JP2009529555A - Novel heterocyclic NF-κB inhibitor - Google Patents

Abstract

The present invention relates to the general formula (Ih) (wherein A is NR ^{2 ′} , S or O; R ^3a is H, OH, SH, NH ₂ , —C (NR ⁷ ) NR ^{7 ′} R ⁸ , — (CH ₂ ) _p aryl, —C (NH 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 ³ is H, —C (O) NR ^a R ^b , halogen, alkyl, haloalkyl, aryl, ^{heteroaryl, OH, SH, NR 4 '} oR 5', NH 2, hydroxyalkyl amino, alkylamino, alkoxy, cycloalkyl, heterocycloalkyl, hydroxyalkyl or Haroarukiruo Be a sheet; X is, NR 2 ^', O or S; or Z is, N or CR ^2' compounds of a), or a pharmaceutically acceptable salt with an acid or a base, or a pharmaceutically, Relates to acceptable prodrugs or stereoisomers.

Description

  The present invention relates to compounds of general formula (Ia), (Ib), (Ic), (Ih), (II) or (III), or their stereoisomers, or their possible pharmaceutically acceptable acids or bases. Possible salts, or pharmaceutically acceptable prodrugs of these compounds. The compounds of the invention can be used as medicaments and are particularly useful for the treatment of diseases associated with cell abnormalities and hyperproliferation in mammals, particularly in humans. In particular they are useful for the treatment of diseases characterized by T cell hyperproliferation. The present invention relates to compounds suitable for the treatment of diseases that can be treated by modulating cellular pathways in eukaryotic cells, such as cancer, immunological or inflammatory disorders, and viral infections. It relates to a process for the preparation of compounds and to their use.

  T cell homeostasis is important for maintaining immune tolerance. A defect in T cell homeostasis can lead to an autoimmune condition. Autoimmune diseases include a wide range of clinically distinct entities that share a common etiology, a false self-determining immune response. Evidence suggests a major role for T cell reactivity in autoimmune diseases. Measurement of proliferative response in T lymphocytes is a widely used assay to measure immunocompetence (Killestein, J. et al. J. Neuroimmunol. 133, 217-24, 2002).

  We used a non-radioactive technique for measuring T cell proliferation in vitro (Messele, T. et al. Clinical and Diagnostic Laboratory Immunology 687-692, 2000). Peripheral blood mononuclear cells (PBMC) were isolated from human blood collected from volunteer donors. PBMC were isolated by centrifugation in an ACCUSPIN tube using a HISTOPAQUE. PBMC were stimulated with PHA and cell proliferation was measured with the Roche colorimetric BromUridin incorporation ELISA kit.

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

  The main neutral proteolytic activity in the cytosol and nucleus is the proteasome, a 20S (700 kDa) particle with multiple peptidase activity. Continuous turnover of cellular proteins via the ubiquitin-proteasome pathway is used by the immune system to screen for the presence of abnormal intracellular proteins (Dantuma, NP et al. Nat. Biotechnol. 2000, 18 (5), 538- 43; Goldberg, AL. Et al. Nature 357, 375, 1993). The ubiquitin-proteasome pathway plays an essential role in the regulation of NF-κB activity and is involved in the degradation of the inhibitor IκB-α. In order to be targeted for degradation by the proteasome, IκB-α must first undergo selective phosphorylation at serine residues 32 and 36 followed by ubiquitination (Chen, ZJ. Et al. Cell 84). 853-862, 1996; Brown, K. et al. Science 267, 1485, 1995). The transcription factor NF-κB regulates the transcription of an important set 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 activation (Traeckner et al. EMBO J. 13, 5433, 1994).

  References describing proteasome inhibitors are in the review (Adams, J. et al. Ann. Rev. Med. Chem. 31, 279-288, 1996), as well as 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 a novel chemical entity with proteasome inhibitory activity.
NF-κB (nuclear factor-κB) is a rel family of eukaryotic transcription factors that are located as homo- or heterodimers in the cytoplasm in an inactive complex. Primarily it exists as a heterodimer consisting of p50 and p65 subunits that are bound to the IκB family, usually IκB-α inhibitory proteins (D. Thanos et al., Cell 80, 529, 1995). NF-κB is activated in response to different stimuli, particularly inflammatory cytokines, UV radiation, phorbol esters, bacterial and viral infections. Stimulation involves the release of NF-κB from IκB as a result of phosphorylation and subsequent degradation of the IκB-α protein by the proteasome (PA Baeuerle et al., Annu. Rev. Immunol. 12, 141, 1995). Trigger. Once unstimulated, NF-κB translocates in the nucleus where it binds to DNA at specific κB sites and is involved in regulating immune and inflammatory responses, particularly interleukins, TNF-α, Induces transcription of various genes encoding NO-synthase and cyclooxygenase 2 (S. Grimm et al., J. Biochem. 290, 297, 1993). NF-κB is therefore considered to be an early mediator of immune and inflammatory responses, and in the control of cell proliferation and in various human diseases such as rheumatoid arthritis (H. Beker et al., Clin. Exp. Immunol. 99, 325, 1995), ischemia (A. Salminen et al., Biochem. Biophys. Res. Comm. 212. 939, 1995), arteriosclerosis (AS Baldwin, Annals Rev. Immunol. 212, 649, 1996) as well as the etiology of AIDS. Inhibition of NF-κB mediated gene transcription is inhibition of phosphorylation of the inhibitory protein IκB, inhibition of IκB degradation, inhibition of NF-κB (p50 / p65) nuclear translocation, NF-κB-DNA binding or NF-κB-mediated It can be achieved by inhibition of DNA transcription (JC Epinat et al., Oncogene 18, 6896, 1999).

（式中、Ｒは、独立して、水素、アルキル、シクロアルキル、ヒドロキシアルキル、ハロアルキル、ハロアルキルオキシ、アリールまたはヘテロアリールであり；
Ｒ¹は、独立して、アルキル、シクロアルキル、ヒドロキシアルキル、ハロアルキル、ハロアルキルオキシ、アリールまたはヘテロアリールであり；
Ｘは、ＣＯ、ＣＳまたはＳＯ₂であり；
Ｙは、ＣＯ、ＣＳまたはＳＯ₂であり；
Ｚは、ＮＲ^2’、ＳまたはＯであり；
Ｒ^2’は、Ｈ、アルキル、-Ｃ（Ｏ）ＮＲ⁷、-Ｃ（Ｏ）Ｒ^e、シクロアルキル、ハロアルキル、ヒドロキシアルキルであり；
Ｒ^cは、独立して、Ｈ、ＯＨ、ＳＨ、ＮＲＯＲ¹、ＮＨ₂、アルキルアミノ、ヒドロキシアルキルアミノ、ハロゲン、ＣＯＮＲ^dＲ^e、アルコキシ、アルキル、シクロアルキル、ヒドロキシアルキル、ハロアルキル、ハロアルキルオキシ、アリールまたはヘテロアリールであり； The present invention relates to a compound of general formula (Ia), or a pharmaceutically acceptable salt thereof with an acid or base, or a pharmaceutically acceptable prodrug or stereoisomer thereof:

Wherein R is independently hydrogen, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl;
R ¹ is independently alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl;
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;
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 is 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 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, hydroxyalkyl, amino, 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 ' table a benzoxazolyl or heteroaryl ;
R ^{4 ′} , R ^{4 ″} and 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 Represents aryl;
p is 1-6;
q is 1-6;

であり；
Ｒ⁵は、独立して、Ｈ、ＣＯＲ⁶、ＣＯ₂Ｒ⁶、ＳＯＲ⁶、ＳＯ₂Ｒ⁶、ＳＯ₃Ｒ⁶、アルキル、シクロアルキル、アルコキシ、-ＮＨ₂、アルキルアミン、-ＮＲ⁷ＣＯＲ⁶、ハロゲン、-ＯＨ、-ＳＨ、アルキルチオ、ヒドロキシアルキル、ハロアルキル、ハロアルキルオキシ、アリールまたはヘテロアリールであり；
Ｒ⁶は、独立して、Ｈ、アルキル、シクロアルキル、アミノ、ハロアルキル、ヒドロキシアルキル、ヒドロキシアルキルアミノ、アルキルアミノ、アリールまたはヘテロアリールであり； R ² is independently

Is;
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;

In this case, unless otherwise specified, alkyl groups are linear or branched C ₁ -C ₆ -alkyl, preferably linear or branched, linear or branched C ₁ -C 5 alkyl atoms. Means ₂ -C ₆ -alkenyl, or a linear or branched C ₂ -C ₆ -alkynyl group, which may be substituted by one or more substituents R ^′ ;
C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl and C ₂ -C ₆ -alkynyl residues are —CH ₃ , —C ₂ H ₅ , —CH═CH ₂ , —C≡CH, —C ₃ H ₇ , —CH (CH ₃ ) ₂ , —CH ₂ —CH═CH ₂ , —CH (CH ₃ ) ═CH ₂ , —CH═CH—CH ₃ , —C≡C—CH ₃ , —CH _{2 -C≡CH, -C 4 H 9, -CH} 2 -CH (CH 3) 2, -CH (CH 3) -C 2 H 5, -C (CH 3) 3, -C 5 H 11, -C ₆ H ₁₃ , —C (R ′) ₃ , —C ₂ (R ′) ₅ , —CH ₂ —C (R ′) ₃ , —C (R ′) ₇ , —C ₂ H ₄ —C (R ′ ₃ , —C ₂ H ₄ —CH═CH ₂ , —CH═CH—C ₂ H ₅ , —CH═C (CH ₃ ) ₂ , —CH ₂ —CH═CH—CH ₃ , —CH═CH— _{CH = CH 2, -C 2 H} 4 -C≡CH, -C≡C-C 2 H 5, -CH 2 -C≡C-CH 3, - _{≡C-CH = CH 2, -CH} = CH-C≡CH, -C≡C-C≡CH, -C 2 H 4 -CH (CH 3) 2, -CH (CH 3) -C 3 H 7 , —CH ₂ —CH (CH ₃ ) —C ₂ H ₅ , —CH (CH ₃ ) —CH (CH ₃ ) ₂ , —C (CH ₃ ) ₂ —C ₂ H ₅ , —CH ₂ —C (CH ₃ ) ₃ , —C ₃ H ₆ —CH═CH ₂ , —CH═CH—C ₃ H ₇ , —C ₂ H ₄ —CH═CH—CH ₃ , —CH ₂ —CH═CH—C ₂ H _{5 , -CH 2 -CH = CH-CH} = CH 2, -CH = CH-CH = CH-CH 3, -CH = CH-CH 2 -CH = CH 2, -C (CH 3) = CH-CH = CH ₂ , —CH═C (CH ₃ ) —CH═CH ₂ , —CH═CH—C (CH ₃ ) = CH ₂ , —CH ₂ —CH═C (CH ₃ ) ₂ , C (CH ₃ ) = C (CH ₃ ) ₂ , —C ₃ H ₆ —C≡CH, —C≡ C—C ₃ H ₇ , —C ₂ H ₄ —C≡C—CH ₃ , —CH ₂ —C≡C—C ₂ H ₅ , —CH ₂ —C≡C—CH═CH ₂ , —CH ₂ — CH = CH—C≡CH, —CH ₂ —C≡C—C≡CH, —C≡C—CH═CH—CH ₃ , —CH═CH—C≡C—CH ₃ , —C≡C—C ≡C—CH ₃ , —C≡C—CH ₂ —CH═CH ₂ , —CH═CH—CH ₂ —C≡CH, —C≡C—CH ₂ —C≡CH, —C (CH ₃ ) = CH—CH═CH ₂ , —CH═C (CH ₃ ) —CH═CH ₂ , —CH═CH—C (CH ₃ ) ═CH ₂ , —C (CH ₃ ) ═CH—C≡CH, —CH ═C (CH ₃ ) —C≡CH, —C≡C—C (CH ₃ ) ═CH ₂ , —C ₃ H ₆ —CH (CH ₃ ) ₂ , —C ₂ H ₄ —CH (CH ₃ ) — _{C 2 H 5, -CH (CH} 3) -C 4 H 9, -CH 2 -CH (CH 3) - _{3 H 7, -CH (CH 3} ) -CH 2 -CH (CH 3) 2, -CH (CH 3) -CH (CH 3) -C 2 H 5, -CH 2 -CH (CH 3) -CH (CH ₃ ) ₂ , —CH ₂ —C (CH ₃ ) ₂ —C ₂ H ₅ , —C (CH ₃ ) ₂ —C ₃ H ₇ , —C (CH ₃ ) ₂ —CH (CH ₃ ) ₂ , _{-C 2 H 4 -C (CH 3} ) 3, -CH (CH 3) -C (CH 3) 3, -C 4 H 8 -CH = CH 2, -CH = CH-C 4 H 9, -C ₃ H ₆ —CH═CH—CH ₃ , —CH ₂ —CH═CH—C ₃ H ₇ , —C ₂ H ₄ —CH═CH—C ₂ H ₅ , —CH ₂ —C (CH ₃ ) ═C (CH ₃ ) ₂ , —C ₂ H ₄ —CH═C (CH ₃ ) ₂ , —C ₄ H ₈ —C≡CH, —C≡C—C ₄ H ₉ , —C ₃ H ₆ —C≡C Selected from the group consisting of —CH ₃ , —CH ₂ —C≡C—C ₃ H ₇ , —C ₂ H ₄ —C≡C—C ₂ H ₅ Can be selected;

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, hydroxy Alkylamino, halogen, haloalkyl, haloalkyloxy, aryl or heteroaryl;
R ″ is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl or heteroaryl;

Cycloalkyl group means a non-aromatic ring system containing 3 to 8 carbon atoms, preferably 4 to 8 carbon atoms, in which case one or more carbon atoms in the ring are the group E And E is O, S, SO, SO ₂ , N or NR ″, R ″ is as above; a C ₃ -C ₈ -cycloalkyl residue is —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 May be selected from the group consisting of 1-alkylpiperazin-4-yl;
An alkoxy group means an O-alkyl group, the alkyl group is as defined above; the alkoxy group is preferably a methoxy, ethoxy, isopropoxy, t-butoxy or pentoxy group;
An alkylthio group means an S-alkyl group, the alkyl group is as defined above;
A haloalkyl group means an alkyl group substituted with 1 to 5 halogen atoms, the alkyl group being the same as described 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- (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 (where R ¹⁰ , R ^{10 ′} , R ^{10 ″} are F , Cl, Br or I, preferably F);

A hydroxyalkyl group means a HO-alkyl group, the alkyl group is as defined above;
A haloalkyloxy group means an alkoxy group substituted by 1 to 5 halogen atoms, the alkyl group is the same as described above; the haloalkyl 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 - (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 (where R ¹⁰ , R ^{10 ′} , R ^{10 ″} are F, Cl, Br or I, preferably F);
A hydroxyalkylamino group means a (HO-alkyl) ₂ -N- group or a HO-alkyl-NH- group, the alkyl group being as defined above;
An alkylamino group means an HN-alkyl or N-dialkyl group, the alkyl group being the same as above;
The halogen group is chlorine, bromine, fluorine or iodine;
An aryl group means an aromatic group having from 5 to 15 carbon atoms that can be optionally substituted by one or more substituents R ′, where R ′ is as defined above; Is preferably a benzyl group, a phenyl group, -o-C ₆ H ₄ -R ', -mC ₆ H ₄ -R', -pC ₆ H ₄ -R ', 1-naphthyl, 2-naphthyl 1-anthracenyl or 2-anthracenyl;

    A heteroaryl group means a 5- or 6-membered heterocyclic group containing at least one heteroatom, such as O, N, S. This heterocyclic group can be fused to another ring. For example, this group may be thiadiazol, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, oxazole-2- Yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, benzoxazol-2-yl, benzoxazol-4-yl, benzo Oxazol-5-yl, benzisoxazol-3-yl, benzisoxazol-4-yl, benzisoxazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4- Oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, benzoisothiazole-3 -Yl, benzoisothiazol-4-yl, benzoisothiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl, 1,2,5-thiadiazol-4-yl 4-imidazolyl, benzimidazol-4-yl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4- Pyridyl, 2-pyranyl, 3-pyranyl, 4-pyranyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2,4-dimeth Ci-6-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 1,2,3-triazol-4-yl, 1,2,3-triazole- 5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,3,5-triazol-6-yl, 2,4-dimethoxy-1,3 5-triazol-6-yl, 1H-tetrazol-2-yl, 1H-tetrazol-3-yl, tetrazolyl, acridyl, furazane, indazolyl, phenazinyl, carbazolyl, phenoxazinyl, indolizine, 2-indolyl, 3-indolyl, 4 -Indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 1-isoindolyl, 3-isoindolyl, 4-isoindolyl, 5- Isoindolyl, 6-isoindolyl, 7-isoindolyl, 2-indolinyl, 3-indolinyl, 4-indolinyl, 5-indolinyl, 6-indolinyl, 7-indolinyl, benzo [b] furanyl, benzofurazan, benzothiofurazan, benzotriazole- 1-yl, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl, benzotriazol-7-yl, benzotriazine, benzo [b] thiophenyl, benzimidazol-2-yl, 1H- Benzimidazolyl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl, benzimidazol-7-yl, benzothiazolyl, quinazolinyl, quinoxazolinyl, cinnoline, quinolinyl, tetrahydroxy Linyl, isoquinolinyl, tetrahydroisoquinolinyl, purine, phthalazine, pteridine, thiatetraazaindene, thiatriazaindene, isothiazolopyrazine, isothiazolopyrimidine, pyrazolotriazine, pyrazolopyrimidine, tetrahydrothieno [3,4-d ] Imidazol-2-one, pyrazolo [5,1-c] [1,2,4] triazine, 2,3-dihydrobenzo [1,4] -dioxin-2-yl, 2,3-dihydrobenzo [1] , 4] -dioxin-3-yl, 2,3-dihydrobenzo [1,4] -dioxin-5-yl, 2,3-dihydrobenzo [1,4] -dioxin-6-yl, 2,6- Dimethoxypyrimidin-3-yl, 2,6-dimethoxypyrimidin-4-yl, imidazopyridazine, imidazopyrimidine, imidazopyridine, imidazolotriazi , Triazolotriazine, triazolopyridine, triazolopyrazine, triazolopyrimidine or 4- [1,2,4] triazolo [4,3-a] pyridin-3-yl, 1-furo [2,3-c] It may be selected from pyridin-4-yl, 1-furo [2,3-c] pyridin-5-yl, 1-furo [2,3-c] pyridin-3-yl and triazolopyridazine groups. This heterocyclic group relates to one or more substituents R ', where R' can be substituted as described above.

（式中、Ｒ¹は、-Ｃ（Ｏ）Ｒ⁷、-Ｃ（Ｏ）ＣＨＲ⁷Ｒ⁸、-Ｃ（Ｏ）ＮＲ⁷Ｒ⁸、-Ｃ（Ｏ）ＯＲ⁷、-Ｒ⁷Ｃ（Ｏ）Ｒ⁸または-Ｃ（Ｓ）Ｒ⁷であり； The present invention relates to a compound of general formula (Ib), or a pharmaceutically acceptable salt thereof with an acid or base, or a pharmaceutically acceptable prodrug or stereoisomer thereof:

(In the formula, 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, hydroxyalkyl, amino, 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 Represents ⁸ or heteroaryl;
R ⁴ is H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl; or

R ¹ and R ⁴ together with the X to which they are attached form a 3-8 membered saturated or at least partially unsaturated monocyclic or polycyclic ring system (in this case at least one ring The 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 ″} and 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 Represents aryl;
p is 1-6;
q is 1-6;

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, hydroxyalkylamino, 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 table ;

であり；
Ａは、Ｎ、ＯまたはＣＲ^2’であり；
Ｒ⁵は、独立して、Ｈ、ＳＯＲ⁷、ＳＯ₂Ｒ⁷、ＳＯ₃Ｒ⁷、-Ｃ（Ｏ）Ｒ⁷、-Ｃ（Ｏ）ＣＨＲ⁷Ｒ⁸、-Ｃ（Ｏ）ＮＲ⁷Ｒ⁸、-Ｃ（Ｏ）ＯＲ⁷、-Ｒ⁷Ｃ（Ｏ）Ｒ⁸、-Ｃ（Ｓ）Ｒ⁷、-Ｃ（ＮＲ⁷）ＮＲ^7’Ｒ⁸、-（ＣＨ₂）_pアリール、-Ｃ（ＮＨ₂）_pＮＲ⁷Ｒ⁸、-Ｃ（Ｏ）ＮＲ⁷Ｒ⁸、-Ｎ＝ＣＲ⁷Ｒ⁸、-ＮＲ⁷Ｃ（Ｏ）Ｒ^7’、アルキル、シクロアルキル、アルコキシ、-ＮＨ₂、アルキルアミノ、ヒドロキシアルキルアミノ、ハロゲン、-ＯＨ、-ＳＨ、アルキルチオ、ヒドロキシアルキル、ハロアルキル、ハロアルキルオキシ、アリールまたはヘテロアリールであり；
ｎは0〜2であり； R ² is independently

Is;
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, -C ( _{^{NH 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, alkyl Amino, hydroxyalkylamino, halogen, —OH, —SH, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl;
n is 0-2;

In this case, unless otherwise specified, alkyl groups are linear or branched C ₁ -C ₆ -alkyl, preferably linear or branched, linear or branched C ₁ -C 5 alkyl atoms. Means ₂ -C ₆ -alkenyl, or a linear or branched C ₂ -C ₆ -alkynyl group, which may be substituted by one or more substituents R ^′ ;
C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl and C ₂ -C ₆ -alkynyl residues are —CH ₃ , —C ₂ H ₅ , —CH═CH ₂ , —C≡CH, —C ₃ H ₇ , —CH (CH ₃ ) ₂ , —CH ₂ —CH═CH ₂ , —CH (CH ₃ ) ═CH ₂ , —CH═CH—CH ₃ , —C≡C—CH ₃ , —CH _{2 -C≡CH, -C 4 H 9, -CH} 2 -CH (CH 3) 2, -CH (CH 3) -C 2 H 5, -C (CH 3) 3, -C 5 H 11, -C ₆ H ₁₃ , —C (R ′) ₃ , —C ₂ (R ′) ₅ , —CH ₂ —C (R ′) ₃ , —C (R ′) ₇ , —C ₂ H ₄ —C (R ′ ₃ , —C ₂ H ₄ —CH═CH ₂ , —CH═CH—C ₂ H ₅ , —CH═C (CH ₃ ) ₂ , —CH ₂ —CH═CH—CH ₃ , —CH═CH— _{CH = CH 2, -C 2 H} 4 -C≡CH, -C≡C-C 2 H 5, -CH 2 -C≡C-CH 3, - _{≡C-CH = CH 2, -CH} = CH-C≡CH, -C≡C-C≡CH, -C 2 H 4 -CH (CH 3) 2, -CH (CH 3) -C 3 H 7 , —CH ₂ —CH (CH ₃ ) —C ₂ H ₅ , —CH (CH ₃ ) —CH (CH ₃ ) ₂ , —C (CH ₃ ) ₂ —C ₂ H ₅ , —CH ₂ —C (CH ₃ ) ₃ , —C ₃ H ₆ —CH═CH ₂ , —CH═CH—C ₃ H ₇ , —C ₂ H ₄ —CH═CH—CH ₃ , —CH ₂ —CH═CH—C ₂ H _{5 , -CH 2 -CH = CH-CH} = CH 2, -CH = CH-CH = CH-CH 3, -CH = CH-CH 2 -CH = CH 2, -C (CH 3) = CH-CH = CH ₂ , —CH═C (CH ₃ ) —CH═CH ₂ , —CH═CH—C (CH ₃ ) = CH ₂ , —CH ₂ —CH═C (CH ₃ ) ₂ , C (CH ₃ ) = C (CH ₃ ) ₂ , —C ₃ H ₆ —C≡CH, —C≡ C—C ₃ H ₇ , —C ₂ H ₄ —C≡C—CH ₃ , —CH ₂ —C≡C—C ₂ H ₅ , —CH ₂ —C≡C—CH═CH ₂ , —CH ₂ — CH = CH—C≡CH, —CH ₂ —C≡C—C≡CH, —C≡C—CH═CH—CH ₃ , —CH═CH—C≡C—CH ₃ , —C≡C—C ≡C—CH ₃ , —C≡C—CH ₂ —CH═CH ₂ , —CH═CH—CH ₂ —C≡CH, —C≡C—CH ₂ —C≡CH, —C (CH ₃ ) = CH—CH═CH ₂ , —CH═C (CH ₃ ) —CH═CH ₂ , —CH═CH—C (CH ₃ ) ═CH ₂ , —C (CH ₃ ) ═CH—C≡CH, —CH ═C (CH ₃ ) —C≡CH, —C≡C—C (CH ₃ ) ═CH ₂ , —C ₃ H ₆ —CH (CH ₃ ) ₂ , —C ₂ H ₄ —CH (CH ₃ ) — _{C 2 H 5, -CH (CH} 3) -C 4 H 9, -CH 2 -CH (CH 3) - _{3 H 7, -CH (CH 3} ) -CH 2 -CH (CH 3) 2, -CH (CH 3) -CH (CH 3) -C 2 H 5, -CH 2 -CH (CH 3) -CH (CH ₃ ) ₂ , —CH ₂ —C (CH ₃ ) ₂ —C ₂ H ₅ , —C (CH ₃ ) ₂ —C ₃ H ₇ , —C (CH ₃ ) ₂ —CH (CH ₃ ) ₂ , _{-C 2 H 4 -C (CH 3} ) 3, -CH (CH 3) -C (CH 3) 3, -C 4 H 8 -CH = CH 2, -CH = CH-C 4 H 9, -C ₃ H ₆ —CH═CH—CH ₃ , —CH ₂ —CH═CH—C ₃ H ₇ , —C ₂ H ₄ —CH═CH—C ₂ H ₅ , —CH ₂ —C (CH ₃ ) ═C (CH ₃ ) ₂ , —C ₂ H ₄ —CH═C (CH ₃ ) ₂ , —C ₄ H ₈ —C≡CH, —C≡C—C ₄ H ₉ , —C ₃ H ₆ —C≡C Selected from the group consisting of —CH ₃ , —CH ₂ —C≡C—C ₃ H ₇ , —C ₂ H ₄ —C≡C—C ₂ H ₅ Can be selected;

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, hydroxy Alkylamino, halogen, haloalkyl, haloalkyloxy, aryl or heteroaryl;

R ″ is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl or heteroaryl;
Cycloalkyl group means a non-aromatic ring system containing 3 to 8 carbon atoms, preferably 4 to 8 carbon atoms, in which case one or more carbon atoms in the ring are the group E And E is O, S, SO, SO ₂ , N or NR ″, R ″ is as above; a C ₃ -C ₈ -cycloalkyl residue is —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 May be selected from the group consisting of 1-alkylpiperazin-4-yl;

An alkoxy group means an O-alkyl group, the alkyl group is as defined above; the alkoxy group is preferably a methoxy, ethoxy, isopropoxy, t-butoxy or pentoxy group;
An alkylthio group means an S-alkyl group, the alkyl group is as defined above;
A haloalkyl group means an alkyl group substituted with 1 to 5 halogen atoms, the alkyl group being the same as described 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- (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 (where R ¹⁰ , R ^{10 ′} , R ^{10 ″} are F , Cl, Br or I, preferably F);

A hydroxyalkyl group means a HO-alkyl group, the alkyl group is as defined above;
A haloalkyloxy group means an alkoxy group substituted by 1 to 5 halogen atoms, the alkyl group is the same as described above; the haloalkyl 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 - (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 (where R ¹⁰ , R ^{10 ′} , R ^{10 ″} are F, Cl, Br or I, preferably F);
A hydroxyalkylamino group means a (HO-alkyl) ₂ -N- group or a HO-alkyl-NH- group, the alkyl group being as defined above;
An alkylamino group means an HN-alkyl or N-dialkyl group, the alkyl group being the same as above;
The halogen group is chlorine, bromine, fluorine or iodine;

An aryl group means an aromatic group having from 5 to 15 carbon atoms that can be optionally substituted by one or more substituents R ′, where R ′ is as defined above; Is preferably a benzyl group, a phenyl group, -o-C ₆ H ₄ -R ', -mC ₆ H ₄ -R', -pC ₆ H ₄ -R ', 1-naphthyl, 2-naphthyl 1-anthracenyl or 2-anthracenyl;
A heteroaryl group means a 5- or 6-membered heterocyclic group containing at least one heteroatom, such as O, N, S. This heterocyclic group can be fused to another ring. For example, this group may be thiadiazol, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, oxazole-2- Yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, benzoxazol-2-yl, benzoxazol-4-yl, benzo Oxazol-5-yl, benzisoxazol-3-yl, benzisoxazol-4-yl, benzisoxazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4- Oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, benzoisothiazole-3 -Yl, benzoisothiazol-4-yl, benzoisothiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl, 1,2,5-thiadiazol-4-yl 4-imidazolyl, benzimidazol-4-yl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4- Pyridyl, 2-pyranyl, 3-pyranyl, 4-pyranyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2,4-dimeth Ci-6-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 1,2,3-triazol-4-yl, 1,2,3-triazole- 5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,3,5-triazol-6-yl, 2,4-dimethoxy-1,3 5-triazol-6-yl, 1H-tetrazol-2-yl, 1H-tetrazol-3-yl, tetrazolyl, acridyl, furazane, indazolyl, phenazinyl, carbazolyl, phenoxazinyl, indolizine, 2-indolyl, 3-indolyl, 4 -Indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 1-isoindolyl, 3-isoindolyl, 4-isoindolyl, 5- Isoindolyl, 6-isoindolyl, 7-isoindolyl, 2-indolinyl, 3-indolinyl, 4-indolinyl, 5-indolinyl, 6-indolinyl, 7-indolinyl, benzo [b] furanyl, benzofurazan, benzothiofurazan, benzotriazole- 1-yl, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl, benzotriazol-7-yl, benzotriazine, benzo [b] thiophenyl, benzimidazol-2-yl, 1H- Benzimidazolyl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl, benzimidazol-7-yl, benzothiazolyl, quinazolinyl, quinoxazolinyl, cinnoline, quinolinyl, tetrahydroxy Linyl, isoquinolinyl, tetrahydroisoquinolinyl, purine, phthalazine, pteridine, thiatetraazaindene, thiatriazaindene, 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-dihydro Benzo [1,4] -dioxin-6-yl, 2,6-dimethoxypyrimidin-3-yl, 2,6-dimethyl Toxipyrimidin-4-yl, triazolopyridine, triazolopyrazine, triazolopyrimidine, 4- [1,2,4] triazolo [4,3-a] pyridin-3-yl, 1-furo [2,3- c] pyridin-4-yl, 1-furo [2,3-c] pyridin-5-yl, 1-furo [2,3-c] pyridin-3-yl and triazolopyridazine groups. This heterocyclic group relates to one or more substituents R ′, where R ′ is as defined above.

（式中、Ｒ¹は、Ｈ、アルキル、シクロアルキル、ヒドロキシアルキル、ハロアルキル、ハロアルキルオキシ、アリールまたはヘテロアリールを表わし；
Ｘは、ＣＯ、ＣＳまたはＳＯ₂であり；
Ｙは、ＣＯ、ＣＳまたはＳＯ₂であり；
Ｚは、ＮＲ^2”、ＳまたはＯであり；
Ｒ^2”は、Ｈ、アルキル、-Ｃ（Ｏ）ＮＲ⁷、-Ｃ（Ｏ）Ｒ^e、シクロアルキル、ハロアルキル、ヒドロキシアルキル、ヒドロキシアルキルアミノ、アルキルアミノ、ヘテロアリールまたはアリールであり；
Ｒ^4’、Ｒ^4”、Ｒ^5’は、独立して、Ｈ、アルキル、シクロアルキル、ハロアルキル、ヒドロキシアルキル、ヒドロキシアルキルアミノ、アルキルアミノ、-Ｃ（ＮＲ⁷）ＮＲ^7’Ｒ⁸、-（ＣＨ₂）_pアリール、-（ＣＨ₂）_pＮＲ⁷Ｒ⁸、-Ｃ（Ｏ）ＮＲ⁷Ｒ⁸、-Ｎ＝ＣＲ⁷Ｒ⁸、-ＮＲ⁷Ｃ（Ｏ）Ｒ⁸、ハロゲン、ヘテロアリールまたはアリールを表わし；
ｐは、1〜6であり；
ｑは、1〜6であり；
ｍは、0〜4であり；
ｒは、0または1であり；
ｔは、0または1であり；
ｓは、0または1であり； The present invention relates to a compound of general formula (Ic), or a pharmaceutically acceptable salt thereof with an acid or base, or a pharmaceutically acceptable prodrug or stereoisomer thereof:

Wherein R ¹ represents 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 ″} and 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 Represents aryl;
p is 1-6;
q is 1-6;
m is 0-4;
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, hydroxyalkylamino, 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 table ;

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;
In this case, unless otherwise specified, alkyl groups are linear or branched C ₁ -C ₆ -alkyl, preferably linear or branched, linear or branched C ₁ -C 5 alkyl atoms. Means ₂ -C ₆ -alkenyl, or a linear or branched C ₂ -C ₆ -alkynyl group, which may be substituted by one or more substituents R ^′ ;

C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl and C ₂ -C ₆ -alkynyl residues are —CH ₃ , —C ₂ H ₅ , —CH═CH ₂ , —C≡CH, —C ₃ H ₇ , —CH (CH ₃ ) ₂ , —CH ₂ —CH═CH ₂ , —CH (CH ₃ ) ═CH ₂ , —CH═CH—CH ₃ , —C≡C—CH ₃ , —CH _{2 -C≡CH, -C 4 H 9, -CH} 2 -CH (CH 3) 2, -CH (CH 3) -C 2 H 5, -C (CH 3) 3, -C 5 H 11, -C ₆ H ₁₃ , —C (R ′) ₃ , —C ₂ (R ′) ₅ , —CH ₂ —C (R ′) ₃ , —C (R ′) ₇ , —C ₂ H ₄ —C (R ′ ₃ , —C ₂ H ₄ —CH═CH ₂ , —CH═CH—C ₂ H ₅ , —CH═C (CH ₃ ) ₂ , —CH ₂ —CH═CH—CH ₃ , —CH═CH— _{CH = CH 2, -C 2 H} 4 -C≡CH, -C≡C-C 2 H 5, -CH 2 -C≡C-CH 3, - _{≡C-CH = CH 2, -CH} = CH-C≡CH, -C≡C-C≡CH, -C 2 H 4 -CH (CH 3) 2, -CH (CH 3) -C 3 H 7 , —CH ₂ —CH (CH ₃ ) —C ₂ H ₅ , —CH (CH ₃ ) —CH (CH ₃ ) ₂ , —C (CH ₃ ) ₂ —C ₂ H ₅ , —CH ₂ —C (CH ₃ ) ₃ , —C ₃ H ₆ —CH═CH ₂ , —CH═CH—C ₃ H ₇ , —C ₂ H ₄ —CH═CH—CH ₃ , —CH ₂ —CH═CH—C ₂ H _{5 , -CH 2 -CH = CH-CH} = CH 2, -CH = CH-CH = CH-CH 3, -CH = CH-CH 2 -CH = CH 2, -C (CH 3) = CH-CH = CH ₂ , —CH═C (CH ₃ ) —CH═CH ₂ , —CH═CH—C (CH ₃ ) = CH ₂ , —CH ₂ —CH═C (CH ₃ ) ₂ , C (CH ₃ ) = C (CH ₃ ) ₂ , —C ₃ H ₆ —C≡CH, —C≡ C—C ₃ H ₇ , —C ₂ H ₄ —C≡C—CH ₃ , —CH ₂ —C≡C—C ₂ H ₅ , —CH ₂ —C≡C—CH═CH ₂ , —CH ₂ — CH = CH—C≡CH, —CH ₂ —C≡C—C≡CH, —C≡C—CH═CH—CH ₃ , —CH═CH—C≡C—CH ₃ , —C≡C—C ≡C—CH ₃ , —C≡C—CH ₂ —CH═CH ₂ , —CH═CH—CH ₂ —C≡CH, —C≡C—CH ₂ —C≡CH, —C (CH ₃ ) = CH—CH═CH ₂ , —CH═C (CH ₃ ) —CH═CH ₂ , —CH═CH—C (CH ₃ ) ═CH ₂ , —C (CH ₃ ) ═CH—C≡CH, —CH ═C (CH ₃ ) —C≡CH, —C≡C—C (CH ₃ ) ═CH ₂ , —C ₃ H ₆ —CH (CH ₃ ) ₂ , —C ₂ H ₄ —CH (CH ₃ ) — _{C 2 H 5, -CH (CH} 3) -C 4 H 9, -CH 2 -CH (CH 3) - _{3 H 7, -CH (CH 3} ) -CH 2 -CH (CH 3) 2, -CH (CH 3) -CH (CH 3) -C 2 H 5, -CH 2 -CH (CH 3) -CH (CH ₃ ) ₂ , —CH ₂ —C (CH ₃ ) ₂ —C ₂ H ₅ , —C (CH ₃ ) ₂ —C ₃ H ₇ , —C (CH ₃ ) ₂ —CH (CH ₃ ) ₂ , _{-C 2 H 4 -C (CH 3} ) 3, -CH (CH 3) -C (CH 3) 3, -C 4 H 8 -CH = CH 2, -CH = CH-C 4 H 9, -C ₃ H ₆ —CH═CH—CH ₃ , —CH ₂ —CH═CH—C ₃ H ₇ , —C ₂ H ₄ —CH═CH—C ₂ H ₅ , —CH ₂ —C (CH ₃ ) ═C (CH ₃ ) ₂ , —C ₂ H ₄ —CH═C (CH ₃ ) ₂ , —C ₄ H ₈ —C≡CH, —C≡C—C ₄ H ₉ , —C ₃ H ₆ —C≡C Selected from the group consisting of —CH ₃ , —CH ₂ —C≡C—C ₃ H ₇ , —C ₂ H ₄ —C≡C—C ₂ H ₅ Can be selected;

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, hydroxy Alkylamino, halogen, haloalkyl, haloalkyloxy, aryl or heteroaryl;
R ″ is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl or heteroaryl;

Cycloalkyl group means a non-aromatic ring system containing 3 to 8 carbon atoms, preferably 4 to 8 carbon atoms, in which case one or more carbon atoms in the ring are the group E And E is O, S, SO, SO ₂ , N or NR ″, R ″ is as above; a C ₃ -C ₈ -cycloalkyl residue is —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 May be selected from the group consisting of 1-alkylpiperazin-4-yl;
An alkoxy group means an O-alkyl group, the alkyl group is as defined above; the alkoxy group is preferably a methoxy, ethoxy, isopropoxy, t-butoxy or pentoxy group;
An alkylthio group means an S-alkyl group, the alkyl group is as defined above;
A haloalkyl group means an alkyl group substituted with 1 to 5 halogen atoms, the alkyl group being the same as described 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- (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 (where R ¹⁰ , R ^{10 ′} , R ^{10 ″} are F , Cl, Br or I, preferably F);

A hydroxyalkyl group means a HO-alkyl group, the alkyl group is as defined above;
A haloalkyloxy group means an alkoxy group substituted by 1 to 5 halogen atoms, the alkyl group is the same as described above; the haloalkyl 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 - (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 (where R ¹⁰ , R ^{10 ′} , R ^{10 ″} are F, Cl, Br or I, preferably F);
A hydroxyalkylamino group means a (HO-alkyl) ₂ -N- group or a HO-alkyl-NH- group, the alkyl group being as defined above;
An alkylamino group means an HN-alkyl or N-dialkyl group, the alkyl group being the same as above;
The halogen group is chlorine, bromine, fluorine or iodine;
An aryl group means an aromatic group having from 5 to 15 carbon atoms that can be optionally substituted by one or more substituents R ′, where R ′ is as defined above; Is preferably a benzyl group, a phenyl group, -o-C ₆ H ₄ -R ', -mC ₆ H ₄ -R', -pC ₆ H ₄ -R ', 1-naphthyl, 2-naphthyl 1-anthracenyl or 2-anthracenyl;

      A heteroaryl group means a 5- or 6-membered heterocyclic group containing at least one heteroatom, such as O, N, S. This heterocyclic group can be fused to another ring. For example, this group may be thiadiazol, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, oxazole-2- Yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, benzoxazol-2-yl, benzoxazol-4-yl, benzo Oxazol-5-yl, benzisoxazol-3-yl, benzisoxazol-4-yl, benzisoxazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4- Oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, benzoisothiazole-3 -Yl, benzoisothiazol-4-yl, benzoisothiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl, 1,2,5-thiadiazol-4-yl 4-imidazolyl, benzimidazol-4-yl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4- Pyridyl, 2-pyranyl, 3-pyranyl, 4-pyranyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2,4-dimeth Ci-6-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 1,2,3-triazol-4-yl, 1,2,3-triazole- 5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,3,5-triazol-6-yl, 2,4-dimethoxy-1,3 5-triazol-6-yl, 1H-tetrazol-2-yl, 1H-tetrazol-3-yl, tetrazolyl, acridyl, furazane, indazolyl, phenazinyl, carbazolyl, phenoxazinyl, indolizine, 2-indolyl, 3-indolyl, 4 -Indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 1-isoindolyl, 3-isoindolyl, 4-isoindolyl, 5- Isoindolyl, 6-isoindolyl, 7-isoindolyl, 2-indolinyl, 3-indolinyl, 4-indolinyl, 5-indolinyl, 6-indolinyl, 7-indolinyl, benzo [b] furanyl, benzofurazan, benzothiofurazan, benzotriazole- 1-yl, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl, benzotriazol-7-yl, benzotriazine, benzo [b] thiophenyl, benzimidazol-2-yl, 1H- Benzimidazolyl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl, benzimidazol-7-yl, benzothiazolyl, quinazolinyl, quinoxazolinyl, cinnoline, quinolinyl, tetrahydroxy Linyl, isoquinolinyl, tetrahydrothieno [3,4-d] imidazol-2-one, pyrazolo [5,1-c] [1,2,4] triazine, tetrahydroisoquinolinyl, purine, phthalazine, pteridine, thiatetra Azaindene, thiatriazaindene, isothiazolopyrazine, isothiazolopyrimidine, pyrazolotriazine, pyrazolopyrimidine, imidazopyridazine, imidazopyrimidine, imidazopyridine, imidazolotriazine, triazolotriazine, triazolopyridine, triazolopyrazine, tria Zolopyrimidine, 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] -dio Xin-6-yl, 2,6-dimethoxypyrimidin-3-yl, 2,6-dimethoxypyrimidin-4-yl, 4- [1,2,4] triazolo [4,3-a] pyridin-3-yl 1-furo [2,3-c] pyridin-4-yl, 1-furo [2,3-c] pyridin-5-yl, 1-furo [2,3-c] pyridin-3-yl and tria It may be selected from a zolopyridazine group. This heterocyclic group relates to one or more substituents R ', where R' can be substituted as described above.

（式中、Ｒ¹は、-Ｃ（Ｏ）Ｒ^7a、-Ｃ（Ｏ）ＣＨＲ⁷Ｒ⁸、-Ｃ（Ｏ）ＮＲ⁷Ｒ⁸、-Ｃ（Ｏ）ＯＲ⁷、-Ｒ⁷Ｃ（Ｏ）Ｒ⁸または-Ｃ（Ｓ）Ｒ^7bであり；
Ｒ²は、Ｈ、アルキル、シクロアルキル、ヘテロシクロアルキル、ハロアルキル、ヒドロキシアルキル、ヒドロキシアルキルアミノ、アルキルアミノ、ヘテロアリールであるか；あるいは
Ｒ¹およびＲ²は、それらが結合されるＮ原子またはＣ原子と一緒になって、３〜８員飽和または少なくとも一部不飽和単環式または多環式環系を形成し（この場合、環中の炭素原子のうちの少なくとも1つまたは複数はＯ、ＮおよびＳから選択され、そして環は１つまたは複数のＲ⁹により置換され得る）； The present invention relates to a compound of general formula (III), or a pharmaceutically acceptable salt thereof with an acid or base, or a pharmaceutically acceptable prodrug or stereoisomer thereof:

(In the formula, 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, heteroaryl; or R ¹ and R ² are the N atom or C to which they are attached Taken together with atoms to form a 3-8 membered saturated or at least partially unsaturated monocyclic or polycyclic ring system (wherein at least one or more of the carbon atoms in the ring are O, Selected from N and S, and the ring may be substituted by 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, Is 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, —C (NH 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, hydroxy cycloalkyl Alkyl, hydroxyalkyl amino, heterocycloalkyl, aryl or heteroaryl represents;
^{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, hydroxyalkyl amino, 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 ;
p is 1-6;
q is 1-6;
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, hydroxy It represents ^{_{(CH 2) p NR 7 COR}} 8, aryl or heteroaryl - alkylamino, halo alkyloxy, heterocycloalkyl;

In this case, a C ₁ -C ₆ -alkyl group, unless stated otherwise, means a linear or branched C ₁ -C ₆ -alkyl, preferably a linear or branched chain having 1 to 5 carbon atoms. And can be optionally substituted by one or more substituents R ′;
C ₂ -C ₆ -alkenyl group, unless stated otherwise, means linear or branched C ₂ -C ₆ -alkenyl, preferably linear or branched having 2 to 6 carbon atoms, Can be optionally substituted by one or more substituents R ′;
Unless otherwise specified, alkyl groups are linear or branched C ₁ -C ₆ -alkyl, preferably linear or branched, linear or branched C ₂ -C having 1 to 6 carbon atoms. Means ₆ -alkenyl, or a linear or branched C ₂ -C ₆ -alkynyl group, which may be substituted by one or more substituents R ^′ ;

R ′ is independently H, —CO ₂ R ″, —CONHR ″, —CR ″ O, —SO ₂ NR ″, —NR ″ —CO-haloalkyl, —NO ₂ , —NR ″ —SO ₂ — haloalkyl, -NR "-SO ₂ - alkyl, -SO ₂ - alkyl, -NR" -CO- alkyl, -CN, alkyl, cycloalkyl, alkylamino, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl, hydroxy Alkylamino, halogen, haloalkyl, haloalkyloxy, aryl or heteroaryl;
R ″ is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl or heteroaryl;
Cycloalkyl group means a non-aromatic ring system containing 3 to 8 carbon atoms, preferably 4 to 8 carbon atoms, in which case one or more carbon atoms in the ring are the radicals R C ₃ -C ₈ -cycloalkyl residues can be substituted with -cyclo-C ₃ H ₅ , -cyclo-C ₄ H ₇ , -cyclo-C ₅ H ₉ , May be selected from the group consisting of -cyclo-C ₆ H ₁₁ , -cyclo-C ₇ H ₁₃ , -cyclo-C ₈ H ₁₅ ;
A heterocycloalkyl group means a non-aromatic ring system containing 2 to 10 carbon atoms and at least one heteroatom selected from O, N and S, wherein 1 of the carbon atoms in the ring One or more may be substituted by R ′ as above; preferred heterocycloalkyl groups are morpholin-4-yl, piperazinyl, 1-alkylpiperazin-4-yl, piperidinyl, pyrrolidinyl, azepan-1-yl Yes;
An alkoxy group means an O-alkyl group, the alkyl group is as defined above; the alkoxy group is preferably a methoxy, ethoxy, isopropoxy, t-butoxy or pentoxy group;

An alkylthio group means an S-alkyl group, the alkyl group being the same as described above;
A haloalkyl group means an alkyl group substituted with 1 to 5 halogen atoms, the alkyl group being the same as described 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- (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 (where R ¹⁰ , R ^{10 ′} , R ^{10 ″} are F , Cl, Br or I, preferably F);
A hydroxyalkyl group means a HO-alkyl group, the alkyl group is as defined above;

A haloalkyloxy group means an alkoxy group substituted by 1 to 5 halogen atoms, the alkyl group is the same as described above; the haloalkyl 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 - (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 (where R ¹⁰ , R ^{10 ′} , R ^{10 ″} are F, Cl, Br or I, preferably F);
A hydroxyalkylamino group means a (HO-alkyl) ₂ -N- group or a HO-alkyl-NH- group, the alkyl group being as defined above;
An alkylamino group means an HN-alkyl or N-dialkyl group, the alkyl group being the same as above;
The halogen group is chlorine, bromine, fluorine or iodine;
An aryl group means an aromatic group having 5 to 15 carbon atoms that may be optionally substituted with one or more substituents R ′, where R ′ is as defined above; Is preferably a benzyl group, a phenyl group, -o-C ₆ H ₄ -R ', -mC ₆ H ₄ -R', -pC ₆ H ₄ -R ', 1-naphthyl, 2-naphthyl 1-anthracenyl or 2-anthracenyl; R ′ is as defined above;
An arylamino group means an HN-aryl or N-diaryl group, the aryl group being the same as described above;

      A heteroaryl group means a 5- or 6-membered heterocyclic group containing at least one heteroatom selected from O, N and S. This heterocyclic group can be fused to another ring. For example, this group may be thiadiazol, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, oxazole-2- Yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, benzoxazol-2-yl, benzoxazol-4-yl, benzo Oxazol-5-yl, benzisoxazol-3-yl, benzisoxazol-4-yl, benzisoxazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4- Oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, benzoisothiazole-3 -Yl, benzoisothiazol-4-yl, benzoisothiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl, 1,2,5-thiadiazol-4-yl 4-imidazolyl, benzimidazol-4-yl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4- Pyridyl, 2-pyranyl, 3-pyranyl, 4-pyranyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2,4-dimeth Ci-6-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 1,2,3-triazol-4-yl, 1,2,3-triazole- 5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,3,5-triazol-6-yl, 2,4-dimethoxy-1,3 5-triazol-6-yl, 1H-tetrazol-2-yl, 1H-tetrazol-3-yl, tetrazolyl, acridyl, furazane, indazolyl, phenazinyl, carbazolyl, phenoxazinyl, indolizine, 2-indolyl, 3-indolyl, 4 -Indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 1-isoindolyl, 3-isoindolyl, 4-isoindolyl, 5- Isoindolyl, 6-isoindolyl, 7-isoindolyl, 2-indolinyl, 3-indolinyl, 4-indolinyl, 5-indolinyl, 6-indolinyl, 7-indolinyl, benzo [b] furanyl, benzofurazan, benzothiofurazan, benzotriazole- 1-yl, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl, benzotriazol-7-yl, benzotriazine, benzo [b] thiophenyl, benzimidazol-2-yl, 1H- Benzimidazolyl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl, benzimidazol-7-yl, benzothiazolyl, quinazolinyl, quinoxazolinyl, cinnoline, quinolinyl, tetrahydroxy Linyl, 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] -dioxin-3-yl, 2,3-dihydrobenzo [1,4] -dioxin-5-yl, 2,3-dihydrobenzo [1,4 ] -Dioxin-6-yl, 2,6-dimethoxypyrimidin-3-yl, 2,6-dimethoxypyrimidin-4-yl, tetrahydroisoquinolinyl, purine, phthalazine, pteridine, thiatetraazaindene, thiatriazain Den, isothiazolopyrazine, isothiazolopyrimidine, pyrazolotriazine, pyrazolopyrimidine, imidazopyridazine, imidazopyrimidine, imidazopyridine, imidazolotriazi , Triazolotriazine, triazolopyridine, triazolopyrazine, triazolopyrimidine, 4- [1,2,4] triazolo [4,3-a] pyridin-3-yl, 1-furo [2,3-c] It may be selected from pyridin-4-yl, 1-furo [2,3-c] pyridin-5-yl, 1-furo [2,3-c] pyridin-3-yl and triazolopyridazine groups. This heterocyclic group also relates to one or more substituents R ′, where R ′ can be substituted as described above.

（式中、Ｒ¹は、独立して、水素、アルキル、シクロアルキル、ヒドロキシアルキル、ハロアルキル、ハロアルキルオキシ、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、アリールアルキルまたは置換アリールアルキルを表わし；
Ｒ²は、独立して、-ＮＲ³Ｒ⁴、

を表わし； The following compounds are excluded from formula (III):

Wherein 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 ,

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. Represents 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 ).

（式中、Ａは、ＮＲ^2’、ＳまたはＯであり；
ｔは、0〜4であり；
ｒは、0または1であり；
Ｒ^2aは、独立して、Ｈ、ＯＨ、ＳＨ、ＮＨ₂、アルキル、シクロアルキル、ヒドロキシアルキル、ハロアルキル、ハロアルキルオキシ、アルコキシ、アルキルアミノ、ヒドロキシアルキルアミノ、ハロゲン、アリールまたはヘテロアリールであり；
Ｒ^3aは、Ｈ、ＯＨ、ＳＨ、ＮＨ₂、-Ｃ（ＮＲ⁷）ＮＲ^7’Ｒ⁸、-（ＣＨ₂）_pアリール、-Ｃ（ＮＨ₂）_pＮＲ⁷Ｒ⁸、-Ｃ（Ｏ）ＮＲ⁷Ｒ⁸、-Ｎ＝ＣＲ⁷Ｒ⁸、-ＮＲ⁷Ｃ（Ｏ）Ｒ⁸、アルキル、シクロアルキル、ヒドロキシアルキル、ハロアルキル、ハロアルキルオキシ、アルコキシ、アルキルアミノ、ヒドロキシアルキルアミノ、ハロゲン、アリールまたはヘテロアリールであり；
Ｒ^dは、Ｈ、ハロゲン、アルキル、-Ｃ（ＮＲ⁷）ＮＲ^7’Ｒ⁸、-（ＣＨ₂）_pアリール、-（ＣＨ₂）_pＮＲ⁷Ｒ⁸、-Ｃ（Ｏ）ＮＲ⁷Ｒ⁸、-Ｎ＝ＣＲ⁷Ｒ⁸、-ＮＲ⁷Ｃ（Ｏ）Ｒ⁸、シクロアルキル、ハロアルキル、ヒドロキシアルキル、ヒドロキシアルキルアミノ、アルキルアミノ、ヘテロアリールまたはアリールであり；
Ｒ¹は、-Ｃ（Ｏ）Ｒ^7a、-Ｃ（Ｏ）ＣＨＲ⁷Ｒ⁸、-Ｃ（Ｏ）ＮＲ⁷Ｒ⁸、-Ｃ（Ｏ）ＯＲ⁷、-Ｒ⁷Ｃ（Ｏ）Ｒ⁸または-Ｃ（Ｓ）Ｒ^7bであり；
Ｒ²は、Ｈ、アルキル、シクロアルキル、ヘテロシクロアルキル、ハロアルキル、ヒドロキシアルキル、ヒドロキシアルキルアミノ、アルキルアミノまたはヘテロアリールであるか、あるいは The invention relates to a compound of general formula (Ih), or a pharmaceutically acceptable salt thereof with an acid or base, or a pharmaceutically acceptable prodrug or stereoisomer thereof:

Wherein A is NR ^{2 ′} , S or O;
t is 0-4;
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, —C (NH 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 hetero Is aryl;
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

R ¹ and R ² together with the N or C atom to which they are attached form a 3-8 membered saturated or at least partially unsaturated monocyclic or polycyclic ring system (in this case, At least one or more of the carbon atoms in the ring are heteroatoms selected from O, N and S, and the ring may be substituted by 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 is 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, Is 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, hydroxy cycloalkyl Alkyl, hydroxyalkyl amino, heterocycloalkyl, aryl or heteroaryl represents;
^{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, hydroxyalkyl amino, 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 ;
p is 1-6;
q is 1-6;

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, hydroxy It represents ^{_{(CH 2) p NR 7 COR}} 8, aryl or heteroaryl - alkylamino, halo alkyloxy, heterocycloalkyl;

In this case, a C ₁ -C ₆ -alkyl group, unless stated otherwise, means a linear or branched C ₁ -C ₆ -alkyl, preferably a linear or branched chain having 1 to 5 carbon atoms. And can be optionally substituted by one or more substituents R ′;
C ₂ -C ₆ -alkenyl group, unless stated otherwise, means linear or branched C ₂ -C ₆ -alkenyl, preferably linear or branched having 2 to 6 carbon atoms, Can be optionally substituted by one or more substituents R ′;
Unless otherwise specified, alkyl groups are linear or branched C ₁ -C ₆ -alkyl, preferably linear or branched, linear or branched C ₂ -C having 1 to 6 carbon atoms. Means ₆ -alkenyl, or a linear or branched C ₂ -C ₆ -alkynyl group, which may be substituted by one or more substituents R ^′ ;
R ′ is independently H, —CO ₂ R ″, —CONHR ″, —CR ″ O, —SO ₂ NR ″, —NR ″ —CO-haloalkyl, —NO ₂ , —NR ″ —SO ₂ — haloalkyl, -NR "-SO ₂ - alkyl, -SO ₂ - alkyl, -NR" -CO- alkyl, -CN, alkyl, cycloalkyl, alkylamino, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl, hydroxy Alkylamino, halogen, haloalkyl, haloalkyloxy, aryl or heteroaryl;
R ″ is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl or heteroaryl;

Cycloalkyl group means a non-aromatic ring system containing 3 to 8 carbon atoms, preferably 4 to 8 carbon atoms, in which case one or more carbon atoms in the ring are the radicals R C ₃ -C ₈ -cycloalkyl residues can be substituted with -cyclo-C ₃ H ₅ , -cyclo-C ₄ H ₇ , -cyclo-C ₅ H ₉ , May be selected from the group consisting of -cyclo-C ₆ H ₁₁ , -cyclo-C ₇ H ₁₃ , -cyclo-C ₈ H ₁₅ ;
A heterocycloalkyl group means a non-aromatic ring system containing 2 to 10 carbon atoms and at least one heteroatom selected from O, N and S, wherein 1 of the carbon atoms in the ring One or more may be substituted by R ′ as above; preferred heterocycloalkyl groups are morpholin-4-yl, piperazinyl, 1-alkylpiperazin-4-yl, piperidinyl, pyrrolidinyl, azepan-1-yl Yes;
An alkoxy group means an O-alkyl group, the alkyl group is as defined above; the alkoxy group is preferably a methoxy, ethoxy, isopropoxy, t-butoxy or pentoxy group;

An alkylthio group means an S-alkyl group, the alkyl group being the same as described above;
A haloalkyl group means an alkyl group substituted with 1 to 5 halogen atoms, the alkyl group being the same as described 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- (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 (where R ¹⁰ , R ^{10 ′} , R ^{10 ″} are F , Cl, Br or I, preferably F);
A hydroxyalkyl group means a HO-alkyl group, the alkyl group is as defined above;

A haloalkyloxy group means an alkoxy group substituted by 1 to 5 halogen atoms, the alkyl group is the same as described above; the haloalkyl 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 - (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 (where R ¹⁰ , R ^{10 ′} , R ^{10 ″} are F, Cl, Br or I, preferably F);
A hydroxyalkylamino group means a (HO-alkyl) ₂ -N- group or a HO-alkyl-NH- group, the alkyl group being as defined above;
An alkylamino group means an HN-alkyl or N-dialkyl group, the alkyl group being the same as above;
The halogen group is chlorine, bromine, fluorine or iodine;
An aryl group means an aromatic group having 5 to 15 carbon atoms that may be optionally substituted with one or more substituents R ′, where R ′ is as defined above; Is preferably a benzyl group, a phenyl group, -o-C ₆ H ₄ -R ', -mC ₆ H ₄ -R', -pC ₆ H ₄ -R ', 1-naphthyl, 2-naphthyl 1-anthracenyl or 2-anthracenyl; R ′ is as defined above;

      An arylamino group means an HN-aryl or N-diaryl group, the aryl group being the same as described above;

      A heteroaryl group means a 5- or 6-membered heterocyclic group containing at least one heteroatom selected from O, N and S. This heterocyclic group can be fused to another ring. For example, this group may be thiadiazol, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, oxazole-2- Yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, benzoxazol-2-yl, benzoxazol-4-yl, benzo Oxazol-5-yl, benzisoxazol-3-yl, benzisoxazol-4-yl, benzisoxazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4- Oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, benzoisothiazole-3 -Yl, benzoisothiazol-4-yl, benzoisothiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl, 1,2,5-thiadiazol-4-yl 4-imidazolyl, benzimidazol-4-yl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4- Pyridyl, 2-pyranyl, 3-pyranyl, 4-pyranyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2,4-dimeth Ci-6-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 1,2,3-triazol-4-yl, 1,2,3-triazole- 5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,3,5-triazol-6-yl, 2,4-dimethoxy-1,3 5-triazol-6-yl, 1H-tetrazol-2-yl, 1H-tetrazol-3-yl, tetrazolyl, acridyl, furazane, indazolyl, phenazinyl, carbazolyl, phenoxazinyl, indolizine, 2-indolyl, 3-indolyl, 4 -Indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 1-isoindolyl, 3-isoindolyl, 4-isoindolyl, 5- Isoindolyl, 6-isoindolyl, 7-isoindolyl, 2-indolinyl, 3-indolinyl, 4-indolinyl, 5-indolinyl, 6-indolinyl, 7-indolinyl, benzo [b] furanyl, benzofurazan, benzothiofurazan, benzotriazole- 1-yl, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl, benzotriazol-7-yl, benzotriazine, benzo [b] thiophenyl, benzimidazol-2-yl, 1H- Benzimidazolyl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl, benzimidazol-7-yl, benzothiazolyl, quinazolinyl, quinoxazolinyl, cinnoline, quinolinyl, tetrahydroxy Linyl, 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] -dioxin-3-yl, 2,3-dihydrobenzo [1,4] -dioxin-5-yl, 2,3-dihydrobenzo [1,4 ] -Dioxin-6-yl, 2,6-dimethoxypyrimidin-3-yl, 2,6-dimethoxypyrimidin-4-yl, tetrahydroisoquinolinyl, purine, phthalazine, pteridine, thiatetraazaindene, thiatriazain Den, isothiazolopyrazine, isothiazolopyrimidine, pyrazolotriazine, pyrazolopyrimidine, imidazopyridazine, imidazopyrimidine, imidazopyridine, imidazolotriazi , Triazolotriazine, triazolopyridine, triazolopyrazine, triazolopyrimidine, 4- [1,2,4] triazolo [4,3-a] pyridin-3-yl, 1-furo [2,3-c] It may be selected from pyridin-4-yl, 1-furo [2,3-c] pyridin-5-yl, 1-furo [2,3-c] pyridin-3-yl and triazolopyridazine groups. This heterocyclic group also relates to one or more substituents R ′, where R ′ can be substituted as described above.

（式中、Ｒ¹は、独立して、水素、アルキル、シクロアルキル、ヒドロキシアルキル、ハロアルキル、ハロアルキルオキシ、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、アリールアルキルまたは置換アリールアルキルを表わし；
Ｒ²は、独立して、-ＮＲ³Ｒ⁴、

を表わし；
Ｒ³は、独立して、アルキル、シクロアルキル、アルコキシ、アルキルアミン、-ＯＨ、-ＳＨ、アルキルチオ、ヒドロキシアルキル、ハロアルキル、ハロアルキルオキシ、アリールまたはヘテロアリールを表わし； The following compounds are excluded from formula (Ih):

Wherein 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 ,

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. Represents 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), the following substituents are selected alone or in combination:
X is preferably S or O, more preferably S.
R ^3a is preferably H.

In one preferred embodiment, Z is CR ^{2 ′} and R ¹ and R ² together with the C atom to which they are attached form a 6-membered saturated ring. In another preferred embodiment, Z is N and R ¹ and R ² together with the N atom to which they are attached form a 6-membered saturated ring.

R ⁹ is preferably aryl or benzyl, more preferably heteroaryl. R ⁹ is more preferably thienopyrimidine, quinazoline, purine, pyrazolopyrimidine or triazolopyrimidine. 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, especially methyl.

（式中、Ｒ¹は、-Ｃ（Ｏ）Ｒ⁷、-Ｃ（Ｏ）ＣＨＲ⁷Ｒ⁸、-Ｃ（Ｏ）ＮＲ⁷Ｒ⁸、-Ｃ（Ｏ）ＯＲ⁷、-Ｒ⁷Ｃ（Ｏ）Ｒ⁸または-Ｃ（Ｓ）Ｒ⁷であり；
Ｒ²は、Ｈ、アルキル、シクロアルキル、ヘテロシクロアルキル、ハロアルキル、ヒドロキシアルキル、アルキルアミノ、ヒドロキシアルキルアミノまたはヘテロアリールであるか、あるいは
Ｒ¹およびＲ²は、それらが結合されるＮ原子またはＣ原子と一緒になって、３〜８員飽和または少なくとも一部不飽和単環式または多環式環系を形成し（この場合、環中の炭素原子のうちの少なくとも1つまたは複数はＯ、ＮおよびＳから選択される異種原子であり、そして環は１つまたは複数のＲ⁹により置換され得る）；
Ｒ³は、Ｈ、-Ｃ（Ｏ）ＮＲ^aＲ^b、ハロゲン、アルキル、ハロアルキル、アリール、ヘテロアリール、ＯＨ、ＳＨ、ＮＲ^4’ＯＲ^5’、ＮＨ₂、ヒドロキシアルキルアミノ、アルキルアミノ、アルコキシ、シクロアルキル、ヘテロシクロアルキル、ヒドロキシアルキルまたはハロアルキルオキシであり； The invention relates to a compound of general formula (II), or a pharmaceutically acceptable salt thereof with an acid or base, or a pharmaceutically acceptable prodrug or stereoisomer thereof:

(In the formula, 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 or heteroaryl, or R ¹ and R ² are the N atom or C to which they are attached Taken together with atoms to form a 3-8 membered saturated or at least partially unsaturated monocyclic or polycyclic ring system (wherein at least one or more of the carbon atoms in the ring are O, A heteroatom selected from N and S, and the ring may be substituted by 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, Is 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, hydroxyalkylene Amino, aryl, heterocycloalkyl or heteroaryl represents;

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 ′} and 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 when Y is O, R ⁶ is absent;
Z is N or CR ^{2 ′} ; when Z is CH, X is O or NR ^{2 ′} ;
R ^{2 ′} is H, alkyl, —C (O) NR ² , —C (O) R ^b , cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl ;

n is 0-2;
p is 1-6;
q is 1-6;
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 represents ⁸ or heteroaryl;
R ^{4 ′} , R ^{4 ″} and 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 is aryl;

In this case, a C ₁ -C ₆ -alkyl group, unless stated otherwise, means a linear or branched C ₁ -C ₆ -alkyl, preferably a linear or branched chain having 1 to 5 carbon atoms. And can be optionally substituted by one or more substituents R ′;
C ₂ -C ₆ -alkenyl group, unless stated otherwise, means linear or branched C ₂ -C ₆ -alkenyl, preferably linear or branched having 2 to 6 carbon atoms, Can be optionally substituted by one or more substituents R ′;
Unless otherwise specified, alkyl groups are linear or branched C ₁ -C ₆ -alkyl, preferably linear or branched, linear or branched C ₂ -C having 1 to 6 carbon atoms. Means ₆ -alkenyl, or a linear or branched C ₂ -C ₆ -alkynyl group, which may be substituted by one or more substituents R ^′ ;

R ′ is independently H, —CO ₂ R ″, —CONHR ″, —CR ″ O, —SO ₂ NR ″, —NR ″ —CO-haloalkyl, —NO ₂ , —NR ″ —SO ₂ — haloalkyl, -NR "-SO ₂ - alkyl, -SO ₂ - alkyl, -NR" -CO- alkyl, -CN, alkyl, cycloalkyl, alkylamino, alkoxy, -OH, -SH, alkylthio, hydroxyalkyl, hydroxy Alkylamino, halogen, haloalkyl, haloalkyloxy, aryl or heteroaryl;
R ″ is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl or heteroaryl;
Heterocycle means heterocycloalkyl or heteroaryl;

Cycloalkyl group means a non-aromatic ring system containing 3 to 8 carbon atoms, preferably 4 to 8 carbon atoms, in which case one or more carbon atoms in the ring are the radicals R C ₃ -C ₈ -cycloalkyl residues can be substituted with -cyclo-C ₃ H ₅ , -cyclo-C ₄ H ₇ , -cyclo-C ₅ H ₉ , May be selected from the group consisting of -cyclo-C ₆ H ₁₁ , -cyclo-C ₇ H ₁₃ , -cyclo-C ₈ H ₁₅ ;
A heterocycloalkyl group means a non-aromatic ring system containing 2 to 10 carbon atoms and at least one heteroatom selected from O, N and S, wherein 1 of the carbon atoms in the ring One or more may be substituted by R ′ as above; preferred heterocycloalkyl groups are morpholin-4-yl, piperazinyl, 1-alkylpiperazin-4-yl, piperidinyl, pyrrolidinyl, azepan-1-yl Yes;
An alkoxy group means an O-alkyl group, the alkyl group is as defined above; the alkoxy group is preferably a methoxy, ethoxy, isopropoxy, t-butoxy or pentoxy group;
An alkylthio group means an S-alkyl group, the alkyl group being the same as described above;

A haloalkyl group means an alkyl group substituted with 1 to 5 halogen atoms, the alkyl group being the same as described 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- (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 (where R ¹⁰ , R ^{10 ′} , R ^{10 ″} are F , Cl, Br or I, preferably F);
A hydroxyalkyl group means a HO-alkyl group, the alkyl group is as defined above;
A haloalkyloxy group means an alkoxy group substituted by 1 to 5 halogen atoms, the alkyl group is the same as described above; the haloalkyl 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 - (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 (where R ¹⁰ , R ^{10 ′} , R ^{10 ″} are F, Cl, Br or I, preferably F);
A hydroxyalkylamino group means a (HO-alkyl) ₂ -N- group or a HO-alkyl-NH- group, the alkyl group being as defined above;

An alkylamino group means an HN-alkyl or N-dialkyl group, the alkyl group being the same as above;
The halogen group is chlorine, bromine, fluorine or iodine;
An aryl group means an aromatic group having 5 to 15 carbon atoms that may be optionally substituted with one or more substituents R ′, where R ′ is as defined above; Is preferably a benzyl group, a phenyl group, -o-C ₆ H ₄ -R ', -mC ₆ H ₄ -R', -pC ₆ H ₄ -R ', 1-naphthyl, 2-naphthyl 1-anthracenyl or 2-anthracenyl; R ′ is as defined above;

      A heteroaryl group means a 5- or 6-membered heterocyclic group containing at least one heteroatom selected from O, N and S. This heterocyclic group can be fused to another ring. For example, this group may be thiadiazol, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, oxazole-2- Yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, benzoxazol-2-yl, benzoxazol-4-yl, benzo Oxazol-5-yl, benzisoxazol-3-yl, benzisoxazol-4-yl, benzisoxazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4- Oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, benzoisothiazole-3 -Yl, benzoisothiazol-4-yl, benzoisothiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl, 1,2,5-thiadiazol-4-yl 4-imidazolyl, benzimidazol-4-yl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4- Pyridyl, 2-pyranyl, 3-pyranyl, 4-pyranyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2,4-dimeth Ci-6-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 1,2,3-triazol-4-yl, 1,2,3-triazole- 5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,3,5-triazol-6-yl, 2,4-dimethoxy-1,3 5-triazol-6-yl, 1H-tetrazol-2-yl, 1H-tetrazol-3-yl, tetrazolyl, acridyl, furazane, indazolyl, phenazinyl, carbazolyl, phenoxazinyl, indolizine, 2-indolyl, 3-indolyl, 4 -Indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 1-isoindolyl, 3-isoindolyl, 4-isoindolyl, 5- Isoindolyl, 6-isoindolyl, 7-isoindolyl, 2-indolinyl, 3-indolinyl, 4-indolinyl, 5-indolinyl, 6-indolinyl, 7-indolinyl, benzo [b] furanyl, benzofurazan, benzothiofurazan, benzotriazole- 1-yl, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl, benzotriazol-7-yl, benzotriazine, benzo [b] thiophenyl, benzimidazol-2-yl, 1H- Benzimidazolyl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl, benzimidazol-7-yl, benzothiazolyl, quinazolinyl, quinoxazolinyl, cinnoline, quinolinyl, tetrahydroxy Linyl, 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] -dioxin-3-yl, 2,3-dihydrobenzo [1,4] -dioxin-5-yl, 2,3-dihydrobenzo [1,4 ] -Dioxin-6-yl, 2,6-dimethoxypyrimidin-3-yl, 2,6-dimethoxypyrimidin-4-yl, tetrahydroisoquinolinyl, purine, phthalazine, pteridine, thiatetraazaindene, thiatriazain Den, isothiazolopyrazine, isothiazolopyrimidine, pyrazolotriazine, pyrazolopyrimidine, imidazopyridazine, imidazopyrimidine, imidazopyridine, imidazolotriazi , Triazolotriazine, triazolopyridine, triazolopyrazine, triazolopyrimidine, 4- [1,2,4] triazolo [4,3-a] pyridin-3-yl, 1-furo [2,3-c] It may be selected from pyridin-4-yl, 1-furo [2,3-c] pyridin-5-yl, 1-furo [2,3-c] pyridin-3-yl and triazolopyridazine groups. This heterocyclic group also relates to one or more substituents R ′, where R ′ can be substituted as described above.

であり、そしてＲ⁵は、任意置換アリール、ベンジルまたはヘテロアリールである。 In one preferred embodiment of the invention, in the compound of formula (Ia), Z is S, Y is CO, X is CO, R is H, R ^c is H and R ¹ is aryl, benzyl or heteroaryl and R ² is:

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

であり、そしてＲ⁵は、任意置換アリール、ベンジルまたはヘテロアリールである。 In one preferred embodiment of the invention, in the compound of formula (Ia), Z is O, Y is CO, X is CO, R is H, R ^c is H and R ¹ is aryl, benzyl or heteroaryl and R ² is:

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

であり、そしてＲ⁵は、任意置換アリール、ベンジルまたはヘテロアリールである。 In one preferred embodiment of the invention, in the compound of formula (Ib), Z is S, Y is CO, X together with R ¹ and R ⁴ forms a piperidine ring, R ^b is H There, R ^c is H or methyl, R ² is:

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

であり、そしてＲ⁵は、任意置換アリール、ベンジルまたはヘテロアリールである。 In one preferred embodiment of the invention, in the compound of formula (Ib), Z is O, Y is CO, X together with R ¹ and R ⁴ forms a piperidine ring, R ^b is H R ^c is H or methyl and R ² is:

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

であり、そしてＲ⁵は、任意置換アリール、ベンジルまたはヘテロアリールである。 In another preferred embodiment, in the compound of formula (Ic), r is 1, Y is CO, Z is O, t is 0, s is 1 and 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.

であり、そしてＲ⁵は、任意置換アリール、ベンジルまたはヘテロアリールである。 In another preferred embodiment, in the compound 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, alkylamino, morpholino, N- methylpiperazine, a CF ₃ or OCF, R ² is:

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

であり、そしてＲ⁵は、任意置換アリール、ベンジルまたはヘテロアリールである。 In another preferred embodiment, in the compound of formula (Ic), r is 1, Y is CO, Z is S, t is 0, s is 1 and 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.

であり、そしてＲ⁵は、任意置換アリール、ベンジルまたはヘテロアリールである。 In another preferred embodiment, in the compound 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, alkylamino, morpholino, N-methylpiperazine, CF ₃ or OCF, R ² is:

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

（式中、Ｒ³、Ｒ⁴、Ｒ⁵、Ｒ^7aおよびＺは上記と同様である）
の化合物である。 One preferred embodiment of the present invention is a compound of formula (III)

(Wherein R ³ , R ⁴ , R ⁵ , R ^7a and Z are the same as above)
It is this compound.

Preferably, R ³ is H, Me, OMe, CF ₃ , OCF ₃ , Cl, OH or SH, more preferably H, Me, OMe, CF ₃ , OCF ₃ , more preferably H.
Preferably Z is N.
Preferably R ⁴ is H.
Preferably R ^7a is aryl or heteroaryl, more preferably aryl, more preferably phenyl. More preferably, R ^7a is substituted by one or more substituents R ′, more preferably by one substituent R ′. In one 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. And in yet another particularly preferred embodiment, R ^7a is 2-methylphenyl.

Preferably R ⁵ is aryl or heteroaryl, more preferably heteroaryl. Heteroaryl preferably contains 2 nitrogen atoms and is particularly preferably 2-imidazolyl or 2-benzimidazolyl, more preferably 2-benzimidazolyl. In another preferred embodiment, the heteroaryl contains one nitrogen atom and one sulfur atom, and is particularly preferably 2-thiazolyl or 2-benzothiazolyl, more preferably 2-benzothiazolyl. Heteroaryl is more preferably substituted by 1 to 4 substituents R ′, more preferably 1 or 2 substituents R ′. In one particularly preferred embodiment, R ⁵ is 5,6-dimethyl-1H-benzimidazol-2-yl. In another particularly preferred embodiment, R ⁵ is 5,6-dimethyl-1H-benzothiazol-2-yl.

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

In one preferred embodiment, X is O. In another preferred embodiment, X is S. In yet another preferred embodiment, X is NR ^{2 ′} .
In one preferred embodiment of the compound of formula (IIIa), R ³ is H, methyl, methoxy, CF ₃ or OCF ₃ ; R ⁴ , R ⁵ , R ^7a are as above; X is NR ^{2 ′} , O or S; and Z is as described above.
Another preferred embodiment of the present invention is a compound of formula (IIIa) having, in formula (III), R ^7a = —NH-aryl.

（式中、Ｒ³はＨ、メチル、メトキシ、ＣＦ₃またはＯＣＦ₃であり；Ｒ⁵は上記と同様であり；ＸはＮＲ^2’、ＯまたはＳであり；ＺがＮである場合にはＸはＮＲ^2’、ＯまたはＳであり；ＺがＣＲ^2’である場合にはＸはＯであり；Ｙ’はＯまたはＮＲ^2’であり；Ｒ²は上記と同様である）。 Another preferred embodiment of the present invention is, for compounds of formula (III), compounds of formula (IIIb):

Wherein R ³ is H, methyl, methoxy, CF ₃ or OCF ₃ ; R ⁵ is as above; X is NR ^{2 ′} , O or S; when Z is N X is NR ^{2 ′} , O or S; when Z is CR ^{2 ′} , X is O; Y ′ is O or NR ^{2 ′} ; R ² is as described above).

（式中、Ｒ¹¹、Ｒ¹²は、独立して、Ｈ、-ＣＮ、-ＯＨ、-ＳＨ、-ＣＯ₂Ｒ^4’、-Ｃ（Ｏ）Ｒ^4’、-ＳＯ₂ＮＲ^4’、-ＮＲ^4’Ｒ^5’、-ＳＯ₂-アルキル、-ＳＯ₂Ｒ^4’、ＳＯ₃Ｒ^4’、-Ｎ＝ＣＲ^4’Ｒ^5’、-ＮＲ^4’Ｃ（Ｏ）Ｒ^4”、-ＮＲ^4’-ＣＯ-ハロアルキル、-ＮＯ₂、-ＮＲ^4’-ＳＯ₂-ハロアルキル、-ＮＲ^4’-ＳＯ₂-アルキル、-ＮＲ^4’-ＣＯ-アルキル、-ＮＲ^4’-（ＣＨ₂）_pヘテロアリール、アルキル、シクロアルキル、アルキルアミノ、アルコキシ、アルキルチオ、-Ｏ（ＣＨ₂）_p［Ｏ（ＣＨ₂）_p］_qＯＣＨ₃、-Ｃ（ＮＲ^4”）ＮＲ^4’ベンズイミダゾリル、-Ｃ（ＮＲ^4”）ＮＲ^4’-ベンズチアゾリル、-Ｃ（ＮＲ^4”）ＮＲ^4’ベンズオキサゾリル、ヒドロキシアルキル、ヒドロキシシクロアルキル、ヒドロキシアルキルアミノ、ハロゲン、ハロアルキル、ハロアルキルオキシ、アリール、アリールアルキルまたは複素環を表わし；Ｒ^4’、Ｒ^4”、Ｒ^5’は上記と同様であり；Ｒ³はＨ、メチル、メトキシ、ＣＦ₃またはＯＣＦ₃であり；ＸはＮＲ^2’、ＯまたはＳであり；Ｒ⁴は上記と同様であり； Another preferred embodiment of the present invention is, for compounds of formula (III), compounds of formula (IIIc):

(Wherein 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, 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, halo Alkyl, haloalkyloxy, aryl, arylalkyl or ^{heterocyclic; 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; R ⁴ is as above;

R ⁷ and R ^{7 ′} are as defined above; 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, 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, hydroxy Al Each represents a alkylamino, halogen, haloalkyl, haloalkyloxy, aryl, arylalkyl or heterocyclic ring; and R ^{4 ′} , R ^{4 ″} and R ^{5 ′} are as defined above.

（式中、Ｒ³はＨ、メチル、ＣＦ₃またはＯＣＦ₃であり；ＸはＮＲ^2’、ＯまたはＳであり；Ｒ⁴は上記と同様であり；Ｒ⁷およびＲ^7’は上記と同様であり；Ｙ”およびＲ^11’、Ｒ^12’は式（ＩＩＩｃ）下で上記と同様であり；Ｙ’はＯまたはＮＲ^2’であり、そしてＲ^2’は上記と同様である）。 In a further preferred embodiment of the invention, the compound of formula (III) is a compound of formula (IIId):

Wherein R ³ is H, methyl, CF ₃ or OCF ₃ ; X is NR ^{2 ′} , O or S; R ⁴ is as above; R ⁷ and R ^{7 ′} are as above. Y ″ and R ^{11 ′} , R ^{12 ′} are as described above under formula (IIIc); Y ′ is O or NR ^{2 ′} and R ^{2 ′} is as described above.

（式中、Ｒ³、Ｒ⁴およびＲ⁵は上記と同様であり；ＸはＯまたはＳであり；Ｒ¹¹およびＲ¹²は式（ＩＩＩｃ）下で上記と同様であり；そしてＺがＮである場合、ＸはＮＲ^2’、ＯまたはＳであり；ＺがＣＨである場合、ＸはＯである）。 Another more preferred embodiment of the present invention is, for compounds of formula (III), compounds of formula (IIIe):

Wherein R ³ , R ⁴ and R ⁵ are as above; X is O or S; R ¹¹ and R ¹² are as above under formula (IIIc); and Z is N In certain instances, X is NR ^{2 ′} , O, or S; when Z is CH, X is O).

（式中、ＺはＮまたはＣＨであり；Ｒ³はＨ、メチル、メトキシ、ＣＦ₃またはＯＣＦ₃であり；ＸはＮＲ^2’、ＯまたはＳであり；Ｒ⁴は上記と同様であり；Ｒ⁷およびＲ⁷⁷は上記と同様であり；Ｒ^2’は上記と同様であり；Ｙ”およびＲ¹¹、Ｒ^11’、Ｒ¹²、Ｒ^12’は式（ＩＩＩｃ）下で上記と同様である）。 Another further preferred embodiment of the present invention, for a compound of formula (III), is a compound of formula (IIIf):

Wherein Z is N or CH; R ³ is H, methyl, methoxy, CF ₃ or OCF ₃ ; X is NR ^{2 ′} , O or S; R ⁴ is as above; R ⁷ and R ⁷⁷ are as above; R ^{2 ′} is as above; Y ″ and R ¹¹ , R ^{11 ′} , R ¹² , R ^{12 ′} are as above under formula (IIIc). ).

（式中、Ｒ¹はＣＯＲ^7aであり；
Ｒ²およびＲ^3aはＨであり；
ＡはＮＨであり；
Ｒ⁷は上記と同様であり；
ＺはＮであり；
ＸはＮＲ^2’、ＯまたはＳであり；
Ｒ³はＨ、メチル、エチル、メトキシ、アミン、アルキルアミン、モルホリノ、Ｎ-メチルピペラジン、ＣＦ₃またはＯＣＦ₃であり；
ｔは0であり；
ｒは1であり；そして
Ｒ^2aは任意置換アリール、ベンジルまたはヘテロアリールである）。 One preferred embodiment of the invention is a compound of formula (Iha):

Wherein R ¹ is COR ^7a ;
R ² and R ^3a are H;
A is NH;
R ⁷ is the same as 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).

（式中、Ｒ^3aはＨであり；
ＡはＮＨであり；
ＸはＮＲ^2’、ＯまたはＳであり；
Ｙ’はＯまたはＮＲ^2’であり；
Ｒ^2’は上記と同様であり；
Ｒ³はＨ、メチル、エチル、メトキシ、アミン、アルキルアミン、モルホリノ、Ｎ-メチルピペラジン、ＣＦ₃またはＯＣＦ₃であり；
ｔは0であり；
ｒは1であり；そして
Ｒ^2aは任意置換アリール、ベンジルまたはヘテロアリールである）。 Another preferred embodiment of the present invention is a compound of formula (Ih), wherein R ^7a is optionally substituted aryl, benzyl or heteroaryl, for compounds of formula (Ih).
Another preferred embodiment of the present invention, for a compound of formula (Ih), is a compound of formula (Ihb):

Wherein R ^3a is H;
A is NH;
X is NR ^{2 ′} , O or S;
Y ′ is O or NR ^{2 ′} ;
R ^{2 ′} is the same as above;
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).

In formula (Ihb), the following substituents are selected alone or in combination:
Z is preferably CR ^{2 ′} .
Y is preferably NR ^{2 ′} . In one 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 yet another preferred embodiment, R ^{2 ′ in} NR ^{2 ′ of} Y ^′ is benzyl. In a further preferred embodiment, R ^{2 ′} in NR ^{2 ′ of} Y ^′ is a pyrimidine or a triazine. In another further preferred embodiment, R ^{2 'is} heteroaryl substituted or unsubstituted in the' NR 2 of ^'Y, more preferably thienopyrimidine, quinazoline, purine, pyrazolopyrimidine or triazolopyrimidine, more preferably Is thienopyrimidine.
In one preferred embodiment, X is S. In another preferred embodiment, X is O. In yet another preferred embodiment, X is NR ^{2 ′} .
R ³ is preferably H.

（式中、Ｒ^3aはＨであり；ＡはＮＨであり；ＸはＮＲ^2’、ＯまたはＳであり；
Ｒ¹¹およびＲ¹²は、独立して、Ｈ、-ＣＮ、-ＯＨ、-ＳＨ、-ＣＯ₂Ｒ^4’、-Ｃ（Ｏ）Ｒ^4’、-ＳＯ₂ＮＲ^4’、-ＮＲ^4’Ｒ^5’、-ＳＯ₂-アルキル、-ＳＯ₂Ｒ^4’、ＳＯ₃Ｒ^4’、-Ｎ＝ＣＲ^4’Ｒ^5’、-ＮＲ^4’Ｃ（Ｏ）Ｒ^4”、-ＮＲ^4’-ＣＯ-ハロアルキル、-ＮＯ₂、-ＮＲ^4’-ＳＯ₂-ハロアルキル、-ＮＲ^4’-ＳＯ₂-アルキル、-ＮＲ^4’-ＣＯ-アルキル、-ＮＲ^4’-（ＣＨ₂）_pヘテロアリール、アルキル、シクロアルキル、アルキルアミノ、アルコキシ、アルキルチオ、-Ｏ（ＣＨ₂）_p［Ｏ（ＣＨ₂）_p］_qＯＣＨ₃、-Ｃ（ＮＲ^4”）ＮＲ^4’ベンズイミダゾリル、-Ｃ（ＮＲ^4”）ＮＲ^4’-ベンズチアゾリル、-Ｃ（ＮＲ^4”）ＮＲ^4’ベンズオキサゾリル、ヒドロキシアルキル、ヒドロキシシクロアルキル、ヒドロキシアルキルアミノ、ハロゲン、ハロアルキル、ハロアルキルオキシ、アリール、アリールアルキルまたは複素環を表わし；
Ｒ^4’、Ｒ^4”、Ｒ^5’は上記と同様であり；
Ｒ^2’は上記と同様であり；
Ｒ³はＨ、メチル、エチル、メトキシ、アミン、アルキルアミン、モルホリノ、Ｎ-メチルピペラジン、ＣＦ₃またはＯＣＦ₃であり；
ｔは0であり；
ｒは1であり；そして
Ｒ^2aは任意置換アリール、ベンジルまたはヘテロアリールである）。
式（Ｉｈｅ）では、以下の置換基が、単独でまたは組合せて選択される：
Ｚは好ましくはＣＲ^2’である。 R ^2a is preferably aryl or heteroaryl, more preferably phenyl.
Another further preferred embodiment of the present invention, for a compound of formula (Ih), is a compound of formula (Ihe):

Wherein 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 , 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, Haroaru Le, haloalkyloxy, aryl, arylalkyl or heterocyclic ring represents;
R ^{4 ′} , R ^{4 ″} and R ^{5 ′} are the same as above;
R ^{2 ′} is the same as above;
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).
In formula (Ihe), the following substituents are selected alone or in combination:
Z is preferably CR ^{2 ′} .

（式中、Ｒ¹およびＲ²は上記と同様であり；Ｚは上記と同様であり；ＸはＯまたはＳであり；Ｒ³はＨ、メチル、メトキシ、ＣＦ₃またはＯＣＦ₃であり；Ｒ¹¹およびＲ¹²は式（ＩＩＩｃ）下で上記と同様である）。 In one preferred embodiment, X is S. In another preferred embodiment, X is O. In yet another preferred embodiment, X is NR ^{2 ′} .
R ¹¹ is preferably —H, —CN, —OH, halogen, haloalkyl, haloalkyloxy, more preferably —CN.
R ¹² is preferably H.
R ^2a is preferably aryl or heteroaryl, more preferably phenyl.
One preferred embodiment of the present invention, for a compound of formula (II), is a compound of formula (IIa):

Wherein R ¹ and R ² are as above; Z is as above; X is O or S; R ³ is H, methyl, methoxy, CF ₃ or OCF ₃ ; ¹¹ and R ¹² are as described above under formula (IIIc)).

（式中、Ｒ¹およびＲ²は上記と同様であり；Ｚは上記と同様であり；ＸはＯまたはＳであり；Ｒ³はＨ、メチル、メトキシ、ＣＦ₃またはＯＣＦ₃である）。 A further preferred embodiment of the present invention, for a compound of formula (II), is a compound of formula (IIb):

(Wherein R ¹ and R ² are the same as above; Z is the same as above; X is O or S; R ³ is H, methyl, methoxy, CF ₃ or OCF ₃ ).

（式中、ＸはＯまたはＳであり；Ｒ³はＨ、メチル、メトキシ、ＣＦ₃またはＯＣＦ₃であり；Ｙ’はＮＲ^2’である）。 Another further preferred embodiment of the present invention, for a compound of formula (II), is a compound of formula (IIc):

(Wherein X is O or S; R ³ is H, methyl, methoxy, CF ₃ or OCF ₃ ; Y ′ is NR ^{2 ′} ).

（式中、Ｚは上記と同様であり；Ｒ³はＨ、メチル、メトキシ、ＣＦ₃またはＯＣＦ₃であり；Ｒ¹¹、Ｒ^11’、Ｒ¹²およびＲ^12’は上記と同様である）。
さらに、本発明は、本発明の化合物、例えば式（Ｉａ）、（Ｉｂ）、（Ｉｃ）、（Ｉｈ）、（ＩＩ）または（ＩＩＩ）の化合物の製造方法を提供する。 Another further preferred embodiment of the present invention, for a compound of formula (II), is a compound of formula (IId):

(Wherein Z is as above; R ³ is H, methyl, methoxy, CF ₃ or OCF ₃ ; R ¹¹ , R ^{11 ′} , R ¹² and R ^{12 ′} are as above).
Furthermore, the present invention provides a process for the preparation of a compound of the invention, for example a compound of formula (Ia), (Ib), (Ic), (Ih), (II) or (III).

Compounds of formula (Ia), (Ib), (Ic), (Ih), (II) or (III) can be obtained by various methods.
Piperidin-4-yl-thiazole-4-carboxamide can be prepared by various methods described in the literature. One such example is the appropriate 2,5-dihydrothiazole oxidation as described in Houben-Weyl, 2002, 730. Dihydrothiazole has been described in the same reference, or You, S., Razavi, H., Kelly, JW Angew. Chem. 2003, 115, 87 or Katritzky, AR., Cai, C., Suzuki, K. , Singh, SK. J. Org. Chem. 2004, 69, 811-814, as well as the methods described in the references in both articles. An alternative method is described in Yasuchika, S. et al. Heterocycles, Vol. 57, No. 5, 2002.

Compounds of formula (II), (Ic) and (III) carrying further substituents on the heterocycle are described in Organic Syntheses, Coll. Vol. 9, p. 155; and Vol. 74, p. 229; Org. Chem., 1975, Vol40, No. 10, page 1521; J. Am. Chem. Soc. 96: 19 / September 18, 1974; J. Org. Chem., 1990, 55, 4484-4487; Chemische Berichte 1968 , 101 (1), 302-307; Agricultural Chemistry and Biotechnology, 2002, 45 (1), pages 37-42.
One possibility for the synthesis of substituted benzimidazole substituents of formula (III) is described in Synthesis, 2006, 4, 597-602.

スキーム１ （ＩＩＩａ、ｃ）および（ＩＩａ、ｂ）型の誘導体の合成 One possibility for the synthesis of compounds of formula (IIIa, c and IIa, b) (see Scheme 1) is under classical amide coupling conditions, eg HBTU, iPt ₂ NEt, DMF, 0 ° C. to room temperature. Reacting a compound of formula (V) with a compound of formula (VI) to give intermediate (VII). Another alternative to this step is to react (V) with the corresponding acid chloride of (VI) to give (VII). In the second step, compound (VII) is saponified with 1 M NaOH solution to give the expected acid (VIII) in near quantitative yield. This step could be realized under acidic conditions as well. Finally, another amide coupling step (using primary or secondary amines) that works similarly to step 1 above completes the synthesis for compounds of type (IIIa, c and IIa and b).

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

スキーム２ （ＩＩＩｂ、ｄ、ｅ、ｆ）および（ＩＩｃ、ｄ）型の誘導体（Ｚ＝Ｎ）の合成 Compounds related to structures (IIIb, d, e, f) and (IIc, d) can be synthesized according to the procedure shown in Scheme 2. Herein, the heterocycle (IX) is reacted with the bromo compound (X) by a nucleophilic substitution reaction to give the bicyclic ester (XI), which is then standard and well-known. Saponified to acid (XII) under conditions to complete the synthesis in a separate coupling step as described in Scheme 1 above.

Scheme 2 Synthesis of derivatives of type (IIIb, d, e, f) and (IIc, d) (Z = N)

スキーム３ （ＩＩＩｂ、ｄ、ｅ、ｆ）および（ＩＩｃ、ｄ）型の誘導体（Ｚ＝ＣＨ）の合成 When Z = CH, structures (IIIb, d, e, f) and (IIc, d) type compounds can be readily synthesized according to the protocol outlined in Scheme 3, in which case the heterocycle (XIII) is It is converted to compound (XV) by a cyclization condensation step. After saponification, (XVI) is coupled with an amine to give the desired product (IIIb, d, e, f) or (IIc, d).

Scheme 3 Synthesis of derivatives of type (IIIb, d, e, f) and (IIc, d) (Z = CH)

２-（１-（ｔｅｒｔ‐ブトキシカルボニル）ピペリジン-４-イル）チアゾール-４-カルボン酸は、ＤＭＦ中のＨＢＴＵ、ＤＩＰＥＡとカップリングさせることにより、適切なＲ¹アミドに転化され得る。異なるＲ¹-アミンは、市販されているか、あるいは容易に合成され得る。Ｂｏｃ-保護基は、標準条件下で、例えば0℃で2〜3時間ＴＦＡでの処理、またはジオキサン中の4 NＨＣｌでの2〜3間の処理により除去され得る。脱保護化ピペリジノ誘導ＨＣｌ塩は次に、以下のように対応するアミド、尿素およびＮ-複素環式類似体に転化され得る。 Compounds of the invention bearing 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 described in part 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 coupling with HBTU, DIPEA in DMF. Different R ¹ -amines are commercially available or can be readily synthesized. The Boc-protecting group can be removed under standard conditions, for example by treatment with TFA for 2 to 3 hours at 0 ° C. or between 2 and 3 with 4 N HCl in dioxane. 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 coupling with commercially available isocyanates in the presence of DIPEA. Piperidino compounds substituted with heterocycles can be synthesized by standard procedures, for example by coupling with the corresponding chlororeturn in the presence of a base. Alternatively, piperidino compounds substituted with heterocycles can be produced by palladium-mediated cross coupling. As a further alternative, hydroxypyridine derivatives can be coupled with piperidino compounds by the HBTU coupling method.

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

The Boc-protecting group can be removed under standard conditions, for example by treatment with TFA for 2 to 3 hours at 0 ° C. or between 2 and 3 with 4 N HCl in dioxane. The deprotected piperidino-derived HCl salt can then be converted to the corresponding N-heterocyclic analog by various methods as described above.
With respect to compounds of formula (Ia), (Ib), (Ic), (Ih), (II) or (III) above, the term “stereoisomer” means cis / trans or E / Z isomerism . More specifically, the possible double bond (s) present in the various substituents of the compounds of the invention are in the E or Z configuration. These pure or impure geometric isomers, alone or as a mixture, form part of a compound of formula (Ia), (Ib), (Ic), (Ih), (II) or (III). The term “stereoisomer” refers to all isomeric forms (alone or as a mixture) that result from the presence of one or more axes and / or centers of symmetry in a molecule and that result in the rotation of polarized light rays. Is also included. More specifically, it includes enantiomers and diastereomers in pure form or as a mixture.

  The compounds of the formula (Ia), (Ib), (Ic), (Ih), (II) or (III) to be used according to the invention can form salts with inorganic or organic acids or bases. Examples of pharmaceutically acceptable salts are non-toxic inorganic or organic salts such as acetate obtained from acetic acid, aconitinate obtained from aconitic acid, ascorbate obtained from ascorbic acid, benzoic acid obtained from benzoic acid Salt, cinnamate obtained from cinnamic acid, citrate obtained from citric acid, embonate obtained from embonic acid, enanthate obtained from heptanoic acid, formate obtained from formic acid, fumaric acid obtained from fumaric acid Salts, glutamate obtained from glutamic acid, glycolate obtained from glycolic acid, chloride obtained from hydrochloric acid, bromide obtained from hydrobromic acid, lactate obtained from lactic acid, maleate obtained from maleic acid, From malonate obtained from malonic acid, mandelate obtained from mandelic acid, methanesulfonic acid Methanesulfonate, naphthalene-2-sulfonate obtained from naphthalene-2-sulfonic acid, nitrate obtained from nitric acid, perchlorate obtained from perchloric acid, phosphate obtained from phosphoric acid, phthalate Phthalates obtained from acids, salicylates obtained from salicylic acid, sorbates obtained from sorbic acid, stearates obtained from stearic acid, succinates obtained from succinic acid, sulfates obtained from sulfuric acid, tartaric acid The tartrate salt obtained from the above, toluene-p-sulfate obtained from p-toluene-sulfonic acid, etc. are not limited thereto. Such salts can be prepared by methods known to those skilled in the art and described in the prior art.

  Other salts, such as oxalate salts obtained from oxalic acid, which are not considered pharmaceutically acceptable, have the formula (Ia), (Ib), (Ic), (Ih), (II) or ( It can be understood as an intermediate for the preparation of a compound of III), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable prodrug or stereoisomer thereof.

  The present invention covers pharmaceutically acceptable salts as described above, but suitable separation of compounds of formula (Ia), (Ib), (Ic), (Ih), (II) or (III) Or it extends to salts which allow crystallization, such as those obtained from chiral amines.

  The compounds of formula (Ia), (Ib), (Ic), (Ih), (II) or (III) above also include prodrugs of these compounds. The term “prodrug” as used herein is not itself pharmaceutically active (“prodrug”) once administered to a patient, but in vivo, ie the compound is administered. In a subject chemically and / or biologically converted to their pharmaceutically active form (compound of formula (Ia), (Ib), (Ic), (Ih), (II) or (III)) Refers to a compound. Prodrugs include compounds of the invention where, for example, a hydroxy, amine or sulfhydryl group is attached to and attached to any group that forms a hydroxy, amine or sulfhydryl group when administered to a patient. Thus, representative examples of prodrugs include, but are not limited to, alcohols, sulfhydryls, and acetate, formate, and benzoate derivatives of the compounds of the present invention. Furthermore, in the case of carboxylic acid (—COOH), esters such as methyl esters, ethyl esters, double esters and the like may be used. Esters can be active independently and / or hydrolyzable under in vivo conditions in the body.

  The compounds according to the invention and the medicaments prepared therewith are generally used for immunological diseases and conditions (for example inflammatory diseases, neuroimmunological diseases, autoimmune diseases etc.) for the treatment of cell proliferation disorders. For treatment or prevention).

  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 the agents prepared therewith are generally used to regulate cell activation, cell proliferation, cell survival, cell differentiation, cell cycle, cell maturation and cell death, or of metabolic Useful for inducing systemic changes, such as changes in sugar, lipid or protein metabolism. They are used for cell generation, such as toxic agents, radiation, immunotherapy, growth defects, malnutrition, malabsorption, immune dysregulation, anemia, etc. It can also be used to support hematopoiesis), or to provide therapeutic control of tissue formation and degradation, and therapeutic modification of cell and tissue maintenance and blood cell homeostasis.

These diseases and symptoms include hematological tumors (e.g. leukemia, lymphoma, myeloma) or solid tumors (e.g. breast, prostate, liver, bladder, lung, esophagus, stomach, colorectal, urogenital, gastrointestinal, skin, Pancreas, brain, uterus, colon, head and neck, cervical and ovarian cancer, melanoma, astrocytoma, small cell lung cancer, glioma, basal and squamous cell carcinoma, sarcoma, eg Kaposi sarcoma and osteosarcoma) Or diseases that are cured or alleviated by inhibition of one or several kinases and / or phosphatases, but are not limited to these. The compounds according to the invention and the medicaments prepared therewith are particularly useful for the treatment of prostate cancer, melanoma, ovarian cancer and multiple myeloma.
“Treatment” according to the present invention is intended to mean complete or partial cure of a disease, alleviation of a disease, or cessation of progression of a given disease.

  Thus, in one embodiment, the present invention preferably comprises Addison's disease, alopecia areata, ankylosing spondylitis, anemia haemolytica, anemia perniciosa, phlegm, aphthous stomatitis, arthritis, arteries Sclerosis disorder, osteoarthritis, rheumatoid arthritis, lack of spermatogenesis, bronchial asthma, autoimmune asthma, autoimmune hemolysis, Behcet's disease, Beck's disease, inflammatory bowel disease, Burkitt's lymphoma, Crohn's disease, choroiditis, ulcerative Colitis, peritoneal disease, cold type globulinemia, herpetic dermatitis, dermatomyositis, insulin-dependent type I diabetes, juvenile diabetes, idiopathic diabetes insipidus, insulin-dependent diabetes mellitus, autoimmune demyelinating disease, Dupuytren contracture, encephalomyelitis, allergic encephalomyelitis, endophthalmitis, lens anaphylaxis, allergic enteritis, autoimmune bowel syndrome, erythema nodosum leprosum Idiopathic facial palsy, chronic fatigue syndrome, rheumatic fever, glomerulonephritis, Goodpasture syndrome, Graves' disease, Haman-Rich disease, Hashimoto's disease, Hashimoto's thyroiditis, sudden hearing loss, sensorineural hearing loss, chronic hepatitis, Hodgkin Disease, paroxysmal hemoglobinuria, hypogonadism, local ileitis, iritis, leukopenia, leukemia, disseminated erythematous lupus, systemic lupus erythematosus, lupus erythematosus lupus, malignant lymphoma granuloma, single Nucleophilia infection, myasthenia gravis, transverse myelitis, primary idiopathic myxedema, nephrosis, sympathetic ophthalmitis, granulo testicularitis, pancreatitis, pemphigus, pemphigus vulgaris, nodular multiple arteries Inflammation, primary chronic polyarthritis, polymyositis, acute polyradiculitis, psoriasis, purpura, pyoderma gangrenosum, Kelvan thyroiditis, Reiter syndrome, sarcoid, ataxic sclerosis, progressive systemic Sclerosis, strong Meningitis, scleroderma, multiple sclerosis, diffuse sclerosis, acquired spleen atrophy, infertility for anti-sperm antibodies, thrombocytopenia, idiopathic thrombocytopenic purpura, thymoma, acute anterior grape Meningitis, vitiligo, AIDS, HIV, SCID, and Epstein-Barr virus related diseases such as Sjogren's syndrome, virus (AIDS or EBV) related B cell lymphoma, parasite diseases such as Leishmania, and immunosuppressive disease states such as different Diseases characterized by hyperproliferation of keratinocytes and / or T cells selected from the group consisting of systemic graft transplantation, AIDS, cancer, chronic active hepatitis diabetes, toxin shock syndrome and post-food poisoning viral infections, in particular A suitable and suitable adjuvant for the manufacture of a medicament for the treatment or prevention of inflammatory and immune disorders And a compound of formula (Ia), (Ib), (Ic), (Ih), (II) or (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable prodrug thereof, Relates to the use of stereoisomers.

  The compounds according to the invention and the medicaments prepared therewith are used for autoimmune and inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, inflammatory bowel diseases (especially colitis and Crohn's disease), inflammatory skin diseases It is particularly useful for the treatment of (especially neurodermatitis and psoriasis), as well as lupus erythematosus.

Furthermore, the present invention provides an effective amount of a compound of formula (Ia), (Ib), (Ic), (Ih), (II) or (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable pro It relates to a method for the treatment or prevention of diseases involving the administration of drugs or stereoisomers.
The present invention provides compounds of formula (Ia), (Ib), (Ic), (Ih), (II) or (III) in free form or in the form of pharmaceutically acceptable salts and pharmaceutically acceptable prodrugs. Also provided are pharmaceutical compositions comprising a compound of the above, together with a pharmaceutically acceptable diluent or carrier.

  In a preferred embodiment, the present invention relates to a skin disease in which T cells play a role; particularly preferably psoriasis, atopic dermatitis, alopecia areata, complete alopecia, subtotal alopecia, systemic alopecia, sporadic Alopecia, lupus erythematosus, lichen planus, cutaneous dermatomyositis, eczema, localized scleroderma, scleroderma, psoriasis vulgaris, psoriasis of the head, psoriasis vulgaris, inverted psoriasis, serpentine type Alopecia areata, androgenetic alopecia, allergic contact eczema, irritant contact eczema, contact eczema, pemphigus vulgaris, deciduous pemphigus, proliferative pemphigus, scarring myxoid pemphigoid, bullous Pemphigoid, mucinous pemphigoid, dermatitis, dermatitis dermatitis, hives, lipoid necrosis, erythema nodosum, vidar lichen, simple urticaria, nodular eruption, acute eczema, linear IgA Dermatosis, polymorphic photodermatosis, erythema, sclerotrophic lichen, skin development , Drug rash, chronic progressive purpura, allergic eczema, eczema, fixed drug rash, photoallergic skin reaction, lichen simplex eriorale, dermatitis and “graft versus host disease”, acne (Ia), (Ib), optionally with suitable adjuvants and additives, for the manufacture of a medicament for the treatment or prevention of skin diseases selected from the group consisting of rosacea, scar, keloid and vitiligo ), (Ic), (Ih), (II) or (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable prodrug or stereoisomer thereof.

  Furthermore, the compounds of the present invention may be used to treat diseases caused by ischemia and / or reperfusion injury of organs and / or parts of the body selected from the group consisting of heart, brain, peripheral limbs, kidney, liver, spleen and lung. In which case endothelial dysfunction is associated with a disease selected from the group consisting of infarctions, for example myocardial infarction and severe limb ischemia, and / or endothelial The dysfunction is a disease selected from the group consisting of ischemic diseases such as peripheral arterial occlusive diseases such as severe foot ischemia, myocardial infarction and organs such as kidney, spleen, brain and lung ischemic diseases Related to.

  The compounds of the present invention may be used to treat neurological diseases or disorders (brain and nervous system related diseases or disorders) such as Alzheimer's disease, Parkinson's disease, Creutzfeldt-Jakob disease, Lewy body dementia, amyotrophic lateral sclerosis. Treatment or prevention of a neurological disease or disorder selected from the group consisting of, but not limited to, stroke, epilepsy, multiple sclerosis, myasthenia gravis, Huntington's disease, Down's syndrome, neurological hearing loss and Meniere's disease Can also be applied for. Other neurological diseases and disorders will be apparent to those skilled in the art and are encompassed by the definitions as used in the present invention. The compounds according to the invention and the medicaments prepared therewith are particularly useful for the treatment of stroke, reperfusion injury and Alzheimer's disease.

  The compounds of the present invention can further be used for diseases caused by protozoan infestations in humans and animals. Such veterinary and human pathogenic protozoa are preferably apicomlexa or hairy rhizobia, in particular trypanosomes, malaria parasites, leishmania, Babesia and Theileria, cryptosporidium, sarcosist, amoeba, coccidium and tricomonadium It is a class of intracellularly active parasites. These active substances or the corresponding agents are used to treat P. falciparum (caused by Plasmodium falciparum), P. falciparum, P. falciparum, P. falciparum, P. falciparum, P. falciparum, P. falciparum And particularly suitable for the treatment of Plasmodium malaria (caused by Plasmodium malariae). They include toxoplasmosis (caused by Toxoplasma gondii), coccidiosis (caused by, for example, Inspora Isospora belli, intestinal), granulocystosis (caused by the porcine cystospores Sarcocystis suihominis), dysentery (red dysentery Entamoeba caused by histolytica), Cryptosporidium disease (caused by Cryptosporidium parvum), Chagas disease (caused by trypanosoma cruzi), sleep disease (Rhodesia trypanosoma Trypanosoma brucei rhodesiense and Gambia trypanosoma trypanosoma It is also suitable for the treatment of skin and viscera and other forms of Leishmania disease. They are veterinary pathogenic protozoa, such as Theileria parva, a pathogen that causes bovine Theileria disease, Trypanosoma congolens congolense or Trypanosoma vivax vivax, a pathogen that causes bovine Nagana disease in Africa. Trypanosoma vivax vivax, Trypanosoma brucei brucei Trypanosoma brucei brucei, Trypanosoma brucei evansi that causes surah disease, Trypanosoma brucei evansi, Babesia vigemina Basesia bigemina, a pathogen that causes Texas fever in cattle and wild cattle, and beef of European cattle Babesia bovis, a pathogen that causes Babesia disease in dogs, cats and sheep, causes granulosporosis in sheep, cattle and pigs The pathogens Sarcocystis ovicanis and Obiferis ovifelis, the pathogens causing cryptosporidiosis in cattle and birds, cryptosporidium Cryptosporidia, rabbits, cattle, sheep, goats, pigs and birds, especially coccidiasis causing chickens and turkeys It is also suitable for the treatment of animals infected with Eimeria and Isospora species. The use of the compounds according to the invention is chosen in particular for the treatment of coccidiosis or malaria infections or for the preparation of medicaments or foods for the treatment of these diseases. This treatment can be prophylactic or curative. In the treatment of malaria, the compounds of the invention can be combined with other antimalarial drugs.

  The compounds according to the invention can furthermore be used for the prevention and / or treatment of infectious diseases caused in particular by bacteria and viruses, for example opportunistic infections in mammals, for example in humans. The above method comprises an amount of the general formula (Ia), (Ib), (Ic), (Ih), (II) effective to prevent and / or treat the above infectious diseases and / or opportunistic infections. ) Or (III) and / or a pharmaceutically acceptable salt thereof.

  Infectious diseases include AIDS, polycystic disease (AHD, Echinococcus disease), amebiasis (dysentery amoeba infection), schistosomiasis infection, anisakiasis, anthrax, babesiosis (Babesia infection), and barantidium infection (Barantidium infection) Disease), roundworm infection (raccoon roundworm), Bilharz schistosomiasis (schistosomiasis), Blast cystis hominis infection (blastosmosis), Lyme disease, botulism, Brainerd diarrhea, brucellosis, BSE (bovine sponge) Encephalopathy), candidiasis, baldness disease (caryotes infection), CFS (chronic fatigue syndrome), Chagas disease (American trypanosomiasis), chickenpox (varicella zoster virus), pneumonia chlamydial infection, cholera, chronic fatigue syndrome , CJD (Kreuzfeld-Jakob disease), hepatic dystomatosis (liver fluke infection), CLM (cutaneous larva migration) Helminth infection), coccidiosis, conjunctivitis, coxsackievirus A16 (hand-foot-and-mouth disease), cryptococcosis, cryptosporidium infection (cryptospodium disease), squid (west Nile virus vector), skin larva migratory disease (CLM), cyclos Polar disease (cyclospora infection), cystic disease (neurocystic disease), cytomegalovirus infection (CMV), dengue / dengue fever, striped worm infection (dogs and cats), Ebola virus hemorrhagic fever, Echinococcus disease (polycystemic disease), encephalitis, colonic amoeba infection, non-pathogenic dysentery amoeba infection, Hartmann amoeba infection, dysentery amoeba infection (amebosis), polek amoeba infection, guilloche (gyochu) Infection), enterovirus infection (non-polio), Epstein Berwil Infection, Escherichia coli infection, food-borne infection, foot-and-mouth disease, fungal dermatitis, gastroenteritis, group A streptococcal disease, group B streptococcal disease, staphylococcal infection (Staphylococcus aureus and other Diseases caused by Staphylococcus species, diseases caused by infection with Pseudomonas aeruginosa and other Pseudomonas species, Cepacia infection, leprosy (Lei disease), Hantavirus lung syndrome, head lice infection (lice louse) Disease), Helicobacter pylori infection, hematological disease, Hendra virus infection, hepatitis, herpes zoster (HIV), HIV infection, human aerichiosis, human parainfluenza virus infection, influenza, isoporosis ( Isospora infection), Lassa fever, leishmaniasis, visceral leishmaniasis (Kala Azar, Lee) Shumania infection), Rye disease, lice (cold lice, head lice, lice), Lyme disease, Marburg hemorrhagic fever, measles, meningitis, mosquito-borne diseases, M. tuberculosis complex (MAC) infection, Negrelia infection, Nosocomial infections, non-pathogenic intestinal amoeba infections, rotiferous disease (river blindness), opistolkis disease (opistolkis infection), parvovirus infection, bad epidemic, PCP (carini pneumonia), polio, Q fever, rabies, respiratory Multinuclear virus (RSV) infection, rheumatic fever, Rift Valley fever, river blindness (rotacilaria), rotavirus infection, roundworm infection, salmonellosis, enterococci, scabies, bacterial dysentery, zonal Herpes zoster, sleeping sickness, pressure ulcer, streptococcal infection, tapeworm infection (Tenia infection), tetanus, toxic shock syndrome, tuberculosis, ulcer (peptic ulcer disease), valley fever, intestine Vibrio infection, Vibrio vulnificus infection, viral hemorrhagic fever, warts, waterborne diseases, West Nile virus infection (West Nile encephalitis), whooping cough, can be selected from the group consisting of yellow fever. The compounds according to the invention and the medicaments prepared therewith are used for viral diseases such as hepatitis B, hepatitis C, influenza virus infection (especially type A virus infection), AIDS (HIV infection) and human papillomavirus infection Particularly useful for the treatment of.

The compounds according to the invention and the medicaments prepared therewith are also particularly useful for the treatment of arteriosclerosis.
The compounds according to the invention and the medicaments prepared therewith 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 preparation of a medicament for the treatment or prevention of diseases characterized by cellular hyperproliferation.
In one embodiment, the present invention results from ischemia and / or reperfusion injury of an organ and / or body part selected from the group consisting of heart, brain, peripheral limb, kidney, liver, spleen and lung A compound or composition of the invention for the preparation of a medicament for the treatment or prevention of a disease to be treated, wherein the endothelial dysfunction is selected from the group consisting of infarctions, for example myocardial infarction and severe limb ischemia And / or the use of a compound or composition in which endothelial dysfunction is associated with a disease selected from the group consisting of ischemic disease, myocardial infarction and organ ischemic injury.

  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, myasthenia gravis, Huntington's disease Relates to the use of a compound or composition of the invention for the preparation of a medicament for the treatment or prevention of a neurological disease or disorder selected from the group consisting of Down syndrome, neurological hearing loss and Meniere's disease.

  The compounds of formula (Ia), (Ib), (Ic), (Ih), (II) or (III), as well as their pharmaceutically acceptable salts, are themselves as therapeutic agents, as mixtures with each other, Alternatively, enteral or parenteral use is possible and an effective dose of at least one of formula (Ia), (Ib), (Ic), (Ih), (II) or (III) as an active component It can be administered to animals, preferably mammals, especially humans, dogs and chickens, in the form of pharmaceutical preparations containing the compounds or their salts in addition to the usual pharmaceutically innocuous excipients and additives. . Compounds of formula (Ia), (Ib), (Ic), (Ih), (II) or (III) are those obtained by reacting the respective compounds with physiologically acceptable acids and bases. It can also be administered in the form of a salt.

The manufacture of medicaments containing the compounds of formula (Ia), (Ib), (Ic), (Ih), (II) or (III) of the present invention and their application can be carried out according to well-known pharmaceutical methods. .
The compounds of formula (Ia), (Ib), (Ic), (Ih), (II) or (III) of the present invention for use in therapy can be administered in the form of a crude chemical compound, while active The ingredient, optionally in the form of a physiologically acceptable salt in a pharmaceutical composition, one or more adjuvants, excipients, carriers, buffers, diluents and / or other conventional pharmaceutical adjuvants It is preferable to introduce together. Such salts of the compounds can be anhydrous or solvated.

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

  The agent of the present invention is oral, rectal, bronchial, nasal, topical, buccal, sublingual, cinnamon, vaginal or parenteral (eg, skin, subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial, intracerebral, intraocular) It may be suitable for administration by injection or infusion) or in a form suitable for administration by inhalation or insufflation, for example suitable for powder and liquid aerosol administration, or suitable for administration by sustained release systems. Suitable examples of sustained release systems include semipermeable matrices of solid hydrophobic polymers containing the compounds of the present invention, which can be in the form of shaped articles such as films or microcapsules.

  Accordingly, the compounds of the present invention are incorporated into the drug and its unit dosage forms together with conventional adjuvants, carriers or diluents. Such forms include solids, especially tablets, filled capsules, powder and pellet forms, and liquids, particularly aqueous or non-aqueous solutions, suspensions, emulsions, elixirs, and capsules filled with them (all oral Use), suppositories for rectal administration, and sterile injectable solutions for parenteral use. Such agents and their unit dosage forms may contain conventional proportions of conventional ingredients, with or without additional active compounds or ingredients, and such unit dosage forms are intended to be used It may contain any suitable effective amount of active ingredient corresponding to the daily dosage range.

The compounds that can be used according to the present invention can be administered in a wide variety of oral and parenteral dosage forms. The following dosage forms may be used as the active component: a compound of formula (Ia), (Ib), (Ic), (Ih), (II) or (III) according to the invention, or a pharmaceutically acceptable salt or It will be apparent to those skilled in the art that stereoisomers can be included.
For preparing a medicament from a compound of formula (Ia), (Ib), (Ic), (Ih), (II) or (III), a pharmaceutically acceptable carrier can be a solid or a liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

  In the case of powders, the carrier is a finely divided solid which is present in a mixture with the finely divided active component. In the case of tablets, the active ingredients are mixed with the carrier having the necessary binding capacity in the appropriate proportions and compressed to the desired shape and size. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth gum, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term “preparation” is intended to include the formulation of the active compound with the active component (with or without the carrier) surrounded by the carrier, and thus with the encapsulant as the carrier present in connection therewith. Is done. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.

  For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active component is dispersed therein homogeneously, for example, by stirring. The molten homogeneous mixture is then poured into convenient sized molds, cooled and thereby solidified. Compositions suitable for vaginal administration are provided as pessaries, tampons, creams, gels, pastes, foams or sprays containing, in addition to the active ingredient, a carrier as known in the art to be suitable. obtain. Liquid preparations include solutions, suspensions and emulsions, such as water or water-propylene glycol solutions. For example, parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.

Thus, the compounds of formula (Ia), (Ib), (Ic), (Ih), (II) or (III) according to the invention are for parenteral administration (eg by injection, eg by bolus injection or continuous infusion) It can be formulated and provided in unit dosage forms in ampoules, drug-filled syringes, small volume infusions or multiple dose containers containing preservatives. The composition takes the form of a suspension, solution or emulsion in an oily or aqueous vehicle and may contain formulating agents such as suspending agents, stabilizers and / or dispersants. Alternatively, the active ingredient is in powder form, obtained by aseptic isolation of sterile solids or lyophilization from solution, for constitution with a suitable vehicle, such as a sterile pyrogen, prior to use. obtain.
Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents, if desired. Aqueous suspensions suitable for oral use are made by dispersing finely divided active ingredients in water with viscous materials such as natural or synthetic rubbers, resins, methylcellulose, sodium carboxymethylcellulose or other well known suspending agents. Can be done.

Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like.
In one embodiment of the invention, the agent is applied locally or systemically or by a combination of the two routes.
In one particularly preferred embodiment of the invention, the drug is applied topically. This reduces possible side effects and limits the necessary treatment to the affected area.

Preferably the medicament is an ointment, gel, plaster, emulsion, lotion, foam, mixed phase or amphiphilic emulsion system (oil / water to water / oil mixed phase) cream, liposome, transfersome, Prepared in paste or powder form.
For example, ointments and creams can be formulated with an aqueous or oily base and with the addition of suitable thickening and / or gelling agents. Lotions are formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.
Compositions suitable for topical administration in the oral cavity include lozenges containing the active agent in a flavored base (usually sucrose and gum arabic or tragacanth); such as gelatin and glycerin or sucrose and gum arabic Pills containing the active ingredient in an inert base; and mouthwashes containing the active ingredient in a suitable liquid carrier.

Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or nebulizer. The composition may be provided in single or multiple dose dosage forms. In the latter case of a dropper or pipette, this can be accomplished by the patient administering an appropriate predetermined volume of solution or suspension. In the case of a nebulizer, this can be achieved, for example, by a metering atomizing spray pump.
Aerosol formulation in which the active ingredient is provided in a pressurized pack with a suitable propellant such as chlorofluorocarbon (CFC), such as dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, carbon dioxide or other suitable gas Depending on the product, administration to the respiratory tract can also be achieved. It may also be convenient for the aerosol to contain a surfactant, such as lecithin. The dose of drug can be controlled by providing a metering valve.

  Alternatively, the active ingredient is in the form of a dry powder, for example in the form of a powder mixture of the compounds in a suitable base such as lactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidone (PVP) Can be provided. 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 a gelatin capsule or cartridge, or in a blister pack in which the powder can be administered by inhaler.

In compositions intended for administration to the respiratory tract, such as intranasal compositions, the compound will generally have a small particle size for example of the order of 5μ or less. Such a particle size is obtained by means known in the art, for example by micronization.
If desired, compositions adapted to produce a sustained release of the active ingredient can be used.
The pharmaceutical preparation is preferably present in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. Unit dosage forms can be packaged preparations, packages containing different amounts of preparation, such as packaged tablets, capsules, and powders in vials or ampoules. Furthermore, the unit dosage form can be a capsule, tablet, cachet or lozenge itself, or it can be any of a suitable number of these packaging forms. Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are preferred compositions.

Further details regarding formulations and techniques for administration can be found in the final edition of Remington's Pharmaceutical Sciences (Maack Publishing Co. Easton, Pa.).
The pharmaceutical composition comprises two or more compounds of formula (Ia), (Ib), (Ic), (Ih), (II) or (III), or a pharmaceutically acceptable salt thereof, and Other therapeutically active substances can also be included.
The compounds of the invention are therefore used in the form of a single compound alone or in combination with other active compounds, for example in combination with known drugs for the treatment of the abovementioned diseases, so that in the latter case a preferred addition The amplification effect is noted. An appropriate amount to be administered to a human can range from 5 to 500 mg.

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

  The dose can vary within wide limits and should be adapted to the individual symptoms in each individual case. For the above uses the appropriate dosage will vary depending on the mode of administration, the particular condition to be treated and the effect desired. In general, however, satisfactory results are achieved at dosage rates of about 1-100 mg / kg animal body weight, preferably 1-50 mg / kg. In general, suitable dosage rates for large mammals such as humans are administered on the order of about 10 mg to 3 g / day, once, divided into 2 to 4 times a day, or in sustained release form. Is convenient.

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

  The following examples and figures are included to demonstrate preferred embodiments of the invention. The techniques disclosed in the following examples represent techniques that have been discovered by the inventors to function well in the practice of the present invention and may therefore be considered a preferred mode for their practice. Should be understood by those skilled in the art. However, in light of the present disclosure, those skilled in the art will recognize that numerous modifications may be made in the specific embodiments disclosed without departing from the spirit and scope of the invention as set forth in the appended claims. Should be understood. All cited references are incorporated herein by reference.

Example abbreviations: min minutes (s); h hours (s); rt room temperature; t-tert-.
NMR spectrum: Bruker Avance 300 MHz. Spectra were recorded at 300 MHz ( ¹ H-NMR), respectively, using the 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 = 1.98; (CD ₃ ) ₂ CO, δ _H = 2.05). Analytical LC / ESI-MS: 2 x Waters 600 multi-solvent delivery system. 50 μl sample loop. Column Chromolith Speed ROD RP18e (Merck, Darmstadt), 50 x 4.6 mm, 2 μm prefilter (Merck) used. 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, MS8minPM-80-800-20V; positive / negative ion mode scan, m / s 80-800 (in 1 s); capillary, 3.5 kV; cone voltage, 20 V; multiplier voltage, 400 V; Desolvation gas temperature, 120 ° C and 350 ° C, respectively. Waters 2487 Dual λ absorbance detector (set to 254 nm).

Preparative HPLC-MS: Waters 600 multi-solvent delivery system (with preparative pump head). 2000 μl or 5000 μl sample loop. Column Waters X-Terra RP18, 7 μm, 19 x 150 mm, X-Terra RP18 guard cartridge 7 μm, 19 x 10 mm; used at a flow rate of 20 ml / min, or YMC ODS-A, 120 mm, 40 x 150 mm, X-Terra RP18 guard cartridge 7 μm, 19 x 10 mm; used at a flow rate of 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. Different linear gradients 5-100% eluent B, suitable for samples. Injection volume: 500 μl to 2000 μl depending on the sample. Waters ZQ single quadrupole mass spectrometer with electrospray source. Positive / negative ion mode scan, m / s 80-800 (at 1 s); capillary, 3.5 kV; cone voltage, 20 V; multiplier voltage, 400 V; probe and desolvation gas temperature, 120 ° C. and 350 respectively ° C. Waters fraction collector II (mass trigger fraction collection). Waters 996 photodiode array detector.

Synthesis of 4- (methoxy-methyl-carbamoyl) -piperidine-1-carboxylic acid t-butyl ester Piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.0 eq, 21.8 mmol) was prepared under inert conditions. , Dissolved in 35 ml of dry N, N-dimethylformamide. O, N-dimethyl-hydroxylamine hydrochloride (1.03 eq, 22.5 mmol), benzotriazol-1-ol monohydrate (1.03 eq, 22.5 mmol) and triethylamine (1.5 eq, 32.7 mmol) were added. The reaction mixture was cooled to 0 ° C., N- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride (1.0 eq, 21.8 mmol) was added over 10 minutes, the mixture was at 0 ° C. for 1 hour, and Stir vigorously 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 3 times with 100 ml 1 M citric acid, aqueous sodium carbonate and 2 times with 100 ml brine, dried over MgSO ₄ and filtered. The solvent was removed and the residue was purified by distillation, giving a yield of 80%.

Synthesis of 4 -formyl-piperidine-1-carboxylic acid t-butyl ester 4- (methoxy-methyl-carbamoyl) -piperidine-1-carboxylic acid tert-butyl ester (1.0 eq, 16.4 mmol) was prepared under inert atmosphere. , Dissolved in 100 ml of dry tetrahydrofuran. This solution was added dropwise over 1 hour to a suspension of lithium alanate (3.0 eq, 49.6 mmol) in 70 ml of dry tetrahydrofuran at -50 ° C. During the addition of the mixture, the temperature was maintained at −50 ° C. and then allowed to rise to 0 ° C. within 3 hours. The mixture was cooled to −78 ° C. and carefully quenched with 100 ml of 1 M citric acid. The mixture was warmed to room temperature and diluted with 400 ml of ethyl acetate. The phases were separated and the aqueous phase was extracted 3 times with 70 ml of ethyl acetate. The combined organic layers were extracted 3 times with 100 ml 1 M citric acid, aqueous sodium carbonate and 2 times with 100 ml brine, dried over MgSO ₄ and filtered. The solvent was removed and the residue was purified by distillation to give a yield of 85%.

Synthesis of 4- (4-ethoxycarbonyl-4,5-dihydro-thiazol-2-yl) -piperidine-1-carboxylic acid t-butyl ester 4-formyl-piperidine-1-carboxylic acid t-butyl ester (1.0 eq. 13 mmol) was dissolved in 40 ml toluene under inert conditions. To this solution was added L-cysteine ethyl ester hydrochloride (1.6 eq, 21 mmol) and triethylamine (1.6 eq, 21 mmol). The mixture was refluxed for 14 hours. The water produced 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 bicarbonate 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%.

Synthesis of 4- (4-ethoxycarbonyl- thiazol-2-yl) -piperidine-1-carboxylic acid t-butyl ester 4- (4-ethoxycarbonyl-4,5-dihydro-thiazol-2-yl) -piperidine- 1-carboxylic acid tert-butyl ester (1.0 eq, 8.7 mmol) was dissolved in 160 ml toluene under inert conditions. To this solution was added MnO ₂ (15.0 eq, 130 mmol). The reaction was heated to 70 ° C. with stirring for 5 hours. The mixture was filtered over celite and the filter agent was washed 3 times with 30 ml toluene and ethyl acetate. The combined organic layer was vacuum distilled. The residue was purified by silica gel chromatography using a DCM / MeOH 95: 5 gradient. Yield: 30%.

C-terminally functionalized 4- (4-ethoxycarbonyl-thiazol-2-yl) -piperidine-1-carboxylic acid tert-butyl ester (1.0 eq, 2.9 mmol) in 40 ml dioxane under inert gas Dissolved in. While stirring, 1.5 ml of aqueous 2 N NaOH was added dropwise over 10 minutes. The mixture was then stirred at room temperature for 2 hours.
The reaction was neutralized with 2 N HCl and the solvent was evaporated in vacuo. The residue was dissolved in 50 ml ethyl acetate. The organic layer was extracted 3 times with 10 ml of 1 M citric acid and water, dried over MgSO ₄ and filtered. The solvent was removed and the residue was dried in vacuo. Yield 95%.
4- (4-Carboxy-thiazol-2-yl) -piperidine-1-carboxylic acid tert-butyl ester (1 eq) was dissolved in dry dimethylacetamide (0.03 mmol / ml) under inert conditions. To this solution was added aryl- or alkylamine (1 equivalent), diisopropylethylamine (2 equivalents) and O-benzotriazol-1-yl-N, N, N ′, N′-tetramethyluronium hexafluorophosphate (2 equivalents). ) Was added. The reaction mixture was stirred at room temperature for 12 hours.
The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The organic layer was extracted 3 times with 1 M citric acid, aqueous potassium bicarbonate, 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%.

The N-terminal functionalized N-protected substrate was treated with 4 M HCl / dioxane (1 mL HCl / 0.03 mmol substrate in dioxane) under inert conditions and stirred at room temperature for 2 hours. The solvent was removed in vacuo to give the HCl salt of the free amine without further purification.
The free amino compound (1 eq) was dissolved in dry dimethylacetamide (0.03 mmol / ml) under inert conditions. To this solution was added aryl- or alkyl carboxylic acid (1 equivalent), diisopropylethylamine (2 equivalents) and O-benzotriazol-1-yl-N, N, N ′, N′-tetramethyluronium hexafluorophosphate (2 Eq.) Were added in this order and the reaction mixture was stirred at room temperature for 12 h.
The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The organic layer was extracted 3 times with 1 M citric acid, aqueous potassium bicarbonate, 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 type (III) and (II)
Procedure for the synthesis of compounds of type (IIIa), (IIIc), (IIa) and (IIb)
7.3 × 10 ⁻⁴ mol of benzoic acid derivative (VI) is dissolved in 5 ml of DMF, 1 equivalent of Hunig's base is added, the reaction mixture is stirred for 2-3 minutes, then 1 equivalent of HBTU is added The mixture was further stirred at room temperature for 2 minutes. Then 1 equivalent of 2-amino-thiazole-4-carboxylic acid ethyl ester was added and the mixture was stirred overnight at the same temperature. The solvent was then removed by filtration and the residue was redissolved in 5 ml dioxane and treated with 0.5 ml of 1 M NaOH solution. After the reaction was completed, the pH was lowered to 1 to 2 with 1 M HCl solution, and the precipitate (VII) was filtered and dried in vacuum. For the next step, intermediate (VII) is dissolved in 3 ml of DMF, 1 equivalent of Hunig's base is added, the reaction mixture is stirred for 2-3 minutes, and then 1 equivalent of HBTU is added. The mixture was further stirred at room temperature for 2 minutes. Then 1 equivalent of amino component was added and the mixture was stirred overnight at the same temperature. The solvent is then removed by filtration and the crude product is redissolved in 10 ml ethyl acetate and twice with 10 ml citric acid (1 M solution), 10 ml saturated NaHCO ₃ solution and 10 ml water. Washed. The organic phase was then evaporated and the residue was dried over MgSO ₄ . The solvent was removed and final purification was achieved by preparative HPLC as described above.

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

Procedure for the synthesis of compounds of type (IIIb, d, e, f) and (IIc, d)
6.3 × 10 ⁻⁴ mol of 2-bromo-thiazole-4-carboxylic acid ethyl ester (X) was dissolved in 10 ml of THF together 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 steps of the reaction were accomplished as described above under the procedure for the synthesis of compounds of type (IIIa) and (IIIc).
See WO 2004/058750 for the synthesis protocol of (IIIb, d, e, f and IIc, d) type compounds (Z = CH).

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

1) Biological data shows results obtained from NF-κB inflammation assay.
[“+” Means 50-80% inhibition, “++” means 80-90%, and “++++” means 90-100% inhibition]

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

1) Biological data shows results obtained from NF-κB inflammation assay.
[“+” Means 50-80% inhibition, “++” means 80-90%, and “++++” means 90-100% inhibition]

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

1) Biological data shows results obtained from NF-κB inflammation assay.
[“+” Means 50-80% inhibition, “++” means 80-90%, and “++++” means 90-100% inhibition]

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

1) Biological data shows results obtained from NF-κB inflammation assay.
[“+” Means 50-80% inhibition, “++” means 80-90%, and “++++” means 90-100% inhibition]

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

1) Biological data shows results obtained from NF-κB inflammation assay.
[“+” Means 50-80% inhibition, “++” means 80-90%, and “++++” means 90-100% inhibition]

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

1) Biological data shows results obtained from NF-κB inflammation assay.
[“+” Means an EC50 of 30-100 μM, “++” means an EC50 of 10-30 μM, and “++” means an EC50 of less than 10 μM]

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

1) Biological data shows results obtained from NF-κB inflammation assay.
[“+” Means an EC50 of 30-100 μM, “++” means an EC50 of 10-30 μM, and “++” means an EC50 of less than 10 μM]

Proteasome assay:
The 20S proteasome (Immatics, Tubingen) chymotrypsin activity was determined using a Tecan Ultra plate reader and Suc-LLVT-AMC (Bachem) as a substrate. In a well of a black 96 well polypropylene plate, 2 μl of each inhibitor dissolved in DMSO was added to 50 μl of substrate solution (25 mM HEPES, pH 7.5 at 20 ° C., 0.5 mM EDTA and Suc-LLVT-AMC (appropriate concentration). And then add 150 μl of proteasome solution (1.3 μg / ml 20S proteasome in 25 mM HEPES (pH 7.5 at 20 ° C.), 0.5 mM EDTA, 0.033% (w / v) SDS). The reaction was started. Substrate hydrolysis was followed by fluorescence spectroscopy (excitation wavelength: 360 nm; emission wavelength; 465 nm) at 30 ° C. for 20 minutes to calculate initial rate and as a change in relative fluorescence units (RFU) / sec Represented.
At least four different inhibitor concentrations were applied for the determination of IC50 values (concentration of inhibitor required for 50% inhibition). Each data point was recorded in triplicate experiments. The curve was fitted with an appropriate program.

T-lymphocyte proliferation assay:
Inhibition of stimulated peripheral blood monocytes (PBMC) PBMCs were isolated from healthy volunteer blood with the help of the ACCUSPIN ^™ System Histopaque-1077 tube, washed, and Dulbecco containing 10% fetal calf serum and 2 mM glutamine Resuspended in modified Eagle's medium at 10 cells / ml. Cells were stimulated with moaglutinin to 2 μg / ml phyto for 72 hours in the presence of test compound or blank vehicle. Five hours before the end of the incubation period, 5-bromo-2′-desoxyuridine (BrdU) was added to label the growing cells. After incubation, the cells were separated by centrifugation and the culture supernatant was removed. Contaminated BrdU was quantified using an enzyme-linked immunosorbent assay. At least four different inhibitor concentrations were applied for the determination of IC50 values (concentration of inhibitor required for 50% inhibition). Each data point was recorded in triplicate experiments. The curve was fitted with an 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.

Inhibition of NF-κB-induced inflammation:
The PRINCESS® NINA Instant Assay (Cell Culture Service GmBH) was used to determine the anti-inflammatory activity of the compounds. This assay is based on recombinant A549-NF-κB-SEAP reporter cells previously seeded in 96 well flat bottom plates. Since the transfected reporter gene for SEAP (secreted embryonic alkaline phosphatase) is under transcriptional control of the NF-κB responsive element, expression of this reporter is activated upon stimulation with TNF-α. SEAP secretion into the culture supernatant can be detected by the chemiluminescent substrate CSPD®. Test compounds that inhibit NF-κB activation exhibit reduced SEAP activity and reduced cold light readout.

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

Claims (19)

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

Wherein A is NR ^{2 ′} , S or O;
t is 0-4;
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, —C (NH 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 hetero Is aryl;
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 R ¹ and R ² are the N atom or C to which they are attached Taken together with atoms to form a 3-8 membered saturated or at least partially unsaturated monocyclic or polycyclic ring system (wherein at least one or more of the carbon atoms in the ring are O, A heteroatom selected from N and S, and the ring may be substituted by 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, Is 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, hydroxy cycloalkyl Alkyl, hydroxyalkyl amino, heterocycloalkyl, aryl or heteroaryl represents;
^{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, hydroxyalkyl amino, 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 ;
p is 1-6;
q is 1-6;
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, hydroxy It represents ^{_{(CH 2) p NR 7 COR}} 8, aryl or heteroaryl - alkylamino, halo alkyloxy, heterocycloalkyl;
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,
In this case, a C ₁ -C ₆ -alkyl group, unless stated otherwise, means a linear or branched C ₁ -C ₆ -alkyl, which is optionally substituted by one or more substituents R ^′. Get;
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, Is hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl or heteroaryl;
R ″ is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl or heteroaryl;
A C ₁ -C ₆ -alkenyl group, unless stated otherwise, means a linear or branched C ₁ -C ₆ -alkenyl, which may optionally be substituted by one or more substituents R ^′ ;
Unless otherwise specified, alkyl groups are linear or branched C ₁ -C ₆ -alkyl, linear or branched C ₂ -C ₆ -alkenyl, or linear or branched C ₂ -C ₆ -alkynyl. Means a group, which may be substituted by one or more substituents R ^′ ; R ′ is as defined above;
A cycloalkyl group means a non-aromatic ring system containing from 3 to 8 carbon atoms, wherein one or more of the carbon atoms in the ring are substituted by one or more substituents R ′. R ′ is defined as above;
A heterocycloalkyl group means a non-aromatic ring system containing 2 to 10 carbon atoms and at least one heteroatom selected from O, N and S, wherein 1 of the carbon atoms in the ring One or more may be substituted by R ′ as described above;
An alkoxy group means an O-alkyl group, the alkyl group is as defined above;
An alkylthio group means an S-alkyl group, the alkyl group being the same as described above;
A haloalkyl group means an alkyl group substituted by 1 to 5 halogen atoms, the alkyl group being the same as described above;
A hydroxyalkyl group means a HO-alkyl group, the alkyl group is as defined above;
A haloalkyloxy group means an alkoxy group substituted by 1 to 5 halogen atoms, the alkyl group being the same as above;
A hydroxyalkylamino group means a (HO-alkyl) ₂ -N- group or a HO-alkyl-NH- group, wherein alkyl is as defined above;
An alkylamino group means a HN-alkyl or N-dialkyl group, the alkyl group being the same as above;
The halogen group is fluorine, chlorine, bromine or iodine;
An aryl group means an aromatic group having 5 to 15 carbon atoms, which may be substituted by one or more substituents R ′ (R ′ is as defined above);
An arylamino group means an HN-aryl or N-diaryl group, the aryl group being the same as described above;
Heteroaryl group means a 5-10 membered aromatic heterocyclic group containing at least one heteroatom selected from O, N and S, wherein the heterocyclic group is another ring and heterocycle Can be fused with a formula group, or both fused rings can be independently substituted by one or more substituents R ′ (where R ′ is as defined above), provided that the following compounds are excluded: :

Wherein 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 ,

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. Represents 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 general formula (Ia), or a pharmaceutically acceptable salt thereof with an acid or base, or a pharmaceutically acceptable prodrug or stereoisomer thereof:

Wherein R is independently hydrogen, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl;
R ¹ is independently alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl;
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;
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 is 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 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, hydroxyalkyl, amino, 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 ' table a benzoxazolyl or heteroaryl ;
R ^{4 ′} , R ^{4 ″} and 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 Represents aryl;
p is 1-6;
q is 1-6;
R ² is independently

Is;
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, amino, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, aryl or heteroaryl;
In this case, unless otherwise stated, alkyl groups are linear or branched C ₁ -C ₆ -alkyl, linear or branched C ₂ -C ₆ -alkenyl, or linear or branched C ₂ -C. Means a ₆ -alkynyl group, which may be substituted by one or more substituents R ^′ ; 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, Is hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl or heteroaryl;
R ″ is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl or heteroaryl;
A cycloalkyl group means a non-aromatic ring system containing from 3 to 8 carbon atoms, wherein one or more of the carbon atoms in the ring can be substituted by the group E; O, S, SO, SO ₂ , N or NR ″, where R ″ is defined as above;
An alkoxy group means an O-alkyl group, the alkyl group is as defined above;
An alkylthio group means an S-alkyl group, the alkyl group being the same as described above;
A haloalkyl group means an alkyl group substituted by 1 to 5 halogen atoms, the alkyl group being the same as described above;
A hydroxyalkyl group means a HO-alkyl group, the alkyl group is as defined above;
A haloalkyloxy group means an alkoxy group substituted by 1 to 5 halogen atoms, the alkyl group being the same as above;
A hydroxyalkylamino group means a (HO-alkyl) ₂ -N- group or a HO-alkyl-NH- group, wherein alkyl is as defined above;
An alkylamino group means a HN-alkyl or N-dialkyl group, the alkyl group being the same as above;
The halogen group is fluorine, chlorine, bromine or iodine;
An aryl group means an aromatic group having 5 to 15 carbon atoms, which may be substituted by one or more substituents R ′ (R ′ is as defined above);
Heteroaryl group means a 5-10 membered aromatic heterocyclic group containing at least one heteroatom selected from O, N and S, wherein the heterocyclic group is another ring and heterocycle Or both fused rings can be independently substituted with one or more substituents R ′, where R ′ is as defined above). A compound of general formula (Ib), or a pharmaceutically acceptable salt thereof with an acid or base, or a pharmaceutically acceptable prodrug or stereoisomer thereof:

(In the formula, 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, heteroarylalkyl, hydroxyalkyl, cycloalkyl, alkylamino, aryl, hydroxyalkyl, amino, 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 It represents OR ⁸ or alkyl;
R ⁴ is H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl; or R ¹ and R ⁴ together with X to which they are attached, Forms 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 is Optionally having 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 ″} and 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 Represents aryl;
p is 1-6;
q is 1-6;
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, hydroxyalkylamino, 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 table ;
R ² is independently

Is;
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, -C ( _{^{NH 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, alkyl Amino, hydroxyalkylamino, halogen, —OH, —SH, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl;
n is 0-2;
In this case, unless otherwise stated, alkyl groups are linear or branched C ₁ -C ₆ -alkyl, linear or branched C ₂ -C ₆ -alkenyl, or linear or branched C ₂ -C. Means a ₆ -alkynyl group, which may be substituted by one or more substituents R ^′ ; 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, Is hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl or heteroaryl;
R ″ is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl or heteroaryl;
A cycloalkyl group means a non-aromatic ring system containing from 3 to 8 carbon atoms, wherein one or more of the carbon atoms in the ring can be substituted by the group E; O, S, SO, SO ₂ , N or NR ″ (R ″ is the same as above);
An alkoxy group means an O-alkyl group, the alkyl group is as defined above;
An alkylthio group means an S-alkyl group, the alkyl group being the same as described above;
A haloalkyl group means an alkyl group substituted by 1 to 5 halogen atoms, the alkyl group being the same as described above;
A hydroxyalkyl group means a HO-alkyl group, the alkyl group is as defined above;
A haloalkyloxy group means an alkoxy group substituted by 1 to 5 halogen atoms, the alkyl group being the same as above;
A hydroxyalkylamino group means a (HO-alkyl) ₂ -N- group or a HO-alkyl-NH- group, wherein alkyl is as defined above;
An alkylamino group means a HN-alkyl or N-dialkyl group, the alkyl group being the same as above;
The halogen group is fluorine, chlorine, bromine or iodine;
An aryl group means an aromatic group having 5 to 15 carbon atoms, which may be substituted by one or more substituents R ′ (R ′ is as defined above);
Heteroaryl group means a 5-10 membered aromatic heterocyclic group containing at least one heteroatom selected from O, N and S, wherein the heterocyclic group is another ring and heterocycle Or both fused rings can be independently substituted with one or more substituents R ′, where R ′ is as defined above). A compound of general formula (Ic), or a pharmaceutically acceptable salt thereof with an acid or base, or a pharmaceutically acceptable prodrug or stereoisomer thereof:

Wherein R ¹ represents 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 ″} and 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 Represents aryl;
p is 1-6;
q is 1-6;
m is 0-4;
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, hydroxyalkylamino, 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 table ;
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;
In this case, unless otherwise stated, alkyl groups are linear or branched C ₁ -C ₆ -alkyl, linear or branched C ₂ -C ₆ -alkenyl, or linear or branched C ₂ -C. Means a ₆ -alkynyl group, which may be substituted by one or more substituents R ^′ ; 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, Is hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl or heteroaryl;
R ″ is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl or heteroaryl;
A cycloalkyl group means a non-aromatic ring system containing from 3 to 8 carbon atoms, wherein one or more of the carbon atoms in the ring can be substituted by the group E; O, S, SO, SO ₂ , N or NR ″ (R ″ is the same as above);
An alkoxy group means an O-alkyl group, the alkyl group is as defined above;
An alkylthio group means an S-alkyl group, the alkyl group being the same as described above;
A haloalkyl group means an alkyl group substituted by 1 to 5 halogen atoms, the alkyl group being the same as described above;
A hydroxyalkyl group means a HO-alkyl group, the alkyl group is as defined above;
A haloalkyloxy group means an alkoxy group substituted by 1 to 5 halogen atoms, the alkyl group being the same as above;
A hydroxyalkylamino group means a (HO-alkyl) ₂ -N- group or a HO-alkyl-NH- group, wherein alkyl is as defined above;
An alkylamino group means a HN-alkyl or N-dialkyl group, the alkyl group being the same as above;
The halogen group is fluorine, chlorine, bromine or iodine;
An aryl group means an aromatic group having 5 to 15 carbon atoms, which may be substituted by one or more substituents R ′ (R ′ is as defined above);
Heteroaryl group means a 5-10 membered aromatic heterocyclic group containing at least one heteroatom selected from O, N and S, wherein the heterocyclic group is another ring and heterocycle Or both fused rings can be independently substituted with one or more substituents R ′, where R ′ is as defined above).   5. 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.   7. A compound according to any one of claims 1 to 4 or a composition according to claim 6 for the treatment or prevention of diseases characterized by cellular hyperproliferation.   For the treatment or prevention of diseases caused by ischemia and / or reperfusion injury of organs and / or parts of the body selected from the group consisting of heart, brain, peripheral limbs, kidney, liver, spleen and lung The compound according to any one of claims 1 to 4 or the composition according to claim 6, wherein the endothelial dysfunction is selected from the group consisting of infarctions such as myocardial infarction and severe limb ischemia. And / or a compound or composition in which endothelial dysfunction is associated with a disease selected from the group consisting of ischemic disease, myocardial infarction and organ ischemic injury.   Alzheimer's disease, Parkinson's disease, Creutzfeldt-Jakob disease, Lewy body dementia, amyotrophic lateral sclerosis, stroke, epilepsy, multiple sclerosis, myasthenia gravis, Huntington's disease, Down's syndrome, neurological hearing loss and Meniere 7. A compound according to any one of claims 1 to 4 or a composition according to claim 6 for the treatment or prevention of a neurological disease or disorder selected from the group consisting of diseases.   The diseases are psoriasis, atopic dermatitis, alopecia areata, lupus erythematosus of the skin, lichen planus, cutaneous dermatomyositis, atopic eczema, localized scleroderma, scleroderma, psoriasis vulgaris, psoriasis of the head , Droplet psoriasis, inverted psoriasis, serpentine alopecia areata, androgenetic alopecia, allergic contact eczema, irritant contact eczema, contact eczema, pemphigus vulgaris, deciduous pemphigus, proliferative pemphigus , Scarring mucous pemphigoid, bullous pemphigoid, mucinous pemphigoid, dermatitis, Duering herpes dermatitis, hives, lipoid necrosis, erythema nodosum, bidar lichen, simple urticaria , Nodular rash, acute eczema, linear IgA dermatosis, polymorphic sun dermatosis, erythema erythema, sclerosing atrophic lichen, skin rash, drug rash, chronic progressive purpura, allergic eczema, eczema, Fixed drug rash, photoallergic skin reaction, lichen simplex eriorale, Dermatitis and “graft-versus-host disease”, acne, rosacea, scar, keloid, vitiligo, actinic keratosis, keratoproliferative diseases such as epidermolytic keratophytosis, permanent keratoproliferative keratosis, pore 8. A compound or composition according to claim 7 selected from the group consisting of keratosis and ichthyosis.   8. A compound or composition according to claim 7, wherein the disease is selected from the group consisting of hematological or solid tumors.   12. A 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.   The compound according to any one of claims 1 to 4 or the composition according to claim 6 for the treatment or prevention of an autoimmune disease or an inflammatory disease.   14. A compound or composition according to claim 13 wherein the disease is rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, inflammatory skin disease or lupus erythematosus.   7. A compound according to any one of claims 1 to 4 or a composition according to claim 6 for the treatment or prevention of stroke, reperfusion injury and Alzheimer's disease.   The compound according to any one of claims 1 to 4 or the composition according to claim 6 for the treatment or prevention of viral diseases.   The compound or composition according to claim 16, wherein the viral diseases are hepatitis B, hepatitis C, influenza virus infection, AIDS (HIV infection) and human papillomavirus infection.   The compound according to any one of claims 1 to 4 or the composition according to claim 6 for the treatment or prevention of arteriosclerosis.   The compound according to any one of claims 1 to 4 or the composition according to claim 6 for the treatment or prevention of osteoporosis.