Transglutaminase Inhibitors

Abstract

The present invention relates to compounds of general formula (I) as novel inhibitors of transglutaminase, processes for producing the compounds of the invention, pharmaceutical compositions containing said compounds of the invention, and their use for the prevention and treatment of diseases associated with transglutaminase.

Description

Detailed Description of the Invention

[0001] The present invention relates to novel or reversible inhibitors of transglutaminase, methods for their synthesis and their use for the prevention and treatment of diseases associated with transglutaminase. [Background of the invention] Transglutaminases are part of the class of transferases, and according to the EC nomenclature, transglutaminases are precisely designated as "protein-glutamine:amine gamma-glutamyltransferases" (EC 2.3.2.13). Transglutaminases link the ε-amino group of the amino acid lysine and the γ-glutamyl group of the amino acid glutamine, forming an isopeptide bond, with the release of ammonia. In the absence of a suitable amine and / or under certain conditions, deamination of glutamine can occur, resulting in the corresponding glutamic acid.

[0002] Furthermore, transglutaminases play an important role in several therapeutic areas such as cardiovascular diseases (thrombosis and atherosclerosis), autoimmune diseases (celiac disease, Duhring-Brocq-disease, gluten ataxia), neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease), dermatological diseases (ichthyosis, psoriasis, acne), as well as wound healing and inflammatory diseases (e.g. tissue fibrosis, etc.) (JM Odzinska, Mini-Reviews in medical chemistry, 2005, 5, 279-292).

[0003] Celiac disease, gluten intolerance, however, is one of the most important manifestations. Celiac disease is characterized by chronic inflammation in the small intestinal mucosa. In susceptible patients, the intestinal epithelium is continuously destroyed after ingestion of gluten-containing foods, leading to a decrease in nutrient absorption, which again greatly affects affected patients and is associated with symptoms such as weight loss, anemia, diarrhea, nausea, decreased appetite, and fatigue. Due to these findings, there is a great demand for the development of drugs for the treatment of celiac disease and other diseases associated with tissue transglutaminase (transglutaminase 2, TG2). Tissue transglutaminase is a key element during pathogenesis. The endogenous enzyme catalyzes the deamidation of gluten / gliadin in the small intestinal mucosa, thus triggering an inflammatory response. Therefore, tissue transglutaminase inhibitors are suitable to be used as activators of drugs.

[0004] Another very important group of indications for tissue transglutaminase inhibitors is fibrotic diseases. Fibrotic diseases are characterized by the accumulation of cross-linked extracellular matrix proteins. Diabetic nephropathy, cystic fibrosis, idiopathic pulmonary fibrosis, renal fibrosis, and hepatic fibrosis are among the most important fibrotic diseases that are addressed using the disclosed compounds.

[0005] The human transglutaminase family consists of eight members that catalyze the unique formation of "cross-links" or isopeptide bonds between different substrate proteins. Since blood coagulation factor XIII (FXIII, F13) is the major factor affecting clot maturation and accretion, the enzyme is considered a suitable target to potentially achieve safer and more effective clot lysis, even with lower doses of clot dissolving agents, and for thrombus prophylaxis.

[0006] Blood coagulation factor XIII (EC 2.3.2.13), also known as plasma transglutaminase or fibrin stabilizing factor (FSF), has the unique function of stabilizing fibrin clots. The enzymatic introduction of a covalent cross-link between the γ-chain and the subsequent α-chain of fibrin is the mechanism It provides mechanical stability and mediates viscoelastic properties.

[0007] In addition, plasma transglutaminase, together with anti-fibrinolytic factors, especially α2-antiplasmin, colors coagulation. For decades, factor XIII has been considered a suitable target for anticoagulation in certain at-risk patients due to its unique mode of action. Targeting factor XIIIa with direct-acting inhibitors would not impair thrombin levels or platelet activity to avoid serious bleeding episodes.

[0008] In addition, certain inhibitors may be beneficial for patients to prevent atherosclerosis. Very few inhibitors of factor XIIIa have been described so far. For example, a 66 amino acid peptide from the salivary glands of the giant Amazon leech Haementeria ghilianii is reported [Finney et al. Biochem. J. 1997, 324, pp. 797-805]. Furthermore, the pharmaceutical company Merck Sharp and Dohme has developed a series of small molecular weight thioimidazole inhibitors that target factor XIII [Freund et al., Biochemistry (1994), 33, 10109-10119].

[0009] However, other transglutaminases can also be considered as targets for drug development. For example, TG6 is expressed in neural tissue. Therefore, TG6 inhibitors can address neurodegenerative diseases characterized by intracellular or extracellular crosslinks and insoluble protein aggregates in brain tissue.

[0010] Since TG1, TG3, and TG5 are expressed in the skin, inhibitors of the enzymes can be used to regulate unregulated transglutaminase activity to treat certain skin disorders. Inhibition of skin-expressed transglutaminase can regulate skin structure ("anti-aging") and improve skin conditions such as acne or scarring.

[0011] Although irreversible inhibitors of transglutaminase are developed by the applicant, the inherent reactivity of these head moieties (e.g. Michael-acceptors such as vinyl esters) can lead to adverse drug reactions. It is known that electrophilic head moieties can react with biological nucleophiles such as thiols. Non-specific reactions involving off-targets can cause serious side effects and trigger specific immune responses. One example is specific drug-related toxicity that dislikes the compound from a more general perspective. Furthermore, direct tissue damage has been described for irreversibly acting compounds or metabolites. Haptenization of proteins by reactive substances can also induce immune responses. Quite frequently, the liver is affected by the side effects.

[0012] It would therefore be advantageous if transglutaminase could be reversibly inhibited. Summary of the Invention

[0013] It is an object of the present invention to provide novel, most preferably reversible, transglutaminase inhibitors, as well as methods for the synthesis of said inhibitors, and some of the uses of these inhibitors.

[0014] Said object is solved by the technical teachings in the independent claims. Further advantageous embodiments, aspects and details of the invention are evident from the independent claims, the description and the examples.

[0015] Surprisingly, the reversible inhibitors having the chemical head moieties disclosed herein are capable of inhibiting trans It has been found that it effectively inhibits transglutaminase, including tissue transglutaminase, also called glutaminase 2 or TG2, and plasma transglutaminase, also called coagulation factor XIII. In this application, these terms are used synonymously. However, depending on each backbone, the tip part also corresponds to other human transglutaminase, such as TG1, TG3, TG4, TG5, TG6 and TG7, or transglutaminase derived from other species, such as animals or microorganisms.

[0016] Preferably, the chemical head moiety is selected from aldehydes (including so-called masked aldehydes), ketones, α-ketoaldehydes, α-ketoketones, α-ketoacids, α-ketoesters, and α-ketoamides, and halogen methyl ketones, among others.The compounds of the present invention most preferably act as reversible transglutaminase inhibitors.

[0017] Thus, the present invention relates to compounds of general formula (I):

[0018] [ka]

[0019] During the ceremony, n is an integer selected from 1, 2, or 3; W is

[0020] [ka]

[0021] represents; R 2 is -H,-R 1 ,-OR 1 ,-NH2,-NH(R 1 ),-NH(OR 1 ),-N(R 1 )(R 3 ) ; R 1 and R3 are, independently of one another, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH(C2H5)2, -CH2CH(C2H5)2, -C(CH3)3, -CH2-C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -cyclo-C6H 11 ,-CH2-cyclo-C3H5,-CH2-cyclo-C4H7,-CH2-cyclo-C5H9,-CH2-cyclo-C6H 11 ,-Ph,-CH2-Ph,-CH2OCH3,-CH2OCH2CH3,-CH2CH2OCH3,-CH2CH2OCH2CH3,-CH2CO2CH3,-CH2CO2CH2CH3,-CH2CH2NHCH3,-CH2CH2N(CH3)2,-CH2S(O)2-(4-methyl-phenyl),

[0022] [ka]

[0023] represents; or -N(R 1 )(R 3 )teeth,

[0024] [ka]

[0025] Forming; Z N E N -,E N -AS N1 -,E N -AS N2 -AS N1 -,E N -AS N3 -AS N2 -AS N1 -, or E N -ASN4 -AS N3 -AS N2 -AS N1 - represents; Z c is, -E C , -AS C1 -E C , -AS C1 -AS C2 -E C , -AS C1 -AS C2 -AS C3 -E C , -AS C1 -AS C2 -AS C3 -AS C4 -E C , -AS C1 -AS C2 -AS C3 -AS C4 -AS C5 -E C , -AS C1 -AS C2 -AS C3 -AS C4 -AS C5 -AS C6 -E C , -AS C1 -AS C2 -AS C3 -AS C4 -AS C5 -AS C6 -AS C7 -E C , -AS C1 -AS C2 -AS C3 -AS C4 -AS C5 -AS C6 -AS C7 -AS C8 -E C - represents; AS C1 ~AS C8 and AS N1 ~AS N4 are, independently of each other,

[0026] [Chemical formula]

[0027] [ka]

[0028] [ka]

[0029] , wherein the group consisting of: N1 teeth

[0030] [ka]

[0031] AS, NOT, and N2 teeth

[0032] [ka]

[0033] Provided that it is not; E C -OR 8 ,-NR 9 R 10 ,-NHSO2R 11 ,-O-L1-R 8 ,-O-L1-OR 8 ,-NH-L1-OR 8 ,-NH-L1-NR 9 R 10 ,-NHSO2-L1-R 11 ,

[0034] [ka]

[0035] and a C-terminal group selected from the group consisting of: E Nis -H,-COCF3,-CH3,-C2H5,-C3H7,-CH(CH3)2,-CH(C2H5)2,-C4H9,-C5H 11 ,-C6H 13 ,-CH2-CH(CH3)2,-CH2-CH(C2H5)2,-CH(CH3)-C2H5,-C(CH3)3,-CH2-C(CH3)3,-cyclo-C3H5,-cyclo-C4H7,-cyclo-C5H9,-cyclo-C6H 11 ,-CH2-cyclo-C3H5,-CH2-cyclo-C4H7,-CH2-cyclo-C5H9,-CH2-cyclo-C6H 11 ,-Ph,-CH2-Ph,-CH2F,-CHF2,-CF3,-CH2Cl,-CH2Br,-CH2I,-CH2-CH2F,-CH2-CHF2,-CH2-CF3,-CH2-CH2Cl,-CH2-CH2Br ,-CH2-CH2I,-CH2-CH=CH2,-CH2-C≡CH,-CHO,-COCH3,-COC2H5,-COC3H7,-COCH(CH3)2,-COCH(C2H5)2,-COC4H9,-COC5H 11 ,-COC6H 13 ,-COCH2-CH(CH3)2,-COCH2-CH(C2H5)2,-COCH(CH3)-C2H5,-COC(CH3)3,-COCH2-C(CH3)3,-CO-cyclo-C3H5,-CO-cyclo-C4H7,-CO-cyclo-C5H9,-CO-cyclo-C6H 11 ,-COCH2-cyclo-C3H5,-COCH2-cyclo-C4H7,-COCH2-cyclo-C5H9,-COCH2-cyclo-C6H 11 ,-COPh,-COCH2-Ph,-COOCH3,-COOC2H5,-COOC3H7,-COOCH(CH3)2,-COOCH(C2H5)2,-COOC4H9,-COOC5H 11 ,-COOC6H 13 ,-COOCH2-CH(CH3)2,-COOCH2-CH(C2H5)2,-COOCH(CH3)-C2H5,-COOC(CH3)3,-COOCH2-C(CH3)3,-COO-cyclo-C3H5,-COO-cyclo-C4H7,-COO-cyclo-C5H9,-COO-cyclo-C6H 11,-COOCH2-cyclo-C3H5,-COOCH2-cyclo-C4H7,-COOCH2-cyclo-C5H9,-COOCH2-cyclo-C6H 11 ,-COOPh,-COOCH2-Ph,

[0036] [ka]

[0037] The N-terminal group is selected from the group consisting of: However, Z N E N and Z C E C Then E C -OR 8 Not and / or E N is not -H, R 4 , R 5 , and R 6 are, independently of one another, -H, -F, -Cl, -Br, -I, -CH3, -CH2CH3, -CH(CH3)2, -cyclo-C3H5, -OCH3, -OCH2CH3, -OCH(CH3)2, -O-cyclo-C3H5, -CF3, -CF2CF3, -OCHF2, -OCF3, -OCF2CF3, -OH, -CN, -CHO, -COCH3, -COCH2CH3, -COCH(CH3)2, -COCH2F, -COCH2Cl, -COCF3, -COCCl3, -CO2H, -CO2H, -CO2Me, -CO2CH2CH3, -CO2CH(CH3)2, -OCOCH3, -OCOCH2CH3 ,-OCOCH(CH3)2,-OCOCF3,-OCOCCl3,-NH2,-NHCH3,-N(CH3)2,-NHCH2CH3,-NHCH(CH3)2,-N(CH2CH3)2,-NH-cyclo-C3H5,-NHCOCH3,-NHCOCF3,-NHSO2CH3,-NHSO2CF3,-SCH3,-SCH2CH3,-SCH(CH3)2,-S-cyclo-C3H5,-SOCH3,-SOCF3,-SO2CH3,-SO2CF3,-SO2NH2,-SO2NHCH3,-SO2N(CH3)2,-SO2NHCH2CH3,-SO2NHCH(CH3)2,-SO2NH-cyclo-C3H5,-SO2N(CH2CH3)2, or R 4 and R 5 , or R 5 and R 6 together form a five- or six-membered ring:

[0038] [ka]

[0039] R 7 represents -H, -CH2CO2H, -CH2CH2CO2H, -CH2CH2CH2CO2H, -CH2CONH2, -CH2CH2CONH2, or -CH2NHCONH2; R 8 , R 9 , R 10 , and R 11 are, independently of each other: -H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH(C2H5)2, -CH2CH(CH3)2, -CH2-CH(C2H5)2, -C4H9, -C5H 11 ,-C6H 13 ,-CH(CH3)-C2H5,-C(CH3)3,-CH2-C(CH3)3,

[0040] [ka]

[0041] represents; R 12 ~R 29 are, independently of one another, -H, -F, -Cl, -Br, -I, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2- CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2Cl, -CH2-CH2Br, -CH2-CH2I, -OCH3, -OC2H5, -OC3H7, -OCH(CH3)2, -OC(CH3)3, -OC4H9, -OCHF2, -OCF3, -OCH2CF3, -OC2F5, -OCH2OCH3, -O-cyclo-C3H5, -OCH2-cyclo-C3H5, -O-C2H 4-cyclo-C3H5, -CHO, -COCH3, -COCF3, -COC2H5, -COC3H7, -COCH(CH3)2, -COC(CH3)3, -COOH, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -OOC-CH3, -OOC-CF3, -OOC-C2H5, -OOC-C3H7, -OOC-CH(CH3)2, -OOC-C(CH3)3, -NH2, -NHCH3, -NHC2H5, -NHC3H7, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC2H5, -NHCOC3H7, -NHCOCH(CH3)2, -NHCOC(CH3)3, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CONHCH(CH3)2, -CONH-cyclo-C3H5, -CONHC(CH3)3, -CON(CH3)2, -CON(C2H5)2, -CON(C3H7)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, -SO2NH2, -SO2NHCH3, -SO2NHC2H5, -SO2NHC3H7, -SO2NHCH(CH3)2, -SO2NH-cyclo-C3H5, -SO2NHC(CH3)3, -SO2N(CH3)2, -SO2N(C2H5)2, -SO2N(C3H7)2, -SO2N[CH(CH3)2]2, -SO2N[C(CH3)3]2, -NHSO2CH3, -NHSO2CF3, -NHSO2C2H5, -NHSO2C3H7, -NHSO2CH(CH3)2, -NHSO2C(CH3)3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -C≡CH, -C≡C-CH3, -CH2-C≡CH, -Ph, -O-Ph, or -O-CH2-Ph,

[0042]

Chem.

[0043] represents; or, R 12 ~R14 , R 24 ~R 29 is substituted with a six-membered ring, R 12 and R 13 , R 13 and R 14 , R 24 and R 25 , R 25 and R 26 , R 27 and R 28 , R 28 and R 29 can be formed with the following five- or six-membered rings:

[0044] [ka]

[0045] R N are each independently -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2 -CHF2,-CH2-CF3,-CH2-CH2Cl,-CH2-CH2Br,-CH2-CH2I,-CH2-CH=CH2,-CH2-C≡CH,-CHO,-COCH 3,-COC2H5,-COC3H7,-COCH(CH3)2,-COC(CH3)3,-COOCH3,-COOC2H5,-COOC3H7,-COOCH(CH3)2, -COOC(CH3)3,

[0046] [ka]

[0047] represents; R N1 ~R N4are, independently of one another, -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH 2-CH2Cl, -CH2-CH2Br, -CH2-CH2I, -CH2-CH=CH2, -CH2-C≡CH, -CH2Ph, -CHO, -COCH3, -COC2H5, -COC3H7, -COCH(CH3)2, -COC(CH3)3, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, or -COOCH2Ph; L 1 ~L 8 are each independently a covalent bond, -CH2-, -CH(CH3)-, -CH(CH3)2-, -CO-, -SO-, -SO2-,

[0048] [ka]

[0049] represents; L 9 and L 10 are, independently of one another: a covalent bond, -CH2-, -CH2CH2-, -CO-, -CH2CO-, -COCH2-, -CO-CH=CH-, -COO-, -O-CO-, -CH2CO2-, -CO2CH2-, -CONH-, -NHCO-, -CH2CONH-, -CONHCH2-, -CSNH-, -NHCS-, -SO2-, -SO2CH2-, -SO2NH-, or -SO2NHCH2-; The present invention relates to compounds of general formula (I) and to diastereomers, enantiomers, mixtures of diastereomers, mixtures of enantiomers, racemates, prodrugs, solvates, hydrates, or pharma- ceutically acceptable salts of compounds of general formula (I).

[0050] Preferably, the compound of general formula (I):

[0051] [ka]

[0052] During the ceremony, n is an integer selected from 1, 2, or 3; W is

[0053] [ka]

[0054] represents; R 2 is -H,-R 1 ,-OR 1 ,-NH2,-NH(R 1 ),-NH(OR 1 ),-N(R 1 )(R 3 ) ; R 1 and R 3 are, independently of one another, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH(C2H5)2, -CH2CH(C2H5)2, -C(CH3)3, -CH2-C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -cyclo-C6H 11 ,-CH2-cyclo-C3H5,-CH2-cyclo-C4H7,-CH2-cyclo-C5H9,-CH2-cyclo-C6H 11 ,-Ph,-CH2-Ph,-CH2OCH3,-CH2OCH2CH3,-CH2CH2OCH3,-CH2CH2OCH2CH3,-CH2CO2CH3,-CH2CO2CH2CH3,-CH2CH2NHCH3,-CH2CH2N(CH3)2,-CH2S(O)2-(4-methyl-phenyl),

[0055] [ka]

[0056] represents; Z N E N -,E N -AS N1 -,E N -AS N2 -AS N1 -,E N -AS N3 -AS N2 -AS N1 -, or E N -AS N4 -AS N3 -AS N2 -AS N1 - stands for; Z c -E C ,-AS C1 -E C ,-AS C1 -AS C2 -E C ,-AS C1 -AS C2 -AS C3 -E C ,-AS C1 -AS C2 -AS C3 -AS C4 -E C ,-AS C1 -AS C2 -AS C3 -AS C4 -AS C5 -E C , or -AS C1 -AS C2 -AS C3 -AS C4 -AS C5 -AS C6 -E C , represents; AS N1 and A.S. N2 are independent of each other,

[0057] [ka]

[0058] [ka]

[0059] [ka]

[0060] selected from the group consisting of; AS C1 ~AS C5 and A.S. N3 are independent of each other,

[0061] [ka]

[0062] [ka]

[0063] [ka]

[0064] selected from the group consisting of; E C -OR 8 ,-NR 9 R 10 ,-NHSO2R 11 ,-O-L1-R 8 ,-O-L1-OR 8 ,-NH-L1-OR 8 ,-NH-L1-NR 9 R 10 ,-NHSO2-L1-R 11 ,

[0065] [ka]

[0066] and a C-terminal group selected from the group consisting of: E N is -H,-COCF3,-CH3,-C2H5,-C3H7,-CH(CH3)2,-CH(C2H5)2,-C4H9,-C5H 11 ,-C6H 13 ,-CH2-CH(CH3)2,-CH2-CH(C2H5)2,-CH(CH3)-C2H5,-C(CH3)3,-CH2-C(CH3)3,-cyclo-C3H5,-cyclo-C4H7,-cyclo-C5H9,-cyclo-C6H 11 ,-CH2-cyclo-C3H5,-CH2-cyclo-C4H7,-CH2-cyclo-C5H9,-CH2-cyclo-C6H 11 ,-Ph,-CH2-Ph,-CH2F,-CHF2,-CF3,-CH2Cl,-CH2Br,-CH2I,-CH2-CH2F,-CH2-CHF2,-CH2-CF3,-CH2-CH2Cl,-CH2-CH2Br ,-CH2-CH2I,-CH2-CH=CH2,-CH2-C≡CH,-CHO,-COCH3,-COC2H5,-COC3H7,-COCH(CH3)2,-COCH(C2H5)2,-COC4H9,-COC5H 11 ,-COC6H 13 ,-COCH2-CH(CH3)2,-COCH2-CH(C2H5)2,-COCH(CH3)-C2H5,-COC(CH3)3,-COCH2-C(CH3)3,-CO-cyclo-C3H5,-CO-cyclo-C4H7,-CO-cyclo-C5H9,-CO-cyclo-C6H 11 ,-COCH2-cyclo-C3H5,-COCH2-cyclo-C4H7,-COCH2-cyclo-C5H9,-COCH2-cyclo-C6H 11 ,-COPh,-COCH2-Ph,-COOCH3,-COOC2H5,-COOC3H7,-COOCH(CH3)2,-COOCH(C2H5)2,-COOC4H9,-COOC5H 11 ,-COOC6H 13,-COOCH2-CH(CH3)2,-COOCH2-CH(C2H5)2,-COOCH(CH3)-C2H5,-COOC(CH3)3,-COOCH2-C(CH3)3,-COO-cyclo-C3H5,-COO-cyclo-C4H7,-COO-cyclo-C5H9,-COO-cyclo-C6H 11 ,-COOCH2-cyclo-C3H5,-COOCH2-cyclo-C4H7,-COOCH2-cyclo-C5H9,-COOCH2-cyclo-C6H 11 ,-COOPh,-COOCH2-Ph,

[0067] [ka]

[0068] The N-terminal group is selected from the group consisting of: However, Z N E N and Z C E C Then E C -OR 8 Not and / or E N is not -H, R 4 , R 5 , and R 6 are, independently of one another, -H, -F, -Cl, -Br, -I, -CH3, -CH2CH3, -CH(CH3)2, -cyclo-C3H5, -OCH3, -OCH2CH3, -OCH(CH3)2, -O-cyclo-C3H5, -CF3, -CF2CF3, -OCHF2, -OCF3, -OCF2CF3, -OH, -CN, -CHO, -COCH3, -COCH2CH3, -COCH(CH3)2, -COCH2F, -COCH 2Cl,-COCF3,-COCCl3,-CO2H,-CO2Me,-CO2CH2CH3,-CO2CH(CH3)2,-OCOCH3,-OCOCH2CH3,-OCOCH(CH3)2,-OCOC F3,-OCOCCl3,-NH2,-NHCH3,-N(CH3)2,-NHCH2CH3,-NHCH(CH3)2,-N(CH2CH3)2,-NH-cyclo-C3H5,-NHCOCH3,-NHCO CF3, -NHSO2CH3, -NHSO2CF3, -SCH3, -SCH2CH3, -SCH(CH3)2, -S-cyclo-C3H5, -SOCH3, -SOCF3, -SO2CH3, -SO2CF3, -SO2NH2, -SO2NHCH3, -SO2N(CH3)2, -SO2NHCH2CH3, -SO2NHCH(CH3)2, -SO2NH-cyclo-C3H5, -SO2N(CH2CH3)2, or R 7 represents -H, -CH2CO2H, -CH2CH2CO2H, -CH2CH2CH2CO2H, -CH2CONH2, -CH2CH2CONH2, or -CH2NHCONH2; R 8 , R 9 , R 10 , and R 11 are, independently of each other: -H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH(C2H5)2, -CH2CH(CH3)2, -CH2-CH(C2H5)2, -C4H9, -C5H 11 ,-C6H 13 ,-CH(CH3)-C2H5,-C(CH3)3,-CH2-C(CH3)3,

[0069] [ka]

[0070] represents; R 12 ~R 29are, independently of one another, -H, -F, -Cl, -Br, -I, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2F, -CHF2, -CF3, -CH2C l,-CH2Br,-CH2I,-CH2-CH2F,-CH2-CHF2,-CH2-CF3,-CH2-CH2Cl,-CH2-CH2Br,-CH2-CH2I,-O CH3,-OC2H5,-OC3H7,-OCH(CH3)2,-OC(CH3)3,-OC4H9,-OCHF2,-OCF3,-OCH2CF3,-OC2F5,-OC H2OCH3, -O-cyclo-C3H5, -OCH2-cyclo-C3H5, -O-C2H4-cyclo-C3H5, -CHO, -COCH3, -COCF3, -COC2H5, -COC3H7, -COCH(CH3)2, -COC(CH3)3, -COOH, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -OOC-CH3, -OOC-CF3, -OOC-C2H5, -OOC-C3H7, -OOC-CH(CH3)2, -OOC-C(CH3)3, -NH2, -NHCH3, -NHC2H5, -NHC3H7, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC2H5, -NHCOC3H7, -NHCOCH(CH3)2, -NHCOC(CH3)3, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CONHCH(CH3)2, -CONH-cyclo-C3H5, -CONHC(CH3)3, -CON(CH3)2, -CON(C2H5)2, -CON(C3H7)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, -SO2NH2, -SO2NHCH3, -SO2NHC2H5, -SO2NHC3H7, -SO2NHCH(CH3)2, -SO2NH-cyclo-C3H5, -SO2NHC(CH3)3, -SO2N(CH3)2, -SO2N(C2H5)2, -SO2N(C3H7)2, -SO2N[CH(CH3)2]2, -SO2N[C(CH3)3]2, -NHSO2CH3, -NHSO2CF3, -NHSO2C2H5, -NHSO2C3H7, -NHSO2CH(CH3)2, -NHSO2C(CH3)3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -C≡CH, -C≡C-CH3, -CH2-C≡CH, -Ph, -O-Ph, and -O-CH2-Ph, represent, R Nare each independently -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, -CH2-CF3,-CH2-CH2Cl,-CH2-CH2Br,-CH2-CH2I,-CH2-CH=CH2,-CH2-C≡CH,-CHO,-COCH3,-COC2H5 ,-COC3H7,-COCH(CH3)2,-COC(CH3)3,-COOCH3,-COOC2H5,-COOC3H7,-COOCH(CH3)2,-COOC(CH3)3,

[0071] [ka]

[0072] represents; R N1 ~R N4 are, independently of each other, -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H 5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2Cl, -CH2-CH2Br, -CH2-CH2I, -CH2-CH=CH2, -CH2-C≡CH, -CH2Ph, -CHO, -COCH3, -COC2H5, -COC3H7, -COCH(CH3)2, -COC(CH3)3, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, or -COOCH2Ph; L 1 ~L 8 are each independently a covalent bond, -CH2-, -CH(CH3)-, -CH(CH3)2-, -CO-, -SO-, -SO2-,

[0073] [ka]

[0074] represents; L 9 and L 10 are, independently of one another: a covalent bond, -CH2-, -CH2CH2-, -CO-, -CH2CO-, -COCH2-, -CO-CH=CH-, -COO-, -O-CO-, -CH2CO2-, -CO2CH2-, -CONH-, -NHCO-, -CH2CONH-, -CONHCH2-, -CSNH-, -NHCS-, -SO2-, -SO2CH2-, -SO2NH-, or -SO2NHCH2-; Compounds of general formula (I), and diastereomers, enantiomers, mixtures of diastereomers, mixtures of enantiomers, racemates, prodrugs, solvates, hydrates, or pharma- ceutically acceptable salts of compounds of general formula (I).

[0075] Preferably, the compound of general formula (IV)

[0076] [ka]

[0077] and During the ceremony, n, R 1 , R 3 , Z C , and Z N has the meaning as defined herein. In formula (IV), R 3 is most preferably hydrogen.

[0078] Compounds E18a to E18k were prepared similarly to compound E18, and all compounds showed IC values ​​in the range of 100 nM to 500 nM, which is the same TG2 inhibition as E18. 50 Indicates the value.

[0079] [ka]

[0080] Compounds E78a-E78c were prepared similarly to compound E78, and all compounds exhibited IC values ​​in the range of 250 nM-550 nM, which is similar to E78 in TG2 inhibition. 50 Indicates the value.

[0081] [ka]

[0082] Compounds E40a-E40i were prepared similarly to compound E40, and all compounds showed IC values ​​in the range of 300 nM-700 nM, which is similar to E40 in TG2 inhibition. 50 Indicates the value.

[0083] [ka]

[0084] Preferred is a compound of general formula (V):

[0085] [ka]

[0086] During the ceremony, E N is -COCF3,-CH3,-C2H5,-C3H7,-CH(CH3)2,-CH(C2H5)2,-C4H9,-C5H 11 ,-C6H 13 ,-CH2-CH(CH3)2,-CH2-CH(C2H5)2,-CH(CH3)-C2H5,-C(CH3)3,-CH2-C(CH3)3,-cyclo-C3H5,-cyclo-C4H7,-cyclo-C5H9,-cyclo-C6H 11 ,-CH2-cyclo-C3H5,-CH2-cyclo-C 4H7, -CH2-cyclo-C5H9, -CH2-cyclo-C6H 11,-Ph,-CH2-Ph,-CH2F,-CHF2,-CF3,-CH2Cl,-CH2Br,-CH2I,-CH2-CH2F,-CH2-CHF2,-CH2-CF3,-CH2-CH2Cl,-CH2-CH2Br ,-CH2-CH2I,-CH2-CH=CH2,-CH2-C≡CH,-CHO,-COCH3,-COC2H5,-COC3H7,-COCH(CH3)2,-COCH(C2H5)2,-COC4H9,-COC5H 11 ,-COC6H 13 ,-COCH2-CH(CH3)2,-COCH2-CH(C2H5)2,-COCH(CH3)-C2H5,-COC(CH3)3,-COCH2-C(CH3)3,-CO-cyclo-C3H5,-CO-cyclo-C4H7,-CO-cyclo-C5H9,-CO-cyclo-C6H 11 ,-COCH2-cyclo-C3H5,-COCH2-cyclo-C4H7,-COCH2-cyclo-C5H9,-COCH2-cyclo-C6H 11 ,-COPh,-COCH2-Ph,-COOCH3,-COOC2H5,-COOC3H7,-COOCH(CH3)2,-COOCH(C2H5)2,-COOC4H9,-COOC5H 11 ,-COOC6H 13 ,-COOCH2-CH(CH3)2,-COOCH2-CH(C2H5)2,-COOCH(CH3)-C2H5,-COOC(CH3)3,-COOCH2-C(CH3)3,-COO-cyclo-C3H5,-COO-cyclo-C4H7,-COO-cyclo-C5H9,-COO-cyclo-C6H 11 ,-COOCH2-cyclo-C3H5,-COOCH2-cyclo-C4H7,-COOCH2-cyclo-C5H9,-COOCH2-cyclo-C6H 11 ,-COOPh,-COOCH2-Ph,

[0087] [ka]

[0088] The N-terminal group is selected from the group consisting of: and n, L9, R 2 , R24 ~R 28 , R N3 , R N4 , and Z C has the meaning defined in this application.

[0089] Preferably, E C is:-OH,-OCH3,-NH2,-NHCH3,-N(CH3)2,-NHCH2CH3,-N(CH2CH3)2,-NHCH2CH2CH3,-N(CH2CH2CH3)2,

[0090] [ka]

[0091] The C-terminus is selected from the group consisting of: Preferably, E N is -H,-COCF3,-CH3,-C2H5,-C3H7,-CH(CH3)2,-CH(C2H5)2,-C4H9,-C5H 11 ,-C6H 13 ,-CH2-CH(CH3)2,-CH2-CH(C2H5)2,-CH(CH3)-C2H5,-C(CH3)3,-CH2-C(CH3)3,-cyclo-C3H5,-cyclo-C4H7,-cyclo-C5H9,-cyclo-C6H 11 ,-CH2-cyclo-C3H5,-CH2-cyclo-C4H7,-CH2-cyclo-C5H9,-CH2-cyclo-C6H 11 ,-Ph,-CH2-Ph,-CH2F,-CHF2,-CF3,-CH2Cl,-CH2Br,-CH2I,-CH2-CH2F,-CH2-CHF2,-CH2-CF3,-CH2-CH2Cl,-CH2-CH2Br ,-CH2-CH2I,-CH2-CH=CH2,-CH2-C≡CH,-CHO,-COCH3,-COC2H5,-COC3H7,-COCH(CH3)2,-COCH(C2H5)2,-COC4H9,-COC5H 11 ,-COC6H 13,-COCH2-CH(CH3)2,-COCH2-CH(C2H5)2,-COCH(CH3)-C2H5,-COC(CH3)3,-COCH2-C(CH3)3,-CO-cyclo-C3H5,-CO-cyclo-C4H7,-CO-cyclo-C5H9,-CO-cyclo-C6H 11 ,-COCH2-cyclo-C3H5,-COCH2-cyclo-C4H7,-COCH2-cyclo-C5H9,-COCH2-cyclo-C6H 11 ,-COPh,-COCH2-Ph,-COOCH3,-COOC2H5,-COOC3H7,-COOCH(CH3)2,-COOCH(C2H5)2,-COOC4H9,-COOC5H 11 ,-COOC6H 13 ,-COOCH2-CH(CH3)2,-COOCH2-CH(C2H5)2,-COOCH(CH3)-C2H5,-CO OC(CH3)3, -COOCH2-C(CH3)3, -COO-cyclo-C3H5, -COO-cyclo-C4H7, -COO-cyclo-C5H9, -COO-cyclo-C6H 11 ,-COOCH2-cyclo-C3H5,-COOCH2-cyclo-C4H7,-COOCH2-cyclo-C5H9,-COOCH2-cyclo-C6H 11 ,-COOPh,-COOCH2-Ph,

[0092] [ka]

[0093] [ka]

[0094] [ka]

[0095] The N-terminal group is selected from the group consisting of: Preferably, R 4 , R 5 , and R 6are, independently of one another, -H, -F, -Cl, -Br, -I, -CH3, -CH2CH3, -CH(CH3)2, -cyclo-C3H5, -OCH3, -OCH2CH3, -OCH(CH3)2, -O-cyclo-C3H5, -CF3, -OCHF2, -OCF3, -OH, -CN, -CHO, -COCH3, -COCH2CH3, -COCH(CH3)2, -COCH2F, -COCH2Cl, -COCF3, -CO2Me, -CO2CH2CH3, -CO2CH(CH3)2, - It represents OCOCH3, -OCOCF3, -OCOCCl3, -NHCH3, -N(CH3)2, -NHCH2CH3, -NHCH(CH3)2, -NH-cyclo-C3H5, -NHCOCH3, -NHCOCF3, -NHSO2CH3, -NHSO2CF3, -SCH3, -SO2CH3, -SO2CF3, -SO2NH2, -SO2NHCH3, -SO2N(CH3)2, -SO2NHCH2CH3, -SO2NHCH(CH3)2, or -SO2NH-cyclo-C3H5.

[0096] Preferably, R 7 represents -H or -CH2CH2CO2H. The term "prodrug" refers to a compound according to one of the general formulae (I) to (XIV-2), wherein the compound contains at least one carboxylate group, which is modified in a known manner with residues generally known to those of skill in the art, such that the carboxylate group of the compound is released under physiological conditions, and / or the compound contains at least one modified hydroxyl group, which is modified in a known manner with residues generally known to those of skill in the art, such that the hydroxyl group of the compound of the invention is released under physiological conditions.

[0097] The specially selected substituent E at the C-terminus of the inventive compound according to the present invention C and the substituent E at the N-terminus N Because of this, the steric dimensions can be very tightly tuned so that the binding pocket of a desired target molecule can be accommodated with a high degree of fidelity.

[0098] Surprisingly, it has been found that the compounds of the present invention reversibly bind to transglutaminase and effectively inhibit transglutaminase. The electrophilic head portion can react with the highly nucleophilic thiol in the active site of transglutaminase. Thus, it has been found that potential non-specific reactions involving off-targets are reduced. It is expected that the compounds of the present invention as reversible transglutaminase inhibitors can be less toxic than irreversible transglutaminase inhibitors.

[0099] Preferably, AS N1 teeth:

[0100] [ka]

[0101] is an amino acid selected from the group consisting of Preferably, AS N2 teeth:

[0102] [ka]

[0103] [ka]

[0104] The amino acid is selected from the group consisting of: Preferably, AS C1 ~AS C4 are, independently of each other:

[0105] [ka]

[0106] [ka]

[0107] is selected from the group consisting of Preferably, AS C5 teeth:

[0108] [ka]

[0109] is selected from the group consisting of Preferably, AS C6 ~AS C8 are, independently of each other:

[0110] [ka]

[0111] is selected from the group consisting of: Compounds E34a-E34h were prepared similarly to compound E34, and all compounds showed IC values ​​in the range of 150 nM-580 nM, which is similar to TG2 inhibition as E34. 50 Indicates the value.

[0112] [ka]

[0113] [ka]

[0114] In the definitions of the following formulae (II-I) to (XIV-2), the term Z C1 ~Z C5 and Z N1 ~Z N3 is used, and the term Z C1 ~Z C5 and Z N1 ~Z N3 is defined as follows: Z C1 -E C ,-AS C2 -E C ,-ASC2 -AS C3 -E C ,-AS C2 -AS C3 -AS C4 -E C ,-AS C2 -AS C3 -AS C4 -AS C5 -E C ,-AS C2 -AS C3 -AS C4 -AS C5 -AS C6 -E C ,-AS C2 -AS C3 -AS C4 -AS C5 -AS C6 -AS C7 -E C , or -AS C2 -AS C3 -AS C4 -AS C5 -AS C6 -AS C7 -AS C8 -E C represents; Z C2 is -E C ,-AS C3 -E C ,-AS C3 -AS C4 -E C ,-AS C3 -AS C4 -AS C5 -E C ,-AS C3 -AS C4 -AS C5 -AS C6 -E C ,-AS C3 -AS C4 -AS C5 -AS C6 -AS C7 -E C , or -AS C3 -AS C4 -AS C5 -AS C6 -AS C7 -AS C8 -EC represents; Z C3 -E C ,-AS C4 -E C ,-AS C4 -AS C5 -E C ,-AS C4 -AS C5 -AS C6 -E C ,-AS C4 -AS C5 -AS C6 -AS C7 -E C , or -AS C4 -AS C5 -AS C6 -AS C7 -AS C8 -E C represents; Z C4 -E C ,-AS C5 -E C ,-AS C5 -AS C6 -E C ,-AS C5 -AS C6 -AS C7 -E C , or -AS C5 -AS C6 -AS C7 -AS C8 -E C represents; Z C5 -E C ,-AS C6 -E C ,-AS C6 -AS C7 -E C , or -AS C6 -AS C7 -AS C8 -E C represents; Z N1 E N -,E N -AS N2 -,E N -AS N3 -AS N2 , or E N -ASN4 -AS N3 -AS N2 - stands for; Z N2 E N -,E N -AS N3 -, or E N -AS N4 -AS N3 and Z N3 E N -, or E N -AS N4 - represents.

[0115] Preferably, the compound has the formula (II-1) to (II-5):

[0116] [ka]

[0117] and During the ceremony, Z C2 -E C ,-AS C3 -E C ,-AS C3 -AS C4 -E C ,-AS C3 -AS C4 -AS C5 -E C ,-AS C3 -AS C4 -AS C5 -AS C6 -E C ,-AS C3 -AS C4 -AS C5 -AS C6 -AS C7 -E C , or -AS C3 -AS C4 -AS C5 -AS C6 -AS C7 -AS C8 -E C represents; Preferably, ZC2 -E C ,-AS C3 -E C , or -AS C3 -AS C4 -E C and Z N E N -,E N -AS N1 -,E N -AS N2 -AS N1 -,E N -AS N3 -AS N2 -AS N1 -; or E N -AS N4 -AS N3 -AS N2 -AS N1 - stands for; Preferably, Z N E N -, or E N -AS N1 - and; E C , E N ,n,A.S. C3 ~AS C8 , A.S. N1 ~AS N4 and W have the same meaning as defined in formula (I).

[0118] More preferably, the formulae (III-1) to (III-5):

[0119] [ka]

[0120] A compound having any one of the following formulas: During the ceremony, Z C3 -E C ,-AS C4 -E C ,-AS C4 -AS C5 -E C ,-AS C4 -ASC5 -AS C6 -E C ,-AS C4 -AS C5 -AS C6 -AS C7 -E C , or -AS C4 -AS C5 -AS C6 -AS C7 -AS C8 -E C represents; Preferably, Z C3 -E C , or -AS C4 -E C and Z N E N -,E N -AS N1 -,E N -AS N2 -AS N1 -,E N -AS N3 -AS N2 -AS N1 -; or E N -AS N4 -AS N3 -AS N2 -AS N1 - stands for; Preferably, Z N E N -, or E N -AS N1 - and; E C , E N ,n,A.S. C4 ~AS C8 , A.S. N1 ~AS N4 and W has the same meaning as defined in formula (I); Preferably, Z C3 is OCH3, or NH2.

[0121] More preferably, the formula (III-6):

[0122] [ka]

[0123] is a compound having the formula During the ceremony, Z N1 E N -, or E N -AS N2 - stands for; Z C2 -E C ,-AS C3 -E C ,-AS C3 -AS C4 -E C ,-AS C3 -AS C4 -AS C5 -E C ,-AS C3 -AS C4 -AS C5 -AS C6 -E C ,-AS C3 -AS C4 -AS C5 -AS C6 -AS C7 -E C , or -AS C3 -AS C4 -AS C5 -AS C6 -AS C7 -AS C8 -E C represents; and AS C3 ~AS C8 , A.S. N2 , E C , E N , n, and W have the same meanings as defined in formula (I).

[0124] Even more preferably, the formulae (VI-1) to (VI-5):

[0125] [ka]

[0126] A compound having any one of the following formulas: During the ceremony, Z N E N -,E N -AS N1 - stands for; Z C3 -E C ,-AS C4 -E C ,-AS C4 -AS C5 -E C ,-AS C4 -AS C5 -AS C6 -E C represents; R 2 represents -H, -OH, -OCH3, -NH2, -NHCH3, or -N(CH3)2; and AS C4 ~AS C6 , A.S. N1 , E C , and E N has the same meaning as defined in formula (I), Preferably, Z N is acetyl or benzyloxycarbonyl, and / or Z C3 is OCH3 or -NH2.

[0127] Even more preferably, the formulae (VII-3) to (VII-4):

[0128] [ka]

[0129] A compound having any one of the following formulas: During the ceremony, Z N1 E N -,E N -AS N2 - stands for; Z C2 -E C ,-AS C3 -E C ,-AS C3 -AS C4 -EC ,-AS C3 -AS C4 -AS C5 -E C , or -AS C3 -AS C4 -AS C5 -AS C6 -E C represents; AS C3 ~AS C6 , A.S. N2 , E C , and E N has the same meaning as defined in formula (I), Preferably, Z N1 is acetyl, and / or Z C2 -AS C3 -AS C4 -AS C5 -E C It is.

[0130] In the above-defined formula (I), (IV), (V), and preferably in the formula (II-1), (III-1) and (VI-1), the proline skeleton can be replaced by a proline analog skeleton. It is clear that the corresponding compounds having the proline analog skeleton have the same or similar biological activity compared with the compounds having the proline skeleton. The proline skeleton can be replaced by the following proline analog skeleton:

[0131] [ka]

[0132] can be replaced by one of: In one embodiment, the present invention provides a compound of formula (VIII):

[0133] [ka]

[0134] With respect to the compound During the ceremony, ZC1 -E C ,-AS C2 -E C ,-AS C2 -AS C3 -E C ,-AS C2 -AS C3 -AS C4 -E C ,-AS C2 -AS C3 -AS C4 -AS C5 -E C ,-AS C2 -AS C3 -AS C4 -AS C5 -AS C6 -E C ,-AS C2 -AS C3 -AS C4 -AS C5 -AS C6 -AS C7 -E C , or -AS C2 -AS C3 -AS C4 -AS C5 -AS C6 -AS C7 -AS C8 -E C represents; and AS C2 ~AS C8 , E C , n, R 4 ~R 7 , W, and Z N has the same meaning as defined in formula (I).

[0135] More preferably, the compound of formula (IX)

[0136] [ka]

[0137] is a compound of During the ceremony, Z C1 -E Crepresents; and R 4 ~R 7 , W, and Z N has the same meaning as defined in formula (I).

[0138] Preferably, Z N E N -, E N -AS N1 represents; and E N is -H,-COCF3,-CH3,-C2H5,-C3H7,-CH(CH3)2,-CH(C2H5)2,-C4H9,-C5H 11 ,-C6H 13 ,-CH2-CH(CH3)2,-CH2-CH(C2H5)2,-CH(CH3)-C2H5,-C(CH3)3,-CH2-C(CH3)3,-cyclo-C3H5,-cyclo-C4H7,-cyclo-C5H9,-cyclo-C6H 11 ,-CH2-cyclo-C3H5,-CH2-cyclo-C4H7,-CH2-cyclo-C5H9,-CH2-cyclo-C6H 11 ,-Ph,-CH2-Ph,-CH2F,-CHF2,-CF3,-CH2Cl,-CH2Br,-CH2I,-CH2-CH2F,-CH2-CHF2,-CH2-CF3,-CH2-CH2Cl,-CH2-CH2Br ,-CH2-CH2I,-CH2-CH=CH2,-CH2-C≡CH,-CHO,-COCH3,-COC2H5,-COC3H7,-COCH(CH3)2,-COCH(C2H5)2,-COC4H9,-COC5H 11 ,-COC6H 13 ,-COCH2-CH(CH3)2,-COCH2-CH(C2H5)2,-COCH(CH3)-C2H5,-COC(CH3)3,-COCH2-C(CH3)3,-CO-cyclo-C3H5,-CO-cyclo-C4H7,-CO-cyclo-C5H9,-CO-cyclo-C6H 11 ,-COCH2-cyclo-C3H5,-COCH2-cyclo-C4H7,-COCH2-cyclo-C5H9,-COCH2-cyclo-C6H 11,-COPh,-COCH2-Ph,-COOCH3,-COOC2H5,-COOC3H7,-COOCH(CH3)2,-COOCH(C2H5)2,-COOC4H9,-COOC5H 11 ,-COOC6H 13 ,-COOCH2-CH(CH3)2,-COOCH2-CH(C2H5)2,-COOCH(CH3)-C2H5,-COOC(CH3)3,-COOCH2-C(CH3)3,-COO-cyclo-C3H5,-COO-cyclo-C4H7,-COO-cyclo-C5H9,-COO-cyclo-C6H 11 ,-COOCH2-cyclo-C3H5,-COOCH2-cyclo-C4H7,-COOCH2-cyclo-C5H9,-COOCH2-cyclo-C6H 11 ,-COOPh,-COOCH2-Ph,

[0139] [ka]

[0140] [ka]

[0141] [ka]

[0142] The N-terminal group is selected from the group consisting of: Preferably, R 4 , R 5 , and R 6 represent, independently of one another, -H, -F, -Cl, -Br, -I, -CH3, -CH2CH3, -CH(CH3)2, -cyclo-C3H5, -OCH3, -CF3, -OCF3, -OH, -CN, -COCH3, -CO2H, -CO2Me, -OCOCH3, -NH2, -NHCH3, -N(CH3)2, -NHCOCH3, -NHCOCF3, -NHSO2CH3, -NHSO2CF3, -SCH3, -SO2CH3, -SO2CF3, -SO2NH2, -SO2NHCH3, or -SO2N(CH3)2; Preferably, R 7 represents -H, or -CH2CH2CO2H, Preferably, Z C1 E C represents, and E C teeth: -OH,-OCH3,-OC2H5,-OC2H4-OCH3,-NH2,-NHCH3,-N(CH3)2,-N(C2H5)2,-NHCH2-OCH3,-NHCH2N(CH3)2,-NHSO2CH3,-NHSO2C2H5,

[0143] [ka]

[0144] The C-terminal group is selected from the group consisting of: Thus, one embodiment of the present invention relates to a compound of formula (IX), wherein W is

[0145] [ka]

[0146] represents Z C1 -E C , or -AS C2 -E C represents; Z N E N - or E N -AS N1 - represents; and R 4 , R 5 , and R 6represent, independently of one another, -H, -F, -Cl, -Br, -I, -CH3, -CH2CH3, -CH(CH3)2, -cyclo-C3H5, -OCH3, -CF3, -OCF3, -OH, -CN, -COCH3, -CO2H, -CO2Me, -OCOCH3, -NH2, -NHCH3, -N(CH3)2, -NHCOCH3, -NHCOCF3, -NHSO2CH3, -NHSO2CF3, -SCH3, -SO2CH3, -SO2CF3, -SO2NH2, -SO2NHCH3, or -SON2N(CH3)2.

[0147] Preferably, R 7 represents -H, or -CH2CH2CO2H, One embodiment of the present invention is represented by the following formulae (X-1) to (X-3);

[0148] [ka]

[0149] With respect to the compound During the ceremony, Z C2 -E C , or -AS C3 -E C represents; and AS C3 , E C , n, R 4 ~R 7 , Z N and W have the same meaning as defined in formula (I).

[0150] More preferably, the compound of formula (XI-3):

[0151] [ka]

[0152] is a compound of During the ceremony, Z C1 -E C represents; Z NE N - or E N -AS N1 -Represents; R 2 are -CH3, -CH2CH3, -CH(CH3)2, -cyclo-C3H5, -Ph, -OCH3, -OCH2CH3, -NH2, -NHCH3, -N(CH3)2, -NH-cyclo-C3H5, -NH-CH2Ph, -NC(CH3)3, -NH-C5H 11 , -NHCH2OCH3, -NHCH2CH2OCH3, -NHCH2COOCH3, -NH-OCH2-cyclo-C5H9; and R 4 , R 5 , and R 6 are, independently of each other, -H, -F, -Cl, -Br, -I, -CH3, -CH2CH3, -CH(CH3)2, -cyclo-C3H5, -OCH3, -CF3, -OCF3, -OH, -CN, -COCH3, -CO2H, -CO2Me, -OC It represents OCH3, -NH2, -NHCH3, -N(CH3)2, -NHCOCH3, -NHCOCF3, -NHSO2CH3, -NHSO2CF3, -SCH3, -SO2CH3, -SO2CF3, -SO2NH2, -SO2NHCH3, or -SO2N(CH3)2.

[0153] R 7 represents -H, or -CH2CH2CO2H; and AS N1 , E C , and E N has the same meaning as defined in formula (I). Even more preferably, the formula (XI-6)

[0154] [ka]

[0155] is a compound of During the ceremony, R 2are -CH3, -CH2CH3, -CH(CH3)2, -cyclo-C3H5, -Ph, -OCH3, -OCH2CH3, -NH2, -NHCH3, -N(CH3)2, -NH-cyclo-C3H5, -NH-CH2Ph, -NC(CH3)3, -NH-C5H 11 , -NHCH2OCH3, -NHCH2CH2OCH3, -NHCH2COOCH3, -NH-OCH2-cyclo-C5H9; and E C teeth,

[0156] [ka]

[0157] represents E N -H, -COCH3, -COCF3,

[0158] [ka]

[0159] [ka]

[0160] [ka]

[0161] and wherein the N-terminal group is selected from the group consisting of Preferably, the general formula (XII):

[0162] [ka]

[0163] During the ceremony, n is an integer selected from 1, 2, or 3; W is

[0164] [ka]

[0165] represents; R 2 is -H,-R 1 ,-OR 1 ,-NH2,-NH(R 1 ),-NH(OR 1 ),-N(R 1 )(R 3 ) ; R 1 and R 3 are, independently of one another, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH(C2H5)2, -CH2CH(C2H5)2, -C(CH3)3, -CH2-C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -cyclo-C6H 11 ,-CH2-cyclo-C3H5,-CH2-cyclo-C4H7,-CH2-cyclo-C5H9,-CH2-cyclo-C6H 11 ,-Ph,-CH2-Ph,-CH2OCH3,-CH2OCH2CH3,-CH2CH2OCH3,-CH2CH2OCH2CH3,-CH2CH2NHCH3,-CH2CH2N(CH3)2,-CH2S(O)2-(4-methyl-phenyl),

[0166] [ka]

[0167] represents; or -N(R 1 )(R 3 )teeth,

[0168] [ka]

[0169] Forming; E C Is:-NR 9 R 10 ,-NHSO2R 11 ,-O-L1-R 8 ,-O-L1-OR 8 ,-NH-L1-OR 8 ,-NH-L1-NR 9 R 10 ,-NHSO2-L1-R 11 ,

[0170] [ka]

[0171] is a C-terminal group selected from: E N is -H,-COCF3,-CH3,-C2H5,-C3H7,-CH(CH3)2,-CH(C2H5)2,-C4H9,-C5H 11 ,-C6H 13 ,-CH2-CH(CH3)2,-CH2-CH(C2H5)2,-CH(CH3)-C2H5,-C(CH3)3,-CH2-C(CH3)3,-cyclo-C3H5,-cyclo-C4H7,-cyclo-C5H9,-cyclo-C6H 11 ,-CH2-cyclo-C3H5,-CH2-cyclo-C4H7,-CH2-cyclo-C5H9,-CH2-cyclo-C6H 11 ,-Ph,-CH2-Ph,-CH2F,-CHF2,-CF3,-CH2Cl,-CH2Br,-CH2I,-CH2-CH2F,-CH2-CHF2,-CH2-CF3,-CH2-CH2Cl,-CH2-CH2Br ,-CH2-CH2I,-CH2-CH=CH2,-CH2-C≡CH,-CHO,-COCH3,-COC2H5,-COC3H7,-COCH(CH3)2,-COCH(C2H5)2,-COC4H9,-COC5H 11 ,-COC6H 13,-COCH2-CH(CH3)2,-COCH2-CH(C2H5)2,-COCH(CH3)-C2H5,-COC(CH3)3,-COCH2-C(CH3)3,-CO-cyclo-C3H5,-CO-cyclo-C4H7,-CO-cyclo-C5H9,-CO-cyclo-C6H 11 ,-COCH2-cyclo-C3H5,-COCH2-cyclo-C4H7,-COCH2-cyclo-C5H9,-COCH2-cyclo-C6H 11 ,-COPh,-COCH2-Ph,-COOCH3,-COOC2H5,-COOC3H7,-COOCH(CH3)2,-COOCH(C2H5)2,-COOC4H9,-COOC5H 11 ,-COOC6H 13 ,-COOCH2-CH(CH3)2,-COOCH2-CH(C2H5)2,-COOCH(CH3)-C2H5,-COOC(CH3)3,-COOCH2-C(CH3)3,-COO-cyclo-C3H5,-COO-cyclo-C4H7,-COO-cyclo-C5H9,-COO-cyclo-C6H 11 ,-COOCH2-cyclo-C3H5,-COOCH2-cyclo-C4H7,-COOCH2-cyclo-C5H9,-COOCH2-cyclo-C6H 11 ,-COOPh,-COOCH2-Ph,

[0172] [ka]

[0173] The N-terminal group is selected from the group consisting of: R 8 , R 9 , R 10 , and R 11 are, independently of each other: -H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH(C2H5)2, -CH2CH(CH3)2, -CH2-CH(C2H5)2, -C4H9, -C5H 11 ,-C6H 13 ,-CH(CH3)-C2H5,-C(CH3)3,-CH2-C(CH3)3,

[0174] [ka]

[0175] represents; R 12 ~R 29 are, independently of one another, -H, -F, -Cl, -Br, -I, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2F, -CHF2, -CF3, -CH2C l,-CH2Br,-CH2I,-CH2-CH2F,-CH2-CHF2,-CH2-CF3,-CH2-CH2Cl,-CH2-CH2Br,-CH2-CH2I,-O CH3,-OC2H5,-OC3H7,-OCH(CH3)2,-OC(CH3)3,-OC4H9,-OCHF2,-OCF3,-OCH2CF3,-OC2F5,-OC H2OCH3, -O-cyclo-C3H5, -OCH2-cyclo-C3H5, -O-C2H4-cyclo-C3H5, -CHO, -COCH3, -COCF3, -COC2H5, -COC3H7, -COCH(CH3)2, -COC(CH3)3, -COOH, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -OOC-CH3, -OOC-CF3, -OOC-C2H5, -OOC-C3H7, -OOC-CH(CH3)2, -OOC-C(CH3)3, -NH2, -NHCH3, -NHC2H5, -NHC3H7, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC2H5, -NHCOC3H7, -NHCOCH(CH3)2, -NHCOC(CH3)3, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CONHCH(CH3)2, -CONH-cyclo-C3H5, -CONHC(CH3)3, -CON(CH3)2, -CON(C2H5)2, -CON(C3H7)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, -SO2NH2, -SO2NHCH3, -SO2NHC2H5, -SO2NHC3H7, -SO2NHCH(CH3)2, -SO2NH-cyclo-C3H5, -SO2NHC(CH3)3, -SO2N(CH3)2, -SO2N(C2H5)2, -SO2N(C3H7)2, -SO2N[CH(CH3)2]2, -SO2N[C(CH3)3]2, -NHSO2CH3, -NHSO2CF3, -NHSO2C2H5, -NHSO2C3H7, -NHSO2CH(CH3)2, -NHSO2C(CH3)3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -C≡CH, -C≡C-CH3, -CH2-C≡CH, -Ph, -O-Ph, or -O-CH2-Ph,

[0176]

Chem.

[0177] represents; Or, R 12 ~R 14 , R 24 ~R 29 is substituted with a six-membered ring, R 12 and R 13 , R 13 and R 14 , R 24 and R 25 , R 25 and R 26 , R 27 and R 28 , R 28 and R 29 can be formed with the following five- or six-membered rings:

[0178] [ka]

[0179] R N are each independently -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH 2-CHF2,-CH2-CF3,-CH2-CH2Cl,-CH2-CH2Br,-CH2-CH2I,-CH2-CH=CH2,-CH2-C≡CH,-CHO,-COCH3,-COC 2H5,-COC3H7,-COCH(CH3)2,-COC(CH3)3,-COOCH3,-COOC2H5,-COOC3H7,-COOCH(CH3)2,-COOC(CH3)3,

[0180] [ka]

[0181] represents; R N1 ~R N4are, independently of one another, -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH 2-CH2Cl, -CH2-CH2Br, -CH2-CH2I, -CH2-CH=CH2, -CH2-C≡CH, -CH2Ph, -CHO, -COCH3, -COC2H5, -COC3H7, -COCH(CH3)2, -COC(CH3)3, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, or -COOCH2Ph; L 1 ~L 8 are each independently a covalent bond, -CH2-, -CH(CH3)-, -CH(CH3)2-, -CO-, -SO-, -SO2-,

[0182] [ka]

[0183] represents; L 9 and L 10 are, independently of one another: a covalent bond, -CH2-, -CH2CH2-, -CO-, -CH2CO-, -COCH2-, -CO-CH=CH-, -COO-, -O-CO-, -CH2CO2-, -CO2CH2-, -CONH-, -NHCO-, -CH2CONH-, -CONHCH2-, -CSNH-, -NHCS-, -SO2-, -SO2CH2-, -SO2NH-, or -SO2NHCH2-; Compounds of general formula (XII), and diastereomers, enantiomers, mixtures of diastereomers, mixtures of enantiomers, racemates, prodrugs, solvates, hydrates, or pharma- ceutically acceptable salts of compounds of general formula (XII).

[0184] Preferably, the general formula (XIII):

[0185] [ka]

[0186] During the ceremony, n is an integer selected from 1, 2, or 3; W is

[0187] [ka]

[0188] represents; R 2 is -H,-R 1 ,-OR 1 ,-NH2,-NH(R 1 ),-N(R 1 )(R 3 ), R 1 and R 3 are, independently of one another, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH(C2H5)2, -CH2CH(C2H5)2, -C(CH3)3, -CH2-C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -cyclo-C6H 11 ,-CH2-cyclo-C3H5,-CH2-cyclo-C4H7,-CH2-cyclo-C5H9,-CH2-cyclo-C6H 11 ,-Ph,-CH2-Ph,-CH2OCH3,-CH2OCH2CH3,-CH2CH2OCH3,-CH2CH2OCH2CH3,-CH2CO2CH3,-CH2CO2CH2CH3,-CH2CH2NHCH3,-CH2CH2N(CH3)2,-CH2S(O)2-(4-methyl-phenyl),

[0189] [ka]

[0190] represents; or -N(R 1 )(R 3 )teeth,

[0191] [ka]

[0192] Forming; R 19 ~R 20 are, independently of one another, -H, -F, -Cl, -Br, -I, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, - represent CH2-CF3, -CH2-CH2Cl, -CH2-CH2Br, -CH2-CH2I, -OCH3, -OC2H5, -OC3H7, -OCH(CH3)2, -OC(CH3)3, -OC4H9, -OCHF2, -OCF3, -OCH2CF3, -OC2F5, -OCH2OCH3, -O-cyclo-C3H5, -OCH2-cyclo-C3H5, -O-C2H4-cyclo-C3H5, -CHO, -COCH3, -COCF3, -COC2H5, -COC3H7, -COCH(CH3)2, -COC(CH3)3, -COOH, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -OOC-CH3, -OOC-CF3, -OOC-C2H5, -OOC-C3H7, -OOC-CH(CH3)2, -OOC-C(CH3)3, -NH2, -NHCH3, -NHC2H5, -NHC3H7, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC2H5, -NHCOC3H7, -NHCOCH(CH3)2, -NHCOC(CH3)3, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CONHCH(CH3)2, -CONH-cyclo-C3H5, -CONHC(CH3)3, -CON(CH3)2, -CON(C2H5)2, -CON(C3H7)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, -SO2NH2, -SO2NHCH3, -SO2NHC2H5, -SO2NHC3H7, -SO2NHCH(CH3)2, -SO2NH-cyclo-C3H5, -SO2NHC(CH3)3, -SO2N(CH3)2, -SO2N(C2H5)2, -SO2N(C3H7)2, -SO2N[CH(CH3)2]2, -SO2N[C(CH3)3]2, -NHSO2CH3, -NHSO2CF3, -NHSO2C2H5, -NHSO2C3H7, -NHSO2CH(CH3)2, -NHSO2C(CH3)3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -C≡CH, -C≡C-CH3, and -CH2-C≡CH; E Nare -H, -COCH3, -COCF3, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CH F2,-CH2-CF3,-CH2-CH2Cl,-CH2-CH2Br,-CH2-CH2I,-CH2-CH=CH2,-CH2-C≡CH,-CHO,-COCH3,-COC2H 5,-COC3H7,-COCH(CH3)2,-COC(CH3)3,-COOCH3,-COOC2H5,-COOC3H7,-COOCH(CH3)2,-COOC(CH3)3,

[0193] [ka]

[0194] The N-terminal group is selected from the group consisting of: R N are each independently -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, -CH2-CF3,-CH2-CH2Cl,-CH2-CH2Br,-CH2-CH2I,-CH2-CH=CH2,-CH2-C≡CH,-CHO,-COCH3,-COC2H5 ,-COC3H7,-COCH(CH3)2,-COC(CH3)3,-COOCH3,-COOC2H5,-COOC3H7,-COOCH(CH3)2,-COOC(CH3)3,

[0195] [ka]

[0196] represents; R 24~R 29are, independently of each other, -H, -F, -Cl, -Br, -I, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2Cl, -CH2-CH2Br, -CH2-CH2I, -OCH3, -OC2H5, -OC3H7, -OCH(CH3)2, -OC(CH3)3, -OC4H9, -OCHF2, -OCF3, -OCH2CF3, -OC2F5, -OCH2OCH3, -O-cyclo-C3H5, -OCH2-cyclo-C3H5, -O-C2H4-cyclo-C3H5, -CHO, -COCH3, -COCF3, -COC2H5, -COC3H7, -COCH(CH3)2, -COC(CH3)3, -COOH, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -OOC-CH3, -OOC-CF3, -OOC-C2H5, -OOC-C3H7, -OOC-CH(CH3)2, -OOC-C(CH3)3, -NH2, -NHCH3, -NHC2H5, -NHC3H7, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC2H5, -NHCOC3H7, -NHCOCH(CH3)2, -NHCOC(CH3)3, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CONHCH(CH3)2, -CONH-cyclo-C3H5, -CONHC(CH3)3, -CON(CH3)2, -CON(C2H5)2, -CON(C3H7)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, -SO2NH2, -SO2NHCH3, -SO2NHC2H5, -SO2NHC3H7, -SO2NHCH(CH3)2, -SO2NH-cyclo-C3H5, -SO2NHC(CH3)3, -SO2N(CH3)2, -SO2N(C2H5)2, -SO2N(C3H7)2, -SO2N[CH(CH3)2]2,-SO2N[C(CH3)3]2,-NHSO2CH3,-NHSO2CF3,-NHSO2C2H5,-NHSO2C3H7,-NHSO2CH(CH3)2,-NHSO2C(CH3)3,-C H=CH2,-CH2-CH=CH2,-C(CH3)=CH2,-CH=CH-CH3,-C≡CH,-C≡C-CH3,-CH2-C≡CH,-Ph,-O-Ph, or -O-CH2-Ph,

[0197] [ka]

[0198] represents; R N3 and R N4 are, independently of one another, -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH 2-CH2Cl, -CH2-CH2Br, -CH2-CH2I, -CH2-CH=CH2, -CH2-C≡CH, -CH2Ph, -CHO, -COCH3, -COC2H5, -COC3H7, -COCH(CH3)2, -COC(CH3)3, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, or -COOCH2Ph; L 9 and L 10 are, independently of one another: a covalent bond, -CH2-, -CH2CH2-, -CO-, -CH2CO-, -COCH2-, -CO-CH=CH-, -COO-, -O-CO-, -CH2CO2-, -CO2CH2-, -CONH-, -NHCO-, -CH2CONH-, -CONHCH2-, -CSNH-, -NHCS-, -SO2-, -SO2CH2-, -SO2NH-, or -SO2NHCH2-, Compounds of general formula (XIII), and diastereomers, enantiomers, mixtures of diastereomers, mixtures of enantiomers, racemates, prodrugs, solvates, hydrates, or pharma- ceutically acceptable salts of compounds of general formula (XIII).

[0199] More preferably, the following formulae (XIV-1) and (XIV-2) are used:

[0200] [ka]

[0201] During the ceremony, n, W, E N , and R 27 ~R 29 has the same meaning as defined above.

[0202] [ka]

[0203] During the ceremony, Z N E N - or E N -AS N1 -; preferably, AS N1 is a proline backbone; n, W, and R 27 ~R 29 has the same meaning as defined above.

[0204] In the present invention, the following amino acids containing chemical head moieties are particularly useful in generating the compounds of the invention:

[0205] [ka]

[0206] [ka]

[0207] According to the present invention: (S)-Methyl 2-((S)-1-((S)-2-((S)-2-acetamido-6-amino-5,6-dioxohexanamido)-3-methylbutanoyl)pyrrolidine-2-carboxamido)-4-methylpentanoate (E01), (S)-Methyl 2-((S)-1-((S)-2-((S)-6-amino-2-(benzyloxycarbonylamino)-5,6-dioxohexanamido)-3-methylbutanoyl)pyrrolidine-2-carboxamide)-4-methylpentanoate (E02), (S)-2-acetamido-N1-((S)-5-amino-1-((2S,3R)-1-((S)-1-amino-3-methyl-1-oxobutan-2-ylamino)-3-methyl-1-oxopentan-2-ylamino)-1,5-dioxopentan-2-yl)-5-oxohexanediamide (E03), (S)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-(1-methyl-1H-imidazole-5-carboxamide)-5-oxohexanediamide (E04), (S)-2-(2-bromo-4-methylthiazole-5-carboxamide)-N1-(1-(2-(isopentylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-5-oxohexanediamide (E05), (S)-5-acetamido-6-(4-(2-chlorophenyl)piperazin-1-yl)-2,6-dioxohexanamide (E06), (S)-1-acetyl-N-((S)-6-amino-1-(4-(3-methylpyridin-2-yl)piperazin-1-yl)-1,5,6-trioxohexan-2-yl)pyrrolidine-2-carboxamide (E07), (S)-1-((S)-2-((S)-1-((4R,7S,10S,13S,16S)-7-(4-amino-3,4-dioxobutyl)-10,13-dibutyl-4-(carboxymethyl)-18-methyl-2,5,8,11,14-pentaoxo-3,6,9,12,15-pentaazanonadecanecarbonyl)pyrrolidine-2-carboxamide)-3-(1H-indol-3-yl)propanoyl)pyrrolidine-2-carboxylic acid (E08), (S)-N1-((S)-1-((R)-2-((S)-2-((S)-2-amino-1-cyclohexyl-2-oxoethylamino)-1-cyclohexyl-2-oxoethylcarbamoyl)piperidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl (6-hydroxy-5-nitronicotinamide)-2-(6-hydroxy-5-nitronicotinamide)-5-oxohexanediamide (E09), 3-((2S)-6-amino-1-((2S)-3-cyclopropyl-1-((1R,2S)-2-((2S)-1-((2S)-2-(1-(2,6-dimethylphenoxy)propan-2-ylcarbamoyl)-2-methylpyrrolidin-1-yl)-1-oxopentan-2-ylcarbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-1-oxopropan-2-ylamino)-1,5,6-trioxohexan-2-ylcarbamoyl)-5-nitrobenzoic acid (E10) (S)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-5-oxo-2-(pyrazine-2-carboxamide)hexanediamide (E11), (S)-2-benzamido-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-5-oxohexanediamide (E12), (S)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-(2-methyl-5-nitrobenzamido)-5-oxohexanediamide (E13), (S)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-(4-methylthiazole-5-carboxamido)-5-oxohexanediamide (E14), (S)-2-(5-(dimethylamino)naphthalene-1-sulfonamide)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-5-oxohexanediamide (E15), (S)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide (E16), (S)-N1-ethyl-N6-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-5-(1-methyl-1H-imidazole-5-carboxamide)-2-oxohexanediamide (E17), (S)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxo-N6-pentylhexanediamide (E18), (S)-N1-cyclopropyl-N6-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-5-(1-methyl-1H-imidazole-5-carboxamide)-2-oxohexanediamide (E19), (S)-N1-benzyl-N6-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-5-(1-methyl-1H-imidazole-5-carboxamide)-2-oxohexanediamide (E20), (S)-N1-tert-butyl-N6-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-5-(1-methyl-1H-imidazole-5-carboxamide)-2-oxohexanediamide (E21), (S)-2-((S)-1-acetylpyrrolidine-2-carboxamide)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-5-oxo-N6-pentylhexanediamide (E22), (S)-2-benzamido-N6-cyclopropyl-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-5-oxohexanediamide (E23), (S)-Methyl 2-((S)-1-((S)-2-((S)-2-benzamido-6-( Cyclopropylamino)-5,6-dioxohexanamido)-3-methylbutanoyl)pyrrolidine-2-carboxamido)-4-methylpentanoate (E24), 4-((S)-1-((S)-1-((S)-2-((S)-2-((S)-2-amino-1-cyclohexyl-2-oxoethylamino)-1-cyclohexyl-2-oxoethylcarbamoyl)-4-oxopyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylamino)-6-(methylamino)-1,5,6-trioxohexan-2-ylcarbamoyl)nicotinic acid (E25), 4-((S)-1-((S)-1-((S)-2-((S)-2-((S)-2-amino-1-cyclohexyl-2-oxoethylamino)-1-cyclohexyl-2-oxoethylcarbamoyl)-4-oxopyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylamino)-6-(ethylamino)-1,5,6-trioxohexan-2-ylcarbamoyl)nicotinic acid (E26), 4-((S)-1-((S)-1-((S)-2-((S)-2-((S)-2-amino-1-cyclohexyl-2-oxoethylamino)-1-cyclohexyl-2-oxoethylcarbamoyl)-4-oxopyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylamino)-1,5,6-trioxo-6-(pentylamino)hexan-2-ylcarbamoyl)nicotinic acid (E27), 4-((S)-1-((S)-1-((S)-2-((S)-2-((S)-2-amino-1-cyclohexyl-2-oxoethylamino)-1-cyclohexyl-2-oxoethylcarbamoyl)-4-oxopyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl-amino)-6-(cyclopropylamino)-1,5,6-trioxohexan-2-ylcarbamoyl)nicotinic acid (E28), 4-((S)-1-((S)-1-((S)-2-((S)-2-((S)-2-amino-1-cyclohexyl-2-oxoethylamino)-1-cyclohexyl-2-oxoethylcarbamoyl)-4-oxopyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylamino)-6-(benzylamino)-1,5,6-trioxohexan-2-ylcarbamoyl)nicotinic acid (E29), 4-((S)-1-((S)-1-((S)-2-((S)-2-((S)-2-amino-1-cyclohexyl-2-oxoethylamino)-1-cyclohexyl-2-oxoethylcarbamoyl)-4-oxopyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylamino)-6-(tert-butylamino)-1,5,6-trioxohexan-2-ylcarbamoyl)nicotinic acid (E30), 4-((S)-6-amino-1-((S)-1-((S)-2-((S)-2-((S)-2-amino-1-cyclohexyl-2-oxoethylamino)-1-cyclohexyl-2-oxoethylcarbamoyl)-4-oxopyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylamino)-1,5,6-trioxohexan-2-ylcarbamoyl)nicotinic acid (E31), (S)-N1-((S)-1-((S)-2-((S)-2-((S)-2-amino-1-cyclohexyl-2-oxoethylamino)-1-cyclohexyl-2-oxoethylcarbamoyl)-4-oxopyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N6-cyclopropyl-2-(2-methylthiazole-4-carboxamide)-5-oxohexanediamide (E32), (S)-N1-((S)-1-((2R,3S)-1-((S)-1-((S)-2-((S)-1-((S)-2-carbamoylpyrrolidin-1-yl)-3-(1H-indol-3-yl)-1-oxopropan-2-ylcarbamoyl)pyrrolidin-1-yl)-4-methyl-1-oxopentan-2-ylamino)-3-methyl-1-oxopentan-2-ylamino)-4-methyl-1-oxopentan-2-yl)-N6-cyclopropyl-2-(2-methylthiazole-4-carboxamide)-5-oxohexanediamide (E33), (S)-2-(2-acetamidoacetamido)-N1-((S)-1-((2S,3S )-1-((S)-1-((S)-2-((S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-ylcarbamoyl)pyrrolidin-1-yl)-4-methyl-1-oxopentan-2-ylamino)-3-methyl-1-oxopentan-2-ylamino)-1-oxohexan-2-yl)-N6-methyl-5-oxohexanediamide (E34), (S)-2-(2-((S)-1-acetylpyrrolidine-2-carboxamide)acetamide)-N1-((S)-1-((2S,3S)-1-((S)-1-((S)-2-((S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-ylcarbamoyl)pyrrolidin-1-yl)-4-methyl-1-oxopentan-2-ylamino)-3-methyl-1-oxopentan-2-ylamino)-1-oxohexan-2-yl)-N6-methyl-5-oxohexanediamide (E35), (S)-2-(2-((S)-1-(2-acetamidoacetyl)pyrrolidine-2-carboxamido)acetamido)-N1-((S)-1-((2S,3S)-1-((S)-1-((S)-2-((S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-ylcarbamoyl)pyrrolidin-1-yl)-4-methyl-1-oxopentan-2-ylamino)-3-methyl-1-oxopentan-2-ylamino)-1-oxohexan-2-yl)-N6-methyl-5-oxohexanediamide (E36), (S)-2-(2-((S)-1-(2-((S)-2-acetamido-4-methylpentanamido)acetyl)pyrrolidine-2-carboxamido)acetamido)-N1-((S)-1-((2S,3S)-1-((S)-1-((S)-2-((S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-ylcarbamoyl)pyrrolidin-1-yl)-4-methyl-1-oxopentan-2-ylamino)-3-methyl-1-oxopentan-2-ylamino)-1-oxohexan-2-yl)-N6-methyl-5-oxohexanediamide (E37), (S)-Methyl 2-(6-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-5-(1-methyl-1H-imidazole-5-carboxamido)-2,6-dioxohexanamide) acetate (E38), (S)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-(methoxymethyl)-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide (E39), (S)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxo-N6-(thiazol-5-yl)hexanediamide (E40), (S)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-(1-methyl-1H-imidazole-5-carboxamide)-5-oxo-N6-(tosylmethyl)hexanediamide (E41), (S)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-4-methyl-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide (E42), (S)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-5-methyl-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide (E43), (S)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-6-methyl (ethyl-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-2-(1-methyl-1H-imidazole-5-carboxamide)-5-oxohexanediamide (E44), (S)-N1-(5-chloro-1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-2-(1-methyl-1H-imidazole-5-carboxamide)-5-oxohexanediamide (E45), (S)-N1-(5-bromo-1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-2-(1-methyl-1H-imidazole-5-carboxamide)-5-oxohexanediamide (E46), (S)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)-N6-methyl-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide (E47), (S)-1-Methyl-N-(6-(methylamino)-1,5,6-trioxo-1-(4-(phenylsulfonyl)piperazin-1-yl)hexan-2-yl)-1H-imidazole-5-carboxamide (E48), (S)-N1-(1-benzylpiperidin-4-yl)-N6-methyl-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide (E49), (S)-N1-(1-(2-(diethylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide (E50), (S)-N1-methyl-5-(1-methyl-1H-imidazole-5-carboxamido)-N6-(1-(2-(methylsulfonamido)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-oxohexanediamide (E51), (S)-Ethyl 2-(3-(2-(1-methyl-1H-imidazole-5-carboxamido)-6-(methylamino)-5,6-dioxohexanamido)-2-oxopyridin-1(2H)-yl)acetate (E52), (S)-2-Methoxyethyl 2-(3-(2-(1-methyl-1H-imidazole-5-carboxamido)-6-(methylamino)-5,6-dioxohexanamido)-2-oxopyridin-1(2H)-yl)acetate (E53), (S)-N1-(1-(2-(methoxymethylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide (E54), (S)-N1-(1-(2-((dimethylamino)methylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide (E55), (S)-N1-(1-(2-(ethylsulfonamido)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide (E56), (S)-Benzyl 1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(methylamino)-1,5,6-trioxohexan-2-ylcarbamate (E57), (S)-tert-Butyl 1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(methylamino)-1,5,6-trioxohexan-2-ylcarbamate (E58), (S)-4-(1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2 -oxo-1,2-dihydropyridin-3-ylamino)-6-(methylamino)-1,5,6-trioxohexan-2-ylamino)-4-oxobutanoic acid (E59), (S)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-5-oxo-2-((S)-4-oxopyrrolidine-2-carboxamide)hexanediamide (E60), (S)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-(furan-3-carboxamido)-N6-methyl-5-oxohexanediamide (E61), (S)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-2-(oxazole-5-carboxamido)-5-oxohexanediamide (E62), (S)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-2-(1-methylpiperidine-4-carboxamido)-5-oxohexanediamide (E63), (S)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-5-oxo-2-(pyrimidine-5-carboxamido)hexanediamide (E64), (S)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-5-oxo-2-(quinoxaline-2-carboxamide)hexanediamide (E65), (S)-2-(2,4-dimethylthiazole-5-sulfonamide)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-5-oxohexanediamide (E66), (S)-2-(6-chloroimidazo[2,1-b]thiazole-5-sulfonamide)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-5-oxohexanediamide (E67), (S)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-2-(1-methyl-1H-imidazole-2-sulfonamido)-5-oxohexanediamide (E68), (S)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-5-oxo-2-(3-phenylureido)hexanediamide (E69), (S)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-5-oxo-2-(3-phenylthioureido)hexanediamide (E70), (S)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N7-methyl-2-(1-methyl-1H-imidazole-5-carboxamide)-6-oxoheptanediamide (E71), (S)-N1-methyl-6-(1-methyl-1H-imidazole-5-carboxamide)-N7-(4-(4-methylpiperazin-1-ylsulfonyl)phenyl)-2-oxoheptanediamide (E72), (S)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N8-methyl-2-(1-methyl-1H-imidazole-5-carboxamide)-7-oxooctanediamide (E73), (S)-N1-(1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-1,5,6-trioxoheptan-2-yl)-1-methyl-1H-imidazole-5-carboxamide (E74), (S)-N-(6-cyclopropyl-1-(1-(2-(2-ethylbutylamino)-2 -oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-1,5,6-trioxohexan-2-yl)-1-methyl-1H-imidazole-5-carboxamide (E75), (S)-N-(1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-1,5,6-trioxo-6-phenylhexan-2-yl)-1-methyl-1H-imidazole-5-carboxamide (E76), (S)-Methyl 6-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-5-(1-methyl-1H-imidazole-5-carboxamido)-2,6-dioxohexanoate (E77), (S)-2-Methoxyethyl 6-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-5-(1-methyl-1H-imidazole-5-carboxamido)-2,6-dioxohexanoate (E78), (S)-N1-(cyclopentylmethoxy)-N6-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-5-(1-methyl-1H-imidazole-5-carboxamide)-2-oxohexanediamide (E79), (S)-N-(1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-8-methyl-1,5,6-trioxononan-2-yl)-1-methyl-1H-imidazole-5-carboxamide (E80), (S)-N-(1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazol-4-yl)-1,5,6-trioxohexan-2-yl)-1-methyl-1H-imidazole-5-carboxamide (E81), (2S)-N1-((S)-1-((S)1-((S)-3-carbamoyl-3,4-dihydroisoquinolin-2(1H)-yl)-3-(4-hydroxyphenyl)-1-oxopropan-2-ylamino)-3-(1H-imidazol-4-yl)-1-oxopropan-2-yl)-2-(2-(5,5-dimethyl-2-oxotetrahydrofuran-3-yl)acetamide)-N6-methyl-5-oxohexanediamide (E82), (S)-N1-(3-((S)-3-(biphenyl-4-yl)-1-((2S,4R)-2-carbamoyl-4-phenoxypyrrolidin-1-yl)-1-oxopropan-2-ylcarbamoyl)phenyl)-2-(2-(1,3-dimethyl-1H-pyrazol-5-yl)acetamide)-N6-methyl-5-oxohexanediamide (E83), and Isopropyl (S)-1-((S)-1-(1-((2S,4R)-2-carbamoyl-4-hydroxypyrrolidin-1-yl)-2-methyl-1-oxopropan-2-ylamino)-5-guanidino-1-oxopentan-2-ylamino)-6-(methylamino)-1,5,6-trioxohexan-2-ylcarbamate (E84) Particularly preferred are compounds selected from the group consisting of:

[0208] A further aspect of the present invention relates to the production of compounds of general formula (I). As shown in Scheme 1, to produce compounds of formula (I), a method for producing compounds of the invention comprises: Step (0): providing a protected amino acid having a chemical head moiety; Step 1A: Carboxyl Protecting Group PG 3 deprotecting the Step 2A: C-Terminal Building Block E C -AG 1 carrying out a coupling reaction with; Step 3A: Two amino protecting groups PG 1 and P.G. 2 deprotecting the Step 4A: N-Terminal Building Block E N -AG 2 carrying out a coupling reaction with; Includes.

[0209] Optionally, step 1A' is performed between steps 1A and 2A. Step 1A': (a) The resulting compound from step 1A and the corresponding C-terminal amino acid building block H2AS Ci -OPG 4 carrying out a coupling reaction with; (b) Protecting group PG 4 deprotecting the (c) repeating steps (a) and (b) i times, where i is 1 to 8.

[0210] In another option, step 3A' is performed between steps 3A and 4A. Step 3A': (d) Synthesis of the resulting compound from step 3A and the corresponding N-terminal amino acid building block (PG 5 )HAS Nj carrying out a coupling reaction with -OH; (e) Protecting group PG 5 deprotecting the (f) repeating steps (a) and (b) j times, where j is 1 to 4.

[0211] Thus, to produce compounds of formula (I), the following process is preferred: 1. Step (0) - Step 1A - Step 1A' - Step 2A - Step 3A - Step 4A: Step (0): providing a protected amino acid having a chemical head moiety; Step 1A: Carboxyl Protecting Group PG 3 deprotecting the Step 1A': (a) The resulting compound from step 1A and the corresponding C-terminal amino acid building block H2AS Ci -OPG 4 carrying out a coupling reaction with; (b) Protecting group PG 4 deprotecting the (c) repeating steps (a) and (b) i times, where i is 1 to 8. Step 2A: C-Terminal Building Block E C -AG 1 carrying out a coupling reaction with; Step 3A: Two amino protecting groups PG 1 and P.G. 2 deprotecting the Step 4A: N-Terminal Building Block E N -AG 2 and carrying out a coupling reaction. 2. To produce a compound of formula (I): STEP (0) - STEP 1A - STEP 2A - STEP 3A - STEP 3A' - STEP 4A: Step (0): providing a protected amino acid having a chemical head moiety; Step 1A: Carboxyl Protecting Group PG 3 deprotecting the Step 2A: C-Terminal Building Block E C -AG 1 carrying out a coupling reaction with; Step 3A: Two amino protecting groups PG 1 and P.G. 2 deprotecting the Step 3A': (d) Synthesis of the resulting compound from step 3A and the corresponding N-terminal amino acid building block (PG 5 )HAS Nj carrying out a coupling reaction with -OH; (e) Protecting group PG 5 deprotecting the (f) repeating steps (a) and (b) j times, where j is 1 to 4; Step 4A: N-Terminal Building Block E N -AG 2 and carrying out a coupling reaction. 3. To produce a compound of formula (I): STEP (0) - STEP 1A - STEP 1A' - STEP 2A - STEP 3A - STEP 3A' - STEP 4A: Step (0): providing a protected amino acid having a chemical head moiety; Step 1A: Carboxyl Protecting Group PG 3 deprotecting the Step 1A': (a) The resulting compound from step 1A and the corresponding C-terminal amino acid building block H2AS Ci -OPG 4 carrying out a coupling reaction with; (b) Protecting group PG 4 deprotecting the (c) repeating steps (a) and (b) i times, where i is 1 to 8. Step 2A: C-Terminal Building Block E C -AG 1 carrying out a coupling reaction with; Step 3A: Two amino protecting groups PG 1 and P.G. 2 deprotecting the Step 3A': (d) Synthesis of the resulting compound from step 3A and the corresponding N-terminal amino acid building block (PG 5 )HAS Nj carrying out a coupling reaction with -OH; (e) Protecting group PG 5 deprotecting the (f) repeating steps (a) and (b) j times, where j is 1 to 4; Step 4A: N-Terminal Building Block E N -AG 2 and carrying out a coupling reaction.

[0212] [ka]

[0213] [ka]

[0214] As shown in Scheme 2, an alternative method for producing compounds of the invention to produce compounds of formula (I) is to: Step (0): providing a protected amino acid having a chemical head moiety; Step 1B: Two amino protecting groups PG 1 and P.G. 2 deprotecting the Step 2B: N-Terminal Building Block E N -AG 2 carrying out a coupling reaction with; Step 3B: Carboxyl Protecting Group PG 3 deprotecting the Step 4B: C-Terminal Building Block E C -AG1 carrying out a coupling reaction with; Includes.

[0215] Optionally, step 1B' is performed between steps 1B and 2B. Step 1B': (a') The resulting compound from step 1A and the corresponding N-terminal amino acid building block (PG 5 )HAS Nj carrying out a coupling reaction with -OH; (b') Protecting group PG 5 deprotecting the (c') repeating steps (a) and (b) j times, where j is 1 to 4.

[0216] In another option, step 3B' is performed between steps 3B and 4B. Step 3B': (d') The resulting compound of step 3B and the corresponding C-terminal amino acid building block H2AS Ci -OPG 4 carrying out a coupling reaction with; (e') Protecting group PG 4 deprotecting the (f') repeating steps (a) and (b) i times, where i is 1 to 8.

[0217] Thus, the following methods are available for producing compounds of formula (I): 1. Step (0) - Step 1B - Step 1B' - Step 2B - Step 3B - Step 4B: Step (0): providing a protected amino acid having a chemical head moiety; Step 1B: Two amino protecting groups PG 1 and P.G. 2 deprotecting the Step 1B': (a') The resulting compound from step 1A and the corresponding N-terminal amino acid building block (PG 5 )HAS Njcarrying out a coupling reaction with -OH; (b') Protecting group PG 5 deprotecting the (c') repeating steps (a) and (b) j times, where j is 1 to 4. Step 2B: N-Terminal Building Block E N -AG 2 carrying out a coupling reaction with; Step 3B: Carboxyl Protecting Group PG 3 deprotecting the Step 4B: C-Terminal Building Block E C -AG 1 and carrying out a coupling reaction. 2. To produce a compound of formula (I): STEP (0) - STEP 1A - STEP 2A - STEP 3A - STEP 3A' - STEP 4A: Step (0): providing a protected amino acid having a chemical head moiety; Step 1B: Two amino protecting groups PG 1 and P.G. 2 deprotecting the Step 2B: N-Terminal Building Block E N -AG 2 carrying out a coupling reaction with; Step 3B: Carboxyl Protecting Group PG 3 deprotecting the Step 3B': (d') The resulting compound of step 3B and the corresponding C-terminal amino acid building block H2AS Ci -OPG 4 carrying out a coupling reaction with; (e') Protecting group PG 4 deprotecting the (f') repeating steps (a) and (b) i times, where i is 1 to 8; Step 4B: C-Terminal Building Block E C -AG 1 and carrying out a coupling reaction. 3. To produce a compound of formula (I): STEP (0) - STEP 1A - STEP 1A' - STEP 2A - STEP 3A - STEP 3A' - STEP 4A: Step (0): providing a protected amino acid having a chemical head moiety; Step 1B: Two amino protecting groups PG 1 and P.G. 2 deprotecting the Step 1B': (a') The resulting compound of step 1A and the corresponding N-terminal amino acid building block (P G 5 )HAS Nj carrying out a coupling reaction with -OH; (b') Protecting group PG 5 deprotecting the (c') repeating steps (a) and (b) j times, where j is 1 to 4. Step 2B: N-Terminal Building Block E N -AG 2 carrying out a coupling reaction with; Step 3B: Carboxyl Protecting Group PG 3 deprotecting the Step 3B': (d') The resulting compound of step 3B and the corresponding C-terminal amino acid building block H2AS Ci -OPG 4 carrying out a coupling reaction with; (e') Protecting group PG 4 deprotecting the (f') repeating steps (a) and (b) i times, where i is 1 to 8; Step 4B: C-Terminal Building Block E C -AG 1 and carrying out a coupling reaction.

[0218] In this application, AS Ci AS C1 , A.S. C2 , A.S. C3 , A.S. C4 , A.S. C5 , A.S. C6 , A.S. C7, and A.S. C8 AS stands for one of the following. Nj AS N1 , A.S. N2 , A.S. N3 , and A.S. N4 It represents one of the H2AS. Ci -OPG 4 AS Ci (AS C1 ~AS C8 (one of the) backbone, and unprotected free amino (H2N-) groups, and PG 4 (PG 5 )HAS Nj -OH is AS Nj (AS N1 ~AS N4 (one of the) skeleton, and PG 5 Group [(PG 5 )HN-] and an unprotected free carboxylic acid (-COH).

[0219] [ka]

[0220] As shown in Scheme 3, an alternative method for producing compounds of the invention to produce compounds of formula (I) is to: Step (0): providing a protected amino acid having a chemical head moiety; Step 1C: Amino Protecting Group PG 2 and a carboxyl protecting group, PG 3 Step 2C: Deprotecting C-Terminal Building Block E C -H and carry out a coupling reaction; Step 3C: Amino Protecting Group PG 1 deprotecting the Step 4C: N-Terminal Building Block E N -AG 1 carrying out a coupling reaction with; Includes.

[0221] Optionally, step 1C' is performed between steps 1C and 2C. Step 1C': (d) The resulting compound of step 1C and the corresponding C-terminal amino acid building block H2AS Ci -OPG 4 carrying out a coupling reaction with; (e) Protecting group PG 4 deprotecting the (c) repeating steps (a) and (b) i times, where i is 1 to 8.

[0222] In another option, step 3C' is performed between steps 3C and 4C. Step 3C': (d) Synthesis of the resulting compound from step 3C and the corresponding N-terminal amino acid building block (PG 5 )HAS Nj carrying out a coupling reaction with -OH; (e) Protecting group PG 5 deprotecting the (f) repeating steps (a) and (b) j times, where j is 1 to 4.

[0223] Thus, to produce compounds of formula (I), the following process is preferred: 1. Step (0) - Step 1C - Step 1C' - Step 2C - Step 3C - Step 4C: Step (0): providing a protected amino acid having a chemical head moiety; Step 1C: Amino Protecting Group PG 2 and a carboxyl protecting group, PG 3 Step 1C': (d) The resulting compound of step 1C and the corresponding C-terminal amino acid building block H2AS Ci -OPG 4 carrying out a coupling reaction with; (e) Protecting group PG 4 deprotecting the (f) repeating steps (a) and (b) i times, where i is 1 to 8. Step 2C: C-Terminal Building Block E C -H and carry out a coupling reaction; Step 3C: Amino Protecting Group PG 1 deprotecting the Step 4C: N-Terminal Building Block E N -AG 1 and carrying out a coupling reaction. 2. To produce a compound of formula (I): STEP(0)-STEP 1C-STEP 2C-STEP 3C-STEP 3C'-STEP 4C: Step (0): providing a protected amino acid having a chemical head moiety; Step 1C: Amino Protecting Group PG 2 and a carboxyl protecting group, PG 3 Step 2C: Deprotecting C-Terminal Building Block E C -H and carry out a coupling reaction; Step 3C: Amino Protecting Group PG 1 deprotecting the Step 3C': (d) Synthesis of the resulting compound from step 3C and the corresponding N-terminal amino acid building block (PG 5 )HAS Nj carrying out a coupling reaction with -OH; (e) Protecting group PG 5 deprotecting the (f) repeating steps (a) and (b) j times, where j is 1 to 4; Step 4C: N-Terminal Building Block E N -AG 1 and carrying out a coupling reaction. 3. To produce a compound of formula (I): STEP (0) - STEP 1C - STEP 1C' - STEP 2C - STEP 3C - STEP 3C' - STEP 4C: Step (0): providing a protected amino acid having a chemical head moiety; Step 1C: Amino Protecting Group PG 2 and a carboxyl protecting group, PG 3Step 1C': (d) The resulting compound of step 1C and the corresponding C-terminal amino acid building block H2AS Ci -OPG 4 carrying out a coupling reaction with; (e) Protecting group PG 4 deprotecting the (f) repeating steps (a) and (b) i times, where i is 1 to 8. Step 2C: C-Terminal Building Block E C -H and carry out a coupling reaction; Step 3C: Amino Protecting Group PG 1 deprotecting the Step 3C': (d) Synthesis of the resulting compound from step 3C and the corresponding N-terminal amino acid building block (PG 5 )HAS Nj carrying out a coupling reaction with -OH; (e) Protecting group PG 5 deprotecting the (f) repeating steps (a) and (b) j times, where j is 1 to 4; Step 4C: N-Terminal Building Block E N -AG 1 and carrying out a coupling reaction.

[0224] [ka]

[0225] As shown in Scheme 4, an alternative method for producing the compounds of the present invention includes the steps of: Step (0): reacting a protected amino acid (1C') having a chemical head moiety precursor (W') with a 4D-1, 4D-2, 4D-3, or 4D-4 as a compound of formula (I). To provide; Step 1D: To obtain compound 1D-1 or 1D-2, a protected amino acid (1C') is reacted with a C-terminal peptide building block (CP) or a C-terminal building block (E C-H); Step 2D: To obtain compound 2D-1 or 2D-2, an amino protecting group PG 1 deprotecting the Step 3D: To obtain compound 3D-1, 3D-2, 3D-3, or 3D-4, compound 2D-1 or 2D-2 is reacted with an N-terminal peptide building block (NP) or an N-terminal building block (E N -H); Step 4D: Converting the chemical tip moiety precursor (W') of compound 3D-1, 3D-2, 3D-3, or 3D-4 to a chemical precursor (W). Includes.

[0226] In this application, AS Ci AS C1 , A.S. C2 , A.S. C3 , A.S. C4 , A.S. C5 , A.S. C6 , A.S. C7 , and A.S. C8 AS stands for one of the following. Nj AS N1 , A.S. N2 , A.S. N3 , and A.S. N4 It represents one of the H2AS. Ci -OPG 4 AS Ci (AS C1 ~AS C8 (one of the) backbone, and unprotected free amino (H2N-) groups, and PG 4 (PG 5 )HAS Nj -OH is AS Nj (AS N1 ~AS N4 (one of the) skeleton, and PG 5 Group [(PG 5 )HN-] and an unprotected free carboxylic acid (-COH).

[0227] In an alternative route, first all protecting groups PG 1 and P.G. 2 and P.G. 3 is simultaneously removed, and the protecting group PG 1 is selectively reintroduced. The term "protecting group" as used herein refers to protecting groups commonly used in organic synthesis, preferably protecting groups for amino and carboxyl groups. 1 , P.G. 2 , and P.G. 5 is preferably a suitable protecting group for an amino group. 3 , and P.G. 4 is preferably a suitable protecting group for a carboxyl group. 1 , P.G. 2 , and P.G. 5 may be selected from the group consisting of or including an acetyl group, a benzoyl group, a benzyloxycarbonyl (Cbz) group, a tert-butylcarbonyl group, a tert-butyloxycarbonyl (Boc) group, and a fluorenylmethylenoxy (Fmoc) group. 3 , and P.G. 4 may be selected from the group consisting of or including a methoxy group, an ethoxy group, an isobutoxy group, a tert-butoxy group, a benzyloxy group, preferably a tert-butoxy group.

[0228] The term "activating group" as used herein relates to activating groups commonly used in peptide synthesis, preferably for the activation of carboxylic acids and for facilitating coupling reactions with amino groups of intermediate compounds. 1 is an activating group of the carboxylic acid in an amino acid. This group may be introduced in a separate reaction or in situ reaction. Preferably, AG 1 are halides such as -F, -Br, -Cl, -I, anhydride groups such as -OCOCH3, N-oxy-benzotriazole groups, and N-oxy-succinimide groups. , or the group comprising. Preferably, AG1 is introduced in situ, which is well known in peptide chemistry. Some of the following coupling reagents can be used to introduce the activating group AG1: BOP, PyBOP, AOP, PyAOP, TBTU, EEDQ, polyphosphate (PPA), DPPA, HATU, HOBt, HOAt, DCC, EDCl, BOP-Cl, TFFH, Brop, PyBrop, and CIP.

[0229] In Scheme 4, the chemical tip moiety precursor is

[0230] [ka]

[0231] In step 4D, the tip moiety precursor is converted to the corresponding chemical tip moiety by oxidative methods, preferably by using Dess-Martin periodinane (DMP), iodoxybenzoic acid (IBX), or hydrogen peroxide (HO), in a polar solvent, in particular DMF, as described in the chemical examples.

[0232] [ka]

[0233] is converted to Therefore, another aspect of the invention relates to the compounds according to general formula (I) as medicine and to the use of the compounds of general formula (I) in medicine, particularly preferably as transglutaminase inhibitors.

[0234] The compounds according to general formula (I) described in the present application are particularly suitable for the treatment and prevention of diseases associated with and / or caused by transglutaminase.

[0235] TG1, TG3 and TG5 are expressed in skin and inhibitors of said enzymes may be used to treat certain skin disorders or modulate transglutaminase activity affecting skin structure.TG6 inhibitors may address neurodegenerative disorders characterized by intra- or extracellular crosslinks and insoluble protein aggregates.

[0236] Celiac disease, gluten intolerance, is associated with tissue transglutaminase (TG2). Another very important group that is subject to tissue transglutaminase inhibitors is fibrotic diseases. Fibrotic diseases are characterized by the accumulation of cross-linked extracellular matrix proteins. Diabetic nephropathy, cystic fibrosis, idiopathic pulmonary fibrosis, renal fibrosis, and hepatic fibrosis are among the most important fibrotic diseases that are addressed with the disclosed compounds.

[0237] Since blood coagulation factor XIII (FXIII, F13) is a major factor influencing clot maturation and accretion, the enzyme is considered an appropriate target to potentially achieve thrombolysis more safely and effectively.

[0238] Therefore, another aspect of the present invention is the use of the compounds of the present invention of general formula (I) for the treatment or prevention of cardiovascular diseases, autoimmune diseases, neurodegenerative diseases, fibrotic diseases, skin diseases, wound healing and inflammatory diseases.

[0239] In particular, atherosclerosis, celiac disease, Duhring-Brocq disease, gluten intolerance, tissue fibrosis, cystic fibrosis, The present invention relates to the use of the compounds of the present invention of general formula (I) for the treatment or prevention of chronic pulmonary fibrosis, renal fibrosis and diabetic nephropathy, liver fibrosis, thrombosis, Huntington's disease, Parkinson's disease, Alzheimer's disease, cataracts, ichthyosis, acne, psoriasis, skin aging, candidiasis, and other transglutaminase-dependent diseases.

[0240] The term "transglutaminase-dependent disease" includes all diseases, dysfunctions, and other impairments in health that are caused by or related to dysfunction, perturbance, or hyperactivity of transglutaminase in the body. Alternatively, prophylactic inhibition of transglutaminase such as FXIII, for example in thrombophilic patients, may certainly be of benefit in at-risk patients.

[0241] The particular stability of the compounds of the present invention of general formula (I) is related to the steric and electronic properties resulting from the molecular structure.It is clear that the electrophilic head moiety is an essential unit of reversible transglutaminase inhibitors, especially in combination with certain peptidomimetic scaffolds, pyridinone-containing scaffolds, conformationally constrained non-natural proline-based amino acids, and piperazine-containing scaffolds, resulting in potential transglutaminase inhibitors, especially of transglutaminase 2 and blood coagulation factor XIII.Selectivity is obtained by implementing said elements at selected positions in the scaffold.

[0242] It is known from the protease literature that certain apical moieties form a covalent but reversible complex with the active site cysteine ​​or serine. This is particularly relevant to confer affinity for the target while forming a thia-hemiacetal or hemiacetal, respectively. We have surprisingly found that this principle is suitable for transglutaminase inhibitors. The apical moiety found needs to be positioned in the correct orientation to substitute for the original substrate glutamine. As the backbone is positioned at the apical moiety, a thio-hemiacetal is formed.

[0243] In Biological Example B-1, it is demonstrated that the compounds of the present invention, as reversible TG inhibitors, effectively inhibit the activity of TGs, particularly TG2 and FXIII. Furthermore, as reversible TG inhibitors, the compounds of the present invention also prove to be less toxic than irreversible TG inhibitors. In biological example B-2, the cytotoxicity of transglutaminase inhibitors is evaluated using two different assays. The irreversible TG inhibitor Z006 is cytotoxic at 125 μM, whereas the compound E02 of the present invention shows no effect on cell proliferation or metabolic activity up to 1 mM (the highest concentration measured). It is a drawback of irreversible TG inhibitors that non-specific reactions involving off-targets can result in significant side effects and trigger specific immune responses. Furthermore, direct damage to tissues of irreversibly acting compounds or metabolites has been described. Haptenization of proteins by reactive substrates can also induce immune responses. Quite frequently, the liver is affected by the side effects.

[0244] It is therefore a technical advantage that the compounds of the present invention are not cytotoxic at high concentrations, ie in the millimolar range. Moreover, in Example B-3, it is also demonstrated that the inhibition of tissue transglutaminase using the compound of the present invention reduces transglutaminase activity and reduces ECM accumulation.These results show that the compound of the present invention has anti-fibrotic effect in renal cells of proximal duct epithelial cells.Therefore, it is supported that the compound of the present invention is useful for treating fibrosis such as tissue fibrosis, cystic fibrosis, idiopathic pulmonary fibrosis, renal fibrosis and liver fibrosis. [Brief description of the drawings]

[0245] [Figure 1] A) Transglutaminase activity of homogenates from NRK52E cells grown at physiological (6 mM) and hyperglycemic (24 mM and 36 mM) glucose concentrations in the presence of compound E06. B) Extracellular matrix protein precipitation from NRK52E cells grown at physiological and hyperglycemic glucose concentrations in the presence of compound E06. [Diagram 2]A) Transglutaminase activity of homogenates from NRK52E cells grown at physiological (6 mM) and hyperglycemic (24 mM and 36 mM) glucose concentrations in the presence of compound E22. B) Extracellular matrix protein precipitation from NRK52E cells grown at physiological and hyperglycemic glucose concentrations in the presence of compound E22. [Diagram 3] A) Dose-dependent effect of compound E25 on the reduction of maximum clot firmness (MCF) compared to control (K). B) Dose-dependent effect of compound E25 on clot lysis at 60 min (LI60) in the presence of 0.02% t-PA. [Figure 4] A) Dose-dependent effect of compound E27 on the reduction of maximum clot firmness (MCF) compared to control (K). B) Dose-dependent effect of compound E27 on clot lysis at 60 min (LI60) in the presence of 0.02% t-PA. [Diagram 5] Determination of the reduction in neurite outgrowth by the antitumor drug nekodazole, the irreversible TG2-inhibitor ZED1537, and the reversible TG2-inhibitor N01. Extinction values ​​determined for stained neurite extracts are shown. [Figure 6] A) Detection of huntingtin (htt) in an ELISA assay. Microtiter plate wells were coated with SDS-soluble and formic acid-solubilized extracts of Htt-exon 1-97Q-transformed N2a-cells grown in the presence of 150 μM and 300 μM of the TG2-inhibitor E22. Anti-Htt antibody 1C2 (1:250, Millipore, MAB1574) was used as detection antibody, followed by a conventional ELISA protocol. B) Detection of isopeptide bonds in an ELISA assay. Microtiter plate wells were coated with SDS-soluble and formic acid-solubilized extracts of Htt-exon 1-97Q-transformed N2a-cells grown in the presence of 150 μM and 300 μM of the TG2-inhibitor E22. The antibody A023 (1:200, Zedira), which recognises the Nε-(γ-L-glutamyl)-L-lysine-isopeptide, was used as detection antibody, following a conventional ELISA-protocol. [Figure 7] A) Transglutaminase activity of homogenates from BEAS-2B-cells grown in the presence of 0-200 μM E22 and stimulated with LPS, determined by the TG2-Selective Tissue Transglutaminase Pico Assay Kit (#M003, Zedira, Darmstadt, Germany) according to the manufacturer's instructions. B) Extracellular matrix protein precipitation of homogenates from BEAS-2B-cells grown in the presence of 0-200 μM E22 and stimulated with LPS, measured by the DC-Protein Assay (BioRad, #5000111). [Figure 8] A) Transglutaminase activity of homogenates from LX-2-cells grown in standard plastic 6-well plates in the presence of 0–200 μM E22, determined by the TG2-Selective Tissue Transglutaminase Pico Assay Kit (#M003, Zedira, Darmstadt, Germany) according to the manufacturer's instructions. B) Extracellular matrix protein precipitation of homogenates from LX-2-cells grown in standard plastic 6-well plates in the presence of 0–200 μM E22, measured by the DC-Protein Assay (BioRad, #5000111). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0246] [Example] The following abbreviations used in the examples have the following meanings: DMAP: 4-(dimethylamino)-pyridine TEA: Triethylamine DMF: Dimethylformamide DIPEA: N-ethyldiisopropylamine TFA: Trifluoroacetic acid EtOAc: ethyl acetate HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate PyAOP (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate [Chemical Examples] The following examples are intended to illustrate the invention with selected compounds without limiting the scope of intellectual property protection that exists in these embodiments. It will be apparent to those skilled in the art that similar compounds and compounds produced according to similar synthetic methods fall within the scope of existing intellectual property protection. Example 1. Preparation of compound E01

[0247] [ka]

[0248] The synthesis was adapted from Venkatraman, S. et al. J. Med. Chem. 2006, 49, 6074-6086. Thiosemicabazone chemistry and protecting group chemistry were performed according to basic literature knowledge. 1.1 Preparation of compound 3a

[0249] [ka]

[0250] 3.14 g (8.10 mmol) of the aldehyde (S)-tert-butyl 2-(bis(tert-butoxycarbonyl)amino)-5-oxopentanoate 1 were dissolved in 10 ml of DMF. 738 mg (1 eq) of thiosemicarbazide 2a and 1.42 ml (1 eq) DIPEA were added and the reaction was stirred at room temperature overnight. The solvent was evaporated and the residue was dissolved in EtOAc. The solution was washed twice with NaHCO3 solution (10%) and with brine. The organic layer was dried over Na2SO4, filtered and the solvent was evaporated. The residue was used without further purification. Yield: 4.18g, >100% ESI-MS: 461.2 [M+H] + 1.2 Preparation of compound 4-1

[0251] [ka]

[0252] 4.18 g (~8.10 mmol) of the raw thiosemicarbazone 3a was dissolved in 20 ml DCM / TFA (1:1) and stirred at room temperature for 2 h. The solvent was evaporated and the residue was dissolved in 10 ml DMF. 1.26 ml (1 eq) DIPEA and 683 μl (1 eq) Ac2O were added and the reaction was stirred at room temperature overnight. The solvent was evaporated and the residue was purified by HPLC. Yield: 1.01g, 51% ESI-MS: 247.3 [M+H] + 1.3 Preparation of compound A01

[0253] [ka]

[0254] 400 mg (1.62 mmol) of thiosemicarbazone 4-1 was dissolved in 5 ml of DMF. 847 mg (1 eq) PyAOP, 555 mg (1 eq) of tripeptide H-VPL-OMe5-1, and 467 μl (3.25 mmol, 2 eq) of DIPEA were added and the reaction was stirred overnight at room temperature. The solvent was evaporated and the residue was purified by HPLC. Yield: 309mg, 33% ESI-MS: 570.5 [M+H] + 1.4 Preparation of compound B01

[0255] [ka]

[0256] 413 mg (0.73 mmol) of thiosemicarbazone A01 was dissolved in a solution of 1 ml formic acid (50%) and 4 ml formaldehyde (37%) (6). The solution was stirred at 40° C. for 1 h and purified by HPLC. Yield: 205mg, 57% ESI-MS: 497.4 [M+H] + 1.5 Preparation of compound C01

[0257] [ka]

[0258] 307 mg (0.62 mmol) of aldehyde B01 was dissolved in 10 ml of DCM under argon. 103 μl (0.74 mmol) NEt3 and 117 μl (1.28 mmol, 2.1 eq) of acetone cyanohydrin 7 were added and the reaction was stirred overnight at room temperature. The solvent was evaporated and the residue was purified by HPLC. Yield: 172mg, 53% ESI-MS: 524.5 [M+H] + 1.6 Preparation of Compound D01

[0259] [ka]

[0260] 172 mg (0.33 mmol) of cyanohydrin C1 was dissolved in 3 ml of MeOH. At 0° C., 16.5 mg (0.39 mmol, 1.2 eq) LiOH * H2O was added. After dropwise addition of 133 μl (3.29 mmol, 10 eq) H2O2 (35%) the reaction was stirred at room temperature for 2 h and purified by HPLC. Yield: 40mg, 23% ESI-MS: 542.5 [M+H] + 1.7 Preparation of compound E01

[0261] [ka]

[0262] 18.0 mg (33.2 μmol) of hydroxyamide D01 was dissolved in 2 ml of EtOAc. 22.6 mg (53.2 μmol, 1.6 eq) Dess-Martin periodinane (DMP) was added in three portions and stirred at room temperature for 2 hours. The precipitate was filtered off and the filtrate was evaporated. The residue was purified by HPLC. Yield: 11mg, 61% ESI-MS: 540.5 [M+H] + Example 2. Preparation of compound E02

[0263] [ka]

[0264] The synthesis of E02 was carried out according to Example 1, using benzyl chloroformate (Cbz-Cl) instead of Ac2O (see compound 4-1). Yield: 16 mg, 57% (final step) ESI-MS: 632.4 [M+H] +

[0265] [ka]

[0266] Example 3. Preparation of compound E03

[0267] [ka]

[0268] Compound E03

[0269] [ka]

[0270] The synthesis of compound E03 was carried out according to Example 1, using 4-phenylsemicarbazide 2b instead of thiosemicarbazide (see compound 3a), and the tripeptide H-QIV-NH2 (compound 5-3) instead of H-VPL-OMe (compound 5-1) (see compound A01). Yield: 14 mg, 49% (final step) ESI-MS: 556.4 [M+H] + Example 4. Preparation of compound E04 Compound E04

[0271] [ka]

[0272] The synthesis of compound E04 was carried out according to Example 1, using 1-methyl-1H-imidazole-5-carboxylic acid instead of AcO (see compound 4-1) and 2-(3-amino-2-oxopyridin-1(2H)-yl)-N-(2-ethylbutyl)acetamide (5-4) instead of H-VPL-OMe (compound 5-1) (see compound A01). Yield: 10 mg, 43% (final step) ESI-MS: 516.4 [M+H] +

[0273] [ka]

[0274] Example 5. Preparation of compound E05

[0275] [ka]

[0276] The synthesis of compound E05 was carried out according to Example 1, using di-tert-butyl dicarbonate (BocO) instead of AcO (see compound 4-1) and 2-(3-amino-2-oxopyridin-1(2H)-yl)-N-isopentylacetamide (compound 5-5) instead of H-VPL-OMe (see compound 5-1). Furthermore, 2-bromo-4-methylthiazole-5-carboxylic acid (compound 9-5) was introduced in the final step according to standard peptide coupling methods. Yield: 15 mg, 72% (final step) ESI-MS: 597.3 [M+H] +

[0277] [ka]

[0278] Example 6. Preparation of compound E06

[0279] [ka]

[0280] The synthesis of compound E06 was carried out according to Example 1, using 1-(2-chlorophenyl)piperazine (compound 5-6) instead of H-VPL-OMe (compound 5-1). Furthermore, the sequence was adjusted by first introducing the α-ketoamide moiety, followed by N-terminal modification and backbone coupling. Yield: 19 mg, 64% (final step) ESI-MS: 395.3 [M+H] +

[0281] [ka]

[0282] Example 7. Preparation of compound E07

[0283] [ka]

[0284] The synthesis of compound E07 was carried out according to Example 6, using Ac-Pro-OSu instead of AcO, and using 1-(3-methylpyridin-2-yl)piperazine (compound 5-7) instead of 1-(2-chlorophenyl)piperazine (compound 5-6). Yield: 11 mg, 52% (final step) ESI-MS: 473.4 [M+H] +

[0285] [ka]

[0286] Example 8. Preparation of compound E08

[0287] [ka]

[0288] The synthesis of compound E08 was carried out according to Example 6, using Ac-Asp-OSu (14-1) instead of AcO (via a Boc intermediate) and H-Nle-Nle-LPWP-OH (compound 5-8) instead of 1-(2-chlorophenyl)piperazine (compound 5-6). Yield: 8 mg, 29% (final step) ESI-MS: 1051.7 [M+H] +

[0289] [ka]

[0290] Example 9. Preparation of compound E09

[0291] [ka]

[0292] The synthesis of compound E09 was carried out according to Example 6, using 6-hydroxy-5-nitropyridine-3-carboxylic acid (compound 13-4) instead of AcO, and (R)-N-((S)-2-((S)-2-amino-1-cyclohexyl-2-oxoethylamino)-1-cyclohexyl-2-oxoethyl)-1-((S)-2-amino-3,3-dimethylbutanoyl)piperidine-2-carboxamide (compound 5-9) instead of 1-(2-chlorophenyl)piperazine (compound 5-6). Yield: 13 mg, 40% (final step) ESI-MS: 842.6 [M+H] + Example 10. Preparation of compound E10

[0293] [ka]

[0294] The synthesis of compound E10 was carried out according to Example 6, using 5-nitroisophthalic acid (compound 14-2) instead of AcO (via Boc intermediate) and (1R,2S)-3-((S)-2-amino-3-cyclopropylpropanoyl)-N-((2S)-1-((2S)-2-(1-(2,6-dimethylphenoxy)propan-2-ylcarbamoyl)-2-methylpyrrolidin-1-yl)-1-oxopentan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (compound 5-10) instead of 1-(2-chlorophenyl)piperazine (compound 5-6). Yield: 6 mg, 27% (final step) ESI-MS: 987.7 [M+H] + Example 11. Preparation of compound E04 via cyanohydrin route Cyanohydrin Route

[0295] [ka]

[0296] 11.1 Preparation of Compound 10

[0297] [ka]

[0298] 15.0 g (38.7 mmol) of the aldehyde (S)-tert-butyl 2-(bis(tert-butoxycarbonyl)amino)-5-oxopentanoate 1 was dissolved in 150 ml of DCM. 6.42 ml (46.3 mmol) trimethylamine and 7.37 ml (79.9 mmol) acetone cyanohydrin were added and the reaction was stirred at room temperature overnight. The solution was washed twice with citric acid solution (10%) and with brine, respectively. The organic layer was dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography. Yield: 16.2g, >100% ESI-MS: 437.6 [M+Na] + 11.2 Preparation of compound 11

[0299] [ka]

[0300] 16.2 g (~38.6 mmol) of cyanohydrin 10 was dissolved in 95 ml of MeOH at 4 °C and 1.91 g (45.5 mmol) of lithium hydroxide monohydrate was added. 18.6 ml of hydrogen peroxide (35%) was added dropwise and the reaction was stirred at room temperature for 1.5 h and quenched with sodium thiosulfate solution (5%). The aqueous layer was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography. Yield: 8.61g, 52% ESI-MS: 455.2 [M+Na] + 11.3 Preparation of compound 15

[0301] [ka]

[0302] 8.61 g (19.9 mmol) of hydroxyamide 10 was dissolved in 55 ml of DCM. 3.45 ml (24.9 mmol) 1.91 g (45.5 mmol) of trimethylamine, 2.12 ml of acetic anhydride, and 62 mg (0.50 mmol) of DMAP were added and the reaction was stirred at room temperature for 3 h. After washing with water and brine, the organic layer was dried over Na2SO4, filtered, and the solvent was evaporated. The product was precipitated from the MTBE solution by the addition of hexane. Yield: 8.08g, 86% ESI-MS: 475.5 [M+H] + 11.4 Preparation of compound 16

[0303] [ka]

[0304] 8.08 g (17.0 mmol) of 15 was dissolved in 140 ml of DCM / TFA (1:1) and stirred at room temperature for 3 h. The solvent was evaporated and the residue was dissolved in 40 ml of DMF. 5.80 ml (2 eq) of DIPEA and a solution of 4.55 g (20.4 mmol) of di-tert-butyl dicarbonate in 20 ml of DMF were added and the reaction was stirred at room temperature overnight. The solvent was evaporated and the residue was dissolved in 80 ml of EtOAc. After extraction with a NaHCO3 solution (1.05 eq in water), the product was precipitated from the aqueous layer by the addition of 1.5 eq of citric acid. Yield: 1.64g, 30% ESI-MS: 319.4 [M+H] + 11.5 Preparation of Compound 17

[0305] [ka]

[0306] 1.64 g (5.15 mmol) of 16, 2.68 g (1 eq) of PyAOP, and 1.29 g (1 eq) of 2-(3-amino-2-oxopyridin-1(2H)-yl)-N-(2-ethylbutyl)acetamide were dissolved in a solution with 15 ml of DMF and 1.75 ml of DIPEA and stirred at 45° C. overnight. The solvent was evaporated; the residue was dissolved in EtOAc and washed twice with citric acid solution (10%), NaHCO3 solution (10%), and brine, respectively. The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated. The product is precipitated from the iPrOH solution by the addition of MTBE. Yield: 2.71g, 95% ESI-MS: 552.4 [M+H] + 11.6 Preparation of Compound 18

[0307] [ka]

[0308] 300 mg (0.54 mmol) of 17 was dissolved in 140 ml of DCM / TFA (1:1) and stirred at room temperature for 1 h. The solvent was evaporated and the residue was dissolved in 4 ml of DMF. 68.6 mg (1 eq) of 1-methyl-1H-imidazole-5-carboxylic acid, 207 mg (1 eq) of HATU, and 370 μl (4 eq) of DIPEA were added and the reaction was stirred overnight at room temperature. The solvent was evaporated and the residue was purified by HPLC. Yield: 241mg, 79% ESI-MS: 560.5 [M+H] + 11.7 Preparation of compound E04

[0309] [ka]

[0310] 240 mg (0.43 mmol) of 18 was dissolved in 5 ml of MeOH. 89.8 mg (1.5 eq) of potassium carbonate was added and the reaction was stirred at room temperature for 1 h. The solution was diluted with DCM and washed with water. The organic layer was dried over Na2SO4, filtered and the solvent was evaporated to give 88 mg of hydroxyamide which was used without further purification.

[0311] 88 mg (0.17 mmol) of hydroxyamide was dissolved in 2 ml of DMF. 115 mg (0.27 mmol, 1.6 eq) of Dess-Martin Periodinane (DMP) was added and the reaction was stirred at room temperature for 2 hours. The precipitate was filtered off and the filtrate was evaporated. The residue was purified by HPLC. Yield: 59mg, 67% ESI-MS: 516.5 [M+H] + Example 12. Preparation of compound E11

[0312] [ka]

[0313] Compound E11 was synthesized according to the synthetic methods described in Examples 11.6-11.7, using pyrazine-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid. Yield: 8 mg, 6% (final step) ESI-MS: 514.4 [M+H] + Example 13. Preparation of compound E12

[0314] [ka]

[0315] Compound E12 was synthesized according to the synthesis method described in Examples 11.6-11.7, using benzoic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid. Yield: 52 mg, 37% (final step); ESI-MS: 512.4 [M+H] +Example 14. Preparation of compound E13

[0316] [ka]

[0317] Compound E13 was synthesized according to the synthetic methods described in Examples 11.6-11.7, using 2-methyl-5-nitrobenzoic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid. Yield: 47 mg, 33% (final step); ESI-MS: 571.4 [M+H] + Example 15. Preparation of compound E14

[0318] [ka]

[0319] Compound E14 was synthesized according to the synthetic methods described in Examples 11.6-11.7, using 4-methylthiazole-5-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid. Yield: 18 mg, 25% (final step); ESI-MS: 533.4 [M+H] + Example 16. Preparation of compound E15

[0320] [ka]

[0321] Compound E15 was synthesized according to the synthetic methods described in Examples 11.6-11.7, using dansyl chloride instead of 1-methyl-1H-imidazole-5-carboxylic acid. Yield: 38 mg, 55% (final step); ESI-MS: 641.4 [M+H] + Example 17. Preparation of compound E02

[0322] [ka]

[0323] Alternatively, compound E02 was synthesized by coupling 16 with the tripeptide H-VPL-OMe, using benzyl chloroformate (Cbz-Cl) instead of 1-methyl-1H-imidazole-5-carboxylic acid, following the synthetic methods described in Examples 11.5-11.7. Yield: 51 mg, 33% (final step); ESI-MS: 632.5 [M+H] + Example 18. Preparation of compound E04 via the Weinreb amide route Weinreb amide route

[0324] [ka]

[0325] 19.1 Preparation of Compound 19

[0326] [ka]

[0327] 20.0 g (47.0 mmol) of Fmoc-Glu(OtBu)-OH in 100 ml DMF. 11.8 g (1 eq) 2-(3-amino-2-oxopyridin-1(2H)-yl)-N-(2-ethylbutyl)acetamide, 17.9 g (1 eq) HATU, and 16.4 ml (2 eq) DIPEA were added and the reaction was stirred at room temperature overnight. The solvent was evaporated; the residue was dissolved in EtOAc and washed twice with citric acid solution (10%), NaHCO3 solution (10%), and brine, respectively. The organic layer was dried over Na2SO4, filtered, and concentrated. The product was precipitated from EtOAc and used without further purification. Yield: 38.3g, >100%;ESI-MS:659.4[M+H] + 19.2 Preparation of compound 20

[0328] [ka]

[0329] 38.3 g (~47.0 mmol) of starting material 19 was dissolved in 500 ml of DMF / piperidine (5:1) and stirred at room temperature for 3 h. The solvent was evaporated and the product was precipitated from diethyl ether (14.3 g, 70%). 5.0 g (11.5 mmol) of the free amine was dissolved in 100 ml of DMF. 1.44 g (1 eq) of 1-methyl-1H-imidazole-5-carboxylic acid, 4.35 g (1 eq) of 1H-imidazole-5-carboxylic acid, of HATU and 4.0 ml (2 eq) of DIPEA were added and the reaction was stirred at room temperature overnight. The solvent was evaporated; the residue was dissolved in EtOAc and washed twice with citric acid solution (10%), NaHCO3 solution (10%), and brine respectively. The organic layer was dried over Na2SO4, filtered, and concentrated. The product was precipitated from diethyl ether and used without further purification. Yield: 5.66g, 91%; ESI-MS: 545.5[M+H] + 19.3 Preparation of compound 21

[0330] [ka]

[0331] 3.0 g (5.51 mmol) of 20 was dissolved in 60 ml of DCM / TFA (1:1) and stirred at room temperature for 3 h. The solvent was evaporated and the residue was dissolved in 60 ml of DMF. 2.09 g (1 eq) of HATU, 537 mg (1 eq) of N,O-dimethylhydroxylamine, and 1.92 ml (2 eq) of DIPEA were added and the reaction was stirred at room temperature overnight. The solvent was evaporated; the residue was dissolved in EtOAc and washed twice with citric acid solution (10%), NaHCO3 solution (10%), and brine, respectively. The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated. The Weinreb amide was used without further purification. Yield: 2.45g, 84% ESI-MS: 532.5 [M+H] + 19.4 Preparation of compound B04

[0332] [ka]

[0333] 500 mg (0.94 mmol) of Weinreb amide 9 was dissolved in 10 ml of THF. At -20°C, 2.35 ml (3 eq) of DIBAL-H (1.2 M in toluene) was added, the reaction was stirred for 30 min and quenched with MeOH. The emulsion was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, the solvent was evaporated and the residue was purified by HPLC. Yield: 146mg, 33% ESI-MS: 473.5 [M+H] + 19.5 Preparation of Compound 22

[0334] [ka]

[0335] The synthesis of compound 22 was carried out according to 10 using aldehyde B04 as entry. Yield: 88mg, 61% ESI-MS: 500.4 [M+H] + Example 19.6 Preparation of Compound 23

[0336] [ka]

[0337] The synthesis of compound 23 was carried out according to 11 using cyanohydrin 22 as entry. Yield: 33mg, 36% ESI-MS: 518.5 [M+H] + Example 19.7 Preparation of Compound E04

[0338] [ka]

[0339] The synthesis of compound E04 was carried out following the oxidation methods described in Example 1.7 and Example 4 using hydroxyamide 23 as an entry. Yield: 24mg, 73% ESI-MS: 516.4 [M+H] + Example 19 Preparation of compound E16 via the Passerini route Passerini Route

[0340] [ka]

[0341] 19.1 Preparation of compound 24

[0342] [ka]

[0343] 15.0 g (38.7 mmol) of the aldehyde (S)-tert-butyl 2-(bis(tert-butoxycarbonyl)amino)-5-oxopentanoate 1 was dissolved in 60 ml of DCM. At 0° C., 2.42 ml (1.05 eq) of methyl isocyanide and 2.33 ml (1.05 eq) of acetic acid were added and the reaction was stirred at room temperature overnight. 75 ml of TFA was added and the reaction was stirred for another 3 hours. The solvent was evaporated and the residue was dissolved in 40 ml of DMF. 13.2 ml (2 eq) of DIPEA and a solution of 10.4 g (46.6 mmol) of di-tert-butyl dicarbonate in 10 ml of DMF were added and the reaction was stirred at room temperature overnight. The solvent was evaporated and the residue was dissolved in DCM. After extraction with NaHCO3 solution (1.05 eq in water), 1.5 eq citric acid was added to the aqueous layer, followed by DC M. The organic layer was dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography. Yield: 12.5g, 95% ESI-MS: 333.5 [M+H] + 19.2 Preparation of compound 25

[0344] [ka]

[0345] The synthesis of compound 25 was carried out according to 17 using 24 as an entry. Yield: 6.65g, 32% ESI-MS: 566.54 [M+H] + 19.3 Preparation of compound 26

[0346] [ka]

[0347] The synthesis of compound 26 was carried out according to 18 using 25 as entry. Yield: 4.67g, 69% ESI-MS: 574.5 [M+H] + 19.4 Preparation of compound E16

[0348] [ka]

[0349] The synthesis of compound E16 was carried out according to the oxidation method described in Example 1.7 and Example 4 using 26 as an entry. Yield: 1.00 g, 31%; ESI-MS: 530.5 [M+H] + Example 20. Preparation of compound E17

[0350] [ka]

[0351] Compound E17 was synthesized according to the synthetic method described in Example 19 using ethyl isocyanide in the Passerini reaction (step 1). Yield: 148 mg, 44% (final step) ESI-MS: 544.5 [M+H] + Example 21. Preparation of compound E18

[0352] [ka]

[0353] Compound E18 was synthesized according to the synthetic method described in Example 19 using pentyl isocyanide in the Passerini reaction (step 1). Yield: 32 mg, 35% (final step) ESI-MS: 586.5 [M+H] + Example 22. Preparation of compound E19

[0354] [ka]

[0355] Compound E19 was synthesized according to the synthetic method described in Example 19 using cyclopropyl isocyanide in the Passerini reaction (step 1). Yield: 42 mg, 54% (final step) ESI-MS: 556.4 [M+H] + Example 23. Preparation of compound E20

[0356] [ka]

[0357] Compound E20 was synthesized according to the synthetic method described in Example 19 using benzyl isocyanide in the Passerini reaction (step 1). Yield: 74 mg, 62% (final step) ESI-MS: 606.5 [M+H] + Example 24. Preparation of compound E21

[0358] [ka]

[0359] Compound E21 was synthesized according to the synthetic method described in Example 19 using tert-butyl isocyanide in the Passerini reaction (step 1). Yield: 40 mg, 51% (final step); ESI-MS: 572.5 [M+H] + Example 25. Preparation of compound E22

[0360] [ka]

[0361] The synthesis of compound E22 was carried out according to the synthetic method described in Example 21 (E18) with coupling with acetylproline in step 3. Yield: 23 mg, 39% (final step); ESI-MS: 617.5 [M+H] + Example 26. Preparation of compound E23

[0362] [ka]

[0363] The synthesis of compound E23 was carried out according to the synthetic method described in Example 22 (E19) by coupling with benzoic acid in Example 19.3. Yield: 4 mg, 24% (final step); ESI-MS: 552.4 [M+H] + Example 27. Preparation of compound E24

[0364] [ka]

[0365] The synthesis of compound E25 was carried out according to the synthetic method described in Example 26 (E23) by coupling with H-VPL-OMe in Example 19.2. Yield: 14 mg, 30% (final step); ESI-MS: 642.5 [M+H] + Example 28. Preparation of compound E25

[0366] [ka]

[0367] 28.1 Preparation of compound 32

[0368] [ka]

[0369] The synthesis of compound 32 was carried out according to 25 by coupling (S)-N-((S)-2-((S)-2-amino-1-cyclohexyl-2-oxoethylamino)-1-cyclohexyl-2-oxoethyl)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-oxopyrrolidine-2-carboxamide with HATU. Yield: 399mg, 65% ESI-MS: 834.7 [M+H] + 28.2 Preparation of compound 33

[0370] [ka]

[0371] The synthesis of compound 33 was carried out according to 26 using 3,4-pyridine-dicarboxylic anhydride as entry. Yield: 196mg, 46% ESI-MS: 883.7 [M+H] + 28.3 Preparation of compound E25

[0372] [ka]

[0373] The synthesis of compound E25 was carried out following the oxidation method described in Example 19.4 using 33 as entry. Yield: 170mg, 24% Example 29. Preparation of compound E26

[0374] [ka]

[0375] The synthesis of compound E26 was carried out according to the synthetic method described in Example 28, with the ethyl analogue being coupled to each tetrapeptide in step 1. Yield: 28 mg, 22% (final step) ESI-MS: 853.7 [M+H] + Example 30. Preparation of compound E27

[0376] [ka]

[0377] The synthesis of compound E27 was carried out according to the synthetic method described in Example 28, with the pentyl analogue being coupled to the respective tetrapeptide in step 1. Yield: 129 mg, 14% (final step) ESI-MS: 995.8 [M+H] + Example 31. Preparation of compound E28

[0378] [ka]

[0379] The synthesis of compound E28 was carried out according to the synthetic method described in Example 28, with the cyclopropyl analogue being coupled to the respective tetrapeptide in step 1. Yield: 33 mg, 27% (final step) ESI-MS: 865.7 [M+H] + Example 32. Preparation of compound E29

[0380] [ka]

[0381] The synthesis of compound E29 was carried out according to the synthetic method described in Example 28, with the benzyl analogue being coupled to each tetrapeptide in step 1. Yield: 14 mg, 33% (final step) ESI-MS: 915.7 [M+H] + Example 33. Preparation of compound E30

[0382] [ka]

[0383] The synthesis of compound E30 was carried out according to the synthetic method described in Example 28, with the tert-butyl analogues being coupled to each tetrapeptide in step 1. Yield: 50 mg, 55% (final step) ESI-MS: 881.7 [M+H] + Example 34. Preparation of compound E31

[0384] [ka]

[0385] The synthesis of compound E31 was carried out according to the synthetic method described in Example 28, with 16 coupled to the respective tetrapeptide in step 1. Yield: 20 mg, 32% (final step) ESI-MS: 825.6 [M+H] + Example 35. Preparation of compound E32

[0386] [ka]

[0387] Compound E32 was synthesized according to the synthetic method described in Example 31, by coupling in step 2 with 2-methylthiazole-4-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid. Yield: 4 mg, 3% (final step) ESI-MS: 841.7 [M+H] + Example 36. Preparation of compound E33

[0388] [ka]

[0389] The synthesis of compound E33 was carried out according to the synthesis method described in Example 35, coupling with the hexapeptide H-Leu-Ile-Leu-Pro-Trp-Pro-NH2 in step 1. Yield: 41 mg, 44% (final step) ESI-MS: 1058.8 [M+H] + Example 37. Preparation of compound E34

[0390] [ka]

[0391] The synthesis of compound E34 was carried out according to E25, coupling with the hexapeptide H-Nle-Ile-Leu-Pro-Trp-Pro-NH2 in step 1 and with Ac-Gly-OH in step 2. Yield: 63 mg, 41% (final step) ESI-MS: 909.8 [M+H] + Example 38. Preparation of compound E35

[0392] [ka]

[0393] The synthesis of compound E35 was carried out according to E34, with coupling in step 2 with Ac-Pro-Gly-OH. Yield: 54 mg, 50% (final step) ESI-MS: 1006.9 [M+H] + Example 39. Preparation of compound E36

[0394] [ka]

[0395] The synthesis of compound E36 was carried out according to E34, coupling with Ac-Gly-Pro-Gly-OH in step 2. Yield: 63 mg, 57% (final step) ESI-MS: 1063.9 [M+H] + Example 40. Preparation of compound E37

[0396] [ka]

[0397] The synthesis of compound E37 was carried out according to E34, coupling in step 2 with Ac-Leu-Gly-Pro-Gly-OH. Yield: 56 mg, 49% (final step) ESI-MS: 1177.1 [M+H] + Example 41. Preparation of compound E38

[0398] [ka]

[0399] The synthesis of compound E38 was carried out according to E16 using methyl isocyanacetate in the Passerini reaction (step 1). Yield: 41 mg, 56% (final step) ESI-MS: 588.4 [M+H] + Example 42. Preparation of compound E39

[0400] [ka]

[0401] The synthesis of compound E39 was carried out according to E16 using isocyano(methoxy)methane in the Passerini reaction (step 1). Yield: 41 mg, 36% (final step) ESI-MS: 560.5 [M+H] + Example 43. Preparation of compound E40

[0402] [ka]

[0403] The synthesis of compound E40 was carried out according to E16 using 5-isocyano-1,3-thiazole in the Passerini reaction (step 1). Yield: 15 mg, 19% (final step) ESI-MS: 599.4 [M+H] + Example 44. Preparation of compound E41

[0404] [ka]

[0405] The synthesis of compound E41 was carried out according to E16 using p-toluenesulfonylmethyl isocyanide in the Passerini reaction (step 1). Yield: 26 mg, 41% (final step); ESI-MS: 684.5 [M+H] + Example 45. Preparation of compound E42

[0406] [ka]

[0407] The synthesis of compound E42 was carried out according to E16 by coupling in step 3 with 2-(3-amino-4-methyl-2-oxopyridin-1(2H)-yl)-N-(2-ethylbutyl)acetamide. Yield: 54 mg, 37% (final step); ESI-MS: 544.5[M+H] + Example 46. Preparation of compound E43

[0408] [ka]

[0409] The synthesis of compound E43 was carried out according to E16 by coupling in step 3 with 2-(3-amino-5-methyl-2-oxopyridin-1(2H)-yl)-N-(2-ethylbutyl)acetamide. Yield: 180 mg, 79% (final step) ESI-MS: 544.5 [M+H] + Example 47. Preparation of compound E44

[0410] [ka]

[0411] The synthesis of compound E44 was carried out according to E16 by coupling in step 3 with 2-(3-amino-6-methyl-2-oxopyridin-1(2H)-yl)-N-(2-ethylbutyl)acetamide. Yield: 9 mg, 12% (final step) ESI-MS: 544.5 [M+H] + Example 48. Preparation of compound E45

[0412] [ka]

[0413] The synthesis of compound E45 was carried out according to E16 by coupling in step 3 with 2-(3-amino-5-chloro-2-oxopyridin-1(2H)-yl)-N-(2-ethylbutyl)acetamide. Yield: 46 mg, 56% (final step) ESI-MS: 564.4 [M+H] + Example 49. Preparation of compound E46

[0414] [ka]

[0415] The synthesis of compound E46 was carried out according to E16 by coupling in step 3 with 2-(3-amino-5-bromo-2-oxopyridin-1(2H)-yl)-N-(2-ethylbutyl)acetamide. Yield: 79 mg, 45% (final step) ESI-MS: 608.4 [M+H] + Example 50. Preparation of compound E47

[0416] [ka]

[0417] The synthesis of compound E47 was carried out according to E16 by coupling in step 3 with 2-(3-amino-2-oxo-5-(trifluoromethyl)pyridin-1(2H)-yl)-N-(2-ethylbutyl)acetamide. Yield: 17 mg, 41% (final step) ESI-MS: 598.5 [M+H] + Example 51. Preparation of compound E48

[0418] [ka]

[0419] The synthesis of compound E48 was carried out according to E16, coupling in step 3 with 1-benzenesulfonyl-piperazine. Yield: 83 mg, 68% (final step); ESI-MS: 505.4 [M+H] + Example 52. Preparation of compound E49

[0420] [ka]

[0421] The synthesis of compound E49 was carried out according to E16, coupling with 4-amino-1-benzylpiperidine in step 3. Yield: 24 mg, 18% (final step) ESI-MS: 469.5 [M+H] + Example 53. Preparation of compound E50

[0422] [ka]

[0423] The synthesis of compound E50 was carried out according to E16 by coupling in step 3 with 2-(3-amino-2-oxopyridin-1(2H)-yl)-N,N-diethylacetamide. Yield: 29 mg, 42% (final step) ESI-MS: 502.4 [M+H] + Example 54. Preparation of compound E51

[0424] [ka]

[0425] The synthesis of compound E51 was carried out according to E16 by coupling in step 3 with 2-(3-amino-2-oxopyridin-1(2H)-yl)-N-(methylsulfonyl)acetamide. Yield: 39 mg, 49% (final step) ESI-MS: 524.4 [M+H] + Example 55. Preparation of compound E52

[0426] [ka]

[0427] The synthesis of compound E52 was carried out according to E16 by coupling with ethyl 2-(3-amino-2-oxopyridin-1(2H)-yl)acetate in step 3. Yield: 12 mg, 19% (final step). ESI-MS: 475.4 [M+H] + Example 56. Preparation of compound E53

[0428] [ka]

[0429] The synthesis of compound E53 was carried out according to E16 by coupling in step 3 with 2-methoxyethyl 2-(3-amino-2-oxopyridin-1(2H)-yl)acetate. Yield: 8 mg, 12% (final step) ESI-MS: 491.4 [M+H] + Example 57. Preparation of compound E54

[0430] [ka]

[0431] The synthesis of compound E54 was carried out according to E16 by coupling in step 3 with 2-(3-amino-2-oxopyridin-1(2H)-yl)-N-(methoxymethyl)acetamide. Yield: 19 mg, 29% (final step) ESI-MS: 490.4 [M+H] + Example 58. Preparation of compound E55

[0432] [ka]

[0433] The synthesis of compound E55 was carried out according to E16 by coupling in step 3 with 2-(3-amino-2-oxopyridin-1(2H)-yl)-N-((dimethylamino)methyl)acetamide. Yield: 14 mg, 20% (final step); ESI-MS: 503.4 [M+H] + Example 59. Preparation of compound E56

[0434] [ka]

[0435] The synthesis of compound E56 was carried out according to E16 by coupling in step 3 with 2-(3-amino-2-oxopyridin-1(2H)-yl)-N-(ethylsulfonyl)acetamide. Yield: 19 mg, 29% (final step); ESI-MS: 490.4 [M+H] + Example 60. Preparation of compound E57

[0436] [ka]

[0437] The synthesis of compound E57 was carried out according to E16 by coupling in step 4 with benzyl chloroformate. Yield: 29 mg, 36% (final step) ESI-MS: 556.5 [M+H] + Example 61. Preparation of compound E58

[0438] [ka]

[0439] The synthesis of compound E58 was carried out according to E16 by cleavage of the acetyl from compound 25 followed by oxidation. Yield: 16 mg, 59% (final step) ESI-MS: 522.5 [M+H] + Example 62. Preparation of compound E59

[0440] [ka]

[0441] The synthesis of compound E59 was carried out according to E16, coupling with succinic anhydride in step 4. Yield: 27 mg, 42% (final step) ESI-MS: 522.4 [M+H] + Example 63. Preparation of compound E60

[0442] [ka]

[0443] The synthesis of compound E60 was carried out according to E16 with coupling with N-Boc-4-oxo-L-proline in step 4 followed by cleavage. Yield: 14 mg, 41% (final step); ESI-MS: 533.5 [M+H] + Example 64. Preparation of compound E61

[0444] [ka]

[0445] The synthesis of compound E61 was carried out according to E16, coupling in step 4 with furan-3-carboxylic acid. Yield: 36 mg, 63% (final step); ESI-MS: 516.4 [M+H] + Example 65. Preparation of compound E62

[0446] [ka]

[0447] The synthesis of compound E62 was carried out according to E16, coupling in step 4 with 5-oxazole carboxylic acid. Yield: 15 mg, 33% (final step) ESI-MS: 517.4 [M+H] + Example 66. Preparation of compound E63

[0448] [ka]

[0449] The synthesis of compound E63 was carried out according to E16, by coupling in step 4 with N-methylisonipecotic acid. Yield: 9 mg, 21% (final step) ESI-MS: 547.5 [M+H] + Example 67. Preparation of compound E64

[0450] [ka]

[0451] The synthesis of compound E64 was carried out according to E16, coupling in step 4 with 5-pyrimidine carboxylic acid. Yield: 17 mg, 29% (final step) ESI-MS: 528.5 [M+H] + Example 68. Preparation of compound E65

[0452] [ka]

[0453] The synthesis of compound E65 was carried out according to E16, coupling in step 4 with 2-quinoxaline carboxylic acid. Yield: 6 mg, 13% (final step); ESI-MS: 578.5 [M+H] + Example 69. Preparation of compound E66

[0454] [ka]

[0455] The synthesis of compound E66 was carried out according to E16 by coupling in step 4 with 2,4-dimethylthiazole-5-sulfonyl chloride. Yield: 26 mg, 61% (final step); ESI-MS: 597.4 [M+H] + Example 70. Preparation of compound E67

[0456] [ka]

[0457] The synthesis of compound E67 was carried out according to E16 by coupling in step 4 with 6-chloroimidazo[2,1-b]thiazole-5-sulfonyl chloride. Yield: 16 mg, 25% (final step) ESI-MS: 642.4 [M+H] + Example 71. Preparation of compound E68

[0458] [ka]

[0459] The synthesis of compound E68 was carried out according to E16 by coupling in step 4 with 1-methyl-1H-imidazole-2-sulfonyl chloride. Yield: 11 mg, 19% (final step) ESI-MS: 566.4 [M+H] + Example 72. Preparation of compound E69

[0460] [ka]

[0461] The synthesis of compound E69 was carried out according to E16, coupling in step 4 with phenyl isocyanate. Yield: 27 mg, 49% (final step) ESI-MS: 541.5 [M+H] + Example 73. Preparation of compound E70

[0462] [ka]

[0463] The synthesis of compound E70 was carried out according to E16, coupling with phenylisothiocyanate in step 4. Yield: 21 mg, 36% (final step) ESI-MS: 557.5 [M+H] + Example 74. Preparation of compound E71

[0464] [ka]

[0465] Preparation of compound 35

[0466] [ka]

[0467] 541 mg (1.27 mmol) of (S)-tert-butyl 2-(bis(tert-butoxycarbonyl)amino)-6-diazo-5-oxohexanoate 34 (prepared from Boc2-Glu-OtBu; method described by Pinkas et al. PLoS Biol. 2007, 5, e327) were dissolved in 2 ml of MeOH. A solution of 16 mg of silver benzoate in triethylamine was added dropwise until the evolution of nitrogen ceased. The suspension was refluxed for 1 h, filtered and the solvent was evaporated. The residue was dissolved in diethyl ether. The organic layer was dried over Na2SO4, filtered and the solvent was evaporated. The product was used without further purification. Yield: 503mg, 92% ESI-MS: 885.7 [2M+Na] + Preparation of compound 36

[0468] [ka]

[0469] 854 mg (1.98 mmol) of 35 was dissolved in 10 ml of diethyl ether. At -78°C, 2.14 ml (1.3 eq) of DIBAL (1.2 M in toluene) was added dropwise, the reaction was stirred for 1 h and quenched with methanol. The solution was washed with Rochelle's salt solution. The organic layer was dried over Na2SO4, filtered and the solvent was evaporated. The product was used without further purification. Yield: 768mg, 97% ESI-MS: 402.5 [M+H] + Preparation of compound 37

[0470] [ka]

[0471] The synthesis of compound 37 was carried out according to 24 using aldehyde 36. Yield: 1.30g, >100% ESI-MS: 347.5 [M+H] + Preparation of compound 38

[0472] [ka]

[0473] The synthesis of compound 38 was carried out according to 25 using carboxylic acid 37. Yield: 580mg, 52% ESI-MS: 580.5 [M+H] + Preparation of compound 39

[0474] [ka]

[0475] The synthesis of compound 39 was carried out according to 26 using 38 as an entry. Yield: 506 mg, 72%; ESI-MS: 588.5[M+H] + Preparation of compound E71 (n=2)

[0476] [ka]

[0477] The synthesis of compound E71 was carried out according to E16 using 39 as entry. Yield: 159 mg, 67%; ESI-MS: 544.5[M+H] + Example 75. Preparation of compound E72 (n=2)

[0478] [ka]

[0479] The synthesis of compound E72 was carried out according to E71 by coupling with 4-(4-methylpiperazin-1-ylsulfonyl)aniline in step 4. Yield: 23 mg, 30%; ESI-MS: 548.5 [M+H] + Example 76. Preparation of compound E73 (n=3)

[0480] [ka]

[0481] The synthesis of compound E73 was carried out according to E71, using (S)-tert-butyl 2-(bis(tert-butoxycarbonyl)amino)-7-diazo-6-oxoheptanoate (prepared from Boc2-Aad-OtBu; method described by Pinkas et al. PLoS Biol. 2007, 5, e327) in step 1. Yield: 41 mg, 56% (final step) ESI-MS: 558.5 [M+H] + Example 77. Preparation of diketone E74 according to Weinrebruth

[0482] [ka]

[0483] Preparation of compound 40

[0484] [ka]

[0485] To a solution of 57 μl (0.58 mmol) of ethyl vinyl ether in 2.4 ml of THF was added 299 μl (0.57 mmol) of tert-butyl lithium (1.9 M in pentane) at −78° C. After warming to 0° C. (2 h), 142 mg (0.54 mmol) of magnesium bromide etherate was added at −30° C. After warming to 0° C. (15 min), a solution of 58 mg (0.11 mmol) of Weinreb amide 21 in THF (0.3 ml) was added and the reaction was stirred overnight at room temperature. The solution was washed with NH4Cl solution and extracted with diethyl ether. The organic layer was dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography. Yield: 41mg, 69% ESI-MS: 543.5 [M+H] + Preparation of compound E74

[0486] [ka]

[0487] To a solution of 41 mg (0.08 mmol) of 40 in MeOH (5 ml) was added concentrated HCl (500 μl) and stirred for 24 h. The solvent was evaporated and the residue was purified by HPLC. Yield: 21mg, 54% ESI-MS: 515.4 [M+H] + Example 77. Preparation of diketone E75 according to Corey-Seebach

[0488] [ka]

[0489] Preparation of compound E75

[0490] [ka]

[0491] 205 mg (0.38 mmol) of tert-butyl ester 20 was dissolved in 4 ml of DCM / TFA (1:1) and stirred at room temperature for 3 h. The solvent was evaporated and the residue was dissolved in a solution of 1 ml of thionyl chloride and 50 μl of DMF. After stirring at room temperature for 2 h, the solvent was evaporated.

[0492] 61 mg (0.38 mmol) of 2-cyclopropyl-1,3-dithiane was dissolved in 1 ml of THF and 25 μl of n-butyllithium (1.6 M in hexanes, 1.05 eq) was added at −30° C. A solution of intermediate acyl chloride 41 in THF was added and the reaction was stirred at room temperature for 24 h. The solution was washed with NH4Cl solution and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered and the solvent was evaporated.

[0493] The residue was dissolved in 2 ml water / DMSO (1:9, 1 mol% acetic acid) with 213 mg 2-iodobenzoic acid (IBX, 2 eq) and stirred for 1 h at 25° C. Saturated Na2S2O3 solution was added and the suspension was extracted with EtOAc. The organic layer was washed with saturated NaHCO3 solution and brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by HPLC. Yield: 13mg, 23% ESI-MS: 541.5 [M+H] + Example 78. Preparation of compound E76

[0494] [ka]

[0495] The synthesis of compound E76 was carried out according to E75 using 2-phenyl-1,3-dithiane in sub-step 3. Yield: 41 mg, 56% (final step) ESI-MS: 558.5 [M+H] + Example 79. Preparation of α-ketoester E77

[0496] [ka]

[0497] Preparation of compound 42

[0498] [ka]

[0499] 557 mg (1.02 mmol) of 20 was dissolved in 6 ml DCM / TFA (1:1) and stirred at room temperature for 3 h. The solvent was evaporated and the residue was dissolved in 5 ml DMF. 294 mg 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC*HCl, 1.5 eq), 12.5 mg DMAP (0.1 eq), and 1.92 ml (2 eq) DIPEA were added, followed by 339 mg (cyanomethylene)triphenylphosphorane (1.1 eq) and the reaction was stirred at room temperature overnight. The solvent was evaporated and the residue was purified by HPLC. Yield: 96mg, 12% ESI-MS: 772.6 [M+H] + Preparation of compound E77

[0500] [ka]

[0501] 96 mg (0.12 mmol) of α-keto-cyanophosphorane 42 was dissolved in MeOH (2 ml) and DMDO (freshly prepared according to Taber et al. Org. Synth. 2013, 90, 350-357) (2 eq, dimethyldioxirane in acetone) was added dropwise at room temperature and the reaction was stirred at room temperature for 1 h. The solvent was evaporated and the residue was purified by HPLC. Yield: 22mg, 35% ESI-MS: 531.5 [M+H]+ Example 80. Preparation of compound E78

[0502] [ka]

[0503] The synthesis of compound E78 was carried out according to E77 from intermediate 43 by carrying out with ethylene glycol monomethyl ether. Yield: 15mg, 23% ESI-MS: 575.5 [M+H] + Example 81. Preparation of compound E79

[0504] [ka]

[0505] The synthesis of compound E79 was carried out according to E77 from intermediate 43 by carrying out with cyclopentanemethanol. Yield: 26mg, 38% ESI-MS: 614.5 [M+H] + Example 82. Preparation of Compound E80 (via Corey-Seebach)

[0506] [ka]

[0507] The synthesis of compound E80 was carried out according to E75 using 2-isobutyl-1,3-dithiane in sub-step 3. Yield: 26 mg, 36% (final step) ESI-MS: 557.5 [M+H] + Example 83. Preparation of Compound E81 (via Corey-Seebach)

[0508] [ka]

[0509] The synthesis of compound E81 was carried out according to E75 using 4-(1,3-dithian-2-yl)-1-methyl-1H-imidazole in sub-step 3. Yield: 12 mg, 28% (final step) ESI-MS: 581.5 [M+H] + Example 84. Preparation of compound E82 (via Passerini route)

[0510] [ka]

[0511] The synthesis of compound E82 was carried out according to E16 by coupling with (S)-2-((S)-2-((S)-2-amino-3-(1H-imidazol-4-yl)propanamido)-3-(4-hydroxyphenyl)propanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide in step 3 and with (5,5-dimethyl-2-oxotetrahydro-3-furanyl)acetic acid in step 4. Yield: 19 mg, 35% (last step). ESI-MS: 801.6 [M+H] + Example 85. Preparation of compound E83 (via Passerini route)

[0512] [ka]

[0513] The synthesis of compound E83 was carried out according to E16 by coupling with (2S,4R)-1-((S)-2-(3-aminobenzamido)-3-(biphenyl-4-yl)propanoyl)-4-phenoxypyrrolidine-2-carboxamide in step 3 and with 1,3-dimethyl-1H-pyrazole-5-acetic acid in step 4. Yield: 8 mg, 19% (final step) ESI-MS: 855.6 [M+H] + Example 86. Preparation of compound E84 (via Passerini route)

[0514] [ka]

[0515] The synthesis of compound E84 was carried out according to E16 by coupling with (2S,4R)-1-(2-((S)-2-amino-5-guanidinopentanamido)-2-methylpropanoyl)-4-hydroxypyrrolidine-2-carboxamide in step 3 and with propan-2-ylcarbonochloridate in step 4. Yield: 28 mg, 31% (final step). ESI-MS: 628.5 [M+H] + Compounds for determination of cytotoxicity Preparation of compound Z006 (''Z-DON'')

[0516] [ka]

[0517] The synthesis of compound Z006 was carried out according to Pinkas et al. (PLoS Biol. 2007, 5, e327.) using Z-Glu-Val-Pro-Leu-OMe as entry. Preparation of compound Z007

[0518] [ka]

[0519] The synthesis of compound Z007 was carried out according to Pinkas et al. (PLoS Biol. 2007, 5, e327.) using (S)-4-(benzyloxycarbonylamino)-5-(1-(2-(2-ethylbutyl-amino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-5-oxopentanoic acid as entry. Preparation of compound DON06

[0520] [ka]

[0521] The synthesis of compound DON06 was carried out according to Pinkas et al. (PLoS Biol. 2007, 5, e327.) using (S)-4-acetamido-5-(4-(2-chlorophenyl)piperazin-1-yl)-5-oxopentanoic acid as entry. DON07

[0522] [ka]

[0523] The synthesis of compound DON07 was carried out according to (S)-4-((S)-1-acetylpyrrolidine-2-carboxamide)-5-(4-(3-methylpyridin-2-yl)piperazin-1-yl)-5-oxopentanoic acid as entry. Biological Examples Example B-1. Inhibitory effect of the compound according to the present invention [Methods for inhibition studies of recombinant human tissue transglutaminase (rhTG2)] 250 μg of lyophilized His-tagged recombinant human tissue transglutaminase (His6-rhTG2, Zedira T022) was reconstituted with HO (volume dependent on original volume before lyophilization) resulting in a buffer containing 10 mM Tris-HCl, 150 mM NaCl, 1 mM EDTA, 5 mM DTT, 189 mg / ml maltodextrin, pH=8.1. The rhTG2 stock solution was diluted with buffer (50 mM Tris-HCl, 7.5 mM CaCl2, 150 mM NaCl, pH=7.4) to give a working solution of 100 U / ml (based on amine-uptake activity measured using T036, described below).

[0524] A 10 mM inhibitor stock solution was prepared in DMSO, from which a series of 1:2 dilutions was also prepared in DMSO. Each of these initial dilutions was subsequently diluted 1:50 in buffer (50 mM Tris-HCl, 7.5 mM CaCl2, 150 mM NaCl, pH=7.4) to give final working dilutions containing 2% (v / v) DMSO.

[0525] 15 μl of inhibitor working dilutions were added to each well of a 96-well microtiter plate. As a control, 15 μl of a 2% (v / v) DMSO solution prepared using the buffer described above was added to each well.

[0526] 600 μl of His6-rhTG2 working solution was added to 11.4 ml of assay buffer (50 mM Tris-HCl, 7.5 mM CaCl2, 150 mM NaCl, 5 mM DTT, 13.4 mM Glycine methyl ester, 50 μM Abz-APE(CAD-DNP)QEA-OH, (Zedira A102; Patent No.: EP1781807B1) pH=7.4). From this master-mix solution, 285 μl was added to each well containing inhibitor. The increase in fluorescence was measured as λ ex = 313 nm and λ em The IC was measured at 418 nm for 20 minutes at 37°C. The slope of the increase in fluorescence from 10 to 20 minutes was calculated as IC50 The values ​​(inhibitor concentration that inhibited 50% of the initial TG2 activity) were calculated. [Methods for inhibition studies of recombinant human coagulation factor XIII (plasma transglutaminase, rhFXIII-A)] 50 μg of lyophilized His-tagged recombinant human factor XIII A-subunit (His6-rhFXIII, Zedira T027) was reconstituted with HO (volume dependent on original volume before lyophilization) resulting in a buffer containing 20 mM Tris-HCl, 150 mM NaCl, 1 mM EDTA, 1 mM DTT, 189 mg / ml maltodextrin, pH=7.5. The rhFXIII stock solution was prepared by adding 100 mM Tris-HCl, 7.5 mM CaCl2, 150 mM NaCl, pH=7.5. = 7.4) to give a working solution of 59 U / ml (based on amine-uptake activity measured using Transglutaminase Activity Assay #T036 (Zedira GmbH), described below).

[0527] A 10 mM inhibitor stock solution is prepared in DMSO, from which a series of 1:2 dilutions are prepared, also in DMSO. Each of the initial dilutions is subsequently diluted 1:50 in buffer (50 mM Tris-HCl, 7.5 mM CaCl, 150 mM NaCl, pH=7.4) to give final working dilutions containing 2% (v / v) DMSO.

[0528] 15 μl of inhibitor working dilutions were added to each well of a 96-well microtiter plate. As a control, 15 μl of a 2% (v / v) DMSO solution prepared using the buffer described above was added to each well.

[0529] 480 μl of His6-rhFXIII working solution and 120 μl of human alpha thrombin (0.5 NIH units / μl) were added to 10.8 ml of assay buffer (50 mM Tris-HCl, 7.5 mM CaCl2, 150 mM NaCl, 5 mM DTT, 13.4 mM glycine methyl ester, 50 μM Abz-NE(CAD-DNP)EQVSPLTLLK-OH, (Zedira A101; Patent No.: EP1781807B1), pH=7.4). From this master-mix solution, 285 μl was added per well containing inhibitor. The increase in fluorescence was measured as λ ex = 313 nm and λ em The IC was measured at 418 nm for 35 minutes at 37°C. The slope of the increase in fluorescence from 20 to 30 minutes was calculated as IC 50 The values ​​(inhibitor concentration that inhibited 50% of the initial FXIII activity) were calculated.

[0530] This assay was also used to determine the selectivity of inhibitors that preferentially inhibit FXIIIa by substituting TG2 for FXIII. [Selectivity Assay (General Transglutaminase Assay; T036)] To determine the selectivity of inhibitors towards different transglutaminases, the incorporation of dansylcadaverine into dimethylcasein (Zedira T036; Lorand et al., Anal Biochem, 1971, 44:221-31) was measured using recombinant human transglutaminase 1 (Zedira T009), transglutaminase 2 (Zedira T022), transglutaminase 3 (Zedira T012), transglutaminase 6 (Zedira T021), and plasma transglutaminase (rhFXIII, Zedira T027).

[0531] The different transglutaminases were diluted in buffer (50 mM Tris-HCl, 7.5 mM CaCl2, 150 mM NaCl, pH=7.4) to their respective working concentrations.

[0532] A 10 mM inhibitor stock solution was prepared in DMSO, from which a series of 1:2 dilutions was prepared, also in DMSO. Each of the initial dilutions was subsequently diluted 1:50 in buffer (50 mM Tris-HCl, 7.5 mM CaCl2, 150 mM NaCl, pH=7.4) to give final working dilutions containing 2% (v / v) DMSO.

[0533] 15 μl of inhibitor working dilutions were added to each well of a 96-well microtiter plate. As a control, 15 μl of a 2% (v / v) DMSO solution prepared using the buffer described above was added to each well.

[0534] Immediately before starting the assay, 600 μl of the transglutaminase working solution was added to 11.4 ml of assay buffer (50 mM Tris-HCl, 10 mM CaCl2, 10 mM glutathione, 2.5% glycerol, 16.7 μM dansylcadaverine, 4 μM N,N-dimethylcasein, 200 mM NaCl, pH=8.0). 285 μl of this reaction mixture was added per well containing inhibitor.

[0535] The increase in fluorescence is denoted as λ ex = 330 nm and λ em The measurement was performed at 37°C for 30 minutes using an IC500 nm wavelength and 500 nm wavelength. The slope of the increase in fluorescence from 20 minutes to 30 minutes was calculated as IC 50 The values ​​(inhibitor concentration that inhibits 50% of the initial activity) were calculated.

[0536] The enzyme activity is analyzed by calculating the slope of the increase in fluorescence intensity. IC 50 Values ​​are calculated by plotting enzyme activity (as a percentage from a control containing 2% DMSO instead of inhibitor) against inhibitor concentration. IC 50is determined as the inhibitor concentration that inhibits 50% of the initial enzyme activity.

[0537] The inhibitory activity of the compounds of the present invention against tissue transglutaminase (TG2) and FXIII-A was evaluated by IC 50 -The values ​​are shown in the following table.

[0538] [Table 1]

[0539] [Table 2-1]

[0540] [Table 2-2]

[0541] [Table 3]

[0542] Example B-2. Cytotoxicity Determination of Transglutaminase Inhibitors The following cell lines are used for the determination of cytotoxicity: ·CaCO2 (human colon cancer cell line) Huh7 (human liver cancer cell line) Cells, 2 x 10 4 Culture in 96-well plates at an initial seeding density of cells / well at 37°C in DMEM / 10% FCS and 5% CO2.

[0543] Transglutaminase inhibitors are added to the cells at final concentrations between 0.1 μM and 1 mM 1 h after seeding. Different inhibitor dilutions are prepared in DMSO resulting in a final concentration of 1% (v / v) DMSO in each well (2 μl of inhibitor in 200 μl cell medium). Cycloheximide (2.5 μg / ml) and camptothecin (0.2 μg / ml) are used as control compounds. All measurements are performed in triplicate.

[0544] The cytotoxicity of transglutaminase inhibitors is assessed using two different assays: [Cell proliferation ELISA, proliferation determined using BrdU] (Roche, Cat. No. 11647229001) After 24 hours of incubation with inhibitors or controls, BrdU is added to the cells. After a further 18 hours of incubation, the cells are fixed and the cellular DNA is denatured. A monoclonal antibody raised against BrdU (conjugated to peroxidase) is added to the wells. It binds to BrdU which is added and incorporated into DNA. Substrate solution is added and the absorbance at 450 nm is recorded. Further analysis is carried out according to the manufacturer's protocol. [Determination of metabolic activity using EZ4U-assay] (Biomedica, Cat. No. BI-5000) After 48 hours of incubation with inhibitors or controls, the tetrazolium substrate is added to the cells and substrate turnover by the cells is measured over 2 hours at 450 nm (using 630 nm as reference wavelength).

[0545] The cytotoxicity of inhibitor pairs characterized by the same backbone but reversible (alpha-ketoamide) or irreversible (diazooxonorleucine) apical moiety is given in Table 4. Compounds with diazooxonorleucine-apical moiety revealed a reduction in cell proliferation and metabolic activity at concentrations between 100 μM and 500 μM (depending on cell type). In striking contrast, the reversible inhibitors had no effect in both parameters up to the highest concentration measured (1 mM). To demonstrate this effect, we compared the commercially available irreversibly acting inhibitor Z006 (Z-DON-VPL-OMe, “Z-DON”, Zedira) with the reversible inhibitor E02, which has the same peptide backbone, but different apical moiety (alpha-ketoamide) and mode of action (irreversible vs. reversible). Z006 was cytotoxic at 125 μM, whereas the novel compound E02 had no effect on cell proliferation or metabolic activity up to 1 mM (the highest concentration measured).

[0546] [Table 4]

[0547] Example B-3. Antifibrotic effects in renal cells Fibrosis is a prominent feature in diabetic nephropathy and chronic kidney disease. Proximal tubular epithelial cells show increased TG2 activity and increased extracellular matrix protein (ECM) deposition under hyperglycemic conditions. ECM deposition is a prominent feature of fibrosis. To demonstrate the antifibrotic effect of reversible transglutaminase inhibitors, compounds E06 and E22 were tested in proximal tubular epithelial cells cultured under normal versus hyperglycemic conditions. TG2-activity and ECM-precipitation were measured.

[0548] The Norway rat (Rattus norvegicus) kidney-derived cell line NRK52E was grown in DMEM (Dulbecco's modified Eagle's medium) containing 100 μg / mL streptomycin, 100 units / ml penicillin, 20 mM glutamine, and 10% (v / v) fetal bovine serum at 37° C. in a humidified atmosphere with 5% (v / v) CO2. For simulations under normal physiological conditions, 6 mM D-glucose was added to the medium, while 24 mM and 36 mM D-glucose were added to simulates under hyperglycemic conditions. The reversible TG2 inhibitor E06 at the concentrations indicated in FIG. 1A was added to the medium at the time of plating. The reversible TG2 inhibitor E22 at the concentrations indicated in FIG. 2A was added to the medium at the time of plating. The medium was added at the time of plating.

[0549] TG2-activity was determined in cell homogenates. Thus, cells were removed from plates with trypsin (2mg / mL)-EDTA (2mM) solution, centrifuged, washed with PBS, and finally stored in sucrose (0.32mM)-Tris-(5mM)-EDTA (1mM)-buffer pH 7.2 containing 1μL / mL protease inhibitor (Halt™ protease and phosphatase inhibitor cocktail, EDTA-free, ThermoFisher, #1861279). Equal amounts of cells were homogenized by sonication.

[0550] TG2-activity was measured using a TG2-selective tissue transglutaminase Pico-assay kit (#M003, Zedira, Darmstadt, Germany) according to the manufacturer's instructions. One unit is defined as the amount of enzyme that catalyzes the reaction between Z-Gln-Gly-OH and hydroxylamine to form 1.0 μmole of hydroxamate per minute at pH 6.0 and 37° C.

[0551] For the determination of extracellular matrix protein (ECM) precipitation, cells grown in 10 cm Petri dishes were removed with 1 mL of sodium deoxycholate (0.1%)-EDTA (2 mM)-solution. ECM proteins remaining on the plate were solubilized by digestion with trypsin (0.2 mg / mL)-EDTA (2 mM) solution. The resulting solution was concentrated by speed-vac. Protein concentration was determined using the DC-protein-assay (BioRad, #5000111).

[0552] Intracellular TG2 is increased in NRK52E-cells at hyperglycemic conditions of 24 mM and 36 mM glucose (Figure 1A, E06 at 0 µM). With increasing concentrations of E06, TG2 activity determined in cell homogenates is decreased (Figure 1A, E06 at 10-100 µM). The production of extracellular matrix proteins is increased at hyperglycemic concentrations (Figure 1B, E06 at 0 µM). The increase in ECM was reduced in a dose-dependent manner by adding E06 to the culture medium.

[0553] Intracellular TG2 is increased in NRK52E-cells at hyperglycemic conditions of 24 mM and 36 mM glucose (Figure 2A, 0 µM E22). With increasing concentrations of E22, TG2 activity determined in cell homogenates is decreased (Figure 2A, 10-100 µM E22). The production of extracellular matrix proteins is increased at hyperglycemic concentrations (Figure 2B, 0 µM E22). The increase in ECM was reduced in a dose-dependent manner by adding E22 to the culture medium.

[0554] In summary, these results show that tissue transglutaminase inhibition with the reversible tissue transglutaminase inhibitors E06 and E22 reduces transglutaminase activity and reduces ECM accumulation. These data indicate that E06 and E22 have antifibrotic effects in proximal tubule epithelial cells. Example B-4. Thromboelastometry (TEM) Thromboelastometry is a visco-elastic method for the evaluation of blood clotting. It measures clotting time (CT), clot formation time (CFT), maximum clot firmness (MCF), and lysis index at 60 minutes (LI). 60 Total blood parameters such as blood glucose level, blood glucose level, and blood glucose concentration were obtained using a ROTEM® delta instrument according to the manufacturer.

[0555] The efficacy of selected compounds (serial dilutions covering final concentrations from 6.25 μM to 50 μM) was investigated in the presence of 0.02 μg / ml tissue plasminogen activator (t-PA, Zedira P016). Briefly, 0.36 μg / ml t-PA and 300 μL of fresh citrated whole blood (human, from healthy consenting donors) were diluted in 18% DMSO / PBS to obtain concentrations of 0.9-0.11 mM, with 20 μL star-TEM® (0.2 mol / l CaCl2), 20 μL r For ex-TEM® (recombinant tissue factor, phospholipid, heparin inhibitor), 10 μL of inhibitor stock solution (1.8-0.23 mM) was combined with 10 μL of t-PA stock solution (0.72 μg / ml) and mixed in a disposable cuvette. As a control, the inhibitor stock solution was replaced by a solution with 36% DMSO / 0.36 μg / ml t-PA in PBS. (Lang T, von Depka M.Possibilities and limitations of thrombelastometry / -graphy.Hamostaseologie.2006;26:S20-S29.) The results of the dose-dependent effects of compounds E25 and E27 on TEM parameters are shown in Figures 3A) / 3B) and 4A) / 4B), respectively.

[0556] Figures 3A) and 4A) show the dose-dependent effect of compounds E25 and E27 in reducing maximum clot firmness (MCF) compared to control (K). Figures 3B) and 4B) show that clot lysis (LI) at 60 min in the presence of 0.02% t-PA 60 ) shows the dose-dependent effects of compounds E25 and E27. Example B-5. Investigation of the reversible mode of inhibition of α-keto compounds To investigate the reversibility of α-ketoamide as TG2-inhibitor, the inhibitor was removed stepwise using Vivaspin® centrifugal concentrators (VS2022, Sartorius Stedim), while the molecular weight of TG2 does not pass through the ultrafiltration membrane. Briefly, recombinant human tissue transglutaminase (Zedira, T002) was incubated with inhibitor 16 at 1.6 μM. Transglutaminase activity was determined using the casein / dansylcadoverine assay (Zedira, T036). Subsequently, buffer was added to dilute the inhibitor into the reaction mixture as shown in Table 5. After concentration to the original volume using Vivaspin centrifugal concentrators, the procedure was repeated twice to obtain 1:100 and 1:1,000 dilutions. Activity increases with increasing dilution indicating that the inhibitor binds to TG2 at equilibrium. As the concentration of the inhibitor decreases, the proportion of uninhibited transglutaminase increases, resulting in increased activity. As a control, the same experiment was performed with REF1, which inhibits the activity of TG2 by binding to the active site cysteine.

[0557] [ka]

[0558] As expected, we could not find any recombination in activity.Finally, the claimed α-keto compounds provide a reversible mode of inhibition.

[0559] [Table 5]

[0560] Example B-6. Inhibition of neurite outgrowth The irreversible-reversible inhibitor pair Z007 and E57 were further compared using a neurite outgrowth assay (Merck, #NS220) with the mouse neuroblastoma cell line N1E-115. Laminin-coated Millicell® 12-well inserts were placed in a 12-well plate containing 1.2 mL of differentiation medium (Merck, NS002). Then, 300 μL of 10 6 N1E-115-cells / mL suspension was added. Differentiation medium contained 0 μM, 75 μM, and 150 μM nocadazole as a positive control, as well as 100 μM, 250 μM, and 500 μM inhibitors Z007 or E57. Nocadazole prevents microtubule polymerization, resulting in an antitumor effect.

[0561] For neurite outgrowth, the plates were incubated at 37°C for 48 hours. The inserts were then transferred to new 12-well plates with 1,200 μL PBS per plate, and finally transferred to the plates with 400 μL -20°C methanol per well, and the cells were fixed in the plates for 20 minutes at room temperature. After rinsing with PBS, the inserts were stained with neurite staining solution for 20 minutes. After rinsing the inserts in PBS, the cell bodies were carefully swabbed off and the inserts were washed again with PBS. The inserts were then transferred to 15 mL tubes and 100 μL of neurite staining extraction buffer was added up to the top of the inserts. After 5 minutes of incubation at ambient temperature, the tubes were centrifuged at 1,200 rpm for 1 minute. Finally, 75 μL of extraction buffer was removed and the absorbance was determined at 590 nm.

[0562] The results are summarized in Figure 5. The irreversible TG2-inhibitor Z007 reduced neurite outgrowth in a dose-dependent manner. At 500 μM, a moderate 36% reduction was observed. The reversible TG2-inhibitor E57 had a dose-dependent, but even more mild effect on neurite outgrowth. At 500 μM, the reduction in neurite outgrowth was 18%. Example B-7. Effect of TG2-inhibition in Huntington-producing cell lines Insoluble protein aggregates composed of the protein huntingtin (htt) are a hallmark of Huntington's disease. Htt is characterized by polyglutamine (PolyQ)-expansion, which induces aggregation and serves as a substrate for cross-linking and catalyzing transglutaminase.

[0563] N2a cells (mouse neuroblastoma) transformed with Htt-exon 1-97Q were grown in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum, 1 mM glutamine, 100 μg / mL streptomycin, and 100 U / mL penicillin in a humidified incubator at 37°C with 5% CO .

[0564] For preparation of SDS-soluble and formic acid-soluble extracts, cells were harvested in 0.5 mL of cold PBS, centrifuged, resuspended in 70 mM Tris-HCl pH 6.8, 1.5% SDS, 20% glycerol, and lysed via sonication. DTT was added to a final concentration of 50 mM, and samples were boiled for 10 min at 1000 rpm in a ThermoMixer®, followed by centrifugation at 14,000 rpm for 1 h. Supernatants were transferred to new tubes and stored at 4° C. before coating microtiter plates.

[0565] For solubilization of SDS-insoluble proteins in the remaining pellet, 10 μl of formic acid was added and mixed by pipetting up and down 10 times, followed by incubation at 1,000 rpm and 37° C. for 40 min in a ThermoMixer®. Formic acid was then removed under vacuum in a SpeedVac™ concentrator at 30° C. The resulting protein precipitate was dissolved in 70 mM Tris-HCl pH 6.8, 1.5% SDS, 20% glycerol. Samples were boiled for 10 min and stored at 4° C. before coating the microtiter plate.

[0566] The SDS-soluble and formic acid-soluble extracts were subsequently used for coating of 96-well micro-titer plates. Thus, 100 μL of cell extract was added to each well and incubated overnight at 4° C. After washing with Tris-buffered saline, 0.1% Tween 20, the plate was blocked with 150 μL of a 1%-BSA-solution in PBS for 60 min at 37° C. After washing, 100 μL of detection antibody was added and incubated for 60 min at ambient temperature. This solution was removed, the plate was washed again vigorously and the secondary antibody was applied (goat anti-mouse IgG-HRP-conjugate) for another 30 min at ambient temperature. The plate was washed vigorously and 100 μL of substrate solution (TMB-H2O2) was added. After incubation for 60 min at room temperature, the reaction was stopped by the addition of 0.2 M sulfuric acid. The absorbance was measured at 450 nm in a plate reader instrument.

[0567] To analyze the effect of E22 on huntingtin aggregation and cross-linking, Htt-exon 1-97Q-transformed N2a-cells were grown in the presence of 150 μM or 300 μM of the TG2-inhibitor E22. SDS-soluble and formic acid-soluble extracts were generated and huntingtin and cross-linking (isopeptide bonds) were determined in an ELISA-format as described above.

[0568] The results are summarized in Figures 6A and 6B. The amount of SDS-soluble htt increases with increasing E22 concentration. Concomitantly, the amount of formic acid-soluble htt decreases. In the soluble and formic acid soluble extracts, the amount of cross-linking decreases in a dose-dependent manner.

[0569] Taken together, E22 reduces protein cross-linking in a dose-dependent manner, and since htt-protein is concomitantly reduced in the formic acid-soluble fraction, the increased amount of htt protein in the SDS-soluble fraction may be explained by a reduction in enzymatic cross-linking of htt, preserving protein solubility.

[0570] The observed htt-aggregation reducing effect of the TG2-inhibitor E22 supports the potential of reversibly acting transglutaminase inhibitors for the treatment of neurodegenerative diseases characterized by cross-linked insoluble protein aggregates. Example B-8. Antifibrotic effects in lung epithelial cells Extracellular matrix deposition is a hallmark of pulmonary fibrosis. The BEAS-2B cell line is derived from normal human bronchial epithelium. To demonstrate the antifibrotic effect of reversible transglutaminase inhibitors, compound E22 was tested in BEAS-2B cells stimulated with lipopolysaccharide (LPS).

[0571] BEAS-2B cells were grown in 25 mM HEPES-buffered M199-medium (Merck, Darmstadt) containing 10% FBS, 100 mg / ml streptomycin, 2 mM glutamine, 100 U / ml penicillin (supplemented with 2.5 mg / ml apotransferrin, 20 ng / ml human epidermal growth factor (EGF), 2.5 mg / ml insulin, and 0.361 mg / ml hydrocortisone) at 37°C and 5% CO2. For induction of airway fibrosis by epithelial-mesenchymal transition (EMT), cells were seeded at 80% confluence in 6-well plates. After 1 day of culture, 4 μg / mL LPS and 0 μM, 100 μM, or 200 μM E22 were added and then incubated for another 72 h.

[0572] Subsequently, cells were harvested and TG2-activity and ECM-precipitation were measured as described above for demonstration of anti-fibrotic effects in renal cells. Transglutaminase activity measured in LPS-stimulated BEAS-2B-cells showed a dose-dependent decrease upon addition of increasing amounts of E22 to the differentiation medium (FIG. 7A).

[0573] In parallel, ECM-protein precipitation was also significantly reduced in a dose-dependent manner (FIG. 7B). Taken together, these data indicate an antifibrotic effect of E22 in lung epithelial cells. Example B-9. Antifibrotic effect in hepatic stellate cells Liver fibrosis is characterized by the formation of scar tissue as a response to liver injury. Activated hepatic stellate cells (HSCs) are the predominant cell type in liver fibrosis that deposit extracellular matrix proteins, primarily collagen, in the space of Disse (perisinusoidal space). Liver fibrosis is the result of inflammation in response to liver injury. Inflammation is characterized by HSC activation to a myofibroblast-like phenotype. LX-2 human hepatic stellate cell line The human hepatic stellate cell line LX-2 was cultured in standard plastic 6-well plates in Dulbecco's modified Eagle's medium containing 100 μg / mL streptomycin, 100 units / mL penicillin, 2 mM glutamine, and 10% (v / v) fetal bovine serum. E22 was added at concentrations of 0 μM, 100 μM, and 200 μM. Cells were grown at 37°C, 5% CO2, humidified air. Medium was changed every 2 days. After 12 days, cells were harvested and analyzed for TG2-activity and extracellular matrix deposition as described above for determination of antifibrotic effects in renal cells.

[0574] Transglutaminase activity was reduced to <5% of the no-inhibitor control already at 100 μM of the reversible transglutaminase inhibitor E22 in the culture medium (Figure 8A). Extracellular matrix deposition in the plates was reduced to approximately 30% of the control at both E22 concentrations.

[0575] These results indicate that TG2 inhibition of HSCs reduces the deposition of extracellular matrix proteins and may therefore provide an antifibrotic effect in liver fibrosis.

[0576] In parallel, ECM-protein deposition was significantly reduced in a dose-dependent manner (FIG. 8B). Taken together, these data indicate an antifibrotic effect of E22 in hepatic stellate cells.

Claims

1. A compound of general formula (I) or a diastereomer, an enantiomer, a mixture of diastereomers, a mixture of enantiomers, a racemate, a solvate, a hydrate, or a pharma- ceutically acceptable salt of a compound of general formula (I), 【Chemistry 1】 During the ceremony, n is an integer 1; W is 【Chemistry 2】 represents; R ２ is -R １ , -OR １ , -NH ２ , -NH(R １ ), or -NH(OR １ ) R １ is -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , -CH(CH ３ ) ２ , -CH ２ CH ２ CH ２ CH ３ , -CH ２ CH ２ CH ２ CH ２ CH ３ , -CH ２ CH ２ CH ２ CH ２ CH ２ CH ３ , -CH ２ CH ２ CH ２ CH ２ CH ２ CH ２ CH ３ , -CH ２ CH (CH ３ ) ２ , -CH(CH ３ ) CH ２ CH ３ , -CH(C ２ H ５ ) ２ , -CH ２ CH (C ２ H ５ ) ２ , -C(CH ３ ) ３ , -CH ２ -C(CH ３ ) ３ , -cyclo-C ３ H ５ , -cyclo-C ４ H ７ , -cyclo-C ５ H ９ , -cyclo-C ６ H １１ , -CH ２ -Cyclo-C ３ H ５ , -CH ２ -Cyclo-C ４ H ７ 、-CH ２ -シクロ-C ５ H ９ 、-CH ２ -シクロ-C ６ H １１ ,-Ph,-CH ２ -Ph、-CH ２ OCH ３ 、-CH ２ OCH ２ CH ３ 、-CH ２ CH ２ OCH ３ 、-CH ２ CH ２ OCH ２ CH ３ 、-CH ２ CO ２ CH ３ 、-CH ２ CO ２ CH ２ CH ３ 、-CH ２ S (O) ２ -(4-methyl-phenyl), 【Chemistry 3】 represents; Z Ｎ Is E Ｎ - or E Ｎ - A.S. Ｎ１ - represents; Z Ｃ , -E Ｃ , -AS Ｃ１ -E Ｃ , -AS Ｃ１ - A.S. Ｃ２ - A.S. Ｃ３ -E Ｃ , or -AS Ｃ１ - A.S. Ｃ２ - A.S. Ｃ３ - A.S. Ｃ４ -E Ｃ represents; A.S. Ｎ１ teeth, 【Chemistry 4】 and Z Ｃ Ga-AS Ｃ１ -E Ｃ When A.S. Ｃ１ teeth 【Chemistry 5】 and Z Ｃ Ga-AS Ｃ１ - A.S. Ｃ２ - A.S. Ｃ３ -E Ｃ When Ｃ１ - A.S. Ｃ２ - A.S. Ｃ３ -teeth 【Chemistry 6】 and Z Ｃ Ga-AS Ｃ１ - A.S. Ｃ２ - A.S. Ｃ３ - A.S. Ｃ４ -E Ｃ When Ｃ１ - A.S. Ｃ２ - A.S. Ｃ３ - A.S. Ｃ４ -teeth 【Chemistry 7】 and E Ｃ is -OR ８ , -NR ９ R １０ , -NHSO ２ R １１ , -O-L １ -R ８ , -O-L １ -O-R ８ , -NH-L １ -O-R ８ , -NH-L １ -NR ９ R １０ , and 【Chemistry 8】 and the C-terminal group is selected from the group consisting of: E Ｎ is -H, -COCH ３ , -COC ２ H ５ , -COC ３ H ７ , -COCH(CH ３ ) ２ , -COCH(C ２ H ５ ) ２ , -COC ４ H ９ , -COC ５ H １１ , -COC ６ H １３ , -COCH ２ -CH(CH ３ ) ２ , -COCH ２ -CH(C ２ H ５ ) ２ , -COCH(CH ３ ) -C ２ H ５ , -COC(CH ３ ) ３ , -COCH ２ -C(CH ３ ) ３ , -CO-cyclo-C ３ H ５ , -CO-cyclo-C ４ H ７ , -CO-cyclo-C ５ H ９ , -CO-cyclo-C ６ H １１ , -COCH ２ -Cyclo-C ３ H ５ , -COCH ２ -Cyclo-C ４ H ７ , -COCH ２ -Cyclo-C ５ H ９ , -COCH ２ -Cyclo-C ６ H １１ , -COPh, -COCH ２ -Ph, -COOCH ３ , -COOC ２ H ５ , -COOC ３ H ７ , -COOCH(CH ３ ) ２ , -COOCH(C ２ H ５ ) ２ , -COOC ４ H ９ , -COOC ５ H １１ , -COOC ６ H １３ , -COOCH ２ -CH(CH ３ ) ２ , -COOCH ２ -CH(C ２ H ５ ) ２ , -COOCH(CH ３ ) -C ２ H ５ , -COOC(CH ３ ) ３ , -COOCH ２ -C(CH ３ ) ３ , -COO-cyclo-C ３ H ５ , -COO-cyclo-C ４ H ７ , -COO-cyclo-C ５ H ９ , -COO-cyclo-C ６ H １１ , -COOCH ２ -Cyclo-C ３ H ５ , -COOCH ２ -Cyclo-C ４ H ７ , -COOCH ２ -Cyclo-C ５ H ９ , -COOCH ２ -Cyclo-C ６ H １１ , -COOPh, -COOCH ２ -Ph, 【Chemistry 9】 The N-terminal group is selected from the group consisting of: However, Z Ｎ E Ｎ and Z Ｃ E Ｃ When E Ｃ teeth 【Chemistry 10】 and R ４ , R ５ , and R ６ are each independently -H, -F, -Cl, -Br, -CH ３ , or -CF ３ represents; R ７ represents -H; R ８ , R ９ , R １０ , and R １１ are each independently -H, -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , -CH(CH ３ ) ２ , -CH(C ２ H ５ ) ２ , -CH ２ CH (CH ３ ) ２ , -CH ２ -CH(C ２ H ５ ) ２ , -C ４ H ９ , -C ５ H １１ , -C ６ H １３ , -CH(CH ３ ) -C ２ H ５ , -C(CH ３ ) ３ , -CH ２ -C(CH ３ ) ３ , 【Chemistry 11】 represents; R １２ ~R １４ , R １８ ~R ２０ , and R ２４ ~R ２９ are each independently -H, -F, -Cl, -Br, -I, -OH, -CN, or -NO ２ , -CH ３ , -C ２ H ５ , -C ３ H ７ , -CH(CH ３ ) ２ , -C ４ H ９ , -CH ２ -CH(CH ３ ) ２ , -CH(CH ３ ) -C ２ H ５ , -C(CH ３ ) ３ , -cyclo-C ３ H ５ , -CH ２ -Cyclo-C ３ H ５ , -CH ２ F, -CHF ２ , -CF ３ , -CH ２ Cl, -CH ２ Br, -CH ２ I, -CH ２ -CH ２ F, -CH ２ -CHF ２ , -CH ２ -CF ３ , -CH ２ -CH ２ Cl, -CH ２ -CH ２ Br, -CH ２ -CH ２ I, -OCH ３ , -OC ２ H ５ , -OC ３ H ７ , -OCH(CH ３ ) ２ , -OC(CH ３ ) ３ , -OC ４ H ９ ,-OCHF ２ ,-OCF ３ ,-OCH ２ CF ３ ,-OC ２ F ５ ,-OCH ２ OCH ３ 、-O-シクロ-C ３ H ５ ,-OCH ２ -シクロ-C ３ H ５ ,-O-C ２ H ４ -シクロ-C ３ H ５ 、-CHOO、-COCH ３ ,-COCF ３ ,-COC ２ H ５ ,-COC ３ H ７ , -COCH (CH ３ ) ２ , -COC (CH) ３ ) ３ 、-COOOH、-COOCH ３ ,-COOC ２ H ５ ,-COO ３ H ７ 、-COOOCH (CH ３ ) ２ , -COOC (CH ３ ) ３ ,-OO--CH ３ ,-OO-CF ３ ,---- ２ H ５ ,---- ３ H ７ 、-OOC-CH (CH ３ ) ２ 、-OOC-C (CH ３ ) ３ ,-NH ２ ,-NHCH ３ ,-NHC ２ H ５ ,-NHC ３ H ７ , -NHCH (CH ３ ) ２ , -NHC (CH) ３ ) ３ , -N (CH) ３ ), ２ , -N(C ２ H ５ ), ２ , -N(C ３ H ７ ), ２ , -N[CH(CH ３ ), ２ , ２ , -N[C(CH ３ ), ３ , ２ , -NHCOCH ３ , -NHCOCF ３ , -NHCOC ２ H ５ , -NHCOC ３ H ７ , -NHCOCH(CH ３ ), ２ , -NHCOC(CH ３ ), ３ , -CONH ２ , -CONHCH ３ , -CONHC ２ H ５ , -CONHC ３ H ７ , -CONHCH(CH ３ ), ２ , -CONH - cyclo - C ３ H ５ , -CONHC(CH ３ ), ３ , -CON(CH ３ ), ２ , -CON(C ２ H ５ ), ２ , -CON(C ３ H ７ ), ２ , -CON[CH(CH ３ ), ２ , ２ , or -CON[C(CH ３ ), ３ , ２ represents; R Ｎ は、-COCH ３ ,---- ２ H ５ ,---- ３ H ７ ,-COEH(COE ３ ) ２ 、 【Chemistry 12】 represents; R Ｎ３ is -H, -CH ３ , -C ２ H ５ , -C ３ H ７ , -CH(CH ３ ) ２ , -COCH ３ , -COC ２ H ５ , -COC ３ H ７ , or -COCH(CH ３ ) ２ represents; L １ ~L ６ are each independently a covalent bond, -CH ２ --, 【Chemistry 13】 represents; L ９ and L １０ are each independently a covalent bond, -CO-, -CO-CH=CH-, -COO-, -CONH-, -NHCO-, -CSNH-, -NHCS-, or -SO ２ - is; A compound of general formula (I), or a diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemate, solvate, hydrate, or pharma- ceutically acceptable salt of a compound of general formula (I).

2. A compound comprising: Formulas (VI-1) to (VI-3): 【Chemistry 14】 and During the ceremony, Z Ｎ Is E Ｎ - represents Z Ｃ３ , -E Ｃ , or -AS Ｃ４ -E Ｃ represents; R ２ is -OCH ３ , -NH ２ , -NHCH ３ , -NHCH ２ CH ３ , -NHCH ２ CH ２ CH ３ , -NHCH ２ CH ２ CH ２ CH ３ , -NHCH ２ CH ２ CH ２ CH ２ CH ３ , -NH-cyclo-C ３ H ５ or -NHCH ２ represents Ph; A.S. Ｃ４ teeth, 【Chemistry 15】 and E C is -OR 8 , -NR 9 R 10 , -NHSO 2 R 11 , -O-L 1 -R 8 , -O-L 1 -O-R 8 , -NH-L 1 -O-R 8 , -NH-L 1 -NR 9 R 10 , and 【Chemistry 16】 and the C-terminal group is selected from the group consisting of: E N is -H, -COCH 3 , -COC 2 H 5 , -COC 3 H 7 , -COCH(CH 3 ) 2 , -COCH(C 2 H 5 ) 2 , -COC 4 H 9 , -COC 5 H 11 , -COC 6 H 13 , -COCH 2 -CH(CH 3 ) 2 , -COCH 2 -CH(C 2 H 5 ) 2 , -COCH(CH 3 )-C 2 H 5 , -COC(CH 3 ) 3 , -COCH 2 -C(CH 3 ) 3 , -CO-cyclo-C 3 H 5 , -CO-cyclo-C 4 H 7 , -CO-cyclo-C 5 H 9 , -CO-cyclo-C 6 H 11, -COCH 2 -cyclo-C 3 H 5 , -COCH 2 -cyclo-C 4 H 7 , -COCH 2 -cyclo-C 5 H 9 , -COCH 2 -cyclo-C 6 H 11 , -COPh, -COCH 2 -Ph, -COOCH 3 , -COOC 2 H 5 , -COOC 3 H 7 , -COOCH(CH 3 ) 2 , -COOCH(C 2 H 5 ) 2 , -COOC 4 H 9 , -COOC 5 H 11 , -COOC 6 H 13 , -COOCH 2 -CH(CH 3 ) 2 , -COOCH 2 -CH(C 2 H 5 ) 2 , -COOCH(CH 3 )-C 2 H 5 , -COOC(CH 3 ) 3 , -COOCH 2 -C(CH 3 ) 3 , -COO-cyclo-C 3 H 5 , -COO-cyclo-C 4 H 7 , -COO-cyclo-C 5 H 9 , -COO-cyclo-C 6 H 11 , -COOCH 2 -cyclo-C 3 H 5 , -COOCH 2 -cyclo-C 4 H 7 , -COOCH 2 -cyclo-C 5 H 9 , -COOCH 2 -cyclo-C 6 H 11 , -COOPh, -COOCH 2 -Ph, 【Chemistry 17】 A compound selected from the N-terminal group consisting of:

3. 2. The compound of claim 1, having the formula (IX): 【Chemistry 18】 having During the ceremony, Z Ｃ１ , -E Ｃ represents E Ｃ , R ４ ~R ７ , W, and Z Ｎ has the same meaning as defined in claim 1.

4. The compound according to claim 3, having the formula (XI-3): 【Chemistry 19】 having During the ceremony, Z Ｃ１ , -E Ｃ represents; Z Ｎ Is E Ｎ - represents; R ２ is -CH ３ , -CH ２ CH ３ , -CH(CH ３ ) ２ , -cyclo-C ３ H ５ , -Ph, -OCH ３ , -OCH ２ CH ３ , -NH ２ , -NHCH ３ , -NH-cyclo-C ３ H ５ , —NH—CH ２ Ph, -NHC(CH ３ ) ３ , -NH-C ５ H １１ , -NHCH ２ OCH ３ , -NHCH ２ CH ２ OCH ３ , -NHCH ２ CO ２ OCH ３ or -NH-OCH ２ -Cyclo-C ５ H ９ represents; and R ４ , R ５ , and R ６ are each independently -H, -F, -Cl, -Br, -CH ３ , or -CF ３ represents R ７ represents -H; and E Ｃ , and E Ｎ has the same meaning as defined in claim 1.

5. The compound according to claim 1, which is represented by formula (XIV-1); 【Chemistry 20】 having During the ceremony, n, W, E Ｎ , and R ２７ ~R ２９ has the same meaning as defined in claim 1, compound.

6. A compound comprising: (S)-Methyl 2-((S)-1-((S)-2-((S)-2-acetamido-6-amino-5,6-dioxohexanamido)-3-methylbutanoyl)pyrrolidine-2-carboxamido)-4-methylpentanoate (E01), (S)-Methyl 2-((S)-1-((S)-2-((S)-6-amino-2-(benzyloxycarbonylamino)-5,6-dioxohexanamido)-3-methylbutanoyl)pyrrolidine-2-carboxamido)-4-methylpentanoate (E02), (S)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-(1-methyl-1H-imidazole-5-carboxamide)-5-oxohexanediamide (E04), (S)-2-(2-bromo-4-methylthiazole-5-carboxamide)-N1-(1-(2-(isopentylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-5-oxohexanediamide (E05), (S)-5-acetamido-6-(4-(2-chlorophenyl)piperazin-1-yl)-2,6-dioxohexanamide (E06), (S)-1-acetyl-N-((S)-6-amino-1-(4-(3-methylpyridin-2-yl)piperazin-1-yl)-1,5,6-trioxohexan-2-yl)pyrrolidine-2-carboxamide (E07), (S)-N1-((S)-1-((R)-2-((S)-2-((S)-2-amino-1-cyclohexyl-2-oxoethylamino)-1-cyclohexyl-2-oxoethylcarbamoyl)piperidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-2-(6-hydroxy-5-nitronicotinamide)-5-oxohexanediamide (E09), 3-((2S)-6-amino-1-((2S)-3-cyclopropyl-1-((1R,2S)-2-((2S)-1-((2S)-2-(1-(2,6-dimethylphenoxy)propan-2-ylcarbamoyl)-2-methylpyrrolidin-1-yl)-1-oxopentan-2-ylcarbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-1-oxopropan-2-ylamino)-1,5,6-trioxohexan-2-ylcarbamoyl)-5-nitrobenzoic acid (E10), (S)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-5-oxo-2-(pyrazine-2-carboxamide)hexanediamide (E11), (S)-2-benzamido-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-5-oxohexanediamide (E12), (S)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-(2-methyl-5-nitrobenzamido)-5-oxohexanediamide (E13), (S)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-(4-methylthiazole-5-carboxamido)-5-oxohexanediamide (E14), (S)-2-(5-(dimethylamino)naphthalene-1-sulfonamide)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-5-oxohexanediamide (E15), (S)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide (E16), (S)-N1-ethyl-N6-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-5-(1-methyl-1H-imidazole-5-carboxamido)-2-oxohexanediamide (E17), (S)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxo-N6-pentylhexanediamide (E18), (S)-N1-cyclopropyl-N6-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-5-(1-methyl-1H-imidazole-5-carboxamido)-2-oxohexanediamide (E19), (S)-N1-benzyl-N6-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-5-(1-methyl-1H-imidazole-5-carboxamido)-2-oxohexanediamide (E20), (S)-N1-tert-butyl-N6-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-5-(1-methyl-1H-imidazole-5-carboxamide)-2-oxohexanediamide (E21), (S)-2-((S)-1-acetylpyrrolidine-2-carboxamide)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-5-oxo-N6-pentylhexanediamide (E22), (S)-2-benzamido-N6-cyclopropyl-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-5-oxohexanediamide (E23), (S)-Methyl 2-((S)-1-((S)-2-((S)-2-benzamido-6-(cyclopropylamino)-5,6-dioxohexanamido)-3-methylbutanoyl)pyrrolidine-2-carboxamido)-4-methylpentanoate (E24), 4-((S)-1-((S)-1-((S)-2-((S)-2-((S)-2-amino-1-cyclohexyl-2-oxoethylamino)-1-cyclohexyl-2-oxoethylcarbamoyl)-4-oxopyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylamino)-6-(methylamino)-1,5,6-trioxohexan-2-ylcarbamoyl)nicotinic acid (E25), 4-((S)-1-((S)-1-((S)-2-((S)-2-((S)-2-amino-1-cyclohexyl-2-oxoethylamino)-1-cyclohexyl-2-oxoethylcarbamoyl)-4-oxopyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylamino)-6-(ethylamino)-1,5,6-trioxohexan-2-ylcarbamoyl)nicotinic acid (E26), 4-((S)-1-((S)-1-((S)-2-((S)-2-((S)-2-amino-1-cyclohexyl-2-oxoethylamino)-1-cyclohexyl-2-oxoethylcarbamoyl)-4-oxopyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylamino)-1,5,6-trioxo-6-(pentylamino)hexan-2-ylcarbamoyl)nicotinic acid (E27), 4-((S)-1-((S)-1-((S)-2-((S)-2-((S)-2-amino-1-cyclohexyl-2-oxoethylamino)-1-cyclohexyl-2-oxoethylcarbamoyl)-4-oxopyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl-amino)-6-(cyclopropylamino)-1,5,6-trioxohexan-2-ylcarbamoyl)nicotinic acid (E28), 4-((S)-1-((S)-1-((S)-2-((S)-2-((S)-2-amino-1-cyclohexyl-2-oxoethylamino)-1-cyclohexyl-2-oxoethylcarbamoyl)-4-oxopyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylamino)-6-(benzylamino)-1,5,6-trioxohexan-2-ylcarbamoyl)nicotinic acid (E29), 4-((S)-1-((S)-1-((S)-2-((S)-2-((S)-2-amino-1-cyclohexyl-2-oxoethylamino)-1-cyclohexyl-2-oxoethylcarbamoyl)-4-oxopyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylamino)-6-(tert-butylamino)-1,5,6-trioxohexan-2-ylcarbamoyl)nicotinic acid (E30), 4-((S)-6-amino-1-((S)-1-((S)-2-((S)-2-((S)-2-amino-1-cyclohexyl-2-oxoethylamino)-1-cyclohexyl-2-oxoethylcarbamoyl)-4-oxopyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylamino)-1,5,6-trioxohexan-2-ylcarbamoyl)nicotinic acid (E31), (S)-N1-((S)-1-((S)-2-((S)-2-((S)-2-amino-1-cyclohexyl-2-oxoethylamino)-1-cyclohexyl-2-oxoethylcarbamoyl)-4-oxopyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N6-cyclopropyl-2-(2-methylthiazole-4-carboxamido)-5-oxohexanediamide (E32), (S)-Methyl 2-(6-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-5-(1-methyl-1H-imidazole-5-carboxamido)-2,6-dioxohexanamide)acetate (E38), (S)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-(methoxymethyl)-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide (E39), (S)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxo-N6-(thiazol-5-yl)hexanediamide (E40), (S)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxo-N6-(tosylmethyl)hexanediamide (E41), (S)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-4-methyl-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide (E42), (S)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-5-methyl-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide (E43), (S)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide (E44), (S)-N1-(5-chloro-1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide (E45), (S)-N1-(5-bromo-1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide (E46), (S)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)-N6-methyl-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide (E47), (S)-N1-(1-(2-(diethylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide (E50), (S)-N1-methyl-5-(1-methyl-1H-imidazole-5-carboxamido)-N6-(1-(2-(methylsulfonamido)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-oxohexanediamide (E51), (S)-Ethyl 2-(3-(2-(1-methyl-1H-imidazole-5-carboxamido)-6-(methylamino)-5,6-dioxohexanamido)-2-oxopyridin-1(2H)-yl)acetate (E52), (S)-2-Methoxyethyl 2-(3-(2-(1-methyl-1H-imidazole-5-carboxamido)-6-(methylamino)-5,6-dioxohexanamido)-2-oxopyridin-1(2H)-yl)acetate (E53), (S)-N1-(1-(2-(methoxymethylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide (E54), (S)-N1-(1-(2-((dimethylamino)methylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide (E55), (S)-N1-(1-(2-(ethylsulfonamido)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide (E56), (S)-Benzyl 1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(methylamino)-1,5,6-trioxohexan-2-ylcarbamate (E57), (S)-tert-butyl 1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(methylamino)-1,5,6-trioxohexan-2-ylcarbamate (E58), (S)-4-(1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(methylamino)-1,5,6-trioxohexan-2-ylamino)-4-oxobutanoic acid (E59), (S)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-5-oxo-2-((S)-4-oxopyrrolidine-2-carboxamido)hexanediamide (E60), (S)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-(furan-3-carboxamido)-N6-methyl-5-oxohexanediamide (E61), (S)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-2-(oxazole-5-carboxamido)-5-oxohexanediamide (E62), (S)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-2-(1-methylpiperidine-4-carboxamido)-5-oxohexanediamide (E63), (S)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-5-oxo-2-(pyrimidine-5-carboxamido)hexanediamide (E64), (S)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-5-oxo-2-(quinoxaline-2-carboxamide)hexanediamide (E65), (S)-2-(2,4-dimethylthiazole-5-sulfonamido)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-5-oxohexanediamide (E66), (S)-2-(6-chloroimidazo[2,1-b]thiazole-5-sulfonamide)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-5-oxohexanediamide (E67), (S)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-2-(1-methyl-1H-imidazole-2-sulfonamido)-5-oxohexanediamide (E68), (S)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-5-oxo-2-(3-phenylureido)hexanediamide (E69), (S)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-5-oxo-2-(3-phenylthioureido)hexanediamide (E70), (S)-N1-(1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-1,5,6-trioxoheptan-2-yl)-1-methyl-1H-imidazole-5-carboxamide (E74), (S)—N-(6-cyclopropyl-1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-1,5,6-trioxohexan-2-yl)-1-methyl-1H-imidazole-5-carboxamide (E75), (S)—N-(1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-1,5,6-trioxo-6-phenylhexan-2-yl)-1-methyl-1H-imidazole-5-carboxamide (E76), (S)-Methyl 6-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-5-(1-methyl-1H-imidazole-5-carboxamido)-2,6-dioxohexanoate (E77), (S)-2-Methoxyethyl 6-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-5-(1-methyl-1H-imidazole-5-carboxamido)-2,6-dioxohexanoate (E78), (S)-N1-(cyclopentylmethoxy)-N6-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-5-(1-methyl-1H-imidazole-5-carboxamido)-2-oxohexanediamide (E79), (S)—N-(1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-8-methyl-1,5,6-trioxononan-2-yl)-1-methyl-1H-imidazole-5-carboxamide (E80), and (S)—N-(1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazol-4-yl)-1,5,6-trioxohexan-2-yl)-1-methyl-1H-imidazole-5-carboxamide (E81) A compound selected from the group consisting of:

7. 1. A pharmaceutical composition for use in the treatment or prevention of any of atherosclerosis, celiac disease, Duhring-Brocq-disease, gluten ataxia, tissue fibrosis, cystic fibrosis, renal fibrosis and diabetic nephropathy, liver fibrosis, thrombosis, Huntington's disease, Parkinson's disease, Alzheimer's disease, cataracts, ichthyosis, acne, psoriasis, skin aging, or candidiasis, comprising A pharmaceutical composition comprising a compound according to any one of claims 1 to 6.

8. 10. A method for producing a compound of claim 1, comprising the steps of: Step (0): Providing a protected amino acid (1P) having a chemical head moiety (W); 【Chemistry 21】 Step 1C: Amino protecting group PG ２ and a carboxyl protecting group PG ３ deprotecting Step 1C': (a) Compound (1C) resulting from step 1C 【Chemistry 22】 and the corresponding C-terminal amino acid building block H ２ A.S. Ｃｉ - OPG ４ carrying out a coupling reaction with (b) Protecting group PG ４ deprotecting (c) repeating steps (a) and (b) i times to obtain compound (1C'), where i is 1 to 3; 【Chemistry 23】 Step 2C: C-Terminal Building Block E Ｃ -H to perform a coupling reaction to obtain compound (2C); 【Chemistry 24】 Step 3C: Amino protecting group PG １ to obtain compound (3C); 【Chemistry 25】 and Step 4C: N-Terminal Building Block E Ｎ -AG １ carrying out a coupling reaction with Including, E Ｎ -AG １ A.G. １ is the activating group of the carboxylic acid in the amino acid, E Ｎ -AG １ E Ｎ and W has the same meaning as defined in claim 1, H ２ A.S. Ｃｉ - OPG ４ A.S. Ｃｉ (A.S. Ｃ１ ~ A.S. Ｃ４ (one of the) backbone, unprotected free amino (H ２ N-) group, and PG ４ The method refers to an amino acid having a carboxyl moiety protected by a group.

9. 9. The method of claim 8, further comprising step 3C′ between step 3C and step 4C: Step 3C' is (d) The N-terminal amino acid building block (PG) corresponding to the resulting compound of step 3C ５ ) H.A.S. Ｎｊ carrying out a coupling reaction with —OH; and (e) Protecting group PG ５ deprotecting (P.G. ５ ) H.A.S. Ｎｊ -OH is AS Ｎｊ (A.S. Ｎ１ ~ A.S. Ｎ４ One of the) skeleton, PG ５ Group [(PG ５ )HN-] and an unprotected free carboxylic acid (-CO ２ H);

10. A method for producing a compound according to claim 1, for producing compound 4D-1, 4D-2, 4D-3 or 4D-4 as a compound of formula (I), comprising: Step (0): Providing a protected amino acid (1C') having a chemical head moiety precursor (W'); 【Chemistry 26】 Step 1D: To obtain compound 1D-1 or 1D-2, a protected amino acid (1C') and a C-terminal amino acid building block (H ２ A.S. Ｃｉ - OPG ４ ) or the C-terminal building block (E Ｃ -H); 【Chemical 27】 Step 2D: To obtain compound 2D-1 or 2D-2, an amino protecting group PG １ deprotecting 【Chemistry 28】 Step 3D: To obtain compound 3D-1, 3D-2, 3D-3, or 3D-4, compound 2D-1 or 2D-2 and an N-terminal amino acid building block (HAS Ｎｊ —OH) or N-terminal building block (E Ｎ -H); and 【Chemical 29】 Step 4D: Converting the chemical tip moiety precursor (W') of compound 3D-1, 3D-2, 3D-3, or 3D-4 to a chemical tip moiety (W); 【Chemistry 30】 Including, The chemical tip moiety precursor (W′) is 【Chemistry 31】 and R ２ has the same meaning as defined in claim 1, the chemical tip moiety (W) has the same meaning as defined in claim 1, H ２ A.S. Ｃｉ - OPG ４ A.S. Ｃｉ (A.S. Ｃ１ ~ A.S. Ｃ４ (one of the) backbone, unprotected free amino (H ２ N-) group, and PG ４ means an amino acid having a carboxyl moiety protected by a (PG ５ ) H.A.S. Ｎｊ -OH is AS Ｎｊ (A.S. Ｎ１ ~ A.S. Ｎ４ One of the) skeleton, PG ５ Group [(PG ５ )HN-] and an unprotected free carboxylic acid (-CO ２ H), method.

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