol-2-yl)-piperidine-l-carboxylic acid t-butyl ester 15 4-(4-Ethoxycarbonyl-4,5 -dihydro-thiazol-2-yl)-piperidine-1 -carboxylic acid tert-butyl ester (1.0 eq, 8.7 mmol) was solved in 160 ml toluene under inert conditions. To this solution MnC>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 20 residue was purified by silica gel chromatography using a DCM/MeOH 95:5 gradient. Yield: 30% C-terminal functionalisation 4-(4-Ethoxycarbonyl-thiazol-2-yl)-piperidine-l-carboxylic acid tert-butyl ester (1.0 eq, 2.9 25 mmol) was dissolved under inert gas in 40 ml dioxane. Under stirring 1.5 ml aqueous 2 N NaOH was added dropwise over a period of 10 min. Afterwards the mixture was stirred for 2 h at r.t. The reaction was neutralized with 2 N HC1 and the solvent was evaporated in vacuo. The residue was dissolved in 50 ml ethylacetate. The organic layer was extracted 3 times with 30 10 ml of 1 M citric acid and water, dried over MgSC>4 and filtered. The solvent was removed and the residue was dried in vacuo. Yield 95% 4-(4-Carboxy-thiazol-2-yl)-piperidine-l-carboxylic acid tert-butyl ester (1 eq) was dissolved under inert conditions in dry dimethylacetamide (0,03 mmol/ml). To this 35 solution aryl- or alkylamine (1 eq), diisopropylethylamine (2 eq) and O-benzotriazol-l-yl-N,N,N',N'-tetramethyluronium hexafiuorophosphate (2 eq) was added. The reaction mixture was stirred for 12 h at r.t. 65 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 MgSC>4 and filtred. The solvent was removed and the residue was purified by silica gel chromatography using a DCM/MeOH 5 95:5gradient Yield: 40-80% N-terminal functionalisation The N-protected substrate was treated under inert condition with 4 M HCl/dioxane (conc. 0,03 mmol substrate in 1 mL HCl/dioxane) and was stirred for 2 h at r.t. 10 The solvent was removed in vacuo to yield the HC1 salt of the free amine without further purification. The free amino compound (1 eq) was dissolved under inert conditions in dry dimethylacetamide (0,03 mmol/ml). To this solution aryl- or alkylcarboxylic acid (1 eq), 15 diisopropylethylamine (2 eq) and O-benzotriazol-1 -yl-N,N,N\N'-tetramethyluronium hexafluorophosphate (2 eq) was added in this sequence and the reaction mixture was stirred for 12 h at r.t. The solvent was removed in vacuo and the residue was dissolved in ethylacetate. The organic layer was extracted 3 times with 1 M citric acid, aqueous potassium hydrogen 20 carbonate and 2 times with brine, dried over MgSC>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% General synthesis for compounds of type (HI) and (ET) 25 Procedure for the synthesis of compounds of type (Ilia), (IIIc), (Ila) and (lib) 7,3x10"4 mol of the benzoic acid derivative (VI) was dissolved in 5 ml DMF and 1 eq. of Hiinig's base was added, stirring the reaction mixture for a few minutes, followed by the addition of 1 eq. of HBTU and further stirring at r.t. for 2 min. Afterwards 1 eq. 2-Amino-thiazole-4-carboxylic acid ethyl ester was added, stirring the mixture overnight at the same 30 temperature. Subsequently, the solvent was removed by filtration and the residue redissolved in 5 ml dioxane and treated with 0,5 ml of a 1M NaOH solution. After the reaction was complete, the pH was decreased to 1-2 with a 1M HC1 solution and the precipitated product (VII) filtered and dried in vacuo. For the next step, intermediate (VII) was dissolved in 3 ml DMF and 1 eq. of Hiinig's base was added, stirring the reaction 35 mixture for a few minutes, followed by the addition of 1 eq. of HBTU and further stirring at r.t. for 2 min. Afterwards 1 eq. the amino component was added, stirring the mixture 66 overnight at the same temperature. Subsequently, the solvent was removed by filtration and the crude product redissolved in 10 ml ethyl acetate, washed twice with 10 ml citric acid (1M solution), 10 ml sat. NaHC03 solution and 10 ml water. The organic phase was then evaporated and the residue dried over MgSC>4. The solvent was removed and final 5 purification was realised by preparative HPLC as described above. As a second variante for the first step, the corresponding acid chloride derivative of (VI) could be reacted with the 2-Amino-thiazole-4-carboxylic acid ethyl ester (1:1) using 1,1 eq. of Hiinig's base. Procedure for the synthesis of compounds of type (Illb, d, e, f) and (lie, d) 10 6,3x1c4 mol of 2-Bromo-thiazole-4-carboxyIic 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 15 the procedure for the synthesis of compounds of type (Ilia) and (IIIc). For as synthesis-protocol of type (Illb, d, e, f and lie, d) compounds with Z = CH, see WO 2004/058750. 20 Examplary compounds of formula (la) of the present invention include, but are not limited to, the followings: Cp. Name Mass LC/(+)-ESI-MS: Biological activity1* 74 4-{4-[4-(3-Trifluoromethyl-phenyl)-piperazine-1 -carbonyl]-thiazol-2-yl} -piperidine-1-carboxylic acid (7-fluoro-2,3-dihydro-benzo[ 1,4]dioxin-5-yl)-amide 619 620 [M+H]+ ++ 75 4-{4-[4-(3-Trifluoromethyl-phenyl)-piperazine-1 -carbonyl] -thiazol-2-yl} -piperidine-1-carboxylic acid (2,3-dihydro-benzo F1,4] dioxin-6-yl)-amide 601 602 [M+H]+ ++ 76 4- {4- [4-(3-Trifluoromethyl-phenyl)-piperazine-1 -carbonyl] -thiazol-2-yl} -piperidine-l-carboxylic acid (5-methyl-2- 615 616 [M+H]+ ++ 67 trifluoromethyl-furan-3 -yl)-amide 77 4- {4- [4-(3 -Trifluoromethyl-plienyl)-piperazine-1 -carbonyl]-tMazol-2-yl} -piperidine-l-carboxylic acid (2-thiophen-2-yl-eth.yl)-amide 577 578 [M+H]+ I i-1 78 4-{4-[4-(3-Trifluoromethyl-phenyl)-piperazine-1 -carbonyl]-thiazol-2-yl} -piperidine-l-carboxylic acid isopropylamide 509 510 [M+Hf + 79 4- {4- [4-(3 -Trifluoromethyl-phenyl)-piperazine-1 -carbonyl]-thiazol-2-yl}-piperidine-1-carboxylic acid (2-trifluoromethoxy-phenyl)-amide 627 628 [M+H]+ I l-1 80 4-{4-[4-(3-Trifluoromethyl-phenyl)-piperazine-1 -carbonyl] -thiazol-2-yl} -piperidine-l-carboxylic acid (3-methoxy-phenyl)-amide 573 574 EM+H]+ + 81 4- {4- [4-(3 -Trifluoromethyl-phenyl)-piperazine-1 -carbonyl]~thiazol-2-yl) -piperidine-l-carboxylic acid (3,4,5-trimethoxy-phenyl)-amide 633 634 [M+H]+ ++ 114 4-(4- {4-[4-(3 -Trifluoromethyl-phenyl)-piperazine-1 -carbonyl]-tbiazol-2-yl}-piperidine-1 -carbonyl)-benzonitrile 568 569 [M+H]+ + 134 4-{4-[4-(3-Trifluoromethyl-phenyl)-piperazine-1 -carbonyl]-thiazoI-2-yl} -piperidine-l-carboxylic acid phenylamide 543 544 [M+Hf + 142 4- {4- [4-(3 -Trifluoromethyl-plienyl)-piperazine-1 -carbonyl]-thiazol-2-yl}-piperidine-1-carboxylic acid (3-fluoro-phenyl)-amide 561 562 [M+H]+ ++ 143 4- {4-[4-(3 -Trifluoromethyl-phenyl)-piperazine-1 -carbonyl]-thiazol-2-yl) -piperidine-l-carboxylic acid (4-fluoro-phenyl)-amide 561 562 [M+Hf + 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] 68 Examplary compounds of formula (lb) of the present invention include, but are not limited to, the followings: Cp. Name Mass LC/(+)-ESI-MS: Biological activity1* 103 2- { 5-Methyl-2-[l -(2-trifluoromethoxy-benzoyl)-piperidin-4-yl] -thiazol-4-yl}-1 -[4-(3-trifluoromethyl-phenyl)-piperazm-l-yl]-ethanone 640 641 [M+Hf ++ 128 1 -[4-(3-Chloro-phenyl)-piperazin-l -yl]-2-{5-methyl-2-[l-(2-trifhioromethoxy-benzoyl)-piperidin-4-yl]-thiazol-4-yl} -ethanone 606 607 [M+Hf +++ 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] 5 Examplary compounds of formula (Ic) of the present invention include, but are not limited to, the followings: Cp. Name Mass LC/(+)-ESI-MS: Biological activity1* 150 [ 1 -(5~Chloro-2-methylamino-phenyl)-3,4-dihydro-1 H-isoquinolin-2-yl]- {2-[ 1 -(2-tri£luoromethoxy-benzoyl)-piperidin-4-yl]-thiazol-4-yl}-methanone 654 655 [M+H]+ ++ 160 l-{4-[4-(6,7-Dihydroxy-3,4-dihydro-lH-isoquinoline-2-carbonyl)-thiazol-2-yl] -piperidin-1 -yl} -2-(4-fluoro-phenyl)-ethanone 495 496 [M+H]+ + 161 1 -{4-[4-(6,7-Dimethoxy-3,4-dihydro-1H-isoquinoline-2-carbonyl)-thiazol-2-yl]-piperidin-1 -yl) -2-(4-fluoro-phenyl)-ethanone 523 524 [M+H]+ + 163 l-{4-[4-(3,4-Dihydro-lH-isoquinoline-2-carbonyl)-thiazol-2-yl]-piperidin-l -yl) -2-(4-fluoro-phenyl)-ethanone 463 464 [M+H]+ + 232 l-{4-[4-(6,7-Dimethoxy-3-methyl-3,4-dihydro-1 H-isoquinoline-2-carbonyl)- 537 538 fM+Hf + 69 thiazol-2-yl]-piperidin-l-yl}-2-(4-£luoro-phenyl)-ethanone 233 1 -{4-[4~(6,7-Dihydroxy-1 -methyl-3,4-dihydro-1 H-isoquinoline-2-carbonyl)-thiazol-2-yl]-piperidin-1 -yl) -2-(4-fluoro-phenyl)-ethanone 509 510 [M+Hf + 234 1 - {4-[4-(6,7-Dimethoxy-1 -methyl-3,4-dihydro-1 H-isoquinoline-2-carbonyl)-thiazol-2-yl]-piperidin-1 -yl} -2-(4-fluoro-phenyl)-ethanone 537 538 [M+Hf + 235 1 -(4- {4-[ 1 -(5-Chloro-2-methylamino-phenyl)-3,4-dihydro-1 H-isoquinoline-2-carbonyl]-thiazol-2-yl} -piperidin-1 -yl)-2~ (4-fluoro-phenyl)-ethanone 602 603 [M+Hf + The biological data refer to results obtained from the NF-kB inflammation assay. ["+" stands for 50-80% inhibition,"++" means 80-90% and "+++" stands for 90-100% inhibition] Examplary compounds of formula (II) of the present invention include, but are not limited 5 to, the followings: Cp. Name Mass LC/(+)-ESI-MS: Biological activity1* 3 N- {4-[4-(4-Fhioro-phenyl)-piperazine-1 - carbonyl]-thiazol-2-yl}-2-trifluoromethoxy- benzamide 494 495 [M+H]+ ++ 5 N-[5-(4-Pyrimidin-2-yl-piperazine-l - carbonyl)-thiazol-2-yl]-2-trifluoromethoxy- benzamide 478 479 [M+Hf + 15 2-Methoxy-N- {4- [4-(3-trifluoromethyl-phenyl)-piperazine-1 -carbonyl] -thiazol-2-yl}-benzamide 490 491 [M+Hf +++ 16 3 -Fluoro-4-trifluoromethyl-N-( 1 - {4-[4-(3 -trifluoromethyl-phenyl)-pipera zine-1 -carbonyl]-thiazol-2-yl}piperidin-4-ylmethyl)-benzamide 643 644 [M+Hf ++ 17 3-Cyclopentyl-N-(l - {4-[4-(3-trifluoromethyl-pheny l)-piperazine-1 -carbonyl]-thiazol-2-yl} -piperidin- 577 578 [M+Hf ++ 70 4ylmethyl)-propionamide 18 2-Trifluoromethoxy-N-(l-{4-[4-(3-Mfluoromethyl-phenyl)-piperazine-1 -carbonyl]-tMazol-2-yl}-piperidin-4ylmethyl)-benzamide. 641 642 [M+Hf ++ 19 4-Cyano-N-(l-{4-[4-(3-trffluoromethyl-phenyl)-piperazine-1 -carbonyl] -thiazol-2-yl} -piperidin-4-ylmethyl)-benzamide 582 583 [M+Hf ++ 20 [4-(3-Trifluorome&yl-phenyl)-piperazin-l-yl]-{2-[4-(4-trifluoromethyl-phenyI)-piperazin-1 -yll-thiazol-4-yl}-methanone 569 570 [M+Hf ++ 21 {2-[4-(4-Trifluoromethoxy-phenyl)-piperazin-1 -yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1 -yl]-methanone 585 586 [M+Hf + 22 {2-[4-(2-Trifluoromethoxy-benzyl)-piperazin-1 -yl] -thiazol-4-yl} - [4-(3 -trifluoromethyl-phenyl)-piperazin-l-yl]-methanone 599 600 [M+Hf +f+ 23 {2-[4-(4-Bromo-benzyl)-piperazin-l-yl]-thiazol-4-yl} -[4-(3 -trifluoromethyl-phenyl)-piperazin-1 -yl] -methanone 593 594 [M+Hf +++ 24 (2-[4-(3-Trifluorometh.oxy-benzyl)-piperazin-1 -y 1]-thiazol-4-yl} - [4-(3 -trifluoromethyl-phenyl)-piperazin-1 -yl] -methanone 599 600 [M+Hf +++ 32 2-Trifluoromethoxy-N- {4-[4-(3-trifluoromethyl-phenyl)-piperazine-1 -carbonyl] -thiazol-2-yl} -benzamide 544 545 [M+Hf I i I 33 3-Cyclopentyl-N-{4-[4-(3-trifluoromethyl-phenyl)-piperazine-1 -carbonyl]-thiazol-2-yl) -propionamide 480 481 [M+Hf +++ 34 3 -Fluoro-4-trifluoromethyl-N- {4-[4-(3 - trifluoromethyl-phenyl)-piperazine-l- carbonyl]-thiazol-2-yl}-benzamide 546 547 [M+Hf +++ 37 3-Cyclopentyl-l -(4- {4-[4-(3-trifluoromethyl-phenyl)-piperazine-l- 549 550 [M+Hf +++ 71 carbonyl]-thiazol-2-yl} -piperazin-1 -yl)-propan-l-one 38 {2-[4-(2-Methoxy-benzoyl)-piperazin-1 - yl]-thiazol-4-yl}-[4-(3-trifluoromethyl- phenyl)-piperazia-l-yl]-methanone 559 560 [M+Hf +++ 39 {2-[4-(2-Trifluoromethoxy-benzoyl)-piperazin-1 -yl]-thiazol-4-yl} -[4-(3-trifluoromethyl-phenyl)-piperazin-1 -yl]-methanone 613 614 [M+Hf +++ 41 N-{4-[4-(3,4-Dichloro-phenyl)-piperazine- l-carbonyl]-thiazol-2-yl}-2- trifluoromethoxy-benzamide 544 545 [M+Hf +++ 44 N- {4-[4-(2-Methoxy-phenyl)-piperazine-l -carbonyl] -thiazol-2-yl} -2-trifluoromethoxy-benzamide 506 507 [M+Hf ++ 55 l-(2-Trifluoromethoxy-phenyl)-3-{4-[4-(3-trifluoromethyI-phenyl)-piperazine-1 -carbonyl] -thiazol-2-yl} -urea 559 560 [M+Hf •1 II" 58 N-[4-(4-Benzhydryl-piperazine-1 - carbonyl)-thiazol-2-yl]-2-trifluoromethoxy- benzamide 566 567 [M+Hf ++ 59 (2-[4-(3,5-Bis-trifluoromethyl-benzoyl)-piperazin-1 -yl] -thiazol-4-yl} - [4-(3 -trifluorometh.yl-phenyI)-piperazin-l-yl]-methanone 665 666 [M+Hf + 60 {2-[4-(3-Fluoro-4-trifluoromethyl-benzoyl)-piperazin-1 -yl]-thiazol-4-yl) -[4-(3 -trifluoromethyl-phenyl)-piperazin-1 -y 1] -methanone 615 616 [M+Hf +++ 61 4-(4- {4-[4-(3 -Trifluoromethyl-phenyl)-piperazine-1 -carbonyl]-thiazol-2-yl} -piperazine-1 -carbonyl)-benzonitrile 554 555 [M+Hf +++ 62 4-(4- {4-[4-(3 -Trifluoromethyl-phenyl)-piperazine-1 -carbonyl]-tbiazol-2-yl}-piperazme-l-ylmeth.yl)-benzonitrile 540 541 [M+Hf +++ 63 4_{4_[4-(3_Trifluoromethyl-plienyl)-piperazine-1 -carbonyl]-thiazol-2-yl) - 525 52 6 [M+Hf ++ 72 piperazine-l-carboxylic acid /erf-butyl ester 64 (2-Piperazin-l-yl-thiazol-4-yl)-[4-(3-trifluoromethyl-phenyl)-piperazin-1 -yl] -methanone 425 426 [M+Hf + 65 {2-[4-(2-Methoxy-phenyl)-piperazin-l-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1 -yl]-methanone 531 532 [M+Hf ++ 66 1 - [4-(4-{4-[4-(3-Trifluoromethyl-phenyl)-piperazine-1 -carbonyl]-thiazol-2-y 1} -piperazin-1 -yl)-phenyl]-ethanone 543 544 [M+Hf ++ 67 [4-(3-Trifluoromethyl-phenyl)-piperazin-1 -yl]-{2-[4-(3-trifluoromethyl-phenyl)-piperazin-1 -yl] -thiazol-4-yl} -methanone 569 570 [M+Hf + 68 [2-(4-Phenyl-piperazin-1 -yl)-thiazol-4-yl]-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-methanone 501 502 [M+Hf + 69 {2-[4-(4-Fluoro-phenyl)-piperazin-1 -yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1 -yl]-methanone 519 520 [M+Hf ++ 71 (4-Benzhydryl-piperazin-1 -yl)-[2-(4-benzyl-piperazin-1 -yl)-thiazol-4-yl]-methanone 537 538 [M+Hf +++ 72 [2-(4-Benzyl-piperazin-1 -yl)-thiazol-4-yl] -[4-(3-trifluoromethyl-phenyl)-piperazin-1 -yl]-methanone 515 516 [M+Hf +++ 99 3-Fluoro-4-trifluoromethyl-N-(l-{4-[4-(3-trifluoromethyl-phenyl)-piperazine-1 -carbonyl]-thiazol-2-yl}-piperidin-4-ylmethyl)-benzamide 642 643 [M+Hf + 100 3-Cyclopentyl-N-(l-{4-[4-(3-trifluoromethyl-phenyl)-piperazine-1 -carbonyl]-thiazol-2-yl}-piperidin-4-ylmethyl)-propionamide 576 577 [M+Hf + 101 2-Trifluoromethoxy-N-(l-{4-[4-(3-trifluoromethyl-phenyl)-piperazine-l -carbonyl]-thiazol-2-yl}-piperidin-4-ylmethyl)-benzamide 640 641 [M+Hf + 73 102 4-Cy ano-N-( 1 - {4- [4-(3 -trifluoromethyl-phenyl)-piperazine-1 -carbonyl]-thiazol-2-yl} -piperidin-4-ylmethyl)-benzamide 581 582 [M+Hf + 241 {2-[l -(2,6-Dimethoxy-pyrimidin-4-yl)-piperidin-4-yl3-5-methoxy-oxazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-methanone 576 577 [M+Efj ++ 242 {2-[l-(4,6-Dimethoxy-[l ,3,5]triazin-2-yl)-piperidin-4-yl]-5-methoxy-oxazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-methanone 577 578 [M+Hfl 4+ 243 {2-[l -(2,6-Dimethoxy-pyrimidin-4-yl)-piperidin-4-yl]-5-methoxy-oxazol-4-yl} - [4-(5 -trifluoromethyl-benzotriazol-1 -yl)-piperidin-1 -yl]-methanone 616 617 [M+H4] ++ 244 {2- [ 1 -(4,6-Dimethoxy-[ 1,3,5]triazin-2-yl)-piperidin-4-yl]-5-methoxy-oxazol-4-yl} - [4-(5-trifluoromethyl-benzotriazol-1 -yl)-piperidin-1 -yl]-methanone 617 618 [M+H*l ++ 245 4-(4-{ 4-[4-(5-Trifluoromethyl-benzotriazol-1 -yl)-piperidine-1 -carbonyl] -thiazol-2-yl} -piperazin-1 -yl-methyl)-benzonitrile 580 581 [M+H]+ ++ 246 (2-Morpholin-4-yl-oxazol-4-yl)-[4-(3- trifluoromethyl-phenyl)-piperazin-l-yl]- methanone 410 411 [M+H]+ + The biological data refer to results obtained from the NF-kB inflammation assay. ["+" stands for 50-80% inhibition,"++" means 80-90% and "+++" stands for 90-100% inhibition] Examplary compounds of formula (III) of the present invention include, but are not limited 5 to, the followings: Cp. Name Mass LC/(+)-ESI-MS: Biological activity1* 1 2-Morpholin-4-yl-thiazole-4-carboxylic acid (5,6-dimethyI-1 H-benzoimidazol-2-yl)-amide 357 358 [M+Hf + 2 2-[3-(2-Trifluoromethoxy-phenyl)-ureido]-thiazole-4-carboxylic acid (1H- 462 463 [M+Hf + 74 benzoimidazol-2-yl)-amide 4 2-(2-Fluoro-benzoylamitio)-thiazole-4-carboxylic acid (5,6-dimethyl-lH-benzoimidazol-2-yl)-amide 409 410 [M+Hf + 6 N-{4-[N'-(lH-Benzoimidazol-2-yl)-guanidinocarbonyl]-thiazol-2-yl}-3,4-difluoro-benzamide 441 442 [M+Hf ++ 7 N-{4-psf'-(lH-BeDzoimidazol-2-yl)- guanidinocarbonyl]-thiazol-2-yl}-4-fluoro- benzamide 423 424 [M+Hf ++ 8 N- {4-[N'-(lH-Benzoimidazol-2-yl)-guanidinocarbonyl]-oxazol-2-yl} -2-trifluoromethoxy-benzamide 473 474 [M+Hf +++ 9 2-(2-Trifhioromethoxy-benzoylammo)-thiazole-4-carboxylic acid (4-dimethylamino-[l ,3,51 triazin-2-yl)-amide 453 454 [M+Hf + 10 N- {4-[N-(1 H-Benzoimidazol-2-yl)- guanidinocarbonyl]-thiazol-2-yi}-4-bromo- benzamide 483 484 [M+Hf ++ 11 N-{4-[N'-( 1 H-Benzormidazol-2-yl)-guanidinocarbonyl]-thiazol-2-yl} -2-methoxy-benzamide 435 436 [M+Hf ++ 12 N-{4-[N'-(lH-Benzoimidazol-2-yl)-guanidinocarbonyl] -thiazol-2-yl} -2-trifluoromethoxy-benzamide 489 490 [M+Hf +++ 13 N-(lH-Benzoimidazol-2-yl)-N'-{2-[4-(2-trifluoromethoxy-benzoyi)-piperazin-1 -yl]-thiazole-4-carbonyl} -guanidine 558 559 [M+Hf + 14 N-(lH-Benzoimidazol-2-yl)-N'-[2-(2,3-dihydro-benzo [ 1,4] dioxin-2-yl)-thiazole~4-carbonyl] -guanidine 420 421 [M+Hf + 25 2-(2-Trifluoroniethoxy-benzoylamino)-thiazole-4-carboxylic acid (5,6-dimethyl-lH-benzoimidazol-2-yl)-amide 475 476 [M+Hf +++ 26 2-(3-Fluoro-4-trifluoromethyl-benzoyIamino)-oxazole-4-carboxylic acid ethyl ester 536 537 [M+Hf +++ 75 27 N- {4-[N'-(l H-Benzoimidazol-2-yl)-guanidinocarbonyl]-oxazol-2-yl} -3 -fluoro-4-trifIuoromethyl-benzamide 475 476 [M+m+ +++ 30 N-(lH-Benzoimidazol-2-yl)-N'-[2-(4-benzyl-piperazin-1 -yl)-thiazole-4-carbonyll -guanidine 460 461 [M+Hf +++ 31 2-(2-Trifluoromethoxy-benzoylaxnino)-tMazole-4-carboxylic acid (1H-benzoimidazol-2-yl)-amide 447 448 [M+Hf +++ 36 N-(lH-Benzoimidazol-2-yl)-N'-{2-[l-(2-trifluoromethoxy-benzoyl)-piperidin-4-yl]~ thiazole-4-carbonyl} -guanidine 557 558 [M+Hf +++ 40 2-(2-Trifluoromethoxy-benzoylamino)-oxazole-4-carboxylic acid (5,6-dimethyl-lH-benzoimidazol-2-yl)-amide 459 460 [M+Hf +++ 42 2-(2-Trifhioromethoxy-benzoylamino)-thiazole-4-carboxylic acid [6-(4-methyl-piperazin-1 -yl)-benzothiazol-2-yl] -amide 562 563 [M+Hf I l i 43 2-(2-Trifluoromethoxy-benzoylatnino)-thiazole-4-carboxylic acid (5-nitro-lH-benzoimidazol-2-yl)-amide 492 493 [M+Hf +++ • 45 N-{4-pSP-(lH-Benzoimidazol-2-yl)-guanidinocarbonyl]-thiazol-2-yl}-2-cyclohexyl-benzamide 487 488 [M+Hf +++ 46 2-(2-Trifluoromethoxy-benzoylamino)-thiazole-4-carboxylic acid (1-methyl-1H-benzoimidazol-2-yl)-amide 461 462 [M+Hf i i i r 47 2-(2-Trifluoromethoxy-benzoylamino)-thiazole-4-carboxylic acid [5-(propane-l-sulfonyl)-1 H-benzoimidazol-2-yl] -amide 553 554 [M+Hf 1 1 1 49 N-(l H-Benzoimidazol-2-yl)-N-(2- morpholin-4-yl-thiazole-4-carbonyl)- guanidine 371 372 [M+Hf +++ 51 N-{4-[N'-(lH-Benzoimidazol-2-yl)-guanidinocarbonyl]-thiazol-2-yl}-4-trifluoromethyl-benzamide 473 474 [M+Hf +++ 52 2-[l -(2-Trifluoromethoxy-benzoyl)- 621 622 +++ 76 piperidin-4-yl]-thiazole-4-carboxylic acid [5-(propane-1 -sulfonyl)-1 H-benzoimidazol-2-yl]-amide [M+Hf 53 N- {4-[N'-( 1 H-Benzoimidazol-2-yl)- guanidinocarbonyl]-Hiiazol-2-yl}-2-fluoro- 4-trifluoromethyl-benzamide 491 492 [M+Hf +++ 54 l-{4-[N'-(l H-Benzoimidazol-2-yl)-guanidinocarbonyl]-thiazol-2-yl} -3-(2-trifluoromethoxy-phenyl)-urea 504 505 [M+Hf +++ 56 N-{4-[N'-(lH-Benzoimidazol-2-yl)- guanidinocarbonyl]-thiazol-2-yl}-3-fluoro- 4-trifluoromethyl-benzamide 491 492 [M+Hf +++ 57 N- {4- pSf'-(l H-Benzoimidazol-2-yl)- guanidinocarbonyl]-thiazol-2-yl}-2,6- difluoro-benzamide 441 442 [M+Hf +++ 91 N-( 1 H-Benzoimidazol-2-yl)-N'-(2- morpholin-4-yl-thiazole-4-carbonyl)- guanidine 371 372 [M+Hf + 250 N-( 1 H-Benzoimidazol-2-yl)-N'~ {2-[l-(4-cyano-benzyi)-piperidin-4-yl]-thiazole-4-carbonyl} -guanidine 484 485 [M+HJ+ ++ 251 N-Benzothiazol-2-yl-N'- {2-[l -(4-cyano-benzyl)-piperidin-4-yl]-thiazole-4-carbonyl} -guanidine 501 502 [M+H]+ ++ 252 N-(lH-Benzoimidazol-2-yl)-N'-{2-[4-(4-cyano-benzyl)-piperazin-1 -yl]-thiazole-4-carbonyl} -guanidine 485 485 [M+H]+ +++ 253 N- (2-[4-(4-Cyano-benzyl)-piperazin-1 -yl] -thiazole-4-carbonyl}-N'-(4-methyl-thiazol-2-yl)-guanidine 466 467 [M+H]+ ++ 254 N-(4-Methyl-thiazol-2-yl)-N'-(2-morpholin-4-yl-thiazole-4-carbonyl)-guanidine 352 353 [M+H]+ + 255 N-(lH-Benzoimidazol-2-yl)-N'-(2- morpholin-4-yl-tMazole-4-carbonyl)- guanidine 371 372 [M+HJ+ +++ 256 N-Benzothiazol-2-yl-N'-(2-morpholin-4-yl-tMazole-4-carbonyl)-guanidine 388 389 [M+H]+ +++ 77 257 N-(lH-Benzoimidazol-2-yl)-N'-(2- morpholin-4-yl-oxazole-4-carbonyl)- guanidine 355 356 [M+H]+ ++ 258 N-Benzooxazol-2-yl-N'-(2-moipholin-4-yl-tMazole-4-carbonyl)-guanidine 372 373 fM+Hl+ ++ 259 N-(2-Morpholin-4-yl-thiazole-4-carbonyl)-N'-(5-nitro-benzooxazol-2-yl)-guamdine 417 418 [M+H1+ ++ 260 N-(5-Methyl-benzooxazol-2-yl)-N'-(2- morpholin-4-yl-thiazole-4-carbonyl)- guanidine 386 387 [M+H]+ + 261 N-(5-Chloro-benzooxazol-2-yl)-N'-(2- morpholin-4-yl-thiazole-4-carbonyl)- guanidine 406 407 [M+H]+ ++ 262 N- {2- [ 1 ~(4-Cyano-benzyl)-piperidin-4-yl]-thiazole-4-carbonyl} -N'-(4-methyl-thiazol-2-yl)-guanidine 465 466 [M+H]+ + 263 N-(6-Chloro-1 H-benzoimidazol-2-yl)-N'-{2-[l -(2-trifluoromethoxy-benzoyl)-piperidin-4-yl] -thiazole-4-carbonyl} -guanidine 591 592 [M+H]+ +++ 264 N-(5,6-Dichloro-1 H-benzoimidazol-2-yl)-N'- {2-[l -(2-trifluoromethoxy-benzoyl)-piperidin-4-yi] -thiazole-4-carbonyl} -guanidine 625 626 [M+H]+ ++ 265 2-Morpholin-4-yl-thiazole-4-carboxylic acid [4-(5-trifluoromethyl-benzothiazol-2-yl)-phenyl]-amide 490 491 [M+H]+ 266 2-Morpholin-4-yl-thiazole-4-carboxylic acid (5-benzothiazol-2-yl-pyridin-2-yl)-amide 423 424 [M+H]+ 267 2-Moipholin-4-yl-tihiazole-4-carboxylic acid (4-benzothiazol-2-yl-2-fluoro-phenyl)-amide 440 441 [M+H]+ 268 2-Morpholin-4-yl-thiazole-4-carboxylic acid (4-benzothiazol-2-yl-2-trifluorometh-oxy-plienyl)-amide 506 507 [M+H]+ 269 2-(l-Furor2,3-clpyridin-4-yl-piperidin-4- 548 549 78 yl)-tbiazole-4-carboxylic acid (5-benzoyl-lH-benzoniudazol-2-yl)-amide [M+H]+ 270 2-[l-(4,6-Dimethoxy-[l,3,5]triazin-2-yl)-piperidin-4-yl]-thiazole-4-carboxylic acid (5-benzoyl-l H-benzoimidazol-2-yl)-amide 570 571 [M+H]+ 271 2-[ 1 -(4,6-Dimethoxy- [1,3,5]triazin-2-yl)~ piperidin-4-yl]-thiazole-4-carboxylic acid (5-fliioro-benzothiazol-2-yl)-amide 501 502 [M+H]+ 272 2-[ 1 -(4-Cyano-benzyl)-piperidin-4-yl]~ thiazole-4-carboxylic acid (5-benzoyl-1H-benzoimidazol-2-yl) -amide 546 547 [M+H^] ++ 273 2-(l -Thieno [3,2-d]pyrimidin-4-yl-piperidin-4-yl)-thiazole-4-carboxylic acid (5-benzoyl-1 H-benzoimidazol-2-yl)-amide 565 566 [M+H4] ++ 274 2-[l -(4,6-Dimethoxy-[l ,3,5]triazin-2-yl)-piperidin-4-yl]-thiazole-4-carboxylic acid (5 -benzoyl-1 H-benzoimidazol-2-yl)-amide 570 571 [M+H4] I l i 275 2-[l -(6-Trifluoromethyl-pyiimidin-4-yl)-piperidia-4-yI]-thiazole-4-carboxylic acid (5-benzoyl-1 H-benzoimidazol-2-yl)-amide 577 578 [M+H4] ++ 276 2-[l-(4-Cyano-benzyl)-piperidin-4-yl]-thiazole-4-carboxylic acid (5-ethoxy-lH-benzoimidazol-2-yl)-amide 486 487 [M+H]+ + 277 2-[l -(4-Cyano-benzyl)-piperidin-4-yl]-thiazole-4-carboxylic acid (5-chloro-lH-benzoimidazol-2-yl)-amide 476 477 [M+H]+ ++ 278 2-[l -(4-Cyano-benzyl)-piperidin-4-yl]-thiazole-4-carboxyIic acid (5,6-dichIoro-lH-benzoimidazol-2-yl)-amide 510 511 [M+H]+ ++ 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] 79 Proteasome assay: The chymotryptic activity of the 20S proteasome (Immatics, Tubingen) was determined using a Tecan Ultra plate reader and Suc-LLVT-AMC as substrate (Bachem). In the wells of a black 96 well polypropylene plate, 2 (J.1 of the respective inhibitor dissolved in DMSO 5 were mixed with 50 jlxI substrate solution (25 mM HEPES pH 7.5 at 20°C, 0.5 mM EDTA and Suc-LLVT-AMC (in the appropriate concentration) and the reaction was initiated by adding 150 pi proteasome solution (1.3 p.g/ml 20S proteasome in 25 mM HEPES pH 7.5 at 20°C, 0.5 mM EDTA, 0.033% (w/v) SDS). Substrate hydrolysis was followed by fluorescence spectroscopy (excitation wavelength: 360 nm; emission wavelength: 465 urn) 10 for 20 min at 30°C and initial velocities were calculated and expressed as change in relative fluorescence units (RFU) per second. For the determination of the IC50 values (concentration of inhibitor required for 50% inhibition) at least four different inhibitor concentrations were applied. Each data point was recorded in triplicates. Curves were fitted with the a suitable program. 15 The Compounds have average activities between 1 and 30 pM T-Lymphocyte Proliferation Assay: Inhibition of stimulated peripheral blood monocytes (PBMC). PBMCs were isolated from the blood of healthy volunteers with the help of ACCUSPIN™ System Histopaque®-1077 tubes, washed and resuspended with 106 cells/ml in Dulbecco's 20 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. 25 Incorporated BrdU was quantified with the help of an enzyme-linked immunosorbent assay. For the determination of the IC50 values (concentration of inhibitor required for 50% inhibition) at least four different inhibitor concentrations were applied. Each data point was recorded in triplicates. Curves were fitted with the a suitable program. 30 Influence of compounds according to the invention on proliferation of T-cells Compounds according to Examples 1-24 resulted in an inhibition of more than 50% compared to control experiments. </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 80 The average EC50 of the compounds were between 3 and 40 (iM. Thus, the compounds of formula I are suitable for treating inflammatory diseases or diseases associated with Tcells. 5 Inhibition of NF-KB-induced inflammation: For the determination of anti-inflammatory activity of the compounds the PRINCESS® NINA Instant Assay from Cell Culture Service GmBH was used. This assay is based on recombinant A549-NF-kB-SEAP reporter cells preseeded in 96-well flat bottom plates. As the transfeeted reportergen for SEAP (secreted embryonic alkaline phosphatase) is under 10 transcriptional control of a NF-KB-responsive element, the expression of this reporter is activated upon stimulation with TNF-a. SEAP secretion into the culture supernatant can be detected by the chemiluminescent substrate CSPD®. Test compounds that inhibit the NF-kB activation show reduced SEAP activity and reduced himinescent readout. Following 18 h of reactivation at 37 °C, 5 % CO2 and 90 % relative humidity, the cells 15 were incubated with 0.01 up to 100 |j.M of test compound for 4.5 h before stimulation with 2ng/ml TNF-a. After stimulation with TNF-a for 22 h endogenous phosphatases were inactivated and CSPD® substrate was supplied for 40 min. SEAP activity then was quantified by measuring luminescence as relative light units (RLU) using a Tecan Ultra reader. Each data point was. recorded in quadruplicates and EC50 values were calculated 20 via fitting function and the Microsoft Excel Solver. RECEIVED at IPONZ on 30 January 2012 CLAIMS

1. A compound of the general formula (III) or pharmaceutically acceptable salt thereof with an acid or a base, or a stereoisomer thereof, R4 / A N wherein R1 is -C(0)R7a, -C(0)CHR7R8, -C(0)NR7R8, -C(0)0R7, -R7C(0)R8, or -C(S)R7b, R2 is H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, R3 is H, -C(0)NRaRb, halogen, allcyl, haloalkyl, aryl, heteroaryl, OH, SH, NR4 OR5, NH2, hydroxyalkylamino, alkylamino, alkoxy, cycloalkyl, heterocycloalkyl, hydroxyalkyl, or haloalkyloxy; R4 is H, OH, SH, NH2, alkoxy, haloalkoxy, halogen, alkyl, -C(NR7)NRrR8, -(CH2)paryl, -(CH2)PNR7R8, -C(0)NR7R8, -N=CR7R8, -NR7C(0)R8, cycloalkyl, heterocycloalkyl, halo-alkyl, hydroxyallcyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl; R5 is halogen, alkyl, -C(NR7)NRrR8, -(CH2)paryl, -(CH2)PNR7R8, -C(0)NR7R8, -N=CR7R8, -NR7C(0)R8, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl; RECEIVED at IPONZ on 30 January 2012 82 Ra is H, halogen, alkyl, -C(NR7)NRrR8, -(CH2)paryl, -(CH2)PNR7R8, aryl, -C(0)NR7R8, -N=CR7R8, -NR7C(0)R8, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, or heteroaryl; Rb independently represents H, -CN, -OH, -SH, -C02R4, -C(0)R4, -S02NR4, -NR4R5', -C(0)NR7R8, -S02-alkyl, -S02R4', S03R4', -N==CR4R5', -NR4 C(0)R4 , -NR4'-CO-haloalkyl, -N02, -NR4'-S02-haloalkyl, -NR4'-S02-alkyl, -NR4 -CO-alkyl, -NR4 (CH2)pheteroaryl, alkyl, cycloalkyl, alkylamino, alkoxy, alkylthio, halogen, haloalkyl, haloalkyloxy, -0(CH2)p[0(CH2)p]q0CH3, -C(NR4")NR4 benzimidazolyl, -C(NR4 )NR4 -benzthiazolyl, -C(NR4")NR4'benzoxazolyl, hydroxyalkyl, hydroxycycloalkyl, hydroxyalkylamino, heterocycloalkyl, aryl or heteroaryl; R4, R4 , R5 independently are H, halogen, alkyl, -C(NR7)NR7 R8, -(CH2)paryl, haloalkyl, -CH2)PNR7R8, -C(0)NR7R8, -N=CR7R8, -NR7C(0)R8, cycloalkyl, heterocycloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl; R7, R7, R8 independently are H, halogen, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, arylamino heteroaryl, or aryl; R7a is cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, heteroaryl, or aryl; R7b is H, halogen, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, heteroaryl, or aryl; A is CO or S02; X is NR2, O, or S; Z is N or CR2'; R2' is H, alkyl, -C(0)NR7, -C(0)Rb, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl; p is 1 to 6; q is 1 to 6; RECEIVED at IPONZ on 30 January 2012 83 wherein an Ci-C6-alkyl group, if not stated otherwise, denotes a linear or branched C1-C6-alkyl, which can optionally be substituted by one or more substituents R"; R' is independently H, -C02R", -CONHR", -CR"0, ~S02NR\ -NR"-CO-haloalkyl, -N02, -NR"-S02-haloalkyl, -NR"-S02-alkyl, -S02-alkyl, -NR"-CO-alkyl, -CN, alkyl, cycloalkyl, alkylamino, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl, or heteroaryl; R" is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, or heteroaryl; an C2-C6-alkenyl group, if not stated otherwise, denotes a linear or branched C2-Ce-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-C6-alkyl, a linear or branched C2-C6-alkenyl or a linear or branched C2-C6-alkynyl group, which can be substituted by one or more substituents R; R being defined as above. RECEIVED at IPONZ on 30 January 2012 84 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; a heterocycloalkyl group denotes a non-aromatic ring system containing two to ten carbon atoms and at least one heteroatom selected from O, N, and S, wherein one or more of the carbon atoms in the ring can be substituted by R being as defined above; 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; an 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 above; an 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 (H0-allcyl)2-N- group or HO-alkyl-NH-group, the alkyl group being as defined above; an alkylamino group denotes an HN-alkyl or N-dialkyl group, the alkyl group being as defined above; a halogen group is fluorine, chlorine, bromine, or iodine; an aryl group denotes an aromatic group having five to fifteen carbon atoms, which can be substituted by one or more substituents R, where R is as defined above; RECEIVED at IPONZ on 30 January 2012 85 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 O, 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; with the proviso that compounds of the general formula (Ih) or pharmaceutically acceptable salts thereof with an acid or a base, or a stereoisomer thereof, R1 \ z wherein A is NR2', S or O; t is 0 to 4; r is 0, orl; R2a is independently H, OH, SH, NH2, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, alkoxy, alkylamino, hydroxyalkylamino, halogen, aryl, or heteroaryl; R3a is independently H, OH, SH, NH2, -C(NR7)NR7 R8, -(CH2)paryl, -(CH2)PNR7R8, -C(0)NR7R8, -N=CR7R8, -NR7C(0)R8, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, alkoxy, alkylamino, hydroxyalkylamino, halogen, aryl, or heteroaryl; Rd is H, halogen, alkyl, -C(NR7)NR7 R8, -(CH2)paryl, -(CH2)PNR7R8, -C(0)NR7R8, -N=CR7R8, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl, and the remainder of the substituents are as described above, are excluded. RECEIVED at IPONZ on 30 January 2012 86

2. The compound according to claim 1 for use as a medicament.

3. A composition containing a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.

4. The use of a compound according to claim 1 or a composition of claim 3 for the preparation of a medicament for the treatment or prevention of a disease characterized by hyperproliferation of cells.

5. The use of a compound according to claim 1 or a composition of claim 3 for the preparation of a medicament for the treatment or prevention of a disease resulting from ischemia and/or reperfiision injury of organs and/or of parts of the body selected from the group comprising heart, brain, peripheral limb, kidney, liver, spleen and lung, and/or wherein the endothelial dysfunction is associated with diseases selected from a group comprising infarctions such as myocardial infarction and critical limb ischemia, and/or wherein the endothelial dysfunction is associated with diseases selected from the group comprising ischemic diseases, myocardial infarction and ischemic diseases of organs.

6. The use of a compound according to claim 1 or a composition of claim 3 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 7. 5 10 15 20 8. 25 9. 10. 11. 12. 13. RECEIVED at IPONZ on 30 January 2012 87 gravis, Huntington's Disease, Down's Syndrome, nerve deafness, and Meniere's disease. The use according to claim 4, wherein the disease is selected from the group consisting of psoriasis, atopic dermatitis, alopecia areata, alopecia totalis, alopecia subtotalis, alopecia universalis, alopecia diffusa, lupus erythematodes of the skin, lichen planus, dermatomyostis of the skin, atopic eczema, morphea, sklerodermia, psoriasis vulgaris, psoriasis capitis, psoriasis guttata, psoriasis inversa, alopecia areata ophiasis-type, androgenetic alopecia, allergic contact eczema, irritative contact eczema, contact eczema, pemphigus vulgaris, pemphigus foliaceus, pemphigus vegetans, scarring mucosal pemphigoid, bullous pemphgoid, mucous pemphigoid, dermatitis, dermatitis herpetiformis duhring, urticaria, necrobiosis lipoidica, erythema nodosum, lichen vidal, prurigo simplex, prurigo nodularis, prurigo acuta, linear IgA dermatosis, polymorphic light dermatoses, erythema solaris, lichen sclerosus et atrophicans, exanthema of the skin, drug exanthema, purpura chronica progressiva, dihidrotic 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, Hyperkeratosis Lenticularis Perstans, Keratosis pilaris and Ichthyoses. The use according to claim 4, wherein the disease is selected from the group consisting of hematological or solid tumors. A compound according to claim 1 substantially as herein described or exemplified. A composition according to claim 3 substantially as herein described or exemplified. A use according to claim 4 substantially as herein described or exemplified. A use according to claim 5 substantially as herein described or exemplified. A use according to claim 6 substantially as herein described or exemplified. 4SC By Their Attorneys </div>