HK1128197A

HK1128197A - Novel heterocyclic nf-kb inhibitors

Info

Publication number: HK1128197A
Application number: HK09105709.2A
Authority: HK
Inventors: 约翰．莱班; 哈拉尔德．施米特; 克里斯蒂娜．沃尔夫; 斯蒂凡诺．彼格拉罗; 安德烈亚斯．伍兹克; 罗尔夫．卡尔尤斯
Original assignee: 4Sc股份公司
Priority date: 2006-03-15
Filing date: 2007-03-14
Publication date: 2009-10-16

Description

Novel heterocyclic NF-kB inhibitors

The invention relates to compounds of general formula (Ia), (Ib), (Ic), (Ih), (II) or (III) or stereoisomers thereof or possible pharmaceutically acceptable salts thereof with acids or bases or pharmaceutically acceptable prodrugs of these compounds. The compounds of the present invention can be used as medicaments and especially for the treatment of diseases associated with abnormal and hyperproliferation of cells in mammals, especially humans. In particular, it is useful for the treatment of diseases characterized by T cell hyperproliferation. The present invention relates to compounds suitable for the treatment of diseases that can be treated by modulating cellular pathways in eukaryotes, such as cancer, immune or inflammatory disorders, and viral infections, to methods of preparing these compounds, and to uses thereof.

T cell homeostasis is critical for maintaining immune tolerance. Defects in T cell homeostasis can lead to autoimmune diseases. Autoimmune diseases encompass a wide range of clinically diverse entities that share etiology, and are misdirected, self-directed immune responses. This immune response can also be the result of organ transplantation. Evidence suggests a major role for T cell activity in autoimmune diseases. Measuring proliferative responses in T lymphocytes is a widely used assay to measure immunocompetence (Killestein, j.et al.j.neurohimnol.133, 217-24, 2002).

We used nonradioactive techniques to measure T cell proliferation in vitro (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 donors. PBMC were isolated by centrifugation in ACCUSPIN tubes using HISTOPAQUE. PBMC were stimulated with PHA and cell proliferation was measured using Roche colorimetry BromUridin in conjunction with an ELISA kit.

Modulation of immune responses is controlled by a variety of signaling pathways, such as T cell or TNF receptor signaling (Chen, g.et al. science 296, 1634-1635, 2002). To further characterize the targets of compounds we found active in T cell proliferation assays, we tested the ability of compounds to inhibit human proteasome.

The predominant neutral proteolytic activity in the cytosol and nucleus is the proteasome, a 20S (700kDa) microparticle with a variety of peptidase activities. The immune system uses a continuous circulation of cellular proteins through the ubiquitin-proteasome pathway to screen for the presence of abnormal intracellular proteins (Dantuma, N.P.et al.Nat.Biotechnol.2000, 18(5), 538-43; Goldberg, AL.et al.Nature357, 375, 1993). The ubiquitin-proteasome pathway plays a crucial role in regulating NF- κ B activity, which is responsible for the degradation of the inhibitor I κ B- α. To be targeted for proteasomal degradation, I.kappa.B-. alpha.must first undergo selective phosphorylation at serine residues 32 and 36, followed by pan-peptidation (Chen, ZJ.et al.Cell 84, 853-862, 1996; Brown, K.et al.science 267, 1485, 1995). NF-. kappa.B is a transcription factor that regulates transcription of a range of important genes involved in inflammatory responses (Baeuerle, PA.et al. cell 87, 1, 13-20, 1996). Proteasome inhibitors block the degradation of I κ B- α and the activation of NF- κ B (Tradeckner et al EMBO J.13, 5433, 1994).

Documents 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, WO00/004954, WO 00/04954, WO 00/170204, WO 00/33654, WO 00/64863, WO 00/114324, WO 99/15183, WO 99/37666.

Here we describe novel chemical entities with proteasome inhibitory activity.

NF-. kappa.B (nuclear factor-. kappa.B) is a rel family eukaryotic transcription factor that is either a homodimer or a heterodimer, and is localized in the cytoplasm in an inactive complex. It exists mainly as a heterodimer consisting of p50 and p65 subunits, associated with inhibitory proteins of the IkB family, usually IkB-alpha (D.Thanos et al. cell 80, 529, 1995). NF- κ B is activated in response to different stimuli, including inflammatory cytokines, UV radiation, phorbol esters, bacterial and viral infections. Stimulation triggers the release of NF- κ B from I κ B due to phosphorylation and subsequent degradation of I κ B- α proteins by proteasomes (p.a. baeuuerleet al. annu. rev. immunol.12, 141, 1995). Once it is released, NF- κ B translocates to the nucleus where it binds to DNA at specific κ B sites and induces transcription of a variety of genes encoding proteins involved in controlling immune and inflammatory responses, including interleukins, TNF- α, NO-synthase, and cyclooxygenase 2(s.grimm et al.j.biochem.290, 297, 1993). Therefore, NF- κ B is considered an early regulator of immune and inflammatory responses and is involved in the control of cell proliferation and pathogenesis of a variety of human diseases such as rheumatoid arthritis (h.beker et al. clin.exp. immunol.99, 325, 1995), ischemia (a.salaminet et al. biochem. biophysis. res. comm.212, 939, 1995), arteriosclerosis (a.s.baldwin, Annals rev. immunol.212, 649, 1996) and AIDS. Inhibition of NF-. kappa.B-mediated gene transcription can be achieved by inhibition of phosphorylation of the arrestin IkB, inhibition of IkB degradation, inhibition of nuclear translocation of NF-. kappa.B (p50/p65), inhibition of NF-. kappa.B-DNA binding or NF-. kappa.B-mediated DNA transcription (J.C.Epinat. oncogene 18, 6896, 1999).

The invention relates to a compound of a general formula (Ia) or a pharmaceutically acceptable salt thereof formed with an acid or a base or a pharmaceutically acceptable prodrug or stereoisomer thereof.

Wherein

R is independently hydrogen, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkoxy, aryl or heteroaryl;

R¹independently is alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, halohydrocarbonoxy, aryl or heteroaryl;

x is CO, CS or SO₂；

Y is CO, CS or SO₂；

Z is NR²', S or O;

R²' is H, hydrocarbyl, -C (O) NR⁷、-C(O)R^eCycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;

R^cindependently H, OH, SH, NROR¹、NH₂Hydrocarbylamino, hydroxyalkylamido, halogen, CONR^dR^eHydrocarbyloxy, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, halohydrocarbyloxy, aryl or heteroaryl;

R^dis H, halogen, hydrocarbyl, -C (NR)⁷)NR⁷’R⁸、-(CH₂)_pAryl, - (CH)₂)_pNR⁷R⁸、-C(O)NR⁷R⁸、-N＝CR⁷R⁸、-NR⁷C(O)R⁸Cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;

R⁷、R⁷' independently represents H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;

R⁸is H, NH₂A hydrocarbyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl group;

R^eindependently represent H, -CN, -OH, -SH, -CO₂R⁴’、-C(O)R⁴’、-SO₂NR⁴’、-NR⁴’R⁵’、-C(O)NR⁷R⁸、-SO₂-hydrocarbyl, -SO₂R⁴’、SO₃R⁴’、-N＝CR⁴’R⁵’、-NR⁴’C(O)R⁴”、-NR⁴' -CO-Halogenoalkyl, -NO₂、-NR⁴’-SO₂-halogenated hydrocarbon radical, -NR⁴’-SO₂-hydrocarbyl, -NR⁴' -CO-hydrocarbyl, -NR⁴’(CH₂)_pHeteroaryl, alkyl, hydroxyalkyl, cycloalkyl, alkylamino, aryl, hydroxyalkylamino, hydrocarbyloxy, hydrocarbylthio, -O (CH)₂)_p[O(CH₂)_p]_qOCH₃、-C(NR⁴”)NR⁴' -benzimidazolyl, -C (NR)⁴”)NR⁴' benzothiazolyl, -C (NR)⁴”)NR⁴' benzoxazolyl or heteroaryl;

R⁴’、R⁴”、R⁵' independently represents H, a hydrocarbon group, a cycloalkyl group, a halogenated hydrocarbon group, a hydroxyhydrocarbon group, a hydroxyhydrocarbylamino group, a hydrocarbylamino group, -C (NR)⁷)NR⁷’R⁸、-(CH₂)_pAryl, - (CH)₂)_pNR⁷R⁸、-C(O)NR⁷R⁸、-N＝CR⁷R⁸、-NR⁷C(O)R⁸Halogen, heteroaryl or aryl

p is 1 to 6;

q is 1 to 6;

R²independently is

R⁵Independently is H, COR⁶、CO₂R⁶、SOR⁶、SO₂R⁶、SO₃R⁶Alkyl, cycloalkyl, alkoxy, -NH₂Hydrocarbyl amine, -NR⁷COR⁶Halogen, -OH, -SH, alkylthio, hydroxyalkyl, haloalkyl, halohydrocarbonoxy, aryl or heteroaryl;

R⁶independently is H, alkyl, cycloalkyl, amino, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, aryl or heteroaryl;

wherein

The hydrocarbon radical denotes, if not otherwise stated, straight-chain or branched C₁-C₆Alkyl, preferably straight or branched chain, C of 1 to 5 carbon atoms₂-C₆Alkenyl or straight or branched C₂-C₆Alkynyl, which may be optionally substituted with one or more substituents R';

said C is₁-C₆Alkyl radical, C₂-C₆Alkenyl and C₂-C₆Alkynyl moieties may be selected from-CH₃、-C₂H₅、-CH＝CH₂、-C≡CH、-C₃H₇、-CH(CH₃)₂、-CH₂-CH＝CH₂、-C(CH₃)＝CH₂、-CH＝CH-CH₃、-C≡C-CH₃、-CH₂-C≡CH、-C₄H₉、-CH₂-CH(CH₃)₂、-CH(CH₃)-C₂H₅、-C(CH₃)₃、-C₅H₁₁、-C₆H₁₃、-C(R”)₃、-C₂(R’)₅、-CH₂-C(R’)₃、-C₃(R’)₇、-C₂H₄-C(R’)₃、-C₂H₄-CH＝CH₂、-CH＝CH-C₂H₅、-CH＝C(CH₃)₂、-CH₂-CH＝CH-CH₃、-CH＝CH-CH＝CH₂、-C₂H₄-C≡CH、-C≡C-C₂H₅、-CH₂-C≡C-CH₃、-C≡C-CH＝CH₂、-CH＝CH-C≡CH、-C≡C-C≡CH、-C₂H₄-CH(CH₃)₂、-CH(CH₃)-C₃H₇、-CH₂-CH(CH₃)-C₂H₅、-CH(CH₃)-CH(CH₃)₂、-C(CH₃)₂-C₂H₅、-CH₂-C(CH₃)₃、-C₃H₆-CH＝CH₂，-CH＝CH-C₃H₇、-C₂H₄-CH＝CH-CH₃、-CH₂-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-C≡C-CH＝CH₂、-CH₂-CH＝CH-C≡CH、-CH₂-C≡C-C≡CH、-C≡C-CH＝CH-CH₃、-CH＝CH-C≡C-CH₃、-C≡C-C≡C-CH₃、-C≡C-CH₂-CH＝CH₂、-CH＝CH-CH₂-C≡CH、-C≡C-CH₂-C≡CH、-C(CH₃)＝CH-CH＝CH₂、-CH＝C(CH₃)-CH＝CH₂、-CH＝CH-C(CH₃)＝CH₂、-C(CH₃)＝CH-C≡CH、-CH＝C(CH₃)-C≡CH 、-C≡C-C(CH₃)＝CH₂、-C₃H₆-CH(CH₃)₂、-C₂H₄-CH(CH₃)-C₂H₅、-CH(CH₃)-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、-C(CH₃)₂-CH(CH₃)₂、-C₂H₄-C(CH₃)₃、-CH(CH₃)-C(CH₃)₃、-C₄H₈-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、-C₄H₈-C≡CH、-C≡C-C₄H₉、-C₃H₆-C≡C-CH₃、-CH₂-C≡C-C₃H₇、-C₂H₄-C≡C-C₂H₅；

R' is independently H, -CO₂R”、-CONHR”、-CR”O、-SO₂NR ', -NR' -CO-halohydrocarbyl, -NO₂、-NR”-SO₂-halogenated hydrocarbon radical, -NR "-SO₂-hydrocarbyl, -SO₂-alkyl, -NR "-CO-alkyl, -CN, alkyl, cycloalkyl, alkylamino, hydrocarbyloxy, -OH, -SH, hydrocarbylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, halohydrocarbyloxy, aryl or heteroaryl;

r "is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, or heteroaryl;

cycloalkyl represents a non-aromatic ring system containing from 3 to 8 carbon atoms, preferably from 4 to 8 carbon atoms, wherein one or more of the carbon atoms of the ring may be substituted by a group E, E being O, S, SO₂N or NR ", R" is as defined above; said C is₃-C₈The cycloalkyl moiety may be selected from-ring-C₃H₅-Ring-C₄H₇-Ring-C₅H₉-Ring-C₆H₁₁-Ring-C₇H₁₃-Ring-C₈H₁₅Morpholin-4-yl, piperazinyl, 1-alkyl piperazin-4-yl;

hydrocarbyloxy represents an O-hydrocarbyl group, the hydrocarbyl group being as defined above; the hydrocarbyloxy group is preferably methoxy, ethoxy, isopropoxy, tert-butoxy or pentyloxy;

the hydrocarbylthio group represents an S-hydrocarbyl group, the hydrocarbyl group being as defined above;

a halogenated hydrocarbyl group represents a hydrocarbyl group substituted with 1 to 5 halogen atoms, the hydrocarbyl group being as defined above; the halogenated hydrocarbon group is preferably-C (R)¹⁰)₃、-CR¹⁰(R¹⁰’)₂、-CR¹⁰(R¹⁰’)R¹⁰”、-C₂(R¹⁰)₅、-CH₂-C(R¹⁰)₃、-CH₂-CR¹⁰(R¹⁰’)₂、-CH₂-CR¹⁰(R¹⁰’)R¹⁰”、-C₃(R¹⁰)₇or-C₂H₄-C(R¹⁰)₃Wherein R is¹⁰、R¹⁰’、R¹⁰"represents F, Cl, Br or I, preferably F;

a hydroxyhydrocarbyl group represents an HO-hydrocarbyl group, the hydrocarbyl group being as defined above;

a halohydrocarbyloxy group represents a hydrocarbyloxy group substituted with from 1 to 5 halogen atoms, the hydrocarbyl group being as defined above; the halohydrocarbyloxy group is preferably-OC (R)¹⁰)₃、-OCR¹⁰(R¹⁰’)₂、-OCR¹⁰(R¹⁰’)R¹⁰”、-OC₂(R¹⁰)₅、-OCH₂-C(R¹⁰)₃、-OCH₂-CR¹⁰(R¹⁰’)₂、-OCH₂-CR¹⁰(R¹⁰’)R¹⁰”、-OC₃(R¹⁰)₇or-OC₂H₄-C(R¹⁰)₃Wherein R is¹⁰、R¹⁰’、R¹⁰"represents F, Cl, Br or I, preferably F;

hydroxyhydrocarbylamino radical denotes (HO-hydrocarbyl)₂-an N-group or an HO-hydrocarbyl-NH-group, the hydrocarbyl group being as defined above;

the hydrocarbylamino group represents a HN-hydrocarbyl or N-dihydrocarbyl group, the hydrocarbyl group being as defined above;

the halogen group is chlorine, bromine, fluorine or iodine;

an aryl group represents an aryl group having from 5 to 15 carbon atoms, which may be optionally substituted with one or more substituents R ', wherein R' is as defined above; the aryl group is preferably benzyl, phenyl, -o-C₆H₄-R', -m-C₆H₄-R', -p-C₆H₄-R', 1-naphthyl, 2-naphthyl, 1-anthryl or 2-anthryl;

heteroaryl group denotes a five or six membered heterocyclic group containing at least one heteroatom selected from O, N or S. The heterocyclic group may be fused with other aromatic rings. For example, the group may be selected from thiadiazoles, 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, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, benzoxazol-2-yl, benzoxazol-4-yl, benzoxazol-5-yl, benzisoxazol-3-yl, benzisoxazol-4-yl, benzisoxazol-5-yl, 1, 2, 4-oxadiazol-3-yl, 1, 2, 4-oxadiazol-5-yl, oxadizol-3-yl, oxadizol-4-yl, oxadizol-3-yl, oxadizol-5-yl, 1, 2, 5-oxadiazol-3-yl, 1, 2, 5-oxadiazol-4-yl, 1, 2, 4-thiadiazol-3-yl, 1, 2, 4-thiadiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, benzisothiazol-3-yl, benzisothiazol-4-yl, benzisothiazol-5-yl, 1, 2, 5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl, 1, 2, 5-thiadiazol-4-yl, 4-imidazolyl, benzimidazol-4-yl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyranyl, 3-pyranyl, 4-pyranyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2, 4-dimethoxy-6-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 1, 2, 3-triazol-4-yl, 1, 2, 3-triazol-5-yl, 1, 2, 4-triazol-3-yl, 1, 2, 4-triazol-5-yl, 1-pyridyl, 3-pyranyl, 4-pyrimidinyl, 2-pyrimidinyl, 4-pyrimidinyl, 6-pyrimidinyl, 2, 4-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3, 1, 3, 5-triazol-6-yl, 2, 4-dimethoxy-1, 3, 5-triazol-6-yl, 1H-tetrazol-2-yl, 1H-tetrazol-3-yl, tetrazolyl, acridinyl, furazan, indazolyl, phenazinyl, carbazolyl, phenoxazine, indolizine, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 1-isoindolyl, 3-isoindolinyl, 4-isoindolinyl, 5-isoindolinyl, 6-isoindolinyl, 7-isoindolinyl, 2-indolinyl, 3-indolinyl, 4-indolinyl, 5-indolinyl, 6-indolinyl, 7-indolinyl, benzo [ b ] furanyl, benzofurazan, benzothiofurazan, benzotriazol-1-yl, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl, benzotriazol-7-yl, benzotriazine, benzo [ b ] thiophenyl, benzimidazol-2-yl, 1H-benzimidazolyl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl, benzimidazol-7-yl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnoline, quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydro-isoquinolyl, purine, 2, 3-naphthyridine, pteridine, Thiotetrazine, thiotriazene, isothiazolopyrazine, isothiazolopyrimidine, pyrazolotriazine, pyrazolopyrimidine, tetrahydrothieno [3, 4-d ] imidazol-2-one, pyrazolo [5, 1-c ] [1, 2, 4] triazine, 2, 3-dihydrobenzo [1, 4] -dioxin-2-yl, 2, 3-dihydrobenzo [1, 4] -dioxin-3-yl, 2, 3-dihydrobenzo [1, 4] -dioxin-5-yl, 2, 3-dihydrobenzo [1, 4] -dioxin-6-yl, 2, 6-dimethoxypyrimidin-3-yl, 2, 6-dimethoxypyrimidin-4-yl, imidazopyridazine, imidazopyrimidine, Imidazopyridine, imidazotriazine, triazolotriazine, triazolopyridine, triazolopyrazine, triazolopyrimidine or 4- [1, 2, 4] triazolo [4, 3-a ] pyridin-3-yl, 1-furo [2, 3-c ] pyridin-4-yl, 1-furo [2, 3-c ] pyridin-5-yl, 1-furo [2, 3-c ] pyridin-3-yl or a triazolopyridazine group. The heterocyclic group may be substituted with one or more substituents R ', wherein R' is as defined above.

The invention relates to a compound of a general formula (Ib) or a pharmaceutically acceptable salt formed by the compound and acid or alkali or a pharmaceutically acceptable prodrug or stereoisomer thereof.

Wherein

R¹is-C (O) R⁷、-C(O)CHR⁷R⁸、-C(O)NR⁷R⁸、-C(O)OR⁷、-R⁷C(O)R⁸or-C (S) R⁷；

R⁹Independently represent H, -CN, -OH, -SH, -CO₂R⁴’、-C(O)R⁴’、-SO₂NR⁴’、-NR⁴’R⁵’、-C(O)NR⁷R⁸、-SO₂-hydrocarbyl, -SO₂R⁴’、SO₃R⁴’、-N＝CR⁴’R⁵’、-NR⁴’C(O)R⁴”、-NR⁴' -CO-Halogenoalkyl, -NO₂、-NR⁴’-SO₂-halogenated hydrocarbon radical, -NR⁴’-SO₂-hydrocarbyl, -NR⁴' -CO-hydrocarbyl, -NR⁴’(CH₂)_pHeteroaryl, alkyl, hydroxyalkyl, cycloalkyl, alkylamino, aryl, hydroxyalkylamino, hydrocarbyloxy, hydrocarbylthio, -O (CH)₂)_p[O(CH₂)_p]_qOCH₃、-C(NR⁴”)NR⁴' -benzimidazolyl, -C (NR)⁴”)NR⁴' benzothiazolyl, -C (NR)⁴”)NR⁴' benzoxazolyl, - (CH)₂)_pNR⁷COR⁸Or a heteroaryl group;

R⁴is H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;

or R¹And R⁴And X attached thereto forms a 3-to 8-membered, saturated or at least partially unsaturated monocyclic or polycyclic ring system, wherein at least one ring atom is a heteroatom selected from O, N, S, and the ring optionally has one or more substituents R⁹；

X is N or CR²’；

Y is CO, CS or SO₂；

Z is NR²", S or O;

R²"is H, hydrocarbyl, -C (O) NR⁷、-C(O)R^eCycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;

R²' is H, hydrocarbyl, -C (O) NR⁴’、-C(O)R⁴', cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;

R⁴’、R⁴”、R⁵' independently represents H, a hydrocarbon group, a cycloalkyl group, a halogenated hydrocarbon group, a hydroxyhydrocarbon group, a hydroxyhydrocarbylamino group, a hydrocarbylamino group, -C (NR)⁷)NR⁷’R⁸、-(CH₂)_pAryl, - (CH)₂)_pNR⁷R⁸、-C(O)NR⁷R⁸、-N＝CR⁷R⁸、-NR⁷C(O)R⁸Halogen, heteroaryl or aryl;

p is 1 to 6;

q is 1 to 6;

R^aindependently of each other H, OH, SH, NH₂Alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, halohydrocarbonoxy, hydrocarbonoxy, alkylamino, hydroxyalkylamino, halogen, aryl or heteroaryl;

R^bindependently of each other H, OH, SH, NH₂Alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, halohydrocarbonoxy, hydrocarbonoxy, alkylamino, hydroxyalkylamino, halogen, aryl or heteroaryl;

R^cindependently H, OH, SH, NR⁴’OR⁵’、NH₂Hydrocarbylamino, hydroxyalkylamido, halogen, CONR^dR^eHydrocarbyloxy, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, halohydrocarbyloxy, aryl or heteroaryl;

R^eindependently represent H, -CN, -OH, -SH, -CO₂R⁴’、-C(O)R⁴’、-SO₂NR⁴’、-NR⁴’R⁵’、-C(O)NR⁷R⁸、-SO₂-hydrocarbyl, -SO₂R⁴’、SO₃R⁴’、-N＝CR⁴’R⁵’、-NR⁴’C(O)R⁴”、-NR⁴' -CO-Halogenoalkyl, -NO₂、-NR⁴’-SO₂-halogenated hydrocarbon radical, -NR⁴’-SO₂-hydrocarbyl, -NR⁴' -CO-hydrocarbyl, -NR⁴’(CH₂)_pHeteroaryl, alkyl, hydroxyalkyl, cycloalkyl, alkylamino, hydroxyalkylamino, hydrocarbyloxy, hydrocarbylthio, -O (CH)₂)_p[O(CH₂)_p]_qOCH₃、-C(NR⁴”)NR⁴' benzimidazolyl, -C (NR)⁴”)NR⁴' benzothiazolyl, -C (NR)⁴”)NR⁴' benzoxazolyl, aryl or heteroaryl;

R²independently is

A is N, O or CR²’；

R⁵Independently is H, SOR⁷、SO₂R⁷、SO₃R⁷、-C(O)R⁷、-C(O)CHR⁷R⁸、-C(O)NR⁷R⁸、-C(O)OR⁷、-R⁷C(O)R⁸、-C(S)R⁷、-C(NR⁷)NR⁷’R⁸、-(CH₂)_pAryl, - (CH)₂)_pNR⁷R⁸、-C(O)NR⁷R⁸、-N＝CR⁷R⁸、-NR⁷C(O)R⁷', hydrocarbyl, cycloalkyl, hydrocarbyloxy, -NH₂Hydrocarbylamino, hydroxyalkylamino, halogen, -OH, -SH, hydrocarbylthio, hydroxyalkyl, haloalkyl, halohydrocarbonoxy, aryl or heteroaryl;

n is 0 to 2;

wherein

said C is₁-C₆Alkyl radical, C₂-C₆Alkenyl and C₂-C₆Alkynyl moieties may be selected from-CH₃、-C₂H₅、-CH＝CH₂、-C≡CH、-C₃H₇、-CH(CH₃)₂、-CH₂-CH＝CH₂、-C(CH₃)＝CH₂、-CH＝CH-CH₃、-C≡C-CH₃、-CH₂-C≡CH、-C₄H₉、-CH₂-CH(CH₃)₂、-CH(CH₃)-C₂H₅、-C(CH₃)₃、-C₅H₁₁、-C₆H₁₃、-C(R”)₃、-C₂(R’)₅、-CH₂-C(R’)₃、-C₃(R’)₇、-C₂H₄-C(R’)₃、-C₂H₄-CH＝CH₂、-CH＝CH-C₂H₅、-CH＝C(CH₃)₂、-CH₂-CH＝CH-CH₃、-CH＝CH-CH＝CH₂、-C₂H₄-C≡CH、-C≡C-C₂H₅、-CH₂-C≡C-CH₃、-C≡C-CH＝CH₂、-CH＝CH-C≡CH、-C≡C-C≡CH、-C₂H₄-CH(CH₃)₂、-CH(CH₃)-C₃H₇、-CH₂-CH(CH₃)-C₂H₅、-CH(CH₃)-CH(CH₃)₂、-C(CH₃)₂-C₂H₅、-CH₂-C(CH₃)₃、-C₃H₆-CH＝CH₂、-CH＝CH-C₃H₇、-C₂H₄-CH＝CH-CH₃、-CH₂-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-C≡C-CH＝CH₂、-CH₂-CH＝CH-C≡CH、-CH₂-C≡C-C≡CH、-C≡C-CH＝CH-CH₃、-CH＝CH-C≡C-CH₃、-C≡C-C≡C-CH₃、-C≡C-CH₂-CH＝CH₂、-CH＝CH-CH₂-C≡CH、-C≡C-CH₂-C≡CH、-C(CH₃)＝CH-CH＝CH₂、-CH＝C(CH₃)-CH＝CH₂、-CH＝CH-C(CH₃)＝CH₂、-C(CH₃)＝CH-C≡CH、-CH＝C(CH₃)-C≡CH、-C≡C-C(CH₃)＝CH₂、-C₃H₆-CH(CH₃)₂、-C₂H₄-CH(CH₃)-C₂H₅、-CH(CH₃)-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、-C(CH₃)₂-CH(CH₃)₂、-C₂H₄-C(CH₃)₃、-CH(CH₃)-C(CH₃)₃、-C₄H₈-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、-C₄H₈-C≡CH、-C≡C-C₄H₉、-C₃H₆-C≡C-CH₃、-CH₂-C≡C-C₃H₇、-C₂H₄-C≡C-C₂H₅；

a halohydrocarbyloxy group represents a hydrocarbyloxy group substituted with from 1 to 5 halogen atoms, the hydrocarbyl group being as defined above; the halohydrocarbyloxy group is preferably-OC (R)¹⁰)₃、-OCR¹⁰(R¹⁰’)₂、-OCR¹⁰(R¹⁰’)R¹⁰”、-OC₂(R¹⁰)₅、-OCH₂-C(R¹⁰)₃、-OCH₂-CR¹⁰(R¹⁰’)₂、-OCH₂-CR¹⁰(R¹⁰’)R¹⁰”、-OC₃(R¹⁰)₇or-OC₂H₄-C(R¹⁰)₃Wherein R is¹⁰、R¹⁰′、R¹⁰"represents F, Cl, Br or I, preferably F;

the halogen group is chlorine, bromine, fluorine or iodine;

heteroaryl group denotes a five or six membered heterocyclic group containing at least one heteroatom selected from O, N or S. The heterocyclic group may be fused with other aromatic rings. For example, the group may be selected from thiadiazoles, 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, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, benzoxazol-2-yl, benzoxazol-4-yl, benzoxazol-5-yl, benzisoxazol-3-yl, benzisoxazol-4-yl, benzisoxazol-5-yl, 1, 2, 4-oxadiazol-3-yl, 1, 2, 4-oxadiazol-5-yl, oxadizol-3-yl, oxadizol-4-yl, oxadizol-3-yl, oxadizol-5-yl, 1, 2, 5-oxadiazol-3-yl, 1, 2, 5-oxadiazol-4-yl, 1, 2, 4-thiadiazol-3-yl, 1, 2, 4-thiadiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, benzisothiazol-3-yl, benzisothiazol-4-yl, benzisothiazol-5-yl, 1, 2, 5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl, 1, 2, 5-thiadiazol-4-yl, 4-imidazolyl, benzimidazol-4-yl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyranyl, 3-pyranyl, 4-pyranyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2, 4-dimethoxy-6-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 1, 2, 3-triazol-4-yl, 1, 2, 3-triazol-5-yl, 1, 2, 4-triazol-3-yl, 1, 2, 4-triazol-5-yl, 1-pyridyl, 3-pyranyl, 4-pyrimidinyl, 2-pyrimidinyl, 4-pyrimidinyl, 6-pyrimidinyl, 2, 4-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3, 1, 3, 5-triazol-6-yl, 2, 4-dimethoxy-1, 3, 5-triazol-6-yl, 1H-tetrazol-2-yl, 1H-tetrazol-3-yl, tetrazolyl, acridinyl, furazan, indazolyl, phenazinyl, carbazolyl, phenoxazine, indolizine, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 1-isoindolyl, 3-isoindolinyl, 4-isoindolinyl, 5-isoindolinyl, 6-isoindolinyl, 7-isoindolinyl, 2-indolinyl, 3-indolinyl, 4-indolinyl, 5-indolinyl, 6-indolinyl, 7-indolinyl, benzo [ b ] furanyl, benzofurazan, benzothiofurazan, benzotriazol-1-yl, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl, benzotriazol-7-yl, benzotriazine, benzo [ b ] thiophenyl, benzimidazol-2-yl, 1H-benzimidazolyl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl, benzimidazol-7-yl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnoline, quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydro-isoquinolyl, purine, 2, 3-naphthyridine, pteridine, Thiotetrazine, thiotriazene, isothiazolopyrazine, isothiazolopyrimidine, pyrazolotriazine, pyrazolopyrimidine, tetrahydro-thieno [3, 4-d ] imidazol-2-one, pyrazolo [5, 1-c ] [1, 2, 4] triazine, imidazopyridazine, imidazopyrimidine, imidazopyridine, imidazotriazine, triazolotriazine, 2, 3-dihydrobenzo [1, 4] -dioxin-2-yl, 2, 3-dihydrobenzo [1, 4] -dioxin-3-yl, 2, 3-dihydrobenzo [1, 4] -dioxin-5-yl, 2, 3-dihydrobenzo [1, 4] -dioxin-6-yl, 2, 6-dimethoxypyrimidin-3-yl, 2, 6-dimethoxypyrimidin-4-yl, triazolopyridine, triazolopyrazine, triazolopyrimidine, 4- [1, 2, 4] triazolo [4, 3-a ] pyridin-3-yl, 1-furo [2, 3-c ] pyridin-4-yl, 1-furo [2, 3-c ] pyridin-5-yl, 1-furo [2, 3-c ] pyridin-3-yl or a triazolopyridazine group. The heterocyclic group may be substituted with one or more substituents R ', wherein R' is as defined above.

The invention relates to a compound of a general formula (Ic) or a pharmaceutically acceptable salt thereof formed with an acid or a base or a pharmaceutically acceptable prodrug or stereoisomer thereof.

Wherein

R¹Independently represent H, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkoxy, aryl or heteroaryl;

x is CO, CS or SO₂；

Y is CO, CS or SO₂；

Z is NR²", S or O;

R⁴’、R⁴”、R⁵' independently represents H, a hydrocarbon group, a cyclic hydrocarbonAlkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, hydrocarbylamino, -C (NR)⁷)NR⁷’R⁸、-(CH₂)_pAryl, - (CH)₂)_pNR⁷R⁸、-C(O)NR⁷R⁸、-N＝CR⁷R⁸、-NR⁷C(O)R⁸Halogen, heteroaryl or aryl;

p is 1 to 6;

q is 1 to 6;

m is 0 to 4;

r is 0 or 1;

t is 0 or 1;

s is 0 or 1;

R^bindependently H, OH, SH, NR⁴’OR⁵’、NH₂Hydrocarbylamino, hydroxyalkylamido, halogen, CONR^dR^eHydrocarbyloxy, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, halohydrocarbyloxy, aryl or heteroaryl;

R⁷、R⁷' independently represents H, a hydrocarbon group, a cyclic hydrocarbon group, a halogenated hydrocarbon group, a hydroxyhydrocarbon group ammoniaAlkyl, alkylamino, heteroaryl or aryl;

R³independently H, OH, SH, NR⁴’OR⁵’、NH₂Hydroxy hydrocarbyl amino, halogen, CONR^dR^eHydrocarbyloxy, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, halohydrocarbyloxy, aryl or heteroaryl;

said C is₁-C₆Alkyl radical, C₂-C₆Alkenyl and C₂-C₆Alkynyl moieties may be selected from-CH₃、-C₂H₅、-CH＝CH₂、-C≡CH、-C₃H₇、-CH(CH₃)₂、-CH₂-CH＝CH₂、-C(CH₃)＝CH₂、-CH＝CH-CH₃、-C≡C-CH₃、-CH₂-C≡CH、-C₄H₉、-CH₂-CH(CH₃)₂、-CH(CH₃)-C₂H₅、-C(CH₃)₃、-C₅H₁₁、-C₆H₁₃、-C(R”)₃、-C₂(R’)₅、-CH₂-C(R’)₃、-C₃(R’)₇、-C₂H₄-C(R’)₃、-C₂H₄-CH＝CH₂、-CH＝CH-C₂H₅、-CH＝C(CH₃)₂、-CH₂-CH＝CH-CH₃、-CH＝CH-CH＝CH₂、-C₂H₄-C≡CH、-C≡C-C₂H₅、-CH₂-C≡C-CH₃、-C≡C-CH＝CH₂、-CH＝CH-C≡CH、-C≡C-C≡CH、-C₂H₄-CH(CH₃)₂、-CH(CH₃)-C₃H₇、-CH₂-CH(CH₃)-C₂H₅、-CH(CH₃)-CH(CH₃)₂、-C(CH₃)₂-C₂H₅、-CH₂-C(CH₃)₃、-C₃H₆-CH＝CH₂、-CH＝CH-C₃H₇、-C₂H₄-CH＝CH-CH₃、-CH₂-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-C≡C-CH＝CH₂、-CH₂-CH＝CH-C≡CH、-CH₂-C≡C-C≡CH、-C≡C-CH＝CH-CH₃、-CH＝CH-C≡C-CH₃、-C≡C-C≡C-CH₃、-C≡C-CH₂-CH＝CH₂、-CH＝CH-CH₂-C≡CH、-C≡C-CH₂-C≡CH、-C(CH₃)＝CH-CH＝CH₂、-CH＝C(CH₃)-CH＝CH₂、-CH＝CH-C(CH₃)＝CH₂、-C(CH₃)＝CH-C≡CH、-CH＝C(CH₃)-C≡CH 、-C≡C-C(CH₃)＝CH₂、-C₃H₆-CH(CH₃)₂、-C₂H₄-CH(CH₃)-C₂H₅、-CH(CH₃)-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、-C(CH₃)₂-CH(CH₃)₂、-C₂H₄-C(CH₃)₃、-CH(CH₃)-C(CH₃)₃、-C₄H₈-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、-C₄H₈-C≡CH、-C≡C-C₄H₉、-C₃H₆-C≡C-CH₃、-CH₂-C≡C-C₃H₇、-C₂H₄-C≡C-C₂H₅；

the halogen group is chlorine, bromine, fluorine or iodine;

an aryl group represents an aryl group having from 5 to 15 carbon atoms, which may be optionally substituted with one or more substituents R ', wherein R' is as defined above; the aryl group is preferably benzyl, phenyl,-ortho-C₆H₄-R', -m-C₆H₄-R', -p-C₆H₄-R', 1-naphthyl, 2-naphthyl, 1-anthryl or 2-anthryl;

heteroaryl group denotes a five or six membered heterocyclic group containing at least one heteroatom selected from O, N or S. The heterocyclic group may be fused with other aromatic rings. For example, the group may be selected from thiadiazoles, 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, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, benzoxazol-2-yl, benzoxazol-4-yl, benzoxazol-5-yl, benzisoxazol-3-yl, benzisoxazol-4-yl, benzisoxazol-5-yl, 1, 2, 4-oxadiazol-3-yl, 1, 2, 4-oxadiazol-5-yl, oxadizol-3-yl, oxadizol-4-yl, oxadizol-3-yl, oxadizol-5-yl, 1, 2, 5-oxadiazol-3-yl, 1, 2, 5-oxadiazol-4-yl, 1, 2, 4-thiadiazol-3-yl, 1, 2, 4-thiadiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, benzisothiazol-3-yl, benzisothiazol-4-yl, benzisothiazol-5-yl, 1, 2, 5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl, 1, 2, 5-thiadiazol-4-yl, 4-imidazolyl, benzimidazol-4-yl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyranyl, 3-pyranyl, 4-pyranyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2, 4-dimethoxy-6-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 1, 2, 3-triazol-4-yl, 1, 2, 3-triazol-5-yl, 1, 2, 4-triazol-3-yl, 1, 2, 4-triazol-5-yl, 1-pyridyl, 3-pyranyl, 4-pyrimidinyl, 2-pyrimidinyl, 4-pyrimidinyl, 6-pyrimidinyl, 2, 4-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3, 1, 3, 5-triazol-6-yl, 2, 4-dimethoxy-1, 3, 5-triazol-6-yl, 1H-tetrazol-2-yl, 1H-tetrazol-3-yl, tetrazolyl, acridinyl, furazan, indazolyl, phenazinyl, carbazolyl, phenoxazine, indolizine, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 1-isoindolyl, 3-isoindolinyl, 4-isoindolinyl, 5-isoindolinyl, 6-isoindolinyl, 7-isoindolinyl, 2-indolinyl, 3-indolinyl, 4-indolinyl, 5-indolinyl, 6-indolinyl, 7-indolinyl, benzo [ b ] furanyl, benzofurazan, benzothiofurazan, benzotriazol-1-yl, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl, benzotriazol-7-yl, benzotriazine, benzo [ b ] thiophenyl, benzimidazol-2-yl, 1H-benzimidazolyl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl, benzimidazol-7-yl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnoline, quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydro-thieno [3, 4-d ] imidazol-2-one, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt thereof, Pyrazolo [5, 1-c ] [1, 2, 4] triazine, tetrahydroisoquinolinyl, purine, 2, 3-naphthyridine, pteridine, thiotetrazine, thiotriazene, isothiazolopyrazine, isothiazolopyrimidine, pyrazolo triazine, pyrazolopyrimidine, imidazopyridazine, imidazopyridine, imidazotriazine, triazolotriazine, triazolopyridine, triazolopyrazine, triazolopyrimidine, 2, 3-dihydrobenzo [1, 4] -dioxin-2-yl, 2, 3-dihydrobenzo [1, 4] -dioxin-3-yl, 2, 3-dihydrobenzo [1, 4] -dioxin-5-yl, 2, 3-dihydrobenzo [1, 4] -dioxin-6-yl, 2, 6-dimethoxypyrimidin-3-yl, piperidine, and their use in the treatment of diabetes, 2, 6-dimethoxypyrimidin-4-yl, 4- [1, 2, 4] triazolo [4, 3-a ] pyridin-3-yl, 1-furo [2, 3-c ] pyridin-4-yl, 1-furo [2, 3-c ] pyridin-5-yl, 1-furo [2, 3-c ] pyridin-3-yl or a triazolopyridazine group. The heterocyclic group may be substituted with one or more substituents R ', wherein R' is as defined above.

The invention also relates to a compound of the general formula (III) or a pharmaceutically acceptable salt formed by the compound and acid or base, or a pharmaceutically acceptable prodrug or stereoisomer thereof.

Wherein

R¹is-C (O) R^7a、-C(O)CHR⁷R⁸、-C(O)NR⁷R⁸、-C(O)OR⁷、-R⁷C(O)R⁸or-C (S) R^7b；

R²Is H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl,

or R¹And R²And the N atom or C atom to which they are attached form a 3-to 8-membered, saturated or at least partially unsaturated monocyclic or polycyclic ring system, wherein at least one or more carbon atoms of the ring is a heteroatom selected from O, N or S, and the ring may be substituted with one or more substituents R⁹Substitution;

R^4ais H, C₁-C₆Alkyl radical, C₂-C₆Alkenyl, cycloalkyl, haloalkyl, hydroxyhydrocarbyl, hydroxyhydrocarbylamino, hydrocarbylamino, -C (NR)⁷)NR⁷’R⁸、-(CH₂)_pAryl, - (CH)₂)_pNR⁷R⁸、-C(O)NR⁷R⁸、-N＝CR⁷R⁸、-NR⁷C(O)R⁸Halogen, heteroaryl or aryl;

R³is H, -C (O) NR^aR^bHalogen, alkyl, haloalkyl, aryl, heteroaryl, OH, SH, NR⁴’OR⁵’、NH₂A hydroxyalkyl amino group, a alkylamino group, a hydrocarbyloxy group, a cycloalkyl group, a heterocycloalkyl group, a hydroxyalkyl group or a halohydrocarbyloxy group;

R⁴is H, OH, SH, NH₂Hydrocarbyloxy, halohydrocarbyloxy, halogen, hydrocarbyl, -C (NR)⁷)NR⁷’R⁸、-(CH₂)_pAryl, - (CH)₂)_pNR⁷R⁸、-C(O)NR⁷R⁸、-N＝CR⁷R⁸、-NR⁷C(O)R⁸Cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;

R⁵is halogen, hydrocarbyl, -C (NR)⁷)NR⁷’R⁸、-(CH₂)_pAryl, - (CH)₂)_pNR⁷R⁸、-C(O)NR⁷R⁸、-N＝CR⁷R⁸、-NR⁷C(O)R⁸Cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;

R^ais H, halogen, hydrocarbyl, -C (NR)⁷)NR⁷’R⁸、-(CH₂)_pAryl, - (CH)₂)_pNR⁷R⁸、-C(O)NR⁷R⁸、-N＝CR⁷R⁸、-NR⁷C(O)R⁸Cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;

R^bindependently represent H, -CN, -OH, -SH, -CO₂R⁴’、-C(O)R⁴’、-SO₂NR⁴’、-NR⁴’R⁵、-C(O)NR⁷R⁸、-SO₂-hydrocarbyl, -SO₂R⁴’、SO₃R⁴’、-N＝CR⁴’R⁵’、-NR⁴’C(O)R⁴”、-NR⁴' -CO-Halogenoalkyl, -NO₂、-NR⁴’-SO₂-halogenated hydrocarbon radical, -NR⁴’-SO₂-hydrocarbyl, -NR⁴' -CO-hydrocarbyl, -NR⁴’(CH₂)_pHeteroaryl, alkyl, cycloalkyl, alkylamino, hydrocarbyloxy, hydrocarbylthio, halogen, haloalkyl, halohydrocarbyloxy, -O (CH)₂)p[O(CH₂)_p]_qOCH₃、-C(NR⁴”)NR⁴' benzimidazolyl, -C (NR)⁴”)NR⁴' benzothiazolyl, -C (NR)⁴”)NR⁴' benzoxazolyl, hydroxyalkyl, hydroxy-cycloalkyl, hydroxyalkylamino, heterocycloalkyl, aryl or heteroaryl;

R⁴’、R⁴”、R⁵' is independently H, halogen, hydrocarbyl, -C (NR)⁷)NR⁷’R⁸、-(CH₂)_pAryl, haloalkyl, - (CH)₂)_pNR⁷R⁸、-C(O)NR⁷R⁸、-N＝CR⁷R⁸、-NR⁷C(O)R⁸Cycloalkyl, heterocycloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;

R⁷、R⁷’、R⁸independently is H, halogen, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, arylamino, heteroaryl or aryl;

R^7ais cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, heteroaryl or aryl;

R^7bis H, halogen, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, heteroaryl or aryl;

a is CO or SO₂；

X is NR²', O or S;

z is N or CR²’；

R²' is H, hydrocarbyl, -C (O) NR⁷、-C(O)R^bCycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;

p is 1 to 6;

q is 1 to 6;

R⁹independently represent H, -CN, -OH, -SH, hydrocarbonoxy, hydrocarbylthio, -CO₂R⁴’、-C(O)R^4a、-C(O)NR⁷R⁸、-SO₂NR⁴’、-NR⁴’R⁵’、-SO₂-hydrocarbyl, -SO₂R⁴’、SO₃R⁴’、-N＝CR⁴’R⁵’、-NR⁴’C(O)R⁴”、-NR⁴' -CO-Halogenoalkyl, -NO₂、-NR⁴’-SO₂-halogenated hydrocarbon radical, -NR⁴’-SO₂-hydrocarbyl, -NR⁴' -CO-hydrocarbyl, -NR⁴’(CH₂)_pHeteroaryl, hydrocarbyl, hydroxyhydrocarbyl, cyclohydrocarbyl, halo, halohydrocarbyl, hydrocarbylamino, -O (CH)₂)_p[O(CH₂)_p]_qOCH₃、-C(NR⁴”)NR⁴' benzimidazolyl, -C (NR)⁴”)NR⁴' benzothiazolyl, -C (NR)⁴”)NR⁴' benzoxazolyl, hydroxycycloalkyl, hydroxyalkylamino, halohydrocarbyloxy, heterocycloalkyl, - (CH)₂)_pNR⁷COR⁸Aryl or heteroaryl;

wherein

If not otherwise stated, C₁-C₆The alkyl radical representing a straight-chain or branched C₁-C₆Alkyl, preferably straight or branched chain of 1 to 5 carbon atoms, which may be optionally substituted with one or more substituents R';

if not otherwise stated, C₂-C₆Alkenyl radical denotes straight-chain or branched C₂-C₆Alkenyl, preferably straight-chain or branched, of 2 to 6 carbon atoms, which may optionally be substituted by one or more substituents R';

the hydrocarbon radical denotes, if not otherwise stated, straight-chain or branched C₁-C₆Alkyl, preferably straight or branched chain, C of 1 to 6 carbon atoms₂-C₆Alkenyl or straight or branched C₂-C₆An alkynyl group which may be optionally substituted with one or more substituents R';

cycloalkyl represents a non-aromatic ring system containing from 3 to 8 carbon atoms, preferably from 4 to 8 carbon atoms, wherein one or more carbon atoms on the ring may be substituted by an R' group as defined above; said C is₃-C₈The cycloalkyl moiety may be selected from-ring-C₃H₅-Ring-C₄H₇-Ring-C₅H₉-Ring-C₆H₁₁-Ring-C₇H₁₃-Ring-C₈H₁₅；

Heterocycloalkyl represents a non-aromatic ring system containing from 2 to 10 carbon atoms and at least one heteroatom selected from O, N or S, wherein one or more carbon atoms of the ring may be substituted by an R' group as defined above; preferred heterocyclic hydrocarbyl groups are morpholin-4-yl, piperazinyl, 1-hydrocarbyl piperazin-4-yl, piperidinyl, pyrrolidinyl, azepan-1-yl;

halogen groups are fluorine, chlorine, bromine or iodine;

an aryl group represents an aryl group having from 5 to 15 carbon atoms, which may be optionally substituted with one or more substituents R ', wherein R' is as defined above; the aryl group is preferably benzyl, phenyl, -o-C₆H₄-R', -m-C₆H₄-R', -p-C₆H₄-R ', 1-naphthyl, 2-naphthyl, 1-anthracenyl or 2-anthracenyl, R' being as defined above;

arylamino represents a HN-aryl or N-diaryl group, the aryl group being as defined above;

heteroaryl group denotes a five or six membered heterocyclic group containing at least one heteroatom selected from O, N or S. The heterocyclic group may be fused with other aromatic rings. For example, the group may be selected from thiadiazoles, 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, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, benzoxazol-2-yl, benzoxazol-4-yl, benzoxazol-5-yl, benzisoxazol-3-yl, benzisoxazol-4-yl, benzisoxazol-5-yl, 1, 2, 4-oxadiazol-3-yl, 1, 2, 4-oxadiazol-5-yl, oxadizol-3-yl, oxadizol-4-yl, oxadizol-3-yl, oxadizol-5-yl, 1, 2, 5-oxadiazol-3-yl, 1, 2, 5-oxadiazol-4-yl, 1, 2, 4-thiadiazol-3-yl, 1, 2, 4-thiadiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, benzisothiazol-3-yl, benzisothiazol-4-yl, benzisothiazol-5-yl, 1, 2, 5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl, 1, 2, 5-thiadiazol-4-yl, 4-imidazolyl, benzimidazol-4-yl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyranyl, 3-pyranyl, 4-pyranyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2, 4-dimethoxy-6-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 1, 2, 3-triazol-4-yl, 1, 2, 3-triazol-5-yl, 1, 2, 4-triazol-3-yl, 1, 2, 4-triazol-5-yl, 1-pyridyl, 3-pyranyl, 4-pyrimidinyl, 2-pyrimidinyl, 4-pyrimidinyl, 6-pyrimidinyl, 2, 4-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3, 1, 3, 5-triazol-6-yl, 2, 4-dimethoxy-1, 3, 5-triazol-6-yl, 1H-tetrazol-2-yl, 1H-tetrazol-3-yl, tetrazolyl, acridinyl, furazan, indazolyl, phenazinyl, carbazolyl, phenoxazine, indolizine, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 1-isoindolyl, 3-isoindolinyl, 4-isoindolinyl, 5-isoindolinyl, 6-isoindolinyl, 7-isoindolinyl, 2-indolinyl, 3-indolinyl, 4-indolinyl, 5-indolinyl, 6-indolinyl, 7-indolinyl, benzo [ b ] furanyl, benzofurazan, benzothiofurazan, benzotriazol-1-yl, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl, benzotriazol-7-yl, benzotriazine, benzo [ b ] thiophenyl, benzimidazol-2-yl, 1H-benzimidazolyl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl, benzimidazol-7-yl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnoline, quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydro-thieno [3, 4-d ] imidazol-2-one, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt thereof, Pyrazolo [5, 1-c ] [1, 2, 4] triazine, 2, 3-dihydrobenzo [1, 4] -dioxin-2-yl, 2, 3-dihydrobenzo [1, 4] -dioxin-3-yl, 2, 3-dihydrobenzo [1, 4] -dioxin-5-yl, 2, 3-dihydrobenzo [1, 4] -dioxin-6-yl, 2, 6-dimethoxypyrimidin-3-yl, 2, 6-dimethoxypyrimidin-4-yl, tetrahydroisoquinolinyl, purine, 2, 3-naphthyridine, pteridine, thiotetrazine, thiotrizine, isothiazolopyrazine, isothiazolopyrimidine, pyrazolotriazine, pyrazolopyrimidine, imidazopyridazine, imidazopyrimidine, Imidazopyridine, imidazotriazine, triazolotriazine, triazolopyridine, triazolopyrazine, triazolopyrimidine, 4- [1, 2, 4] triazolo [4, 3-a ] pyridin-3-yl, 1-furo [2, 3-c ] pyridin-4-yl, 1-furo [2, 3-c ] pyridin-5-yl, 1-furo [2, 3-c ] pyridin-3-yl or a triazolopyridazine group. The heterocyclic group may be substituted with one or more substituents R ', wherein R' is as defined above.

The following compounds are excluded from the general formula (III):

wherein

R¹Independently represent hydrogen, hydrocarbyl, cycloalkyl, hydroxyAlkyl, haloalkyl, halocarbyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, or substituted arylalkyl groups;

R²independently represent-NR³R⁴、

R³Independently represents a hydrocarbyl, cycloalkyl, hydrocarbyloxy, hydrocarbylamine, -OH, -SH, hydrocarbylthio, hydroxyhydrocarbyl, halohydrocarbyl, halohydrocarbyloxy, aryl or heteroaryl group,

R⁴independently represent a hydrocarbyl, cycloalkyl, hydrocarbyloxy, hydrocarbylamine, hydrocarbylthio, hydroxyalkyl, halohydrocarbyl, halohydrocarbyloxy, aryl or heteroaryl group;

R⁵independently represent H, COR⁶、CO₂R⁶、SOR⁶、SO₂R⁶、SO₃R⁶Alkyl, cycloalkyl, alkoxy, -NH₂Hydrocarbyl amine, -NR⁷COR⁶Halogen, -OH, -SH, alkylthio, hydroxyalkyl, haloalkyl, halohydrocarbonoxy, aryl or heteroaryl;

R⁶independently represents H, hydrocarbyl, cycloalkyl, -NH₂Hydrocarbyl amine, aryl or heteroaryl;

R⁷independently represent H, alkyl, cycloalkyl, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl, aryl or heteroaryl;

p is 0 or 1;

q is 0 or 1;

x is CO or SO₂。

The invention also relates to a compound of the general formula (Ih) or a pharmaceutically acceptable salt thereof with an acid or a base or a pharmaceutically acceptable prodrug or stereoisomer thereof,

wherein

A is NR²', S or O;

t is 0 to 4;

r is 0 or 1;

R^2aindependently of each other H, OH, SH, NH₂Alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, halohydrocarbonoxy, hydrocarbonoxy, alkylamino, hydroxyalkylamino, halogen, aryl or heteroaryl;

R^3ais H, OH, SH, NH₂、-C(NR⁷)NR⁷’R⁸、-(CH₂)_pAryl, - (CH)₂)_pNR⁷R⁸、-C(O)NR⁷R⁸、-N＝CR⁷R⁸、-NR⁷C(O)R⁸Alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, halohydrocarbonoxy, hydrocarbonoxy, alkylamino, hydroxyalkylamino, halogen, aryl or heteroaryl;

R²Is H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino or heteroaryl;

R^bindependently represent H, -CN, -OH, -SH, -CO₂R⁴’、-C(O)R⁴’、-SO₂NR⁴’、-NR⁴’R⁵’、-C(O)NR⁷R⁸、-SO₂-hydrocarbyl, -SO₂R⁴’、SO₃R⁴’、-N＝CR⁴’R⁵’、-NR⁴’C(O)R⁴”、-NR⁴' -CO-Halogenoalkyl, -NO₂、-NR⁴’-SO₂-halogenated hydrocarbon radical, -NR⁴’-SO₂-hydrocarbyl, -NR⁴' -CO-hydrocarbyl, -NR⁴’(CH₂)_pHeteroaryl, alkyl, cycloalkyl, alkylamino, hydrocarbyloxy, hydrocarbylthio, halogen, haloalkyl, halohydrocarbyloxy, -O (CH)₂)_p[O(CH₂)_p]_qOCH₃、-C(NR⁴”)NR⁴' benzimidazolyl, -C (NR)⁴”)NR⁴' benzothiazolyl, -C (NR)⁴”)NR⁴' benzoxazolyl, hydroxyalkyl, hydroxy-cycloalkyl, hydroxyalkylamino, heterocycloalkyl, aryl or heteroaryl;

R^7bis H, halogen, hydrocarbyl, cycloalkyl, heterocycloalkyl, halocarbyl, hydroxyhydrocarbyl, hydroxyhydrocarbylamino, heterocarbylAryl or aryl;

x is NR²', O or S;

z is N or CR²’；

p is 1 to 6;

q is 1 to 6;

R⁹independently represent H, -CN, -OH, -SH, hydrocarbonoxy, hydrocarbylthio, -CO₂R⁴’、-C(O)R^4a、-C(O)NR⁷R⁸、-SO₂NR⁴’、-NR⁴’R⁵’、-SO₂-hydrocarbyl, -SO₂R⁴’、SO₃R⁴’、-N＝CR⁴’R⁵’、-NR⁴’C(O)R⁴”、-NR⁴' -CO-Halogenoalkyl, -NO₂、-NR⁴’-SO₂-halogenated hydrocarbon radical, -NR⁴’-SO₂-hydrocarbyl, -NR⁴' -CO-hydrocarbyl, -NR⁴’(CH₂)_pHeteroaryl, hydrocarbyl, hydroxyhydrocarbyl, cyclohydrocarbyl, halo, halohydrocarbyl, hydrocarbylamino, -O (CH)₂)_p[O(CH₂)_p]_qOCH₃、-C(NR⁴”)NR⁴' benzimidazolyl, -C (NR)₄”)NR₄' benzothiazolyl, -C (NR)₄”)NR₄' benzoxazolyl, hydroxycycloalkyl, hydroxyalkylamino, halohydrocarbyloxy, heterocycloalkyl, - (CH)₂)_pNR⁷COR⁸Aryl or heteroaryl;

wherein

If not otherwise stated, C₁-C₆The alkyl radical representing a straight-chain or branched C₁-C₆Alkyl, preferably straight chain of 1 to 5 carbon atomsOr branched, which may be optionally substituted with one or more substituents R';

cycloalkyl represents a non-aromatic ring system containing from 3 to 8 carbon atoms, preferably from 4 to 8 carbon atoms, wherein one or more carbon atoms of the ring may be substituted by a group R ', R' being as defined above; said C is₃-C₈The cycloalkyl moiety may be selected from-ring-C₃H₅-Ring-C₄H₇-Ring-C₅H₉-Ring-C₆H₁₁-Ring-C₇H₁₃-Ring-C₈H₁₅；

a halohydrocarbyloxy group represents a hydrocarbyloxy group substituted with from 1 to 5 halogen atoms, the hydrocarbyl group being as defined above; the halohydrocarbyloxy group is preferably-OC (R)¹⁰)₃、-OCR¹⁰(R¹⁰’)₂、-OCR¹⁰(R¹⁰’)R¹⁰”、-OC₂(R¹⁰)₅、-OCH₂C(R¹⁰)₃、-OCH₂CR¹⁰(R¹⁰’)₂、-OCH₂CR¹⁰(R¹⁰’)R¹⁰”、-OC₃(R¹⁰)₇or-OC₂H₄C(R¹⁰)₃Wherein R is¹⁰、R¹⁰’、R¹⁰"represents F, Cl, Br or I, preferably F;

halogen groups are fluorine, chlorine, bromine or iodine;

heteroaryl group denotes a five or six membered heterocyclic group containing at least one heteroatom selected from O, N or S. The heterocyclic group may be fused with other aromatic rings. For example, the group may be selected from thiadiazoles, 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, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, benzoxazol-2-yl, benzoxazol-4-yl, benzoxazol-5-yl, benzisoxazol-3-yl, benzisoxazol-4-yl, benzisoxazol-5-yl, 1, 2, 4-oxadiazol-3-yl, 1, 2, 4-oxadiazol-5-yl, oxadizol-3-yl, oxadizol-4-yl, oxadizol-3-yl, oxadizol-5-yl, 1, 2, 5-oxadiazol-3-yl, 1, 2, 5-oxadiazol-4-yl, 1, 2, 4-thiadiazol-3-yl, 1, 2, 4-thiadiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, benzisothiazol-3-yl, benzisothiazol-4-yl, benzisothiazol-5-yl, 1, 2, 5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl, 1, 2, 5-thiadiazol-4-yl, 4-imidazolyl, benzimidazol-4-yl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyranyl, 3-pyranyl, 4-pyranyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2, 4-dimethoxy-6-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 1, 2, 3-triazol-4-yl, 1, 2, 3-triazol-5-yl, 1, 2, 4-triazol-3-yl, 1, 2, 4-triazol-5-yl, 1-pyridyl, 3-pyranyl, 4-pyrimidinyl, 2-pyrimidinyl, 4-pyrimidinyl, 6-pyrimidinyl, 2, 4-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3, 1, 3, 5-triazol-6-yl, 2, 4-dimethoxy-1, 3, 5-triazol-6-yl, 1H-tetrazol-2-yl, 1H-tetrazol-3-yl, tetrazolyl, acridinyl, furazan, indazolyl, phenazinyl, carbazolyl, phenoxazine, indolizine, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 1-isoindolyl, 3-isoindolinyl, 4-isoindolinyl, 5-isoindolinyl, 6-isoindolinyl, 7-isoindolinyl, 2-indolinyl, 3-indolinyl, 4-indolinyl, 5-indolinyl, 6-indolinyl, 7-indolinyl, benzo [ b ] furanyl, benzofurazan, benzothiofurazan, benzotriazol-1-yl, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl, benzotriazol-7-yl, benzotriazine, benzo [ b ] thiophenyl, benzimidazol-2-yl, 1H-benzimidazolyl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl, benzimidazol-7-yl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnoline, quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydro-thieno [3, 4-d ] imidazol-2-one, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt thereof, Pyrazolo [5, 1-c ] [1, 2, 4] triazine, 2, 3-dihydrobenzo [1, 4] -dioxin-2-yl, 2, 3-dihydrobenzo [1, 4] -dioxin-3-yl, 2, 3-dihydrobenzo [1, 4] -dioxin-5-yl, 2, 3-dihydrobenzo [1, 4] -dioxin-6-yl, 2, 6-dimethoxypyrimidin-3-yl, 2, 6-dimethoxypyrimidin-4-yl, tetrahydroisoquinolinyl, purine, 2, 3-naphthyridine, pteridine, thiotetrazine, thiotriazene, isothiazolopyrazine, isothiazolopyrimidine, pyrazolotriazine, pyrazolopyrimidine, imidazopyridazine, imidazopyrimidine, and the like, Imidazopyridine, imidazotriazine, triazolotriazine, triazolopyridine, triazolopyrazine, triazolopyrimidine, 4- [1, 2, 4] triazolo [4, 3-a ] pyridin-3-yl, 1-furo [2, 3-c ] pyridin-4-yl, 1-furo [2, 3-c ] pyridin-5-yl, 1-furo [2, 3-c ] pyridin-3-yl, and triazolopyridazine groups. The heterocyclic group may be substituted with one or more substituents R ', wherein R' is as defined above.

The following compounds are excluded from the general formula (Ih):

wherein

R¹Independently represent hydrogen, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl or substituted arylalkyl;

R²independently represent-NR³R⁴、

R³Independently represent a hydrocarbyl, cycloalkyl, hydrocarbyloxy, hydrocarbylamine, -OH, -SH, hydrocarbylthio, hydroxyhydrocarbyl, halohydrocarbyl, halohydrocarbyloxy, aryl or heteroaryl group;

R⁵independently represent H, COR⁶、CO₂R⁶、SOR⁶、SO₂R⁶、SO₃R⁶Hydrocarbyl, cyclic hydrocarbonAlkyl, alkoxy, -NH₂Hydrocarbyl amine, -NR⁷COR⁶Halogen, -OH, -SH, alkylthio, hydroxyalkyl, haloalkyl, halohydrocarbonoxy, aryl or heteroaryl;

p is 0 or 1;

q is 0 or 1;

x is CO or SO₂。

The following substituents, alone or in combination, are preferred in formula (Ih):

x is preferably S or O, more preferably S.

R^3aH is preferred.

In a preferred embodiment, Z is CR²' and R¹And R²And the C atom to which it is attached forms a 6-membered saturated ring. In another preferred embodiment, Z is N and R¹And R²And the N atom to which it is attached forms a 6-membered saturated ring.

R⁹Preferably a heteroaryl, aryl or benzyl group, more preferably a heteroaryl group. R⁹Even more preferred are thienopyrimidines, quinazolines, purines, pyrazolopyrimidines or triazolopyrimidines. Even more preferably, R⁹Is a thienopyrimidine.

t is preferably 0.

r is preferably 1.

R^2aPreferably OH, hydrocarbyl, aryl or heteroaryl, more preferably hydrocarbyl, especially methyl.

The invention also relates to a compound of the general formula (II) or a pharmaceutically acceptable salt formed by the compound and acid or alkali or a pharmaceutically acceptable prodrug or stereoisomer thereof,

wherein

R²Is H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, alkylamino, hydroxyalkylamino or heteroaryl;

R^bindependently represent H, -CN, -OH, -SH、-CO₂R⁴’、-C(O)R⁴’、-SO₂NR⁴’、-NR⁴’R⁵’、-C(O)NR⁷R⁸、-SO₂-hydrocarbyl, -SO₂R⁴’、SO₃R⁴’、-N＝CR⁴’R⁵’、-NR⁴’C(O)R⁴”、-NR⁴' -CO-Halogenoalkyl, -NO₂、-NR⁴’-SO₂-halogenated hydrocarbon radical, -NR⁴’-SO₂-hydrocarbyl, -NR⁴' -CO-hydrocarbyl, -NR⁴’(CH₂)_pHeterocycle, hydrocarbyl, cycloalkyl, hydrocarbylamino, hydrocarbyloxy, hydrocarbylthio, halogen, halohydrocarbyl, halohydrocarbyloxy, -O (CH)₂)_p[O(CH₂)_p]_qOCH₃、-C(NR⁴”)NR⁴' benzimidazolyl, -C (NR)⁴”)NR⁴' benzothiazolyl, -C (NR)⁴”)NR⁴' benzoxazolyl, hydroxyalkyl, hydroxyalkylamino, aryl, heterocycloalkyl, or heteroaryl;

R⁶is halogen, -C (O) R⁷、-C(O)CHR⁷R⁸、-C(O)NR⁷R⁸、-C(O)OR⁷、-R⁷C(O)R⁸、-C(S)R⁷、-C(NR⁷)NR⁷’R⁸、-(CH₂)_pAryl, - (CH)₂)_pNR⁷R⁸、-C(O)NR⁷R⁸、-N＝CR⁷R⁸、-NR⁷C(O)R⁷', alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or aryl;

R⁷、R⁷’、R⁸independently is H, halogen, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, -NH aryl, heteroaryl or aryl;

a is CO or SO₂；

X is NR²', O or S;

y is N, CR²' or R is absent if Y is O⁶；

Z is N or CR²'; if Z is CH then X is O or NR²’

R²' is H, hydrocarbyl, -C (O) NR²、-C(O)R^bCycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;

n is 0 to 2;

p is 1 to 6;

q is 1 to 6;

R⁹independently represent H, -CN, -OH, -SH, -CO₂R⁴’、-C(O)R^4a、-C(O)NR⁷R⁸、-SO₂NR⁴’、-NR⁴’R⁵’、-SO₂-hydrocarbyl, -SO₂R⁴’、SO₃R⁴’、-N＝CR⁴’R⁵’、-NR⁴’C(O)R⁴”、-NR⁴' -CO-Halogenoalkyl, -NO₂、-NR⁴’-SO₂-halogenated hydrocarbon radical, -NR⁴’-SO₂-hydrocarbyl, -NR⁴' -CO-hydrocarbyl, -NR⁴’(CH₂)_pHeteroaryl, alkyl, cycloalkyl, heterocycloalkyl, alkylamino, hydrocarbyloxy, alkylthio, halogen, haloalkyl, halohydrocarbyloxy, hydroxyalkylamino, hydroxyalkyl, hydroxycycloalkyl, aryl, -O (CH)₂)_p[O(CH₂)_p]_qOCH₃、-C(NR⁴”)NR⁴' benzimidazolyl, -C (NR)⁴”)NR⁴' benzothiazolyl, -C (NR)⁴”)NR⁴' benzoxazolyl, - (CH)₂)_pNR⁷COR⁸Or a heteroaryl group;

R⁴’、R⁴”、R⁵' independently is HHalogen, hydrocarbyl, -C (NR)⁷)NR⁷’R⁸、-(CH₂)_pAryl, - (CH)₂)_pNR⁷R⁸、-C(O)NR⁷R⁸、-N＝CR⁷R⁸、-NR⁷C(O)R⁸Cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;

wherein

r' is independently H, -CO₂R”、-CONHR”、-CR”O、-SO₂NR”-NR' -CO-haloalkyl, -NO₂、-NR”-SO₂-halogenated hydrocarbon radical, -NR "-SO₂-hydrocarbyl, -SO₂-alkyl, -NR "-CO-alkyl, -CN, alkyl, cycloalkyl, alkylamino, hydrocarbyloxy, -OH, -SH, hydrocarbylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, halohydrocarbyloxy, aryl or heteroaryl;

heterocycle represents a heterocycloalkyl group or a heteroaryl group;

a halogenated hydrocarbyl group represents a hydrocarbyl group substituted with 1 to 5 halogen atoms, the hydrocarbyl group being as defined above; said halogenated hydrocarbon grouppreferably-C (R)¹⁰)₃、-CR¹⁰(R¹⁰’)₂、-CR¹⁰(R¹⁰’)R¹⁰”、-C₂(R¹⁰)₅、-CH₂-C(R¹⁰)₃、-CH₂-CR¹⁰(R¹⁰’)₂、-CH₂-CR¹⁰(R¹⁰’)R¹⁰”、-C₃(R¹⁰)₇or-C₂H₄-C(R¹⁰)₃Wherein R is¹⁰、R¹⁰”、R¹⁰"represents F, Cl, Br or I, preferably F;

halogen groups are fluorine, chlorine, bromine or iodine;

an aryl group denotes an aryl group having 5 to 15 carbon atoms, which may optionally be substituted by oneOr a plurality of substituents R 'wherein R' is as defined above; the aryl group is preferably benzyl, phenyl, -o-C₆H₄-R', -m-C₆H₄-R', -p-C₆H₄-R ', 1-naphthyl, 2-naphthyl, 1-anthracenyl or 2-anthracenyl, R' being as defined above;

heteroaryl group denotes a five or six membered heterocyclic group containing at least one heteroatom selected from O, N or S. The heterocyclic group may be fused with other aromatic rings. For example, the group may be selected from thiadiazoles, 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, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, benzoxazol-2-yl, benzoxazol-4-yl, benzoxazol-5-yl, benzisoxazol-3-yl, benzisoxazol-4-yl, benzisoxazol-5-yl, 1, 2, 4-oxadiazol-3-yl, 1, 2, 4-oxadiazol-5-yl, oxadizol-3-yl, oxadizol-4-yl, oxadizol-3-yl, oxadizol-5-yl, 1, 2, 5-oxadiazol-3-yl, 1, 2, 5-oxadiazol-4-yl, 1, 2, 4-thiadiazol-3-yl, 1, 2, 4-thiadiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, benzisothiazol-3-yl, benzisothiazol-4-yl, benzisothiazol-5-yl, 1, 2, 5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl, 1, 2, 5-thiadiazol-4-yl, 4-imidazolyl, benzimidazol-4-yl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyranyl, 3-pyranyl, 4-pyranyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2, 4-dimethoxy-6-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 1, 2, 3-triazol-4-yl, 1, 2, 3-triazol-5-yl, 1, 2, 4-triazol-3-yl, 1, 2, 4-triazol-5-yl, 1-pyridyl, 3-pyranyl, 4-pyrimidinyl, 2-pyrimidinyl, 4-pyrimidinyl, 6-pyrimidinyl, 2, 4-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3, 1, 3, 5-triazol-6-yl, 2, 4-dimethoxy-1, 3, 5-triazol-6-yl, 1H-tetrazol-2-yl, 1H-tetrazol-3-yl, tetrazolyl, acridinyl, furazan, indazolyl, phenazinyl, carbazolyl, phenoxazine, indolizine, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 1-isoindolyl, 3-isoindolinyl, 4-isoindolinyl, 5-isoindolinyl, 6-isoindolinyl, 7-isoindolinyl, 2-indolinyl, 3-indolinyl, 4-indolinyl, 5-indolinyl, 6-indolinyl, 7-indolinyl, benzo [ b ] furanyl, benzofurazan, benzothiofurazan, benzotriazol-1-yl, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl, benzotriazol-7-yl, benzotriazine, benzo [ b ] thiophenyl, benzimidazol-2-yl, 1H-benzimidazolyl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl, benzimidazol-7-yl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnoline, quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydro-thieno [3, 4-d ] imidazol-2-one, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt thereof, Pyrazolo [5, 1-c ] [1, 2, 4] triazine, 2, 3-dihydrobenzo [1, 4] -dioxin-2-yl, 2, 3-dihydrobenzo [1, 4] -dioxin-3-yl, 2, 3-dihydrobenzo [1, 4] -dioxin-5-yl, 2, 3-dihydrobenzo [1, 4] -dioxin-6-yl, 2, 6-dimethoxypyrimidin-3-yl, 2, 6-dimethoxypyrimidin-4-yl, tetrahydroisoquinolinyl, purine, 2, 3-naphthyridine, pteridine, thiotetrazine, thiotriazene, isothiazolopyrazine, isothiazolopyrimidine, pyrazolotriazine, pyrazolopyrimidine, imidazopyridazine, imidazopyrimidine, and the like, Imidazopyridine, imidazotriazine, triazolotriazine, triazolopyridine, triazolopyrazine, triazolopyrimidine, 4- [1, 2, 4] triazolo [4, 3-a ] pyridin-3-yl, 1-furo [2, 3-c ] pyridin-4-yl, 1-furo [2, 3-c ] pyridin-5-yl, 1-furo [2, 3-c ] pyridin-3-yl or a triazolopyridazine group. The heterocyclic group may be substituted with one or more substituents R ', wherein R' is as defined above.

In a preferred embodiment of the invention, in the compounds of the general formula (Ia), Z is S, Y is CO, X is CO, R is H, R is^cIs H and R¹Is aryl, benzyl or heteroaryl, R²Is thatAnd R is⁵Optionally substituted aryl, benzyl or heteroaryl.

In a preferred embodiment of the present invention,in the compounds of the formula (Ia), Z is O, Y is CO, X is CO, R is H, R^cIs H and R¹Is aryl, benzyl or heteroaryl, R²Is thatAnd R is⁵Optionally substituted aryl, benzyl or heteroaryl.

In a preferred embodiment of the invention, in the compounds of the general formula (Ib), Z is S, Y is CO, X and R¹And R⁴Together form a piperidine ring, R^aAnd R^bIs H, R^cIs H or methyl, R²Is thatAnd R is⁵Optionally substituted aryl, benzyl or heteroaryl.

In a preferred embodiment of the invention, in the compounds of the general formula (Ib), Z is O, Y is CO, X and R¹And R⁴Together form a piperidine ring, R^aAnd R^bIs H, R^cIs H or methyl, R²Is thatAnd R is⁵Optionally 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, R is^cIs H, methyl, ethyl, methoxy, alkylamino, morpholinyl, N-methylpiperazine, CF₃Or OCF, R²Is thatAnd R is⁵Optionally substituted aryl, benzyl or heteroaryl.

In another preferred embodiment, in the compounds of formula (Ic), R is 1, Y is CO, Z is S, t is 0, S is 0, R is^cIs H, methyl, ethyl, methoxy, alkyl amino,Morpholinyl, N-methylpiperazine, CF₃Or OCF, R²Is thatAnd R is⁵Optionally substituted aryl, benzyl or heteroaryl.

In another preferred embodiment, in the compounds of formula (Ic), R is 1, Y is CO, Z is S, t is 0, S is 1, X is CO, R is^cIs H, methyl, ethyl, methoxy, alkylamino, morpholinyl, N-methylpiperazine, CF₃Or OCF, R²Is thatAnd R is⁵Optionally 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, morpholinyl, N-methylpiperazine, CF₃Or OCF, R²Is thatAnd R is⁵Optionally substituted aryl, benzyl or heteroaryl.

Among the compounds of the formula (III), a preferred embodiment of the present invention is a compound of the formula (IIIa)

R³、R⁴、R⁵、R^7aAnd Z is as defined above.

Preferably, R³Is H, Me, OMe, CF₃、OCF₃Cl, OH or SH, more preferably H, Me, OMe, CF₃、OCF₃Still more preferably, H.

Preferably, Z is N.

Preferably, R⁴Is H.

Preferably, R^7aIs aryl or heteroaryl, more preferably aryl, still more preferably phenyl. Further preferably, R^7aSubstituted with one or two substituents R ', more preferably one substituent R'. In a particularly preferred embodiment, R^7aIs 2-trifluoromethoxyphenyl. In another particularly preferred embodiment, R^7aIs 2-methoxyphenyl. In another particularly preferred embodiment, R^7aIs 2-chlorophenyl. And in yet another particularly preferred embodiment, R^7aIs 2-methylphenyl.

Preferably, R⁵Is aryl or heteroaryl, more preferably heteroaryl. The heteroaryl group preferably contains 2 nitrogen atoms and is particularly preferably a 2-imidazolyl or 2-benzimidazolyl group, still more preferably a 2-benzimidazolyl group. In another preferred embodiment, the heteroaryl group contains 1 nitrogen atom and 1 sulfur atom and is particularly preferably 2-thiazolyl or 2-benzothiazolyl, still more preferably 2-benzothiazolyl. The heteroaryl group is further preferably substituted with 1 to 4 substituents R ', more preferably with 1 or 2 substituents R'. In a particularly preferred embodiment, R⁵Is 5, 6-dimethyl-1H-benzimidazol-2-yl. In another particularly preferred embodiment, R⁵Is 5, 6-dimethyl-1H-benzothiazol-2-yl.

Preferably, R' is-SO₂-hydrocarbyl, -NO₂Halogen, -CO₂H. -OH, halohydrocarbyloxy, hydrocarbyloxy or hydrocarbyl. R' is particularly preferably: methylsulfonyl, nitro, fluoro, chloro, bromo, carboxy, hydroxy, trifluoromethoxy, methoxy, ethoxy, methyl, ethyl, or trifluoroethyl.

In a preferred embodiment, X is O. In another preferred embodiment, X is S. In yet another preferred embodiment, X is NR²’。

In the general formula (IIIa)In a preferred embodiment of the compounds, R³Is H, methyl, methoxy, CF₃Or OCF₃；R⁴、R⁵、R^7aAs defined above; x is NR²', O or S; and Z is as defined above.

Of the compounds of the formula (III), another preferred embodiment of the invention is a compound of the formula (IIIa), R^7a-NH-aryl.

Of the compounds of the formula (III), a further preferred embodiment of the present invention is a compound of the formula (IIIb),

wherein

R³Is H, methyl, methoxy, CF₃Or OCF₃；R⁵As defined above; x is NR²', O or S; if Z is N then X is NR²', O or S; if Z is CR²' then X is O; y' is O or NR²’、R²' is as defined above.

Of the compounds of the formula (III), a further preferred embodiment of the present invention are compounds of the formula (IIIc),

wherein

R¹¹、R¹²Independently represent H, -CN, -OH, -SH, -CO₂R⁴’、-C(O)R⁴’、-SO₂NR⁴’、-NR⁴’R⁵’、-SO₂-hydrocarbyl, -SO₂R⁴’、SO₃R⁴’、-N＝CR⁴’R⁵’、-NR⁴’C(O)R⁴”、-NR⁴' -CO-Halogenoalkyl, -NO₂、-NR⁴’-SO₂-halogenated hydrocarbon radical, -NR⁴’-SO₂-hydrocarbyl, -NR⁴' -CO-hydrocarbyl, -NR⁴’(CH₂)_pHeteroaryl, alkyl, cycloalkyl, alkylamino, hydrocarbyloxy, hydrocarbylthio, -O (CH)₂)_p[O(CH₂)_p]_qOCH₃、-C(NR⁴”)NR⁴' benzimidazolyl, -C (NR)⁴”)NR⁴' benzothiazolyl, -C (NR)⁴”)NR⁴' benzoxazolyl hydroxyalkyl, hydroxycycloalkyl, hydroxyalkylamino, halogen, haloalkyl, halohydrocarbonoxy, aryl, arylalkyl or heterocycle; r⁴’、R⁴”、R⁵' as defined above; r³Is H, methyl, methoxy, CF₃Or OCF₃(ii) a X is NR²', O or S; r⁴As defined above;

R⁷and R⁷' as defined above; r¹¹’、R¹²' independently represents H, -CN, -OH, -SH, -CO₂R⁴’、-C(O)R⁴’、-SO₂NR⁴’、-NR⁴’R⁵’、-SO₂-hydrocarbyl, -SO₂R⁴’、SO₃R⁴’、-N＝CR⁴’R⁵’、-NR⁴’C(O)R⁴”、-NR⁴' -CO-Halogenoalkyl, -NO₂、-NR⁴’-SO₂-halogenated hydrocarbon radical, -NR⁴’-SO₂-hydrocarbyl, -NR⁴' -CO-hydrocarbyl, -NR⁴’(CH₂)_pHeteroaryl, alkyl, cycloalkyl, alkylamino, hydrocarbyloxy, hydrocarbylthio, -O (CH)₂)_p[O(CH₂)_p]_qOCH₃、-C(NR⁴”)NR⁴' benzimidazolyl, -C (NR)⁴”)NR⁴' benzothiazolyl, -C (NR)⁴”)NR⁴' benzoxazolyl hydroxyhydrocarbyl, hydroxycyclohydrocarbyl, hydroxyhydrocarbylamino, halo, halohydrocarbyl, haloHydrocarbyloxy, aryl, arylalkyl, or heterocycle; and R is⁴’、R⁴”、R⁵' is as defined above.

Of the compounds of the formula (III), a more preferred embodiment of the present invention is a compound of the formula (IIId),

wherein

R³Is H, methyl, methoxy, CF₃Or OCF₃(ii) a X is NR²', O or S; r⁴As defined above; r⁷And R⁷' as defined above; y' and R¹¹’、R¹²' as defined above for formula (IIIc); y' is O or NR²' and R²' is as defined above.

Of the compounds of the formula (III), a further preferred embodiment of the present invention is a compound of the formula (IIIe),

wherein

R³、R⁴And R⁵As defined above; x is O or S; r¹¹And R¹²As defined above in formula (IIIc); and if Z is N, X is NR²', O or S; if Z is CH, X is O.

Of the compounds of the formula (III), a further preferred embodiment of the present invention is a compound of the formula (IIIf),

wherein

Z is N or CH; r³Is H, methyl, methoxy, CF₃Or OCF₃(ii) a X is NR²', O or S; r⁴As defined above; r⁷And R⁷' as defined above; r²' as defined above; y' and R¹¹、R¹¹’、R¹²、R¹²' is as defined above for formula (IIIc).

A preferred embodiment of the present invention is a compound of formula (Iha),

wherein

R¹Is COR^7a；

R²And R^3aIs H;

a is NH;

R⁷as defined above;

z is N;

x is NR²', O or S;

R³is H, methyl, ethyl, methoxy, amine, hydrocarbyl amine, morpholinyl, N-methylpiperazine, CF₃Or OCF₃；

t is 0;

r is 1; and is

R^2aOptionally substituted aryl, benzyl or heteroaryl.

Of the compounds of formula (Ih), another preferred embodiment of the present invention is a compound of formula (Iha), wherein R is^7aOptionally substituted arylBenzyl or heteroaryl.

Of the compounds of the formula (Ih), another preferred embodiment of the present invention is a compound of the formula (Ihb),

wherein

R^3aIs H;

a is NH;

x is NR²', O or S;

y' is O or NR²’；

R²' as defined above;

t is 0;

r is 1; and is

R^2aOptionally substituted aryl, benzyl or heteroaryl.

In the general formula (Ihb), the following substituents are preferred, alone or in combination:

z is preferably CR²’。

Y' is preferably NR²'. In a preferred embodiment, NR of Y²R in `²' is preferably a substituted or unsubstituted heteroaryl group. In another preferred embodiment, NR of Y²R in `²' is aryl. In yet another preferred embodiment, NR of Y²R in `²' is benzyl. In a more preferred embodiment, NR of Y²R in `²' is a pyrimidine or triazine. In another more preferred embodimentIn an embodiment of (2), NR of Y²R in `²' is a substituted or unsubstituted bicyclic heteroaryl group, more preferably a thienopyrimidine, quinazoline, purine, pyrazolopyrimidine or triazolopyrimidine, and still more preferably a thienopyrimidine.

In a preferred embodiment, X is S. In another preferred embodiment, X is O. In yet another preferred embodiment, X is NR²’。

R³H is preferred.

R^2aPreferably aryl or heteroaryl, more preferably phenyl.

Of the compounds of formula (Ih), another more preferred embodiment of the present invention is a compound of formula (Ihe),

wherein

R^3aIs H; a is NH; x is NR²', O or S;

R¹¹and R¹²Independently represent H, -CN, -OH, -SH, -CO₂R⁴’、-C(O)R⁴’、-SO₂NR⁴’、-NR⁴’R⁵’、-SO₂-hydrocarbyl, -SO₂R⁴’、SO₃R⁴’、-N＝CR⁴’R⁵’、-NR⁴’C(O)R⁴”、-NR⁴' -CO-Halogenoalkyl, -NO₂、-NR⁴’-SO₂-halogenated hydrocarbon radical, -NR⁴’-SO₂-hydrocarbyl, -NR⁴' -CO-hydrocarbyl, -NR⁴’(CH₂)_pHeteroaryl, alkyl, cycloalkyl, alkylamino, hydrocarbyloxy, hydrocarbylthio, -O (CH)₂)_p[O(CH₂)_p]_qOCH₃、-C(NR⁴”)NR⁴' benzimidazoleAzolyl, -C (NR)⁴”)NR⁴' benzothiazolyl, -C (NR)⁴”)NR⁴' benzoxazolyl hydroxyalkyl, hydroxycycloalkyl, hydroxyalkylamino, halogen, haloalkyl, halohydrocarbonoxy, aryl, arylalkyl or heterocycle;

R⁴’、R⁴”、R⁵' as defined above;

R²' as defined above;

t is 0;

r is 1; and is

R^2aOptionally substituted aryl, benzyl or heteroaryl.

In formula (Ihe), the following substituents are preferred, alone or in combination:

z is preferably CR²’。

R¹¹preferably-H, -CN, -OH, halogen, halohydrocarbyl, halohydrocarbyloxy, more preferably-CN.

R¹²H is preferred.

R^2aPreferably aryl or heteroaryl, more preferably phenyl.

Among the compounds of the formula (II), a preferred embodiment of the present invention is a compound of the formula (IIa),

wherein

R¹And R²As defined above; z is as defined above; x is O or S; r³Is H, methyl, methoxy, CF₃Or OCF₃；R¹¹And R¹²As defined above for formula (IIIc).

Among the compounds of formula (II), a more preferred embodiment of the present invention is a compound of formula (IIb),

wherein

R¹And R²As defined above; z is as defined above; x is O or S; r³Is H, methyl, methoxy, CF₃Or OCF₃。

Of the compounds of the formula (II), another more preferred embodiment of the present invention is a compound of the formula (IIc),

wherein

X is O or S; r³Is H, methyl, methoxy, CF₃Or OCF 3; y' is NR²’。

Of the compounds of the formula (II), another more preferred embodiment of the present invention is a compound of the formula (IId),

wherein

Z is as defined above; r³Is H, methyl, methoxy, CF₃Or OCF₃；R¹¹、R¹¹' and R¹²、R¹²' is as defined above.

Furthermore, the present invention provides a process for the preparation of the compounds of the invention, for example of the general formulae (Ia), (Ib), (Ic), (Ih), (II) or (III).

The compounds of formula (Ia), (Ib), (Ic), (Ih), (II) or (III) can be obtained by various methods.

Piperidin-4-yl-thiazole-4-carboxycarboxamides can be prepared by a variety of methods described in the literature. One such example is the oxidation of suitable 2, 5-dihydrothiazoles as described in Houben-Weyl, 2002, 730. Dihydrothiazoles can also be synthesized by methods described in the same references, or by methods described in You, s., Razavi, h., Kelly, j.w.angelw.chem.2003, 115, 87 or Katritzky, ar., Cai, C, Suzuki, k., Singh, sk.j.org.chem.2004, 69, 811-one 814 and the references of both papers. Additional methods are described in Yasuchika, s.et al. heterocycles, vol.57, No.5, 2002.

The compounds of the general formulae (II), (Ic) and (III) with further substituents on the heterocyclic ring can be obtained by the methods described in the following documents: organic Syntheses, Coll, Vol.9, p.155; and Vol.74, p.229; chem., 1975, vol.40, No.10, 1521; j.am.chem.soc.96: 9/18/19/1974; chem., 1990, 55, 4484-; chemische Berichte 1968, 101(1), 302-; agricultural Chemistry and Biotechnology, 2002, 45(1), 37-42.

One possible synthetic approach to substituted benzimidazole substituents of formula (III) is described in Synthesis, 2006, 4, 597-602.

One possible synthesis of the compounds of the general formulae (IIIa, c and IIa, b) (cf. scheme 1) consists in the classical coupling of amidesUnder combined conditions, e.g. HBTU, iPr₂Reaction of compound of formula (V) with compound of formula (VI) to obtain intermediate (VII) at NEt, DMF, 0 ℃ to room temperature. An alternative to this step may be the reaction of (V) with the corresponding acid chloride of (VI) to give (VII). In the second step, compound (VII) is saponified with a 1M NaOH solution to give the desired acid (VIII) almost quantitatively. This step can also be carried out under acidic conditions. Finally, another amide coupling step (with primary or secondary amines) completes the synthesis of compounds of types (IIIa, c and IIa, and b) similarly to step 1 above.

Scheme 1 Synthesis of type (IIIa, c) and (IIa, b) derivatives

Compounds related to structures (IIIb, d, e, f) and (IIc, d) can be synthesized according to the methods shown in scheme 2. Here, heterocycle (IX) is reacted with bromo compound (X) by affinity substitution to give bicyclic ester (XI), which is then saponified to acid (XII) under standard and well known conditions, using another coupling step as described in scheme 1 above to complete the synthesis.

Scheme 2 synthesis of derivatives of types (IIIb, d, e, f) and (IIc, d), wherein Z ═ N

Compounds of the structures (IIIb, d, e, f) and (IIc, d) can be readily synthesized according to the scheme outlined in scheme 3, where heterocycle (XIII) is converted to compound (XV) by a cyclized condensation step, if Z ═ CH. After saponification (XVI) is coupled with an amine to give the desired product (IIIb, d, e, f) or (IIc, d).

Scheme 3 synthesis of derivatives of types (IIIb, d, e, f) and (IIc, d), Z ═ CH

The compounds of the present invention having a piperidin-4-yl substituent at the 2-position of the thiazole ring can be prepared, for example, by the following schemes. This synthetic route is partially described in WO 2004/058750.

2- (1- (tert-Butoxycarbonyl) piperidin-4-yl) thiazole-4-carboxylic acid can be converted to the appropriate R by coupling with HBTU, DIPEA in DMF¹An amide. Different R¹Amines are commercially available or can be readily synthesized. The Boc protecting group can be removed under standard conditions, e.g., treatment with TFA at 0 ℃ for 2 hours to 3 hours or 4N HCl in dioxane for 2 hours to 3 hours. The deprotected piperidinyl derivative HCl salt can then be converted to the corresponding amide, urea, and N-heterocyclic analogs as follows.

Urea-substituted piperidinyl compounds can be synthesized by coupling with commercially available isocyanates in the presence of DIPEA. Heterocycle-substituted piperidinyl compounds can be synthesized by standard methods, for example, coupling with the corresponding chlorinated heterocycle in the presence of a base. Alternatively, the heterocycle-substituted piperidinyl compounds can be obtained by palladium-mediated cross-coupling. As a further alternative, the hydroxypyridine derivative can be coupled to the piperidinyl compound by HBTU coupling methods.

Another route for the compounds of the present invention bearing a piperidin-4-yl substituent at the 2-position of the thiazole ring is shown in the following scheme.

The Boc protecting group can be removed under standard conditions, for example, by treatment with TFA at 0 ℃ for 2 hours to 3 hours or 4N HCl in dioxane for 2 hours to 3 hours. The deprotected piperidinyl derivative HCl salt can then be converted to the corresponding N-heterocyclic analog by a variety of methods as described above.

For the compounds of the above general formula (Ia), (Ib), (Ic), (Ih), (II) or (III), the term "stereoisomer" means cis/trans or E/Z isomerism. More specifically, the possible double bonds present in the various substituents of the compounds of the invention may be in the E or Z configuration. These pure or impure geometric isomers form an integral part of the compounds of the general formula (Ia), (Ib), (Ic), (Ih), (II) or (III), alone or in a mixture. The term "stereoisomer" also includes all isomeric forms, alone or as a mixture, which result from the presence of one or more axes of symmetry and/or centers of symmetry in the molecule and which result in a rotation of the polarized beam. More specifically, it includes enantiomers and diastereomers, either pure or as mixtures.

The compounds of the general formula (Ia), (Ib), (Ic), (Ih), (II) or (III) to be used according to the invention are capable of forming salts with inorganic or organic acids or bases. Examples of pharmaceutically acceptable salts include, but are not limited to, 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 derived from cinnamic acid, citrate derived from citric acid, pamoate derived from pamoic acid, heptanoate derived from heptanoic acid, formate derived from formic acid, fumarate derived from fumaric acid, glutamate derived from glutamic acid, glycolate derived from glycolic acid, chloride derived from hydrochloric acid, bromide derived from hydrobromic acid, lactate derived from lactic acid, maleate derived from maleic acid, methanesulfonate derived from methanesulfonic acid, naphthalene-2-sulfonate derived from naphthalene-2-sulfonic acid, nitrate derived from nitric acid, nitrate, Perchlorates derived from perchloric acid, phosphates derived from phosphoric acid, phthalates derived from phthalic acid, salicylates derived from salicylic acid, sorbates derived from sorbic acid, stearates derived from stearic acid, succinates derived from succinic acid, sulfates derived from sulfuric acid, tartrates derived from tartaric acid, p-toluenesulfonate derived from p-toluenesulphonic acid, and others. Such salts can be produced by methods well known to those skilled in the art and described in the prior art.

Other salts which are not considered pharmaceutically acceptable, such as oxalate salts derived from oxalic acid, may be suitable as intermediates for the production of a compound of formula (Ia), (Ib), (Ic), (Ih), (II) or (III) or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable prodrug thereof or a stereoisomer thereof.

As indicated above, the present invention encompasses pharmaceutically acceptable salts and also salts allowing a suitable separation or crystallization of the compounds of general formula (Ia), (Ib), (Ic), (Ih), (II) or (III), for example with chiral amines.

The above compounds of the general formula (Ia), (Ib), (Ic), (Ih), (II) or (III) also include prodrugs of these compounds. The term "prodrug" as used herein refers to a compound that: once administered to a patient, it is not itself pharmaceutically active ("prodrug"), but it is chemically and/or biologically converted in vivo, i.e. in the subject to which the compound is administered, to its pharmaceutically active form (compound of general formula (Ia), (Ib), (Ic), (Ih), (II) or (III)). Prodrugs include, for example, compounds of the present invention wherein a hydroxy, amine or sulfhydryl group is bonded to any group that, when administered to a patient, cleaves to form a hydroxy, amine or sulfhydryl group. Thus, representative examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol, sulfhydryl and amine functional groups of the compounds of the present invention. Further, in the case of carboxylic acid (-COOH), esters such as methyl ester, ethyl ester, diester, and the like can be used. The esters may be self-reactive and/or may be hydrolysable under in vivo conditions in the human body.

The compounds of the invention and the medicaments prepared therefrom are generally useful for the treatment of cell proliferative disorders, for the treatment or prevention of immune diseases and conditions (e.g., inflammatory diseases, neuroimmune diseases, autoimmune diseases, or others).

The compounds of the invention are useful in the treatment of diseases caused by the proliferation of malignant cells, such as solid tumors, leukemias, and lymphomas. Thus, the compounds of the invention and the medicaments prepared therefrom are generally useful for modulating cell activation, cell proliferation, cell survival, cell differentiation, cell cycle, cell maturation and cell death or for inducing systemic changes in metabolism, such as changes in sugar, lipid or protein metabolism. It can also be used to maintain cellular production, including blood cell growth and production (hematopoiesis) following cell depletion or cell destruction due to, for example, toxic agents, radiation, immunotherapy, growth defects, malnutrition, malabsorption, immunoregulatory abnormalities, anemia, etc., or to provide therapeutic control of tissue production and degradation, and therapeutic correction of cell and tissue maintenance and blood cell homeostasis.

Such diseases and conditions include, but are not limited to, cancer, for example, hematological tumors (e.g., leukemia, lymphoma, myeloma) or solid tumors (e.g., breast, prostate, liver, bladder, lung, esophagus, stomach, colorectal, genitourinary, gastrointestinal, skin, pancreas, brain, uterus, colon, head and neck, cervix and ovary, melanoma, astrocytoma, small cell lung cancer, glioma, basal cell carcinoma and squamous cell carcinoma, sarcomas such as kaposi's sarcoma and osteosarcoma), or for the treatment of a disease that is treated or alleviated by inhibition of one or more kinases and/or phosphatases. The compounds of the invention and the medicaments prepared therefrom are particularly useful for the treatment of prostate cancer, melanoma, ovarian cancer and multiple myeloma.

"treatment" in the context of the present invention means a complete or partial cure of a disease or a remission of a disease or a retardation of the progression of a given disease.

Thus, in one embodiment, the invention relates to the use of a compound of general formula (Ia), (Ib), (Ic), (Ih), (II) or (III), or a pharmaceutically acceptable salt or a pharmaceutically acceptable prodrug or stereoisomer thereof, if desired together with suitable adjuvants and additives, in the manufacture of a medicament for the treatment or prevention of diseases characterized by hyperproliferation of keratinocytes and/or T cells, in particular inflammatory and immune disorders, preferably selected from the group consisting of addison's disease, alopecia areata, ankylosing spondylitis, hemolytic anemia, pernicious anemia, aphtha, aphthous stomatitis, arthritis, arteriosclerotic disorders, osteoarthritis, rheumatoid arthritis, aspermic-ogene, bronchial asthma, autoimmune hemolytic disease, heightheighth's disease, burkholdt's disease, inflammatory bowel disease, burkitt lymphoma, burkitt's lymphoma, osteoarthritis, rheumatoid arthritis, aspergillosis, inflammatory bowel disease, autoimmune asthma, autoimmune hemolytic disease, autoimmune hemolytic anemia, bur, Crohn's disease, choroiditis, ulcerative colitis, celiac disease, cryoglobulinemia, dermatitis herpetiformis, dermatomyositis, insulin-dependent type I diabetes, juvenile diabetes, idiopathic diabetes insipidus, insulin-dependent diabetes mellitus, autoimmune demyelinating disease, Dupuytren's contracture, encephalomyelitis, allergic encephalomyelitis, phacoanaphylactic endophthalmitis, allergic enteritis, autoimmune bowel disease syndrome, leprosy erythema nodosum, idiopathic facial palsy, chronic fatigue syndrome, rheumatic fever (febris rheutamia), glomerulonephritis, Goodpasture's syndrome, Graves ' disease, Hei-Ribis's disease, Hashimoto's thyroiditis, sudden hearing loss, neuropathic hearing loss, chronic hepatitis, Hodgkin's disease, paroxysmal hemoglobinuria, hypogonadism, regional ileitis, Crohn's disease, Hashimoto's disease, Gra, Iritis, leukopenia, leukocytosis, disseminated lupus erythematosus, systemic lupus erythematosus, cutaneous lupus erythematosus, malignant lymphogranulomatosis, infectious mononucleosis, myasthenia gravis, transverse myelitis, primary idiopathic myxedema, nephrosis, sympathetic ophthalmia, granulomatous orchitis, pancreatitis, pemphigus vulgaris, polyarteritis nodosa, primary chronic polyarthritis, polymyositis, acute polyarteritis, psoriasis, purpura, pyoderma gangrenosum, quinavan thyroiditis, reiter's syndrome, sarcoidosis, ataxia sclerosis, progressive systemic sclerosis, scleritis, ligament sclerosis, multiple sclerosis, disseminated sclerosis, acquired splenorexia, infertility caused by antisperm antibodies, thrombocytopenia, primary thrombocytopenic purpura, idiopathic thrombocytopenic purpura, cutaneous lupus erythematosus, myasthenia gravis, polymyositis, scleroderma, Thymoma, acute anterior uveitis, vitiligo, diseases associated with AIDS, HIV, SCID and Epstein-Barr virus such as Sjogren's syndrome, B cell lymphoma associated with virus (AIDS or EBV), parasitic diseases such as Leishmania, and immunosuppressive disease states such as viral infection after allograft transplantation, AIDS, cancer, chronic active hepatitis diabetes, toxic shock syndrome or food poisoning.

The compounds of the invention and the medicaments prepared therefrom are particularly useful for the treatment of autoimmune and inflammatory diseases, such as rheumatoid arthritis, multiple sclerosis, inflammatory bowel diseases (especially colitis and crohn's disease), inflammatory skin diseases (especially neurodermatitis and psoriasis) and lupus erythematosus.

Furthermore, the present invention relates to a method for treating or preventing diseases, which comprises administering an effective amount of a compound of (Ia), (Ib), (Ic), (Ih), (II) or (III) or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable prodrug or stereoisomer thereof.

The invention also provides a pharmaceutical composition comprising a compound of formula (Ia), (Ib), (Ic), (Ih), (II) or (III) in free form or in pharmaceutically acceptable salt form and a pharmaceutically acceptable prodrug form, in association with a pharmaceutically acceptable diluent or carrier therefor.

In a preferred embodiment, the invention relates to the use of a compound of the general formula (Ia), (Ib), (Ic), (Ih), (II) or (III) or a pharmaceutically acceptable salt or a pharmaceutically acceptable prodrug or stereoisomer thereof, if desired together with suitable adjuvants and additives, for the production of a medicament for the treatment or prevention of a skin disorder in which T cells play a role, which is particularly preferably selected from the group consisting of psoriasis, atopic dermatitis, alopecia areata, alopecia totalis, alopecia subtotalis, alopecia universalis, disseminated alopecia (alpoteca difussa), cutaneous lupus erythematosis, lichen planus, dermatomyositis, atopic eczema, scleroderma, Skrodermia, psoriasis, head psoriasis (psoriasis capitis), trichomonas psoriasis, recurrent psoriasis (psoriasis invetera), alopecia areata, androgenetic alopecia, allergic contact eczema, irritant contact alopecia, alopecia areata, alopecia, Contact eczema, pemphigus vulgaris, pemphigus foliaceus, proliferative pemphigus, cicatricial mucosal pemphigoid (scarring mucosae pemphigoid), bullous pemphigoid, mucous pemphigoid (mucous pemphigoid), dermatitis-like dermatitis-durlin (dermatitis herpetiformis duhring), urticaria, lipoid progressive necrosis, erythema nodosum, vedahler's lichen (lichen vidal), prurigo simplex, prurigo nodularis, acute prurigo, linear IgA dermatosis, pleomorphic sun dermatosis, solar erythema, lichen sclerosus atrophysa, skin rash, drug eruption, chronic progressive purpura, dyshidrosis eczema, fixed drug eruption, photoallergic skin reaction, eriorlistate simple lichen (lichen simplex), vitiligo and "graft-versus-host disease", acne, keloid and scar.

Furthermore, the compounds of the invention can be used for the treatment of diseases caused by ischemia and/or reperfusion injury of an organ and/or a part of the body selected from heart, brain, peripheral limb, kidney, liver, spleen or lung, and/or wherein said endothelial dysfunction is associated with a disease selected from infarction such as myocardial infarction, critical limb ischemia, and/or wherein said endothelial dysfunction is associated with a disease selected from ischemic diseases, myocardial infarction or organ ischemic diseases, e.g. peripheral arterial occlusive diseases, such as severe leg ischemia; the organs include kidney, spleen, brain, and lung.

The compounds of the present invention can also be used for the prevention and treatment of neurological diseases or disorders (diseases or disorders related to the brain or nervous system) including, but not limited to, alzheimer's disease, parkinson's disease, creutzfeldt-jakob disease, lewy body dementia, amyotrophic lateral sclerosis, stroke, epilepsy, multiple sclerosis, myasthenia gravis, huntington's disease, down syndrome, nerve deafness, and meniere's disease. Other neurological diseases and conditions will be apparent to those skilled in the art and are included in the definition used in the present invention. The compounds of the invention and the medicaments prepared therefrom are particularly useful for the treatment of stroke, reperfusion injury and alzheimer's disease.

The compounds of the invention can also be used for diseases in humans and animals caused by protozoan infections. Such pathogenic protozoa of livestock or humans are preferably intracellular active parasites of the phylum apicomplexa or the phylum sarcotrichina, especially the genera Trypanosoma, Plasmodium, Leishmania, Babesia and Theileria, Cryptosporidium, Sarcocystidae, amoeba, coccidioides and Trichomonas. These active substances or corresponding medicaments are particularly suitable for the treatment of malaria tropica caused by plasmodium falciparum, malaria tertiana caused by plasmodium vivax or plasmodium ovale and for the treatment of malaria quartana caused by plasmodium malariae. It is also suitable for the treatment of toxoplasmosis caused by Toxoplasma gondii, coccidiosis caused by, for example, Eisenia bailii, sarcocystis intestinalis caused by porcine-human Sarcocystis, dysentery caused by Entamoeba histolytica, Cryptosporidiosis caused by Cryptosporidium parvum, Chagas disease caused by Trypanosoma cruzi, comatosis caused by Trypanosoma brucei rhodesiense or Trypanosoma brucei gambiae, epidermal and visceral and other forms of Leishmaniasis. It is also suitable for the treatment of animals infected with livestock pathogenic protozoa, for example, pathogens causing bovine dirobis disease, Theileria parva; pathogens causing livestock African trypanosomiasis in Africa, Trypanosoma congolense or active trypanosoma interri subsp, Trypanosoma brucei named subsp; trypanosoma brucei ehrlichia, which causes sura disease; a pathogen that causes texas fever in livestock and buffalos, babesia bigemina; the causative agent of babesiosis in cattle in europe and in dogs, cats and sheep, babesia bovis; pathogens causing Sarcocystis in sheep, livestock and pigs, Sarcocystis caninum and Sarcocystis ovifolia; the causative agent of cryptosporidiosis in livestock and birds, cryptosporidium; pathogens causing coccidiosis in rabbits, livestock, sheep, goats, pigs and birds, especially chickens and turkeys, the genus eimeria and isospora. The compounds of the invention are particularly preferably used for the treatment of coccidiosis or malaria infections, or for the preparation of medicaments or feeds for the treatment of these diseases. The treatment may be prophylactic or therapeutic. In the treatment of malaria, the compounds of the invention may be combined with other anti-malarial agents.

The compounds of the present invention can also be used for the prevention and/or treatment of infectious diseases caused by bacteria, viruses and the like, including opportunistic infections in mammals, including humans. The method comprises administering to the mammal at least one compound of formula (Ia), (Ib), (Ic), (Ih), (II) or (III) and/or a pharmaceutically acceptable salt thereof, in an amount effective to prevent and/or treat the infectious disease and/or opportunistic infection.

The infectious disease may be selected from AIDS, alveolar echinococcosis (AHD, echinococcosis), amebiasis (amoebic infection in lysostaxis), strongyloides infection, anisakiasis, anthrax, babesiosis (babesia infection), infusorium infection (ciliate), ascaris bailii (raccoon ascaris), schizophyllum (schizophragma), human yeast infection (yeast), Boreliosis, botulism, Brainerd Diarrhea (Brainerd Diarrhea), brucellosis, BSE (spongiform encephalopathy of cattle), candidiasis, capillariosis (capillariosis infection), CFS (chronic fatigue syndrome), chagas disease (trypanosomiasis), varicella (varicella zoster virus), pneumonitis infection, cholera, chronic fatigue syndrome, CJD (creutzfeldt-jacob disease), clonorchiasis (trematosis infection), CLM (cutaneous larval immigration, hookworm infection), coccidioidomycosis, conjunctivitis, coxsackie virus a16 (hand-foot-and-mouth disease), cryptococcosis, cryptosporidiosis (cryptosporidiosis), culex (west nile virus banded sclerotium), cutaneous larval immigration (CLM), coccidioidomycosis (coccidioidomycosis), cysticercosis (neurocysticercosis), cytomegalovirus infection (CMV), dengue/dengue fever, taenia infections (flea tapeworm of dogs and cats), ebola hemorrhagic fever, echinococcosis (alveolar echinococcosis), encephalitis, intracolonic amebic infections, dissymonade infections, hartmann-amoeba infections, entamoeba histolytica infections (amebiasis), endoamebiasis infections, enterobiasis (enterobiasis), enterovirus infections (non-poliomyelitis), epstein-bavirus infections, Coli infections, food-borne infections, foot-and-mouth disease, fungal dermatitis, gastroenteritis, group A streptococcosis, group B streptococcosis, diseases caused by infection with staphylococci (Staphylococcus aureus and other staphylococci species), diseases caused by infection with Pseudomonas aeruginosa and other Pseudomonas species, Burkholderia cepacia infection, Hansen's disease (leprosy), Hantaan virus 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, isosporococcidiosis (isosporococcidiosis), Lassa fever, leishmaniasis, kala fever (kala, leishmania), leprosy, lice (body lice, head lice, Leishmania, leprosy protozoa infection, leprosy disease, and combinations thereof, Pubic lice), lyme disease, marburg hemorrhagic fever, measles, meningitis, mosquito-transmitted diseases, Mycobacterium Avium Complex (MAC) infection, grisea infection, nosocomial infection, nonpathogenic intestinal amoeba infection, onchocerciasis (river blindness), epididymis (epididymis infection), parvovirus infection, plague, PCP (interstitial plasma cell pneumonia), poliomyelitis, Q fever, rabies, Respiratory Syncytial Virus (RSV) infection, rheumatic fever, rift valley fever, river blindness (onchocerciasis), rotavirus infection, ascaris infection, salmonellosis, salmonella enteritidis, scabies, shigellosis, herpes zoster, narcolepsy, smallpox, streptococcus infection, Tapeworm (Tapeworm) infection (Taenia) infection, wind, toxic shock syndrome, tuberculosis, ulceration (peptic ulcer), valley fever, canker, and tetanus, Vibrio parahaemolyticus infection, Vibrio vulnificus infection, viral hemorrhagic fever, wart, water-borne infectious disease, West Nile virus infection (West Nile encephalitis), pertussis, yellow fever. The compounds of the invention and the medicaments prepared therefrom are particularly useful for the treatment of viral diseases such as hepatitis b, hepatitis c, influenza virus infections (especially influenza a virus infections), AIDS (HIV infections) and human papilloma virus infections.

The compounds of the invention and the medicaments prepared therefrom are also particularly useful for the treatment of atherosclerosis.

The compounds of the invention and the medicaments prepared therefrom are also particularly useful for the treatment of osteoporosis.

In one embodiment, the invention relates to the use of a compound or composition of the invention in the manufacture of a medicament for the treatment or prevention of a disease characterized by cellular hyperproliferation.

In one embodiment, the invention relates to the use of a compound or composition of the invention for the preparation of a medicament for the treatment or prevention of a disease caused by ischemia and/or reperfusion injury of an organ and/or a part of the body selected from the group consisting of heart, brain, peripheral limb, kidney, liver, spleen and lung, and/or wherein the endothelial dysfunction is associated with a disease selected from the group consisting of infarction such as myocardial infarction, critical limb ischemia, and/or wherein the endothelial dysfunction is associated with a disease selected from the group consisting of ischemic disease, myocardial infarction or organ ischemic disease.

In one embodiment, the invention relates to the use of a compound or composition of the invention in the manufacture of a medicament for the treatment or prevention of a neurological disease or disorder selected from alzheimer's disease, parkinson's disease, creutzfeldt-jakob disease, lewy body dementia, amyotrophic lateral sclerosis, stroke, epilepsy, multiple sclerosis, myasthenia gravis, huntington's disease, down's syndrome, nerve deafness, and meniere's disease.

The compounds of the general formula (Ia), (Ib), (Ic), (Ih), (II) or (III) and their pharmaceutically acceptable salts can be administered to animals, preferably mammals, and in particular humans, dogs and chickens as therapeutic agents on their own, in admixture with one another or in the form of pharmaceutical preparations which allow enteral or parenteral use and which comprise an effective dose of at least one compound of the general formula (Ia), (Ib), (Ic), (Ih), (II) or (III) or a salt thereof as active ingredient, together with customary pharmaceutically harmless excipients and additives. The compounds of the general formula (Ia), (Ib), (Ic), (Ih), (II) or (III) can also be administered in the form of their salts, which are obtainable by reacting the individual compounds with physiologically acceptable acids and bases.

The production of the medicaments containing the compounds of the general formula (Ia), (Ib), (Ic), (Ih), (II) or (III) according to the invention and their use can be carried out according to known pharmaceutical methods.

When the compounds of the general formula (Ia), (Ib), (Ic), (Ih), (II) or (III) according to the invention for use in therapy can be administered as raw compounds, it is preferred to introduce the active ingredient(s) together with one or more adjuvants, excipients, carriers, buffers, diluents, and/or other conventional pharmaceutical adjuvants, optionally in the form of physiologically acceptable salts in pharmaceutical compositions. Such salts of the compounds may be anhydrous or solvated.

In a preferred embodiment, the present invention provides a medicament comprising a compound of formula (Ia), (Ib), (Ic), (Ih), (II) or (III) according to the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable prodrug thereof, or a stereoisomer thereof, together with one or more pharmaceutically acceptable carriers thereof, and optionally, other therapeutic and/or prophylactic ingredients. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The medicament of the present invention may be one suitable for oral, rectal, bronchial, nasal, topical, buccal, sublingual, transdermal, vaginal or parenteral (including cutaneous, subcutaneous, intramuscular, intraperitoneal intravenous, intraarterial, intracerebral, intraocular injection or infusion) administration, or in a form suitable for administration by inhalation or insufflation, including powder 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 the form of shaped articles, e.g. films, or microcapsules.

Thus, the compounds of the present invention may be incorporated in pharmaceutical forms and unit dosages thereof, in conjunction with conventional adjuvants, carriers or diluents. Such forms include solid forms, especially in the form of tablets, filled capsules, powders and pills; and liquid forms, especially aqueous or non-aqueous solutions, suspensions, emulsions, elixirs and capsules filled with the same, all of which can be used for suppositories for oral, rectal administration and sterile injectable solutions for parenteral administration. Such medicaments 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 contain any suitable effective dose of the active ingredient corresponding to the intended daily dosage range to be employed.

The compounds useful in the present invention can be administered in a variety of oral or parenteral dosage forms. As will be apparent to those skilled in the art, the following dosage forms may comprise a compound of the general formula (Ia), (Ib), (Ic), (Ih), (II) or (III) of the present invention or a pharmaceutically acceptable salt or stereoisomer thereof as an active ingredient.

For the preparation of a medicament from a compound of formula (Ia), (Ib), (Ic), (Ih), (II) or (III), the pharmaceutically acceptable carrier may be 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, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid in admixture with a finely divided active component. In tablets, the active ingredient is mixed with a carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethylcellulose, a low-melting paraffin, cocoa butter, and the like. The term "formulation" is intended to include a formulation of the active compound as well as an encapsulating material as a carrier providing a capsule, wherein the active component, with or without a carrier, is surrounded by and thus associated with a carrier. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.

To prepare suppositories, a low melting paraffin such as a fatty acid glyceride mixture or cocoa butter is first melted and the active ingredient is then homogeneously dispersed therein, for example by stirring. The molten homogeneous mixture is then poured into a conveniently sized mold, cooled and thereby solidified. Compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate. Liquid formulations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions. For example, liquid formulations for parenteral injection can be formulated as solutions in aqueous solutions of polyethylene glycol solutions.

Thus, the compounds of formula (Ia), (Ib), (Ic), (Ih), (II) or (III) of the present invention may be formulated for parenteral administration (e.g. by injection, such as bolus injection or continuous infusion) and may be presented in unit dosage form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be formulated in powder form for use with a suitable carrier, e.g., sterile, pyrogen-free water, the powder being obtained by sterile isolation of a sterile solid or by lyophilization from solution.

Aqueous solutions suitable for oral administration can be prepared by dissolving the active ingredient in water and then adding appropriate colorants, flavors, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use can be prepared by dispersing the ground active ingredient in water together with a viscous material, such as a natural or synthetic gum, resin, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents.

Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions and emulsions. In addition to the active ingredient, these formulations may contain coloring agents, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

In one embodiment of the invention, the drug is applied topically or systemically or by a combination of both routes.

In a particularly preferred embodiment of the invention, the medicament is applied topically. This reduces possible side effects and limits the necessary treatment to those infected areas.

Preferably, the medicament is prepared in the form of an ointment, gel, plaster, emulsion, lotion, foam, cream of mixed phase or amphiphilic emulsion system (oil/water-water/oil mixed phase), liposome, carrier, paste or powder.

For example, ointments and creams may be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.

Compositions suitable for topical administration in the mouth include: lozenges comprising the active agent in a flavor base, usually sucrose and acacia or tragacanth; aromatic fumigants comprising the active ingredient in an inert matrix such as gelatin and glycerol or sucrose and acacia; and mouth washes comprising an active ingredient in a suitable liquid carrier.

The solution or suspension is applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or nebulizer. The composition may be provided in a single dose or in multiple dose form. In the case of a multi-dose form of dropper or pipette, this may be achieved by the patient administering an appropriate, pre-set volume of solution or suspension. In the case of a nebulizer, this can be achieved, for example, by means of a metering atomizing pump (metering pump).

Administration to the respiratory tract may also be achieved by the aerosol method, in which the active ingredient is provided in pressurized packs with a suitable propellant, e.g., a chlorofluorocarbon (CFC) such as dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, carbon dioxide or other suitable gas. The aerosol may also conveniently contain a surfactant, for example lecithin. The dose of medicament may be controlled by providing a metering valve.

Alternatively, the active ingredient may be provided in the form of a dry powder, for example a powder mixture of the compound in a suitable powder base, for example lactose, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP). Conveniently, the powder carrier will form a gel within the nasal cavity. The powder compositions may be presented in unit dosage form, for example in capsules or cartridges of, for example, gelatin, or in 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 compositions, the compounds will generally have a relatively small particle size, for example of the order of 5 microns or less. Such particle sizes may be obtained by methods well known in the art, for example by micronisation.

Compositions adapted to provide sustained release of the active ingredient may be used, if desired.

The pharmaceutical preparation is preferably in unit dosage form. In such forms, the formulation is subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form may be a packaged preparation, the package containing discrete quantities of preparation, for example tablets, capsules and powders, packaged in vials or ampoules. The unit dosage form may also be a capsule, tablet, cachet, or lozenge itself, or it may be the packaged form of any of these in a suitable number. The compositions are preferably tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion.

More details of dispensing and administration techniques can be found in the latest version of Remington's pharmaceutical Sciences (Remington pharmacy) (Maack Publishing Co. Easton, Pa.).

The pharmaceutical compositions may also comprise two or more compounds of the general formula (Ia), (Ib), (Ic), (Ih), (II) or (III) or a pharmacologically acceptable salt thereof and further therapeutically active substances.

The compounds of the invention can therefore be used as single compounds or in combination with other active compounds, for example with drugs which are known to be useful for the treatment of the aforementioned diseases, so that in the latter case a beneficial additional amplifying effect is noted. Suitable amounts for administration to humans may be 5mg to 500 mg.

The pharmaceutical formulation can be prepared using pharmaceutically inert inorganic or organic excipients. For example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used to prepare pills, tablets, coated tablets and hard gelatin capsules. Excipients for soft gelatine capsules and suppositories are, for example, fats, waxes, semi-solid and liquid polyols, natural or hardened oils and the like. Suitable excipients for the production of solutions and syrups are, for example, water, sucrose, invert sugar, glucose, polyols and the like. Suitable excipients for the production of injection solutions are, for example, water, alcohols, glycerol, polyols or vegetable oils.

The dosage can vary within wide limits and should be adapted to the individual disease state in each individual case. For the above uses, the appropriate dosage will vary depending upon the mode of administration, the particular disease state being treated, and the desired effect. However, satisfactory results are generally obtained at dosage rates of from about 1mg/kg to 100mg/kg, preferably from 1mg/kg to 50mg/kg, of animal body weight. Typically, the dosage rate for large mammals, e.g., humans, is on the order of about 10 mg/day to 3 g/day, and is conveniently administered once daily, in divided doses 2 to 4 times daily, or in sustained release form.

In general, in the case of oral administration, a daily dose of about 10mg to 5000mg, preferably 50mg to 500mg, per human individual is suitable. In the case of other modes of administration, the daily dosage is also in a similar range. For local delivery, different concentrations of the active compound within the drug may be sufficient to elicit a therapeutic effect by topical application, depending on the permeability of the skin, the type and severity of the disease, and depending on the type of formulation and frequency of administration. Preferably, the concentration of the active compound or a pharmaceutically acceptable salt or physiologically functional derivative thereof or a stereoisomer thereof in the medicament of the invention is from 1. mu. mol/l to 100 mmol/l.

The following examples and figures are included to illustrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. Those skilled in the art, having benefit of this disclosure, will appreciate that many changes can be made in the specific embodiments which are disclosed and still remain within the spirit and scope of the invention as set forth in the appended claims. All cited references are incorporated herein by reference.

Examples

Abbreviations: min, min; h, hours; r.t., room temperature; t-, tert-.

NMR spectra: bruker Avance 300 MHz. Residual solvent peak was used as internal standard (DMSO-d)₆，δ_H＝2.49；CD₃OD，δ_H＝3.31；CDCl₃，δ_H＝7.26；CD₃CN，δ_H＝1.93；(CD₃)₂CO，δ_H2.05) at 300MHz (m: (m) ((m))¹H-NMR) were recorded separately.

Analysis LC/ESI-MS: 2x Waters 600 multi-solvent delivery system. 50 μ l sample loop. Column, Chromolith Speed ROD RP18e (Merck, Darmstadt), 50X 4.6mm with a 2 μm prefilter (Merck). Eluent A, H₂O+0.1％HCO₂H; eluent B, MeCN. Gradient, 5% B to 100% B within 5 min; flow rate, 3 ml/min. A waters lcz single quadrupole mass spectrometer with electrospray source. MS method, MS8 minPM-80-800-20V; positive/negative ion mode scanning, m/z 80 to 800 within 1 s; capillary, 3.5 kV; cone voltage, 20V; multiplier voltage, 400V; the probe and desolvation gas temperatures were 120 ℃ and 350 ℃, respectively. Waters2487 double lambda absorbance detector set at 254 nm.

Preparation of HPLC-MS: waters 600 multiple solvent delivery system with prepared pump head. 2000. mu.l or 5000. mu.l sample loop. Chromatography column, Waters X-Terra RP18, 7 μm, 19X 150mm, X-Terra RP18 guard column with 7 μm, 19X 10 mm; used at A flow rate of 20ml/min, or YMC ODS-A,40X 150mm with a 7 μm, 19X 10mm X-TerrarP18 guard column; the flow rate was 50 ml/min. And (3) solvent supplement: MeCN-H₂O-HCO₂H80: 20: 0.05 (v: v). Eluent A, H₂O+0.1％HCO₂H; eluent B, MeCN. Different linear gradients of 5% to 100% eluent B were used, as appropriate to the sample. Injection volume: 500. mu.l to 2000. mu.l, depending on the sample. A Waters ZQ single quadrupole mass spectrometer with electrospray source. Positive or negative ion mode scanning, m/z 80 to 800 within 1 s; capillary, 3.5kV or 3.0 kV; cone voltage, 20V; multiplier voltage, 400V; the probe and desolvation gas temperatures were 120 ℃ and 350 ℃, respectively. (mass-triggered fraction collection) Waters debris collector II with mass-triggered debris collection. Waters 996 photodiode array detector.

Synthesis of 4- (methoxy-methyl-carbamoyl) -piperidine-1-carboxylic acid tert-butyl ester

Monotert-butyl piperidine-1, 4-dicarboxylate (1.0eq, 21.8mmol) was dissolved in 35ml of dry N, N-dimethylformamide under inert conditions. O, N-dimethyl-hydroxylamine hydrochloride (1.03eq, 22.5mmol), benzotriazole-1-ol monohydrate (1.03eq, 22.5mmol) and triethylamine (1.5eq, 32.7mmol) were added. The reaction mixture was cooled to 0 ℃, N- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride (1.0eq, 21.8mmol) was added over a period of 10 minutes and then the mixture was stirred vigorously at 0 ℃ for 1h and r.t. for 18 h.

The solvent was removed in vacuo and the residue was suspended in 400ml of ethyl acetate. The organic layer was extracted 3 times with 100ml 1M aqueous citric acid, sodium carbonate and 2 times with 100ml brine, MgSO₄Dried and filtered. The solvent was removed and the residue was purified by distillation to give a yield of 80%.

Synthesis of 4-formyl-piperidine-1-carboxylic acid tert-butyl ester

4- (methoxy-methyl-carbamoyl) -piperidine-1-carboxylic acid tert-butyl ester (1.0eq, 16.4mmol) was dissolved in 100ml of dry tetrahydrofuran under an inert atmosphere. To this solution was added dropwise a suspension of lithium aluminium hydride (3.0eq, 49.6mmol) in 70ml of dry tetrahydrofuran at-50 ℃ over a period of 1 h. During the addition of the mixture, the temperature was kept at-50 ℃ and then allowed to warm to 0 ℃ over 3 h.

The mixture was cooled to-78 ℃ and carefully quenched with 100ml of 1M citric acid. The mixture was warmed to r.t. and diluted with 400ml ethyl acetate. The phases were separated and the aqueous phase was extracted 3 times with 70ml ethyl acetate. The combined organic layers were extracted 3 times with 100ml of 1M aqueous citric acid, sodium carbonate solution and 2 times with 100ml brine, MgSO₄Dried and filtered. The solvent was removed and the residue was purified by distillation to give a yield of 85%.

Synthesis of 4- (4-ethoxycarbonyl-4, 5-dihydro-thiazol-2-yl) -piperidine-1-carboxylic acid tert-butyl ester

Tert-butyl 4-formyl-piperidine-1-carboxylate (1.0eq, 13mmol) was dissolved in 40ml of toluene under inert conditions. To this solution were added L-cysteine ethyl ester hydrochloride (1.6eq, 21mmol) and triethylamine (1.6eq, 21 mmol). The mixture was refluxed for 14 h. The water produced was removed with a dean-stark trap.

The solvent was removed and the residue was dissolved in 100ml of ethyl acetate. The organic layer was extracted 3 times with 50ml 1M aqueous citric acid, potassium bicarbonate and 2 times with 50ml brine, MgSO₄Dried and filtered. The solvent was removed and the residue was purified by silica gel chromatography using a PE/EA 4: 1 gradient. Yield: 75 percent.

Synthesis of 4- (4-ethoxycarbonyl-thiazol-2-yl) -piperidine-1-carboxylic acid tert-butyl ester

Tert-butyl 4- (4-ethoxycarbonyl-4, 5-dihydro-thiazol-2-yl) -piperidine-1-carboxylate (1.0eq, 8.7mmol) was dissolved in 160ml toluene under inert conditions. Adding MnO to the solution₂(15.0eq, 130 mmol). The reaction was heated to 70 ℃ for 5h with stirring. The mixture was filtered through celite and the filter washed 3 times with 30ml of toluene and ethyl acetate. The combined organic layers were distilled under vacuum. The residue was purified by silica gel chromatography using a gradient of DCM/MeOH 95: 5. Yield: 30 percent.

C-terminal functionalization

Tert-butyl 4- (4-ethoxycarbonyl-thiazol-2-yl) -piperidine-1-carboxylate (1.0eq, 2.9mmol) was dissolved in 40ml dioxane under an inert atmosphere. 1.5ml of 2N NaOH aqueous solution was added dropwise with stirring over 10 min. The mixture was then stirred at room temperature for 2 h.

The reaction was neutralized with 2N HCl and the solvent was evaporated under vacuum. The residue was dissolved in 50ml of ethyl acetate. The organic layer was extracted 3 times with 10ml 1M citric acid and water, MgSO₄Dried and filtered. The solvent was removed and the residue was dried in vacuo. Yield: 95 percent.

4- (4-carboxy-thiazol-2-yl) -piperidine-1-carboxylic acid tert-butyl ester (1eq) was dissolved in dry dimethylacetamide (0.03mmol/ml) under inert conditions. To this solution was added arylamine or hydrocarbylamine (1eq), diisopropylethylamine (2eq) and O-benzotriazol-1-yl-N, N' -tetramethyluronium hexafluorophosphate (2 eq). The reaction mixture was stirred at r.t. for 12 h.

The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The organic layer was extracted 3 times with 1M aqueous citric acid, potassium bicarbonate and 2 times with brine, MgSO₄Dried and filtered. The solvent was removed and the residue was purified by silica gel chromatography using a gradient of DCM/MeOH 95: 5. Yield: 40% to 80%.

N-terminal functionalization

The N-protected substrate (concentration 0.03mmol substrate in 1ml HCl/dioxane) was treated with 4M HCl/dioxane under inert conditions and stirred at r.t. for 2 h.

The solvent was removed in vacuo to give the HCl salt of the free amine without further purification.

The free amine compound (1eq) was dissolved in dry dimethylacetamide (0.03mmol/ml) under inert conditions. To this solution was added sequentially an aryl or hydrocarbyl carboxylic acid (1eq), diisopropylethylamine (2eq) and O-benzotriazol-1-yl-N, N' -tetramethyluronium hexafluorophosphate (2eq) and the reaction mixture was stirred at r.t. for 12 h.

General synthetic methods for Compounds of types (III) and (II)

Synthesis procedures for Compounds of types (IIIa), (IIIc), (IIa) and (IIb)

Mix 7.3X 10^-4mol benzoic acid derivatives(VI) dissolved in 5ml DMF and 1 eq.Hunig's base added, the reaction mixture stirred for several minutes, then 1eq.HBTU added and stirred at r.t. for another 2 min. Then 1 eq.2-amino-thiazole-4-carboxylic acid ethyl ester was added and the mixture was stirred at the same temperature overnight. Next, the solvent was removed by filtration and the residue was redissolved in 5ml dioxane and then treated with 0.5ml 1M NaOH solution. After the reaction was complete, the pH was lowered to 1-2 with 1M HCl solution, and the precipitated product (VII) was filtered and dried in vacuo. For the next step, intermediate (VII) was dissolved in 3ml DMF and 1eq. Then 1eq. of amine component was added and the mixture was stirred at the same temperature overnight. Subsequently, the solvent was removed by filtration and the crude product was redissolved in 10ml ethyl acetate and washed with 10ml citric acid (1M solution), 10ml saturated NaHCO₃The solution was washed 2 times with 10ml of water. The organic phase is then evaporated and MgSO₄The residue was dried. The solvent was removed and the final purification was then accomplished by preparative HPLC as described above.

As a second variant of the first step, the corresponding acid chloride derivative of (VI) can be reacted with ethyl 2-amino-thiazole-4-carboxylate (1: 1) using 1.1eq. Hunig's base.

Synthesis procedures for Compounds of types (IIIb, d, e, f) and (IIc, d)

Mixing 6.3X 10^-4mol of ethyl 2-bromo-thiazole-4-carboxylate (X) and 2.2eq. various piperazines (IX) were dissolved in 10ml of THF and allowed to reflux overnight. The solvent was then removed in vacuo and the residue purified by pTLC (PE/EE 2/1).

The second and third steps of the reaction are carried out as synthesis steps for compounds of type (IIIa) and (IIIc) as described above.

For the synthesis schemes for compounds of the type (IIIb, d, e, f and IIc, d) where Z ═ CH, see WO 2004/058750.

Exemplary compounds of general formula (Ia) of the present invention include, but are not limited to, the following:

compound (I)	Name (R)	Quality of	LC/(+)-ESI-MS：	Biological activity¹⁾
compound (I)	Name (R)	Quality of	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) -amides	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 [1, 4]]Dioxin-6-yl) -amides	601	602[M+H]⁺	++	74		619	620[M+H]⁺	++
75		601	602[M+H]⁺	++	76	4- {4- [4- (3-trifluoromethyl-phenyl) -piperazine-1-carbonyl]-thiazol-2-yl } -piperidine-1-carboxylic acid (5-methyl-2-trifluoromethyl-furan-3-yl) -amide	615	616[M+H]⁺	++
77	4- {4- [4- (3-trifluoromethyl-phenyl) -piperazine-1-carbonyl]-thiazol-2-yl } -piperidine-1-carboxylic acid (2-thiophen-2-yl-ethyl) -amide	577	578[M+H]⁺	+++	76		615	616[M+H]⁺	++
77		577	578[M+H]⁺	+++	78	4- {4- [4- (3-trifluoromethyl-phenyl) -piperazine-1-carbonyl]-thiazol-2-yl } -piperidine-1-carboxylic acid isopropylamide	509	510[M+H]⁺	+
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]⁺	+++	78		509	510[M+H]⁺	+
79		627	628[M+H]⁺	+++	80	4- {4- [4- (3-trifluoromethyl-phenyl) -piperazine-1-carbonyl]-thiazol-2-yl } -piperidine-1-carboxylic acid (3-methoxy-phenyl) -amide	573	574[M+H]⁺	+
81	4- {4- [4- (3-trifluoromethyl-phenyl) -piperazine-1-carbonyl]-thiazol-2-yl } -piperidine-1-carboxylic acid (3, 4, 5-trimethoxy-phenyl) -amide	633	634[M+H]⁺	++	80		573	574[M+H]⁺	+
81		633	634[M+H]⁺	++	114	4- (4- {4- [4- (3-trifluoromethyl-phenyl) -piperazine-1-carbonyl]Thiazol-2-yl } -piperidine-1-carbonyl) -benzonitrile	568	569[M+H]⁺	+
134	4- {4- [4- (3-trifluoromethyl-phenyl) -piperazine-1-carbonyl]-thiazol-2-yl } -piperidine-1-carboxylic acid phenylamide	543	544[M+H]⁺	+	114		568	569[M+H]⁺	+
134		543	544[M+H]⁺	+	142	4- {4- [4- (3-trifluoromethyl-phenyl) -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-1-carboxylic acid (4-fluoro-phenyl) -amide	561	562[M+H]⁺	+	142		561	562[M+H]⁺	++

¹⁾Biological data refers to results obtained from NF-. kappa.B inflammation assays.

[ "+" indicates 50% to 80% inhibition, "+ + +" indicates 80% to 90% and "+ + + + + +" indicates 90% to 100% inhibition ]

Exemplary compounds of formula (Ib) of the present invention include, but are not limited to, the following:

compound (I)	Name (R)	Quality of	LC/(+)-ESI-MS：	Biological activity¹⁾
compound (I)	Name (R)	Quality of	LC/(+)-ESI-MS：	Biological activity¹⁾	103	2- { 5-methyl-2- [1- (2-trifluoromethoxy-benzoyl) -piperidin-4-yl]-thiazol-4-yl } -1- [4- (3-trifluoromethyl-phenyl) -piperazin-1-yl]-ethanones	640	641[M+H]⁺	++
128	1- [4- (3-chloro-phenyl) -piperazin-1-yl]-2- { 5-methyl-2- [1- (2-trifluoromethoxy-benzoyl) -piperidin-4-yl]-thiazol-4-yl } -ethanone	606	607[M+H]⁺	+++	103		640	641[M+H]⁺	++

Exemplary compounds of general formula (Ic) of the present invention include, but are not limited to, the following:

compound (I)	Name (R)	Quality of	LC/(+)-ESI-MS：	Biological activity¹⁾
compound (I)	Name (R)	Quality of	LC/(+)-ESI-MS：	Biological activity¹⁾	150	[1- (5-chloro-2-methylamino-phenyl) -3, 4-dihydro-1H-isoquinolin-2-yl]- {2- [1- (2-trifluoromethoxy-benzoyl)) -piperidin-4-yl]-thiazol-4-yl } -methanone	654	655[M+H]⁺	++
160	1- {4- [4- (6, 7-dihydroxy-3, 4-dihydro-1H-isoquinoline-2-carbonyl) -thiazol-2-yl]-piperidin-1-yl } -2- (4-fluoro-phenyl) -ethanone	495	496[M+H]⁺	+	150		654	655[M+H]⁺	++
160		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	1- {4- [4- (3, 4-dihydro-1H-isoquinoline-2-carbonyl) -thiazol-2-yl]-piperidin-1-yl } -2- (4-fluoro-phenyl) -ethanone	463	464[M+H]⁺	+	161		523	524[M+H]⁺	+
163		463	464[M+H]⁺	+	232	1- {4- [4- (6, 7-dimethoxy-3-methyl-3, 4-dihydro-1H-isoquinoline-2-carbonyl) -thiazol-2-yl]-piperidin-1-yl } -2- (4-fluoro-phenyl) -ethanone	537	538[M+H]⁺	+
233	1- {4- [4- (6, 7-dihydroxy-1-methyl-3, 4-dihydro-1H-isoquinoline-2-carbonyl) -thiazol-2-yl]-piperidin-1-yl } -2- (4-fluoro-phenyl) -ethanone	509	510[M+H]⁺	+	232		537	538[M+H]⁺	+
233		509	510[M+H]⁺	+	234	1- {4- [4- (6, 7-dimethoxy-1-methyl-3, 4-dihydro-1H-isoquinoline-2-carbonyl) -thiazol-2-yl]-piperidin-1-yl } -2- (4-fluoro-phenyl) -ethanone	537	538[M+H]⁺	+

235

1- (4- {4- [1- (5-chloro-2-methylamino-phenyl) -3, 4-dihydro-1H-isoquinoline-2-carbonyl]-thiazol-2-yl } -piperidin-1-yl) -2- (4-fluoro-phenyl) -ethanone

602

603[M+H]⁺

+

Exemplary compounds of formula (II) of the present invention include, but are not limited to, the following:

compound (I)	Name (R)	Quality of	LC/(+)-ESI-MS：	Biological activity¹⁾
compound (I)	Name (R)	Quality of	LC/(+)-ESI-MS：	Biological activity¹⁾	3	N- {4- [4- (4-fluoro-phenyl) -piperazine-1-carbonyl]-thiazol-2-yl } -2-trifluoromethoxy-benzamide	494	495[M+H]⁺	++
5	N- [5- (4-pyrimidin-2-yl-piperazine-1-carbonyl) -thiazol-2-yl]-2-trifluoromethoxy-benzamide	478	479[M+H]⁺	+	3		494	495[M+H]⁺	++
5		478	479[M+H]⁺	+	15	2-methoxy-N- {4- [4- (3-trifluoromethyl-phenyl) -piperazine-1-carbonyl]-thiazol-2-yl } -benzamide	490	491[M+H]⁺	+++
16	3-fluoro-4-trifluoromethyl-N- (1- {4- [4- (3-trifluoromethyl-phenyl) -piperazine-1-carbonyl]-thiazol-2-yl } piperidin-4-ylmethyl) -benzamide	643	644[M+H]⁺	++	15		490	491[M+H]⁺	+++
16		643	644[M+H]⁺	++	17	3-cyclopentyl-N- (1- {4- [4- (3-trifluoromethyl-phenyl) -piperazine-1-carbonyl]-thiazol-2-yl } -piperidin-4-ylmethyl) -propionamide	577	578[M+H]⁺	++
18	2-trifluoromethoxy-N- (1- {4- [4- (3-trifluoromethyl-phenyl) -piperazine-1-carbonyl]-thiazol-2-yl } -piperidin-4-ylmethyl) -benzamide	641	642[M+H]⁺	++	17		577	578[M+H]⁺	++
18		641	642[M+H]⁺	++	19	4-cyano-N- (1- {4- [4- (3-trifluoromethyl-phenyl) -piperazine-1-carbonyl]-thiazol-2-yl } -piperidin-4-ylmethyl) -benzamide	582	583[M+H]⁺	++
20	[4- (3-trifluoromethyl-phenyl) -piperazin-1-yl]- {2- [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl]-thiazol-4-yl } -methanone	569	570[M+H]⁺	++	19		582	583[M+H]⁺	++
20		569	570[M+H]⁺	++	21	{2- [4- (4-trifluoromethoxy-phenyl) -piperazin-1-yl]-thiazol-4-yl } - [4- (3-trifluoromethyl-phenyl) -piperazin-1-yl]-methanones	585	586[M+H]⁺	+
22	{2- [4- (2-trifluoromethoxy-benzyl) -piperazin-1-yl]-thiazol-4-yl } - [4- (3-trifluoromethyl-phenyl) -piperazin-1-yl]-methanones	599	600[M+H]⁺	+++	21		585	586[M+H]⁺	+

23	{2- [4- (4-bromo-benzyl) -piperazin-1-yl]-thiazol-4-yl } - [4- (3-trifluoromethyl-phenyl) -piperazin-1-yl]-methanones	593	594[M+H]⁺	+++
23		593	594[M+H]⁺	+++	24	{2- [4- (3-trifluoromethoxy-benzyl) -piperazin-1-yl]-thiazol-4-yl } - [4- (3-trifluoromethyl-phenyl) -piperazin-1-yl]-methanones	599	600[M+H]⁺	+++
32	2-trifluoromethoxy-N- {4- [4- (3-trifluoromethyl-phenyl) -piperazine-1-carbonyl]-thiazol-2-yl } -benzamide	544	545[M+H]⁺	+++	24		599	600[M+H]⁺	+++
32		544	545[M+H]⁺	+++	33	3-cyclopentyl-N- {4- [4- (3-trifluoromethyl-phenyl) -piperazine-1-carbonyl]-thiazol-2-yl } -propionamide	480	481[M+H]⁺	+++
34	3-fluoro-4-trifluoromethyl-N- {4- [4- (3-trifluoromethyl-phenyl) -piperazine-1-carbonyl]-thiazol-2-yl } -benzamide	546	547[M+H]⁺	+++	33		480	481[M+H]⁺	+++
34		546	547[M+H]⁺	+++	37	3-cyclopentyl-1- (4- {4- [4- (3-trifluoromethyl-phenyl) -piperazine-1-carbonyl]-thiazol-2-yl } -piperazin-1-yl) -propan-1-one	549	550[M+H]⁺	+++
38	{2- [4- (2-methoxy-benzoyl) -piperazin-1-yl]-thiazol-4-yl } - [4- (3-trifluoromethyl-phenyl) -piperazin-1-yl]-methanones	559	560[M+H]⁺	+++	37		549	550[M+H]⁺	+++
38		559	560[M+H]⁺	+++	39	{2- [4- (2-trifluoromethoxy-benzoyl) -piperazin-1-yl]-thiazol-4-yl } - [4- (3-trifluoromethyl-phenyl) -piperazin-1-yl]-methanones	613	614[M+H]⁺	+++
41	N- {4- [4- (3, 4-dichloro-phenyl) -piperazine-1-carbonyl]-thiazol-2-yl } -2-trifluoromethoxy-benzamide	544	545[M+H]⁺	+++	39		613	614[M+H]⁺	+++
41		544	545[M+H]⁺	+++	44	N- {4- [4- (2-methoxy-phenyl) -piperazine-1-carbonyl]-thiazol-2-yl } -2-trifluoromethoxy-benzamide	506	507[M+H]⁺	++
55	1- (2-trifluoromethoxy-phenyl) -3- {4- [4- (3-trifluoromethyl-phenyl) -piperazine-1-carbonyl]-thiazol-2-yl } -urea	559	560[M+H]⁺	+++	44		506	507[M+H]⁺	++
55		559	560[M+H]⁺	+++	58	N- [4- (4-benzhydryl-piperazine-1-carbonyl) -thiazol-2-yl]-2-trifluoromethoxy-benzamide	566	567[M+H]⁺	++
59	{2- [4- (3, 5-Bis-trifluoromethyl-benzoyl) -piperazin-1-yl]-thiazol-4-yl } - [4- (3-trifluoromethyl-phenyl) -piperazin-1-yl]-methanones	665	666[M+H]⁺	+	58		566	567[M+H]⁺	++
59		665	666[M+H]⁺	+	60	{2- [4- (3-fluoro-4)-trifluoromethyl-benzoyl) -piperazin-1-yl]-thiazol-4-yl } - [4- (3-trifluoromethyl-phenyl) -piperazin-1-yl]-methanones	615	616[M+H]⁺	+++
61	4- (4- {4- [4- (3-trifluoromethyl-phenyl) -piperazine-1-carbonyl]-thiazol-2-yl } -piperazine-1-carbonyl) -benzonitrile	554	555[M+H]⁺	+++	60		615	616[M+H]⁺	+++
61		554	555[M+H]⁺	+++	62	4- (4- {4- [4- (3-trifluoromethyl-phenyl) -piperazine-1-carbonyl]-thiazol-2-yl } -piperazin-1-ylmethyl) -benzonitrile	540	541[M+H]⁺	+++

63	4- {4- [4- (3-trifluoromethyl-phenyl) -piperazine-1-carbonyl]-Thiazol-2-yl } -piperazine-1-carboxylic acid tert-butyl ester	525	526[M+H]⁺	++
63		525	526[M+H]⁺	++	64	(2-piperazin-1-yl-thiazol-4-yl) - [4- (3-trifluoromethyl-phenyl) -piperazin-1-yl]-methanones	425	426[M+H]⁺	+
65	{2- [4- (2-methoxy-phenyl) -piperazin-1-yl]-thiazol-4-yl } - [4- (3-trifluoromethyl-phenyl) -piperazin-1-yl]-methanones	531	532[M+H]⁺	++	64		425	426[M+H]⁺	+
65		531	532[M+H]⁺	++	66	1- [4- (4- {4- [4- (3-trifluoromethyl-phenyl) -piperazine-1-carbonyl]-thiazol-2-yl } -piperazin-1-yl) -phenyl]-ethanones	543	544[M+H]⁺	++
67	[4- (3-trifluoromethyl-phenyl) -piperazin-1-yl]- {2- [4- (3-trifluoromethyl-phenyl) -piperazin-1-yl]-thiazol-4-yl } -methanone	569	570[M+H]⁺	+	66		543	544[M+H]⁺	++
67		569	570[M+H]⁺	+	68	[2- (4-phenyl-piperazin-1-yl) -thiazol-4-yl]- [4- (3-trifluoromethyl-phenyl) -piperazin-1-yl]-methanones	501	502[M+H]⁺	+
69	{2- [4- (4-fluoro-phenyl) -piperazin-1-yl]-thiazol-4-yl } - [4- (3-trifluoromethyl-phenyl) -piperazin-1-yl]-methanones	519	520[M+H]⁺	++	68		501	502[M+H]⁺	+
69		519	520[M+H]⁺	++	71	(4-benzhydryl-piperazin-1-yl) - [2- (4-benzyl-piperazin-1-yl) -thiazol-4-yl]-methanones	537	538[M+H]⁺	+++
72	[2- (4-benzyl-piperazin-1-yl) -thiazol-4-yl]- [4- (3-trifluoromethyl-phenyl) -piperazin-1-yl]-methanones	515	516[M+H]⁺	+++	71		537	538[M+H]⁺	+++
72		515	516[M+H]⁺	+++	99	3-fluoro-4-trifluoromethyl-N- (1- {4- [4- (3-trifluoromethyl-phenyl) -piperazine-1-carbonyl]-thiazol-2-yl } -piperidin-4-ylmethyl) -benzamide	642	643[M+H]⁺	+
100	3-cyclopentyl-N- (1- {4- [4- (3-trifluoromethyl-phenyl) -piperazine-1-carbonyl]-thiazol-2-yl } -piperidin-4-ylmethyl) -propionamide	576	577[M+H]⁺	+	99		642	643[M+H]⁺	+
100		576	577[M+H]⁺	+	101	2-trifluoromethoxy-N- (1- {4- [4- (3-trifluoromethyl-phenyl) -piperazine-1-carbonyl]-thiazol-2-yl } -piperidin-4-ylmethyl) -benzamide	640	641[M+H]⁺	+
102	4-cyano-N- (1- {4- [4- (3-trifluoromethyl-phenyl) -piperazine-1-carbonyl]-thiazol-2-yl } -piperidin-4-ylmethyl) -benzamide	581	582[M+H]⁺	+	101		640	641[M+H]⁺	+
102		581	582[M+H]⁺	+	241	{2- [1- (2, 6-dimethoxy-pyrimidin-4-yl) -piperidin-4-yl ] -piperidine]-5-methoxy-oxazol-4-yl } - [4- (3-trifluoromethyl-phenyl) -piperazin-1-yl]-methanones	576	577[M+H⁺]	++
242	{2- [1- (4, 6-dimethoxy- [1, 3, 5 ]]Triazin-2-yl) -piperidines-4-yl]-5-methoxy-oxazol-4-yl } - [4- (3-trifluoromethyl-phenyl) -piperazin-1-yl]-methanones	577	578[M+H⁺]	++	241		576	577[M+H⁺]	++

243	{2- [1- (2, 6-dimethoxy-pyrimidin-4-yl) -piperidin-4-yl ] -piperidine]-5-methoxy-oxazol-4-yl } - [4- (5-trifluoromethyl-benzotriazol-1-yl) -piperidin-1-yl]-methanones	616	617[M+H⁺]	++
243		616	617[M+H⁺]	++	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]-methanones	617	618[M+H⁺]	++
245	4- (4- {4- [4- (5-trifluoromethyl-benzotriazol-1-yl) -piperazinePyridine-1-carbonyl]-thiazol-2-yl } -piperazin-1-yl-methyl) -benzonitrile	580	581[M+H]+	++	244		617	618[M+H⁺]	++
245		580	581[M+H]+	++	246	(2-morpholin-4-yl-oxazol-4-yl) - [4- (3-trifluoromethyl-phenyl) -piperazin-1-yl]-methanones	410	411[M+H]+	+

Exemplary compounds of formula (III) of the present invention include, but are not limited to, the following:

compound (I)	Name (R)	Quality of	LC/(+)-ESI-MS：	Biological activity¹⁾
compound (I)	Name (R)	Quality of	LC/(+)-ESI-MS：	Biological activity¹⁾	1	2-morpholin-4-yl-thiazole-4-carboxylic acid (5, 6-dimethyl-1H-benzimidazol-2-yl) -amide	357	358[M+H]⁺	+
2	2- [3- (2-trifluoromethoxy-phenyl) -ureido]-thiazole-4-carboxylic acid (1H-benzimidazol-2-yl) -amide	462	463[M+H]⁺	+	1		357	358[M+H]⁺	+
2		462	463[M+H]⁺	+	4	2- (2-fluoro-benzoylamino) -thiazole-4-carboxylic acid (5, 6-dimethyl-1H-benzoimidazol-2-yl) -amide	409	410[M+H]⁺	+
6	N- {4- [ N' - (1H-benzimidazol-2-yl) -guanidinocarbonyl]-thiazol-2-yl } -3, 4-difluoro-benzamide	441	442[M+H]⁺	++	4		409	410[M+H]⁺	+
6		441	442[M+H]⁺	++	7	N- {4- [ N' - (1H-benzimidazol-2-yl) -guanidinocarbonyl]-thiazol-2-yl } -4-fluoro-benzamide	423	424[M+H]⁺	++
8	N- {4- [ N' - (1H-benzimidazol-2-yl) -guanidinocarbonyl]-oxazol-2-yl } -2-trifluoromethoxy-benzamides	473	474[M+H]⁺	+++	7		423	424[M+H]⁺	++
8		473	474[M+H]⁺	+++	9	2- (2-trifluoromethoxy-benzoylamino) -thiazole-4-carboxylic acid (4-dimethylamino- [1, 3, 5)]Triazin-2-yl) -amides	453	454[M+H]⁺	+
10	N- {4- [ N' - (1H-benzimidazol-2-yl) -guanidinocarbonyl]-thiazol-2-yl } -4-bromo-benzamide	483	484[M+H]⁺	++	9		453	454[M+H]⁺	+
10		483	484[M+H]⁺	++	11	N- {4- [ N' - (1H-benzimidazol-2-yl) -guanidinocarbonyl]-thiazol-2-yl } -2-methoxy-benzamide	435	436[M+H]⁺	++

12	N- {4- [ N' - (1H-benzimidazol-2-yl) -guanidinocarbonyl]-thiazol-2-yl } -2-trifluoromethoxy-benzamide	489	490[M+H]⁺	+++
12		489	490[M+H]⁺	+++	13	N- (1H-benzimidazol-2-yl) -N' - {2- [4- (2-trifluoromethoxy-benzoyl) -piperazin-1-yl]-thiazole-4-carbonyl } -guanidine	558	559[M+H]⁺	+
14	N- (1H-benzimidazol-2-yl) -N' - [2- (2, 3-dihydro-benzo [1, 4]]Dioxin-2-yl-thiazole-4-carbonyl]-guanidine (II)	420	421[M+H]⁺	+	13		558	559[M+H]⁺	+
14		420	421[M+H]⁺	+	25	2- (2-trifluoromethoxy-benzoylamino) -thiazole-4-carboxylic acid (5, 6-dimethyl-1H-benzoimidazol-2-yl) -amide	475	476[M+H]⁺	+++
26	2- (3-fluoro-4-trifluoromethyl-benzoylamino) -oxazole-4-carboxylic acid ethyl ester	536	537[M+H]⁺	+++	25		475	476[M+H]⁺	+++
26		536	537[M+H]⁺	+++	27	N- {4- [ N' - (1H-benzimidazol-2-yl) -guanidinocarbonyl]-oxazol-2-yl } -3-fluoro-4-trifluoromethyl-benzamide	475	476[M+H]⁺	+++
30	N- (1H-benzimidazol-2-yl) -N' - [2- (4-benzyl-piperazin-1-yl) -thiazole-4-carbonyl]-guanidine (II)	460	461[M+H]⁺	+++	27		475	476[M+H]⁺	+++
30		460	461[M+H]⁺	+++	31	2- (2-trifluoromethoxy-benzoylamino) -thiazole-4-carboxylic acid (1H-benzoimidazol-2-yl) -amide	447	448[M+H]⁺	+++
36	N- (1H-benzimidazol-2-yl) -N' - {2- [1- (2-trifluoromethoxy-benzoyl) -piperidin-4-yl]-thiazole-4-carbonylRadical-guanidine	557	558[M+H]⁺	+++	31		447	448[M+H]⁺	+++
36		557	558[M+H]⁺	+++	40	2- (2-trifluoromethoxy-benzoylamino) -oxazole-4-carboxylic acid (5, 6-dimethyl-1H-benzimidazol-2-yl) -amide	459	460[M+H]⁺	+++
42	2- (2-trifluoromethoxy-benzoylamino) -thiazole-4-carboxylic acid [6- (4-methyl-piperazin-1-yl) -benzothiazol-2-yl]-amides of	562	563[M+H]⁺	+++	40		459	460[M+H]⁺	+++
42		562	563[M+H]⁺	+++	43	2- (2-trifluoromethoxy-benzoylamino) -thiazole-4-carboxylic acid (5-nitro-1H-benzoimidazol-2-yl) -amide	492	493[M+H]⁺	+++
45	N- {4- [ N' - (1H-benzimidazol-2-yl) -guanidinocarbonyl]-thiazol-2-yl } -2-cyclohexyl-benzamide	487	488[M+H]⁺	+++	43		492	493[M+H]⁺	+++
45		487	488[M+H]⁺	+++	46	2- (2-trifluoromethoxy-benzoylamino) -thiazole-4-carboxylic acid (1-methyl-1H-benzoimidazol-2-yl) -amide	461	462[M+H]⁺	+++
47	2- (2-trifluoromethoxy-benzoylamino) -thiazole-4-carboxylic acid [5- (propane-1-sulfonyl) -1H-benzimidazol-2-yl]-amides of	553	554[M+H]⁺	+++	46		461	462[M+H]⁺	+++
47		553	554[M+H]⁺	+++	49	N- (1H-benzimidazol-2-yl) -N' - (2-morpholin-4-yl-thiazole-4-carbonyl) -guanidine	371	372[M+H]⁺	+++
51	N- {4- [ N' - (1H-benzimidazol-2-yl) -guanidinocarbonyl]-thiazol-2-yl } -4-trifluoromethyl-benzamide	473	474[M+H]⁺	+++	49		371	372[M+H]⁺	+++
51		473	474[M+H]⁺	+++	52	2- [1- (2-trifluoromethoxy-benzoyl) -piperidin-4-yl]-thiazole-4-carboxylic acid [5- (propane-1-sulfonyl) -1H-benzimidazol-2-yl]-amides of	621	622[M+H]⁺	+++

53	N- {4- [ N' - (1H-benzimidazol-2-yl) -guanidinocarbonyl]-thiazol-2-yl } -2-fluoro-4-trifluoromethyl-benzamide	491	492[M+H]⁺	+++
53		491	492[M+H]⁺	+++	54	1- {4- [ N' - (1H-benzimidazol-2-yl) -guanidinocarbonyl]-thiazol-2-yl } -3- (2-trifluoromethoxy-phenyl) -urea	504	505[M+H]⁺	+++
56	N- {4- [ N' - (1H-benzimidazol-2-yl) -guanidinocarbonyl]-thiazol-2-yl } -3-fluoro-4-trifluoromethyl-benzamide	491	492[M+H]⁺	+++	54		504	505[M+H]⁺	+++
56		491	492[M+H]⁺	+++	57	N- {4- [ N' - (1H-benzimidazol-2-yl) -guanidinocarbonyl]-thiazol-2-yl } -2, 6-difluoro-benzamide	441	442[M+H]⁺	+++
91	N- (1H-benzimidazol-2-yl) -N' - (2-morpholin-4-yl-thiazole-4-carbonyl) -guanidine	371	372[M+H]⁺	+	57		441	442[M+H]⁺	+++
91		371	372[M+H]⁺	+	250	N- (1H-benzimidazol-2-yl) -N' - {2- [1- (4-cyano-benzyl) -piperidin-4-yl]-thiazole-4-carbonyl } -guanidine	484	485[M+H]+	++
251	N-benzothiazol-2-yl-N' - {2- [1- (4-cyano-benzyl) -piperidin-4-yl]-thiazole-4-carbonyl } -guanidine	501	502[M+H]+	++	250		484	485[M+H]+	++
251		501	502[M+H]+	++	252	N- (1H-benzimidazol-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]+	++	252		485	485[M+H]+	+++
253		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- (1H-benzimidazol-2-yl) -N' - (2-morpholin-4-yl-thiazole-4-carbonyl) -guanidine	371	372[M+H]+	+++	254		352	353[M+H]+	+
255		371	372[M+H]+	+++	256	N-benzothiazol-2-yl-N' - (2-morpholin-4-yl-thiazole-4-carbonyl) -guanidine	388	389[M+H]+	+++
257	N- (1H-benzimidazol-2-yl) -N' - (2-morpholin-4-yl-oxazole-4-carbonyl) -guanidine	355	356[M+H]+	++	256		388	389[M+H]+	+++
257		355	356[M+H]+	++	258	N-benzoxazol-2-yl-N' - (2-morpholin-4-yl-thiazole-4-carbonyl) -guanidine	372	373[M+H]+	++
259	N- (2-morpholin-4-yl-thiazole-4-carbonyl) -N' - (5-nitro-benzoxazol-2-yl) -guanidine	417	418[M+H]+	++	258		372	373[M+H]+	++
259		417	418[M+H]+	++	260	N- (5-methyl-benzoxazol-2-yl) -N' - (2-morpholin-4-yl-thiazole-4-carbonyl) -guanidine	386	387[M+H]+	+
261	N- (5-chloro-benzoxazol-2-yl) -N' - (2-morpholin-4-yl-thiazole-4-carbonyl) -guanidine	406	407[M+H]+	++	260		386	387[M+H]+	+
261		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-1H-benzimidazol-2-yl) -N' - {2- [1- (2-trifluoromethoxy-benzoyl) -piperidin-4-yl]-thiazole-4-carbonyl } -guanidine	591	592[M+H]+	+++
263		591	592[M+H]+	+++	264	N- (5, 6-dichloro-1H-benzimidazol-2-yl) -N' - {2- [1- (2-trifluoromethoxy-benzoyl) -piperidin-4-yl]-thiazole-4-carbonyl } -guanidine	625	626[M+H]+	++
265	2-morpholin-4-yl-thiazole-4-carboxylic acid [4- (5-trifluoromethyl-benzothiazol-2-yl) -phenyl]-amides of	490	491[M+H]+		264		625	626[M+H]+	++
265		490	491[M+H]+		266	2-morpholin-4-yl-thiazole-4-carboxylic acid (5-benzo)Thiazol-2-yl-pyridin-2-yl) -amides	423	424[M+H]+
267	2-morpholin-4-yl-thiazole-4-carboxylic acid (4-benzothiazol-2-yl-2-fluoro-phenyl) -amide	440	441[M+H]+		266		423	424[M+H]+
267		440	441[M+H]+		268	2-morpholin-4-yl-thiazole-4-carboxylic acid (4-benzothiazol-2-yl-2-trifluoromethoxy-phenyl) -amide	506	507[M+H]+
269	2- (1-furo [2, 3-c ]]Pyridin-4-yl-piperidin-4-yl) -thiazole-4-carboxylic acid (5-benzoyl-1H-benzimidazol-2-yl) -amide	548	549[M+H]+		268		506	507[M+H]+
269		548	549[M+H]+		270	2- [1- (4, 6-dimethoxy- [1, 3, 5 ]]Triazin-2-yl) -piperidin-4-yl]-thiazole-4-carboxylic acid (5-benzoyl-1H-benzimidazol-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-fluoro-benzothiazol-2-yl) -amide	501	502[M+H]+		270		570	571[M+H]+
271		501	502[M+H]+		272	2- [1- (4-cyano-benzyl) -piperidin-4-yl]-thiazole-4-carboxylic acid (5-benzoyl-1H-benzimidazol-2-yl) -amide	546	547[M+H⁺]	++
273	2- (1-thieno [3, 2-d ]]Pyrimidin-4-yl-piperidin-4-yl) -thiazole-4-carboxylic acid (5-benzoyl-1H-benzoimidazol-2-yl) -amide	565	566[M+H⁺]	++	272		546	547[M+H⁺]	++
273		565	566[M+H⁺]	++	274	2- [1- (4, 6-dimethoxy- [1, 3, 5 ]]Triazin-2-yl) -piperidin-4-yl]-thiazole-4-carboxylic acid (5-benzoyl-1H-benzimidazol-2-yl) -amide	570	571[M+H⁺]	+++
275	2- [1- (6-trifluoromethyl-pyrimidin-4-yl) -piperidin-4-yl]-thiazole-4-carboxylic acid (5-benzoyl-1H-benzimidazol-2-yl) -amide	577	578[M+H⁺]	++	274		570	571[M+H⁺]	+++
275		577	578[M+H⁺]	++	276	2- [1- (4-cyano-benzyl) -piperidin-4-yl]-thiazole-4-carboxylic acid (5-ethoxy-1H-benzimidazol-2-yl) -amide	486	487[M+H]+	+
277	2- [1- (4-cyano-benzyl) -piperidin-4-yl]-thiazole-4-carboxylic acid (5-chloro-1H-benzimidazol-2-yl) -amide	476	477[M+H]+	++	276		486	487[M+H]+	+
277		476	477[M+H]+	++	278	2- [1- (4-cyano-benzyl) -piperidin-4-yl]-thiazole-4-carboxylic acid (5, 6-dichloro-1H-benzimidazol-2-yl) -amide	510	511[M+H]+	++

Exemplary compounds of general formula (Ih) of the present invention include, but are not limited to, the following:

compound (I)	Name (R)	Quality of	LC/(+)-ESI-MS：[M+H]⁺	Biological activity
compound (I)	Name (R)	Quality of	LC/(+)-ESI-MS：[M+H]⁺	Biological activity	279	2- (1- (2, 6-dimethoxypyrimidin-4-yl) piperidin-4-yl) -N- (6- (thiophene-3-carbonyl) -1H-benzo [ d]Imidazol-2-yl) thiazole-4-carboxamide	575	576	+
280	2- (1- (thieno [3, 2-d ]]Pyrimidin-4-yl) piperidin-4-yl) -N- (6- (thiophene-3-carbonyl) -1H-benzo [ d]Imidazol-2-yl) thiazole-4-carboxamide	571	572	+++	279		575	576	+
280		571	572	+++	281	2- (1- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) piperidin-4-yl) -N- (6- (thiophene-3-carbonyl) -1H-benzo [ d]Imidazol-2-yl) thiazole-4-carboxamide	576	577	+++
282	N- (6-benzoyl-1H-benzo [ d ]]Imidazol-2-yl) -2- (1- (2, 6-dimethoxypyrimidin-4-yl) piperidin-4-yl) thiazole-4-carboxamide	569	570	+++	281		576	577	+++
282		569	570	+++	283	N- (5-acetylbenzo [ d ]]Thiazol-2-yl) -2- (1- (thieno [3, 2-d)]Pyrimidin-4-yl) piperidin-4-yl) thiazole-4-carboxamide	520	521	+++
284	N- (5- (3-fluoro-4-methoxybenzoyl) benzo [ d]Thiazol-2-yl) -2- (1- (thieno [3, 2-d)]Pyrimidin-4-yl) piperidin-4-yl) thiazole-4-carboxamide	630	631	+	283		520	521	+++
284		630	631	+	285	N- (5- (4-hydroxy-3-methoxybenzoyl) benzo [ d]Thiazol-2-yl) -2- (1- (thieno [3, 2-d)]Pyrimidin-4-yl) piperidin-4-yl) thiazole-4-carboxamide	628	629	+
286	N- (6-benzoyl-1H-benzo [ d ]]Imidazol-2-yl) -2- (1- (thien-2-ylsulfonyl) piperidin-4-yl) thiazole-4-carboxamide	577	578	++	285		628	629	+
286		577	578	++	287	N- (5-benzoyl-1H-benzo [ d ]]Imidazol-2-yl) -2- (1- (6, 7-dimethoxyquinazolin-4-yl) piperidin-4-yl) thiazole-4-carboxamide	619	620	+++
288	N- (5- (3-methoxybenzoyl) benzo [ d ]]Thiazol-2-yl) -2- (1- (thieno [3, 2-d)]Pyrimidin-4-yl) piperidin-4-yl) thiazole-4-carboxamide	612	613	+	287		619	620	+++

289	2- (1- (7H-purin-6-yl) piperidin-4-yl) -N- (6-benzoyl-1H-benzo [ d)]Imidazol-2-yl) thiazole-4-carboxamide	549	550	+++
289		549	550	+++	290	N- (6-benzoyl-1H-benzo [ d ]]Imidazol-2-yl) -2- (1- (2, 6-dichloropyridin-4-ylcarbamoyl) piperidin-4-yl) thiazole-4-carboxamide	619	620	+++
291	N- (6-benzoyl-1H-benzo [ d ]]Imidazol-2-yl) -2- (1- (4-cyanopyridin-2-yl) piperidin-4-yl) thiazole-4-carboxamide	533	534	+	290		619	620	+++
291		533	534	+	292	N- (5-benzoyl-1H-benzo [ d ]]Imidazol-2-yl) -2- (1- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) piperidin-4-yl) thiazole-4-carboxamide	570	571	+++
293	N- (6-benzoyl-1H-benzo [ d ]]Imidazol-2-yl) -2- (1- (thieno [3, 2-d)]Pyrimidin-4-yl) piperidin-4-yl) thiazole-4-carboxamide	565	566	++	292		570	571	+++
293		565	566	++	294	N- (6-benzoyl-1H-benzo [ d ]]Imidazol-2-yl) -2- (1- (6- (trifluoromethyl) pyrimidin-4-yl) piperidin-4-yl) thiazole-4-carboxamide	577	578	++
295	N- (5-benzoyl-1H-benzo [ d ]]Imidazol-2-yl) -2- (1- (4-cyanobenzyl) piperidin-4-yl) thiazole-4-carboxamide	546	547	++	294		577	578	++
295		546	547	++	296	2-(1-([1，2，4]Triazolo [1, 5-a]Pyrimidin-7-yl) piperidin-4-yl) -N- (5-benzoyl-1H-benzo [ d]Imidazol-2-yl) thiazole-4-carboxamide	549	550	+++
297	N- (5-benzoyl-1H-benzo [ d ]]Imidazol-2-yl) -2- (1- (2-methylpyrazolo [1, 5-a)]Pyrimidin-7-yl) piperidin-4-yl) thiazole-4-carboxamide	562	563	+++	296		549	550	+++
297		562	563	+++	298	4- {4- [4- (5-benzoyl-1H-benzimidazol-2-ylcarbamoyl) -thiazol-2-yl]-piperidin-1-yl } -5-methyl-pyrrolo [2, 1-f)][1，2，4]Triazine-6-carboxylic acid methyl ester	620	621	+
299	Methyl 7- (4- (4- (5-benzoyl-1H-benzo [ d ]]Imidazol-2-ylcarbamoyl) thiazol-2-yl) piperidin-1-yl) - [1, 2, 4]Triazolo [1, 5-a]Pyrimidine-2-carboxylic acid esters	607	608	++	298		620	621	+

[ "+" denotes EC50 of 30 μ M to 100 μ M, "+ +" denotesEC 50 of 10 μ M to 30 μ M and "+++" denotes EC50 of less than 10 μ M ]

Exemplary compounds of formula (IIIa) of the present invention include, but are not limited to, the following:

compound (I)	Name (R)	Quality of	LC/(+/-)-ESI-MS：[M+H]⁺([M-H]^-)	Biological activity¹⁾
compound (I)	Name (R)	Quality of	LC/(+/-)-ESI-MS：[M+H]⁺([M-H]^-)	Biological activity¹⁾	300	2- (Isonicotinamido) -N- (6- (methylsulfonyl) benzo [ d]Thiazol-2-yl) thiazole-4-carboxamides	459	460	+
301	2-cinnamylamido-N- (6- (methylsulfonyl) benzo [ d]Thiazol-2-yl) thiazole-4-carboxamides	484	485	+	300		459	460	+
301		484	485	+	302	2- (furan-2-carboxamido) -N- (6- (methylsulfonyl) benzo [ d]Thiazol-2-yl) thiazole-4-carboxamides	448	449	+
303	N- (5, 6-dimethyl-1H-benzo [ d ]]Imidazol-2-yl) -2- (furan-2-carboxamido) thiazole-4-carboxamide	381	382	+	302		448	449	+
303		381	382	+	304	N- (5, 6-dimethyl-1H-benzo [ d ]]Imidazol-2-yl) -2- (isonicotinamido) thiazole-4-carboxamide	392	393	+
305	2-cinnamylamido-N- (5, 6-dimethyl-1H-benzo [ d]Imidazol-2-yl) thiazole-4-carboxamide	417	418	+	304		392	393	+
305		417	418	+	306	Ethyl 2- (2- (2- (trifluoromethoxy) benzoylamino) thiazole-4-carboxamido) -1H-benzo [ d]Imidazole-6-carboxylic acid esters	519	518[M-H]^-	+++
307	Ethyl 2- (2- (2- (trifluoromethoxy) benzoylamino) thiazole-4-carboxamido) benzo [ d]Thiazole-6-carboxylic acid esters	536	535[M-H]^-	++	306		519	518[M-H]^-	+++
307		536	535[M-H]^-	++	308	2- (2-chlorobenzoylamino) -N- (6- (phenylsulfanyl) -1H-benzo [ d]Imidazol-2-yl) thiazole-4-carboxamide	506	505[M-H]^-	+
309	N- (5-benzoyl-1H-benzo [ d ]]Imidazol-2-yl) -2- (2-chlorobenzoylamino) thiazole-4-carboxamide	501	500[M-H]^-	++	308		506	505[M-H]^-	+
309		501	500[M-H]^-	++	310	Ethyl 2- (2- (2-chlorobenzoylamino) thiazole-4-carboxamido) benzo [ d]Thiazole-6-carboxylic acid esters	486	485[M-H]^-	+
311	2- (2-chlorobenzoylamino) -N- (6- (trifluoromethyl) benzo [ d]Thiazol-2-yl) thiazole-4-carboxamides	482	481[M-H]^-	++	310		486	485[M-H]^-	+
311		482	481[M-H]^-	++	312	2- (2-chlorobenzoylamino) -N- (4-methoxybenzo [ d ]]Thiazol-2-yl) thiazole-4-carboxamides	444	443[M-H]-	++
313	2- (2-chlorobenzoylamino) -N- (6-methylbenzo [ d ]]Thiazol-2-yl) thiazole-4-carboxamides	428	427[M-H]-	+++	312		444	443[M-H]-	++
313		428	427[M-H]-	+++	314	2- (2-chlorobenzoylamino) -N- (6-nitrobenzo [ d)]Thiazol-2-yl) thiazole-4-carboxamides	459	458[M-H]-	++
315	2- (2-chlorobenzoylamino) -N- (6-ethoxybenzo [ d ]]Thiazol-2-yl) thiazole-4-carboxamides	458	457[M-H]-	+	314		459	458[M-H]-	++
315		458	457[M-H]-	+	316	2- (2-chlorobenzoylamino) -N- (6-hydroxybenzo [ d ]]Thiazol-2-yl) thiazole-4-carboxamides	430	429[M-H]-	++

317	2- (2-chlorobenzoylamino) -N- (6-methoxybenzo [ d ]]Thiazol-2-yl) thiazole-4-carboxamides	444	443[M-H]-	++
317		444	443[M-H]-	++	318	2- (2-chlorobenzoylamino) -N- (4-methylbenzo [ d ]]Thiazol-2-yl) thiazole-4-carboxamides	428	427[M-H]-	+
319	2- (2-chlorobenzoylamino) -N- (6-fluorobenzo [ d ]]Thiazol-2-yl) thiazole-4-carboxamides	432	431[M-H]-	+++	318		428	427[M-H]-	+
319		432	431[M-H]-	+++	320	2- (2-chlorobenzoylamino) -N- (6-chlorobenzo [ d ]]Thiazol-2-yl) thiazole-4-carboxamides	448	447[M-H]-	+
321	N- (6-bromobenzo [ d ]]Thiazol-2-yl) -2- (2-chlorobenzoylamino) thiazole-4-carboxamide	493	492[M-H]-	+	320		448	447[M-H]-	+
321		493	492[M-H]-	+	322	2- (2-chlorobenzoylamino) -N- (4-chlorobenzo [ d ]]Thiazol-2-yl) thiazole-4-carboxamides	448	447[M-H]-	+++
323	2- (2-chlorobenzoylamino) -N- (5, 6-dimethylbenzo [ d ]]Thiazol-2-yl) thiazole-4-carboxamides	442	441[M-H]-	++	322		448	447[M-H]-	+++
323		442	441[M-H]-	++	324	2- (2-chlorobenzene)Formylamino) -N- (6- (trifluoromethoxy) benzo [ d]Thiazol-2-yl) thiazole-4-carboxamides	498	497[M-H]-	+++
325	2- (2-chlorobenzoylamino) -N- (6- (methylsulfonyl) benzo [ d]Thiazol-2-yl) thiazole-4-carboxamides	492	491[M-H]-	+	324		498	497[M-H]-	+++
325		492	491[M-H]-	+	326	N- (5, 6-dimethyl-1H-benzo [ d ]]Imidazol-2-yl) -2- (1- (thiophen-2-yl) cyclohexanecarboxamido) thiazole-4-carboxamide	479	478[M-H]-	+
327	N- (5, 6-dimethyl-1H-benzo [ d ]]Imidazol-2-yl) -2- (1-phenylcyclopropylamino) thiazole-4-carboxamide	431	430[M-H]-	+	326		479	478[M-H]-	+
327		431	430[M-H]-	+	328	N- (5, 6-dimethyl-1H-benzo [ d ]]Imidazol-2-yl) -2- (2, 5-dimethylthiophene-3-carboxamido) thiazole-4-carboxamide	425	424[M-H]-	+
329	N- (5, 6-dimethyl-1H-benzo [ d ]]Imidazol-2-yl) -2- (tetrahydrofuran-3-carboxamido) thiazole-4-carboxamide	385	386	+	328		425	424[M-H]-	+
329		385	386	+	330	N- (5, 6-dimethyl-1H-benzo [ d ]]Imidazol-2-yl) -2- (5-methyl-2- (trifluoromethyl) furan-3-carboxamido) thiazole-4-carboxamide	463	462[M-H]-	+
331	N- (5, 6-dimethyl-1H-benzo [ d ]]Imidazol-2-yl) -2- (2- (dimethylamino) acetamido) thiazole-4-carboxamide	372	373	+	330		463	462[M-H]-	+
331		372	373	+	332	N- (5, 6-dimethyl-1H-benzo [ d ]]Imidazol-2-yl) -2- (5- (morpholinomethyl) furan-2-carboxamido) thiazole-4-carboxamide	480	479[M-H]-	+

333	2- (2- (2-methoxybenzamido) thiazole-4-carboxamido) benzo [ d]Thiazole-6-carboxylic acids	454	453[M-H]-	+++
333		454	453[M-H]-	+++	334	2- (2-methoxybenzoylamino) -N- (6- (phenylsulfanyl) -1H-benzo [ d]Imidazol-2-yl) thiazole-4-carboxamide	501	502	++
335	N- (4- (5, 6-dimethyl-1H-benzo [ d ]]Imidazol-2-ylcarbamoyl) thiazol-2-yl) thieno [2, 3-b]Pyrazine-6-carboxamides	449	448[M-H]-	+++	334		501	502	++
335		449	448[M-H]-	+++	336	N- (5, 6-dimethyl-1H-benzo [ d ]]Imidazol-2-yl) -2- (2-morpholinylisonicotinamido) thiazole-4-carboxamide	477	476[M-H]-	+
337	Ethyl 2- (2- (2-methoxybenzamido) thiazole-4-carboxamido) benzo [ d]Thiazole-6-carboxylic acid esters	482	481[M-H]-	+	336		477	476[M-H]-	+
337		482	481[M-H]-	+	338	N- (5-benzoyl-1H-benzo [ d ]]Imidazol-2-yl) -2- (2-methoxybenzamido) thiazole-4-carboxamide	496	495[M-H]-	+++
339	2- (2-methoxybenzoylamino) -N- (6- (trifluoromethoxy) benzo [ d]Thiazol-2-yl) thiazole-4-carboxamides	494	493[M-H]-	+++	338		496	495[M-H]-	+++
339		494	493[M-H]-	+++	340	2- (2-methoxybenzoylamino) -N- (6- (trifluoromethyl) benzo [ d]Thiazol-2-yl) thiazole-4-carboxamides	478	477[M-H]-	+
341	2- (2-methoxybenzoylamino) -N- (4-methoxybenzo [ d]Thiazol-2-yl) thiazole-4-carboxamides	440	441	+++	340		478	477[M-H]-	+
341		440	441	+++	342	2- (2-methoxybenzoylamino) -N- (6-methylbenzo [ d ]]Thiazol-2-yl) thiazole-4-carboxamides	424	423[M-H]-	+
343	2- (2-methoxybenzoylamino) -N- (6-nitrobenzo [ d]Thiazol-2-yl) thiazole-4-carboxamides	455	454[M-H]-	+	342		424	423[M-H]-	+
343		455	454[M-H]-	+	344	N- (6-ethoxybenzo [ d ]]Thiazol-2-yl) -2- (2-methoxybenzamido) thiazole-4-carboxamide	454	453[M-H]-	+
345	Tert-butyl 4- (5, 6-dimethyl-1H-benzo [ d ]]Imidazol-2-ylcarbamoyl) thiazol-2-ylcarbamate	387	388	+	344		454	453[M-H]-	+
345		387	388	+	346	N- (6-methyl-1H-benzo [ d ]]Imidazol-2-yl) -2- (2- (trifluoromethoxy) benzoylamino) thiazole-4-carboxamide	461	462	+++
347	N- (5-ethoxy-1H-benzo [ d ]]Imidazol-2-yl) -2- (2- (trifluoromethoxy) phenyl) Benzoylamino) thiazole-4-carboxamides	491	492	+++	346		461	462	+++
347		491	492	+++	348	N- (6-fluoro-1H-benzo [ d)]Imidazol-2-yl) -2- (2- (trifluoromethoxy) benzoylamino) thiazole-4-carboxamide	465	466	+++
349	N- (1-ethyl-1H-benzo [ d ]]Imidazol-2-yl) -2- (2- (trifluoromethoxy) benzoylamino) thiazole-4-carboxamide	475	476	+++	348		465	466	+++
349		475	476	+++	350	N- (5-nitro-1H-benzo [ d ]]Imidazol-2-yl) -2- (2- (trifluoromethoxy) benzoylamino) thiazole-4-carboxamide	492	493	+++

351	N- (5-methyl-7- (trifluoromethyl) - [1, 2, 4]]Triazolo [1, 5-a]Pyrimidin-2-yl) -2- (2- (trifluoromethoxy) benzoylamino) thiazole-4-carboxamide	531	532	+
351		531	532	+	352	N- (6-benzoyl-1H-benzo [ d ]]Imidazol-2-yl) -2- (2- (trifluoromethoxy) benzoylamino) thiazole-4-carboxamide	551	552	+
353	N- (1-methyl-1H-benzo [ d ]]Imidazol-2-yl) -2- (2- (trifluoromethoxy) benzoylamino) thiazole-4-carboxamide	461	462	+++	352		551	552	+
353		461	462	+++	354	N- (6-hydroxybenzo [ d ]]Thiazol-2-yl) -2- (2-methoxybenzamido) thiazole-4-carboxamide	426	425[M-H]-	+++
355	2- (2-methoxybenzoylamino) -N- (4-methylbenzo [ d ]]Thiazol-2-yl) thiazole-4-carboxamides	424	425	+++	354		426	425[M-H]-	+++
355		424	425	+++	356	N- (6-fluorobenzo [ d ]]Thiazol-2-yl) -2- (2-methoxybenzamido) thiazole-4-carboxamide	428	429	+++
357	N- (6-bromobenzo [ d ]]Thiazol-2-yl) -2- (2-methoxybenzamido) thiazole-4-carboxamide	488	487[M-H]-	+++	356		428	429	+++
357		488	487[M-H]-	+++	358	N- (6-chlorobenzo [ d ]]Thiazol-2-yl) -2- (2-methoxybenzamido) thiazole-4-carboxamide	444	445	+++
359	N- (4-chlorobenzo [ d ]]Thiazol-2-yl) -2- (2-methoxybenzamido) thiazole-4-carboxamide	444	445	+++	358		444	445	+++
359		444	445	+++	360	N- (5, 6-dimethylbenzo [ d ]]Thiazol-2-yl) -2- (2-methoxybenzamido) thiazole-4-carboxamide	438	439	+++
361	2- (2-methoxybenzoylamino) -N- (6- (trifluoromethoxy) benzo [ d]Thiazol-2-yl) thiazole-4-carboxamides	494	495	+++	360		438	439	+++
361		494	495	+++	362	2- (2-methoxybenzoylamino) -N- (6- (methylsulfonyl) benzo [ d]Thiazol-2-yl) thiazole-4-carboxamides	488	489	+++
363	2- { [2- (2-trifluoromethoxy-benzoylamino) -thiazole-4-carbonyl]-amino } -benzothiazole-6-carboxylic acid ethyl ester	536	537	++	362		488	489	+++
363		536	537	++	364	N- (6-hydroxybenzo [ d ]]Thiazol-2-yl) -2- (2- (trifluoromethoxy) benzoylamino) thiazole-4-carboxamide	480	481	++
365	N- (6-chlorobenzo [ d ]]Thiazol-2-yl) -2- (2- (trifluoromethoxy) benzoylamino) thiazole-4-carboxamide	498	499	++	364		480	481	++
365		498	499	++	366	N- (6-fluorobenzo [ d ]]Thiazol-2-yl) -2- (2- (trifluoromethoxy) benzoylamino) thiazole-4-carboxamide	482	483	+++
367	N- (6-bromobenzo [ d ]]Thiazol-2-yl) -2- (2- (trifluoromethoxy) benzoylamino) thiazole-4-carboxamide	542	543	+++	366		482	483	+++
367		542	543	+++	368	N- (7-chlorobenzo [ d ]]Thiazol-2-yl) -2- (2- (trifluoromethoxy) benzoylamino) thiazole-4-carboxamide	498	499	+

369	N- (6- (methylsulfonyl) benzo [ d ]]Thiazol-2-yl) -2- (2- (trifluoro)Methoxy) benzoylamino) thiazole-4-carboxamide	542	541[M-H]-	++
369		542	541[M-H]-	++	370	N- (6-nitrobenzo [ d ]]Thiazol-2-yl) -2- (2- (trifluoromethoxy) benzoylamino) thiazole-4-carboxamide	509	510	+
371	N- (5-nitrobenzo [ d ]]Thiazol-2-yl) -2- (2- (trifluoromethoxy) benzoylamino) thiazole-4-carboxamide	509	510	+	370		509	510	+
371		509	510	+	372	N- (5-methoxybenzo [ d ]]Thiazol-2-yl) -2- (2- (trifluoromethoxy) benzoylamino) thiazole-4-carboxamide	494	495	+
373	N- (7-methoxybenzo [ d ]]Thiazol-2-yl) -2- (2- (trifluoromethoxy) benzoylamino) thiazole-4-carboxamide	494	495	+	372		494	495	+
373		494	495	+	374	N- (5-ethoxybenzo [ d ]]Thiazol-2-yl) -2- (2- (trifluoromethoxy) benzoylamino) thiazole-4-carboxamide	508	509	+
375	2- (2- (trifluoromethoxy) benzoylamino) -N- (5- (trifluoromethyl) benzo [ d]Thiazol-2-yl) thiazole-4-carboxamides	532	533	+	374		508	509	+
375		532	533	+	376	2- (2- (trifluoromethoxy) benzoylamino) -N- (5- (trifluoromethoxy) benzo [ d]Thiazol-2-yl) thiazole-4-carboxamides	548	549	+
377	N- (5-fluorobenzo [ d ]]Thiazol-2-yl) -2- (2- (trifluoromethoxy) benzoylamino) thiazole-4-carboxamide	482	481[M-H]-	+	376		548	549	+

And (3) protease body determination:

chymotrypsin activity of the 20S proteasome (Immatics, Tubingen) was determined using a Tecan microplate reader (Tecan Ultra plate reader) with Suc-LLVT-AMC (Bachem) as substrate. In wells of a black 96-well polypropylene plate, 2. mu.l of each inhibitor dissolved in DMSO were mixed with 50. mu.l of a substrate solution (25 mM HEPES at pH 7.5 at 20 ℃, 0.5mM EDTA and Suc-LLVT-AMC) (at appropriate concentrations), and then the reaction was initiated by adding 150. mu.l of a proteasome solution (1.3. mu.g/ml 20S proteasome, 0.5mM EDTA, 0.033% (w/v) SDS in 25mM HEPES at pH 7.5 at 20 ℃). The substrate hydrolysis was followed by fluorescence spectroscopy (excitation wavelength: 360 nm; emission wavelength: 465nm) at 30 ℃ for 20min, then the initial velocity was calculated and expressed as the change in relative fluorescence units per second (RFU).

To measure IC₅₀Values (inhibitor concentration required for 50% inhibition) at least 4 different inhibitor concentrations were used. Each data point was recorded 3 times. The curve was fitted using a suitable procedure.

T lymphocyte proliferation assay:

inhibition of stimulated Peripheral Blood Mononuclear Cells (PBMC).

Through ACCUSPIN^TMSystem for controlling a power supply-1077 tubes, PBMC were isolated from blood of healthy volunteers, washed and washed at 10⁶The cells/ml were resuspended in Dulbecco's modified eagle's medium containing 10% fetal bovine serum and 2mM glutamine. Cells were stimulated with 2. mu.g/ml phytohemagglutinin in the presence of test compound or blank vehicle for 72 hours. 4h before the end of the incubation period, 5-bromo-2' -deoxyuridine (BrdU) was added to label proliferating cells. After incubation, the cells were separated by centrifugation and the culture supernatant was removed. Bound BrdU was quantified using an enzyme-linked immunosorbent assay. To measure IC₅₀Value (inhibitor concentration required for 50% inhibition), at least 4 were usedDifferent inhibitor concentrations. Each data point was recorded 3 times. The curve was fitted using a suitable procedure.

Based on the results obtained in the T lymphocyte proliferation assay, the compounds of the invention are suitable for the treatment of inflammatory diseases or T cell related diseases.

Inhibition of NF-. kappa.B-induced inflammation:

for the determination of the anti-inflammatory activity of the compounds, Cell Culture Service GmBH was usedNINA immediate test. The assay is based on recombinant A549-NF-. kappa.B-SEAP reporter cells pre-seeded in 96-well flat-bottom plates. Since the transfection reporter gene for SEAP (secreted embryonic alkaline phosphatase) is under the transcriptional control of the NF-. kappa.B-responsive element, expression of this indicator is activated by TNF-. alpha.stimulation. Substrates capable of chemiluminescenceThe secretion of SEAP into the culture broth was examined. Test compounds that inhibit NF-. kappa.B activity exhibit reduced SEAP activity and reduced luminescence readings.

At 37 deg.C, 5% CO₂And 90% relative humidity for 18h, cells were incubated with 0.01. mu.M up to 100. mu.M of test compound for 4.5h before stimulation with 2ng/ml TNF-. alpha.. After 22h of stimulation with TNF-alpha, the endogenous phosphatase was inactivated and providedSubstrate for 40 min. SEAP activity was then quantified by measuring luminescence expressed as relative luminescence values (RLU) using a Tecan microplate reader. Each data point was recorded 4 times and EC50 values were calculated by fitting a function and microsoft excel solver.

Claims

1. A compound of the general formula (Ih) or a pharmaceutically acceptable salt thereof with an acid or a base or a pharmaceutically acceptable prodrug thereof or a stereoisomer thereof,

wherein

A is NR²', S or O;

t is 0 to 4;

r is 0 or 1;

R²Is H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino or heteroaryl,

Or R¹And R²And the N atom or C atom to which they are attached form a 3-to 8-membered, saturated or at least partially unsaturated monocyclic or polycyclic ring system, wherein at least one or more carbon atoms of the ring is a heteroatom selected from O, N, S, and the ring can be substituted with one or more R⁹Substitution;

R^ais H, halogen, hydrocarbyl, -C (NR)⁷)NR⁷’R⁸、-(CH₂)_pAryl, - (CH)₂)_pNR⁷R⁸Aryl group, -C (O) NR⁷R⁸、-N＝CR⁷R⁸、-NR⁷C(O)R⁸Cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino or heteroaryl;

R^bindependently represent H, -CN, -OH, -SH, -CO₂R⁴’、-C(O)R⁴’、-SO₂NR⁴’、-NR⁴’R⁵’、-C(O)NR⁷R⁸、-SO₂-hydrocarbyl, -SO₂R⁴’、SO₃R⁴’、-N＝CR⁴’R⁵’、-NR⁴’C(O)R⁴”、-NR⁴' -CO-Halogenoalkyl, -NO₂、-NR⁴’-SO₂-halogenated hydrocarbon radical, -NR⁴’-SO₂-hydrocarbyl, -NR⁴' -CO-hydrocarbyl, -NR⁴’(CH₂)_pHeteroaryl, alkyl, cycloalkyl, alkylamino, hydrocarbyloxy, hydrocarbylthio, halogen, haloalkyl, halohydrocarbyloxy, -O (CH)₂)_p[O(CH₂)_p]_qOCH₃、-C(NR⁴”)NR⁴' benzimidazolyl, -C (NR)⁴”)NR⁴' -benzothiazolyl, -C (NR)⁴”)NR⁴' benzoxazolyl, hydroxyalkyl, hydroxy-cycloalkyl, hydroxyalkylamino, heterocycloalkyl, aryl or heteroaryl;

R⁴’、R⁴”、R⁵' is independently H, halogen, hydrocarbyl, -C (NR)⁷)NR⁷’R⁸、-(CH₂)_pAryl, haloalkyl, - (CH)₂)_pNR⁷R⁸、-C(O)NR⁷R⁸、-N＝CR⁷R⁸、-NR⁷C(O)R⁸Ring ofAlkyl, heterocycloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;

x is NR²', O or S;

z is N or CR²’；

p is 1 to 6;

q is 1 to 6;

R⁹independently represent H, -CN, -OH, -SH, hydrocarbonoxy, hydrocarbylthio, -CO₂R⁴’、-C(O)R^4a、-C(O)NR⁷R⁸、-SO₂NR⁴’、-NR⁴’R⁵’、-SO₂-hydrocarbyl, -SO₂R⁴’、SO₃R⁴’、-N＝CR⁴’R⁵’、-NR⁴’C(O)R⁴”、-NR⁴' -CO-Halogenoalkyl, -NO₂、-NR⁴’-SO₂-halogenated hydrocarbon radical, -NR⁴’-SO₂-hydrocarbyl, -NR⁴' -CO-hydrocarbyl, -NR⁴’(CH₂)_pHeteroaryl, hydrocarbyl, hydroxyhydrocarbyl, cyclohydrocarbyl, halo, halohydrocarbyl, hydrocarbylamino, -O (CH)₂)_p[O(CH₂)_p]_qOCH₃、-C(NR⁴”)NR⁴' benzimidazolyl, -C (NR)⁴”)NR⁴' -benzothiazolyl, -C (NR)⁴”)NR⁴' benzoxazolyl, hydroxycycloalkyl, hydroxyalkylamino, halohydrocarbyloxy, heterocycloalkyl, - (CH)₂)_pNR⁷COR⁸Aryl or heteroaryl;

wherein

If not otherwise stated, C₁-C₆The alkyl radical representing a straight-chain or branched C₁-C₆Alkyl, which may be optionally substituted with one or more substituents R';

r' is independently H, -CO₂R”、-CONHR”、-CR”O、-SO₂NR ', -NR ' -CO-halohydrocarbyl, -NO2, -NR ' -SO₂-halogenated hydrocarbon radical, -NR "-SO₂-hydrocarbyl, -SO₂-alkyl, -NR "-CO-alkyl, -CN, alkyl, cycloalkyl, alkylamino, hydrocarbyloxy, -OH, -SH, hydrocarbylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, halohydrocarbyloxy, aryl or heteroaryl;

if not otherwise stated, C₂-C₆Alkenyl radical denotes straight-chain or branched C₂-C₆Alkenyl, which can be optionally substituted with one or more substituents R';

the hydrocarbon radical denotes, if not otherwise stated, straight-chain or branched C₁-C₆Alkyl, straight or branched C₂-C₆Alkenyl or straight or branched C₂-C₆An alkynyl group which may be optionally substituted with one or more substituents R'; r' is as defined above;

cycloalkyl represents a non-aromatic ring system containing from 3 to 8 carbon atoms, wherein one or more carbon atoms on the ring can be substituted by one or more substituents R'; r' is as defined above;

heterocycloalkyl represents a non-aromatic ring system containing from 2 to 10 carbon atoms and at least one heteroatom selected from O, N or S, wherein one or more carbon atoms of the ring can be substituted by a R' group as defined above;

hydrocarbyloxy represents an O-hydrocarbyl group, the hydrocarbyl group being as defined above;

a halogenated hydrocarbyl group represents a hydrocarbyl group substituted with 1 to 5 halogen atoms, the hydrocarbyl group being as defined above;

a halohydrocarbyloxy group represents a hydrocarbyloxy group substituted with from 1 to 5 halogen atoms, the hydrocarbyl group being as defined above;

halogen groups are fluorine, chlorine, bromine or iodine;

aryl group means an aromatic group having from 5 to 15 carbon atoms, which can be optionally substituted by one or more substituents R ', wherein R' is as defined above;

heteroaryl group denotes a five to ten membered aromatic heterocyclic group containing at least one heteroatom selected from O, N or S, wherein the heterocyclic group may be fused to another ring and either the heterocyclic group or the fused rings may be independently substituted by one or more substituents R ', wherein R' is as defined above;

with the proviso that the following compounds are excluded

Wherein

R²independently represent-NR³R⁴、

p is 0 or 1;

q is 0 or 1;

x is CO or SO₂。

2. A compound of the general formula (Ia) or a pharmaceutically acceptable salt thereof with an acid or a base or a pharmaceutically acceptable prodrug thereof or a stereoisomer thereof,

x is CO, CS or SO₂；

Y is CO, CS or SO₂；

Z is NR²', S or O;

R^eindependently represent H, -CN, -OH, -SH, -CO₂R⁴’、-C(O)R⁴’、-SO₂NR⁴’、-NR⁴’R⁵’、-C(O)NR⁷R⁸、-SO₂-hydrocarbyl, -SO₂R⁴’、SO₃R⁴’、-N＝CR⁴’R⁵’、-NR⁴’C(O)R⁴”、-NR⁴' -CO-Halogenoalkyl, -NO₂、-NR⁴’-SO₂-halogenated hydrocarbon radical, -NR⁴’-SO₂-hydrocarbyl, -NR⁴' -CO-hydrocarbyl, -NR⁴’(CH₂)_pHeteroaryl, alkyl, hydroxyalkyl, cycloalkyl, alkylamino, aryl, hydroxyalkylamino, hydrocarbyloxy, hydrocarbylthio, -O (CH)₂)_p[O(CH₂)_p]_qOCH₃、-C(NR⁴”)NR⁴' benzimidazolyl, -C (NR)⁴”)NR⁴' -benzothiazolyl, -C (NR)⁴”)NR⁴' benzoxazolyl or heteroaryl;

p is 1 to 6;

q is 1 to 6;

R²independently is

wherein

The hydrocarbon radical denotes, if not otherwise stated, straight-chain or branched C₁-C₆Alkyl, straight or branched C₂-C₆Alkenyl or straight or branched C₂-C₆Alkynyl, which can be substituted by one or more substituents R'; r' is as defined above;

cycloalkyl represents a non-aromatic ring system containing from 3 to 8 carbon atoms, wherein one or more of the carbon atoms of the ring can be substituted by a group E, E being O, S, SO₂N or NR ", R" is as defined above;

halogen groups are fluorine, chlorine, bromine or iodine;

aryl group means an aromatic group having from 5 to 15 carbon atoms, which can be substituted by one or more substituents R ', wherein R' is as defined above;

a heteroaryl group denotes a five to ten membered aromatic heterocyclic group containing at least one heteroatom selected from O, N or S, wherein the heterocyclic group may be fused to another ring and either the heterocyclic group or the fused rings may be independently substituted by one or more substituents R ', wherein R' is as defined above.

3. A compound of the general formula (Ib) or a pharmaceutically acceptable salt thereof with an acid or a base or a pharmaceutically acceptable prodrug thereof or a stereoisomer thereof,

wherein

R⁹Independently represent H, -CN, -OH, -SH, -CO₂R⁴’、-C(O)R⁴’、-SO₂NR⁴’、-NR⁴’R⁵’、-C(O)NR⁷R⁸、-SO₂-hydrocarbyl, -SO₂R⁴’、SO₃R⁴’、-N＝CR⁴’R⁵’、-NR⁴’C(O)R⁴”、-NR⁴' -CO-Halogenoalkyl, -NO₂、-NR⁴’-SO₂-halogenated hydrocarbon radical, -NR⁴’-SO₂-hydrocarbyl, -NR⁴' -CO-hydrocarbyl, -NR⁴’(CH₂)_pHeteroaryl, hydroxyalkyl, cycloalkyl, alkylamino, aryl, hydroxyalkylamino, hydrocarbyloxy, hydrocarbylthio, -O (CH)₂)_p[O(CH₂)_p]_qOCH₃、-C(NR⁴”)NR⁴' benzimidazolyl, -C (NR)⁴”)NR⁴' benzothiazolyl, -C (NR)⁴”)NR⁴' benzoxazolyl, - (CH)₂)_pNR⁷COR⁸Or a hydrocarbyl group;

or R¹And R⁴And X attached thereto, wherein at least one ring atom is a heteroatom selected from O, N or S, and the ring optionally has one or more substituents R⁹；

X is N or CR²’；

Y is CO, CS or SO₂；

Z is NR²", S or O;

R⁴’、R⁴”、R⁵' independently represents H, a hydrocarbon group, a cyclic hydrocarbon group, a halogenated hydrocarbon group, a hydroxyhydrocarbon group, a hydroxyl groupHydrocarbylamino, -C (NR)⁷)NR⁷’R⁸、-(CH₂)_pAryl, - (CH)₂)_pNR⁷R⁸、-C(O)NR⁷R⁸、-N＝CR⁷R⁸、-NR⁷C(O)R⁸Halogen, heteroaryl or aryl;

p is 1 to 6;

q is 1 to 6;

R^eindependently represent H, -CN, -OH, -SH,-CO₂R⁴’、-C(O)R⁴’、-SO₂NR⁴’、-NR⁴’R⁵’、-C(O)NR⁷R⁸、-SO₂-hydrocarbyl, -SO₂R⁴’、SO₃R⁴’、-N＝CR⁴’R⁵’、-NR⁴’C(O)R⁴”、-NR⁴' -CO-Halogenoalkyl, -NO₂、-NR⁴’-SO₂-halogenated hydrocarbon radical, -NR⁴’-SO₂-hydrocarbyl, -NR⁴' -CO-hydrocarbyl, -NR⁴’(CH₂)_pHeteroaryl, alkyl, hydroxyalkyl, cycloalkyl, alkylamino, hydroxyalkylamino, hydrocarbyloxy, hydrocarbylthio, -O (CH)₂)_p[O(CH₂)_p]_qOCH₃、-C(NR⁴”)NR⁴' benzimidazolyl, -C (NR)⁴”)NR⁴' -benzothiazolyl, -C (NR)⁴”)NR⁴' benzoxazolyl, aryl or heteroaryl;

R²independently is

A is N, O or CR²’；

n is 0 to 2;

wherein

The hydrocarbon radical denotes, if not otherwise stated, straight-chain or branched C₁-C₆Alkyl, straight or branched C₂-C₆Alkenyl or straight or branched C₂-C₆An alkynyl group which can be substituted by one or more substituents R'; r' is as defined above;

cycloalkyl represents a non-aromatic ring system containing from 3 to 8 carbon atoms, wherein one or more of the carbon atoms of the ring can be substituted by a group E, E is O, S, SO₂N or NR ", R" is as defined above;

hydrocarbyloxy represents an O-hydrocarbyl group, the hydrocarbyl group being as defined above; (ii) a

halogen groups are fluorine, chlorine, bromine or iodine;

an aryl group denotes an aryl group having 5 to 15 carbon atoms, which can be substituted by one or more substituents R ', wherein R' is as defined above;

a heteroaryl group denotes a five to ten membered aromatic heterocyclic group containing at least one heteroatom selected from O, N, S, wherein the heterocyclic group may be fused to another ring and either the heterocyclic group or the fused rings may be independently substituted by one or more substituents R ', wherein R' is as defined above.

4. A compound of formula (Ic) or a pharmaceutically acceptable salt thereof with an acid or a base or a pharmaceutically acceptable prodrug thereof or a stereoisomer thereof,

wherein

x is CO, CS or SO₂；

Y is CO, CS or SO₂；

Z is NR²", S or O;

p is 1 to 6;

q is 1 to 6;

m is 0 to 4;

r is 0 or 1;

t is 0 or 1;

s is 0 or 1;

R^eindependently represent H, -CN, -OH, -SH, -CO₂R⁴’、-C(O)R⁴’、-SO₂NR⁴’、-NR⁴’R⁵’、-C(O)NR⁷R⁸、-SO₂-hydrocarbyl, -SO₂R⁴’、SO₃R⁴’、-N＝CR⁴’R⁵’、-NR⁴’C(O)R⁴”、-NR⁴' -CO-Halogenoalkyl, -NO₂、-NR⁴’-SO₂-halogenated hydrocarbon radical, -NR⁴’-SO₂-hydrocarbyl, -NR⁴' -CO-hydrocarbyl, -NR⁴’(CH₂)_pHeteroaryl, alkyl, hydroxyalkyl, cycloalkyl, alkylamino, hydroxyalkylamino, hydrocarbyloxy, hydrocarbylthio, -O (CH)₂)_p[O(CH₂)_p]_qOCH₃、-C(NR⁴”)NR⁴' benzimidazolyl, -C (NR)⁴”)NR⁴' -benzothiazolyl, -C (NR)⁴”)NR⁴' benzoxazolyl, aryl or heteroaryl;

wherein

cycloalkyl represents a non-aromatic ring system containing 3 to 8 carbon atoms, wherein one of the rings isOne or more carbon atoms being able to be substituted by E groups, E being O, S, SO₂N or NR ", R" is as defined above;

halogen groups are fluorine, chlorine, bromine or iodine;

5. A compound according to any one of claims 1 to 4 for use as a medicament.

6. A composition comprising a compound according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier or diluent.

7. A compound according to any one of claims 1 to 4 or a composition according to claim 6 for use in the treatment or prevention of a disease characterised by cellular hyperproliferation.

8. A compound according to any one of claims 1 to 4 or a composition according to claim 6 for use in the treatment or prevention of a disease caused by ischemia and/or reperfusion injury of an organ and/or part of the body selected from heart, brain, peripheral limb, kidney, liver, spleen and lung, and/or wherein the endothelial dysfunction is associated with a disease selected from infarction such as myocardial infarction, critical limb ischemia, and/or wherein the endothelial dysfunction is associated with a disease selected from ischemic disease, myocardial infarction, organ ischemic disease, etc.

9. A compound according to any one of claims 1 to 4 or a composition according to claim 6 for use in the treatment or prophylaxis of a neurological disease or disorder selected from alzheimer's disease, parkinson's disease, creutzfeldt-jakob disease, lewy body dementia, amyotrophic lateral sclerosis, stroke, epilepsy, multiple sclerosis, myasthenia gravis, huntington's disease, down's syndrome, nerve deafness and meniere's disease.

10. The compound or composition of claim 7, wherein the disease is selected from psoriasis, atopic dermatitis, alopecia areata, total alopecia, sub-total alopecia, systemic alopecia, diffuse alopecia (alpecidia effusis), cutaneous lupus erythematosus, lichen planus, dermatomyositis, atopic eczema, localized scleroderma, sklerodermia, psoriasis, head psoriasis (psioriasis capitis), trichomonas psoriasis, inverse psoriasis (psioriasis inverase), serpentine alopecia, androgenetic alopecia, allergic contact eczema, irritant contact eczema, pemphigus vulgaris, pemphigus foliaceus, proliferative pemphigus, cicatricial mucosal pemphigoid (scarring mucocutaneous pemphigoid), bullous pemphigoid, mucoid pemphigoid (mucoid), dermatitis herpetiformis (dermatitis), urticaria, necrobiosis nodularis, progressive necrotizing erythema nodosum, and necrobiosis Lichen virdal (lichen vidal), prurigo simplex, prurigo nodularis, acute prurigo, linear IgA dermatosis, polymorphous solar dermatosis, solar erythema, lichen sclerosus, skin rash, drug eruptions, chronic progressive purpura, dyshidrosis eczema, fixed drug eruptions, photoallergic skin reactions, eriorlale lichen simplex (lichen simplex), dermatitis and "graft-versus-host disease", acne, rosacea, scarring, keloids, vitiligo, actinic keratosis, hyperkeratosis such as epidermolytic hyperkeratosis, persistent lenticular hyperkeratosis, keratosis pilaris or ichthyosis.

11. The compound or composition of claim 7, wherein the disease is selected from a hematological tumor or a solid tumor.

12. The compound or composition of claim 11, wherein the disease is selected from prostate cancer, melanoma, ovarian cancer, or multiple myeloma.

13. A compound according to any one of claims 1 to 4 or a composition according to claim 6 for use in the treatment or prophylaxis of an autoimmune or inflammatory disease.

14. The compound or composition of claim 13, wherein the disease is rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, inflammatory skin disease, or lupus erythematosus.

15. A compound according to any one of claims 1 to 4 or a composition according to claim 6 for use in the treatment or prevention of stroke, reperfusion injury and alzheimer's disease.

16. The compound of any one of claims 1 to 4 or the composition of claim 6 for use in the treatment or prevention of a viral disease.

17. The compound or composition of claim 16, wherein the viral disease is hepatitis b, hepatitis c, influenza infection, AIDS (HIV infection), and human papilloma virus infection.

18. A compound according to any one of claims 1 to 4 or a composition according to claim 6 for use in the treatment or prevention of atherosclerosis.

19. A compound according to any one of claims 1 to 4 or a composition according to claim 6 for use in the treatment or prevention of osteoporosis.