KR20080104147A - Novel heterocyclic nf-kappa;b inhibitors - Google Patents

Abstract

The present invention relates to compounds of the general formula (Ih) or pharmaceutically acceptable salts thereof with an acid or a base, or pharmaceutically acceptable prodrugs or a stereoisomer thereof, (Ih) wherein A is NR2, S or O; R3a is H, OH, SH, NH2,-C(NR7)NR7'R8,-(CH2)paryl,-(CH2)PNR7R8,-C(O)NR7R8,-N=CR7R8,-NR7C(O)R8, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, alkoxy, alkylamino, hydroxyalkylamino, halogen, aryl, or heteroaryl; R3 is H,-C(0)NRaRb, halogen, alkyl, haloalkyl, aryl, heteroaryl, OH, SH, NR4' OR5', NH2, hydroxyalkylamino, alkylamino, alkoxy, cycloalkyl, hetero-cycloalkyl, hydroxyalkyl, or haloalkyloxy; X is NR2', O, or S; Z is N or CR2'. ® KIPO & WIPO 2009

Description

NOVEL HETEROCYCLIC NF-κB INHIBITORS

The present invention relates to a compound of formula (Ia), (Ib), (Ic), (Ih), (II) or (III) or a possible pharmaceutically acceptable salt thereof with stereoisomers or acids or bases, or pharmaceutically acceptable prodrugs of such compounds . The compounds of the present invention can be used as medicaments and are particularly useful for the treatment of diseases associated with abnormal and hyperproliferation of cells in mammals, especially humans. In particular, they are useful for the treatment of diseases characterized by hyperproliferation of T-cells. 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, immunological or inflammatory diseases, and viral infections, methods of making such compounds, and their use. .

T-cell homeostasis is important for maintaining immune tolerance. Defects of T-cell homeostasis can lead to autoimmune lesions. Autoimmune diseases include a wide range of clinically distinct subjects that share a common etiology, misleading spontaneous immune response. This immune response may be the result of organ transplantation. Evidence suggests a major role of T-cell responsiveness in autoimmune diseases. Measurement of proliferative response in T-lymphocytes is a widely used assay for measuring immune capacity [Killestein, J. et al., J. Neuroimmunol. 133, 217-24, 2002.

We used non-radioactive techniques for the measurement of 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 resource donors. PBMCs were isolated by centrifugation in ACCUSPIN tubes using HISTOPAQUE. PBMCs were stimulated with PHA and cell proliferation was measured with a Roche calorimeter BromUridin incorporation ELISA kit.

Regulation of the immune response was controlled by various signaling pathways such as T-cell or TNF receptor signaling (Chen, G. et al., Science 296, 1634-1635, 2002) .T-cell proliferation assays found to be active To further characterize the targets of the compounds, we tested the compounds for their ability to inhibit human proteasomes.

The main neutral proteolytic activity in the cytoplasm and nucleus is the proteasome, a 20S (700 kDa) particle with multiple peptidase activity. To screen for the presence of abnormal intracellular proteins, continuous conversion of cellular proteins by the ubiquitin-proteasome pathway is used by the immune system [Dantuma, N.P. Et al., Nat. Biotechnol. 2000, 18 (5) 538-43; Gold Berg, AL. Et al., Nature 357, 375, 1993. The ubiquitin-proteasome pathway plays an essential role in the regulation of NF-κB activity and contributes to the degradation of the inhibitor IκB-α. To be targeted for degradation by proteasomes, IκB-α must first undergo selective phosphorylation at serine residues 32 and 36 and then ubiquitination [Chen, ZJ et al., Cell 84, 853-862, 1996 ; Brown, K et al., Science 267, 1485, 1995]. The transcription factor NF-κaryl or aryl regulates the transcription of an important series of genes involved in the inflammatory response [Baeuerle, PA. Et al. Cell 87, 1, 13-20, 1996]. Proteasome inhibitors block IκB-α degradation and NF-κB activity (Traeckner et al., EMBO J. 13, 5433, 1994).

Documents describing proteasome inhibitors are described in Adams, J. et al., Ann. Rev. Med. Chem. 31, 279-288, 1996 and patents US 6117887, US 5834487, WO 00/004954, WO 00/04954, WO 00/170204, WO 00/33654, WO 00/64863, WO 00/114324, WO 99/15183 , WO 99/37666.

Here, we describe novel chemicals with proteasome inhibitory activity.

NF-κB (nuclear factor-κB) is a eukaryotic transcription factor of the rel lineage, which is an inactive complex located in the cytoplasm as homo- or heterodimer. Primarily it exists as a heterodimer consisting of p50 and p65 subunits and is bound to inhibitory proteins of the IκB line, usually IκB-α [D.Thanos et al., Cell 80, 529, 1995]. It is activated in response to various stimuli such as NF-κaryl or aryl inflammatory cytokines, UV radiation, phorbol esters, bacterial and viral infections. Stimulation causes release of NF-κB from IκB as a result of phosphorylation and subsequent degradation of the IκB-α protein by proteasomes [P.A.Baeuerle et al., Annu. Rev. Immunol. 12, 141, 1995]. Once freed, proteins that are translocated in the NF-κaryl or aryl nucleus, where they bind DNA at specific κB-sites and are involved in regulating immune and inflammatory responses, among others interleukin, TNF-α, NO-synthase And induce transcription of various genes encoding cyclooxygenase 2 [S. Grimm et al., J. Biochem. 290, 297, 1993]. Thus, NF-κaryl or aryl is considered as an early mediator of immune and inflammatory responses, controls cell proliferation and various human diseases such as rheumatoid arthritis [H. Beker et al., Clin. Exp. Immunol. 99, 325, 1995], ischemia [A. Salminen et al., Biochem. Biophys. Res. Comm. 212, 939, 1995], atherosclerosis [A.S.Baldwin, Annals Rev. Immunol. 212, 649, 1996, as well as the pathogenesis of AIDS. Inhibition of NF-κB mediated gene transcription can be achieved by phosphorylation of the inhibitory protein IκB, inhibition of IκB degradation, inhibition of NF-κB (p50 / p65) nuclear translocation, inhibition of NF-κB-DNA binding, or NF-κB-mediated DNA Can be achieved through inhibition of transcription [JCEpinat et al., Oncogene 18, 6896, 1999].

The present invention relates to compounds of formula (Ia), or acids or bases and pharmaceutically acceptable salts thereof, or pharmaceutically acceptable prodrugs or stereoisomers thereof.

Where

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

R ¹ is independently alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl;

X is CO, CS or SO ₂ ;

Y is CO, CS or SO ₂ ;

Z is NR ^{2 '} , S or O;

R ^{2 '} is H, alkyl, -C (O) NR ⁷ , -C (O) R ^e , cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;

R ^c is independently H, OH, SH, NROR ¹ , NH ₂ , alkylamino, hydroxyalkylamino, halogen, CONR ^d R ^e , alkoxy, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, Aryl or heteroaryl;

R ^d is H, halogen, alkyl, -C (NR ⁷ ) NR ^{7 '} R ⁸ ,-(CH ₂ ) _p aryl, -(CH ₂ ) _p NR ⁷ R ⁸ , -C (O) NR ⁷ R ⁸ , -N = CR ⁷ R ⁸ , -NR ⁷ C (O) R ⁸ , cycloalkyl, haloalkyl, hydroxyalkyl, hydroxide Oxyalkylamino, alkylamino, heteroaryl or aryl;

R ⁷ , R ^{7 ′} are independently H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;

R ⁸ is H, NH ₂ , alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;

R ^e is independently H, —CN, —OH, —SH, —CO ₂ R ^{4 ′} , —C (O) R ^{4 ′} , —SO ₂ NR ^{4 ′} , —NR ^{4 ′} R ^{5 ′} , —C ( O) NR ⁷ R ⁸ , -SO ₂ -alkyl, -SO ₂ R ^{4 '} , -SO ₃ R ^4' , -N = CR ^{4 '} R ^5' , -NR ^{4 '} C (O) R ^{4 "} ,- NR ^{4 '} -CO-haloalkyl, -NO ₂ , -NR ^4' -SO ₂ -haloalkyl, -NR ^{4 '} -SO ₂ -alkyl, -NR ^4' -CO-alkyl, -NR ^{4 '} (CH ₂ ) _p heteroaryl, alkyl, hydroxyalkyl, cycloalkyl, alkylamino, aryl, hydroxyalkylamino, alkoxy, alkylthio, -O (CH ₂ ) _p [O (CH ₂ ) _p ] _q OCH ₃ , -C (NR ^{4 ″} ) NR ^{4 ′} -benzimidazolyl, —C (NR ^{4 ″} ) NR ^{4 ′} benzthiazolyl, —C (NR ^{4 ″} ) NR ^{4 ′} benzoxazolyl or heteroaryl;

R ^{4 '} , R ^{4 "} , R ^5' are independently H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, -C (NR ⁷ ) NR ^{7 '} R ⁸ ,-( CH ₂ ) _p aryl,-(CH ₂ ) _p NR ⁷ R ⁸ , -C (O) NR ⁷ R ⁸ , -N = CR ⁷ R ⁸ , -NR ⁷ C (O) R ⁸ , halogen, heteroaryl or Aryl;

p is 1 to 6;

q is 1 to 6;

또는

이고;R ² is independently

or

ego;

R ⁵ is independently H, COR ⁶ , CO ₂ R ⁶ , SOR ⁶ , SO ₂ R ⁶ , SO ₃ R ⁶ , alkyl, cycloalkyl, alkoxy, -NH ₂ , alkylamine, -NR ⁷ COR ⁶ , halogen, -OH, -SH, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl;

R ⁶ is independently H, alkyl, cycloalkyl, amino, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, aryl or heteroaryl;

Unless stated otherwise, an alkyl group is straight or branched chain C ₁ -C ₆ alkyl which may be optionally substituted with one or more substituents R ′, preferably straight or branched chain, straight chain or branched chain C of 1 to 5 carbon atoms. ₂ -C ₆ alkenyl, or a straight or branched C ₂ -C ₆ alkynyl group;

C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl and C ₂ -C ₆ alkynyl moieties may be selected from the group consisting of:

R 'is independently H, -CO ₂ R ", -CONHR", -CR "O, -SO ₂ NR", -NR "-CO-haloalkyl, -NO ₂ , -NR" -SO ₂ -haloalkyl , -NR "-SO ₂ -alkyl, -SO ₂ -alkyl, -NR" -CO-alkyl, -CN, alkyl, cycloalkyl, alkylamino, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl, Hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl or heteroaryl;

R ″ is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl or heteroaryl;

Cycloalkyl groups represent non-aromatic ring systems containing 3 to 8 carbon atoms, preferably 4 to 8 carbon atoms, wherein one or more carbon atoms in the ring may be substituted by the group E, where E is O , S, SO, SO ₂ , N or NR ″, R ″ is as defined above; C ₃ -C ₈ cycloalkyl moieties include -cyclo-C ₃ H ₅ , -cyclo-C ₄ H ₇ , -cyclo-C ₅ H ₉ , -cyclo-C ₆ H ₁₁ , -cyclo-C ₇ H ₁₃ ,- May be selected from the group consisting of cyclo-C ₈ H ₁₅ , morpholin-4-yl, piperazinyl, 1-alkylpiperazin-4-yl;

The alkoxy group represents an O-alkyl group and the alkyl group is as defined above; The alkoxy group is preferably a methoxy, ethoxy, isopropoxy, t-butoxy or pentoxy group;

The alkylthio group represents an S-alkyl group, wherein the alkyl group is as defined above;

Haloalkyl group represents an alkyl group substituted with 1 to 5 halogen atoms, the alkyl group being as defined above; The haloalkyl group is preferably -C (R ¹⁰ ) ₃ , -CR ¹⁰ (R ^{10 '} ) ₂ , -CR ¹⁰ (R ^10' ) R ^{10 "} , -C ₂ (R ¹⁰ ) ₅ , -CH ₂ -C (R ¹⁰ ) ₃ , -CH ₂ -CR ¹⁰ (R ^{10 '} ) ₂ , -CH ₂ -CR ¹⁰ (R ^10' ) R ^{10 "} , -C ₃ (R ¹⁰ ) ₇ or -C ₂ H ₄ -C (R ¹⁰ ) ₃ , wherein R ¹⁰ , R ^{10 ′} , R ^{10 ″} is F, Cl, Br or I, preferably F;

A hydroxyalkyl group represents a HO-alkyl group, wherein the alkyl group is as defined above;

Haloalkyloxy group represents an alkoxy group substituted with 1 to 5 halogen atoms, the alkyl group being as defined above; The haloalkyloxy group is preferably -OC (R ¹⁰ ) ₃ , -OCR ¹⁰ (R ^{10 '} ) ₂ , -OCR ¹⁰ (R ^10' ) R ^{10 "} , -OC ₂ (R ¹⁰ ) ₅ , -OCH _2- C (R ¹⁰ ) ₃ , -OCH ₂ -CR ¹⁰ (R ^{10 '} ) ₂ , -OCH ₂ -CR ¹⁰ (R ^10' ) R ^{10 "} , -OC ₃ (R ¹⁰ ) ₇ or -OC ₂ H _4- C (R ¹⁰ ) ₃ , wherein R ¹⁰ , R ^{10 ′} , R ^{10 ″} is F, Cl, Br or I, preferably F;

Hydroxyalkylamino group represents a (HO-alkyl) ₂ -N- group or a HO-alkyl-NH- group, wherein the alkyl group is as defined above;

The alkylamino group represents an HN-alkyl or N-dialkyl group, wherein the alkyl group is as defined above;

Halogen groups are chlorine, bromine, fluorine or iodine;

An aryl group represents an aromatic group having 5 to 15 carbon atoms which may be substituted with one or more substituents R ', wherein R' is as defined above; The aryl group is preferably a benzyl group, a phenyl group, -oC ₆ H ₄ -R ', -mC ₆ H ₄ -R', -pC ₆ H ₄ -R ', 1-naphthyl, 2-naphthyl, 1-anthra Cenyl or 2-anthracenyl;

Heteroaryl groups represent 5- or 6-membered heterocyclic groups containing one or more heteroatoms selected from O, N and S. This heterocyclic group may be fused to another aromatic ring. For example, this group is thiadiazole, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazole -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, benzoisoxazol-3-yl, benzoisoxazol-4-yl, benzoisoxazol-5-yl, 1, 2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazole- 4-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothia Sol-5-yl, benzoisothiazol-3-yl, benzoisothiazol-4-yl, benzoisothiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1-im Dazolyl, 2-imidazolyl, 1,2,5-thiadiazol-4-yl, 4-imidazolyl, benzoimidazol-4-yl, 1-pyrrolyl, 2-pyrrolyl, 3-py Rollyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl , 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyranyl, 3-pyranyl, 4-pyranyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6 -Pyrimidinyl, 2,4-dimethoxy-6-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazole-5- 1,3,5-triazol-6-yl, 2,4-dimethoxy-1,3,5-triazol-6-yl, 1H-tetrazol-2-yl, 1H-tetrazol-3 -Yl, tetrazolyl, acridil, furazane, indazolyl, phenazinyl, carbazolyl, phenoxazinyl, indolizine, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 1-isoindoleyl, 3-isoindolyl, 4-isoindolyl, 5-isoindolyl, 6-isoindolyl, 7-isoindolyl, 2-indolynyl , 3-indolinyl, 4-indolinyl, 5-indolinyl, 6-indolinyl, 7-indolinyl, benzo [b] furanyl, benzofurazane, benzothiofurazane, benzotriazole-1- 1, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl, benzotriazol-7-yl, benzotriazine, benzo [b] thiophenyl, benzimidazole-2 -Yl, 1H-benzimidazolyl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl, benzimidazol-7-yl, benzothiazolyl, quinazolinyl, Quinoxazolinyl, cinnoline, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, purine, phthalazine, pteridine, thiatetrazaindene, thiatriazindene , 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-dimethoxypyrimidine-3 -Day, 2,6- Methoxypyrimidin-4-yl, imidazopyridazine, imidazopyrimidine, imidazopyridine, imidazolotriazine, triazolotriazine, triazolopyridine, triazolopyrazine, triazolopyrimidine or 4- [1,2,4] triazolo [4,3-a] pyridin-3-yl, 1-furo [2,3-c] pyridin-4-yl, 1-furo [2,3-c] pyridine- 5-yl, 1-furo [2,3-c] pyridin-3-yl and triazolopyridazine groups. Such heterocyclic groups may be substituted with one or more substituents R ', wherein R' is as defined above.

The present invention relates to a compound of formula (Ib), or a pharmaceutically acceptable salt thereof with an acid or base, or a pharmaceutically acceptable prodrug or stereoisomer thereof.

Where

R ¹ is —C (O) R ⁷ , —C (O) CHR ⁷ R ⁸ , —C (O) NR ⁷ R ⁸ , —C (O) OR ⁷ , —R ⁷ C (O) R ⁸ , or -C (S) R ⁷ ;

R ⁹ is independently H, —CN, —OH, —SH, —CO ₂ R ^{4 ′} , —C (O) R ^{4 ′} , —SO ₂ NR ^{4 ′} , —NR ^{4 ′} R ^{5 ′} , —C ( O) NR ⁷ R ⁸ , -SO ₂ -alkyl, -SO ₂ R ^{4 '} , SO ₃ R ^4' , -N = CR ^{4 '} R ^5' , -NR ^{4 '} C (O) R ^{4 "} , -NR ^{4 '-CO- _{haloalkyl, -NO 2, -NR 4' -SO}} 2 - haloalkyl, -NR ^{4 '-SO} ₂ - alkyl, -NR ^4' -CO- alkyl, -NR ^{4 '(CH} _{2) p} heteroaryl, alkyl, hydroxyalkyl, cycloalkyl, alkylamino, aryl, hydroxyalkylamino, alkoxy, alkylthio, -O (CH ₂ ) _p [O (CH ₂ ) _p ] _q OCH ₃ , -C ( NR ^{4 "} ) NR ^{4 '} -benzimidazolyl, -C (NR ^4" ) NR ^4' benzthiazolyl, -C (NR ^{4 "} ) NR ^{4 '} benzoxazolyl,-(CH ₂ ) _p NR ⁷ COR ⁸ or heteroaryl;

R ⁴ is H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, aryl, or

R ¹ and R ⁴ together with X to which they are attached form a 3-8 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 and S, and The ring optionally has one or more substituents R ⁹ ;

X is N or CR ² ;

Y is CO, CS or SO ₂ ;

Z is NR ^{2 ″} , S or O;

R ^{2 ″} is H, alkyl, —C (O) NR ⁷ , —C (O) R ^e , cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;

R ^{2 '} is H, alkyl, -C (O) NR ^4' , -C (O) R ^{4 '} , cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;

R ^{4 '} , R ^{4 "} , R ^5' are independently H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, -C (NR ⁷ ) NR ^{7 '} R ⁸ ,-( CH ₂ ) _p aryl,-(CH ₂ ) _p NR ⁷ R ⁸ , -C (O) NR ⁷ R ⁸ , -N = CR ⁷ R ⁸ , -NR ⁷ C (O) R ⁸ , halogen, heteroaryl or Aryl;

p is 1 to 6;

q is 1 to 6;

R ^a is independently H, OH, SH, NH ₂ , alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, alkoxy, alkylamino, hydroxyalkylamino, halogen, aryl or heteroaryl;

R ^b is independently H, OH, SH, NH ₂ , alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, alkoxy, alkylamino, hydroxyalkylamino, halogen, aryl or heteroaryl;

R ^c is independently H, OH, SH, NR ^{4 ′} OR ^{5 ′} , NH ₂ , alkylamino, hydroxyalkylamino, halogen, CONR ^d R ^e , alkoxy, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, Haloalkyloxy, aryl or heteroaryl;

R ^d is H, halogen, alkyl, -C (NR ⁷ ) NR ^{7 '} R ⁸ ,-(CH ₂ ) _p aryl, -(CH ₂ ) _p NR ⁷ R ⁸ , -C (O) NR ⁷ R ⁸ , -N = CR ⁷ R ⁸ , -NR ⁷ C (O) R ⁸ , cycloalkyl, haloalkyl, hydroxyalkyl, hydroxide Oxyalkylamino, alkylamino, heteroaryl or aryl;

R ⁷ , R ^{7 ′} are independently H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;

R ⁸ is H, NH ₂ , alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;

R ^e is independently H, —CN, —OH, —SH, —CO ₂ R ^{4 ′} , —C (O) R ^{4 ′} , —SO ₂ NR ^{4 ′} , —NR ^{4 ′} R ^{5 ′} , —C ( O) NR ⁷ R ⁸ , -SO ₂ -alkyl, -SO ₂ R ^{4 '} , -SO ₃ R ^4' , -N = CR ^{4 '} R ^5' , -NR ^{4 '} C (O) R ^{4 "} ,- NR ^{4 '} -CO-haloalkyl, -NO ₂ , -NR ^4' -SO ₂ -haloalkyl, -NR ^{4 '} -SO ₂ -alkyl, -NR ^4' -CO-alkyl, -NR ^{4 '} (CH ₂ ) _p heteroaryl, alkyl, hydroxyalkyl, cycloalkyl, alkylamino, hydroxyalkylamino, alkoxy, alkylthio, -O (CH ₂ ) _p [O (CH ₂ ) _p ] _q OCH ₃ , -C (NR ^{4 ”} ) NR ^{4 ′} -benzimidazolyl, —C (NR ^{4 ″} ) NR ^{4 ′} benzthiazolyl, —C (NR ^{4 ″} ) NR ^{4 ′} benzoxazolyl, aryl or heteroaryl;

R ² is independently

Wherein A is N, O or CR ^{2 '} ;

R ⁵ is independently H, SOR ⁷ , SO ₂ R ⁷ , SO ₃ R ⁷ , -C (O) R ⁷ , -C (O) CHR ⁷ R ⁸ , -C (O) NR ⁷ R ⁸ , -C (O) OR ⁷ , -R ⁷ C (O) R ⁸ , -C (S) R ⁷ , -C (NR ⁷ ) NR ^{7 '} R ⁸ ,-(CH ₂ ) _p aryl,-(CH ₂ ) _p NR ⁷ R ⁸ , -C (O) NR ⁷ R ⁸ , -N = CR ⁷ R ⁸ , -NR ⁷ C (O) R ^{7 '} , alkyl, cycloalkyl, alkoxy, -NH ₂ , alkylamino, hydroxy Alkyl amino, halogen, -OH, -SH, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl;

n is 0 to 2;

Here, unless stated otherwise, an alkyl group is straight or branched chain, straight or branched chain, straight chain or branched chain of C ₁ -C ₆ alkyl, preferably 1 to 5 carbon atoms, which may be optionally substituted with one or more substituents R ′. Branched C ₂ -C ₆ alkenyl, or straight or branched C ₂ -C ₆ alkynyl groups;

C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl and C ₂ -C ₆ alkynyl residues may be selected from the group consisting of:

R 'is independently H, -CO ₂ R ", -CONHR", -CR "O, -SO ₂ NR", -NR "-CO-haloalkyl, -NO ₂ , -NR" -SO ₂ -haloalkyl , -NR "-SO ₂ -alkyl, -SO ₂ -alkyl, -NR" -CO-alkyl, -CN, alkyl, cycloalkyl, alkylamino, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl, Hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl or heteroaryl;

R ″ is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl or heteroaryl;

Cycloalkyl groups represent non-aromatic ring systems containing 3 to 8 carbon atoms, preferably 4 to 8 carbon atoms, wherein one or more carbon atoms in the ring may be substituted by the group E, where E is O , S, SO, SO ₂ , N or NR ″, R ″ is as defined above; C ₃ -C ₈ cycloalkyl moieties include -cyclo-C ₃ H ₅ , -cyclo-C ₄ H ₇ , -cyclo-C ₅ H ₉ , -cyclo-C ₆ H ₁₁ , -cyclo-C ₇ H ₁₃ ,- May be selected from the group consisting of cyclo-C ₈ H ₁₅ , morpholin-4-yl, piperazinyl, 1-alkylpiperazin-4-yl;

The alkoxy group represents an O-alkyl group and the alkyl group is as defined above; The alkoxy group is preferably a methoxy, ethoxy, isopropoxy, t-butoxy or pentoxy group;

The alkylthio group represents an S-alkyl group, wherein the alkyl group is as defined above;

Haloalkyl group represents an alkyl group substituted with 1 to 5 halogen atoms, the alkyl group being as defined above; The haloalkyl group is preferably -C (R ¹⁰ ) ₃ , -CR ¹⁰ (R ^{10 '} ) ₂ , -CR ¹⁰ (R ^10' ) R ^{10 "} , -C ₂ (R ¹⁰ ) ₅ , -CH ₂ -C (R ¹⁰ ) ₃ , -CH ₂ -CR ¹⁰ (R ^{10 '} ) ₂ , -CH ₂ -CR ¹⁰ (R ^10' ) R ^{10 "} , -C ₃ (R ¹⁰ ) ₇ or -C ₂ H ₄ -C (R ¹⁰ ) ₃ , wherein R ¹⁰ , R ^{10 ′} , R ^{10 ″} is F, Cl, Br or I, preferably F;

A hydroxyalkyl group represents a HO-alkyl group, wherein the alkyl group is as defined above;

Haloalkyloxy group represents an alkoxy group substituted with 1 to 5 halogen atoms, the alkyl group being as defined above; The haloalkyloxy group is preferably -OC (R ¹⁰ ) ₃ , -OCR ¹⁰ (R ^{10 '} ) ₂ , -OCR ¹⁰ (R ^10' ) R ^{10 "} , -OC ₂ (R ¹⁰ ) ₅ , -OCH _2- C (R ¹⁰ ) ₃ , -OCH ₂ -CR ¹⁰ (R ^{10 '} ) ₂ , -OCH ₂ -CR ¹⁰ (R ^10' ) R ^{10 "} , -OC ₃ (R ¹⁰ ) ₇ or -OC ₂ H _4- C (R ¹⁰ ) ₃ , wherein R ¹⁰ , R ^{10 ′} , R ^{10 ″} is F, Cl, Br or I, preferably F;

Hydroxyalkylamino group represents a (HO-alkyl) ₂ -N- group or a HO-alkyl-NH- group, wherein the alkyl group is as defined above;

The alkylamino group represents an HN-alkyl or N-dialkyl group, wherein the alkyl group is as defined above;

Halogen groups are chlorine, bromine, fluorine or iodine;

An aryl group represents an aromatic group having 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 a benzyl group, a phenyl group, -oC ₆ H ₄ -R ', -mC ₆ H ₄ -R', -pC ₆ H ₄ -R ', 1-naphthyl, 2-naphthyl, 1-anthra Cenyl or 2-anthracenyl;

Heteroaryl groups represent 5- or 6-membered heterocyclic groups containing one or more heteroatoms selected from O, N and S. This heterocyclic group may be fused to another aromatic ring. For example, this group is thiadiazole, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazole -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, benzoisoxazol-3-yl, benzoisoxazol-4-yl, benzoisoxazol-5-yl, 1, 2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazole- 4-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothia Zol-5-yl, benzoisothiazol-3-yl, benzoisothiazol-4-yl, benzoisothiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1-im Dazolyl, 2-imidazolyl, 1,2,5-thiadiazol-4-yl, 4-imidazolyl, benzoimidazol-4-yl, 1-pyrrolyl, 2-pyrrolyl, 3-py Rollyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl , 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyranyl, 3-pyranyl, 4-pyranyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6 -Pyrimidinyl, 2,4-dimethoxy-6-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazole-5- 1,3,5-triazol-6-yl, 2,4-dimethoxy-1,3,5-triazol-6-yl, 1H-tetrazol-2-yl, 1H-tetrazol-3 -Yl, tetrazolyl, acridil, furazane, indazolyl, phenazinyl, carbazolyl, phenoxazinyl, indolizine, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 1-isoindoleyl, 3-isoindolyl, 4-isoindolyl, 5-isoindolyl, 6-isoindolyl, 7-isoindolyl, 2-indolynyl , 3-indolinyl, 4-indolinyl, 5-indolinyl, 6-indolinyl, 7-indolinyl, benzo [b] furanyl, benzofurazane, benzothiofurazane, benzotriazole-1- 1, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl, benzotriazol-7-yl, benzotriazine, benzo [b] thiophenyl, benzimidazole-2 -Yl, 1H-benzimidazolyl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl, benzimidazol-7-yl, benzothiazolyl, quinazolinyl, Quinoxazolinyl, cinnoline, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, purine, phthalazine, pteridine, thiatetrazaindene, thiatriazindene , Isothiazolopyrazine, isothiazolopyrimidine, pyrazolotriazine, pyrazolopyrimidine, tetrahydrothieno [3,4-d] imidazol-2-one, pyrazolo [5,1-c] [ 1,2,4] triazine, imidazopyridazine, imidazopyrimidine, imidazopyridine, imidazolotriazine, triazolotriazine, 2,3-dihydrobenzo [1,4] -dioxin 2-yl, 2,3-dihydrobenzo [1,4] -dioxin-3-yl , 2,3-dihydrobenzo [1,4] -dioxin-5-yl, 2,3-dihydrobenzo [1,4] -dioxin-6-yl, 2,6-dimethoxypyrimidine -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] pyridine- 3-yl and triazolopyridazine groups. Such heterocyclic groups may be substituted with one or more substituents R ', wherein R' is as defined above.

The present invention relates to compounds of formula (Ic), or acids or bases and pharmaceutically acceptable salts thereof, or pharmaceutically acceptable prodrugs or stereoisomers thereof.

Where

R ¹ is independently H, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl;

X is CO, CS or SO ₂ ;

Y is CO, CS or SO ₂ ;

Z is NR ^{2 ″} , S or O;

R ^{2 ''} is H, alkyl, -C (O) NR ⁷ , -C (O) R ^e , cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;

R ^{4 '} , R ^{4 "} , R ^5' are independently H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, -C (NR ⁷ ) NR ^{7 '} R ⁸ ,-( CH ₂ ) _p aryl,-(CH ₂ ) _p NR ⁷ R ⁸ , -C (O) NR ⁷ R ⁸ , -N = CR ⁷ R ⁸ , -NR ⁷ C (O) R ⁸ , halogen, 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 ^b is independently H, OH, SH, NR ^{4 ′} OR ^{5 ′} , NH ₂ , alkylamino, hydroxyalkylamino, halogen, CONR ^d R ^e , alkoxy, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, Haloalkyloxy, aryl or heteroaryl;

R ^c is independently H, OH, SH, NR ^{4 ′} OR ^{5 ′} , NH ₂ , alkylamino, hydroxyalkylamino, halogen, CONR ^d R ^e , alkoxy, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, Haloalkyloxy, aryl or heteroaryl;

R ^d is H, halogen, alkyl, -C (NR ⁷ ) NR ^{7 '} R ⁸ ,-(CH ₂ ) _p aryl, -(CH ₂ ) _p NR ⁷ R ⁸ , -C (O) NR ⁷ R ⁸ , -N = CR ⁷ R ⁸ , -NR ⁷ C (O) R ⁸ , cycloalkyl, haloalkyl, hydroxyalkyl, hydroxide Oxyalkylamino, alkylamino, heteroaryl or aryl;

R ⁷ , R ^{7 ′} are independently H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;

R ⁸ is H, NH ₂ , alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;

R ^e is independently H, —CN, —OH, —SH, —CO ₂ R ^{4 ′} , —C (O) R ^{4 ′} , —SO ₂ NR ^{4 ′} , —NR ^{4 ′} R ^{5 ′} , —C ( O) NR ⁷ R ⁸ , -SO ₂ -alkyl, -SO ₂ R ^{4 '} , SO ₃ R ^4' , -N = CR ^{4 '} R ^5' , -NR ^{4 '} C (O) R ^{4 "} , -NR ^{4 '-CO- _{haloalkyl, -NO 2, -NR 4' -SO}} 2 - haloalkyl, -NR ^{4 '-SO} ₂ - alkyl, -NR ^4' -CO- alkyl, -NR ^{4 '(CH} _{2) p} heteroaryl, alkyl, hydroxyalkyl, cycloalkyl, alkylamino, hydroxyalkylamino, alkoxy, alkylthio, -O (CH ₂ ) _p [O (CH ₂ ) _p ] _q OCH ₃ , -C (NR ^{4 ”} ) NR ^{4 ′} -benzimidazolyl, —C (NR ^{4 ″} ) NR ^{4 ′} benzthiazolyl, —C (NR ^{4 ″} ) NR ^{4 ′} benzoxazolyl, aryl or heteroaryl;

R ³ is independently H, OH, SH, NR ^{4 ′} OR ^{5 ′} , NH ₂ , hydroxyalkylamino, alkylamino, halogen, CONR ^d R ^e , alkoxy, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, Haloalkyloxy, aryl or heteroaryl;

Unless stated otherwise, an alkyl group is straight or branched chain C ₁ -C ₆ alkyl which may be optionally substituted with one or more substituents R ′, preferably straight or branched chain, straight chain or branched chain C of 1 to 5 carbon atoms. ₂ -C ₆ alkenyl, or a straight or branched C ₂ -C ₆ alkynyl group;

C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl and C ₂ -C ₆ alkynyl moieties may be selected from the group consisting of:

R 'is independently H, -CO ₂ R ", -CONHR", -CR "O, -SO ₂ NR", -NR "-CO-haloalkyl, -NO ₂ , -NR" -SO ₂ -haloalkyl , -NR "-SO ₂ -alkyl, -SO ₂ -alkyl, -NR" -CO-alkyl, -CN, alkyl, cycloalkyl, alkylamino, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl, Hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl or heteroaryl;

R ″ is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl or heteroaryl;

Cycloalkyl groups represent non-aromatic ring systems containing 3 to 8 carbon atoms, preferably 4 to 8 carbon atoms, wherein one or more carbon atoms in the ring may be substituted by the group E, where E is O , S, SO, SO ₂ , N or NR ″, R ″ is as defined above; C ₃ -C ₈ -cycloalkyl moieties include -cyclo-C ₃ H ₅ , -cyclo-C ₄ H ₇ , -cyclo-C ₅ H ₉ , -cyclo-C ₆ H ₁₁ , -cyclo-C ₇ H ₁₃ , -Cyclo-C ₈ H ₁₅ , morpholin-4-yl, piperazinyl, 1-alkylpiperazin-4-yl;

The alkoxy group represents an O-alkyl group and the alkyl group is as defined above; The alkoxy group is preferably a methoxy, ethoxy, isopropoxy, t-butoxy or pentoxy group;

The alkylthio group represents an S-alkyl group, wherein the alkyl group is as defined above;

Haloalkyl group represents an alkyl group substituted with 1 to 5 halogen atoms, the alkyl group being as defined above; The haloalkyl group is preferably -C (R ¹⁰ ) ₃ , -CR ¹⁰ (R ^{10 '} ) ₂ , -CR ¹⁰ (R ^10' ) R ^{10 "} , -C ₂ (R ¹⁰ ) ₅ , -CH ₂ -C (R ¹⁰ ) ₃ , -CH ₂ -CR ¹⁰ (R ^{10 '} ) ₂ , -CH ₂ -CR ¹⁰ (R ^10' ) R ^{10 "} , -C ₃ (R ¹⁰ ) ₇ or -C ₂ H ₄ -C (R ¹⁰ ) ₃ , wherein R ¹⁰ , R ^{10 ′} , R ^{10 ″} is F, Cl, Br or I, preferably F;

A hydroxyalkyl group represents a HO-alkyl group, wherein the alkyl group is as defined above;

Haloalkyloxy group represents an alkoxy group substituted with 1 to 5 halogen atoms, the alkyl group being as defined above; The haloalkyloxy group is preferably -OC (R ¹⁰ ) ₃ , -OCR ¹⁰ (R ^{10 '} ) ₂ , -OCR ¹⁰ (R ^10' ) R ^{10 "} , -OC ₂ (R ¹⁰ ) ₅ , -OCH _2- C (R ¹⁰ ) ₃ , -OCH ₂ -CR ¹⁰ (R ^{10 '} ) ₂ , -OCH ₂ -CR ¹⁰ (R ^10' ) R ^{10 "} , -OC ₃ (R ¹⁰ ) ₇ or -OC ₂ H _4- C (R ¹⁰ ) ₃ , wherein R ¹⁰ , R ^{10 ′} , R ^{10 ″} is F, Cl, Br or I, preferably F;

Hydroxyalkylamino group represents a (HO-alkyl) ₂ -N- group or a HO-alkyl-NH- group, wherein the alkyl group is as defined above;

The alkylamino group represents an HN-alkyl or N-dialkyl group, wherein the alkyl group is as defined above;

Halogen groups are chlorine, bromine, fluorine or iodine;

An aryl group represents an aromatic group having 5 to 15 carbon atoms which may be substituted with one or more substituents R ', wherein R' is as defined above; The aryl group is preferably a benzyl group, a phenyl group, -oC ₆ H ₄ -R ', -mC ₆ H ₄ -R', -pC ₆ H ₄ -R ', 1-naphthyl, 2-naphthyl, 1-anthra Cenyl or 2-anthracenyl;

Heteroaryl groups represent 5- or 6-membered heterocyclic groups containing one or more heteroatoms selected from O, N and S. This heterocyclic group may be fused to another aromatic ring. For example, this group is thiadiazole, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazole -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, benzoisoxazol-3-yl, benzoisoxazol-4-yl, benzoisoxazol-5-yl, 1, 2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazole- 4-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothia Sol-5-yl, benzoisothiazol-3-yl, benzoisothiazol-4-yl, benzoisothiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1-im Dazolyl, 2-imidazolyl, 1,2,5-thiadiazol-4-yl, 4-imidazolyl, benzoimidazol-4-yl, 1-pyrrolyl, 2-pyrrolyl, 3-py Rollyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl , 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyranyl, 3-pyranyl, 4-pyranyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6 -Pyrimidinyl, 2,4-dimethoxy-6-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazole-5- 1,3,5-triazol-6-yl, 2,4-dimethoxy-1,3,5-triazol-6-yl, 1H-tetrazol-2-yl, 1H-tetrazol-3 -Yl, tetrazolyl, acridil, furazane, indazolyl, phenazinyl, carbazolyl, phenoxazinyl, indolizine, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 1-isoindoleyl, 3-isoindolyl, 4-isoindolyl, 5-isoindolyl, 6-isoindolyl, 7-isoindolyl, 2-indolynyl , 3-indolinyl, 4-indolinyl, 5-indolinyl, 6-indolinyl, 7-indolinyl, benzo [b] furanyl, benzofurazane, benzothiofurazane, benzotriazole-1- 1, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl, benzotriazol-7-yl, benzotriazine, benzo [b] thiophenyl, benzimidazole-2 -Yl, 1H-benzimidazolyl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl, benzimidazol-7-yl, benzothiazolyl, quinazolinyl, Quinoxazolinyl, cinnoline, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydrothieno [3,4-d] imidazol-2-one, pyrazolo [5,1-c] [1,2,4] triazine, tetrahydroisoquinolinyl, purine, phthalazine, pteridine, tiatetrazaindene, titiazaindene, isothiazolopyrazine, isothiazolopyrimidine, pyrazin Zolotriazine, pyrazolopyrimidine, imidazopyridazine, imidazopyrimidine, imidazopyridine, imidazotriazine, triazolotriazine, triazolopyridine, triazolopyrazine, triazolopyrimidine, 2, 3- Hydrobenzo [1,4] -dioxin-2-yl, 2,3-dihydrobenzo [1,4] -dioxin-3-yl, 2,3-dihydrobenzo [1,4] -dioxine -5-yl, 2,3-dihydrobenzo [1,4] -dioxin-6-yl, 2,6-dimethoxypyrimidin-3-yl, 2,6-dimethoxypyrimidine-4 -Yl, 4- [1,2,4] triazolo [4,3-a] pyridin-3-yl, 1-furo [2,3-c] pyridin-4-yl, 1-furo [2,3 -c] pyridin-5-yl, 1-furo [2,3-c] pyridin-3-yl and triazolopyridazine groups. Such heterocyclic groups may be substituted with one or more substituents R ', wherein R' is as defined above.

The present invention relates to a compound of formula III, or a pharmaceutically acceptable salt thereof with an acid or base, or a pharmaceutically acceptable prodrug or stereoisomer thereof.

Where

R ¹ is —C (O) R ^7a , -C (O) CHR ⁷ R ⁸ , -C (O) NR ⁷ R ⁸ , -C (O) OR ⁷ , -R ⁷ C (O) R ⁸ or- C (S) R ^7b ;

R ² is H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino or heteroaryl, or

R ¹ and R ² together with the N- 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 carbon atom in the ring is O, A heteroatom selected from N and S, said ring may be substituted with one or more R ⁹ ;

R ^4a is H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, —C (NR ⁷ ) NR ^{7 ′} R ⁸ , -(CH ₂ ) _p aryl,-(CH ₂ ) _p NR ⁷ R ⁸ , -C (O) NR ⁷ R ⁸ , -N = CR ⁷ R ⁸ , -NR ⁷ C (O) R ⁸ , halogen, hetero Aryl or aryl;

R ³ is H, —C (O) NR ^a R ^b , halogen, alkyl, haloalkyl, aryl, heteroaryl, OH, SH, NR ^{4 ′} OR ^{5 '} , NH ₂ , hydroxyalkylamino, alkylamino, alkoxy , Cycloalkyl, heterocycloalkyl, hydroxyalkyl or haloalkyloxy;

R ⁴ is H, OH, SH, NH ₂ , alkoxy, haloalkyloxy, halogen, alkyl, -C (NR ⁷ ) NR ^{7 ′} R ⁸ ,-(CH ₂ ) _p aryl,-(CH ₂ ) _p NR ⁷ R ⁸ , -C (O) NR ⁷ R ⁸ , -N = CR ⁷ R ⁸ , -NR ⁷ C (O) R ⁸ , cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, Alkylamino, heteroaryl or aryl;

R ⁵ is halogen, alkyl, -C (NR ⁷ ) NR ^{7 '} R ⁸ ,-(CH ₂ ) _p aryl,-(CH ₂ ) _p NR ⁷ R ⁸ , -C (O) NR ⁷ R ⁸ , -N = CR ⁷ R ⁸ , -NR ⁷ C (O) R ⁸ , cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;

R ^a is H, halogen, alkyl, -C (NR ⁷ ) NR ^{7 '} R ⁸ ,-(CH ₂ ) _p aryl,-(CH ₂ ) _p NR ⁷ R ⁸ , -C (O) NR ⁷ R ⁸ , -N = CR ⁷ R ⁸ , -NR ⁷ C (O) R ⁸ , cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;

R ^b is independently H, —CN, —OH, —SH, —CO ₂ R ^{4 ′} , —C (O) R ^{4 ′} , —SO ₂ NR ^{4 ′} , —NR ^{4 ′} R ^{5 ′} , —C ( O) NR ⁷ R ⁸ , -SO ₂ -alkyl, -SO ₂ R ^{4 '} , SO ₃ R ^4' , -N = CR ^{4 '} R ^5' , -NR ^{4 '} C (O) R ^{4 "} , -NR ^{4 '-CO- _{haloalkyl, -NO 2, -NR 4' -SO}} 2 - haloalkyl, -NR ^{4 '-SO} ₂ - alkyl, -NR ^4' -CO- alkyl, -NR ^{4 '(CH} _{2) p} heteroaryl, alkyl, cycloalkyl, alkylamino, alkoxy, alkylthio, halogen, haloalkyl, haloalkyloxy, -O (CH ₂ ) _p [O (CH ₂ ) _p ] _q OCH ₃ , -C (NR ^{4 "} ) NR ^{4 '} benzimidazolyl, -C (NR ^4" ) NR ^4' benzthiazolyl, -C (NR ^{4 "} ) NR ^{4 '} benzoxazolyl, hydroxyalkyl, hydroxycycloalkyl, hydroxyalkyl Amino, heterocycloalkyl, aryl or heteroaryl;

R ^{4 '} , R ^{4 "} , R ^5' are independently H, halogen, alkyl, -C (NR ⁷ ) NR ^{7 '} R ⁸ ,-(CH ₂ ) _p aryl, haloalkyl,-(CH ₂ ) _p NR ⁷ R ⁸ , -C (O) NR ⁷ R ⁸ , -N = CR ⁷ R ⁸ , -NR ⁷ C (O) R ⁸ , cycloalkyl, heterocycloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino , Heteroaryl or aryl;

R ⁷ , R ^{7 ′} , R ⁸ are independently H, halogen, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, arylamino, heteroaryl or aryl;

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

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

A is CO or SO ₂ ;

X is NR ^{2 '} , O or S;

Z is N or CR ^{2 '} ;

R ^{2 ′} is H, alkyl, —C (O) NR ⁷ , —C (O) R ^b , cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl ego;

p is 1 to 6;

q is 1 to 6;

R ⁹ is independently H, —CN, —OH, —SH, alkoxy, alkylthio, —CO ₂ R ^{4 ′} , —C (O) R ^4a , —C (O) NR ⁷ R ⁸ , -SO ₂ NR ^{4 '} , -NR ^4' R ^{5 '} , -SO ₂ -alkyl, -SO ₂ R ^4' , SO ₃ R ^{4 '} , -N = CR ^4' R ^{5 '} , -NR ^4' C (O) R ^{4 "} , -NR ^{4 '} -CO-haloalkyl, -NO ₂ , -NR ^4' -SO ₂ -haloalkyl, -NR ^{4 '} -SO ₂ -alkyl, -NR ^4' -CO-alkyl, -NR ^{4 '} (CH ₂ ) _p heteroaryl, alkyl, hydroxyalkyl, cycloalkyl, halogen, haloalkyl, alkylamino, -O (CH ₂ ) _p [O (CH ₂ ) _p ] _q OCH ₃ , -C (NR ^{4 "} ) NR ^{4 '} benzimidazolyl, -C (NR ^{4 "} ) NR ^4' benzthiazolyl, -C (NR ⁴ ) NR ^{4 '} benzoxazolyl, hydroxycycloalkyl, hydroxyalkylamino, haloalkyloxy, Heterocycloalkyl,-(CH ₂ ) _p NR ⁷ COR ⁸ , aryl or heteroaryl;

From here

C ₁ -C ₆ alkyl groups, unless stated otherwise, represent straight or branched chain C ₁ -C ₆ alkyl, preferably 1 to 5 carbon atoms, which may be optionally substituted with one or more substituents R ′. Represent;

C ₂ -C ₆ alkenyl groups, unless stated otherwise, are straight or branched C ₂ -C ₆ alkenyl, preferably 2 to 6 carbon atoms, optionally substituted with one or more substituents R ′. Represent chains;

Alkyl groups are straight or branched, straight or branched, straight or branched chain C ₁ -C ₆ alkyl, preferably 1 to 6 carbon atoms, which may be optionally substituted with one or more substituents R ', unless stated otherwise. ₂ -C ₆ alkenyl, or a straight or branched C ₂ -C ₆ alkynyl group;

R 'is independently H, -CO ₂ R ", -CONHR", -CR "O, -SO ₂ NR", -NR "-CO-haloalkyl, -NO ₂ , -NR" -SO ₂ -haloalkyl , -NR "-SO ₂ -alkyl, -SO ₂ -alkyl, -NR" -CO-alkyl, -CN, alkyl, cycloalkyl, alkylamino, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl, Hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl or heteroaryl;

R ″ is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl or heteroaryl;

Cycloalkyl groups represent non-aromatic ring systems containing 3 to 8 carbon atoms, preferably 4 to 8 carbon atoms, wherein one or more carbon atoms in the ring may be substituted by the groups R 'as defined above There is; C ₃ -C ₈ cycloalkyl moieties include -cyclo-C ₃ H ₅ , -cyclo-C ₄ H ₇ , cyclo-C ₅ H ₉ , -cyclo-C ₆ H ₁₁ , -cyclo-C ₇ H ₁₃ , -cyclo May be selected from the group consisting of -C ₈ H ₁₅ ;

Heterocycloalkyl groups represent non-aromatic ring systems containing 2 to 10 carbon atoms and at least one heteroatom selected from O, N and S, wherein at least one carbon atom in the ring is defined by R 'as defined above. May be substituted; Preferred heterocycloalkyl groups are morpholin-4-yl, piperazinyl, 1-alkylpiperazin-4-yl, piperidinyl, pyrrolidinyl, azepan-1-yl;

The alkoxy group represents an O-alkyl group and the alkyl group is as defined above; The alkoxy group is preferably a methoxy, ethoxy, isopropoxy, t-butoxy or pentoxy group;

The alkylthio group represents an S-alkyl group, wherein the alkyl group is as defined above;

The haloalkyl group represents an alkyl group substituted with 1 to 5 halogen atoms, the alkyl group is as defined above, and the haloalkyl group is preferably -C (R ¹⁰ ) ₃ , -CR ¹⁰ (R ^{10 '} ) ₂ , -CR ¹⁰ (R ^{10 '} ) R ^{10 "} , -C ₂ (R ¹⁰ ) ₅ , -CH ₂ C (R ¹⁰ ) ₃ , -CH ₂ CR ¹⁰ (R ^10' ) ₂ , -CH ₂ CR ¹⁰ (R ^{10 '} ) R ^{10 "} , -C ₃ (R ¹⁰ ) ₇ or -C ₂ H ₄ C (R ¹⁰ ) ₃ , wherein R ¹⁰ , R ^{10 '} , R ^{10 "} is F, Cl, Br or I, preferably Is F;

A hydroxyalkyl group represents a HO-alkyl group, wherein the alkyl group is as defined above;

Haloalkyloxy group represents an alkoxy group substituted by 1 to 5 halogen atoms, the alkyl group being as defined above; The haloalkyloxy group is preferably -OC (R ¹⁰ ) ₃ , -OCR ¹⁰ (R ^{10 '} ) ₂ , -OCR ¹⁰ (R ^10' ) R ^{10 "} , -OC ₂ (R ¹⁰ ) ₅ , -OCH ₂ C (R ¹⁰ ) ₃ , -OCH ₂ CR ¹⁰ (R ^{10 '} ) ₂ , -OCH ₂ CR ¹⁰ (R ^10' ) R ^{10 "} , -OC ₃ (R ¹⁰ ) ₇ or -OC ₂ H ₄ C (R ¹⁰ ) ₃ , wherein R ¹⁰ , R ^{10 '} , R ^{10 "} represents F, Cl, Br or I, preferably F;

Hydroxyalkylamino group represents a (HO-alkyl) ₂ -N- group or a HO-alkyl-NH- group, wherein the alkyl group is as defined above;

The alkylamino group represents an HN-alkyl or N-dialkyl group, wherein the alkyl group is as defined above;

Halogen groups are fluorine, chlorine, bromine or iodine;

An aryl group represents an aromatic group having 5 to 15 carbon atoms which may be substituted with one or more substituents R ', wherein R' is as defined above; The aryl group is preferably a benzyl group, a phenyl group, -oC ₆ H ₄ -R ', -mC ₆ H ₄ -R', -pC ₆ H ₄ -R ', 1-naphthyl, 2-naphthyl, 1-anthra Cenyl or 2-anthracenyl, and R 'is as defined above;

The arylamino group is an HN-aryl or N-diaryl group and the aryl group is as defined above;

Heteroaryl groups represent 5- or 6-membered heterocyclic groups containing one or more heteroatoms selected from O, N and S. Such heterocyclic groups can be fused to other aromatic rings. For example, such groups are thiadiazole, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazole -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, benzoisoxazol-3-yl, benzoisoxazol-4-yl, benzoisoxazol-5-yl, 1, 2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazole- 4-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothia Sol-5-yl, benzoisothiazol-3-yl, benzoisothiazol-4-yl, benzoisothiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1-im Dazolyl, 2-imidazolyl, 1,2,5-thiadiazol-4-yl, 4-imidazolyl, benzoimidazol-4-yl, 1-pyrrolyl, 2-pyrrolyl, 3-py Rollyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-ti Nilyl, 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-triazole-5 -Yl, 1,3,5-triazol-6-yl, 2,4-dimethoxy-1,3,5-triazol-6-yl, 1H-tetrazol-2-yl, 1H-tetrazol- 3-yl, tetrazolyl, acridil, furazane, indazolyl, phenazinyl, carbazolyl, phenoxazinyl, indolizine, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl , 6-indolyl, 7-indolyl, 1-isoindoleyl, 3-isoindolyl, 4-isoindolyl, 5-isoindolyl, 6-isoindolyl, 7-isoindoleyl, 2-indole Linyl, 3-indolinyl, 4-indolinyl, 5-indolinyl, 6-indolinyl, 7-indolinyl, benzo [b] furanyl, benzofurazane, benzothiofurazane, benzotria Zol-1-yl, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl, benzotriazol-7-yl, benzotriazine, benzo [b] thiophenyl, benz Imidazol-2-yl, 1H-benzimidazolyl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl, benzimidazol-7-yl, benzothiazolyl, Quinazolinyl, quinoxazolinyl, cinnoline, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, 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] -dioxine- 3-yl, 2,3-dihydrobenzo [1,4] -dioxin-5-yl, 2,3-dihydrobenzo [1,4] -dioxin-6-yl, 2,6-dimethok Cypyrimidin-3-yl, 2,6-dimethoxypyrimidin-4-yl, tetrahydroisoquinolinyl, purine, phthalazine, pteridine, tiatetraazaindene, thiatriazindene, Isothiazolopyrazine, Isothiazolopyrimidine, Pyrazolot Azine, pyrazolopyrimidine, imidazopyridazine, imidazopyrimidine, imidazopyridine, imidazolotriazine, triazolotriazine, triazolopyridine, triazolopyrazine, triazolopyrimidine, 4- [1 , 2,4] triazolo [4,3-a] pyridin-3-yl, 1-furo [2,3-c] pyridin-4-yl, 1-furo [2,3-c] pyridine-5- One, 1-furo [2,3-c] pyridin-3-yl and triazolopyridazine groups. Such heterocyclic groups may be substituted with one or more substituents R ', wherein R' is as defined above;

Provided that the following compounds are excluded from Formula Ih:

Where

R ¹ independently represents hydrogen, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl or substituted arylalkyl;

또는

를 나타내고;R ² is independently —NR ³ R ⁴ ,

or

Represents;

R ³ independently represents alkyl, cycloalkyl, alkoxy, alkylamine, -OH, -SH, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl;

R ⁴ independently represents alkyl, cycloalkyl, alkoxy, alkylamine, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl;

R ⁵ is independently H, COR ⁶ , CO ₂ R ⁶ , SOR ⁶ , SO ₂ R ⁶ , SO ₃ R ⁶ , alkyl, cycloalkyl, alkoxy, -NH ₂ , alkylamine, -NR ⁷ COR ⁶ , halogen , -OH, -SH, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl;

R ⁶ independently represents H, alkyl, cycloalkyl, —NH ₂ , alkylamine, aryl or heteroaryl;

R ⁷ independently represents H, alkyl, cycloalkyl, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl, aryl or heteroaryl;

p is 0 or 1;

q is 0 or 1;

X is CO or SO ₂ .

The present invention relates to compounds of formula (Ih), or acids or bases and pharmaceutically acceptable salts thereof, or pharmaceutically acceptable prodrugs or stereoisomers thereof.

Where

A is NR ^{2 '} , S or O;

t is 0 to 4;

r is 0 or 1;

R ^2a is independently H, OH, SH, NH ₂ , alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, alkoxy, alkylamino, hydroxyalkylamino, halogen, aryl or heteroaryl;

R ^3a is H, OH, SH, NH ₂ , -C (NR ⁷ ) NR ^{7 ′} R ⁸ ,-(CH ₂ ) _p aryl,-(CH ₂ ) _p NR ⁷ R ⁸ , -C (O) NR ⁷ R ⁸ , -N = CR ⁷ R ⁸ , -NR ⁷ C (O) R ⁸ , alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, alkoxy, alkylamino, hydroxyalkylamino, halogen, aryl Or heteroaryl;

R ^d is H, halogen, alkyl, -C (NR ⁷ ) NR ^{7 '} R ⁸ ,-(CH ₂ ) _p aryl,-(CH ₂ ) _p NR ⁷ R ⁸ , -C (O) NR ⁷ R ⁸ , -N = CR ⁷ R ⁸ , -NR ⁷ C (O) R ⁸ , cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;

R ¹ is —C (O) R ^7a , -C (O) CHR ⁷ R ⁸ , -C (O) NR ⁷ R ⁸ , -C (O) OR ⁷ , -R ⁷ C (O) R ⁸ or- C (S) R ^7b ;

R ² is H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino or heteroaryl, or

Or R ¹ and R ² together with the N- 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 carbon atom in the ring Is a heteroatom selected from O, N and S, said ring may be substituted with one or more R ⁹ ;

R ^4a is H, C ₁ -C ₆ alkyl, C ₂ -C ₆ -alkenyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, —C (NR ⁷ ) NR ^{7 ′} R ⁸ ,-(CH ₂ ) _p aryl,-(CH ₂ ) _p NR ⁷ R ⁸ , -C (O) NR ⁷ R ⁸ , -N = CR ⁷ R ⁸ , -NR ⁷ C (O) R ⁸ , halogen, Heteroaryl or aryl;

R ³ is H, —C (O) NR ^a R ^b , halogen, alkyl, haloalkyl, aryl, heteroaryl, OH, SH, NR ^{4 ′} OR ^{5 '} , NH ₂ , hydroxyalkylamino, alkylamino, alkoxy , Cycloalkyl, heterocycloalkyl, hydroxyalkyl or haloalkyloxy;

R ^a is H, halogen, alkyl, -C (NR ⁷ ) NR ^{7 '} R ⁸ ,-(CH ₂ ) _p aryl,-(CH ₂ ) _p NR ⁷ R ⁸ , -C (O) NR ⁷ R ⁸ , -N = CR ⁷ R ⁸ , -NR ⁷ C (O) R ⁸ , cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;

R ^b is independently H, —CN —OH, —SH, —CO ₂ R ^{4 ′} , —C (O) R ^{4 ′} , —SO ₂ NR ^{4 ′} , —NR ^{4 ′} R ^{5 ′} , —C (O ) NR ⁷ R ⁸ , -SO ₂ -alkyl, -SO ₂ R ^{4 '} , SO ₃ R ^4' , -N = CR ^{4 '} R ^5' , -NR ^{4 '} C (O) R ^{4 "} , -NR ^{4 '} -CO-haloalkyl, -NO ₂ , -NR ^4' -SO ₂ -haloalkyl, -NR ^{4 '} -SO ₂ -alkyl, -NR ^4' -CO-alkyl, -NR ^{4 '} (CH ₂ ) _p Heteroaryl, alkyl, cycloalkyl, alkylamino, alkoxy, alkylthio, halogen, haloalkyl, haloalkyloxy, -O (CH ₂ ) _p [O (CH ₂ ) _p ] _q OCH ₃ , -C (NR ^{4 "} ) NR ^{4 '} benzimidazolyl, -C (NR ^{4 "} ) NR ^4' benzthiazolyl, -C (NR ^4" ) NR ^{4 '} benzoxazolyl, hydroxyalkyl, hydroxycycloalkyl, hydroxyalkylamino , Heterocycloalkyl, aryl or heteroaryl;

R ^{4 '} , R ^{4 "} , R ^5' are independently H, halogen, alkyl, -C (NR ⁷ ) NR ^{7 '} R ⁸ ,-(CH ₂ ) _p aryl, haloalkyl,-(CH ₂ ) _p NR ⁷ R ⁸ , -C (O) NR ⁷ R ⁸ , -N = CR ⁷ R ⁸ , -NR ⁷ C (O) R ⁸ , cycloalkyl, heterocycloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino , Heteroaryl or aryl;

R ⁷ , R ^{7 ′} , R ⁸ are independently H, halogen, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, arylamino, heteroaryl or aryl;

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

R ^7b is H, halogen, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxy alkyl, hydroxyalkylamino, heteroaryl or aryl;

X is NR ^{2 '} , O or S;

Z is N or CR ^{2 '} ;

R ^{2 ′} is H, alkyl, —C (O) NR ⁷ , —C (O) R ^b , cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl ego;

p is 1 to 6;

q is 1 to 6;

R ⁹ is independently H, —CN, —OH, —SH, alkoxy, alkylthio, —CO ₂ R ^{4 ′} , —C (O) R ^4a , —C (O) NR ⁷ R ⁸ , -SO ₂ NR ^{4 '} , -NR ^4' R ^{5 '} , -SO ₂ -alkyl, -SO ₂ R ^4' , SO ₃ R ^{4 '} , -N = CR ^4' R ^{5 '} , -NR ^4' C (O) R ^{4 "} , -NR ^{4 '} -CO-haloalkyl, -NO ₂ , -NR ^4' -SO ₂ -haloalkyl, -NR ^{4 '} -SO ₂ -alkyl, -NR ^4' -CO-alkyl, -NR ^{4 '} (CH ₂ ) _p heteroaryl, alkyl, hydroxyalkyl, cycloalkyl, halogen, haloalkyl, alkylamino, -O (CH ₂ ) _p [O (CH ₂ ) _p ] _q OCH ₃ , -C (NR ^{4 "} ) NR ^{4 '} benzimidazolyl, -C (NR ^{4 "} ) NR ^4' benzthiazolyl, -C (NR ^4" ) NR ^{4 '} benzoxazolyl, hydroxycycloalkyl, hydroxyalkylamino, haloalkyloxy , Heterocycloalkyl,-(CH ₂ ) _p NR ⁷ COR ⁸ , aryl or heteroaryl;

From here

C ₁ -C ₆ alkyl groups, unless stated otherwise, represent straight or branched chain C ₁ -C ₆ alkyl, preferably 1 to 5 carbon atoms, which may be optionally substituted with one or more substituents R ′. Represent;

C ₂ -C ₆ alkenyl groups, unless stated otherwise, are straight or branched C ₂ -C ₆ alkenyl, preferably 2 to 6 carbon atoms, optionally substituted with one or more substituents R ′. Represent chains;

Alkyl groups are straight or branched, straight or branched, straight or branched chain C ₁ -C ₆ alkyl, preferably 1 to 6 carbon atoms, which may be optionally substituted with one or more substituents R ', unless stated otherwise. ₂ -C ₆ alkenyl, or a straight or branched C ₂ -C ₆ alkynyl group;

R 'is independently H, -CO ₂ R ", -CONHR", -CR "O, -SO ₂ NR", -NR "-CO-haloalkyl, -NO ₂ , -NR" -SO ₂ -haloalkyl , -NR "-SO ₂ -alkyl, -SO ₂ -alkyl, -NR" -CO-alkyl, -CN, alkyl, cycloalkyl, alkylamino, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl, Hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl or heteroaryl;

R ″ is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl or heteroaryl;

Cycloalkyl groups represent non-aromatic ring systems containing 3 to 8 carbon atoms, preferably 4 to 8 carbon atoms, wherein one or more carbon atoms in the ring may be substituted by the groups R 'as defined above There is; C ₃ -C ₈ -cycloalkyl moieties include -cyclo-C ₃ H ₅ , -cyclo-C ₄ H ₇ , cyclo-C ₅ H ₉ , -cyclo-C ₆ H ₁₁ , -cyclo-C ₇ H ₁₃ ,- May be selected from the group consisting of cyclo-C ₈ H ₁₅ ;

Heterocycloalkyl groups represent non-aromatic ring systems containing 2 to 10 carbon atoms and at least one heteroatom selected from O, N and S, wherein at least one carbon atom in the ring is defined by R 'as defined above. May be substituted; Preferred heterocycloalkyl groups are morpholin-4-yl, piperazinyl, 1-alkylpiperazin-4-yl, piperidinyl, pyrrolidinyl, azepan-1-yl;

The alkoxy group represents an O-alkyl group and the alkyl group is as defined above; The alkoxy group is preferably a methoxy, ethoxy, isopropoxy, t-butoxy or pentoxy group;

The alkylthio group represents an S-alkyl group, wherein the alkyl group is as defined above;

The haloalkyl group represents an alkyl group substituted with 1 to 5 halogen atoms, the alkyl group is as defined above, and the haloalkyl group is preferably -C (R ¹⁰ ) ₃ , -CR ¹⁰ (R ^{10 '} ) ₂ , -CR ¹⁰ (R ^{10 '} ) R ^{10 "} , -C ₂ (R ¹⁰ ) ₅ , -CH ₂ C (R ¹⁰ ) ₃ , -CH ₂ CR ¹⁰ (R ^10' ) ₂ , -CH ₂ CR ¹⁰ (R ^{10 '} ) R ^{10 "} , -C ₃ (R ¹⁰ ) ₇ or -C ₂ H ₄ C (R ¹⁰ ) ₃ , wherein R ¹⁰ , R ^{10 '} , R ^{10 "} is F, Cl, Br or I, preferably F;

A hydroxyalkyl group represents a HO-alkyl group, wherein the alkyl group is as defined above;

Haloalkyloxy group represents an alkoxy group substituted by 1 to 5 halogen atoms, the alkyl group being as defined above; Haloalkyloxy groups are preferably -OC (R ¹⁰ ) ₃ , -OCR ¹⁰ (R ^{10 '} ) ₂ , -OCR ¹⁰ (R ^10' ) R ^{10 "} , -OC ₂ (R ¹⁰ ) ₅ , -OCH ₂ C (R ¹⁰ ) ₃ , -OCH ₂ CR ¹⁰ (R ^{10 '} ) ₂ , -OCH ₂ CR ¹⁰ (R ^10' ) R ^{10 "} , -OC ₃ (R ¹⁰ ) ₇ or -OC ₂ H ₄ C (R ¹⁰ ) ₃ , wherein R ¹⁰ , R ^{10 '} , R ^{10 "} represents F, Cl, Br or I, preferably F;

Hydroxyalkylamino group represents a (HO-alkyl) ₂ -N- group or a HO-alkyl-NH- group, wherein the alkyl group is as defined above;

The alkylamino group represents an HN-alkyl or N-dialkyl group, wherein the alkyl group is as defined above;

Halogen groups are fluorine, chlorine, bromine or iodine;

An aryl group represents an aromatic group having 5 to 15 carbon atoms which may be substituted with one or more substituents R ', wherein R' is as defined above; The aryl group is preferably a benzyl group, a phenyl group, -oC ₆ H ₄ -R ', -mC ₆ H ₄ -R', -pC ₆ H ₄ -R ', 1-naphthyl, 2-naphthyl, 1-anthra Cenyl or 2-anthracenyl, and R 'is as defined above;

The arylamino group is an HN-aryl or N-diaryl group and the aryl group is as defined above;

Heteroaryl groups represent 5- or 6-membered heterocyclic groups containing one or more heteroatoms selected from O, N and S. Such heterocyclic groups can be fused to other aromatic rings. For example, such groups are thiadiazole, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazole -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, benzoisoxazol-3-yl, benzoisoxazol-4-yl, benzoisoxazol-5-yl, 1, 2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazole- 4-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothia Sol-5-yl, benzoisothiazol-3-yl, benzoisothiazol-4-yl, benzoisothiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1-im Dazolyl, 2-imidazolyl, 1,2,5-thiadiazol-4-yl, 4-imidazolyl, benzoimidazol-4-yl, 1-pyrrolyl, 2-pyrrolyl, 3-py Rollyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-ti Nilyl, 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-triazole-5 -Yl, 1,3,5-triazol-6-yl, 2,4-dimethoxy-1,3,5-triazol-6-yl, 1H-tetrazol-2-yl, 1H-tetrazol- 3-yl, tetrazolyl, acridil, furazane, indazolyl, phenazinyl, carbazolyl, phenoxazinyl, indolizine, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl , 6-indolyl, 7-indolyl, 1-isoindoleyl, 3-isoindolyl, 4-isoindolyl, 5-isoindolyl, 6-isoindolyl, 7-isoindolyl, 2-indole Linyl, 3-indolinyl, 4-indolinyl, 5-indolinyl, 6-indolinyl, 7-indolinyl, benzo [b] furanyl, benzofurazane, benzothiofurazane, benzotria Zol-1-yl, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl, benzotriazol-7-yl, benzotriazine, benzo [b] thiophenyl, benz Imidazol-2-yl, 1H-benzimidazolyl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl, benzimidazol-7-yl, benzothiazolyl, Quinazolinyl, quinoxazolinyl, cinnoline, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, 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] -dioxine- 3-yl, 2,3-dihydrobenzo [1,4] -dioxin-5-yl, 2,3-dihydrobenzo [1,4] -dioxin-6-yl, 2,6-dimethok Cypyrimidin-3-yl, 2,6-dimethoxypyrimidin-4-yl, tetrahydroisoquinolinyl, purine, phthalazine, pteridine, tiatetraazaindene, thiatriazindene, Isothiazolopyrazine, Isothiazolopyrimidine, Pyrazolot Azine, pyrazolopyrimidine, imidazopyridazine, imidazopyrimidine, imidazopyridine, imidazolotriazine, triazolotriazine, triazolopyridine, triazolopyrazine, triazolopyrimidine or 4- [1 , 2,4] triazolo [4,3-a] pyridin-3-yl, 1-furo [2,3-c] pyridin-4-yl, 1-furo [2,3-c] pyridine-5- One, 1-furo [2,3-c] pyridin-3-yl and triazolopyridazine groups. Such heterocyclic groups may be substituted with one or more substituents R ', wherein R' is as defined above;

With the exception of the following compounds:

<Formula I>

Where

R ¹ independently represents hydrogen, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl or substituted arylalkyl;

또는

를 나타내고;R ² is independently —NR ³ R ⁴ ,

or

Represents;

R ³ independently represents alkyl, cycloalkyl, alkoxy, alkylamine, -OH, -SH, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl;

R ⁴ independently represents alkyl, cycloalkyl, alkoxy, alkylamine, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl;

R ⁵ is independently H, COR ⁶ , CO ₂ R ⁶ , SOR ⁶ , SO ₂ R ⁶ , SO ₃ R ⁶ , alkyl, cycloalkyl, alkoxy, -NH ₂ , alkylamine, -NR ⁷ COR ⁶ , halogen, -OH, -SH, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl;

R ⁶ independently represents H, alkyl, cycloalkyl, —NH ₂ , alkylamine, aryl or heteroaryl;

R ⁷ independently represents H, alkyl, cycloalkyl, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl, aryl or heteroaryl;

p is 0 or 1;

q is 0 or 1;

X is CO or SO ₂ .

In formula (Ih), it is preferable to combine the following substituents alone or in combination:

X is preferably S or O, more preferably S.

R ^3a is preferably H.

In a preferred embodiment, Z is CR ^{2 '} and R ¹ and R ² together with the C-atom to which they are attached form a six-membered saturated ring. In another preferred embodiment, Z is N and R ¹ and R ² together with the N-atom to which they are attached form a six-membered saturated ring.

R ⁹ is preferably heteroaryl, aryl or benzyl, more preferably heteroaryl. R ⁹ is more preferably thienopyrimidine, quinazoline, purine, pyrazolo pyrimidine or triazolepyrimidine. Even more preferably R ⁹ is thienopyrimidine.

t is preferably 0.

r is preferably 1.

R ^2a is preferably OH, alkyl, aryl or heteroaryl, more preferably alkyl and especially methyl.

The present invention relates to a compound of formula (II), or a pharmaceutically acceptable salt thereof with an acid or base, or a pharmaceutically acceptable prodrug or stereoisomer thereof.

Where

R ¹ is —C (O) R ⁷ , -C (O) CHR ⁷ R ⁸ , -C (O) NR ⁷ R ⁸ , -C (O) OR ⁷ , -R ⁷ C (O) R ⁸ or- C (S) R ⁷ ;

R ² is H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, alkylamino, hydroxyalkylamino, heteroaryl; or

R ¹ and R ² together with the N- 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 carbon atom in the ring is A heteroatom selected from O, N and S, said ring may be substituted with one or more R ⁹ ;

R ³ is H, —C (O) NR ^a R ^b , halogen, alkyl, haloalkyl, aryl, heteroaryl, OH, SH, NR ^{4 ′} OR ^{5 '} , NH ₂ , hydroxyalkylamino, alkylamino, alkoxy , Cycloalkyl, heterocycloalkyl, hydroxyalkyl or haloalkyloxy;

R ^a is H, halogen, alkyl, -C (NR ⁷ ) NR ^{7 '} R ⁸ ,-(CH ₂ ) _p aryl,-(CH ₂ ) _p NR ⁷ R ⁸ , -C (O) NR ⁷ R ⁸ , -N = CR ⁷ R ⁸ , -NR ⁷ C (O) R ⁸ , cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;

R ^b is independently H, —CN, —OH, —SH, —CO ₂ R ^{4 ′} , —C (O) R ^{4 ′} , —SO ₂ NR ^{4 ′} , —NR ^{4 ′} R ^{5 ′} , —C ( O) NR ⁷ R ⁸ , -SO ₂ -alkyl, -SO ₂ R ^{4 '} , SO ₃ R ^4' , -N = CR ^{4 '} R ^5' , -NR ^{4 '} C (O) R ^{4 "} , -NR ^{4 '-CO- _{haloalkyl, -NO 2, -NR 4' -SO}} 2 - haloalkyl, -NR ^{4 '-SO} ₂ - alkyl, -NR ^4' -CO- alkyl, -NR ^{4 '(CH} _{2) p} heterocycle, alkyl, cycloalkyl, alkylamino, alkoxy, alkylthio, halogen, haloalkyl, haloalkyloxy, -O (CH ₂ ) _p [O (CH ₂ ) _p ] _q OCH ₃ , -C (NR ^{4 "} ) NR ^{4 '} benzimidazolyl, -C (NR ^4" ) NR ^4' benzthiazolyl, -C (NR ^{4 "} ) NR ^{4 '} benzoxazolyl, hydroxyalkyl, hydroxyalkylamino, aryl, hetero Cycloalkyl or heteroaryl;

R ⁶ is halogen, -C (O) R ⁷ , -C (O) CHR ⁷ R ⁸ , -C (O) NR ⁷ R ⁸ , -C (O) OR ⁷ , -R ⁷ C (O) R ⁸ , -C (S) R ⁷ , -C (NR ⁷ ) NR ^{7 '} R ⁸ ,-(CH ₂ ) _p aryl,-(CH ₂ ) _p NR ⁷ R ⁸ , -C (O) NR ⁷ R ⁸ , -N = CR ⁷ R ⁸ , -NR ⁷ C (O) R ^{7 ′} , alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;

R ⁷ , R ^{7 ′} , R ⁸ are independently H, halogen, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, —NHaryl, heteroaryl or aryl;

A is CO or SO ₂ ;

X is NR ^{2 '} , O or S;

Y is N, CR ^{2 '} or-or Y is O, then R ⁶ is absent;

Z is N or CR ^{2 '} or X is O or NR ^2' if Z is CH;

R ^{2 ′} is H, alkyl, —C (O) NR ² , —C (O) R ^b , cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or Aryl;

n is 0 to 2;

p is 1 to 6;

q is 1 to 6;

R ⁹ is independently H, —CN, —OH, —SH, —CO ₂ R ^{4 ′} , —C (O) R ^4a , —C (O) NR ⁷ R ⁸ , —SO ₂ NR ^{4 ′} , -NR ^{4 '} R ^5' , -SO ₂ -alkyl, -SO ₂ R ^{4 '} , SO ₃ R ^4' , -N = CR ^{4 '} R ^5' , -NR ^{4 '} C (O) R ^{4 "} , -NR ^{4 '} -CO-haloalkyl, -NO ₂ , -NR ^4' -SO ₂ -haloalkyl, -NR ^{4 '} -SO ₂ -alkyl, -NR ^4' -CO-alkyl, -NR ^{4 '} (CH ₂ ) _p Heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, alkylamino, alkoxy, alkylthio, halogen, haloalkyl, haloalkyloxy, hydroxyalkylamino, hydroxyalkyl, hydroxycycloalkyl, aryl, -O (CH ₂ ) _p [O (CH ₂ ) _p ] _q OCH ₃ , -C (NR ^{4 "} ) NR ^{4 '} -benzimidazolyl, -C (NR ^4" ) NR ^4' benzthiazolyl, -C (NR ^{4 "} ) NR ^{4 '} benzoxazolyl,-(CH ₂ ) _p NR ⁷ COR ⁸ or heteroaryl;

R ^{4 '} , R ^{4 "} , R ^5' are independently H, halogen, alkyl, -C (NR ⁷ ) NR ^{7 '} R ⁸ ,-(CH ₂ ) _p aryl,-(CH ₂ ) _p NR ⁷ R ⁸ , -C (O) NR ⁷ R ⁸ , -N = CR ⁷ R ⁸ , -NR ⁷ C (O) R ⁸ , cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino , Heteroaryl or aryl;

R ^4a is H, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, —C (NR ⁷ ) NR ^{7 ′} R ⁸ ,-(CH ₂ ) _p aryl,-(CH ₂ ) _p NR ⁷ R ⁸ , -C (O) NR ⁷ R ⁸ , -N = CR ⁷ R ⁸ , -NR ⁷ C (O) R ⁸ , halogen , Heteroaryl or aryl,

From here

C ₁ -C ₆ -alkyl groups, unless stated otherwise, are straight or branched straight or branched C ₁ -C ₆ -alkyl, preferably 1 to 5 carbon atoms which may be optionally substituted with one or more substituents R ′. Represent chains;

C ₂ -C ₆ -alkenyl groups, unless stated otherwise, are straight or branched C ₂ -C ₆ -alkenyl, preferably straight chains of 2 to 6 carbon atoms which may be optionally substituted with one or more substituents R ′. Or branched chains;

Alkyl groups, unless stated otherwise, are straight or branched C ₁ -C ₆ alkyl which may be substituted with one or more substituents R ′, preferably straight or branched, straight or branched chain C ₂ of 1 to 6 carbon atoms. -C ₆ -alkenyl or a straight or branched C ₂ -C _6- alkynyl group;

R 'is independently H, -CO ₂ R ", -CONHR", -CR "O, -SO ₂ NR", -NR "-CO-haloalkyl, -NO ₂ , -NR" -SO ₂ -haloalkyl , -NR "-SO ₂ -alkyl, -SO ₂ -alkyl, -NR" -CO-alkyl, -CN, alkyl, cycloalkyl, alkylamino, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl , Hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl or heteroaryl;

R ″ is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl or heteroaryl;

Heterocycle represents a heterocycloalkyl group or a heteroaryl group;

Cycloalkyl groups represent non-aromatic ring systems containing 3 to 8 carbon atoms, preferably 4 to 8 carbon atoms, wherein one or more carbon atoms in the ring may be substituted by the groups R 'as defined above There is; C ₃ -C ₈ -cycloalkyl moieties include -cyclo-C ₃ H ₅ , -cyclo-C ₄ H ₇ , -cyclo-C ₅ H ₉ , -cyclo-C ₆ H ₁₁ , -cyclo-C ₇ H ₁₃ , -Cyclo-C ₈ H ₁₅ may be selected from the group consisting of;

Heterocycloalkyl groups represent non-aromatic ring systems containing 2 to 10 carbon atoms and at least one heteroatom selected from O, N and S, wherein at least one carbon atom in the ring is defined by R 'as defined above. May be substituted; Preferred heterocycloalkyl groups are morpholin-4-yl, piperazinyl, 1-alkylpiperazin-4-yl, piperidinyl, pyrrolidinyl, azocan-1-yl;

The alkoxy group represents an O-alkyl group and the alkyl group is as defined above; The alkoxy group is preferably a methoxy, ethoxy, isopropoxy, t-butoxy or pentoxy group;

The alkylthio group represents an S-alkyl group, wherein the alkyl group is as defined above;

The haloalkyl group represents an alkyl group substituted with 1 to 5 halogen atoms, the alkyl group is as defined above, and the haloalkyl group is preferably -C (R ¹⁰ ) ₃ , -CR ¹⁰ (R ^{10 '} ) ₂ , -CR ¹⁰ (R ^{10 '} ) R ^{10 "} , -C ₂ (R ¹⁰ ) ₅ , -CH ₂ C (R ¹⁰ ) ₃ , -CH ₂ CR ¹⁰ (R ^10' ) ₂ , -CH ₂ CR ¹⁰ (R ^{10 '} ) R ^{10 "} , -C ₃ (R ¹⁰ ) ₇ or -C ₂ H ₄ C (R ¹⁰ ) ₃ , wherein R ¹⁰ , R ^{10 '} , R ^{10 "} is F, Cl, Br or I, preferably F;

A hydroxyalkyl group represents a HO-alkyl group, wherein the alkyl group is as defined above;

Haloalkyloxy group represents an alkoxy group substituted by 1 to 5 halogen atoms, the alkyl group being as defined above; The haloalkyloxy group is preferably -OC (R ¹⁰ ) ₃ , -OCR ¹⁰ (R ^{10 '} ) ₂ , -OCR ¹⁰ (R ^10' ) R ^{10 "} , -OC ₂ (R ¹⁰ ) ₅ , -OCH ₂ C (R ¹⁰ ) ₃ , -OCH ₂ CR ¹⁰ (R ^{10 '} ) ₂ , -OCH ₂ CR ¹⁰ (R ^10' ) R ^{10 "} , -OC ₃ (R ¹⁰ ) ₇ or -OC ₂ H ₄ C (R ¹⁰ ) ₃ , wherein R ¹⁰ , R ^{10 '} , R ^{10 "} represents F, Cl, Br or I, preferably F;

Hydroxyalkylamino group represents a (HO-alkyl) ₂ -N- group or a HO-alkyl-NH- group, wherein the alkyl group is as defined above;

The alkylamino group represents an HN-alkyl or N-dialkyl group, wherein the alkyl group is as defined above;

Halogen atoms are fluorine, chlorine, bromine or iodine;

An aryl group represents an aromatic group having 5 to 15 carbon atoms which may be substituted with one or more substituents R ', wherein R' is as defined above; The aryl group is preferably a benzyl group, a phenyl group, -oC ₆ H ₄ -R ', -mC ₆ H ₄ -R', -pC ₆ H ₄ -R ', 1-naphthyl, 2-naphthyl, 1-anthra Cenyl or 2-anthracenyl, and R 'is as defined above;

Heteroaryl groups represent 5- or 6-membered heterocyclic groups containing one or more heteroatoms selected from O, N and S. Such heterocyclic groups can be fused to other aromatic rings. For example, such groups are thiadiazole, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazole -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, benzoisoxazol-3-yl, benzoisoxazol-4-yl, benzoisoxazol-5-yl, 1, 2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazole- 4-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothia Sol-5-yl, benzoisothiazol-3-yl, benzoisothiazol-4-yl, benzoisothiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1-im Dazolyl, 2-imidazolyl, 1,2,5-thiadiazol-4-yl, 4-imidazolyl, benzoimidazol-4-yl, 1-pyrrolyl, 2-pyrrolyl, 3-py Rollyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-ti Nilyl, 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-triazole-5 -Yl, 1,3,5-triazol-6-yl, 2,4-dimethoxy-1,3,5-triazol-6-yl, 1H-tetrazol-2-yl, 1H-tetrazol- 3-yl, tetrazolyl, acridil, furazane, indazolyl, phenazinyl, carbazolyl, phenoxazinyl, indolizine, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl , 6-indolyl, 7-indolyl, 1-isoindoleyl, 3-isoindolyl, 4-isoindolyl, 5-isoindolyl, 6-isoindolyl, 7-isoindoleyl, 2-indole Linyl, 3-indolinyl, 4-indolinyl, 5-indolinyl, 6-indolinyl, 7-indolinyl, benzo [b] furanyl, benzofurazane, benzothiofurazane, benzotria Zol-1-yl, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl, benzotriazol-7-yl, benzotriazine, benzo [b] thiophenyl, benz Imidazol-2-yl, 1H-benzimidazolyl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl, benzimidazol-7-yl, benzothiazolyl, Quinazolinyl, quinoxazolinyl, cinnoline, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, 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] -dioxine- 3-yl, 2,3-dihydrobenzo [1,4] -dioxin-5-yl, 2,3-dihydrobenzo [1,4] -dioxin-6-yl, 2,6-dimethok Cypyrimidin-3-yl, 2,6-dimethoxypyrimidin-4-yl, tetrahydroisoquinolinyl, purine, phthalazine, pteridine, tiatetraazaindene, thiatriazindene, Isothiazolopyrazine, Isothiazolopyrimidine, Pyrazolot Azine, pyrazolopyrimidine, imidazopyridazine, imidazopyrimidine, imidazopyridine, imidazolotriazine, triazolotriazine, triazolopyridine, triazolopyrazine, triazolopyrimidine, 4- [1 , 2,4] triazolo [4,3-a] pyridin-3-yl, 1-furo [2,3-c] pyridin-4-yl, 1-furo [2,3-c] pyridine-5- One, 1-furo [2,3-c] pyridin-3-yl and triazolopyridazine groups. Such heterocyclic groups may be substituted with one or more substituents R ', wherein R' is as defined above.

이고, R⁵는 임의로 치환된 아릴, 벤질 또는 헤테로아릴이다.In a preferred embodiment of the invention, in the compounds of formula (la), Z is S, Y is CO, X is CO, R is H, R ^c is H, R ¹ is aryl, benzyl or heteroaryl , R ² is

And R ⁵ is optionally substituted aryl, benzyl or heteroaryl.

이고, R⁵는 임의로 치환된 아릴, 벤질 또는 헤테로아릴이다.In a preferred embodiment of the invention, in the compounds of formula (la), Z is O, Y is CO, X is CO, R is H, R ^c is H, R ¹ is aryl, benzyl or heteroaryl , R ² is

And R ⁵ is optionally substituted aryl, benzyl or heteroaryl.

이고, R⁵는 임의로 치환된 아릴, 벤질 또는 헤테로아릴이다.In a preferred embodiment of the invention, in the compounds of formula (lb), Z is S, Y is CO, X together with R ¹ and R ⁴ forms a piperidine ring, R ^a and R ^b are H, R ^c is H or methyl and R ² is

And R ⁵ is optionally substituted aryl, benzyl or heteroaryl.

이고, R⁵는 임의로 치환된 아릴, 벤질 또는 헤테로아릴이다.In a preferred embodiment of the invention, in the compounds of formula (lb), Z is O, Y is CO, X together with R ¹ and R ⁴ forms a piperidine ring, R ^a and R ^b are H, R ^c is H or methyl and R ² is

And R ⁵ is optionally substituted aryl, benzyl or heteroaryl.

이고, R⁵는 임의로 치환된 아릴, 벤질 또는 헤테로아릴이다.In another preferred embodiment, in compounds of Formula (Ic), r is 1, Y is CO, Z is O, t is 0, s is 1, X is CO, R ^c is H, methyl, ethyl , Methoxy, alkylamino, morpholino, N-methylpiperazine, CF ₃ or OCF, R ² is

And R ⁵ is optionally substituted aryl, benzyl or heteroaryl.

이고, R⁵는 임의로 치환된 아릴, 벤질 또는 헤테로아릴이다.In another preferred embodiment, in compounds of Formula (Ic), r is 1, Y is CO, Z is S, t is 0, s is 0, R ^c is H, methyl, ethyl, methoxy, alkyl Amino, morpholino, N-methylpiperazine, CF ₃ or OCF, R ² is

And R ⁵ is optionally substituted aryl, benzyl or heteroaryl.

이고, R⁵는 임의로 치환된 아릴, 벤질 또는 헤테로아릴이다.In another preferred embodiment, in compounds of Formula (Ic), r is 1, Y is CO, Z is S, t is 0, s is 1, X is CO, R ^c is H, methyl, Ethyl, methoxy, alkylamino, morpholino, N-methylpiperazine, CF ₃ or OCF, and R ² is

And R ⁵ is optionally substituted aryl, benzyl or heteroaryl.

이고, R⁵는 임의로 치환된 아릴, 벤질 또는 헤테로아릴이다.In another preferred embodiment, in compounds of Formula (Ic), r is 1, Y is CO, Z is O, t is 0, s is 0, R ^c is H, methyl, ethyl, methoxy, alkyl Amino, morpholino, N-methylpiperazine, CF ₃ or OCF, R ² is

And R ⁵ is optionally substituted aryl, benzyl or heteroaryl.

Preferred embodiments of the invention in compounds of formula III are compounds of formula IIIa

Where

R ³ , R ⁴ , R ⁵ , R ^7a and Z are as defined above.

R ³ is preferably H, Me, OMe, CF ₃ , OCF ₃ , Cl, OH or SH, more preferably H, Me, OMe, CF ₃ , OCF ₃ , even more preferably H.

Preferably, Z is N.

Preferably, R ⁴ is H.

Preferably, R ^7a is aryl or heteroaryl, more preferably aryl, even more preferably phenyl. More preferably, R ^7a is substituted with one or two substituents R ', more preferably with one R'. In a particularly preferred embodiment, R ^7a is 2-trifluoromethoxyphenyl. In another particularly preferred embodiment, R ^7a is 2-methoxyphenyl. In another particularly preferred embodiment, R ^7a is 2-chlorophenyl. In another particularly preferred embodiment, R ^7a is 2-methylphenyl.

R ⁵ is preferably aryl or heteroaryl, more preferably heteroaryl. Heteroaryl preferably contains two nitrogen atoms, particularly preferably 2-imidazolyl or 2-benzoimidazolyl, even more preferably 2-benzoimidazolyl. In another preferred embodiment, heteroaryl contains one nitrogen atom and one sulfur atom, particularly preferably 2-thiazolyl or 2-benzothiazolyl, even more preferably 2-benzothiazolyl. Heteroaryl is more preferably substituted with 1 to 4 substituents R ', more preferably with 1 or 2 substituents R'. In a particularly preferred embodiment, R ⁵ is 5,6-dimethyl-1H-benzoimidazol-2-yl. In another particularly preferred embodiment, R ⁵ is 5,6-dimethyl-1H-benthiazol-2-yl.

Preferably, R 'is -SO ₂ -alkyl, -NO ₂ , halogen, -CO ₂ H, -OH, haloalkyloxy, alkoxy or alkyl. Particularly preferred as R 'are methanesulfonyl, nitro, fluorine, chlorine, bromine, carboxyl groups, hydroxyl, trifluoromethoxy, methoxy, ethoxy, methyl, ethyl or trifluoroethyl.

In one preferred embodiment X is O. In another preferred embodiment X is S. In another preferred embodiment X is NR ^{2 ′} .

In a preferred embodiment of formula IIIa, R ³ is H, methyl, methoxy, CF ₃ or OCF ₃ ; R ⁴ , R ⁵ , R ^7a are as defined above; X is NR ^{2 '} , O or S and Z is as defined above.

Another preferred embodiment of the invention in compounds of Formula III is a compound of Formula IIIa with R ^7a = —NH-aryl.

Another preferred embodiment of the invention in compounds of Formula III is a compound of Formula IIIb.

Where

R ³ is H, methyl, methoxy, CF ₃ or OCF ₃ ; R ⁵ is as defined above; X is NR ^{2 '} , O or S; X is NR ^{2 '} , O or S if Z is N, or X is O if Z is CR ^2' ;

Y 'is O or NR ^2' and R ^{2 '} is as defined above.

Another preferred embodiment of the invention in compounds of formula III is a compound of formula IIIc

Where

R ¹¹ , R ¹² are independently H, —CN, —OH, —SH, —CO ₂ R ^{4 ′} , —C (O) R ^{4 ′} , —SO ₂ NR ^{4 ′} , —NR ^{4 ′} R ^{5 ′} , -SO ₂ -alkyl, -SO ₂ R ^{4 '} , SO ₃ R ^4' , -N = CR ^{4 '} R ^5' , -NR ^{4 '} C (O) R ^{4 "} , -NR ^4' -CO-haloalkyl , -NO ₂ , -NR ^{4 '} -SO ₂ -haloalkyl, -NR ^4' -SO ₂ -alkyl, -NR ^{4 '} -CO-alkyl, -NR ^4' (CH ₂ ) _p heteroaryl, alkyl, cyclo Alkyl, alkylamino, alkoxy, alkylthio, -O (CH ₂ ) _p [O (CH ₂ ) _p ] _q OCH ₃ , -C (NR ^{4 "} ) NR ^{4 '} benzimidazolyl, -C (NR ^4" ) NR ^{4 '} benzthiazolyl, -C (NR ^{4 "} ) NR ^4' benzoxazolyl hydroxyalkyl, hydroxycycloalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl, arylalkyl or hetero Ring; R ^{4 '} , R ^{4 "} , R ^5' are as defined above; R ³ is H, methyl, methoxy, CF ₃ or OCF ₃ ; X is NR ^{2 '} , O or S, and R ⁴ is As defined above, R ⁷ and R ^{7 ′} are as defined above,

R ^{11 '} , R ^12' are independently H, -CN, -OH, -SH, -CO ₂ R ^{4 '} , -C (O) R ^4' , -SO ₂ NR ^{4 '} , -NR ^4' R ^{5 '} , -SO ₂ -alkyl, -SO ₂ R ^4' , SO ₃ R ^{4 '} , -N = CR ^4' R ^{5 '} , -NR ^4' C (O) R ^{4 "} , -NR ^{4 '} -CO- Haloalkyl, -NO ₂ , -NR ^{4 '} -SO ₂ -haloalkyl, -NR ^4' -SO ₂ -alkyl, -NR ^{4 '} -CO-alkyl, -NR ^4' (CH ₂ ) _p heteroaryl, alkyl , Cycloalkyl, alkylamino, alkoxy, alkylthio, -O (CH ₂ ) _p [O (CH ₂ ) _p ] _q OCH ₃ , -C (NR ^{4 "} ) NR ^{4 '} benzimidazolyl, -C (NR ^{4 "} ) NR ^{4 '} benzthiazolyl, -C (NR ^4" ) NR ^4' benzoxazolyl hydroxyalkyl, hydroxycycloalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl, arylalkyl Or heterocyclic; R ^{4 '} , R ^{4 "} , R ^5' are as defined above.

More preferred embodiments of the invention in compounds of Formula III are compounds of Formula IIId

Where

R ³ is H, methyl, methoxy, CF ₃ or OCF ₃ ; X is NR ^{2 ′} , O or S, R ⁴ is as defined above, R ⁷ and R ^{7 ′} are as defined above, and Y ″ and R ^{11 ′} , R ^{12 ′} are defined above in Formula IIIc And Y 'is O or NR ^2' and R ^{2 '} is as defined above.

More preferred embodiments of the invention in compounds of Formula III are compounds of Formula IIIe.

Where

R ³ , R ⁴ and R ⁵ are as defined above and X is O or S;

R ¹¹ and R ¹² are as defined in Formula IIIc,

If Z is N, X is NR ^{2 '} , O or S, and if Z is CH, X is O.

Another more preferred embodiment of the invention in compounds of Formula III is a compound of Formula IIIf.

Where

Z is N or CH and R ³ is H, methyl, methoxy, CF ₃ or OCF ₃ ; X is NR ^{2 '} , O or S,

R ⁴ is as defined above, R ⁷ and R ^{7 '} are as defined above and R ^2' is as defined above;

Y ″ and R ¹¹ , R ^{11 ′} , R ¹² , R ^{12 ′} are as defined above in Formula IIIc.

Preferred embodiments of the invention are compounds of formula Iha.

Where

R ¹ is COR ^7a ; R ² and R ^3a are H; A is NH; R ⁷ is as defined above; Z is N; X is NR ² , O or S; R ³ is H, methyl, ethyl, methoxy, amine, alkylamine, morpholino, N-methylpiperazine, CF ₃ or OCF ₃ ; t is 0; r is 1 and R ^2a is optionally substituted aryl, benzyl or heteroaryl.

Another preferred embodiment of the invention in compounds of formula Ih is a compound of formula Iha wherein R ^7a is optionally substituted aryl, benzyl or heteroaryl.

Another preferred embodiment of the invention in compounds of formula Ih is compounds of formula Ihb.

Where

R ^3a is H; A is NH; X is NR ^{2 '} , O or S; Y 'is O or NR ^2' ;

R ^{2 '} is as defined above; R ³ is H, methyl, ethyl, methoxy, amine, alkylamine, morpholino, N-methylpiperazine, CF ₃ or OCF ₃ ; t is 0; r is 1; R ^2a is optionally substituted aryl, benzyl or heteroaryl.

In formula (Ihb), it is preferable to combine the following substituents alone or in combination:

Z is preferably CR ^{2 '} .

Y 'is preferably NR ^2' . In a preferred embodiment, R ^{2 ′} in NR ^{2 ′} of Y ′ is preferably substituted or unsubstituted heteroaryl. In another preferred embodiment, R ^{2 ′} in NR ^{2 ′} of Y ^′ is aryl. In another preferred embodiment, R ^{2 ′} in NR ^{2 ′} of Y ^′ is benzyl. In a more preferred embodiment, R ^{2 ′} in NR ^{2 ′} of Y ^′ is pyrimidine or triazine. In another more preferred embodiment, R ^{2 '} in NR ^2' of Y 'is a substituted or unsubstituted cyclic heteroaryl, more preferably thienopyrimidine, quinazoline, purine, pyrazolopyrimidine or triazolepyri Midine, even more preferably thienopyrimidine.

In a preferred embodiment, X is S. In other preferred embodiments, X is O. In another preferred embodiment, X is NR ^{2 '} .

R ³ is preferably H.

R ^2a is preferably aryl or heteroaryl, more preferably phenyl.

Another more preferred embodiment of the invention in compounds of formula Ih is a compound of formula Ihe.

Where

R ^3a is H; A is NH; X is NR ^{2 '} , O or S;

R ¹¹ and R ¹² are independently H, —CN, —OH, —SH, —CO ₂ R ^{4 ′} , —C (O) R ^{4 ′} , —SO ₂ NR ^{4 ′} , —NR ^{4 ′} R ^{5 ′} , -SO ₂ -alkyl, -SO ₂ R ^{4 '} , SO ₃ R ^4' , -N = CR ^{4 '} R ^5' , -NR ^{4 '} C (O) R ^{4 "} , -NR ^4' -CO-haloalkyl , -NO ₂ , -NR ^{4 '} -SO ₂ -haloalkyl, -NR ^4' -SO ₂ -alkyl, -NR ^{4 '} -CO-alkyl, -NR ^4' (CH ₂ ) _p heteroaryl, alkyl, cyclo Alkyl, alkylamino, alkoxy, alkylthio, -O (CH ₂ ) _p [O (CH ₂ ) _p ] _q OCH ₃ , -C (NR ^{4 "} ) NR ^{4 '} benzimidazolyl, -C (NR ^4" ) NR ^{4 '} benzthiazolyl, -C (NR ^{4 "} ) NR ^4' benzoxazolyl hydroxyalkyl, hydroxycycloalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl, arylalkyl or hetero A ring;

R ^{4 '} , R ^{4 "} , R ^5' are as defined above;

R ^{2 '} is as defined above;

R ³ is H, methyl, ethyl, methoxy, amine, alkylamine, morpholino, N-methylpiperazine, CF ₃ or OCF ₃ ;

t is 0;

r is 1;

R ^2a is optionally substituted aryl, benzyl or heteroaryl.

In the formula (Ihe), it is preferable to combine the following substituents alone or in combination:

Z is preferably CR ^{2 '} .

In a preferred embodiment, X is S. In other preferred embodiments, X is O. In another preferred embodiment, X is NR ^{2 '} .

R ¹¹ is preferably -H, -CN, -OH, halogen, haloalkyl, haloalkyloxy, and more preferably -CN.

R ¹² is preferably H.

R ^2a is preferably aryl or heteroaryl, more preferably phenyl.

Preferred embodiments of the invention in compounds of formula II are compounds of formula IIa.

Where

R ¹ and R ² are as defined above and Z is as defined above; X is O or S;

R ³ is H, methyl, methoxy, CF ₃ or OCF ₃ ;

R ¹¹ and R ¹² are as defined in formula IIIc.

A more preferred embodiment of the invention in compounds of formula II is a compound of formula IIb.

Where

R ¹ and R ² are as defined above and Z is as defined above; X is O or S;

R ³ is H, methyl, methoxy, CF ₃ or OCF ₃ .

Another more preferred embodiment of the invention in compounds of Formula II is a compound of Formula IIc.

Where

X is O or S; R ³ is H, methyl, methoxy, CF ₃ or OCF ₃ and Y 'is NR ^2' .

Another more preferred embodiment of the invention in compounds of Formula II is a compound of Formula IId.

Where

Z is as defined above; R ³ is H, methyl, methoxy, CF ₃ or OCF ₃ ;

R ¹¹ , R ^{11 '} and R ¹² , R ^12' are as defined above.

The present invention also provides a method for preparing a compound of the present invention, such as a compound of formula la, lb, lc, lh, ii or iii.

Compounds of formulas Ia, Ib, Ic, Ih, II or III can be obtained through various methods.

Piperidin-4-yl-thiazole-4-carboxamides can be prepared by a variety of methods described in the literature. One example is the oxidation of suitable 2,5-dihydrothiazoles as described in Houben-Weyl, 2002, 730. Dihydrothiazole can be obtained by the methods described in the same reference or by You, S., Razavi, H., Kelly, J. W. Angew. Chem. 2003, 115, 87 or Katrizky, AR ,. Cai, C., Suzuki, K., Singh, SK. J. Org. Chem. 2004, 69, 811-814 and references therein. Alternative methods are described in Yasuchika, S. et al., Heterocycles, Vol. 57, No. 5, 2002.

Compounds of formulas (II), (Ic) and (III) with additional substituents on heterocycles are described in Organic Syntheses, Coll. Vol. 9, p. 155 and Vol. 74, p. 229; J. Org. Chem. 1975, Vol. 40, no. 10, pp. 1521, J. Am. Chem. Soc. 96: 19 / September 18, 1974; J. Org. Chem. 1990, 55, 4484-4487; Chemische Berichte 1968, 101 (1) 302-307; It can be obtained by various methods described in Agricultural Chemistry and Biotechnology, 2002, 45 (1), p37-42.

The possibility of synthesizing substituted benzimidazole-substituents of formula III is described in Synthesis, 2006, 4, 597-602.

The possibility of syntheses of formulas IIIa, c and IIa, b (see Scheme 1) is that, for example, the compounds of formula (V) are combined with compounds of formula (VI) at temperatures from 0 ° C. to room temperature under traditional amide binding conditions such as HBTU, iPr ₂ NEt, DMF. Reacting to obtain intermediate (VII). Another alternative for this step may be the reaction of formula V with the corresponding acid chloride of formula VI to yield formula VII. In the second step, formula VII is saponified with 1M NaOH solution to give the acid (VIII) in near quantitative yield. This step may be realized under acidic conditions. Finally, another amide linkage step (with primary or secondary amines) which acts similarly to step 1 described above completes the synthesis for compounds of type (IIIa, c and IIa and b).

Synthesis of Derivatives of Types (IIIa, c) and (IIa, b)

Compounds handling structures (IIIb, d, e, f and IIc, d) can be synthesized according to the procedure shown in Scheme 2 below. Here, heterocyclic ring (IX) is reacted with bromo compound (X) by nucleophilic substitution reaction to obtain cyclic ester (XI), and then saponified with acid (XII) under standard and known conditions, and the reaction scheme 1 The synthesis is completed by another binding step as shown.

Synthesis of Derivatives of Types (IIIb, d, e, f) and (IIc, d) When Z = N

In the case of Z = CH, structures (IIIb, d, e, f) and (IIc, d) type compounds can be readily synthesized according to the protocol shown in Scheme 3, wherein the heterocycle (XIII) is a ring condensation step To compound (XV). After saponification, (XVI) is combined with an amine to give the desired product (IIIb, d, e, f) or (IIc, d).

Synthesis of Derivatives of Types (IIIb, d, e, f) and (IIc, d) When Z = CH

Compounds of the invention having a piperidin-4-yl substituent at the 2-position of the thiazole ring can be prepared, for example, as shown in the following scheme. This synthetic route is partly described in WO 2004/058750.

2- (1- (tert-butoxycarbonyl) piperidin-4-yl) thiazole-4-carboxylic acid can be converted to the appropriate R ¹ amide by combining HBTU, DIPEA in DMF. Various R ¹ -amines are commercially available or can be readily synthesized. Boc-protecting groups can be removed under standard conditions by treatment with TFA for 2 to 3 hours at 0 ° C. or with 4 N HCl in dioxane for 2 to 3 hours. The deprotected piperidino derived HCl salt can then be converted to the corresponding amide, urea and N-heterocyclic analogs as follows.

Urea substituted piperidino compounds can be synthesized by combining with commercial isocyanates in the presence of DIPEA. Piperidino compounds substituted with heterocycles can be synthesized by standard procedures, such as by combining with the corresponding chloroheterocycle in the presence of a base. Alternatively, the piperidino compound substituted with a heterocycle can be obtained by palladium-mediated crosslinking. Alternatively, the hydroxypyridine derivative can be bound to the piperidino compound by the HBTU binding method.

A separate route to the compound of the invention having a piperidin-4-yl substituent at the 2-position of the thiazole ring is shown in the following scheme.

Boc-protecting groups can be removed under standard conditions by treatment with TFA for 2 to 3 hours at 0 ° C. or with 4 N HCl in dioxane for 2 to 3 hours. Thereafter, the deprotected piperidino derived HCl salt can be converted to the corresponding N-heterocyclic analog by the various methods described above.

In the compounds of Formulas Ia, Ib, Ic, Ih, II or III, the term “stereoisomers” refers to cis / trans or E / Z isomers. In more detail, the possible double bond (s) present in the various substituents of the compounds of the present invention may be in the E or Z configuration. These pure or impure geometric isomers, alone or as a mixture, form the entire part of the compound of formula (la), (lb), (lc), (Ih), (II) or (III). The term “stereoisomers” includes all isomeric forms (alone or as a mixture) of those obtained from the presence of a center of symmetry in one or more axes and / or molecules and from rotation of polarized light. More specifically, this includes the enantiomers and diastereomers in pure form or as a mixture.

The compounds of the formulas Ia, Ib, Ic, Ih, II or III used according to the invention can form 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 acetates derived from acetic acid, aconitates derived from asconic acid, ascorbates derived from ascorbic acid, derived from benzoic acid. Benzoate, cinnamates derived from cinnamic acid, citrate derived from citric acid, embonate derived from embonic acid, enanthate derived from heptanoic acid, formiate derived from formic acid, fumarate derived from fumaric acid, glutamic acid Glutamate derived from, glycolate derived from glycolic acid, chloride derived from hydrochloric acid, bromide derived from hydrobromic acid, lactate derived from lactic acid, maleate derived from maleic acid, malonate derived from malonic acid,Mandelate derived from dell acid, methanesulfonate derived from methanesulfonic acid, naphthalin-2-sulfonate derived from naphthalin-2-sulfonic acid, nitrate derived from nitric acid, perchlorate derived from perchloric acid, derived from phosphoric acid Phosphates, 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, tartaric acid Tartrate, toluene-p-sulfate derived from p-toluenesulfonic acid, and the like. Such salts can be prepared by methods known to those skilled in the art and described in the prior art.

Other salts, such as oxalates derived from oxalic acid, which are not considered pharmaceutically acceptable, are those of formula (Ia), (Ib), (Ic), (Ih), (II) or (III) or their pharmaceutically acceptable salts or pharmaceutically acceptable prodrugs thereof. Or as an intermediate for the preparation of stereoisomers thereof.

The present invention includes salts capable of appropriately separating or crystallizing the compounds of formula (la), (lb), (lc), (h), or (III) as well as the pharmaceutically acceptable salts indicated above as well as the salts obtained by chiral amines.

Compounds of Formulas Ia, Ib, Ic, Ih, II or III include prodrugs of such compounds. As used herein, the term “prodrug” is not pharmaceutically active in itself (“prodrug”) when administered to a patient, but its pharmaceutically active form in vivo, ie in a patient receiving the compound (Formula Ia, Ib, Ic, Ih, II or III) to compounds that are chemically and / or biologically modified. Prodrugs include, for example, compounds of the present invention in which a hydroxyl group, an amine group or a sulfhydryl group is bonded to any group that splits when administered to a patient to form a hydroxyl group, an amine group or a 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. In addition, in the case of carboxylic acid (-COOH), esters such as methyl ester, ethyl ester, double ester and the like can be used. The ester may itself be active and / or hydrolysable under in vivo conditions in the human body.

The compounds according to the invention and medicaments prepared therefrom are generally useful for the treatment of cell proliferative diseases, for the treatment or prevention of immunological diseases and conditions (e.g., inflammatory diseases, neuroimmune diseases, autoimmune diseases or the like). Do.

The compounds of the present invention are useful for the treatment of diseases caused by malignant cell proliferation, such as all forms of solid tumors, leukemias and lymphomas. Thus, the compounds according to the invention and medicaments prepared therefrom generally modulate cell activation, cell proliferation, cell survival, cell differentiation, cell cycle, cell maturation and cell death, or with changes in sugar, lipid or protein metabolism. It is useful for inducing such systemic metabolic changes. These include, for example, blood cell growth and production (progenitor-hematopoietic effect) after depletion or destruction of cells caused by toxic agents, radiation, immunotherapy, growth deficiency, malnutrition, malabsorption, dysregulation, anemia, etc. It may be used to support cell development, or to provide therapeutic control of tissue development and degradation and therapeutic modification of cell and tissue maintenance and blood cell homeostasis.

Such diseases and conditions may include hematological (eg, leukemia, lymphoma, myeloma) or solid tumors (eg, breast, prostate, liver, bladder, lung, esophagus, stomach, rectal colon, urogenital, gastrointestinal, skin, Such as pancreas, brain, uterus, rectum, head and neck, cerebral and ovary, melanoma, astrocytoma, small cell lung cancer, glioma, basal and squamous cell carcinoma, sarcomas such as Kaposi's sarcoma, and bone sarcoma) Cancer) or the treatment of a disease that is treated or alleviated by the inhibition of one or several kinases and / or phosphatase. The compounds according to the invention and the medicaments prepared therefrom are particularly useful for the treatment of prostate cancer, melanoma, ovarian cancer and multiple myeloma.

"Treatment" according to the present invention is understood to mean the complete or partial treatment of a disease, or the alleviation of a disease or the stopping of a given disease.

Thus, in one embodiment, the present invention relates to a disease characterized by a hyperproliferation of keratinocytes and / or T cells, in particular inflammatory and immune diseases, preferably Addison's disease, alopecia areata, ankylosing spondylitis, hemolytic anemia (Anemia Hemolytica), pernicious anemia (Anemia punisiosa), aphtha, aphtha bleeding, arthritis, arteriosclerosis, osteoarthritis, rheumatoid arthritis, aspermiogenese, bronchial asthma, auto-immune asthma, autologous Immune hemolysis, Behcet's disease, Shank's disease, inflammatory bowel disease, Burkitt's lymphoma, Crohn's disease, choroiditis, ulcerative colitis, celiac disease, cold globulinemia, herpes dermatitis, cutaneous myositis, insulin-dependent type I diabetes, childhood diabetes, Idiopathic diabetes insipidus, insulin-dependent diabetes mellitus, autoimmune debilitating disease, dupitren construction, encephalomyelitis, allergic encephalomyelitis, lens hypersensitivity, allergic Inflammation, autoimmune bowel disease, leprosy nodules erythema, idiopathic facial paralysis, chronic fatigue syndrome, rheumatic fever, glomerulonephritis, goodpasture syndrome, Graves' disease, Harnmann-Rich disease, Hasimoto disease, Hasimoto thyroiditis, sudden deafness , Sensorineural hearing loss, chronic hepatitis, Hodgkin's disease, paroxysmal hemochromatosis, gonadal dysfunction, local ileitis, iris infection, leukopenia, leukemia, disseminated lupus erythematosus, systemic lupus erythematosus, cutaneous lupus erythematosus, malignant lymphoblastoma, Infectious mononucleosis, myasthenia gravis, transverse myelitis, primary idiopathic myxedema, nephropathy, sympathetic ophthalmitis, granulomatous testicles, pancreatitis, cystic swelling, normal bleb, nodular polyarthritis, chronic primary polyarthritis, polymyositis, polyneuropathy, psoriasis , Purple thrombosis, necrotizing pyoderma, querbain thyroiditis, lighter syndrome, sarcoidosis, aphasia sclerosis, progressive systemic sclerosis, scleritis, transdermal Ephrsteines, such as hyperplasia, multiple sclerosis, seeding sclerosis, acquired spleen atrophy, infertility due to anti-sperm antibodies, hypoplatelets, idiopathic thrombocytopenia, thyroidoma, acute anterior uveitis, vitiligo, AIDS, HIV, SCID and Sjogren's syndrome Barbar virus-related diseases, viruses associated with B-cell lymphoma (AIDS or EBV), parasitic diseases such as Rischmann's flagella, and viral infections after allografts, AIDS, cancer, chronic active hepatitis diabetes, toxic chronic shock syndrome and food poisoning To prepare a medicament for the treatment or prophylaxis of a disease selected from the group consisting of immunosuppressive disease states, a compound of formula (Ia), (Ib), (Ic), (Ih), (II) or (III) or a pharmaceutically acceptable, if appropriate, with appropriate adjuvants and additives It relates to the use of possible salts or pharmaceutically acceptable prodrugs or stereoisomers thereof.

The compounds according to the invention and the medicaments prepared therefrom include autoimmune diseases and inflammatory diseases such as rheumatoid arthritis, polysclerosis, inflammatory bowel disease (especially colitis and Crohn's disease), inflammatory skin diseases (especially neurodermatitis and psoriasis) and lupus erythematosus It is particularly useful for treatment.

In addition, the present invention provides a method of treating a disease comprising administering an effective amount 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. It relates to a method of treatment or prevention.

The present invention provides a pharmaceutical composition comprising a compound of Formula (la), (lb), (c), (Ih), (II) or (III) together with a pharmaceutically acceptable diluent or carrier in free form or in a pharmaceutically acceptable salt and a pharmaceutically acceptable prodrug. To provide a composition.

In a preferred embodiment, the invention provides compounds of formula (Ia), (Ib), (Ic), (Ih), (II) or (III) together with suitable adjuvants and additives, if desired, for the manufacture of a medicament for the treatment or prevention of skin diseases in which T cells play an important role. To a compound or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable prodrug thereof or a stereoisomer thereof; Especially preferably the skin disease is psoriasis, atopic dermatitis, alopecia areata, total alopecia, partial alopecia, concurrent alopecia, extensive alopecia, erythematous lupus erythematosus, squamous gland, skin myositis, atopic eczema, local sclerosis, skin sclerosis , Psoriasis, head psoriasis, severity psoriasis, inversa psoriasis, mutant-type alopecia areata, androgenetic alopecia, allergic contact eczema, irritant contact eczema, contact eczema, normal sacral swelling, deciduous herniation, hyperplasia swelling, scar Formation mucosal swelling, bullous swelling, mucosal swelling, dermatitis, herpes dermatitis, urticaria, fatty necrosis, nodular erythema, thyroid, simple itching, nodular itching, acute itching, glandular IgA dermatitis, polymorphic dermatitis Sunburn, erythema, percutaneous atrophy, thyroid, skin erythema, drug lancet, chronic progressive purple erythema, hanpo eczema, eczema, fixed drug pidgin, Photoallergic skin reactions, simple tachycardia, dermatitis, and graft-versus-host-diseases, acne, rosacea, scarring, keloids and vitiligo.

In addition, the compounds of the present invention can be used for the treatment of diseases resulting from ischemia and / or reperfusion injury of organs and / or parts of the body selected from the group including the heart, brain, peripheral limbs, kidneys, liver, spleen and lungs. And endothelial dysfunction is associated with a disease selected from the group including infarctions such as myocardial infarction and urgent limb ischemia and / or endothelial dysfunction is a peripheral arterial obstructive disease such as urgent lower limb ischemia, myocardial infarction and eg kidney And ischemic diseases, such as ischemic diseases of organs such as the spleen, brain and lungs.

The compounds of the present invention are also useful for Alzheimer's disease, Parkinson's disease, Creutzfeldt-Jakob disease, Louis Bovine dementia, amyotrophic lateral sclerosis, stroke, epilepsy, multiple sclerosis, severe myasthenia, huntington chorea, Down syndrome, neuropneumonia and meniscus It can be applied for the prevention and treatment of diseases or diseases of the nervous system (including but not limited to the Er syndrome) (disorders or diseases related to the brain and nervous system). Other nervous system diseases and disorders will be apparent to those skilled in the art and are included in the definitions used in the present invention. The compounds according to 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 present invention can also be used in diseases caused by protozoan infections in humans and animals. Such veterinary and human pathogenic protozoa are preferably intracellular active parasites of Apicomplexa or Sarcomastigophora, in particular Trypanosoma, Plasmodia, Leishmania. ), Babesia and Theileria, Cryptosporidia, Sacrocystida, Amoebia, Coccidia and Trichomonadia. Such active substances or corresponding drugs include tropical malaria induced by Plasmodium falciparum, Plasmodium vivax, or triplet malaria caused by Plasmodium ovale, and Particularly suitable for the treatment of silencing fever malaria caused by Plasmodium malariae. In addition, they are intestinal spores caused by Toxoplasma gondii, intestines caused by Sarcocystis suihominis, coccidiasis caused by Isospora belli, and sarcocystis suihominis. Myosporosis, dysentery caused by Entamoeba histolytica, spores caused by Cryptosporidium parvum, Chargas caused by Trypanosoma cruzi ), Sleeppanes caused by Trypanosoma brucei rhodesiense or gambiense, as well as other forms of Rischman's flagellosis. They are protozoan pathogens such as Theileria parva, pathogens that cause bovine copper coastal fever, trypanosoma congolense congolense or trypanosoma vivax vivax. , Trypanosoma brucei brucei, pathogens that cause Nagana disease in Africa, Trypanosoma brucei evansi, which causes Surra, Babesia bigemina, Texas fever-induced pathogens in cattle and buffalo, Babesia bovis, European bovine barbecia disease, as well as pathogens that cause Barbacea disease in dogs, cats, and sheep, Sarkosistis obicanis and obifelis (Sarcocystis ovicanis and ovifelis), a pathogen causing myosporosis in sheep, cattle and pigs, Cryptosporidia (Cry ptosporidia), a pathogen that causes Cryptosporidium disease in cattle and birds, and pathogens that cause coccidiosis in Eimeria and Isospora species, rabbits, cattle, sheep, goats, pigs and birds, especially chickens and turkeys It is suitable for the treatment of animals infected by The use of the compounds of the present invention is particularly preferred for the treatment of coccidiosis or malaria infection, or for the manufacture of drugs or foods for the treatment of such diseases. Such treatment may be prophylactic or cure. In the treatment of malaria, the compounds of the present invention can be combined with other anti-malarial agents.

The compounds of the invention can also be used for the prevention and / or treatment of infectious diseases caused by bacteria and viruses, including opportunistic infections in mammals including humans, among others. The method may be directed to an effective amount of one or more compounds of Formulas Ia, Ib, Ic, Ih, II or III and / or pharmaceutically acceptable salts thereof to prevent and / or treat the infectious disease and / or opportunistic infection. Administering to the animal.

Infectious diseases include AIDS, multi-site insect repellent disease (AHD, insect repellent), amoebiasis (heterogeneous amoeba infection), angiostron gillus infection, whale larva larvae, anthrax, Barbes pyrophyllemia (Barbes pyelone infection), valan Tidium Infection (Vallantidium), Bairisascarris Infection (Raccoon Roundworm), Bladder Schistosomiasis (Sclerosis), Blastocystis Hominis Infection (Branemia), Borreliasis, Botulinum Toxinosis, Brainerd ) Diarrhea, brucellosis, BSE (bovine spongiform encephalopathy), candidiasis, capillary nematode (capillary nematode infection), CFS (chronic fatigue syndrome), Chagas disease (American wave schistosoma), chickenpox (chickenpox shingles virus), pneumonia Chlamydia Infection, Cholera, Chronic Fatigue Syndrome, CJD (Creutzfeldt-Jakob Disease), Gandistomiasis (Gandistomitis Infection), CLM (Skin Larva Transit, Insect Repellent Infection), Coccidioidecoccus, Conjunctivitis, Coxsackie Virus A16 (can Polio disease), yeast fungal infections, schizophrenic infection (schizophrenic disease), red colony (vector of West Nile virus), cutaneous larva transition (CLM), spermatozoa (cyclospora infection), schizophrenia (brain Insect repellent), cytomegalovirus infection (CMV), dengue / dengue fever, converting insect infection (dog and cat flea tapeworm), ebola virus hemorrhagic fever, insect repellent (polycystic disease), encephalitis, colon amoeba infection, isoform amoeba infection, Small amoeba infection, dysentery amoeba infection (amoebiasis), polekee amoeba infection, urethritis (pyrasitis infection), enterovirus infection (non-folio), Epstein-Barr virus infection, Escherichia coli infection, food poisoning infection, foot and mouth disease , Fungal dermatitis, gastroenteritis, Streptococcus group A disease, Streptococcus group B disease, Staphylococcus (Staphylcoccus aures and other Staphylococcus spp.) Infections , Pseudomona Diseases caused by infections with Pseudomonas aeruginosa and other Pseudomonas species, Burkholderia cepacia infection, Hansen's disease (leprosy), Hantavirus pulmonary syndrome, Lice infection (parasitic), Helicobacter Helicobacter pylori infection, blood diseases, hendra virus infection, hepatitis, herpes zoster (herpes zoster), HIV infection, human erlichia, human parainfluenza virus infection, influenza, sporeworm infection (sporestag infection), Lhasa fever , Leishman's flagellitis, Cala-Azar (color-a-zar, Leishman's flagellitis infection), leprosy, teeth (body, head lice, aerial teeth), Lyme disease, Marburg hemorrhagic fever, measles, meningitis, mosquito caused disease, mycobacterium Leeum Avium Complex (MAC) Infection, Naegleria Infection, Intra-hospital Infection, Nonpathogenic Intestinal Amoeba Infection, Necrosis (Petosis), Hepatic Insufficiency (Hepatitis Infection), Parvoby Infections, plague, PCP (Poles alveoli), polio, Q fever, rabies, respiratory syncytia virus (RSV) infection, rheumatic fever, Rift valley fever, filamentous nematode (rotary nematode), rotavirus infection, roundworm infection, Salmonella, Salmonella Entericitis, scabies, bacterial dysentery, ti herpes, sleep sickness, smallpox, streptococcal infection, tapeworm infection (Tania infection), tetanus, toxic shock syndrome, tuberculosis, ulcers (digestive ulcer disease), canker fever, enteritis Vibrio infection, sepsis Vibrio infection, viral hemorrhagic fever, warts, waterborne infectious disease, West Nile virus infection (West Nile encephalitis), whooping cough, yellow fever. The compounds according to the invention and 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. .

In addition, the compounds according to the invention and the medicaments prepared therefrom are particularly useful for the treatment of atherosclerosis.

The compounds according to 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 for the manufacture of a medicament for the treatment or prevention of a disease characterized by hyperproliferation of cells.

In one embodiment, the invention relates to a disease resulting from ischemia and / or reperfusion injury of organs and / or portions of the body selected from the group including the heart, brain, peripheral limbs, kidneys, liver, spleen and lungs, and / or myocardium To treat or prevent endothelial dysfunction associated with diseases selected from the group including infarctions such as infarction and severe limb ischemia, and / or endothelial dysfunction associated with diseases selected from the group including ischemic diseases, myocardial infarction and organ ischemic diseases. To the use of a compound or composition of the invention for the manufacture of a medicament.

In one embodiment, the present invention provides Alzheimer's disease, Parkinson's disease, Creutzfeldt-Jakob disease, Lewy body dementia, amyotrophic lateral sclerosis, stroke, epilepsy, multiple sclerosis, severe myasthenia, Huntington's chorea, Down syndrome, neuropneumonia And the use of a compound or composition of the present invention for the manufacture of a medicament for the treatment or prevention of a neurological disease or condition selected from the group comprising Meniere's disease.

Compounds of formula (Ia), (Ib), (Ic), (Ih), (II) or (III), and pharmacologically acceptable salts thereof, as animals, preferably mammals, in particular humans, dogs and chickens, as their own therapeutics, as a mixture with each other, or Pharmaceutical formulations which enable enteral or parenteral use and which contain an effective amount of at least one compound or salt thereof of the formula (Ia), (Ib), (Ic), (Ih), (II) or (III) as an active ingredient in addition to conventional pharmaceutically harmless excipients and additives. It may be administered in the form of a formulation. Compounds of Formulas Ia, Ib, Ic, Ih, II or III can also be administered in the form of their salts, which can be obtained by reacting each compound with a physiologically acceptable acid and base.

The preparation of medicaments containing the compounds of the formulas Ia, Ib, Ic, Ih, II or III according to the invention and their application can be carried out according to known pharmaceutical methods.

Although the compounds of formula (Ia), (Ib), (Ic), (Ih), (II) or (III) according to the invention for use in therapy may also be administered in the form of source compounds, the active ingredient may optionally contain one or more adjuvants, excipients, carriers, buffers, Incorporation in the form of physiologically acceptable salts in pharmaceutical compositions with diluents and / or other conventional pharmaceutical auxiliaries is preferred. Salts of these compounds may be anhydrous or solvated.

In a preferred embodiment, the present invention provides 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 according to the present invention. A medicament comprising the above pharmaceutically acceptable carrier and, optionally, other therapeutic and / or prophylactic ingredients is provided. The carrier (s) should be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof.

The medicaments of the invention may be oral, rectal, bronchial, nasal, topical, buccal, sublingual, transdermal, vaginal or parenteral (skin, subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial, intracranial, intraocular injection or infusion) A medicament suitable for administration, or a medicament in a suitable form for administration by inhalation or aeration, or by a sustained release system, including powder and liquid aerosol administration, may be employed. Suitable examples of sustained release systems include semipermeable matrices of solid hydrophobic polymers containing the compounds of the present invention, which matrices may be in the form of shaped articles, eg films, or microcapsules.

The compounds according to the invention can be prepared in medicaments and their unit dosage forms together with conventional adjuvants, carriers or diluents. Such forms include solid, in particular tablet, filled capsules, powder and pellet forms, and liquids, especially aqueous or non-aqueous solutions, suspensions, emulsions, elixirs, and capsules filled with them (all oral use), rectal administration Suppositories, and sterile injectable solutions for parenteral use. Such agents and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or elements, which unit dosage forms may suitably include the active ingredient corresponding to the daily dosage range employed. It may contain an effective amount.

The compounds that can be used according to the invention can be administered in a variety of oral and non-oral dosage forms. It will be apparent to those skilled in the art that the dosage form may comprise a compound of formula (Ia), (Ib), (Ic), (Ih), (II) or (III) or a pharmaceutically acceptable salt thereof or stereoisomer thereof as the active ingredient.

To prepare a medicament from a compound of Formula (la), (lb), (lc), (Ih), (II) or (III), the pharmaceutically acceptable carrier can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. The solid carrier may be one or more substances that may act as diluents, flavors, solubilizers, lubricants, suspending agents, binders, preservatives, tablet de-aerated or encapsulated materials.

In powders, the carrier is a finely divided solid which is a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugars, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting waxes, cacao butters and the like. The term “formulation” is intended to include the formulation of the active compound with an encapsulating material as a carrier which encapsulates the active ingredient with or without a carrier and thus provides a capsule in association with the carrier. Similarly, cachets and sugar tablets are included. Tablets, powders, capsules, pills, cachets and glycosides can be used as solid forms suitable for oral administration.

To prepare suppositories, low melting waxes such as mixtures of fatty acid glycerides or cacao butters are first melted and the active ingredients are homogeneously dispersed therein by stirring. Thereafter, the molten homogeneous mixture is poured into a mold of the usual size, cooled and thereby solidified. Suitable compositions for rectal administration may be presented as a suppository, tampons, creams, gels, pastes, foams or sprays which contain a carrier in addition to the active ingredient as is known in the art. Liquid formulations include solutions, suspensions and emulsions, such as water or water-propylene glycol solutions. For example, parenteral injection solution formulations may be formulated as solutions in aqueous polyethylene glycol solution.

Thus, the compounds of formulas Ia, Ib, Ic, Ih, II or III according to the invention may also be formulated for parenteral administration (for example by injection, for example by bolus injection or continuous infusion), and ampoules It may also be presented in unit dosage form in a multi-dose container with a pre-filled injection, a small volume infusion or a preservative added. The compositions may take the form of suspensions, solutions or emulsions in oily or aqueous excipients, and may contain formulations such as suspensions, stabilizers and / or dispersants. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable excipient, for example, sterile, non-pathogenic water, before use. May exist.

Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers and thickeners, if desired. The finely divided active ingredients can be dispersed in water with viscous materials such as natural or synthetic rubbers, resins, methylcellulose, sodium carboxymethylcellulose or other known suspending agents to make aqueous suspensions suitable for oral use.

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. Such formulations may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers and the like.

In one embodiment of the invention, the medicament is applied locally or systemically or via a combination of the two 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 the affected area.

Preferably, the medicament is in the form of an ointment, gel, plaster, emulsion, lotion, foam, mixed phase cream or amphiphilic emulsion system (oil / water-water / milk mixed phase), liposomes, transfersomes, pastes or powders To manufacture.

Ointments and creams may be formulated with an aqueous or oily base, for example, by the addition of suitable thickening and / or gelling agents. Lotions are formulated with an aqueous or oily base and will generally also contain one or more emulsifiers, stabilizers, dispersants, suspensions, thickeners or colorants.

Compositions suitable for topical administration to the mouth include sugar-containing tablets comprising the active agent in a flavor base, typically sucrose and gum arabic or tragacanth; Pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and gum arabic; And mouthwashes comprising the active ingredient in a suitable liquid carrier.

The solution or suspension is applied directly to the nasal cavity by conventional means, eg by dropper, pipette or spray. The composition may be provided in single or multi-dose form. In the case of a dropper or pipette, this may be achieved by administering to the patient an appropriate predetermined volume of solution or suspension. In the case of a spray, this can be achieved by a metering atomizing spray pump.

Administration to the respiratory tract may be carried out by a suitable propellant such that the active ingredient is chlorofluorocarbon (CFC), for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide or other suitable gas. Together with the aerosol formulation provided in the pressurized pack. Aerosols may also conventionally contain surfactants such as lecithin. The dose of drug may be controlled by the provision of a metered valve.

Alternatively, the active ingredient may be provided in the form of a dry powder, for example a powder mixture of compounds, in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP). have. Conveniently, the powder carrier will form a gel in the nasal cavity. The powder composition may be provided in unit dosage form, for example in capsules or cartridges of gelatin or in blister packs in which the powder may be administered by an inhaler.

In compositions intended to be administered to the respiratory tract, including intranasal compositions, the compounds will generally have a small particle size of, for example, 5 microns or less. Such particle size can be obtained by means known to those skilled in the art, for example by micronization.

If desired, compositions suitable for providing sustained release of the active ingredient can also be used.

The pharmaceutical composition is preferably present in unit dosage form. In this form the formulation is subdivided into unit doses containing appropriate amounts of the active ingredient. The unit dosage form can be a packaged preparation, the package containing tablets, capsules and powders packaged in separate quantities of the preparation, such as vials or ampoules. In addition, the unit dosage form may be a capsule, a tablet, a cachet or the tablet itself, or may have a number appropriate for the package form. Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are preferred compositions.

Details regarding formulations and techniques for administration can be found in a recent edition of Remington's Pharmaceutical Sciences, (Maack Publishing Co. Easton, Pa.).

The pharmaceutical composition may also contain two or more compounds of formula (la), (lb), (lc), (h), (II) or (III), or pharmacologically acceptable salts thereof and other pharmaceutically active substances.

Thus, the compounds of the present invention can be used either alone or in combination with other active compounds-for example in combination with known agents for the treatment of the above-mentioned diseases, which is advantageous in the latter case. Further amplification effects are noted. Amounts suitable for administration to a human may range from 5 to 500 mg.

To prepare pharmaceutical formulations, pharmaceutical inert inorganic or organic excipients can be used. To prepare pills, tablets, coated tablets and hard gelatin capsules, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used. Excipients for soft gelatin capsules and suppositories are, for example, fats, waxes, semi-solid and liquid polyols, natural or hardened oils and the like. Suitable excipients for the preparation of solutions and syrups are, for example, water, sucrose, invert sugar, glucose, polyol and the like. Suitable excipients for the preparation of injectable solutions are, for example, water, alcohols, glycerol, polyols or vegetable oils.

In individual cases the dosage can vary within wide limits and suits the individual conditions. For such use, the appropriate dosage will vary depending upon the mode of administration, the particular condition being treated and the desired effect. In general, however, satisfactory results are achieved at a dosage ratio of about 1 to 100 mg / kg animal body, preferably 1 to 50 mg / kg. Generally, suitable dosage ratios for larger mammals, such as humans, may be about 10 mg to 3 g / day, conveniently administered once daily, divided two to four times daily, or in sustained release form. Administered.

In general, for oral administration, a daily dosage of about 10 mg to 5000 mg, preferably 50 to 500 mg per human individual is appropriate. For other dosage forms, the daily dosage is in a similar range. For topical delivery, depending on the penetration rate of the skin, the type and severity of the disease, and the type and frequency of application of the formulation, different concentrations of active ingredient in the medicament may be sufficient to elicit a therapeutic effect by topical application. Preferably, the concentration of the active compound or pharmaceutically acceptable salt or physiologically functional derivative or stereoisomer thereof in the medicament according to the invention is in the range of 1 micromolar / l to 100 mmol / l.

The following examples and figures are included to demonstrate preferred embodiments of the present invention. Those skilled in the art should understand that the techniques disclosed in the following examples are techniques which have been found by the inventors to function in carrying out the present invention, and thus can be regarded as a preferred manner of implementation. However, in light of the disclosure of this invention, it should be understood by those skilled in the art that many changes may be made in the specific embodiments disclosed herein without departing from the spirit and scope of the invention as set forth in the appended claims. All references cited are hereby incorporated by reference.

Abbreviation: min, min; h, time; r.t. Room temperature; t-, tert-.

NMR spectrum: Bruker Avance 300 MHz. Spectra were recorded at 300 MHz ( ¹ H-NMR) using residual solvent peak as internal standard (DMSO-d ₆ , δ _H = 2.49; CD ₃ OD, δ _H = 3.31; CDCl ₃ , δ _H = 7.26; CD ₃ CN, δ _H = 1.93; (CD ₃ ) ₂ CO, δ _H = 2.05).

Analytical LC / ESI-MS: 2 × Waters 600 multisolvent delivery system. 50 μl sample loop. Column, with Chromolith speed ROD RP18e (Merck, Darmstadt), 50 × 4.6 mm, 2 μm prefilter (Merck). Eluent A, H ₂ O + 0.1% HCO ₂ H; Eluent B, MeCN. Gradient, 5% B to 100% B within 5 minutes; Flow rate, 3 ml / min. Waters LCZ single quadrupole mass spectrometer with electrospray source. MS method, MS8min PM-80-800-20V; Positive / negative ion scanning, m / z 80-800, 1 s; Capillary, 3.5 kV; Cone voltage, 20V; Multiplier voltage, 400 V; Probe and desolvent gas temperatures, 120 ° C. and 350 ° C., respectively. Waters 2487 dual λ absorbance detector set at 254 nm.

Preparative HPLC-MS: Waters 600 multi-solvent delivery system with a preform pump head. 2000 μl or 5000 μl sample loop. Column, Waters X-Terra RP18 with X-terra RP18 guard cartridge 7 μm, 19 × 10 mm, 7 μm, 19 × 150 mm; Flow rate 20 ml / min or YMC ODS-A, 120 mm 3, 40 × 150 mm, with X-terra RP 18 guard cartridge 7 μm, 19 × 10 mm; Used at flow rate 50 ml / min. Makeup Solvent: MeCN-H ₂ O-HCO ₂ H 80: 20: 0.05 (v: v: v). Eluent A, H ₂ O + 0.1% HCO ₂ H; Eluent B, MeCN. Various linear gradients of 5-100% eluate B, adapted to the sample. Injection volume: 500 μl-2000 μl depending on the sample. Waters ZQ Single Quadrupole Mass Spectrometer with Electrospray Source; Positive / negative ion scanning, m / z 80-800, 1 s; Capillary, 3.5 kV; Cone voltage, 20 V; Multiplier voltage, 400 V; Probe and desolvent gas temperatures, 120 ° C. and 350 ° C., respectively. Waters Fraction Collector II with mass-induced fraction collection; Waters 996 Photodiode Array Detector.

4-( Methoxy -methyl- Carbamoyl Synthesis of) -piperidine-1-carboxylic Acid t-butyl Ester

Piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.0 equiv, 21.8 mmol) was dissolved in 35 ml anhydrous N, N-dimethylformamide under inert conditions. O, N-dimethylhydroxylamine hydrochloride (1.03 equiv, 22.5 mmol), benzotriazol-1-ol monohydrate (1.03 equiv, 22.5 mmol) and triethylamine (1.5 equiv, 32.7 mmol) were added. The reaction mixture is cooled to 0 ° C. and N- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride (1.0 equiv, 21.8 mmol) is added over 10 minutes and the mixture is stirred at 0 ° C. for 1 hour. And vigorously stirred at room temperature for 18 hours.

The solvent was removed in vacuo and the residue was suspended in 400 ml ethyl acetate. The organic layer was extracted three times with 100 ml of 1M citric acid, aqueous sodium carbonate and twice with 100 ml brine, dried over MgSO ₄ and filtered. The solvent was removed and the residue was purified by distillation to yield 80% yield.

4- Formyl -Synthesis of piperidine-1-carboxylic acid t-butyl ester

4- (methoxy-methyl-carbamoyl) -piperidine-1-carboxylic acid tert-butyl ester (1.0 equiv, 16.4 mmol) was dissolved in 100 ml anhydrous tetrahydrofuran under inert atmosphere. This solution was added dropwise to lithium alanate suspension (3.0 equiv, 49.6 mmol) in 70 ml anhydrous tetrahydrofuran at −50 ° C. over 1 h. During the addition of the mixture, the temperature was maintained at -50 ° C and then warmed to 0 ° C within 3 hours. The mixture was cooled to -78 ° C and carefully quenched with 100 ml 1 M citric acid. The mixture was allowed to warm to rt and diluted with 400 ml ethyl acetate. The phases were separated and the aqueous phase was extracted three times with 70 ml ethyl acetate. The combined organic layers were extracted three times with 100 ml 1M citric acid, aqueous sodium carbonate and twice with 100 ml brine, dried over MgSO ₄ and filtered. The solvent was removed and the residue was purified by distillation to give a yield of 85%.

4- (4- Ethoxycarbonyl -4,5- Dehydro Synthesis of -thiazol-2-yl) -piperidine-1-carboxylic acid t-butyl ester

4-formyl-piperidine-1-carboxylic acid tert-butyl ester (1.0 equiv, 13 mmol) was dissolved in 40 ml toluene under inert conditions. To this solution was added sterol hydrochloride (1.6 equiv, 21 mmol) and triethylamine (1.6 equiv, 21 mmol) to L-cysteine ethyl. The mixture was refluxed for 14 h. The resulting water was removed with a Dean & Stark trap. The solvent was removed and the residue was dissolved in 100 ml ethyl acetate. The organic layer was extracted three times with 50 ml 1 M citric acid, aqueous potassium hydrogen carbonate and twice with 50 ml brine, dried over MgSO ₄ and filtered. The solvent was removed and the residue was purified by silica gel chromatography using a PE / EA 4: 1 gradient. Yield 75%.

4- (4- Ethoxycarbonyl Synthesis of -thiazol-2-yl) -piperidine-1-carboxylic acid t-butyl ester

160 ml of 4- (4-ethoxycarbonyl-4,5-dihydro-thiazol-2-yl) -piperidine-1-carboxylic acid tert-butyl ester (1.0 equiv, 8.7 mmol) under inert conditions Dissolved in toluene. MnO ₂ (15.0 equiv, 130 mmol) was added to this solution. The reaction was heated to 70 ° C. for 5 hours under stirring. The mixture was filtered over celite and the filter was washed three times with 30 ml toluene and ethyl acetate. The combined organic layers were distilled under vacuum. The residue was purified by silica gel chromatography using a DCM / MeOH 95: 5 gradient. Yield: 30%.

C-terminal Functionalization

4- (4-ethoxycarbonyl-thiazol-2-yl) -piperidine-1-carboxylic acid tert-butyl ester (1.0 equiv, 2.9 mmol) was dissolved in 40 ml dioxane under inert gas. Under stirring 1.5 ml aqueous 2N NaOH was added dropwise over 10 minutes. Then the mixture was stirred at rt for 2 h. The reaction was neutralized with 2N HCl and the solvent was evaporated in vacuo. The residue was dissolved in 50 ml ethyl acetate. The organic layer was extracted three times with 10 ml of 1 M citric acid and water, dried over MgSO ₄ and filtered. Solvent was removed and the residue was dried in vacuo. Yield 95%.

4- (4-carboxy-thiazol-2-yl) -piperidine-1-carboxylic acid tert-butyl ester (1 equiv) was dissolved in anhydrous dimethylacetamide (0.03 mmol / ml) under inert conditions. To this solution aryl- or alkylamine (1 equiv), diisopropylethylamine (2 equiv) and O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium hexafluoro Phosphate (2 equiv) was added. The reaction mixture was stirred at rt for 12 h.

The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The organic layer was extracted three times with 1M citric acid, aqueous potassium hydrogen carbonate and twice with brine, dried over MgSO ₄ and filtered. The solvent was removed and the residue was purified by silica gel chromatography using a DCM / MeOH 95: 5 gradient. Yield: 40-80%.

N-terminal Functionalization

The N-protected substrate was treated with 4M HCl / dioxane (0.03 mmol mol of 1 mL HCl / dioxane) under inert conditions and stirred at room temperature for 2 hours. The solvent was removed in vacuo to yield the HCl salt of the free amine without further purification.

The free amino compound (1 equiv) was dissolved in anhydrous dimethylacetamide (0.03 mmol / ml) under inert conditions. To this solution aryl- or alkylcarboxylic acid (1 equiv), diisopropylethylamine (2 equiv) and O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium hexa Fluorophosphate (2 equiv) was added in sequence and the reaction mixture was stirred at rt for 12 h.

The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The organic layer was extracted three times with 1M citric acid, aqueous potassium hydrogen carbonate and twice with brine, dried over MgSO ₄ and filtered. The solvent was removed and the residue was purified by silica gel chromatography using a DCM / MeOH 95: 5 gradient. Yield: 40-80%.

General Synthesis of Compounds of Types (III) and (II)

type IIIa , IIIc , IIa  And IIb Synthesis procedure of compound

Dissolve 7.3 × 10 ⁻⁴ mole of benzoic acid derivative (VI) in 5 ml DMF, add 1 equivalent of Huenig base, stir the reaction mixture for several minutes, then add 1 equivalent of HBTU and add 2 at room temperature. Stir for further minutes. Then 1 equivalent of 2-amino-thiazole-4-carboxylic acid ethyl ester was added and the reaction was stirred at the same temperature overnight. The solvent was then removed by filtration and the residue was redissolved in 5 ml dioxane and treated with 0.5 ml 1M NaOH solution. After completion of the reaction, the pH was lowered to 1-2 with 1M HCl solution, and the precipitated product (VII) was filtered and dried under vacuum. For subsequent steps, Intermediate (VII) is dissolved in 3 ml DMF, 1 equivalent of Wunich base is added and the reaction mixture is stirred for several minutes, then 1 equivalent of HBTU is added and further at room temperature for 2 minutes Stirred. Then 1 equivalent of the amino component was added and the mixture was stirred at the same temperature overnight. Thereafter, the solvent was removed by filtration and the crude product was redissolved in 10 ml ethyl acetate and washed twice with 10 ml citric acid (1M solution), 10 ml saturated NaHCO ₃ solution and 10 ml water. The organic phase was then evaporated and the residue was dried over MgSO ₄ . Solvent was removed and final purification was performed by preparative HPLC as described above.

As a second variant for the first step, the corresponding acid chloride derivative of VI can be reacted with 2-amino-thiazole-4-carboxylic acid ethyl ester (1: 1) using 1.1 equivalents of Wiener base. have.

type ( IIIb , d, e, f) and ( IIc procedure for the synthesis of compounds of

6.3 × 10 ⁻⁴ mole of 2-bromo-thiazole-4-carboxylic acid ethyl ester (X) was dissolved in 10 ml THF with 2.2 equivalents of each piperazine (IX) and refluxed overnight. The solvent was then removed in vacuo and the residue was purified by pTLC (PE / EE 2/1).

The second and third stages of the reaction were carried out as described in the synthesis procedure for compounds of type (IIIa) and (IIIc) above.

See WO 2004/058750 for the synthesis protocol of type (IIIb, d, e, f and IIc, d) compounds with Z = CH.

Exemplary compounds of Formula Ia of the present invention include, but are not limited to:

Compound number designation mass LC / (+)-ESI-MS: Biological activity ¹⁾ 74 4- {4- [4- (3-Trifluoromethyl-phenyl) -piperazin-1-carbonyl] -thiazol-2-yl} -piperidine-1-carboxylic acid (7-fluoro -2,3-dihydro-benzo [1,4] dioxin-5-yl) -amide 619 620 [M + H] ⁺ ++ 75 4- {4- [4- (3-Trifluoromethyl-phenyl) -piperazin-1-carbonyl] -thiazol-2-yl} -piperidine-1-carboxylic acid (2,3- Dihydro-benzo [1,4] dioxan-6-yl) -amide 601 602 [M + H] ⁺ ++ 76 4- {4- [4- (3-Trifluoromethyl-phenyl) -piperazin-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) -piperazin-1-carbonyl] -thiazol-2-yl} -piperidine-1-carboxylic acid (2-thiophene -2-yl-ethyl) -amide 577 578 [M + H] ⁺ +++ 78 4- {4- [4- (3-Trifluoromethyl-phenyl) -piperazin-1-carbonyl] -thiazol-2-yl} -piperidine-1-carboxylic acid isopropylamide 509 510 [M + H] ⁺ + 79 4- {4- [4- (3-Trifluoromethyl-phenyl) -piperazin-1-carbonyl] -thiazol-2-yl} -piperidine-1-carboxylic acid (2-trifluoro Lomethoxy-phenyl) -amide 627 628 [M + H] ⁺ +++ 80 4- {4- [4- (3-Trifluoromethyl-phenyl) -piperazin-1-carbonyl] -thiazol-2-yl} -piperidine-1-carboxylic acid (3-methoxy Phenyl) -amide 573 574 [M + H] ⁺ + 81 4- {4- [4- (3-Trifluoromethyl-phenyl) -piperazin-1-carbonyl] -thiazol-2-yl} -piperidine-1-carboxylic acid (3,4, 5-trimethoxy-phenyl) -amide 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) -piperazin-1-carbonyl] -thiazol-2-yl} -piperidine-1-carboxylic acid phenylamide 543 544 [M + H] ⁺ + 142 4- {4- [4- (3-Trifluoromethyl-phenyl) -piperazin-1-carbonyl] -thiazol-2-yl} -piperidine-1-carboxylic acid (3-fluoro Phenyl) -amide 561 562 [M + H] ⁺ ++ 143 4- {4- [4- (3-Trifluoromethyl-phenyl) -piperazin-1-carbonyl] -thiazol-2-yl} -piperidine-1-carboxylic acid (4-fluoro Phenyl) -amide 561 562 [M + H] ⁺ + 1) Biological data indicate the results obtained from NF-κB inflammation assay. ["+" Indicates 50-80% inhibition, "++" means 80-90% and "+++" indicates 90-100% inhibition]

Compounds of one example of Formula Ib of the present invention include, but are not limited to:

Compound number designation mass LC / (+)-ESI-MS: Biological activity ¹⁾ 103 2- {5-methyl-2- [1- (2-trifluoromethoxybenzoyl) -piperidin-4-yl] -thiazol-4-yl} -1- [4- (3-trifluoro Methyl-phenyl) -piperazin-1-yl] -ethanone 640 641 [M + H] ⁺ ++ 128 1- [4- (3-Chloro-phenyl) -piperazin-1-yl] -2- {5-methyl-2- [1- (2-trifluoromethoxy-benzoyl) -piperidine-4- Yl] -thiazol-4-yl} -ethanone 606 607 [M + H] ⁺ +++ 1) Biological data indicate the results obtained from NF-κB inflammation assay. ["+" Indicates 50-80% inhibition, "++" means 80-90% and "+++" indicates 90-100% inhibition]

Exemplary compounds of Formula (Ic) of the present invention include, but are not limited to, the following.

Compound number designation mass LC / (+)-ESI-MS: Biological activity ¹⁾ 150 [1- (5-chloro-2-methylamino-phenyl) -3,4-dihydro-1H-isoquinolin-2-yl]-{2- [1- (2-trifluoromethoxy-benzoyl) pi Ferridin-4-yl] -thiazol-4-yl} methanone 654 655 [M + H] ⁺ ++ 160 1- {4- [4- (6,7-Dihydroxy-3,4-dihydro-1 H-isoquinolin-2-carbonyl) -thiazol-2-yl] -piperidin-1-yl } -2- (4-fluoro-phenyl) -ethanone 495 496 [M + H] ⁺ + 161 1- {4- [4- (6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-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 Rho-phenyl) -ethanone 463 464 [M + H] ⁺ + 232 1- {4- [4- (6,7-Dimethoxy-3-methyl-3,4-dihydro-1 H-isoquinolin-2-carbonyl) -thiazol-2-yl] -piperidine- 1-yl} -2- (4-fluoro-phenyl) -ethanone 537 538 [M + H] ⁺ + 233 1- {4- [4- (6,7-Dihydroxy-1-methyl-3,4-dihydro-1H-isoquinolin-2-carbonyl) -thiazol-2-yl] -piperidine -1-yl} -2- (4-fluoro-phenyl) -ethanone 509 510 [M + H] ⁺ + 234 1- {4- [4- (6,7-Dimethoxy-1-methyl-3,4-dihydro-1H-isoquinolin-2-carbonyl) -thiazol-2-yl] -piperidine- 1-yl} -2- (4-fluoro-phenyl) -ethanone 537 538 [M + H] ⁺ + 235 1- (4- {4- [1- (5-chloro-2-methylaminophenyl) -3,4-dihydro-1H-isoquinolin-2-carbonyl] -thiazol-2-yl} -pi Ferridin-1-yl) -2- (4-fluoro-phenyl) -ethanone 602 603 [M + H] ⁺ + 1) Biological data indicate the results obtained from NF-κB inflammation assay. ["+" Indicates 50-80% inhibition, "++" means 80-90% and "+++" indicates 90-100% inhibition]

Exemplary compounds of Formula II of the present invention include, but are not limited to:

Compound number designation mass LC / (+)-ESI-MS: Biological activity ¹⁾ 3 N- {4- [4- (4-Fluoro-phenyl) -piperazin-1-carbonyl] -thiazol-2-yl} -2-trifluoromethoxy-benzamide 494 495 [M + H] ⁺ ++ 5 N- [5- (4-Pyrimidin-2-yl-piperazin-1-carbonyl) -thiazol-2-yl] -2-trifluoromethoxy-benzamide 478 479 [M + H] ⁺ + 15 2-methoxy-N- {4- [4- (3-trifluoromethylphenyl) -piperazine-1-carbonyl] -thiazol-2-yl} benzamide 490 491 [M + H] ⁺ +++ 16 3-fluoro-4-trifluoromethyl-N- (1- {4- [4- (3-trifluoromethyl-phenyl) -piperazin-1-carbonyl] -thiazol-2-yl} Piperidin-4-ylmethyl) -benzamide 643 644 [M + H] ⁺ ++ 17 3-cyclopentyl-N- (1- {4- [4- (3-trifluoromethyl-phenyl) -piperazin-1-carbonyl] -thiazol-2-yl} -piperidine-4- Monomethyl) -propionamide 577 578 [M + H] ⁺ ++ 18 2-trifluoromethoxy-N- (1- {4- [4- (3-trifluoromethyl-phenyl) -piperazin-1-carbonyl] -thiazol-2-yl} -piperidine -4-ylmethyl) -benzamide 641 642 [M + H] ⁺ ++ 19 4-cyano-N- (1- {4- [4- (3-trifluoromethyl-phenyl) -piperazin-1-carbonyl] -thiazol-2-yl} -piperidine-4- Monomethyl) -benzamide 582 583 [M + H] ⁺ ++ 20 [4- (3-Trifluoromethyl-phenyl) -piperazin-1-yl]-{2- [4- (4-trifluoromethyl-phenyl) -piperazin-1-yl] -thiazole- 4-day} -Methanone 569 570 [M + H] ⁺ ++ 21 {2- [4- (4-Trifluoromethoxy-phenyl) -piperazin-1-yl] -thiazol-4-yl}-[4- (3-trifluoromethyl-phenyl) -piperazine- 1-day] -Methanone 585 586 [M + H] ⁺ + 22 {2- [4- (2-Trifluoromethoxy-benzyl) -piperazin-1-yl] -thiazol-4-yl}-[4- (3-trifluoromethyl-phenyl) -piperazine- 1-day] -Methanone 599 600 [M + H] ⁺ +++ 23 {2- [4- (4-Bromo-benzyl) -piperazin-1-yl] -thiazol-4-yl}-[4- (3-trifluoromethyl-phenyl) -piperazin-1- Sun] -Methanone 593 594 [M + H] ⁺ +++ 24 {2- [4- (3-Trifluoromethoxy-benzyl) -piperazin-1-yl] -thiazol-4-yl}-[4- (3-trifluoromethyl-phenyl) -piperazine- 1-day] -Methanone 599 600 [M + H] ⁺ +++ 32 2-trifluoromethoxy-N- {4- [4- (3-trifluoromethyl-phenyl) -piperazine-1-carbonyl] -thiazol-2-yl} -benzamide 544 545 [M + H] ⁺ +++ 33 3-cyclopentyl-N- {4- [4- (3-trifluoromethyl-phenyl) -piperazin-1-carbonyl] -thiazol-2-yl} -propionamide 480 481 [M + H] ⁺ +++ 34 3-Fluoro-4-trifluoromethyl-N- {4- [4- (3-trifluoromethyl-phenyl) -piperazin-1-carbonyl] -thiazol-2-yl} -benzamide 546 547 [M + H] ⁺ +++ 37 3-cyclopentyl-1- (4- {4- [4- (3-trifluoromethyl-phenyl) -piperazin-1-carbonyl] -thiazol-2-yl} -piperazin-1-yl ) -Propane-1-one 549 550 [M + H] ⁺ +++

Compound number designation mass LC / (+)-ESI-MS: Biological activity ¹⁾ 38 {2- [4- (2-methoxy-benzoyl) -piperazin-1-yl] -thiazol-4-yl}-[4- (3-trifluoromethylphenyl) -piperazin-1-yl] -Metanon 559 560 [M + H] ⁺ +++ 39 {2- [4- (2-Trifluoromethoxy-benzoyl) -piperazin-1-yl] -thiazol-4-yl}-[4- (3-trifluoromethylphenyl) -piperazine-1- Sun] -Methanone 613 614 [M + H] ⁺ +++ 41 N- {4- [4- (3,4-Dichloro-phenyl) -piperazin-1-carbonyl] -thiazol-2-yl} -2-trifluoromethoxy-benzamide 544 545 [M + H] ⁺ +++ 44 N- {4- [4- (2-methoxy-phenyl) -piperazin-1-carbonyl] -thiazol-2-yl} -2-trifluoromethoxy-benzamide 506 507 [M + H] ⁺ ++ 55 1- (2-Trifluoromethoxy-phenyl) -3- {4- [4- (3-trifluoromethyl-phenyl) -piperazin-1-carbonyl] -thiazol-2-yl} -urea 559 560 [M + H] ⁺ +++ 58 N- [4- (4-Benzhydryl-piperazin-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] -methanone 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] -methanone 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] ⁺ +++ 62 4- (4- {4- [4- (3-Trifluoromethyl-phenyl) -piperazin-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] ⁺ ++ 64 (2-piperazin-1-yl-thiazol-4-yl)-[4- (3-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone 425 426 [M + H] ⁺ + 65 {2- [4- (2-methoxy-phenyl) -piperazin-1-yl] -thiazol-4-yl}-[4- (3-trifluoromethyl-phenyl) piperazin-1-yl ] Methanone 531 532 [M + H] ⁺ ++ 66 1- [4- (4- {4- [4- (3-trifluoromethylphenyl) -piperazin-1-carbonyl] thiazol-2-yl] piperazin-1-yl) phenyl] -ethanone 543 544 [M + H] ⁺ ++ 67 [4- (3-Trifluoromethyl-phenyl) -piperazin-1-yl]-{2- [4- (3-trifluoromethyl-phenyl) -piperazin-1-yl] -thiazole- 4-day} -Methanone 569 570 [M + H] ⁺ + 68 [2- (4-phenyl-piperazin-1-yl) -thiazol-4-yl]-[4- (3-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone 501 502 [M + H] ⁺ +

Compound number designation mass LC / (+)-ESI-MS: Biological activity ¹⁾ 69 {2- [4- (4-Fluoro-phenyl) -piperazin-1-yl] -thiazol-4-yl}-[4- (3-trifluoromethyl-phenyl) -piperazin-1- Japan] Metanon 519 520 [M + H] ⁺ ++ 71 (4-benzhydryl-piperazin-1-yl)-[2- (4-benzyl-piperazin-1-yl) -thiazol-4-yl] -methanone 537 538 [M + H] ⁺ +++ 72 [2- (4-Benzyl-piperazin-1-yl) -thiazol-4-yl]-[4- (3-trifluoromethyl-phenyl) -piperazin-1-yl) -methanone 515 516 [M + H] ⁺ +++ 99 3-fluoro-4-trifluoromethyl-N- (1- {4- [4- (3-trifluoromethyl-phenyl) -piperazin-1-carbonyl] -thiazol-2-yl} -Piperidin-4-ylmethyl) -benzamide 642 643 [M + H] ⁺ + 100 3-cyclopentyl-N- (1- {4- [4- (3-trifluoromethyl-phenyl) -piperazin-1-carbonyl] -thiazol-2-yl} -piperidine-4- Monomethyl) -propionamide 576 577 [M + H] ⁺ + 101 2-trifluoromethoxy-N- (1- {4- [4- (3-trifluoromethyl-phenyl) -piperazin-1-carbonyl] -thiazol-2-yl} -piperidine- 4-ylmethyl) -benzamide 640 641 [M + H] ⁺ + 102 4-cyano-N- (1- {4- [4- (3-trifluoromethyl-phenyl) -piperazin-1-carbonyl] -thiazol-2-yl} -piperidine-4- Monomethyl) -benzamide 581 582 [M + H] ⁺ + 241 {2- [1- (2,6-Dimethoxy-pyrimidin-4-yl) -piperidin-4-yl] -5-methoxy-oxazol-4-yl}-[4- (3- Trifluoromethyl-phenyl) -piperazin-1-yl] -methanone 576 577 [M + H] ⁺ ++ 242 {2- [1- (4,6-Dimethoxy- [1,3,5] triazin-2-yl) -piperidin-4-yl] -5-methoxy-oxazol-4-yl} -[4- (3-Trifluoromethyl-phenyl) -piperazin-1-yl] -methanone 577 578 [M + H] ⁺ ++ 243 {2- [1- (2,6-Dimethoxy-pyrimidin-4-yl) -piperidin-4-yl] -5-methoxy-oxazol-4-yl}-[4- (5- Trifluoromethyl-benzothiazol-1-yl) -piperidin-1-yl] -methanone 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-benzothiazol-1-yl) -piperidin-1-yl] -methanone 617 618 [M + H] ⁺ ++ 245 4- (4- {4- [4- (5-Trifluoromethyl-benzotriazol-1-yl) -piperidine-1-carbonyl] -thiazol-2-yl} -piperazin-1 -Yl-methyl) -benzonitrile 580 581 [M + H] ⁺ ++ 246 (2-Morpholin-4-yl-oxazol-4-yl)-[4- (3-trifluoromethyl-phenyl) -piperazin-1-yl] -methanone 410 411 [M + H] ⁺ + 1) Biological data indicate the results obtained from NF-κB inflammation assay. ["+" Indicates 50-80% inhibition, "++" means 80-90% and "+++" indicates 90-100% inhibition]

Exemplary compounds of Formula III of the present invention include, but are not limited to:

Compound number designation mass LC / (+)-ESI-MS: Biological activity ¹⁾ One 2-Morpholin-4-yl-thiazole-4-carboxylic acid (5,6-dimethyl-1H-benzoimidazol-2-yl) -amide 357 358 [M + H] ⁺ + 2 2- [3- (2-Trifluoromethoxy-phenyl) -ureido] -thiazole-4-carboxylic acid (1H-benzoimidazol-2-yl) -amide 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-benzoimidazol-2-yl) -guanidinocarbonyl] -thiazol-2-yl} -3,4-difluoro-benzamide 441 442 [M + H] ⁺ ++ 7 N- {4- [N '-(1H-benzoimidazol-2-yl) -guanidinocarbonyl] -thiazol-2-yl} -4-fluoro-benzamide 423 424 [M + H] ⁺ ++ 8 N- {4- [N '-(1H-benzoimidazol-2-yl) -guanidinocarbonyl] -oxazol-2-yl} -2-trifluoro-methoxybenzamide 473 474 [M + H] ⁺ +++ 9 2- (2-Trifluoromethoxy-benzoylamino) -thiazole-4-carboxylic acid (4-dimethylamino- [1,3,5] -triazin-2-yl) -amide 453 454 [M + H] ⁺ + 10 N- {4- [N '-(1H-benzoimidazol-2-yl) -guanidinocarbonyl] -thiazol-2-yl} -4-bromo-benzamide 483 484 [M + H] ⁺ ++ 11 N- {4- [N '-(1H-benzoimidazol-2-yl) -guanidinocarbonyl] -thiazol-2-yl} -2-methoxy-benzamide 435 436 [M + H] ⁺ ++ 12 N- {4- [N '-(1H-benzoimidazol-2-yl) -guanidinocarbonyl] -thiazol-2-yl} -2-trifluoromethoxy-benzamide 489 490 [M + H] ⁺ +++ 13 N- (1H-Benzoimidazol-2-yl) -N '-{2- [4- (2-trifluoromethoxy-benzoyl) -piperazin-1-yl] -thiazole-4-carbonyl} Guanidine 558 559 [M + H] ⁺ + 14 N- (1H-benzoimidazol-2-yl) -N '-[2- (2,3-dihydro-benzo [1,4] dioxin-2-yl) -thiazole-4-carbonyl} Guanidine 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] ⁺ +++ 27 N- {4- [N '-(1H-benzoimidazol-2-yl) -guanidinocarbonyl] -oxazol-2-yl} -3-fluoro-4-trifluoromethyl-benzamide 475 476 [M + H] ⁺ +++ 30 N- (1H-Benzoimidazol-2-yl) -N '-[2- (4-benzyl-piperazin-1-yl) -thiazole-4-carbonyl] -guanidine 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-benzoimidazol-2-yl) -N '-{2- [1- (2-trifluoromethoxy-benzoyl) -piperidin-4-yl] -thiazole-4-carbonyl } -Guanidine 557 558 [M + H] ⁺ +++  40 2- (2-Trifluoromethoxy-benzoylamino) -oxazole-4-carboxylic acid (5,6-dimethyl-1H-benzoimidazol-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] -amide 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-benzoimidazol-2-yl) -guanidinocarbonyl] -thiazol-2-yl} -2-cyclohexyl-benzamide 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-benzoimidazol-2-yl] -amide 553 554 [M + H] ⁺ +++ 49 N- (1H-benzoimidazol-2-yl) -N '-(2-morpholin-4-yl-thiazole-4-carbonyl) -guanidine 371 372 [M + H] ⁺ +++ 51 N- {4- [N '-(1H-benzoimidazol-2-yl) -guanidinocarbonyl] -thiazol-2-yl} -4-trifluoromethyl-benzamide 473 474 [M + H] ⁺ +++ 52 2- [1- (2-Trifluoromethoxy-benzoyl) -piperidin-4-yl] -thiazole-4-carboxylic acid [5- (propane-1-sulfonyl) -1H-benzoimidazole -2-yl] -amide 621 622 [M + H] ⁺ +++ 53 N- {4- [N '-(1H-benzoimidazol-2-yl) -guanidinocarbonyl] -thiazol-2-yl} -2-fluoro-4-trifluoromethyl-benzamide 491 492 [M + H] ⁺ +++ 54 1- {4- [N '-(1H-benzoimidazol-2-yl) -guanidinocarbonyl] -thiazol-2-yl} -3- (2-trifluoromethoxy-phenyl) -urea 504 505 [M + H] ⁺ +++ 56 N- {4- [N '-(1H-benzoimidazol-2-yl) -guanidinocarbonyl] -thiazol-2-yl} -3-fluoro-4-trifluoromethyl-benzamide 491 492 [M + H] ⁺ +++ 57 N- {4- [N '-(1H-benzoimidazol-2-yl) -guanidinocarbonyl] -thiazol-2-yl} -2,6-difluoro-benzamide 441 442 [M + H] ⁺ +++ 91 N- (1H-benzoimidazol-2-yl) -N '-(2-morpholin-4-yl-thiazole-4-carbonyl) -guanidine 371 372 [M + H] ⁺ + 250 N- (1H-benzoimidazol-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] ⁺ ++ 252 N- (1H-Benzoimidazol-2-yl) -N '-{2- [4- (4-cyano-benzyl) -piperazin-1-yl] -thiazole-4-carbonyl} -guanidine 485 485 [M + H] ⁺ +++ 253 N- {2- [4- (4-cyano-benzyl) -piperazin-1-yl] -thiazole-4-carbonyl} -N '-(4-methyl-thiazol-2-yl)- Guanidine 466 467 [M + H] ⁺ ++  254 N- (4-Methyl-thiazol-2-yl) -N '-(2-morpholin-4-yl-thiazole-4-carbonyl) -guanidine 352 353 [M + H] ⁺ + 255 N- (1H-benzoimidazol-2-yl) -N '-(2-morpholin-4-yl-thiazole-4-carbonyl) -guanidine 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-benzoimidazol-2-yl) -N '-(2-morpholin-4-yl-oxazole-4-carbonyl) -guadinin 355 356 [M + H] ⁺ ++ 258 N-benzooxazol-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-benzooxazol-2-yl) -guanidine 417 418 [M + H] ⁺ ++ 260 N- (5-Methyl-benzooxazol-2-yl) -N '-(2-morpholin-4-yl-thiazole-4-carbonyl) -guanidine 386 387 [M + H] ⁺ + 261 N- (5-Chloro-benzooxazol-2-yl) -N '-(2-morpholin-4-yl-thiazole-4-carbonyl) -guanidine 406 407 [M + H] ⁺ ++ 262 N- {2- [1- (4-cyano-benzyl) -piperidin-4-yl] -thiazole-4-carbonyl} -N '-(4-methyl-thiazol-2-yl) Guanidine 465 466 [M + H] ⁺ + 263 N- (6-Chloro-1H-benzoimidazol-2-yl) -N '-{2- [1- (2-trifluoromethoxy-benzoyl) -piperidin-4-yl] -thiazole- 4-carbonyl} -guanidine 591 592 [M + H] ⁺ +++ 264 N- (5,6-Dichloro-lH-benzoimidazol-2-yl) -N '-{2- [1- (2-trifluoromethoxy-benzoyl) -piperidin-4-yl] -thia Sol-4-carbonyl} -guanidine 625 626 [M + H] ⁺ ++ 265 2-Morpholin-4-yl-thiazole-4-carboxylic acid [4- (5-trifluoromethyl-benzothiazol-2-yl) phenyl] -amide 490 491 [M + H] ⁺ 266 2-Morpholin-4-yl-thiazole-4-carboxylic acid (5-benzothiazol-2-yl-pyridin-2-yl) -amide 423 424 [M + H] ⁺ 267 2-Morpholin-4-yl-thiazole-4-carboxylic acid (4-benzothiazol-2-yl-2-fluoro-phenyl) -amide 440 441 [M + H] ⁺ 268 2-Morpholin-4-yl-thiazole-4-carboxylic acid (4-benzothiazol-2-yl-2-trifluoromethoxy-phenyl) -amide 506 507 [M + H] ⁺ 269 2- (1-Furo [2,3-c] pyridin-4-yl-piperidin-4-yl) -thiazol-4-carboxylic acid (5-benzoyl-1H-benzoimidazol-2-yl )-amides 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-benzoimidazol-2-yl) -amide 570 571 [M + H] ⁺ 271 2- [1- (4,6-Dimethoxy- [1,3,5] -triazin-2-yl) -piperidin-4-yl] -thiazole-4-carboxylic acid (5-fluor Ro-benzoimidazol-2-yl) -amide 501 502 [M + H] ⁺ 272 2- [1- (4-Cyano-benzyl) -piperidin-4-yl] -thiazole-4-carboxylic acid (5-benzoyl-1H-benzoimidazol-2-yl) -amide 546 547 [M + H] ⁺ ++ 273 2- (1-Teno [3,2-d] pyrimidin-4-yl-piperidin-4-yl) -thiazole-4-carboxylic acid (5-benzoyl-1 H-benzoimidazole-2 -Yl) -amide 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-benzoimidazol-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-benzoimidazole-2 -Yl) -amide 577 578 [M + H] ⁺ ++ 276 2- [1- (4-Cyano-benzyl) -piperidin-4-yl] -thiazole-4-carboxylic acid (5-ethoxy-1H-benzoimidazol-2-yl) -amide 486 487 [M + H] ⁺ + 277 2- [1- (4-Cyano-benzyl) -piperidin-4-yl] -thiazole-4-carboxylic acid (5-chloro-lH-benzoimidazol-2-yl) -amide 476 477 [M + H] ⁺ ++ 278 2- [1- (4-Cyano-benzyl) -piperidin-4-yl] -thiazole-4-carboxylic acid (5,6-dichloro-1 H-benzoimidazol-2-yl) -amide 510 511 [M + H] ⁺ ++ 1) Biological data indicate the results obtained from NF-κB inflammation assay. ["+" Indicates 50-80% inhibition, "++" means 80-90% and "+++" indicates 90-100% inhibition]

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

Compound number designation mass LC / (+)-ESI-MS: [M + H] ⁺ Biological activity ¹⁾ 279 2- (1- (2,6-dimethoxypyrimidin-4-yl) piperidin-4-yl) -N- (6- (thiophen-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- (thiophen-3-carbonyl) -1H-benzo [ d] imidazol-2-yl) thiazole-4-carboxamide 571 572 +++ 281 2- (1- (4,6-dimethoxy-1,3,5-triazin-2-yl) piperidin-4-yl) -N- (6- (thiophen-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) thia Sol-4-carboxamide 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 + 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- (thiophen-2-ylsulfonyl) piperidin-4-yl) thiazole-4-carbox amides 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) piperidine- 4-yl) thiazole-4-carboxamide 612 613 + 289 2- (1- (7H-purin-6-yl) piperidin-4-yl) -N- (6-benzoyl-1H-benzo [d] imidazol-2-yl) thiazole-4-carbox amides 549 550 +++ 290 N- (6-benzoyl-1H-benzo [d] imidazol-2-yl) -2- (1- (2,6-dichloropyridin-4-ylcarbamoyl) piperidin-4-yl) thia Sol-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 + 292 N- (5-benzoyl-1H-benzo [d] imidazol-2-yl) -2- (1- (4,6-dimethoxy-1,3,5-triazin-2-yl) piperidine -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 ++ 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 ++ 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) piperidine- 4-yl) thiazole-4-carboxamide 562 563 +++ 298 4- {4- [4- (5-benzoyl-1H-benzoimidazol-2-ylcarbamoyl) thiazol-2-yl] piperidin-1-yl} -5-methylpyrrolo [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-carboxylate 607 608 ++ 1) Biological data indicate the results obtained from NF-κB inflammation assay. ["+" Represents an EC50 of 30 to 100 µM, "++" represents an EC50 of 10 to 30 µM, and "+++" represents an EC50 of less than 10 µM.]

Exemplary compounds of Formula IIIa of the present invention include, but are not limited to:

Compound number designation mass LC / (+/-)-ESI-MS: [M + H] ⁺ ([MH] ⁻ ) Biological Activity ^{1 )} 300 2- (isonicotinamido) -N- (6-methylsulfonyl) benzo [d] thiazol-2-yl) thiazole-4-carboxamide 459 460 + 301 2-cinnaamido-N- (6-methylsulfonyl) benzo [d] thiazol-2-yl) thiazole-4-carboxamide 484 485 + 302 2- (furan-2-carboxamido) -N- (6-methylsulfonyl) benzo [d] thiazol-2-yl) thiazole-4-carboxamide 448 449 + 303 N- (5,6-dimethyl-1H-benzo [d] imidazol-2-yl) -2- (furan-2-carboxamido) thiazole-4-carboxamide 381 382 + 304 N- (5,6-dimethyl-1H-benzo [d] imidazol-2-yl) -2- (isonicotinamido) thiazole-4-carboxamide 392 393 + 305 2-cinnaamido-N- (5,6-dimethyl-1H-benzo [d] thiazol-2-yl) thiazole-4-carboxamide 417 418 + 306 Ethyl 2- (2- (2- (trifluoromethoxy) benzamido) thiazole-4-carboxamido) -1H-benzo [d] imidazole-6-carboxylate 519 518 [MH] ^- +++ 307 Ethyl 2- (2- (2- (trifluoromethoxy) benzamido) thiazole-4-carboxamido) benzo [d] thiazole-6-carboxylate 536 535 [MH] ^- ++ 308 2- (2-chlorobenzamido) -N- (6- (phenylthio) -1H-benzo [d] imidazol-2-yl) thiazole-4-carboxamide 506 505 [MH] ^- + 309 N- (5-benzoyl-1H-benzo [d] imidazol-2-yl) -2- (2-chlorobenzamido) thiazole-4-carboxamide 501 500 [MH] ^- ++ 310 Ethyl 2- (2- (2- (chlorobenzamido) thiazole-4-carboxamido) benzo [d] thiazole-6-carboxylate 486 485 [MH] ^- + 311 2- (2-chlorobenzamido) -N- (6- (trifluoromethyl) benzo [d] thiazol-2-yl) thiazole-4-carboxamide 482 481 [MH] ^- ++ 312 2- (2-chlorobenzamido) -N- (4- (methoxybenzo [d] thiazol-2-yl) thiazole-4-carboxamide 444 443 [MH] ^- ++ 313 2- (2-chlorobenzamido) -N- (6- (methylbenzo [d] thiazol-2-yl) thiazole-4-carboxamide 428 427 [MH] ^- +++ 314 2- (2-chlorobenzamido) -N- (6- (nitrobenzo [d] thiazol-2-yl) thiazole-4-carboxamide 459 458 [MH] ^- ++ 315 2- (2-chlorobenzamido) -N- (6- (ethoxybenzo [d] thiazol-2-yl) thiazole-4-carboxamide 458 457 [MH] ^- + 316 2- (2-chlorobenzamido) -N- (6- (hydroxybenzo [d] thiazol-2-yl) thiazole-4-carboxamide 430 429 [MH] ^- ++ 317 2- (2-chlorobenzamido) -N- (6- (methoxybenzo [d] thiazol-2-yl) thiazole-4-carboxamide 444 443 [MH] ^- ++ 318 2- (2-chlorobenzamido) -N- (4- (methylbenzo [d] thiazol-2-yl) thiazole-4-carboxamide 428 427 [MH] ^- + 319 2- (2-chlorobenzamido) -N- (6- (fluorobenzo [d] thiazol-2-yl) thiazole-4-carboxamide 432 431 [MH] ^- +++ 320 2- (2-chlorobenzamido) -N- (6- (chlorobenzo [d] thiazol-2-yl) thiazole-4-carboxamide 448 447 [MH] ^- +  321 N- (6-bromobenzo [d] thiazol-2-yl) -2- (2-chlorobenzamido) thiazole-4-carboxamide 493 492 [MH] ^- + 322 2- (2-chlorobenzamido) -N- (4- (chlorobenzo [d] thiazol-2-yl) thiazole-4-carboxamide 448 447 [MH] ^- +++ 323 2- (2-chlorobenzamido) -N- (5,6- (dimethylbenzo [d] thiazol-2-yl) thiazole-4-carboxamide 442 441 [MH] ^- ++ 324 2- (2-chlorobenzamido) -N- (6- (trifluoromethoxy) benzo [d] thiazol-2-yl) thiazole-4-carboxamide 498 497 [MH] ^- +++ 325 2- (2-chlorobenzamido) -N- (6- (methylsulfonyl) benzo [d] thiazol-2-yl) thiazole-4-carboxamide 492 491 [MH] ^- + 326 N- (5,6-dimethyl-1H-benzo [d] imidazol-2-yl) -2- (1- (thiophen-2-yl) cyclohexanecarboxamido) thiazole-4-carbox amides 479 478 [MH] ^- + 327 N- (5,6-dimethyl-1H-benzo [d] imidazol-2-yl) -2- (1- (phenylcyclopropanecarboxamido) thiazole-4-carboxamide 431 430 [MH] ^- + 328 N- (5,6-dimethyl-1H-benzo [d] imidazol-2-yl) -2- (2,5-dimethylthiophen-3-carboxamido) thiazole-4-carboxamide 425 424 [MH] ^- + 329 N- (5,6-dimethyl-1H-benzo [d] imidazol-2-yl) -2- (tetrahydrofuran-3-carboxamido) thiazole-4-carboxamide 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 [MH] ^- + 331 N- (5,6-dimethyl-1H-benzo [d] imidazol-2-yl) -2- (2- (dimethylamino) acetamido) thiazole-4-carboxamide 372 373 + 332 N- (5,6-dimethyl-1H-benzo [d] imidazol-2-yl) -2- (5- (morpholinomethyl) furan-2-carboxamido) thiazole-4-carbox amides 480 479 [MH] ^- + 333 2- (2- (2-methoxybenzamido) thiazole-4-carboxamido) benzo [d] thiazole-6-carboxylic acid 454 453 [MH] ^- +++ 334 2- (2-methoxybenzamido) -N- (6- (phenylthio) -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-carbox amides 449 448 [MH] ^- +++ 336 N- (5,6-dimethyl-1H-benzo [d] imidazol-2-yl) -2- (2-morpholinoisonicotinamido) thiazole-4-carboxamide 477 476 [MH] ^- + 337 Ethyl 2- (2- (2-methoxybenzamido) thiazole-4-carboxamido) benzo [d] thiazole-6-carboxylate 482 481 [MH] ^- + 338 N- (5-benzoyl-1H-benzo [d] imidazol-2-yl) -2- (2-methoxybenzamido) thiazole-4-carboxamide 496 495 [MH] ^- +++ 339 2- (2-methoxybenzamido) -N- (6- (trifluoromethoxy) benzo [d] thiazol-2-yl) thiazole-4-carboxamide 494 493 [MH] ^- +++ 340 2- (2-methoxybenzamido) -N- (6- (trifluoromethyl) benzo [d] thiazol-2-yl) thiazole-4-carboxamide 478 477 [MH] ^- +  341 2- (2-methoxybenzamido) -N- (4-methoxybenzo [d] thiazol-2-yl) thiazole-4-carboxamide 440 441 +++ 342 2- (2-methoxybenzamido) -N- (6-methylbenzo [d] thiazol-2-yl) thiazole-4-carboxamide 424 423 [MH] ^- + 343 2- (2-methoxybenzamido) -N- (6-nitrobenzo [d] thiazol-2-yl) thiazole-4-carboxamide 455 454 [MH] ^- + 344 N- (6-ethoxybenzo [d] thiazol-2-yl) -2- (2-methoxybenzamido) thiazole-4-carboxamide 454 453 [MH] ^- + 345 tert-butyl 4- (5,6-dimethyl-1H-benzo [d] imidazol-2-ylcarbamoyl) thiazol-2-ylcarbamate 387 388 + 346 N- (6-methyl-1H-benzo [d] imidazol-2-yl) -2- (2- (trifluoromethoxy) benzamido) thiazole-4-carboxamide 461 462 +++ 347 N- (5-ethoxy-1H-benzo [d] imidazol-2-yl) -2- (2- (trifluoromethoxy) benzamido) thiazole-4-carboxamide 491 492 +++ 348 N- (6-fluoro-1H-benzo [d] imidazol-2-yl) -2- (2- (trifluoromethoxy) benzamido) thiazole-4-carboxamide 465 466 +++ 349 N- (1-ethyl-1H-benzo [d] imidazol-2-yl) -2- (2- (trifluoromethoxy) benzamido) thiazole-4-carboxamide 475 476 +++ 350 N- (5-nitro-1H-benzo [d] imidazol-2-yl) -2- (2- (trifluoromethoxy) benzamido) thiazole-4-carboxamide 492 493 +++ 351 N- (5-methyl-7- (trifluoromethyl)-[1,2,4] triazolo [1,5-a] pyrimidin-2-yl) -2- (2- (trifluoromethoxy ) Benzamido) thiazole-4-carboxamide 531 532 + 352 N- (6-benzoyl-1H-benzo [d] imidazol-2-yl) -2- (2- (trifluoromethoxy) benzamido) thiazole-4-carboxamide 551 552 + 353 N- (1-methyl-1H-benzo [d] imidazol-2-yl) -2- (2- (trifluoromethoxy) benzamido) thiazole-4-carboxamide 461 462 +++ 354 N- (6-hydroxybenzo [d] thiazol-2-yl) -2- (2-methoxybenzamido) thiazole-4-carboxamide 426 425 [MH] ^- +++ 355 2- (2-methoxybenzamido) -N- (4-methylbenzo [d] thiazol-2-yl) thiazole-4-carboxamide 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 [MH] ^- +++ 358 N- (6-chlorobenzo [d] thiazol-2-yl) -2- (2-methoxybenzamido) thiazole-4-carboxamide 444 445 +++ 359 N- (4-chloromobenzo [d] thiazol-2-yl) -2- (2-methoxybenzamido) thiazole-4-carboxamide 444 445 +++ 360 N- (5,6-dimethylbenzo [d] thiazol-2-yl) -2- (2-methoxybenzamido) thiazole-4-carboxamide 438 439 +++ 361 2- (2-methoxybenzamido) -N- (6- (trifluoromethoxy) benzo [d] thiazol-2-yl) thiazole-4-carboxamide 494 495 +++  362 2- (2-methoxybenzamido) -N- (6- (methylsulfonyl) benzo [d] thiazol-2-yl) thiazole-4-carboxamide 488 489 +++ 363 2-{[2- (2-trifluoromethoxybenzoylamino) thiazole-4-carbonyl] amino} benzothiazole-6-carboxylic acid ethyl ester 536 537 ++ 364 N- (6-hydroxybenzo [d] thiazol-2-yl) -2- (2- (trifluoromethoxy) benzamido) thiazole-4-carboxamide 480 481 ++ 365 N- (6-chlorobenzo [d] thiazol-2-yl) -2- (2- (trifluoromethoxy) benzamido) thiazole-4-carboxamide 498 499 ++ 366 N- (6-fluorobenzo [d] thiazol-2-yl) -2- (2- (trifluoromethoxy) benzamido) thiazole-4-carboxamide 482 483 +++ 367 N- (6-bromobenzo [d] thiazol-2-yl) -2- (2- (trifluoromethoxy) benzamido) thiazole-4-carboxamide 542 543 +++ 368 N- (7-chlorobenzo [d] thiazol-2-yl) -2- (2- (trifluoromethoxy) benzamido) thiazole-4-carboxamide 498 499 + 369 N- (6- (methylsulfonyl) benzo [d] thiazol-2-yl) -2- (2- (trifluoromethoxy) benzamido) thiazole-4-carboxamide 542 541 [MH] ^- ++ 370 N- (6-nitrobenzo [d] thiazol-2-yl) -2- (2- (trifluoromethoxy) benzamido) thiazole-4-carboxamide 509 510 + 371 N- (5-nitrobenzo [d] thiazol-2-yl) -2- (2- (trifluoromethoxy) benzamido) thiazole-4-carboxamide 509 510 + 372 N- (5-methoxybenzo [d] thiazol-2-yl) -2- (2- (trifluoromethoxy) benzamido) thiazole-4-carboxamide 494 495 + 373 N- (7-methoxybenzo [d] thiazol-2-yl) -2- (2- (trifluoromethoxy) benzamido) thiazole-4-carboxamide 494 495 + 374 N- (5-ethoxybenzo [d] thiazol-2-yl) -2- (2- (trifluoromethoxy) benzamido) thiazole-4-carboxamide 508 509 + 375 2- (2- (trifluoromethoxy) benzamido) -N- (5- (trifluoromethyl) benzo [d] thiazol-2-yl) thiazole-4-carboxamide 532 533 + 376 2- (2- (trifluoromethoxy) benzamido) -N- (5- (trifluoromethoxy) benzo [d] thiazol-2-yl) thiazole-4-carboxamide 548 549 + 377 N- (5-fluorobenzo [d] thiazol-2-yl) -2- (2- (trifluoromethoxy) benzamido) thiazole-4-carboxamide 482 481 [MH] ^- + 1) Biological data indicate the results obtained from NF-κB inflammation assay. ["+" Represents an EC50 of 30 to 100 µM, "++" represents an EC50 of 10 to 30 µM, and "+++" represents an EC50 of less than 10 µM.]

Proteasome  analysis:

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

For the determination of IC ₅₀ values (concentrations of inhibitor required for 50% inhibition) at least four different inhibitor concentrations were applied. Each data point was recorded three times. The curve was fitted with the appropriate program.

T-lymphocyte proliferation assay:

Suppression of Stimulated Peripheral Blood Monocytes (PBMC)

ACCUSPIN System Histopaque® 1077 Tube, isolated, washed, and Dulbecco containing 10% fetal bovine serum and 2 mM glutamine Resuspended at 10 ⁶ cells / ml in modified Eagle's medium. Cells were stimulated for 72 hours with 2 μg / ml phytohemoglutinin in the presence of test compound or blank excipient. Four hours before the end of the incubation period, 5-bromo-2'-desoxyuridine (BrdU) was added to label proliferating cells. After incubation, the cells were separated by centrifugation and the culture supernatant was removed. The incorporated BrdU was quantified with the aid of an enzyme-linked immunosorbent assay. For the determination of IC ₅₀ values (concentrations of inhibitor required for 50% inhibition) at least four different inhibitor concentrations were applied. Each data point was recorded three times. The curve was fitted with the appropriate program.

Based on the results obtained in the T-lymphocyte proliferation assay, the compounds of the present invention are suitable for treating inflammatory diseases or diseases associated with T cells.

NF Inhibition of -κB-induced inflammation:

To determine the anti-inflammatory activity of the compounds, a PRIINCESS® NINA immediate assay from Cell Culture Service GmBH was used. This assay is based on recombinant A549-NF-κB-SEAP reporter cells preinoculated on 96-well flat bottom plates. Since the transfected reporter gene for SEAP (secreted embryo alkaline phosphatase) is under the transcriptional control of the NF-κB-reactive element, expression of this reporter is activated upon stimulation with TNF-α. The secretion of SEAP into the culture supernatant can be detected by the chemiluminescent substrate CSPD®. Test compounds that inhibit NF-κB activation show decreased SEAP activity and reduced luminescence readings.

After 18 hours reactivation at 37 ° C., 5% CO ₂ and 90% relative humidity, cells were incubated with 0.01-100 μM test compound for 4.5 hours prior to stimulation with 2ng / ml TNF-α. After stimulation with TNF-α for 22 hours, endogenous phosphatase was inactivated and CSPD® substrate was fed for 40 minutes. SEAP activity was quantified by measuring luminescence as relative light units (RLU) using a Tecan Ultra reader. Each data point was recorded four times and EC50 values were calculated via a fitting function and Microsoft Excel solver.

Claims (19)

A compound of formula (Ih), or a pharmaceutically acceptable salt thereof with an acid or a base, or a pharmaceutically acceptable prodrug or stereoisomer thereof. <Formula Ih>

Where A is NR ^{2 '} , S or O; t is 0 to 4; r is 0 or 1; R ^2a is independently H, OH, SH, NH ₂ , alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, alkoxy, alkylamino, hydroxyalkylamino, halogen, aryl or heteroaryl; R ^3a is H, OH, SH, NH ₂ , -C (NR ⁷ ) NR ^{7 ′} R ⁸ ,-(CH ₂ ) _p aryl,-(CH ₂ ) _p NR ⁷ R ⁸ , -C (O) NR ⁷ R ⁸ , -N = CR ⁷ R ⁸ , -NR ⁷ C (O) R ⁸ , alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, alkoxy, alkylamino, hydroxyalkylamino, halogen, aryl Or heteroaryl; R ^d is H, halogen, alkyl, -C (NR ⁷ ) NR ^{7 '} R ⁸ ,-(CH ₂ ) _p aryl,-(CH ₂ ) _p NR ⁷ R ⁸ , -C (O) NR ⁷ R ⁸ , -N = CR ⁷ R ⁸ , -NR ⁷ C (O) R ⁸ , cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl; R ¹ is —C (O) R ^7a , -C (O) CHR ⁷ R ⁸ , -C (O) NR ⁷ R ⁸ , -C (O) OR ⁷ , -R ⁷ C (O) R ⁸ or- C (S) R ^7b ; R ² is H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino or heteroaryl, or Or R ¹ and R ² together with the N- 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 carbon atom in the ring Is a heteroatom selected from O, N and S, said ring may be substituted with one or more R ⁹ ; R ³ is H, —C (O) NR ^a R ^b , halogen, alkyl, haloalkyl, aryl, heteroaryl, OH, SH, NR ^{4 ′} OR ^{5 '} , NH ₂ , hydroxyalkylamino, alkylamino, alkoxy , Cycloalkyl, heterocycloalkyl, hydroxyalkyl or haloalkyloxy; R ^a is H, halogen, alkyl, -C (NR ⁷ ) NR ^{7 '} R ⁸ ,-(CH ₂ ) _p aryl,-(CH ₂ ) _p NR ⁷ R ⁸ , aryl, -C (O) NR ⁷ R ⁸ , -N = CR ⁷ R ⁸ , -NR ⁷ C (O) R ⁸ , cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino or heteroaryl; R ^b is independently H, —CN —OH, —SH, —CO ₂ R ^{4 ′} , —C (O) R ^{4 ′} , —SO ₂ NR ^{4 ′} , —NR ^{4 ′} R ^{5 ′} , —C (O ) NR ⁷ R ⁸ , -SO ₂ -alkyl, -SO ₂ R ^{4 '} , SO ₃ R ^4' , -N = CR ^{4 '} R ^5' , -NR ^{4 '} C (O) R ^{4 "} , -NR ^{4 '} -CO-haloalkyl, -NO ₂ , -NR ^4' -SO ₂ -haloalkyl, -NR ^{4 '} -SO ₂ -alkyl, -NR ^4' -CO-alkyl, -NR ^{4 '} (CH ₂ ) _p Heteroaryl, alkyl, cycloalkyl, alkylamino, alkoxy, alkylthio, halogen, haloalkyl, haloalkyloxy, -O (CH ₂ ) _p [O (CH ₂ ) _p ] _q OCH ₃ , -C (NR ^{4 "} ) NR ^{4 '} benzimidazolyl, -C (NR ^{4 "} ) NR ^4' benzthiazolyl, -C (NR ^4" ) NR ^{4 '} benzoxazolyl, hydroxyalkyl, hydroxycycloalkyl, hydroxyalkylamino , Heterocycloalkyl, aryl or heteroaryl; R ^{4 '} , R ^{4 "} , R ^5' are independently H, halogen, alkyl, -C (NR ⁷ ) NR ^{7 '} R ⁸ ,-(CH ₂ ) _p aryl, haloalkyl,-(CH ₂ ) _p NR ⁷ R ⁸ , -C (O) NR ⁷ R ⁸ , -N = CR ⁷ R ⁸ , -NR ⁷ C (O) R ⁸ , cycloalkyl, heterocycloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino , Heteroaryl or aryl; R ⁷ , R ^{7 ′} , R ⁸ are independently H, halogen, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, arylamino, heteroaryl or aryl; R ^7a is cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, heteroaryl or aryl; R ^7b is H, halogen, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, heteroaryl or aryl; X is NR ^{2 '} , O or S; Z is N or CR ^{2 '} ; R ^{2 ′} is H, alkyl, —C (O) NR ⁷ , —C (O) R ^b , cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl ego; p is 1 to 6; q is 1 to 6; R ⁹ is independently H, —CN, —OH, —SH, alkoxy, alkylthio, —CO ₂ R ^{4 ′} , —C (O) R ^4a , —C (O) NR ⁷ R ⁸ , -SO ₂ NR ^{4 '} , -NR ^4' R ^{5 '} , -SO ₂ -alkyl, -SO ₂ R ^4' , SO ₃ R ^{4 '} , -N = CR ^4' R ^{5 '} , -NR ^4' C (O) R ^{4 "} , -NR ^{4 '} -CO-haloalkyl, -NO ₂ , -NR ^4' -SO ₂ -haloalkyl, -NR ^{4 '} -SO ₂ -alkyl, -NR ^4' -CO-alkyl, -NR ^{4 '} (CH ₂ ) _p heteroaryl, alkyl, hydroxyalkyl, cycloalkyl, halogen, haloalkyl, alkylamino, -O (CH ₂ ) _p [O (CH ₂ ) _p ] _q OCH ₃ , -C (NR ^{4 "} ) NR ^{4 '} benzimidazolyl, -C (NR ^{4 "} ) NR ^4' benzthiazolyl, -C (NR ^4" ) NR ^{4 '} benzoxazolyl, hydroxycycloalkyl, hydroxyalkylamino, haloalkyloxy , Heterocycloalkyl,-(CH ₂ ) _p NR ⁷ COR ⁸ , aryl or heteroaryl; R ^4a is H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, —C (NR ⁷ ) NR ^{7 ′} R ⁸ , -(CH ₂ ) _p aryl,-(CH ₂ ) _p NR ⁷ R ⁸ , -C (O) NR ⁷ R ⁸ , -N = CR ⁷ R ⁸ , -NR ⁷ C (O) R ⁸ , halogen, hetero Aryl or aryl; From here C ₁ -C ₆ alkyl group, unless stated otherwise, represents straight or branched C ₁ -C ₆ alkyl which may be optionally substituted with one or more substituents R ′; R 'is independently H, -CO ₂ R ", -CONHR", -CR "O, -SO ₂ NR", -NR "-CO-haloalkyl, -NO ₂ , -NR" -SO ₂ -haloalkyl , -NR "-SO ₂ -alkyl, -SO ₂ -alkyl, -NR" -CO-alkyl, -CN, alkyl, cycloalkyl, alkylamino, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl, Hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl or heteroaryl; R ″ is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl or heteroaryl; C ₂ -C ₆ alkenyl groups, unless stated otherwise, represent straight or branched C ₂ -C ₆ alkenyl which may be optionally substituted with one or more substituents R ′; Alkyl groups, unless stated otherwise, are straight or branched C ₁ -C ₆ alkyl, straight or branched C ₂ -C ₆ alkenyl, or straight or branched, which may be substituted with one or more substituents R ′ as defined above. A chain C ₂ -C ₆ alkynyl group; Cycloalkyl groups represent non-aromatic ring systems containing 3 to 8 carbon atoms, wherein one or more carbon atoms in the ring can be substituted by one or more substituents R 'as defined above; Heterocycloalkyl groups represent non-aromatic ring systems containing 2 to 10 carbon atoms and at least one heteroatom selected from O, N and S, wherein at least one carbon atom in the ring is defined by R 'as defined above. May be substituted; The alkoxy group represents an O-alkyl group and the alkyl group is as defined above; The alkylthio group represents an S-alkyl group, wherein the alkyl group is as defined above; Haloalkyl group represents an alkyl group substituted with 1 to 5 halogen atoms, the alkyl group being as defined above; A hydroxyalkyl group represents a HO-alkyl group, wherein the alkyl group is as defined above; Haloalkyloxy group represents an alkoxy group substituted by 1 to 5 halogen atoms, the alkyl group being as defined above; Hydroxyalkylamino group represents a (HO-alkyl) ₂ -N- group or a HO-alkyl-NH- group, wherein the alkyl group is as defined above; The alkylamino group represents an HN-alkyl or N-dialkyl group, wherein the alkyl group is as defined above; Halogen groups are fluorine, chlorine, bromine or iodine; An aryl group represents an aromatic group having 5 to 15 carbon atoms which may be substituted with one or more substituents R ', wherein R' is as defined above; The arylamino group is an HN-aryl or N-diaryl group and the aryl group is as defined above; Heteroaryl groups represent 5- to 10-membered aromatic heterocyclic groups containing one or more heteroatoms selected from O, N and S, the heterocyclic group may be fused to another ring and the heterocyclic group or fused ring may be May be independently substituted by a substituent R ', wherein R' is as defined above, With the exception of the following compounds: <Formula I>

Where R ¹ independently represents hydrogen, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl or substituted arylalkyl; R ² is independently —NR ³ R ⁴ ,

or

Represents; R ³ independently represents alkyl, cycloalkyl, alkoxy, alkylamine, -OH, -SH, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl; R ⁴ independently represents alkyl, cycloalkyl, alkoxy, alkylamine, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl; R ⁵ is independently H, COR ⁶ , CO ₂ R ⁶ , SOR ⁶ , SO ₂ R ⁶ , SO ₃ R ⁶ , alkyl, cycloalkyl, alkoxy, -NH ₂ , alkylamine, -NR ⁷ COR ⁶ , halogen, -OH, -SH, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl; R ⁶ independently represents H, alkyl, cycloalkyl, —NH ₂ , alkylamine, aryl or heteroaryl; R ⁷ independently represents H, alkyl, cycloalkyl, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl, aryl or heteroaryl; p is 0 or 1; q is 0 or 1; X is CO or SO ₂ . A compound of formula (Ia), or a pharmaceutically acceptable salt thereof with an acid or base, or a pharmaceutically acceptable prodrug thereof, or a stereoisomer thereof. <Formula Ia>

Where R is independently hydrogen, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl; R ¹ is independently alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl; X is CO, CS or SO ₂ ; Y is CO, CS or SO ₂ ; Z is NR ^{2 '} , S or O; R ^{2 '} is H, alkyl, -C (O) NR ⁷ , -C (O) R ^e , cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl; R ^c is independently H, OH, SH, NROR ¹ , NH ₂ , alkylamino, hydroxyalkylamino, halogen, CONR ^d R ^e , alkoxy, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, Aryl or heteroaryl; R ^d is H, halogen, alkyl, -C (NR ⁷ ) NR ^{7 '} R ⁸ ,-(CH ₂ ) _p aryl, -(CH ₂ ) _p NR ⁷ R ⁸ , -C (O) NR ⁷ R ⁸ , -N = CR ⁷ R ⁸ , -NR ⁷ C (O) R ⁸ , cycloalkyl, haloalkyl, hydroxyalkyl, hydroxide Oxyalkylamino, alkylamino, heteroaryl or aryl; R ⁷ , R ^{7 ′} are independently H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl; R ⁸ is H, NH ₂ , alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl; R ^e is independently H, —CN, —OH, —SH, —CO ₂ R ^{4 ′} , —C (O) R ^{4 ′} , —SO ₂ NR ^{4 ′} , —NR ^{4 ′} R ^{5 ′} , —C ( O) NR ⁷ R ⁸ , -SO ₂ -alkyl, -SO ₂ R ^{4 '} , -SO ₃ R ^4' , -N = CR ^{4 '} R ^5' , -NR ^{4 '} C (O) R ^{4 "} ,- NR ^{4 '} -CO-haloalkyl, -NO ₂ , -NR ^4' -SO ₂ -haloalkyl, -NR ^{4 '} -SO ₂ -alkyl, -NR ^4' -CO-alkyl, -NR ^{4 '} (CH ₂ ) _p heteroaryl, alkyl, hydroxyalkyl, cycloalkyl, alkylamino, aryl, hydroxyalkylamino, alkoxy, alkylthio, -O (CH ₂ ) _p [O (CH ₂ ) _p ] _q OCH ₃ ,- C (NR ^{4 ″} ) NR ^{4 ′} -benzimidazolyl, —C (NR ^{4 ″} ) NR ^{4 ′} benzthiazolyl, —C (NR ^{4 ″} ) NR ^{4 ′} benzoxazolyl or heteroaryl; R ^{4 '} , R ^{4 "} , R ^5' are independently H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, -C (NR ⁷ ) NR ^{7 '} R ⁸ ,-( CH ₂ ) _p aryl,-(CH ₂ ) _p NR ⁷ R ⁸ , -C (O) NR ⁷ R ⁸ , -N = CR ⁷ R ⁸ , -NR ⁷ C (O) R ⁸ , halogen, heteroaryl or Aryl; p is 1 to 6; q is 1 to 6; R ² is independently

or

ego; R ⁵ is independently H, COR ⁶ , CO ₂ R ⁶ , SOR ⁶ , SO ₂ R ⁶ , SO ₃ R ⁶ , alkyl, cycloalkyl, alkoxy, -NH ₂ , alkylamine, -NR ⁷ COR ⁶ , halogen, -OH, -SH, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl; R ⁶ is independently H, alkyl, cycloalkyl, amino, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, aryl or heteroaryl; From here, Alkyl groups are straight or branched C ₁ -C ₆ alkyl, straight or branched C ₂ -C ₆ alkenyl, or straight or branched C ₂ -groups, which may be substituted with one or more substituents R ', unless stated otherwise. A C ₆ alkynyl group, R 'is as defined above; R 'is independently H, -CO ₂ R ", -CONHR", -CR "O, -SO ₂ NR", -NR "-CO-haloalkyl, -NO ₂ , -NR" -SO ₂ -haloalkyl , -NR "-SO ₂ -alkyl, -SO ₂ -alkyl, -NR" -CO-alkyl, -CN, alkyl, cycloalkyl, alkylamino, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl, Hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl or heteroaryl; R ″ is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl or heteroaryl; Cycloalkyl groups represent a non-aromatic ring system containing 3 to 8 carbon atoms, one or more carbon atoms in the ring may be substituted by the group E, where E is O, S, SO, SO ₂ , N or NR ″, R ″ is as defined above; The alkoxy group represents an O-alkyl group and the alkyl group is as defined above; The alkylthio group represents an S-alkyl group, wherein the alkyl group is as defined above; Haloalkyl group represents an alkyl group substituted with 1 to 5 halogen atoms, the alkyl group being as defined above; A hydroxyalkyl group represents a HO-alkyl group, wherein the alkyl group is as defined above; Haloalkyloxy group represents an alkoxy group substituted with 1 to 5 halogen atoms, the alkyl group being as defined above; Hydroxyalkylamino group represents a (HO-alkyl) ₂ -N- group or a HO-alkyl-NH- group, wherein the alkyl group is as defined above; The alkylamino group represents an HN-alkyl or N-dialkyl group, wherein the alkyl group is as defined above; Halogen groups are fluorine, chlorine, bromine or iodine; An aryl group represents an aromatic group having 5 to 15 carbon atoms which may be substituted with one or more substituents R ', wherein R' is as defined above; Heteroaryl groups represent 5- to 10-membered aromatic heterocyclic groups containing one or more heteroatoms selected from O, N and S, wherein the heterocyclic group can be fused to another ring and the heterocyclic group or fused ring is May be independently substituted with one or more substituents R ', wherein R' is as defined above. A compound of formula (Ib), or a pharmaceutically acceptable salt thereof with an acid or base, or a pharmaceutically acceptable prodrug or stereoisomer thereof. <Formula Ib>

Where R ¹ is —C (O) R ⁷ , -C (O) CHR ⁷ R ⁸ , -C (O) NR ⁷ R ⁸ , -C (O) OR ⁷ , -R ⁷ C (O) R ⁸ or- C (S) R ⁷ ; R ⁹ is independently H, —CN, —OH, —SH, —CO ₂ R ^{4 ′} , —C (O) R ^{4 ′} , —SO ₂ NR ^{4 ′} , —NR ^{4 ′} R ^{5 ′} , —C ( O) NR ⁷ R ⁸ , -SO ₂ -alkyl, -SO ₂ R ^{4 '} , SO ₃ R ^4' , -N = CR ^{4 '} R ^5' , -NR ^{4 '} C (O) R ^{4 "} , -NR ^{4 '-CO- _{haloalkyl, -NO 2, -NR 4' -SO}} 2 - haloalkyl, -NR ^{4 '-SO} ₂ - alkyl, -NR ^4' -CO- alkyl, -NR ^{4 '(CH} _{2) p} heteroaryl, heteroaryl, hydroxyalkyl, cycloalkyl, alkylamino, aryl, hydroxyalkylamino, alkoxy, alkylthio, -O (CH ₂ ) _p [O (CH ₂ ) _p ] _q OCH ₃ , -C (NR ^{4 ″} ) NR ^{4 ′} -benzimidazolyl, —C (NR ^{4 ″} ) NR ^{4 ′} benzthiazolyl, —C (NR ^{4 ″} ) NR ^{4 ′} benzoxazolyl, — (CH ₂ ) _p NR ⁷ COR ⁸ or alkyl; R ⁴ is H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, aryl, or R ¹ and R ⁴ together with X to which they are attached form a 3-8 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 and S, and The ring optionally has one or more substituents R ⁹ ; X is N or CR ^{2 '} ; Y is CO, CS or SO ₂ ; Z is NR ^{2 ″} , S or O; R ^{2 ″} is H, alkyl, —C (O) NR ⁷ , —C (O) R ^e , cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl; R ^{2 '} is H, alkyl, -C (O) NR ^4' , -C (O) R ^{4 '} , cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl; R ^{4 '} , R ^{4 "} , R ^5' are independently H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, -C (NR ⁷ ) NR ^{7 '} R ⁸ ,-( CH ₂ ) _p aryl,-(CH ₂ ) _p NR ⁷ R ⁸ , -C (O) NR ⁷ R ⁸ , -N = CR ⁷ R ⁸ , -NR ⁷ C (O) R ⁸ , halogen, heteroaryl or Aryl; p is 1 to 6; q is 1 to 6; R ^a is independently H, OH, SH, NH ₂ , alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, alkoxy, alkylamino, hydroxyalkylamino, halogen, aryl or heteroaryl; R ^b is independently H, OH, SH, NH ₂ , alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, alkoxy, alkylamino, hydroxyalkylamino, halogen, aryl or heteroaryl; R ^c is independently H, OH, SH, NR ^{4 ′} OR ^{5 ′} , NH ₂ , alkylamino, hydroxyalkylamino, halogen, CONR ^d R ^e , alkoxy, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, Haloalkyloxy, aryl or heteroaryl; R ^d is H, halogen, alkyl, -C (NR ⁷ ) NR ^{7 '} R ⁸ ,-(CH ₂ ) _p aryl, -(CH ₂ ) _p NR ⁷ R ⁸ , -C (O) NR ⁷ R ⁸ , -N = CR ⁷ R ⁸ , -NR ⁷ C (O) R ⁸ , cycloalkyl, haloalkyl, hydroxyalkyl, hydroxide Oxyalkylamino, alkylamino, heteroaryl or aryl; R ⁷ , R ^{7 ′} are independently H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl; R ⁸ is H, NH ₂ , alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl; R ^e is independently H, —CN, —OH, —SH, —CO ₂ R ^{4 ′} , —C (O) R ^{4 ′} , —SO ₂ NR ^{4 ′} , —NR ^{4 ′} R ^{5 ′} , —C ( O) NR ⁷ R ⁸ , -SO ₂ -alkyl, -SO ₂ R ^{4 '} , -SO ₃ R ^4' , -N = CR ^{4 '} R ^5' , -NR ^{4 '} C (O) R ^{4 "} ,- NR ^{4 '} -CO-haloalkyl, -NO ₂ , -NR ^4' -SO ₂ -haloalkyl, -NR ^{4 '} -SO ₂ -alkyl, -NR ^4' -CO-alkyl, -NR ^{4 '} (CH ₂ ) _p heteroaryl, alkyl, hydroxyalkyl, cycloalkyl, alkylamino, hydroxyalkylamino, alkoxy, alkylthio, -O (CH ₂ ) _p [O (CH ₂ ) _p ] _q OCH ₃ , -C ( NR ^{4 ″} ) NR ^{4 ′} -benzimidazolyl, —C (NR ^{4 ″} ) NR ^{4 ′} benzthiazolyl, —C (NR ^{4 ″} ) NR ^{4 ′} benzoxazolyl, aryl or heteroaryl; R ² is independently

Wherein A is N, O or CR ^{2 '} ; R ⁵ is independently H, SOR ⁷ , SO ₂ R ⁷ , SO ₃ R ⁷ , -C (O) R ⁷ , -C (O) CHR ⁷ R ⁸ , -C (O) NR ⁷ R ⁸ , -C (O) OR ⁷ , -R ⁷ C (O) R ⁸ , -C (S) R ⁷ , -C (NR ⁷ ) NR ^{7 '} R ⁸ ,-(CH ₂ ) _p aryl,-(CH ₂ ) _p NR ⁷ R ⁸ , -C (O) NR ⁷ R ⁸ , -N = CR ⁷ R ⁸ , -NR ⁷ C (O) R ^{7 '} , alkyl, cycloalkyl, alkoxy, -NH ₂ , alkylamino, hydroxy Alkylamino, halogen, -OH, -SH, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl; n is 0 to 2; From here, Alkyl groups, straight or branched C ₁ -C ₆ alkyl, straight or branched C ₂ -C ₆ alkenyl, or straight or branched C ₂ , which may be optionally substituted with one or more substituents R ′, unless stated otherwise -C ₆ alkynyl group, R 'is as defined above; R 'is independently H, -CO ₂ R ", -CONHR", -CR "O, -SO ₂ NR", -NR "-CO-haloalkyl, -NO ₂ , -NR" -SO ₂ -haloalkyl , -NR "-SO ₂ -alkyl, -SO ₂ -alkyl, -NR" -CO-alkyl, -CN, alkyl, cycloalkyl, alkylamino, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl, Hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl or heteroaryl; R ″ is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl or heteroaryl; Cycloalkyl groups represent a non-aromatic ring system containing 3 to 8 carbon atoms, one or more carbon atoms in the ring may be substituted by the group E, where E is O, S, SO, SO ₂ , N or NR ″, R ″ is as defined above; The alkoxy group represents an O-alkyl group and the alkyl group is as defined above; The alkylthio group represents an S-alkyl group, wherein the alkyl group is as defined above; Haloalkyl group represents an alkyl group substituted with 1 to 5 halogen atoms, the alkyl group being as defined above; A hydroxyalkyl group represents a HO-alkyl group, wherein the alkyl group is as defined above; Haloalkyloxy group represents an alkoxy group substituted with 1 to 5 halogen atoms, the alkyl group being as defined above; Hydroxyalkylamino group represents a (HO-alkyl) ₂ -N- group or a HO-alkyl-NH- group, wherein the alkyl group is as defined above; The alkylamino group represents an HN-alkyl or N-dialkyl group, wherein the alkyl group is as defined above; Halogen groups are fluorine, chlorine, bromine or iodine; An aryl group represents an aromatic group having 5 to 15 carbon atoms which may be substituted with one or more substituents R ', wherein R' is as defined above; Heteroaryl groups represent 5- to 10-membered aromatic heterocyclic groups containing one or more heteroatoms selected from O, N and S, wherein such heterocyclic groups can be fused to other rings, heterocyclic groups or fused rings May be independently substituted with one or more substituents R ', wherein R' is as defined above. A compound of formula (Ic), or a pharmaceutically acceptable salt thereof with an acid or base, or a pharmaceutically acceptable prodrug thereof, or a stereoisomer thereof. <Formula Ic>

Where R ¹ is independently H, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl; X is CO, CS or SO ₂ ; Y is CO, CS or SO ₂ ; Z is NR ^{2 ″} , S or O; R ^{2 ″} is H, alkyl, —C (O) NR ⁷ , —C (O) R ^e , cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl; R ^{4 '} , R ^{4 "} , R ^5' are independently H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, -C (NR ⁷ ) NR ^{7 '} R ⁸ ,-( CH ₂ ) _p aryl,-(CH ₂ ) _p NR ⁷ R ⁸ , -C (O) NR ⁷ R ⁸ , -N = CR ⁷ R ⁸ , -NR ⁷ C (O) R ⁸ , halogen, 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 ^b is independently H, OH, SH, NR ^{4 ′} OR ^{5 ′} , NH ₂ , alkylamino, hydroxyalkylamino, halogen, CONR ^d R ^e , alkoxy, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, Haloalkyloxy, aryl or heteroaryl; R ^c is independently H, OH, SH, NR ^{4 ′} OR ^{5 ′} , NH ₂ , alkylamino, hydroxyalkylamino, halogen, CONR ^d R ^e , alkoxy, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, Haloalkyloxy, aryl or heteroaryl; R ^d is H, halogen, alkyl, -C (NR ⁷ ) NR ^{7 '} R ⁸ ,-(CH ₂ ) _p aryl, -(CH ₂ ) _p NR ⁷ R ⁸ , -C (O) NR ⁷ R ⁸ , -N = CR ⁷ R ⁸ , -NR ⁷ C (O) R ⁸ , cycloalkyl, haloalkyl, hydroxyalkyl, hydroxide Oxyalkylamino, alkylamino, heteroaryl or aryl; R ⁷ , R ^{7 ′} are independently H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl; R ⁸ is H, NH ₂ , alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl; R ^e is independently H, —CN, —OH, —SH, —CO ₂ R ^{4 ′} , —C (O) R ^{4 ′} , —SO ₂ NR ^{4 ′} , —NR ^{4 ′} R ^{5 ′} , —C ( O) NR ⁷ R ⁸ , -SO ₂ -alkyl, -SO ₂ R ^{4 '} , SO ₃ R ^4' , -N = CR ^{4 '} R ^5' , -NR ^{4 '} C (O) R ^{4 "} , -NR ^{4 '-CO- _{haloalkyl, -NO 2, -NR 4' -SO}} 2 - haloalkyl, -NR ^{4 '-SO} ₂ - alkyl, -NR ^4' -CO- alkyl, -NR ^{4 '(CH} _{2) p} heteroaryl, alkyl, hydroxyalkyl, cycloalkyl, alkylamino, hydroxyalkylamino, alkoxy, alkylthio, -O (CH ₂ ) _p [O (CH ₂ ) _p ] _q OCH ₃ , -C (NR ^{4 "} ) NR ^{4 '} -benzimidazolyl, -C (NR ^4" ) NR ^4' benzthiazolyl, -C (NR ^{4 "} ) NR ^{4 '} benzoxazolyl, aryl or heteroaryl; R ³ is independently H, OH, SH, NR ^{4 ′} OR ^{5 ′} , NH ₂ , hydroxyalkylamino, alkylamino, halogen, CONR ^d R ^e , alkoxy, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, Haloalkyloxy, aryl or heteroaryl; From here, Alkyl groups are straight or branched C ₁ -C ₆ alkyl, straight or branched C ₂ -C ₆ alkenyl, or straight or branched C ₂ -groups, which may be substituted with one or more substituents R ', unless stated otherwise. A C ₆ alkynyl group, R 'is as defined above; R 'is independently H, -CO ₂ R ", -CONHR", -CR "O, -SO ₂ NR", -NR "-CO-haloalkyl, -NO ₂ , -NR" -SO ₂ -haloalkyl , -NR "-SO ₂ -alkyl, -SO ₂ -alkyl, -NR" -CO-alkyl, -CN, alkyl, cycloalkyl, alkylamino, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl, Hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl or heteroaryl; R ″ is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl or heteroaryl; Cycloalkyl groups represent a non-aromatic ring system containing 3 to 8 carbon atoms, one or more carbon atoms in the ring may be substituted by the group E, where E is O, S, SO, SO ₂ , N or NR ″, R ″ is as defined above; The alkoxy group represents an O-alkyl group and the alkyl group is as defined above; The alkylthio group represents an S-alkyl group, wherein the alkyl group is as defined above; Haloalkyl group represents an alkyl group substituted with 1 to 5 halogen atoms, the alkyl group being as defined above; A hydroxyalkyl group represents a HO-alkyl group, wherein the alkyl group is as defined above; Haloalkyloxy group represents an alkoxy group substituted with 1 to 5 halogen atoms, the alkyl group being as defined above; Hydroxyalkylamino group represents a (HO-alkyl) ₂ -N- group or a HO-alkyl-NH- group, wherein the alkyl group is as defined above; The alkylamino group represents an HN-alkyl or N-dialkyl group, wherein the alkyl group is as defined above; Halogen groups are fluorine, chlorine, bromine or iodine; An aryl group represents an aromatic group having 5 to 15 carbon atoms which may be substituted with one or more substituents R ', wherein R' is as defined above; Heteroaryl groups represent 5- to 10-membered aromatic heterocyclic groups containing one or more heteroatoms selected from O, N and S, wherein the heterocyclic group can be fused to another ring and the heterocyclic group or fused ring is May be independently substituted with one or more substituents R ', wherein R' is as defined above. A compound according to any one of claims 1 to 4 for use as a medicament. A composition comprising a compound according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier or diluent. The compound according to any one of claims 1 to 4 or the composition of claim 6 for the treatment or prevention of diseases characterized by hyperproliferation of cells. Diseases resulting from ischemia and / or reperfusion injury of organs and / or portions of the body selected from the group including the heart, brain, peripheral limbs, kidneys, liver, spleen and lungs, and / or infarctions such as myocardial infarction and severe limb ischemia For the treatment or prevention of endothelial dysfunction associated with a disease selected from the group comprising, and / or ischemic disease, myocardial infarction and ischemic disease of the organ, A compound according to claim 4 or a composition of claim 6. In groups including Alzheimer's disease, Parkinson's disease, Creutzfeldt-Jakob disease, Lewy body dementia, amyotrophic lateral sclerosis, stroke, epilepsy, multiple sclerosis, myasthenia gravis, Huntington's chorea, Down's syndrome, neuron and Meniere's disease A compound according to any one of claims 1 to 4 or a composition of claim 6 for the treatment or prevention of a selected neurological disease or condition. The method of claim 7, wherein the disease is psoriasis, atopic dermatitis, alopecia areata, alopecia areata, partial alopecia, concurrent alopecia, broad spectrum alopecia, erythematous lupus erythematosus, squamous gland, skin myositis, atopic eczema, topical sclerosis, Scleroderma, vulgaris, psoriasis, head psoriasis, inguinal psoriasis, inverse psoriasis, mutant-type alopecia areata, androgenetic alopecia, allergic contact eczema, irritant contact eczema, contact eczema, normal bleb, deciduous bleb, proliferative bleb, scarring mucosa Swelling, blistering swelling, mucosal swelling, dermatitis, herpes dermatitis, urticaria, fat necrosis, nodular erythema, thyroid, simple itching rash, nodular itching, acute itching, glandular IgA dermatitis, polymorphic dermatitis, sunrays Erythema, percutaneous atrophic salivary gland, skin rash, drug rash, chronic progressive purple erythema, hanpo eczema, eczema, fixed drug pidgin, photoallergic blood Reactions, simple tachycardia, dermatitis, and graft-versus-host disease, acne, rosacea, scarring, keloids, vitiligo, actinic keratosis, epidermal keratosis, persistent lenticular hyperkeratosis, hair keratosis, and scleroderma. Compound or composition selected from the group consisting of. 8. A compound or composition according to claim 7, wherein said disease is selected from the group consisting of hematological or solid tumors. The compound or composition according to claim 11, wherein the disease is selected from the group consisting of prostate cancer, melanoma, ovarian cancer and multiple myeloma. A compound according to any one of claims 1 to 4 or a composition of claim 6 for the treatment or prevention of autoimmune diseases or inflammatory diseases. The compound or composition according to claim 13, wherein the disease is selected from the group consisting of rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, inflammatory skin disease or lupus erythematosus. The compound according to any one of claims 1 to 4 or the composition of claim 6 for the treatment or prevention of stroke, reperfusion injury and Alzheimer's disease. A compound according to any one of claims 1 to 4 or a composition of claim 6 for the treatment or prevention of a viral disease. The compound or composition of claim 16, wherein the viral disease is selected from the group consisting of hepatitis B, hepatitis C, influenza virus infection, AIDS (HIV infection), and human papilloma virus infection. A compound according to any one of claims 1 to 4 or a composition of claim 6 for the treatment or prevention of atherosclerosis. A compound according to any one of claims 1 to 4 or a composition of claim 6 for the treatment or prevention of osteoporosis.