Inhibitor of transglutaminase

Abstract

The present invention relates to compounds of general formula (I) as novel inhibitors of transglutaminase, to processes for the production of the compounds of the invention, to pharmaceutical compositions containing said compounds of the invention, and to their use for the prevention and treatment of diseases associated with transglutaminase, in particular with transglutaminase 2. [Formula 1] TIFF2024524458000345.tif38168

Description

Detailed Description of the Invention

[0001] The present invention relates to novel inhibitors of transglutaminase, particularly transglutaminase 2, methods for their synthesis, and their use for the prevention and treatment of diseases associated with transglutaminase, particularly transglutaminase 2.

[0002] [Background of the Invention] Transglutaminase is part of the class of transferases and, according to the EC nomenclature, is precisely designated as "protein-glutamine:amine γ-glutamyltransferase" (EC 2.3.2.13). Transglutaminase links the ε-amino group of the amino acid lysine to the γ-glutamyl group of the amino acid glutamine, forming an isopeptide bond while releasing ammonia. In the absence of a suitable amine and / or under certain conditions, deamidation of glutamine occurs, and as a result, the corresponding glutamic acid can be produced.

[0003] Furthermore, transglutaminase plays an important role in many therapeutic fields 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), skin diseases (ichthyosis, psoriasis, acne), etc., as well as in wound healing and inflammatory diseases (e.g., tissue fibrosis) (J.M. Wodzinska, Mini-Reviews in medical chemistry, 2005, 5, 279-292).

[0004] However, celiac disease, gluten intolerance disease, is one of the most important indications. Celiac disease is characterized by chronic inflammation of the small intestine mucosa. In susceptible patients, after ingestion of gluten-containing foods, the intestinal epithelium is continuously disrupted, resulting in a decrease in nutrient absorption, which again has a great impact on affected patients and is associated with symptoms such as weight loss, anemia, diarrhea, nausea, vomiting, loss of appetite, and fatigue. These findings have created a great need for the development of drugs for the treatment of celiac disease and other diseases associated with tissue transglutaminase (transglutaminase 2, TG2, tTG). Tissue transglutaminase is a central element during the onset of the disease. The endogenous enzyme catalyzes the deamidation of gluten / gliadin in the small intestine mucosa, thus causing an inflammatory reaction. Therefore, inhibitors of tissue transglutaminase are suitable for use as active agents for drug treatment.

[0005] Another very important group of indications for tissue transglutaminase inhibitors are 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 liver fibrosis belong to the most important fibrotic diseases to be addressed using the disclosed compounds.

[0006] US9,434,763 B2 discloses pyridinone derivatives having a reaction group (warhead) containing at least one acceptor-substituted double bond, such as a Michael system, as irreversible transglutaminase inhibitors. Alkylacetamide and arylacetamide pyridinones showed inhibitory activity in the nanomolar range (IC 50 ) with respect to tissue transglutaminase TG2.

[0007] Tse et al. (J. Med. Chem. 2020, 63, 11585 - 11601) modified the solubility and metabolic stability of the compound with an antimalarial triazolopyrazine compound Herein, we report on the substitution of phenyl residues with non-classical biological equivalents, such as cubane and bicyclo[1.1.1]pentane (BCP). We further evaluated the in vitro antiplasmodial activity of biologically equivalent modified triazolopyrazines against the 3D7 strain of Plasmodium falciparum. Substitution of phenyl with saturated heterocyclic residues of biological equivalents results in a complete loss of activity. Adamantyl residues, and other hydrocarbon-caged derivatives, resulted in up to 2- to 9-fold lower efficacy compared to the corresponding phenyltriazolopyrazine compounds. In contrast, higher efficacy was achieved by replacing phenyl with closo-1,2- and 1,7-carborane isomers. We conclude that the effect of non-classical biological equivalent substitution on biological properties cannot be accurately predicted, and that a range of possible biological equivalents should first be tested to identify the appropriate substitution to achieve the desired properties of a given molecule.

[0008] Subbaiah et al. (J. Med. Chem. 2021, 64, 19, 14046-14128) reported on the biological equivalents of the phenyl ring in lead optimization and drug design. It is noted that substitution of the phenyl ring of biological equivalents with heterocyclic and carbocyclic moieties can lead to improvements in efficacy, solubility, and metabolic stability while reducing lipophilicity, plasma protein binding, phospholipidosis potential, and inhibition of cytochrome P450 enzymes and hERG channels. However, this effect strongly depends on the properties of the compound itself and the target being addressed.

[0009] US11,072,634 B2 discloses reversible transglutaminase inhibitors containing an aldehyde, ketone, α-ketoaldehyde, α-ketoketone, α-ketoacid, α-ketoester, α-ketoamide or halogenomethyl ketone as a warhead. The inhibitors showed inhibitory activity in the nanomolar and micromolar ranges (IC 50 ) against tissue transglutaminase TG2.

[0010] The object of the present invention is to provide novel, possibly reversible inhibitors of transglutaminase, particularly transglutaminase 2, a method for synthesizing said inhibitors, and some uses of these inhibitors.

[0011] Said object is solved by the technical teaching of the independent claims. Further advantageous embodiments, aspects and details of the present invention are apparent from the dependent claims, the description and the examples.

[0012] Surprisingly, it has been shown that reversible inhibitors having a chemical warhead disclosed herein effectively inhibit transglutaminases, including tissue transglutaminase called transglutaminase 2 or TG2. In this specification, these terms are used synonymously.

[0013] Preferably, the warhead moiety is particularly selected from reversible warheads such as α-ketoamides. The compounds of the present invention act as selective inhibitors of transglutaminase 2.

[0014] To demonstrate the inventiveness of the compounds of the present application, reference compounds were synthesized and tested in comparison with the most similar compounds in the present application. Those skilled in the art may notice compound A8 from our patent US9,434,763B2, which we introduce as Ref.3 to emphasize the inventiveness and preferred features of the compounds described in the claims. From US9,434,763B2, it is clear that the aromatic moiety (C-terminus) limits the effectiveness of these compounds (compared to A1, A8, A37, A44, A47). In a remarkable contrast, as shown by more potent compounds (A28, A29, A59, A61, A63, A67, A68, A79), a branched alkyl moiety is highly preferred.

[0015] ​To illustrate the advantages of the branched alkyl moiety compared to the aromatic moiety, we refer to reference compounds Ref.2 (ZED1227, US9,434,763B2) and Ref.3 (A8, ZED1047). Inhibition data were determined as described using the classical fluorescent amidotransferase assay (dansylcadaverine uptake into methylated casein, DCC-assay) [Buchold, C.; Hils, M.; Gerlach, U.; Weber, J.; Pelzer, C.; Heil, A.; Aeschlimann, D.; Pasternack, R. Features of ZED1227: The First-In-Class Tissue Transglutaminase Inhibitor Undergoing Clinical Evaluation for the Treatment of Celiac Disease. Cells 2022, 11, 1667. https: / / doi.org / 10.3390 / cells11101667]. Casein is one of the best-known high molecular weight (24 kDa) protein substrates for transglutaminase. The IC 50 value of Ref.3 (A8) published in US9,434,763 B2 is dependent on a fluorescence-generating isopeptidase assay and should be noted that it cannot be compared with the current data. The Ref.2 (IC 50 = 53 nM) measured in the DCC-assay is 80-fold more potent compared to Ref.3 (IC 50 = 4,268 nM).

[0016] Therefore, a person skilled in medicinal chemistry would select a branched alkyl moiety as the lead structure, excluding aromatic moieties such as, for example, phenyl groups. It is a well-known fact that a bridged cycloalkyl group is a non-classical biological equivalent of a phenyl group. By substituting the phenyl group in A8 with, for example, an adamantyl group, a person skilled in the art would expect similar physicochemical or biochemical properties without much effort. Since the aromatic moiety is clearly not preferred, a bridged cycloalkyl group would not be considered to improve the compound.

[0017] This is further supported by additional reference compounds. ZED3641 (disclosed in Ref. 1, US11,072,634B2; Ref. 2, a reversibly acting α-ketomethylamide analogue of ZED1227) is approximately 15 times more potent compared to Ref. 4 (see comparison in Table 1). Ref. 4 is similar to compound A8 disclosed in US9,434,763B2 with respect to the skeleton, and once again demonstrates the superiority of the branched alkyl moiety compared to an aromatic derivative combined with a reversible acting warhead.

[0018] However, surprisingly, as shown in Table 1, substitution of the preferred branched alkyl moiety with a bridged cycloalkyl group further significantly improves the effectiveness of the compound. Therefore, we evaluate that the bridged cycloalkyl group as disclosed is an excellent inventive method.

[0019] In summary, the compounds of the present invention evaluated as "A" show approximately 30 times higher effectiveness compared to Ref. 3 (compare with A8, Table 1). Furthermore, compounds having activities evaluated as "B" or "C" are even more preferred than Ref. 3 (A8) (lower IC 50 value). Since peripheral ligands affect physicochemical or biochemical properties, these compounds can also be considered inventive. Therefore, depending on the application, compounds with weak effects can also have high value.

[0020] Accordingly, the present invention relates to a compound of general formula (I), or a diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemate, solvate, hydrate, or pharmaceutically acceptable salt of a compound of general formula (I): wherein:

[0021]

Chemical formula

[0022] In the formula: L represents -L 1 -L 2 -; L 1 represents -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CO-, or -CH2CH2CO-; L 2 represents a bond, -NR N1 -, -NR N1 CH2-, -NR N1 CH2CH2-, or -NR N1 CH(CH3)-; R 1 represents

[0023]

Chemical formula

[0024] R 2 represents

[0025]

Chemical formula

[0026]

Chemical formula

[0027]

Chemical formula

[0028] [Chemistry]

[0029] [Chemistry]

[0030] [Chemistry] represents;

[0031] wherein the unsubstituted bicyclic residue is substituted with 1 to 5 substituents R 9 ~R 14 and R N preferably with 1 to 3 substituents R 11 ~R 13 and can be substituted; R 3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, adamantyl, diamantyl, or hexamethylenetetraminyl, and the aforementioned residues optionally contain one or more C=C double bonds and / or are optionally substituted by one or more R a R b R c R d R e and R R a R b R c R d R eare, independently of one another, -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -CO2C2H5, -CONH2, -CONHCH3, -CON(CH3)2, -CONHC2H5, -CH2CO2H, -CH2CO2CH3, -CH2CO2C2H5, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2H5, -NHCOCH3, -NHCOC2H5, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C2H5, -NHSO2CHF2, -NHSO2CF3, or -NHSO2CH2CF3; R 4 is -NR 6 R 7 and represents; R 6 represents -CH2CH3, and R 7 represents -H;

[0032] R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、and R 14are, 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, -CH2OH, -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, -CH2-C≡CH, -Ph, -O-Ph, -O-CH2-Ph,

[0033]

Chem.

[0034] or, R 8 and R 9 or, R 9 and R 10 can together form one of the following 5-membered or 6-membered rings:

[0035]

Chem.

[0036] or, R 12 and R 13 or, R 13 and R 14 can together form one of the following 5-membered or 6-membered rings:

[0037]

Chem.

[0038] R Nrepresents -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-C5H9, -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, -CO-cyclo-C3H5, -CO-cyclo-C4H7, -CO-cyclo-C5H9, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -SO2CH3, -SO2CF3, -SO2C2H5, -SO2C3H7, -SO2CH(CH3)2, -SO2-cyclo-C3H5, or -SO2C(CH3)3; R N1 represents -H, -CH3, or -CH2CH3.

[0039] The inventors have shown that the reversible inhibitors of formula (I) disclosed herein having the bridged bicyclic residue R 3 exhibit an increase in efficacy over the compounds of the prior art. In particular, the compounds of the present invention are demonstrated herein to have improved inhibitory activity compared to known compounds having an aromatic moiety R 3 in place of the bridged bicyclic residue. To demonstrate the inventiveness of the compounds of the present application, known compounds from US9,434,763B2 and US11,072,634B2 (Reference 1 (E16 from US11,072,634 B2), Reference 3 (A8 from US9,434,763B2), and Reference 4) were synthesized and tested as reference compounds against the most similar compounds of the present application.

[0040] Within the scope of the present application, the inhibition data was determined using the classical fluorescence amino group translocation assay (dansylcadaverine incorporation into methylated casein, DCC-assay) as described in Buchold et al. [Buchold, C.; Hils, M.; Gerlach, U.; Weber, J.; Pelzer, C.; Heil, A.; Aeschlimann, D.; Pasternack, R. Features of ZED1227: The First-In-Class Tissue Transglutaminase Inhibitor Undergoing Clinical Evaluation for the Treatment of Celiac Disease. Cells 2022, 11, 1667. https: / / doi.org / 10.3390 / cells11101667]. Casein is one of the best-known high molecular weight (24 kDa) protein substrates for transglutaminase. The inhibition data of the compounds of the present invention was compared with the inhibition of the compounds disclosed in US 9,434,763 B2, in particular Compound A8 shown herein as Reference 3. It should be noted that the IC e values of Compound A8 disclosed in US 9,434,763 B2 and E16 from US 11,072,634 B2 depend on the fluorescence-generating isopeptidase assay and cannot be compared with the current data. Therefore, the compounds of the present invention of formula (I) evaluated as "A" showed approximately 100% higher efficacy compared to Ref. 3 (A8). The same argument applies to Ref. 4. Ref. 4 also shows that the aromatic moiety of this reference compound strongly reduces the inhibitory activity against TG2. 50

[0041]

[0042] ​​Thus, one of ordinary skill in the art would exclude aromatic moieties, such as a phenyl group. It is well known that a bridged cycloalkyl group is a non-classical biological equivalent of a phenyl group. Substitution of the phenyl group in A8 with, for example, an adamantyl group, one of ordinary skill in the art would expect similar physicochemical or biochemical properties, barring effort. Since the aromatic moiety is clearly not preferred, a bridged cycloalkyl group is not considered to improve the compound.

[0043] Surprisingly, the compounds of the present invention demonstrate that the bridged cycloalkyl group improves the potency of the compound by several orders of magnitude compared to the aromatic reference compound. Thus, we consider the disclosed bridged cycloalkyl group to be an excellent inventive method.

[0044] In another set of preferred compounds R 2 is

[0045]

Chemical formula

[0046]

Chemical formula

[0047]

Chemical formula

[0048]

Chemical formula

[0049]

Chemical formula

[0050]

Chemical formula

[0051] Here, the unsubstituted bicyclic residue can be substituted with one to five substituents R 9 ~R 14 and R N ; preferably, it can be substituted with one to three substituents R 11 ~R 13 ; the substituents R 9 ~R 14 and R N have the meanings defined in formula (I); more preferably, R 2 is

[0052]

Chemical formula

[0053]

Chemical formula

[0054]

Chemical formula

[0055]

Chemical formula

[0056]

Chemical formula

[0057]

Chemical formula

[0058] Here, the unsubstituted bicyclic residue can be substituted with one to five substituents R 9 ~R 14 and R N ; preferably, it can be substituted with one to three substituents R 11 ~R 13can be replaced; the substituent R 9 ~R 14 and R N have the meanings defined herein.

[0059] Preferably, the unsubstituted bicyclic residue that can be substituted with 1 to 5 substituents R 9 ~R 14 and R N has the following structure, and the substituents R 9 ~R 14 and R N have the meanings defined herein:

[0060]

Chemical formula

[0061]

Chemical formula

[0062]

Chemical formula

[0063]

Chemical formula

[0064]

Chemical formula

[0065]

Chemical formula

[0066]

Chemical formula

[0067]

Chemical formula

[0068] More preferably, it is a compound of general formula (I), or a diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemate, solvate, hydrate, or pharmaceutically acceptable salt of a compound of general formula (I):

[0069]

Chemical formula

[0070] In the formula, L represents -L 1 -L 2 -; L 1 represents -CH2CO-; L 2 represents -NR N1 -; R 3 represents 1-adamantyl; or L 2 represents -NR N1 CH2-; R 3 represents 2-bicyclo[3.1.1]heptyl, and the aforementioned 1-adamantyl and 2-bicyclo[3.1.1]heptyl residues optionally contain one or more C=C double bonds and / or are optionally substituted by one or more R a 、R b 、R c 、R d 、and R e ; R 1 is

[0071]

Chemical formula

[0072] R 2 is

[0073]

Chemical formula

[0074] R 6 represents -C2H5; R a R b R c R d and R e each independently represents -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -CO2C2H5, -CONH2, -CONHCH3, -CON(CH3)2, -CONHC2H5, -CH2CO2H, -CH2CO2CH3, -CH2CO2C2H5, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2H5, -NHCOCH3, -NHCOC2H5, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C2H5, -NHSO2CHF2, -NHSO2CF3, or -NHSO2CH2CF3; R 8 R 10 and R 11are, 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-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, -O-CH2-Ph

[0075]

Chem.

[0076] R Nrepresents -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-C5H9, -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, -CO-cyclo-C3H5, -CO-cyclo-C4H7, -CO-cyclo-C5H9, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -SO2CH3, -SO2CF3, -SO2C2H5, -SO2C3H7, -SO2CH(CH3)2, -SO2-cyclo-C3H5, or -SO2C(CH3)3; R N1 represents -H, -CH3, or -CH2CH3.

[0077] In a preferred set of compounds R 2 is

[0078] [Chemical formula] represents,

[0079] R 8 R 10 R 11 and R N have the meanings defined herein. As used herein, the residues bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisostilbene, adamantyl, diamantyl, and hexamethylenetetraminyl each have the following parent structures:

[0080]

Chem.

[0081] The foregoing residues optionally contain one or more C=C double bonds and / or are optionally substituted by one or more R a 、R b 、R c 、R d 、and R e . Preferably, it is a compound of formula (Ia):

[0082]

Chem.

[0083] L, R 2 、R 3 、R 6 have the same meanings as defined in formula (I). Preferably, the present invention relates to a compound of formula (I), or a diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemate, solvate, hydrate, or pharmaceutically acceptable salt of a compound of formula (I):

[0084]

Chem.

[0085] wherein L is -L 1 -L2 represents -; L 1 represents -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CO-; L 2 represents -NR N1 -, or -NR N1 CH2-; Preferably, L represents -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CONH-, -CH2CONH-CH2-, -CH2CON(CH3)-CH2-, or -CH2CONH-CH(CH3)-, R 1 is

[0086]

Chemical formula

[0087] R 2 is

[0088]

Chemical formula

[0089] R 3 is bicyclo[1.1.1]pentan-1-yl, bicyclo[2.1.1]hexan-1-yl, bicyclo[3.1.1]heptan-3-yl, bicyclo[2.2.1]heptan-2-yl, bicyclo[2.2.1]hept-5-en-2-yl, bicyclo[2.2.1]heptan-7-yl, bicyclo[2.2.1]heptan-2-yl, bicyclo[2.2.2]octan-2-yl, 1-adamantyl, 2-adamantyl, 4-homoisotwistyl, 1-diamantyl, or 4-diamantyl, and the aforementioned bicyclo[1.1.1]pentan-1-yl, bicyclo[2.1.1]hexan-1-yl, bicyclo[3.1.1]heptan-3-yl, bicyclo[2.2.1]heptan-2-yl, bicyclo[2.2.1]hept-5-en-2- An iL, bicyclo[2.2.1]heptan-7-yl, bicyclo[2.2.1]heptan-2-yl, bicyclo[2.2.2]octan-2-yl, 1-adamantyl, 2-adamantyl, 4-homoisotwistyl, 1-diamantyl, or 4-diamantyl residue optionally contains one or more C=C double bonds and / or is optionally substituted by one or more R a , R b , R c , R d , and R e ; R 6 represents -C2H5; R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R a , R b , R c , R d , R e , R N , and R N1 have the same meaning as defined in formula (I).

[0090] In some embodiments, the present invention relates to a compound of formula (I), or a diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemate, solvate, hydrate, or pharmaceutically acceptable salt of a compound of formula (I):

[0091]

Chemical formula

[0092] wherein L represents -L 1 -L 2 -; L 1 represents -CH2CO-, L 2 represents -NR N1 -, and R 3represents 1-adamantyl; or L 2 represents -NR N1 CH2-, and R 3 represents 2-bicyclo[3.1.1]heptyl, the aforementioned 1-adamantyl, and 2-bicyclo[3.1.1]heptyl residues optionally contain one or more C=C double bonds and / or are optionally substituted by one or more R a s, R b s, R c s, R d s, and R e ; R 1 is

[0093]

Chemical formula

[0094] R 2 is

[0095]

Chemical formula

[0096] R 6 represents -C2H5; R 8 s, R 9 s, R 10 s, R 11 s, R 12 s, R 13 s, R 14 s, R a s, R b s, R c s, R d s, R e s, R N s, and R N1 have the same meaning as defined in formula (I).

[0097] In some embodiments, the present invention relates to a compound of formula (I), or a diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemate, solvate, hydrate, or pharmaceutically acceptable salt of a compound of formula (I):

[0098]

Chemical formula

[0099] wherein, L represents -L 1 -L 2 -; L 1 represents -CH2CO-, L 2 represents -NR N1 -, and R 3 represents 1-adamantyl; or L 2 represents -NR N1 CH2-, and R 3 represents 2-bicyclo[3.1.1]heptyl, the aforementioned 1-adamantyl, and 2-bicyclo[3.1.1]heptyl residues optionally contain one or more C=C double bonds and / or are optionally substituted by one or more R a 、R b 、R c 、R d 、and R e ; R 1 is

[0100]

Chemical formula

[0101] R 2 is

[0102]

Chemical formula

[0103] R6 represents -C2H5; and R 8 R 10 R 11 R a R b R c R d R e R N and R N1 have the same meaning as defined in formula (I).

[0104] In some embodiments, the present invention relates to a compound of formula (Ia), or a diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemate, solvate, hydrate, or pharmaceutically acceptable salt of a compound of formula (Ia):

[0105]

Chemical formula

[0106] wherein L represents -L 1 -L 2 -; L 1 represents -CH2CO-, L 2 represents -NR N1 -, and R 3 represents 1-adamantyl; or L 2 represents -NR N1 CH2-, and R 3 represents 2-bicyclo[3.1.1]heptyl, the aforementioned 1-adamantyl and 2-bicyclo[3.1.1]heptyl residues optionally contain one or more C=C double bonds and / or are optionally substituted by one or more R a R b R c R d and R e ; R 2 is

[0107] [Chem.] represents;

[0108] R 6 represents -C2H5; R a R b R c R d and R e are, independently of each other, -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -CO2C2H5, -CONH2, -CONHCH3, -CON(CH3)2, -CONHC2H5, -CH2CO2H, -CH2CO2CH3, -CH2CO2C2H5, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2H5, -NHCOCH3, -NHCOC2H5, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C2H 5, -NHSO2CHF2, -NHSO2CF3, or -NHSO2CH2CF3, represents; R 8 R 9 R 10 R 11 R 12 R 13 and R 14are, 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, -CH2-OH, -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, -CH2-C≡CH, -Ph, -O-Ph, -O-CH2-Ph

[0109]

Chem.

[0110] R N is -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -CH2-cyclo-C3H 5, -CH2-cyclo-C4H7, -CH2-cyclo-C5H9, -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, -CO-cyclo-C3H5, -CO-cyclo-C4H7, -CO-cyclo-C5H9, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -SO2CH3, -SO2CF3, -SO2C2H5, -SO2C3H7, -SO2CH(CH3)2, -SO2-cyclo-C3H5, or -SO2C(CH3)3; R N1 is -H, -CH3, or -C2H5.

[0111] Preferably, the present invention relates to a compound of formula (Ia), or a diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemate, solvate, hydrate, or pharmaceutically acceptable salt of a compound of formula (Ia):

[0112]

Chemical formula

[0113] wherein, L represents -L 1 -L 2 -; L 1 represents -CH2CO-, L 2 represents -NR N1 -, and R 3 represents 1-adamantyl; or L 2 represents -NR N1 CH2-, and R 3 represents 2-bicyclo[3.1.1]heptyl, the aforementioned 1-adamantyl, and 2-bicyclo[3.1.1]heptyl residues optionally contain one or more C=C double bonds, and / or are optionally substituted by one or more R a s, R b s, R c s, R d s, and R e ; R 2 is

[0114]

Chemical formula

[0115] R 6 represents -C2H5; R a s, R b s, R c s, R d s, and R eare, independently of one another, -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -CO2C2H5, -CONH2, -CONHCH3, -CON(CH3)2, -CONHC2H5, -CH2CO2H, -CH2CO2CH3, -CH2CO2C2H5, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2H5, -NHCOCH3, -NHCOC2H5, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C2H5, -NHSO2CHF2, -NHSO2CF3, or -NHSO2CH2CF3, and represent; R 8 R 10 and R 11are, 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, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -C≡CH, -C≡C-CH3, -CH2-C≡CH, -Ph, -O-Ph, -O-CH2-Ph,

[0116]

Chem.

[0117] R N is -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-C5H9, -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, -CO-cyclo-C3H5, -CO-cyclo-C4H7, -CO-cyclo-C5H9, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -SO2CH3, -SO2CF3, -SO2C2H5, -SO2C3H7, -SO2CH(CH3)2, -SO2-cyclo-C3H5, or -SO2C(CH3)3; R N1 is -H, -CH3, or -C2H5.

[0118] Preferably, the compound of the present invention has the formula (II), or a diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemate, solvate, hydrate, or pharmaceutically acceptable salt of formula (II):

[0119]

Chemical formula

[0120] Wherein, L 2 represents -NR N1 -, and R 3 represents 1-adamantyl; or L 2 represents -NR N1 CH2-, and R 3 represents 2-bicyclo[3.1.1]heptyl, The aforementioned adamantyl and 2-bicyclo[3.1.1]heptyl residues optionally contain one or more C=C double bonds and / or are optionally substituted by one or more R a , R b , R c , R d , and R e ; R 2 is

[0121]

Chemical formula

[0122] R a , R b , R c , R d , and R e are independently of each other, -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -CO2C2H5, -CONH2, -CONHCH3, -CON(CH3)2, -CONHC2H5, -CH2CO2H, -CH2CO2CH3, -CH2CO2C2H5, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2H5, -NHCOCH3, -NHCOC2H5, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C2H5, -NHSO2CHF2, -NHSO2CF3, or -NHSO2CH2CF3; R N is -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-C5H9, -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, -CO-cyclo-C3H5, -CO-cyclo-C4H7, -CO-cyclo-C5H9, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -SO2CH3, -SO2CF3, -SO2C2H5, -SO2C3H7, -SO2CH(CH3)2, or -SO2C(CH3)3; R N1 is -H, -CH3, or -CH2CH3; R 8 R 10 and R 11are, 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, -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, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -C≡CH, -C≡C-CH3, -CH2-C≡CH, or -Ph.

[0123] The terms "1-adamantyl" and "2-bicyclo[3.1.1]heptyl" each have the following structures:

[0124] [Chemical formula]

[0125] R a 、R b 、R c 、R d and R e have the same meanings as defined herein. Preferably, 2-bicyclo[3.1.1]heptyl has the following structure:

[0126] [Chemical formula] R a and R b have the same meanings as defined herein.

[0127] More preferably, the compound has any one of formulas (II-a) to (II-1), (II-b1) to (II-b2), and (III-a) to (III-1):

[0128]

Chem.

[0129]

Chem.

[0130] wherein L 1 , L 2 , R 2 , R N , R a , R b , R c , R d and R e have the same meanings as defined in formula (I), preferably in formula (Ia), and more preferably in formula (II).

[0131]

Chem.

[0132]

Chem.

[0133] wherein L 1 , L 2 , R 8 , R 10 , R 11 , R 12 , R 13 , R 11 , R N , R a , R b , R c , R d and R e have the same meanings as defined in formula (I), preferably in formula (Ia).

[0134] In a preferred embodiment, the present invention refers to compounds of formula (I), (Ia), and (II), wherein R 3 is

[0135]

Chemical formula

[0136] More preferably, R 3 is

[0137]

Chemical formula

[0138] Even more preferably, R 3 is

[0139]

Chemical formula

[0140] In a preferred embodiment, the present invention refers to any one compound of formula (I), (Ia), and (II), (II-a) to (II-I), (II-b1) to (II-b2), wherein R 2 is

[0141]

Chemical formula

[0142] wherein R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14are, 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, -CH2OH, -OCH3, -OC2H5, -OC3H7, -OCH(CH3)2, -OC(CH3)3, -OC4H9, -OCH F2, -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, -CH2-C≡CH, -Ph, -O-Ph, -O-CH2-Ph,

[0143]

Chem.

[0144] Preferably, R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 are, independently of one another, -H, -F, -Cl, -Br, -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, -CH2OH, -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, -OO C-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, -Ph, -O-Ph, -O-CH2-Ph, or

[0145] [Chemical formula] represents;

[0146] more preferably, R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 are, independently of each other, -H, -F, -Cl, -Br, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C(CH3)3, -cyclo-C3H5, -CF3, -CH2OH, -OCH3, -OCF3, -CHO, -COCH3, -COOH, -COOCH3, -NH2, -N(CH3)2, -CONH2, -SO2NH2, -Ph, or

[0147] [Chemical formula] represents;

[0148] RN is -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-C5H9, -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, -CO-cyclo-C3H5, -CO-cyclo-C4H7, -CO-cyclo-C5H9, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -SO2CH3, -SO2CF3, -SO2C2H5, -SO2C3H7, -SO2CH(CH3)2, -SO2-cyclo-C3H5, or -SO2C(CH3)3; Preferably, R N is -H, -CH3, -C2H5, -CH(CH3)2, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-C5H9, or -COCH3, more preferably, R N is -H, -CH3, -C2H5, -CH(CH3)2, -cyclo-C4H7, -cyclo-C5H9, or -COCH3.

[0149] In a preferred embodiment, the present invention refers to any one compound of formulas (I), (Ia), and (II), (II-a) to (II-I), (II-b1) to (II-b2), wherein R 2 is

[0150]

Chemical formula

[0151] [Chemical formula] represents;

[0152] More preferably, R 2 is

[0153] [Chemical formula] represents.

[0154] Even more preferably, R 2 is

[0155] [Chemical formula] represents.

[0156] In a preferred embodiment, the present invention refers to any one compound of formula (I), (Ia), and (II), (II-a) to (II-I), (II-b1) to (II-b2), wherein L represents -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CONH-, -CH2CONH-CH2-, -CH2CON(CH3)-CH2-, -CH2CONH-CH(CH3)-, Most preferably, it is the compound of the following formula (I):

[0157] [Chemical formula]

[0158] [Chemical formula]

[0159] [Chemical formula]

[0160] [Chemical formula]

[0161]

Chem.

[0162]

Chem.

[0163]

Chem.

[0164]

Chem.

[0165]

Chem.

[0166]

Chem.

[0167]

Chem.

[0168]

Chem.

[0169]

Chem.

[0170]

Chem.

[0171] [Chemical]

[0172] [Chemical]

[0173] [Chemical]

[0174] [Chemical]

[0175] [Chemical]

[0176] [Chemical]

[0177] [Chemical]

[0178] [Chemical]

[0179] [Chemical]

[0180] [Chemical]

[0181] [Chemical]

[0182]

Chem.

[0183]

Chem.

[0184]

Chem.

[0185]

Chem.

[0186]

Chem.

[0187]

Chem.

[0188]

Chem.

[0189]

Chem.

[0190]

Chem.

[0191]

Chem.

[0192] [Chemical]

[0193] [Chemical]

[0194] [Chemical]

[0195] [Chemical]

[0196] [Chemical]

[0197] [Chemical] .

[0198] Method for preparing the compound of the present invention In some embodiments, the present invention relates to a method for synthesizing a compound of formula (I), particularly any compound of formula (Ia):

[0199] [Chemical]

[0200] As shown in Scheme 1, The method for preparing the compound of formula (Ia) includes the following: Step 1A: Providing compound 4a

[0201] [Chemical] ;

[0202] Step 2A: Perform the coupling reaction of compound 4a and compound 5

[0203]

Chem.

[0204]

Chem.

[0205] Step 3A: Deprotect the amino protecting group PG 3 to obtain compound 7a

[0206]

Chem.

[0207] Step 4A: Perform the coupling reaction of compound 7a and carboxylic acid (R 2 -CO2H 8) to obtain compound 9a

[0208]

Chem.

[0209] Step 5A: Perform the oxidation reaction of compound 9a to produce the compound of formula (Ia)

[0210]

Chem.

[0211] wherein L, R 2 , R 3 , and R 6 have the same meanings as defined above in formula (Ia), PG 3 is an amino protecting group.

[0212]

Chem.

[0213] Optionally, step 1A’ is carried out before step 1A: (a) Providing a protected aldehyde 1

[0214]

Chemical formula

[0215]

Chemical formula

[0216]

Chemical formula

[0217] wherein R 2 , R 6 have the same meanings as defined in formula (Ia), PG 1 and PG 3 are amino protecting groups, PG 2 is a carboxyl protecting group.

[0218] Therefore, the following method for the production of the compound of formula (Ia) is preferred: Step 1A’: (a) Providing a protected aldehyde 1

[0219]

Chemical formula

[0220]

Chemical formula

[0221]

Chemical formula

[0222]

Chemical formula

[0223]

Chemical formula

[0224]

Chemical formula

[0225]

Chemical formula

[0226] [Chem.] ; Step 5A: Performing the oxidation reaction of compound 9a to produce the compound of formula (Ia)

[0227] [Chem.] ;

[0228] In the formula, L, R 2 , R 3 , and R 6 have the same meanings as defined above in formula (Ia), PG 1 and PG 3 are amino protecting groups, PG 2 is a carboxyl protecting group.

[0229] In an alternative route, first all the protecting groups PG 1 and PG 2 are removed simultaneously, and the protecting group PG 3 is introduced selectively. Preferably, PG 1 and PG 3 are the same.

[0230] As used herein, the term "protecting group" refers to protecting groups commonly used in organic synthesis, preferably protecting groups for amino and carboxyl groups. PG 1 , PG 3 , and PG 5 are preferably protecting groups suitable for amino groups. PG 2 and PG 4 are preferably protecting groups suitable for carboxyl groups. Preferably, PG 1 , PG 3 , and PG 5PG may be selected from the group consisting of, or including, acetyl, benzoyl, benzyloxycarbonyl (Cbz), tert-butylcarbonyl, tert-butoxycarbonyl (Boc), and fluorenylmethyleneoxy group (Fmoc). 2 and PG 4 may be selected from the group consisting of, or including, methoxy, ethoxy, isobutoxy, tert-butoxy, benzyloxy; preferably, it may be a tert-butoxy group.

[0231] In step 2A, to promote the coupling reaction with the amino group of the intermediate compound, an activating reagent is generally used to activate the carboxylic acid ("Peptide Coupling Reagents, More than a Letter Soup", Ayman El-Faham and Fernando Albericio, Chemical Reviews, 2011, 111(11), p. 6557-6602). The activation may be introduced as a separate reaction or an in situ reaction.Preferably, the following coupling reagents: BOP (benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate), PyBOP (benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate), AOP (7-(azabenzotriazol-1-yl)oxytris(dimethylamino)phosphonium hexafluorophosphate), PyAOP ((7-azabenzotriazol-1-yl-oxy)tripyrrolidinophosphonium hexafluorophosphate), TBTU (2-(1H-benzotriazol-1)-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate), EEDQ (N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline), polyphosphoric acid (PPA), DPPA (diphenylphosphoryl azide), HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate), HBTU (O-benzotriazol-1-yl-N,N,N’,N’-tetramethyluronium hexafluorophosphate), HOBt (1-hydroxybenzotriazole), HOAt (1-hydroxy-7-azabenzotriazole), DCC (N,N’-dicyclohexylcarbodiimide), EDC (or EDAC or EDCI, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), BOP-Cl (bis(2-oxo-3-oxazolidinyl)phosphine chloride), TFFH (tetramethylfluorohomomidinium hexafluorophosphate), BroP (bromotris(dimethylamino)phosphonium hexafluorophosphate, PyBroP (bromo-tris-pyrrolidino-phosphonium hexafluorophosphate) and CIP (2-chloro-1,3-dimethylimidazolinium hexafluorophosphate), or further any of similar acting reagents can be used to activate the carboxylic acid group, providing activated intermediates, or mixtures thereof.

[0232] Pharmaceutical Compositions and Medical Uses Accordingly, another aspect of the present invention relates to compounds of general formula (I) as medicaments and their use in medicaments. Particularly preferably, it is for use as an inhibitor of transglutaminase, particularly transglutaminase 2 (TG2).

[0233] Accordingly, the compounds of formula (I) described herein or according to the present invention may be administered by themselves or in the form of a pharmaceutically acceptable salt. The compounds of the present invention may form pharmaceutically acceptable salts with organic or inorganic acids or organic or inorganic bases. Examples of acids suitable for forming said acid addition salts are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, p-aminosalicylic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, sulfonic acid, phosphonic acid, perchloric acid, nitric acid, formic acid, propionic acid, gluconic acid, lactic acid, tartaric acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, p-hydroxybenzoic acid, methanesulfonic acid, ethanesulfonic acid, nitrous acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, p-toluenesulfonic acid, naphthylsulfonic acid, sulfanilic acid, camphorsulfonic acid, china acid, mandelic acid, o-methylmandelic acid, hydrogen-benzenesulfonic acid, picric acid, adipic acid, d-o-tolyltartaric acid, tartronic acid, (o, m, p)-toluylic acid, naphthylaminesulfonic acid , trifluoroacetic acid, and other mineral or carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base form in a conventional manner with a sufficient amount of the desired acid to produce the salt. Preferably, they are mesylate, hydrochloride, and trifluoroacetate, and particularly preferably, trifluoroacetate and hydrochloride.

[0234] When the compound of the present invention has an acidic group, it is also possible to form a salt using an inorganic base or an organic base. Examples of suitable inorganic bases or organic bases are, for example, NaOH, KOH, NH4OH, tetraalkylammonium hydroxide, lysine or arginine. The salt may be prepared by a conventional method using a method well known in the art, for example, by treating a solution of the compound of general formula (I) with a solution of an acid selected from the above group.

[0235] Method of use In a further aspect of the present invention, the novel compound according to general formula (I) is used as a pharmaceutically active agent, that is, the compound of formula (I) is used in medicine.

[0236] Furthermore, the present invention relates to a pharmaceutical composition comprising at least one compound according to general formula (I) as an active ingredient, or a pharmaceutically acceptable salt thereof as an active ingredient, together with at least one pharmaceutically acceptable carrier, excipient and / or diluent.

[0237] The compounds according to general formula (I) described herein are particularly suitable for the treatment and prevention of diseases related to and / or caused by transglutaminase 2.

[0238] Celiac disease, gluten intolerance is associated with tissue transglutaminase (TG2). 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 liver fibrosis belong to the most important fibrotic diseases to be addressed using the disclosed compounds.

[0239] In biological example B-1, the compound of the present invention as a reversible inhibitor has proven to effectively inhibit the activity of TG, particularly TG2. As used herein, the term "inhibit" or "inhibition" refers to the ability of a compound to downregulate, decrease, reduce, suppress, inactivate, or at least partially inhibit the activity of an enzyme, or the expression of an enzyme or protein.

[0240] Accordingly, another aspect of the invention is the use of a compound of the invention of general formula (I) as described, or a pharmaceutical composition thereof, in the treatment or prevention of autoimmune and inflammatory diseases, vascular diseases, fibrotic diseases, liver diseases, cholestatic liver diseases, cancer, neurodegenerative diseases, eye diseases, and skin diseases.

[0241] A further aspect of the invention relates to the use of a compound of general formula (I) for the preparation of a pharmaceutical composition useful for the prevention and / or treatment of autoimmune and inflammatory diseases, vascular diseases, fibrotic diseases, liver diseases, cholestatic liver diseases, cancer, neurodegenerative diseases, eye diseases, and skin diseases.

[0242] In a further aspect of the invention, there is a method of preventing and / or treating autoimmune and inflammatory diseases, vascular diseases, fibrotic diseases, liver diseases, cholestatic liver diseases, cancer, neurodegenerative diseases, eye diseases, and skin diseases, the method comprising administering to a subject, particularly a human, a pharmaceutically effective amount of at least one compound of general formula (I) for preventing and / or treating said autoimmune and inflammatory diseases, vascular diseases, fibrotic diseases, liver diseases, cholestatic liver diseases, cancer, neurodegenerative diseases, eye diseases, and skin diseases.

[0243] Preferably, the autoimmune and inflammatory diseases include multiple sclerosis, celiac disease, Duhring-Brocq-disease (dermatitis herpetiformis), gluten ataxia, gluten neuropathy, diabetes, rheumatoid arthritis, Graves' disease, inflammatory bowel disease, systemic lupus erythematosus psoriasis, and gingivitis; The vascular diseases include atherosclerosis, thrombosis, and arteriosclerosis; Fibrous diseases affect the lungs, kidneys, liver, skin, or digestive tract, such as cystic fibrosis, kidney fibrosis, and diabetic nephropathy, intestinal fibrosis, idiopathic pulmonary fibrosis, liver fibrosis, etc.; Liver diseases include alcoholic hepatitis, alcoholic steatohepatitis, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, cirrhosis, autoimmune hepatitis, or liver inflammation, etc.; Cholestatic liver diseases include primary biliary cholangitis and primary sclerosing cholangitis; Cancers include glioblastoma, melanoma, pancreatic cancer, renal cell carcinoma, meningioma, and breast cancer, and neurodegenerative diseases include Parkinson's disease, Huntington's disease, or Alzheimer's disease; Eye diseases include glaucoma, cataract, macular degeneration, or uveitis; Skin diseases include acne, psoriasis, scarring, and skin aging.

[0244] More preferably, the compound of formula (I), or its pharmaceutical composition, is useful for the treatment or prevention of celiac disease. Furthermore, the compounds of general formula (I) can be administered in the form of their pharmaceutically active salts, optionally using essentially non-toxic pharmaceutically acceptable carriers, adjuvants or diluents. The drugs are prepared by known methods in suitable dosages with conventional solid or fluid carriers, or diluents and conventional pharmaceutically acceptable adjuvants / expedients. Preferred formulations are provided in administrable forms suitable for oral application, such as pills, tablets, film tablets, coated tablets, capsules and powders.

[0245] Tablets, film tablets, coated tablets, gelatin capsules and opaque capsules are preferred pharmaceutical formulations. Any pharmaceutical composition contains at least one compound of general formula (I), and / or its pharmaceutically acceptable salt, in an amount of 5 mg to 500 mg, preferably 10 mg to 250 mg, and most preferably 10 mg to 100 mg per formulation.

[0246] Furthermore, the object of the present invention also includes pharmaceutical preparations for oral, parenteral, dermal, intradermal, intragastric, intracutaneous, intravascular, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, buccal, percutaneous, rectal, subcutaneous, sublingual, topical, transdermal, or inhalation administration, which contain, in addition to typical vehicles and extenders, a compound of general formula (I) and / or a pharmaceutically acceptable salt of a compound of general formula (I) as an active ingredient.

[0247] The pharmaceutical composition of the present invention contains, as an active ingredient, one of the compounds of formula (I) disclosed herein, and is typically mixed, according to conventional pharmacy practice, with an appropriate carrier material selected with respect to the intended dosage form, i.e., tablets, capsules (filled with any of solid, semi-solid, or liquid), powders, orally administrable gels, elixirs, dispersible granules, syrups, suspensions, etc. for oral administration. For example, a compound of formula (I) as an active agent component can be combined, for oral administration in the form of tablets or capsules, with an oral, non-toxic, pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (in liquid form), etc. Furthermore, appropriate binders, lubricants, disintegrants, and colorants can be added to the mixture, if necessary. Powders and tablets consist of about 5% to about 95% by weight of said inert carrier of the composition of the present invention.

[0248] ​Suitable binders include starch, gelatin, natural sugars, sweeteners made from corn, natural and synthetic gums such as acacia gum, sodium alginate, carboxymethyl cellulose, polyethylene glycol, and waxes. Lubricants possible for use in the dosage form include boric acid, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrants include starch, methyl cellulose, cyclodextrin, guar gum, etc. Optionally, sweeteners, flavoring additives, and preservatives can also be included. Some of the terms used above, namely disintegrants, diluents, lubricants, binders, etc., are described in more detail below.

[0249] Furthermore, the composition of the present invention can be formulated in a sustained-release form in order to optimize the therapeutic effect, i.e., inhibitory activity, etc., or to provide a controlled release rate of any one or more components or active ingredients. Dosage forms suitable for sustained release include layered tablets containing layers with various degradation rates impregnated with the active ingredient or having a controlled-release polymer matrix, and tablets or capsules containing the impregnated or encapsulated porous polymer matrix.

[0250] Formulations in fluid form include solutions, suspensions, and emulsions. Mentioned by way of example are water or water-propylene glycol solutions for parenteral injection, or the addition of sweeteners and opacifiers for oral solutions, suspensions, and emulsions.

[0251] Aerosol formulations suitable for inhalation can contain solids in the form of solutions and powders that can be combined with a pharmaceutically acceptable carrier, such as a compressed inert gas, such as nitrogen.

[0252] For the preparation of suppositories, a low-melting wax such as a mixture of fatty acid glycerides, such as cocoa butter, etc., is first melted, and the active ingredient is homogeneously dispersed therein by stirring or a similar mixing operation. Then, the melted homogeneous mixture is poured into a suitable mold and cooled, and thus hardened.

[0253] Furthermore, it also includes a solid-form preparation that is converted into a liquid-form preparation for either oral or parenteral administration immediately before use. The fluid form includes solutions, suspensions, and emulsions.

[0254] Furthermore, the compounds of the present invention may be administered by transdermal application. The transdermal composition can have the form of a cream, lotion, aerosol and / or emulsion.

[0255] The term capsule refers to a special container or casing composed of methylcellulose, polyvinyl alcohol, or modified gelatin or starch, and the active agent can be encapsulated in the capsule. Typically, hard-shell capsules are prepared from a mixture of bone and porcine skin gelatin having a relatively high gel strength. The capsule itself can contain a small amount of coloring agent, opacifying agent, softening agent, and preservative.

[0256] Tablet means a compressed or molded solid dosage form containing the active ingredient together with a suitable bulking agent. Tablets can be produced by compressing a mixture or granules obtained by wet granulation, dry granulation, or compression known to those skilled in the art.

[0257] An oral gel refers to an active ingredient dispersed or solubilized in a hydrophilic semi-solid matrix thereof. Powder for a composition refers to a powder mixture containing the active ingredient and a suitable bulking agent that can be suspended in water or juice.

[0258] A suitable bulking agent is usually a substance that forms the majority of the composition or dosage form. Suitable bulking agents include sugars such as lactose, sucrose, mannitol, sorbitol, etc.; starches derived from wheat, corn, rice, and potatoes; and celluloses such as microcrystalline cellulose. The amount of bulking agent in the composition can range from about 5% to about 95% by weight of the total composition, preferably from about 25% to about 75% by weight, and more preferably from about 30% to about 60% by weight.

[0259] The term disintegrant refers to a substance added to the composition to support the disintegration and release of the pharmaceutical substance. Suitable disintegrants include starches, modified starches soluble in cold water such as sodium carboxymethyl starch, etc.; natural and synthetic gums such as locust bean gum, karaya, guar gum, tragacanth, and agar, etc.; cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose, etc., microcrystalline cellulose, and cross-linked microcrystalline cellulose such as croscarmellose sodium, etc.; alginates such as alginic acid and sodium alginate, etc.; clays such as bentonite, etc., and foaming mixtures. The amount of disintegrant used in the composition can range from about 2% to 20% by weight of the composition, and more preferably from about 5% to about 10% by weight.

[0260] A binder is a substance that binds powders together or "adheres" them, and the binder functions as an "adhesive" in the resulting formulation. The binder adds agglomerated starch already available in bulking agents or disintegrants. Suitable binders include sugars such as sucrose; starches from wheat, corn, rice, and potatoes; natural gums such as acacia gum, gelatin, and tragacanth; derivatives of seaweed such as alginic acid, sodium alginate, and calcium ammonium alginate; cellulose materials such as methylcellulose, sodium carboxymethylcellulose, and hydroxypropylmethylcellulose; polyvinylpyrrolidone; and inorganic compounds such as magnesium aluminum silicate. The amount of binder in the composition can range from about 2% to about 20% by weight of the total composition, preferably from about 3% to about 10% by weight, and more preferably from about 3% to about 6% by weight.

[0261] The term lubricant refers to a substance added to a dosage form to enable release of tablets, granules, etc. from a mold or press die by reducing friction after compression. Suitable lubricants include metal salts of stearic acid such as magnesium stearate, calcium stearate, or potassium stearate; stearic acid; waxes having a high melting point; and water-soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycol, and D,L-leucine. Due to the fact that the lubricant must be present on the surface of the granules and between the granules and the parts of the tablet press, the lubricant is typically added during the last step before compression. The amount of lubricant in the composition can range from about 0.2% to about 5% by weight of the total composition, preferably from about 0.5% to about 2% by weight, and more preferably from about 0.3% to about 1.5% by weight.

[0262] The lubricant is a substance that prevents solidification and improves the flow characteristics of the granules, thus making the flow smooth and uniform. Suitable lubricants include silicon dioxide and talc. The amount of lubricant in the composition can range from about 0.1% to about 5% by weight of the total composition, preferably from about 0.5% to about 2% by weight.

[0263] The coloring agent is an adjuvant that colors the composition or dosage form. The adjuvant can include a food-quality coloring agent adsorbed to a suitable adsorbing means such as, for example, clay or aluminum oxide. The amount of coloring agent used can vary from about 0.1% to about 5% by weight of the composition, and preferably from about 0.1% to about 1% by weight.

[0264] As used herein, a "pharmaceutically effective amount" of a transglutaminase inhibitor is an amount or activity effective to achieve a desired physiological result in either cells treated in vitro or patients treated in vivo. Specifically, a pharmaceutically effective amount is an amount sufficient to inhibit one or more of the clinically defined pathological processes associated with transglutaminase 2 for a specified period of time. The effective amount can vary according to the particular compound of formula (I) and further depends on a plurality of factors and conditions related to the patient being treated and the severity of the disease. For example, when the inhibitor is administered in vivo, among the data to be considered are factors such as the patient's age, weight, health status, etc., as well as dose-response curves and data on toxicity obtained from preclinical animal experiments. When the inhibitor in the form of a compound of formula (I) described herein is brought into contact with cells in vivo, a plurality of preclinical in vitro studies will be designed to determine parameters such as absorption, half-life, dosage, toxicity, etc. Determining the pharmaceutically effective amount for a given pharmaceutically active ingredient is part of the ordinary skill of a person skilled in the art.

[0265] [Examples] The following abbreviations used in the examples have the following meanings. Boc (tert-butoxycarbonyl), BocOSu (N-tert-butoxycarbonyloxysuccinimide), DCM (dichloromethane), DMAP (4-(dimethylamino)-pyridine), TEA (triethylamine), DMF (dimethylformamide), DMP (dess-martin periodinane), DIPEA (N-ethyldiisopropylamine), Glu (glutamic acid), EDC (1-ethyl-3-(3’-dimethylaminopropyl)carbodiimide), TFA (trifluoroacetic acid), THF (tetrahydrofuran), EtOAc (ethyl acetate), HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate), HOBt (hydroxybenzotriazole), MTBE (methyl tert-butyl ether), tBu (tert-butyl) Chemical Example The following examples are intended to illustrate the present invention using the selected compounds without limiting the scope of protection of the intellectual property rights with respect to these specific examples. 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 protection of the intellectual property rights.

[0266] Example I. Synthetic Method I

[0267]

Chemical Structure

[0268] Preparation of Compound ZED1657

[0269]

Chemical Structure

[0270] 30.0 g (214 mmol) of 2-hydroxy-3-nitropyridine and 40.5 g (2 eq) of chloroacetic acid were suspended in 600 mL of water. At 40 °C, 245 g (3 eq) of trisodium phosphate dodecahydrate was added and the reaction was stirred overnight at room temperature. 250 mL of HCl (32%) was added and the suspension was stirred for a further overnight at 4 °C. The precipitate was filtered off and dried. Yield: 41.2 g, 97% ESI-MS: 199.3 [M+H] + Preparation of Compound ZED3912

[0271]

Chemical Structure

[0272] 7.0 g (35.3 mmol) of ZED1657, 6.63 g (1 eq) of 1-adamantanamine hydrochloride, and 4.77 g (1 eq) of HOBt were dissolved in 80 mL of DMF and 7.38 mL (1.2 eq) of DIPEA. 7.45 g (1.1 eq) of 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride was added and the reaction was stirred overnight at room temperature. The solvent was evaporated and the residue was dissolved in 200 mL of DCM. The solution was washed with 100 mL each of citric acid solution (10%), NaHCO3 solution (10%), and brine. The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated. Yield: 10.3 g, 88% ESI-MS: 332.4 [M+H] + Preparation of Compound ZED3913

[0273]

Chemical Structure

[0274] 10.0 g (31.0 mmol) of ZED3912 was suspended in 200 mL of MeOH, and then palladium (10%) on activated carbon (1.0 g, unreduced) was added. The suspension was stirred overnight at room temperature under a hydrogen atmosphere. The catalyst was filtered off and the solvent was evaporated. Yield: 7.51 g, 78% ESI-MS: 302.3 [M+H] +

[0275]

Chemical Structure

[0276] Preparation of Compound ZED788

[0277]

Chemical Structure

[0278] 12.0 g of Boc-L-Glu-OtBu (39.6 mmol), and 7.09 g of cesium carbonate (21.8 mmol, 0.55 eq) were suspended in 100 ml of DMF and stirred at room temperature for 1 hour. 2.47 ml of iodomethane (39.6 mmol) was added and the mixture was stirred overnight at room temperature. The solvent was evaporated and the residue was dissolved in ethyl acetate and washed twice with each of citric acid solution (10%), NaHCO3 solution (10%) and brine. The organic layer was dried over Na2SO4, filtered and the solvent was evaporated. The raw product was used without further purification. Yield: 13.4 g, >100% ESI-MS: 318.3 [M+H] + Preparation of Compound ZED720

[0279]

Chemical Structure

[0280] 13.4 g of ZED788 (~39.6 mmol) and 986 mg of N,N-dimethyl-4-aminopyridine (DMAP) were dissolved in 30 ml of acetonitrile. A solution having 17.6 g of di-tert-butyl dicarbonate (77.1 mmol) in 100 ml of acetonitrile was added, and the solution was stirred overnight at room temperature. The solvent was evaporated, and the residue was dissolved in ethyl acetate and washed twice with each of citric acid solution (10%), NaHCO3 solution (10%) and brine. The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated. The raw product was used without further purification. Yield: 13.7 g, 83% ESI-MS: 418.3 [M+H] + Preparation of Compound ZED721

[0281]

Chemical formula

[0282] 13.7 g of ZED720 (32.8 mmol) was dissolved in 200 ml of dry diethyl ether and cooled to -78 °C under an argon atmosphere. 36.1 ml of diisobutylaluminum hydride (1 M in hexane) was added dropwise, and the solution was stirred at -78 °C for 30 minutes, then quenched with potassium sodium tartrate (Rochelle salt) solution. The organic layer was separated, dried over Na2SO4, filtered, and concentrated to dryness. The raw product was used without further purification. Yield: 13.3 g, >100% ESI-MS: 388.3 [M+H] + Preparation of Compound ZED3221

[0283]

Chemical formula

[0284] 7.0 g (18.1 mmol) of the aldehyde (S)-tert-butyl 2-(bis(tert-butoxycarbonyl)amino)-5-oxopentanoate (ZED721) was dissolved in 30 mL of DCM. At 0 °C, 1.04 (1.05 eq) of ethyl isocyanide and 1.09 mL (1.05 eq) of acetic acid were added, and the reaction mixture was stirred at room temperature overnight. 35 mL of TFA was added, and the reaction mixture was stirred for an additional 3 hours. The solvent was evaporated, and the residue was dissolved in 20 mL of DMF. A solution having 6.29 mL (2 eq) of DIPEA and 4.73 g (1.2 eq) of di-tert-butyl dicarbonate in 5 mL of DMF was added, and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was dissolved in DCM. After extraction with a NaHCO3 solution (1.05 eq in water), 1.5 eq of citric acid was added to the aqueous layer, followed by re-extraction with DCM. The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated. The residue was purified by flash chromatography. A solution having 6.29 mL (2 eq) of DIPEA and 4.73 g (1.2 eq) of di-tert-butyl dicarbonate in 5 mL of DMF was added, and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was dissolved in DCM. After extraction with a NaHCO3 solution (1.05 eq in water), 1.5 eq of citric acid was added to the aqueous layer, followed by re-extraction with DCM. The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated. The residue was purified by flash chromatography. Yield: 5.77 g, 92% ESI-MS: 347.3 [M+H] + Preparation of Compound I-1a

[0285]

Chemical formula

[0286] 5.77 g (16.7 mmol) of ZED3221, 6.33 g (1 eq) of HATU, and 5.02 g (1 eq) of ZED3913 were dissolved in a solution having 100 mL of DMF and 5.80 mL of DIPEA (2 eq), and the mixture was stirred at 45 °C overnight. The solvent was evaporated; the residue was dissolved in 50 mL of EtOAc and washed twice each with 35 mL of a citric acid solution (10%), a NaHCO3 solution (10%), and brine. The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated. Yield: 7.41 g, 71% ESI-MS: 630.5 [M+H] + Preparation of Compound I-1b

[0287]

Chem.

[0288] 600 mg (0.95 mmol) of I-1a was dissolved in 5 ml of DCM / TFA (1:1) and stirred at room temperature for 1 hour. The solvent was evaporated and the residue was dissolved in 5 ml of DMF. 120 mg (1 eq) of 1-methyl-1H-imidazole-5-carboxylic acid, 362 mg (1 eq) of HATU, and 272 μl (2 eq) of DIPEA were added and the reaction was stirred at room temperature overnight. The solvent was evaporated; the residue was dissolved in 20 mL of EtOAc and washed with 15 mL of citric acid solution (10%), NaHCO3 solution (10%), and brine, respectively. The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated. Yield: 527 mg, 87% ESI-MS: 638.5 [M+H] + Preparation of Compound I-1c

[0289]

Chem.

[0290] 527 mg (0.83 mmol) of I-1b was dissolved in 7 ml of MeOH. 171 mg (1.5 eq) of potassium carbonate was added and the reaction was stirred at room temperature for 1 hour. The solution was diluted with DCM and washed with water. The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated. Yield: 469 mg, 95% ESI-MS: 596.5 [M+H] + Preparation of Compound I-1

[0291]

Chem.

[0292] 469 mg (0.60 mmol) of I-1c was dissolved in 5 ml of DMF. 534 mg (1.6 eq) of Dess-Martin periodinane (DMP) was added, and the reaction mixture 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: 362 mg, 77% ESI-MS: 594.5 [M+H] + 1 1H-NMR (DMSO-D6, 500 MHz, δ [ppm]): 1.27 (t, 3H, ethyl-CH3), 1.74 (m, 6H, adamantyl-C4-H2), 1.97 / / 2.15 (m / / m, 1H / / 1H, β-CH2), 2.09 (m, 3H, adamantyl-C3-H), 2.17 (m, 6H, adamantyl-C2-H2), 3.23 (m, 2H, ethyl-CH2), 2.91 (t, 2H, γ-CH2), 3.74 (s, 3H, imidazole-N-CH3), 4.54 (ddd, 1H, a-CH2), 4.61 (s, 2H, N-CH2), 6.26 (t, 1H, pyridinone-C5-H), 7.31 (d, 1H, pyridinone-C6-H), 7.69 (s, 1H, imidazole-CH), 7.77 (s, 1H, imidazole-CH), 8.04 (d, 1H, adamantyl-NH), 8.17 (d, 1H, pyridinone-C4-H), 8.44 (q, 1H, ethylamide-NH), 8.56 (d, 1H, α-NH), 9.16 (s, 1H, pyridinone-NH).

[0293] 1313C-NMR (DMSO-D6, 500 MHz, δ [ppm]: 15.14 (ethyl - CH3), 24.54 (β - CH2), 29.19 (adamantyl - C3 - H), 33.54 (imidazole - N - CH3), 33.71 (γ - CH2), 34.41 (ethyl - CH2), 35.89 (adamantyl - C4 - H2), 40.77 (adamantyl - C2 - H2), 44.12 (adamantyl - C1), 51.74 (N - CH2), 52.42 (α - CH2), 104.66 (pyridinone - C5 - H), 122.39 (pyridinone - C4 - H), 125.22 (imidazole - Cq), 127.92 (pyridinone - N - Cq), 132.85 (imidazole - CH), 133.27 (pyridinone - C6 - H), 142.23 (imidazole - CH), 156.63 (pyridinone - C = O), 160.32 (imidazole - C = O), 161.10 (C = O - NH - CH2CH3), 165.75 (C = O - adamantyl amide), 170.56 (C = O - NH - pyridinone), 198.43 (C = O - ethyl amide).

[0294] Preparation of Compound I - 2

[0295]

Chem.

[0296] The synthesis of Compound I - 2 was carried out according to Compound I - 1 using 1 - Boc - imidazole - 4 - carboxylic acid instead of 1 - methyl - 1H - imidazole - 5 - carboxylic acid. The final product was obtained by the above - mentioned de - protection (DCM / TFA) and purified by HPLC. Yield: 45 mg, 63% (final step) ESI - MS: 580.4 [M + H] + Preparation of Compound I - 3

[0297]

Chem.

[0298] The synthesis of Compound I-3 was carried out according to Compound I-1, using N-methyl-1-adamantanamine instead of 1-adamantanamine in Step 2 (according to ZED3912). Yield: 26 mg, 52% (final step) ESI-MS: 608.5 [M+H] + Preparation of Compound I-4

[0299]

Chemical Structure

[0300] To a solution of the α-hydroxy ester precursor of Compound I-4 (382 mg, 0.61 mmol, prepared using 3,5-dimethyl-1-adamantanamine in Step 2 according to Compound ZED3912) in 10 mL of acetonitrile was added 1 mg of TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl, 1 mol %). 88 mg of calcium hypochlorite (1 equivalent) was added at 0 °C, and the reaction mixture was stirred at 25 °C for 2 hours. The suspension was filtered, diluted with ethyl acetate, and washed with NaHCO3 solution (10%) and brine. The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated. The residue was purified by HPLC. Yield: 176 mg, 46% ESI-MS: 622.5 [M+H] + Preparation of Compound I-5

[0301]

Chemical Structure

[0302] A solution having the α-hydroxy ester precursor of Compound I-5 (162 mg, 0.26 mmol, prepared using 3-ethyl-1-adamantanamine in Step 2 according to Compound ZED3912) in 5 ml of DMSO was added with 145 mg of 2-iodoxybenzoic acid (IBX, 2 eq), and the reaction mixture was stirred at room temperature for 3 hours. A NaHCO3 solution (10%) was added, and the suspension was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated. The residue was purified by HPLC. Yield: 59 mg, 37% (final step) ESI-MS: 622.5 [M+H] + Preparation of Compound I-6

[0303]

Chemical formula

[0304] The synthesis of Compound I-6 was carried out according to Compound I-1, using 3-trifluoromethyl-1-adamantanamine instead of 1-adamantanamine in Step 2 (according to ZED3912). Yield: 36 mg, 51% (final step) ESI-MS: 662.4 [M+H] + Preparation of Compound I-7

[0305]

Chemical formula

[0306] The synthesis of Compound I-7 was carried out according to Compound I-1, using 3-hydroxy-1-adamantanamine instead of 1-adamantanamine in Step 2 (according to ZED3912). Yield: 21 mg, 45% (final step) ESI-MS: 610.5 [M+H] + Preparation of Compound I-8

[0307]

Chem.

[0308] The synthesis of Compound I-8 was carried out according to Compound I-1, using 3-fluoro-1-adamantanamine instead of 1-adamantanamine in Step 2 (according to ZED3912). Yield: 52 mg, 61% (final step) ESI-MS: 612.5 [M+H] + Preparation of Compound I-9

[0309]

Chem.

[0310] The synthesis of Compound I-9 was carried out according to Compound I-1, using 3-chloro-1-adamantanamine instead of 1-adamantanamine in Step 2 (according to ZED3912). Yield: 49 mg, 68% (final step) ESI-MS: 628.3 / 630.3 [M+H] + Preparation of Compound I-10

[0311]

Chem.

[0312] The synthesis of Compound I-10 was carried out according to Compound I-1, using 3-bromo-1-adamantanamine instead of 1-adamantanamine in Step 2 (according to ZED3912). Yield: 59 mg, 71% (final step) ESI-MS: 672.3 / 674.3 [M+H] + Preparation of Compound I-11

[0313]

Chem.

[0314] The synthesis of compound I-11 was carried out according to compound I-1, using methyl 3-aminoadamantane-1-carboxylate instead of 1-adamantanamine in step 2 (according to ZED3912). Yield: 85 mg, 74% (final step) ESI-MS: 652.5 [M+H] + Preparation of compound I-12

[0315]

Chem.

[0316] The synthesis of compound I-12 was carried out according to compound I-1, using 4,4-difluoro-1-adamantanamine instead of 1-adamantanamine in step 2 (according to ZED3912). Yield: 23 mg, 47% (final step) ESI-MS: 630.4 [M+H] + Preparation of compound I-13

[0317]

Chem.

[0318] The synthesis of compound I-13 was carried out according to compound I-1, using (-)-cis-miltanyl amine instead of 1-adamantanamine in step 2 (according to ZED3912). Yield: 74 mg, 68% (final step) ESI-MS: 596.5 [M+H] + Preparation of compound I-14

[0319]

Chem.

[0320] The synthesis of compound I-14 was carried out by using (-)-cis-(pinan-2-ylmethyl)amine instead of 1-adamantanamine in step 2 (according to ZED3912). The procedure was carried out according to compound I-1. Yield: 52 mg, 63% (final step) ESI-MS: 596.5 [M+H] + Preparation of compound I-15

[0321] [ka]

[0322] The synthesis of compound I-15 was carried out according to compound I-5, using 1-methyl-1H-imidazole-4-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b). Yield: 26mg, 67% (final step) ESI-MS: 622.5 [M+H] + Preparation of Compound I-16

[0323] [ka]

[0324] The synthesis of compound I-16 was carried out according to compound I-5, using 1-methyl-1H-imidazole-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b). Yield: 46mg, 71% (final step) ESI-MS: 622.5 [M+H] + Preparation of compound I-17

[0325] [ka]

[0326] The synthesis of Compound I-17 was carried out according to Compound I-5, using 1,4-dimethyl-1H-imidazole-5-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 69 mg, 75% (final step) ESI-MS: 636.5 [M+H] + Preparation of Compound I-18

[0327]

Chemical formula

[0328] The synthesis of Compound I-18 was carried out according to Compound I-5, using 1-isobutyl-1H-imidazole-4-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 38 mg, 62% (final step) ESI-MS: 664.5 [M+H] + Preparation of Compound I-19

[0329]

Chemical formula

[0330] The synthesis of Compound I-19 was carried out according to Compound I-5, using 1-cyclopentyl-1H-imidazole-4-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 24 mg, 57% (final step) ESI-MS: 676.5 [M+H] + Preparation of Compound I-20

[0331]

Chemical formula

[0332] The synthesis of Compound I-20 was carried out according to Compound I-5, using 1-cyclobutyl-1H-imidazole-4-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in Step 6 (following Compound I-1b). Yield: 32 mg, 66% (final step) ESI-MS: 662.5 [M+H] + Preparation of Compound I-21

[0333]

Chemical formula

[0334] The synthesis of Compound I-21 was carried out according to Compound I-4, using 1,4-dimethyl-1H-imidazole-5-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in Step 6 (following Compound I-1b). Yield: 25 mg, 56% (final step) ESI-MS: 636.5 [M+H] + Preparation of Compound I-22

[0335]

Chemical formula

[0336] The synthesis of Compound I-22 was carried out according to Compound I-4, using 1-methyl-1H-imidazole-4-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in Step 6 (following Compound I-1b). Yield: 45 mg, 77% (final step) ESI-MS: 622.5 [M+H] + Preparation of Compound I-23

[0337]

Chemical formula

[0338] The synthesis of Compound I-23 was carried out according to Compound I-4, using 1-methyl-1H-imidazole-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 18 mg, 50% (final step) ESI-MS: 622.5 [M+H] + Preparation of Compound I-24

[0339]

Chemical Structure

[0340] The synthesis of Compound I-24 was carried out according to Compound I-4, using 1,2-dimethyl-1H-imidazole-5-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 44 mg, 72% (final step) ESI-MS: 636.5 [M+H] + Preparation of Compound I-25

[0341]

Chemical Structure

[0342] The synthesis of Compound I-25 was carried out according to Compound I-1, using 3-methyl-1-adamantanamine instead of 1-adamantanamine in Step 2 (according to ZED3912). Yield: 37 mg, 59% (final step) ESI-MS: 608.5 [M+H] + Preparation of Compound I-26

[0343]

Chemical Structure

[0344] The synthesis of Compound I-26 was carried out according to Compound I-4, using 2-chloro-1-methyl-1H-imidazole-5-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 57 mg, 71% (final step) ESI-MS: 656.5 / 658.5 [M+H] + Preparation of Compound I-27

[0345]

Chemical Structure

[0346] The synthesis of Compound I-27 was carried out according to Compound I-25, using 1,2-dimethyl-1H-imidazole-5-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 29 mg, 52% (final step) ESI-MS: 622.5 [M+H] + Preparation of Compound I-28

[0347]

Chemical Structure

[0348] The synthesis of Compound I-28 was carried out according to Compound I-1, using 3,5,7-trimethyl-1-adamantanamine instead of 1-adamantanamine in Step 2 (according to ZED3912). Yield: 48 mg, 63% (final step) ESI-MS: 636.5 [M+H] + Preparation of Compound I-29

[0349]

Chemical Structure

[0350] The synthesis of Compound I-29 was carried out according to Compound I-28, using 2-chloro-1-methyl-1H-imidazole-5-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 23 mg, 52% (final step) ESI-MS: 670.5 / 672.5 [M+H] + Preparation of Compound I-30

[0351]

Chemical Structure

[0352] The synthesis of Compound I-30 was carried out according to Compound I-1, using 1-adamantanamine instead of 1-adamantanamine in Step 2 (according to ZED3912), and using benzofuran-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 73 mg, 68% (final step) ESI-MS: 630.4 [M+H] + Preparation of Compound I-31

[0353]

Chemical Structure

[0354] The synthesis of Compound I-31 was carried out according to Compound I-30, using 3-methylbenzo[b]furan-2-carboxylic acid instead of benzofuran -2-carboxylic acid. Yield: 90 mg, 77% (final step) ESI-MS: 644.5 [M+H] + Preparation of Compound I-32

[0355]

Chemical Structure

[0356] The synthesis of Compound I-32 was carried out according to Compound I-30 using 3-chlorobenzofuran-2-carboxylic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 56 mg, 72% (final step) ESI-MS: 664.4 / 666.4 [M+H] + Preparation of Compound I-33

[0357]

Chemical Structure

[0358] The synthesis of Compound I-33 was carried out according to Compound I-30 using 4-bromo-1-benzofuran-2-carboxylic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 64 mg, 69% (final step) ESI-MS: 708.3 / 710.3 [M+H] + Preparation of Compound I-34

[0359]

Chemical Structure

[0360] The synthesis of Compound I-34 was carried out according to Compound I-30 using benzothiophene-2-carboxylic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 51 mg, 67% (final step) ESI-MS: 646.4 [M+H] + Preparation of Compound I-35

[0361]

Chemical Structure

[0362] The synthesis of Compound I-35 was carried out according to Compound I-30 using 7-fluorobenzo[b]thiophene-2-carboxylic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 36 mg, 64% (final step) ESI-MS: 664.4 [M+H] + Preparation of Compound I-36

[0363] [Chemical formula]

[0364] The synthesis of Compound I-36 was carried out according to Compound I-30 using 4,5-difluoro-1H-indole-2-carboxylic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 48 mg, 67% (final step) ESI-MS: 665.4 [M+H] + Preparation of Compound I-37

[0365] [Chemical formula]

[0366] The synthesis of Compound I-37 was carried out according to Compound I-30 using 3-methyl-1H-indole-2-carboxylic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 42 mg, 64% (final step) ESI-MS: 643.5 [M+H] + Preparation of Compound I-38

[0367] [Chemical formula]

[0368] The synthesis of Compound I-38 was carried out according to Compound I-30 using 1H-benzo[d]imidazole-2-carboxylic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 26 mg, 55% (final step) ESI-MS: 630.5 [M+H] + Preparation of Compound I-39

[0369]

Chemical formula

[0370] The synthesis of Compound I-39 was carried out according to Compound I-30 using 2,3-dihydro-1H-inden-2-carboxylic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 19 mg, 46% (final step) ESI-MS: 630.5 [M+H] + Preparation of Compound I-40

[0371]

Chemical formula

[0372] The synthesis of Compound I-40 was carried out according to Compound I-30 using 4-methyl-2-(trifluoromethyl)thiazole-5-carboxylic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 34 mg, 61% (final step) ESI-MS: 679.4 [M+H] + Preparation of Compound I-41

[0373]

Chemical formula

[0374] The synthesis of Compound I-41 was carried out according to Compound I-30, using 4-bromo-2-(trifluoromethyl)thiazole-5-carboxylic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 39 mg, 56% (final step) ESI-MS: 743.3 / 745.3 [M+H] + Preparation of Compound I-42

[0375]

Chem.

[0376] The synthesis of Compound I-42 was carried out according to Compound I-30, using 4-methyl-2-phenylthiazole-5-carboxylic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 43 mg, 69% (final step) ESI-MS: 687.5 [M+H] + Preparation of Compound I-43

[0377]

Chem.

[0378] The synthesis of Compound I-43 was carried out according to Compound I-30, using 5-bromo-3-methylthiophene-2-carboxylic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 55 mg, 67% (final step) ESI-MS: 688.3 / 690.3 [M+H] + Preparation of Compound I-44

[0379]

Chem.

[0380] The synthesis of Compound I-44 was carried out according to Compound I-30 using 3,5-dibromothiophene-2-carboxylic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 43 mg, 60% (final step) ESI-MS: 752.2 / 754.2 / 756.2 [M+H] + Preparation of Compound I-45

[0381]

Chemical formula

[0382] The synthesis of Compound I-45 was carried out according to Compound I-30 using 5-bromo-3-methylfuran-2-carboxylic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 52 mg, 71% (final step) ESI-MS: 672.3 / 674.3 [M+H] + Preparation of Compound I-46

[0383]

Chemical formula

[0384] The synthesis of Compound I-46 was carried out according to Compound I-30 using 2,5-dichlorothiophene-3-carboxylic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 85 mg, 72% (final step) ESI-MS: 664.3 / 666.3 [M+H] + Preparation of Compound I-47

[0385]

Chemical formula

[0386] The synthesis of Compound I-47 was carried out according to Compound I-30, using 2,5-dibromothiophene-3-carboxylic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 64 mg, 68% (final step) ESI-MS: 752.2 / 754.2 / 756.2 [M+H] + Preparation of Compound I-48

[0387]

Chemical Structure

[0388] The synthesis of Compound I-48 was carried out according to Compound I-30, using 2,5-dichlorothiazole-4-carboxylic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 26 mg, 48% (final step) ESI-MS: 665.3 / 667.3 [M+H] + Preparation of Compound I-49

[0389]

Chemical Structure

[0390] The synthesis of Compound I-49 was carried out according to Compound I-30, using 2,5-dimethylfuran-3-carboxylic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 53 mg, 74% (final step) ESI-MS: 608.5 [M+H] + Preparation of Compound I-50

[0391]

Chemical Structure

[0392] The synthesis of Compound I-50 was carried out according to Compound I-30 using 4-bromothiazole-2-carboxylic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 37 mg, 59% (final step) ESI-MS: 675.3 / 677.3 [M+H] + Preparation of Compound I-51

[0393]

Chemical formula

[0394] The synthesis of Compound I-51 was carried out according to Compound I-30 using 4-bromothiophene-2-carboxylic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 52 mg, 66% (final step) ESI-MS: 674.3 / 676.3 [M+H] + Preparation of Compound I-52

[0395]

Chemical formula

[0396] The synthesis of Compound I-52 was carried out according to Compound I-30 using 4-bromo-5-chlorothiophene-2-carboxylic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 48 mg, 65% (final step) ESI-MS: 708.2 / 710.2 [M+H] + Preparation of Compound I-53

[0397]

Chemical formula

[0398] The synthesis of Compound I-53 was carried out according to Compound I-30 using 4,5-dibromothiophene-2-carboxylic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 52 mg, 63% (final step) ESI-MS: 752.2 / 754.2 / 756.2 [M+H] + Preparation of Compound I-54

[0399]

Chemical Structure

[0400] The synthesis of Compound I-54 was carried out according to Compound I-30 using 4,5-dichlorothiophene-2-carboxylic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 63 mg, 68% (final step) ESI-MS: 664.2 / 666.2 [M+H] + Preparation of Compound I-55

[0401]

Chemical Structure

[0402] The synthesis of Compound I-55 was carried out according to Compound I-30 using (S)-1-acetylpyrrolidine-2-carboxylic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 76 mg, 73% (final step) ESI-MS: 625.5 [M+H] + Preparation of Compound I-56

[0403]

Chemical Structure

[0404] The synthesis of Compound I-56 was carried out according to Compound I-30 using 1-methyl-1H-1,2,3-triazole-5-carboxylic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 50 mg, 61% (final step) ESI-MS: 595.5 [M+H] + Preparation of Compound I-57

[0405]

Chem.

[0406] The synthesis of Compound I-57 was carried out according to Compound I-30 using 2H-tetrazole-5-carboxylic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 32 mg, 48% (final step) ESI-MS: 582.4 [M+H] + Preparation of Compound I-58

[0407]

Chem.

[0408] The synthesis of Compound I-58 was carried out according to Compound I-1 using 5-hydroxy-2-adamantanamine instead of 1-adamantanamine in Step 2 (according to ZED3912), and using pyrazine-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 26 mg, 53% (final step) ESI-MS: 608.5 [M+H] + Preparation of Compound I-59

[0409] [Chemical formula]

[0410] The synthesis of Compound I-59 was carried out according to Compound I-1, using 5-fluoro-2-adamantanamine instead of 1-adamantanamine in Step 2 (according to ZED3912), and using (S)-1-Boc-pyrrolidine-3-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in Step 6 (according to Compound I-1b). The final product was obtained by the above-mentioned deprotection (DCM / TFA) and purified by HPLC. Yield: 35 mg, 83% (final step) ESI-MS: 601.5 [M+H] + Preparation of Compound I-60

[0411] [Chemical formula]

[0412] The synthesis of Compound I-60 was carried out according to Compound I-1, using 5-chloro-2-adamantanamine instead of 1-adamantanamine in Step 2 (according to ZED3912), and using (S)-1-Boc-piperidine-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in Step 6 (according to Compound I-1b). The final product was obtained by the above-mentioned deprotection (DCM / TFA) and purified by HPLC. Yield: 37 mg, 78% (final step) ESI-MS: 631.4 / 633.4 [M+H] + Preparation of Compound I-61

[0413] [Chemical formula]

[0414] The synthesis of compound I-61 was carried out according to compound I-1, using 5-bromo-2-adamantanamine instead of 1-adamantanamine in step 2 (according to ZED3912), and using (R)-1-Boc-piperidine-3- instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b). The final product was obtained by the above-mentioned deprotection (DCM / TFA) and purified by HPLC. Yield: 35 mg, 72% (final step) ESI-MS: 675.3 / 677.3 [M+H] + Preparation of compound I-62

[0415]

Chemical formula

[0416] The synthesis of compound I-62 was carried out according to compound I-1, using 5-methyl-2-adamantanamine instead of 1-adamantanamine in step 2 (according to ZED3912), and using (R)-4-Boc-morpholine-3- instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b). The final product was obtained by the above-mentioned deprotection (DCM / TFA) and purified by HPLC. Yield: 31 mg, 80% (final step) ESI-MS: 613.5 [M+H] + Preparation of compound I-63

[0417]

Chemical formula

[0418] The synthesis of compound I-63 was carried out according to compound I-1, using 2-aminoadamantane-2-carbonitrile instead of 1-adamantanamine in step 2 (according to ZED3912), and using quinuclidine-3-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b). Yield: 24 mg, 56% (final step) ESI-MS: 648.5 [M+H] + Preparation of compound I-64

[0419]

Chemical formula

[0420] The synthesis of compound I-64 was carried out according to compound I-1, using 2-methyl-2-aminoadamantane-2-carboxylate instead of 1-adamantanamine in step 2 (according to ZED3912), and using mono-methyl 5-nitroisophthalate instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b). Yield: 46 mg, 71% (final step) ESI-MS: 751.5 [M+H] + Preparation of compound I-65

[0421]

Chemical formula

[0422] The synthesis of compound I-65 was carried out according to compound I-1, using 1-adamantanemethylamine instead of 1-adamantanamine in step 2 (according to ZED3912), and using 5-nitro nicotinic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b). Yield: 61 mg, 74% (final step) ESI-MS: 650.5 [M+H] + Preparation of Compound I-66

[0423]

Chem.

[0424] The synthesis of Compound I-66 was carried out according to Compound I-1, using 1-rimantadine instead of 1-adamantanamine in Step 2 (according to ZED3912), and using 3,5-pyridinedicarboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 31 mg, 56% (final step) ESI-MS: 663.5 [M+H] + Preparation of Compound I-67

[0425]

Chem.

[0426] The synthesis of Compound I-67 was carried out according to Compound I-1, using N-methyl-2-adamantanamine instead of 1-adamantanamine in Step 2 (according to ZED3912), and using 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 23 mg, 52% (final step) ESI-MS: 664.5 [M+H] + Preparation of Compound I-68

[0427]

Chem.

[0428] ​The synthesis of Compound I-68 was carried out according to Compound I-1, using (±)-endo-2-norbornylamine instead of 1-adamantanamine in Step 2 (according to ZED3912), and using 3-methylbenzo[b]furan-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 106 mg, 78% (final step) ESI-MS: 604.4 [M+H] + Preparation of Compound I-69

[0429]

Chemical Structure

[0430] The synthesis of Compound I-69 was carried out according to Compound I-1, using (R)-(+)-bornylamine instead of 1-adamantanamine in Step 2 (according to ZED3912), and using 3-methylbenzo[b]furan-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 86 mg, 72% (final step) ESI-MS: 646.5 [M+H] + Preparation of Compound I-70

[0431]

Chemical Structure

[0432] The synthesis of Compound I-70 was carried out according to Compound I-1, using exo-2-aminonorbornane instead of 1-adamantanamine in Step 2, and using 3-methylbenzo[b]furan-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 94 mg, 79% (final step) ESI-MS: 604.4 [M+H]+ Preparation of Compound I-71

[0433]

Chem.

[0434] The synthesis of Compound I-71 was carried out according to Compound I-1, using bicyclo[2.2.1]heptan-1-ylamine instead of 1-adamantanamine in Step 2 (according to ZED3912), and using isonicotinic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 77 mg, 72% (final step) ESI-MS: 551.4 [M+H] + Preparation of Compound I-72

[0435]

Chem.

[0436] The synthesis of Compound I-72 was carried out according to Compound I-1, using bicyclo[2.2.1]heptan-7-ylamine instead of 1-adamantanamine in Step 2 (according to ZED3912), and using pyridazine-4-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in Step 6 (according to Compound I-1b). and was carried out. Yield: 44 mg, 61% (final step) ESI-MS: 552.4 [M+H] + Preparation of Compound I-73

[0437]

Chem.

[0438] The synthesis of compound I-73 was carried out according to compound I-1, using bicyclo[2.2.1]hept-5-en-2-amine instead of 1-adamantanamine in step 2 (according to ZED3912), and using pyridazine-3-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b). Yield: 31 mg, 52% (final step) ESI-MS: 550.4 [M+H] + Preparation of compound I-74

[0439]

Chemical formula

[0440] The synthesis of compound I-74 was carried out according to compound I-1, using bicyclo[2.2.2]oct-2-ylamine instead of 1-adamantanamine in step 2 (according to ZED3912), and using 2H-1,2,3-triazole-4-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b). Yield: 35 mg, 57% (final step) ESI-MS: 555.4 [M+H] + Preparation of compound I-75

[0441]

Chemical formula

[0442] The synthesis of compound I-75 was carried out according to compound I-1, using (R)-(-)-isobornylamine instead of 1-adamantanamine in step 2 (according to ZED3912), and using 1-methyl-1H-1,2,3-triazole-4-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b). ​Yield: 44 mg, 68% (final step) ESI-MS: 597.5 [M+H] + Preparation of Compound I-76

[0443]

Chem.

[0444] The synthesis of Compound I-76 was carried out according to Compound I-1, using (1R,2R,3R,5S)-(-)-isopinocampheylamine instead of 1-adamantanamine in Step 2 (according to ZED3912), and using 1-methyl-1H-1,2,4-triazole-3-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 51 mg, 72% (final step) ESI-MS: 597.5 [M+H] + Preparation of Compound I-77

[0445]

Chem.

[0446] The synthesis of Compound I-77 was carried out according to Compound I-1, using (1S,2S,3S,5R)-(+)-isopinocampheylamine instead of 1-adamantanamine in Step 2 (according to ZED3912), and using benzofuran-3-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 66 mg, 75% (final step) ESI-MS: 632.5 [M+H] + Preparation of Compound I-78

[0447]

Chem.

[0448] The synthesis of Compound I-78 was carried out according to Compound I-1, using 3-amino-4-homoisotwistane instead of 1-adamantanamine in Step 2 (according to ZED3912), and using benzo[b]thiophene-3-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 42 mg, 59% (final step) ESI-MS: 660.4 [M+H] + Preparation of Compound I-79

[0449]

Chemical Structure

[0450] The synthesis of Compound I-79 was carried out according to Compound I-1, using 1-aminodiamantane instead of 1-adamantanamine in Step 2 (according to ZED3912), and using 1-methyl-1H-pyrazole-4-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 28 mg, 53% (final step) ESI-MS: 646.5 [M+H] + Preparation of Compound I-80

[0451]

Chemical Structure

[0452] The synthesis of Compound I-80 was carried out according to Compound I-1, using 4-aminodiamantane instead of 1-adamantanamine in Step 2 (according to ZED3912), and using 1-methyl-1H-pyrazole-3-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 36 mg, 59% (final step) ESI-MS: 646.5 [M+H] + Scheme I-3 New Components

[0453]

Chem.

[0454] 1 Preparation of Compound ZED4893

[0455]

Chem.

[0456] 500 mg (3.57 mmol) of 2-hydroxy-3-nitropyridine and 818 mg (1 eq) of 1-(bromomethyl)adamantane were dissolved in a solution having 10 mL of DMF and 1.24 mL of DIPEA (2 eq), and stirred overnight at room temperature. The solvent was evaporated; the residue was dissolved in 30 mL of EtOAc and washed twice with 10 mL of citric acid solution (10%), NaHCO3 solution (10%), and brine, respectively. The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated. The residue was purified by HPLC. Yield: 484 mg, 47% ESI-MS: 289.3 [M+H] + 2 Preparation of Compound ZED4894

[0457]

Chem.

[0458] 484 mg (1.68 mmol) of ZED4893 was suspended in 30 mL of MeOH, and then palladium on carbon (10%) (unreduced) (50 mg) was added. The suspension was stirred for 3 h at room temperature under a hydrogen atmosphere. The catalyst was filtered and the solvent was evaporated. Yield: 339 mg, 78% ESI-MS: 259.4 [M+H] + Preparation of Compound I-81

[0459]

Chem.

[0460] The synthesis of Compound I-81 was carried out according to Compound I-1, using ZED4894 instead of ZED3913 in Step 5 (according to I-1a), and using 1-methyl-1H-pyrazole-5-carboxylic acid instead of 1-methyl-1H-pyrazole-5-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 43 mg, 65% (final step) ESI-MS: 551.5 [M+H] + Preparation of Compound I-82

[0461]

Chem.

[0462] The synthesis of Compound I-82 was carried out according to Compound I-81, using 3-(bromomethyl)-1-adamantanol instead of 1-(bromomethyl)adamantane (according to ZED4893), and using 4-cyclopropyl-[1,2,3] thiadiazole-5-carboxylic acid instead of 1-methyl-1H-pyrazole-5-carboxylic acid. Yield: 26 mg, 46% (final step) ESI-MS: 611.4 [M+H] + Preparation of Compound I-83

[0463]

Chem.

[0464] The synthesis of compound I-83 was carried out according to compound I-81, using 1-bromo-3-(bromomethyl)adamantane instead of 1-(bromomethyl)adamantane (according to ZED4893), and using 1,2,5-thiadiazole-3-carboxylic acid instead of 1-methyl-1H-pyrazole-5-carboxylic acid. Yield: 42 mg, 61% (final step) ESI-MS: 633.3 / 635.3 [M+H] + Preparation of compound I-84

[0465]

Chemical Structure

[0466] The synthesis of compound I-84 was carried out according to compound I-81, using 2-(bromomethyl)adamantane instead of 1-(bromomethyl)adamantane (according to ZED4893), and using 4-((tetrahydro-2H-pyran-2-yloxy)methyl)-1,2,3-thiadiazole-5-carboxylic acid instead of 1-methyl-1H-pyrazole-5-carboxylic acid. The tetrahydropyranyl (Thp) protecting group was cleaved with TFA in the final step. Yield: 15 mg, 68% (final step) ESI-MS: 585.4 [M+H] + Preparation of compound I-85

[0467]

Chemical Structure

[0468] The synthesis of compound I-85 was carried out according to compound I-81, using 1-(2-bromoethyl)adamantane instead of 1-(bromomethyl)adamantane (according to ZED4893), and using 5-tert-butyl-1H-pyrrole-3-carboxylic acid instead of 1-methyl-1H-pyrazole-5-carboxylic acid. Yield: 32 mg, 58% (final step) ESI-MS: 606.5 [M+H] + Preparation of Compound I-86

[0469]

Chem.

[0470] The synthesis of Compound I-86 was carried out according to Compound I-81, using 1-(3-bromopropyl)adamantane instead of 1-(bromomethyl)adamantane (according to ZED4893), and 4-cyano-1-methyl-1H-pyrrole-2-carboxylic acid instead of 1-methyl-1H-pyrazole-5-carboxylic acid. Yield: 28 mg, 51% (final step) ESI-MS: 603.5 [M+H] + Preparation of Compound I-87

[0471]

Chem.

[0472] The synthesis of Compound I-87 was carried out according to Compound I-1, using 3-chloropropionic acid instead of chloroacetic acid (according to ZED1657), and 5-methyloxazole-2-carboxylic acid instead of 1-methyl-1H-pyrazole-5-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 39 mg, 64% (final step) ESI-MS: 625.5 [M+H] + Preparation of Compound I-88

[0473]

Chem.

[0474] ​The synthesis of Compound I-88 was carried out according to Compound I-1, using 1-bicyclo[1.1.1]pentylamine instead of 1-adamantanamine in Step 2 (according to ZED3912), and using 3-methylbenzo[b]furan-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 107 mg, 81% (final step) ESI-MS: 576.4 [M+H] + Preparation of Compound I-89

[0475]

Chemical Structure

[0476] The synthesis of Compound I-89 was carried out according to Compound I-1, using 1-bicyclo[1.1.1]pentylamine instead of 1-adamantanamine in Step 2 (according to ZED3912), and using 2-acetoxazole-4-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 68 mg, 75% (final step) ESI-MS: 555.4 [M+H] ESI-MS: 555.4 [M+H] + Preparation of Compound I-90

[0477]

Chemical Structure

[0478] The synthesis of Compound I-90 was carried out according to Compound I-1, using 1-bicyclo[2.1.1]hexane-1-amine instead of 1-adamantanamine in Step 2 (according to ZED3912), and using 2-isopropyloxazole-5-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 46 mg, 60% (final step) ESI-MS: 569.4 [M+H] + Preparation of Compound I-91

[0479]

Chem.

[0480] The synthesis of Compound I-91 was carried out according to Compound I-1, using 1-bicyclo[3.2.1]octan-8-amine instead of 1-adamantanamine in Step 2 (according to ZED3912), and using 3,5-dimethylisoxazole-4-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 32 mg, 54% (final step) ESI-MS: 583.4 [M+H] + Preparation of Compound I-92

[0481]

Chem.

[0482] The synthesis of Compound I-92 was carried out according to Compound I-1, using 4-aminoadamantane-1-carboxylic acid instead of 1-adamantanamine in Step 2 (according to ZED3912), and using 4-methylpyrimidine-5-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 35 mg, 46% (final step) ESI-MS: 650.5 [M+H] + Preparation of Compound I-93

[0483]

Chem.

[0484] The synthesis of Compound I-93 was carried out according to Compound I-1, using 4-aminoadamantane-N,N-dimethyl-1-carboxamide instead of 1-adamantanamine in Step 2 (according to ZED3912), and using 1,2,3,4-tetrahydronaphthalene-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 31 mg, 55% (final step) ESI-MS: 672.5 [M+H] + Preparation of Compound I-94

[0485]

Chemical Structure

[0486] The synthesis of Compound I-94 was carried out according to Compound I-30, using 1,4-diazabicyclo[2.2.2]octane-2-carboxylic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 39 mg, 58% (final step) ESI-MS: 624.5 [M+H] + Preparation of Compound I-95

[0487]

Chemical Structure

[0488] The synthesis of Compound I-95 was carried out according to Compound I-30, using 1H-indole-3-carboxylic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 56 mg, 74% (final step) ESI-MS: 629.5 [M+H] + Preparation of Compound I-96

[0489] [Chemical]

[0490] The synthesis of Compound I-96 was carried out according to Compound I-30 using 6-methylimidazo[2,1-b][1,3]thiazole-3-carboxylic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 33 mg, 56% (final step) ESI-MS: 650.5 [M+H] + Preparation of Compound I-97

[0491] [Chemical]

[0492] The synthesis of Compound I-97 was carried out according to Compound I-1 using (±)-endo-2-norbornylamine instead of 1-adamantanamine in Step 2 (according to ZED3912) and using 1,3-benzothiazole-2-carboxylic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 45 mg, 73% (final step) ESI-MS: 607.4 [M+H] + Preparation of Compound I-98

[0493] [Chemical]

[0494] The synthesis of Compound I-98 was carried out according to Compound I-1 using (±)-endo-2-norbornylamine instead of 1-adamantanamine in Step 2 (according to ZED3912) and using imidazo[2,1-b][1,3]thiazole-6-carboxylic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 26 mg, 50% (final step) ESI-MS: 596.4 [M+H] + Preparation of Compound I-99

[0495]

Chem.

[0496] The synthesis of Compound I-99 was carried out according to Compound I-1, using (±)-endo-2-norbornylamine instead of 1-adamantanamine in Step 2 (according to ZED3912), and using 4-hydroxy-6-(trifluoromethoxy)quinoline-3-carboxylic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 15 mg, 42% (final step) ESI-MS: 701.4 [M+H] + Preparation of Compound I-100

[0497]

Chem.

[0498] The synthesis of Compound I-100 was carried out according to Compound I-1, using 1-bicyclo[1.1.1]pentylamine instead of 1-adamantanamine in Step 2 (according to ZED3912), and using 3-cinnolinecarboxylic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 37 mg, 65% (final step) Yield: 37 mg, 65% (final step) ESI-MS: 574.4 [M+H] + Preparation of Compound I-101

[0499]

Chem.

[0500] The synthesis of Compound I-101 was carried out according to Compound I-1, using 1-bicyclo[1.1.1]pentylamine instead of 1-adamantanamine in Step 2 (according to ZED3912), and using 3-ethylbenzofuran-2-carboxylic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 55 mg, 73% (final step) ESI-MS: 590.4 [M+H] + Preparation of Compound I-102

[0501]

Chemical Structure

[0502] The synthesis of Compound I-102 was carried out according to Compound I-1, using 1-bicyclo[1.1.1]pentylamine instead of 1-adamantanamine in Step 2 (according to ZED3912), and using 1-ethyl-1H-indole-2-carboxylic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 43 mg, 68% (final step) ESI-MS: 589.4 [M+H] + Preparation of Compound I-103

[0503]

Chemical Structure

[0504] The synthesis of Compound I-103 was carried out according to Compound I-1, using 1-bicyclo[1.1.1]pentylamine instead of 1-adamantanamine in Step 2 (according to ZED3912), and using 2-methyl-1,8-naphthyridine-3-carboxylic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 55 mg, 73% (final step) Yield: 40 mg, 64% (final step) ESI-MS: 588.4 [M+H] + Preparation of Compound I-104

[0505]

Chem.

[0506] The synthesis of Compound I-104 was carried out according to Compound I-1, using bicyclo[2.1.1]hexane-1-amine instead of 1-adamantanamine in Step 2 (according to ZED3912), and using N-Boc-1,2,3,4-tetrahydroquinoline-6-carboxylic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). The final product was obtained by the above-mentioned deprotection (DCM / TFA) and purified by HPLC. Yield: 27 mg, 73% (final step) ESI-MS: 591.4 [M+H] + Preparation of Compound I-105

[0507]

Chem.

[0508] The synthesis of Compound I-105 was carried out according to Compound I-1, using 2-amino-5-(trifluoromethyl)adamantane-2-carboxylic acid instead of 1-adamantanamine in Step 2 (according to ZED3912), and using 3-oxo-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 19 mg, 44% (final step) ESI-MS: 771.5 [M+H] + Preparation of Compound I-106

[0509] [Chemistry]

[0510] The synthesis of Compound I-106 was carried out according to Compound I-1, using 5-ethyladamantan-2-amine instead of 1-adamantanamine in Step 2 (according to ZED3912) and using 1,6-naphthyridine-2-carboxylic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 25 mg, 54% (final step) ESI-MS: 670.5 [M+H] + Preparation of Compound I-107

[0511] [Chemistry]

[0512] The synthesis of Compound I-107 was carried out according to Compound I-1, using bicyclo[2.1.1]hexane-1-amine instead of 1-adamantanamine in Step 2 (according to ZED3912) and using 2,6-naphthyridine-1-carboxylic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 58 mg, 74% (final step) ESI-MS: 588.4 [M+H] + Preparation of Compound I-108

[0513] [Chemistry]

[0514] The synthesis of Compound I-108 was carried out according to Compound I-1, using 1-bicyclo[1.1.1]pentylamine instead of 1-adamantanamine in Step 2 (according to ZED3912), and using 4-Boc-amino-1,2,5-oxadiazole-3-carboxylic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). The final product was obtained by the above-mentioned deprotection (DCM / TFA) and purified by HPLC. Yield: 27 mg, 77% (final step) ESI-MS: 529.4 [M+H] + Preparation of Compound I-109

[0515]

Chemical Structure

[0516] The synthesis of Compound I-109 was carried out according to Compound I-1, using 1-bicyclo[1.1.1]pentylamine instead of 1-adamantanamine in Step 2 (according to ZED3912), and using 6-(dimethylamino)benzofuran-2-carboxylic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 35 mg, 57% (final step) ESI-MS: 605.4 [M+H] ESI-MS: 605.4 [M+H] + Preparation of Compound I-110

[0517]

Chemical Structure

[0518] The synthesis of compound I-110 was carried out according to compound I-1, using 1-bicyclo[1.1.1]pentylamine instead of 1-adamantanamine in step 2 (according to ZED3912), and using 2-acetylamino-5-thiazolecarboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b). Yield: 25 mg, 49% (final step) ESI-MS: 586.4 [M+H] + Preparation of compound I-111

[0519]

Chemical Structure

[0520] The synthesis of compound I-111 was carried out according to compound I-1, using 1-bicyclo[1.1.1]pentylamine instead of 1-adamantanamine in step 2 (according to ZED3912), and using 5-carbamoyl-1H-pyrrole-3-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b). Yield: 19 mg, 42% (final step) ESI-MS: 554.4 [M+H] + Preparation of compound I-112

[0521]

Chemical Structure

[0522] The synthesis of compound I-112 was carried out according to compound I-1, using 1-acetylamino-4-aminoadamantane instead of 1-adamantanamine in step 2 (according to ZED3912), and using 5-sulfamoyl-furan-3-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b). Yield: 24 mg, 53% (final step) ESI-MS: 716.4 [M+H] + Preparation of Compound I-113

[0523]

Chemical Structure

[0524] The synthesis of Compound I-113 was carried out according to Compound I-1, using 1-acetylamino-4-aminoadamantane instead of 1-adamantanamine in Step 2 (according to ZED3912), and using benzofuran-5-carboxylic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 30 mg, 58% (final step) ESI-MS: 687.5 [M+H] + Preparation of Compound I-114

[0525]

Chemical Structure

[0526] The synthesis of Compound I-114 was carried out according to Compound I-1, using 4-aminoadamantane-1-carboxamide instead of 1-adamantanamine in Step 2 (according to ZED3912), and using benzofuran-6-carboxylic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 37 mg, 65% (final step) ESI-MS: 673.5 [M+H] + Preparation of Compound I-115

[0527]

Chemical Structure

[0528] The synthesis of compound I-115 was carried out according to compound I-1, using 4-aminoadamantane-1-carboxamide instead of 1-adamantanamine in step 2 (according to ZED3912), and using 3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b). and using 3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b). Yield: 23 mg, 47% (final step) ESI-MS: 679.5 [M+H] + Preparation of compound I-116

[0529]

Chemical Structure

[0530] The synthesis of compound I-116 was carried out according to compound I-1, using 1-bicyclo[1.1.1]pentylamine instead of 1-adamantanamine in step 2 (according to ZED3912), and using 5-methyl-1,2,4-oxadiazole-3-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b). Yield: 36 mg, 62% (final step) ESI-MS: 528.4 [M+H] + Preparation of compound I-117

[0531]

Chemical Structure

[0532] The synthesis of compound I-117 was carried out according to compound I-1, using 1-bicyclo[1.1.1]pentylamine instead of 1-adamantanamine in step 2 (according to ZED3912), and using 1,2,3-thiadiazole-4-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b). Yield: 31 mg, 57% (final step) ESI-MS: 530.3 [M+H] + Preparation of Compound I-118

[0533]

Chem.

[0534] The synthesis of Compound I-118 was carried out according to Compound I-1, using 1-bicyclo[1.1.1]pentylamine instead of 1-adamantanamine in Step 2 (according to ZED3912) and using 1,2,4-thiadiazole-4-carboxylic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 39 mg, 63% (final step) Yield: 39 mg, 63% (final step) ESI-MS: 530.3 [M+H] + Preparation of Compound I-119

[0535]

Chem.

[0536] The synthesis of Compound I-119 was carried out according to Compound I-1, using 1-bicyclo[1.1.1]pentylamine instead of 1-adamantanamine in Step 2 (according to ZED3912) and using 1,3,4-thiadiazole-5-carboxylic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 28 mg, 52% (final step) ESI-MS: 530.3 [M+H] + Preparation of Compound I-120

[0537]

Chem.

[0538] The synthesis of Compound I-120 was carried out according to Compound I-30 using 4-(hydroxymethyl)-1,2,3-thiadiazole-5-carboxylic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 17 mg, 41% (final step) ESI-MS: 626.4 [M+H] + Preparation of Compound I-121

[0539]

Chemical Structure

[0540] The synthesis of Compound I-120 was carried out according to Compound I-1 using nicotinic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 56 mg, 60% (final step) ESI-MS: 591.5 [M+H] + Preparation of Reference Compound Ref.4

[0541]

Chemical Structure

[0542] The synthesis of Reference Compound Ref.4 was carried out according to Compound I-1 using 2-phenylethylamine instead of 1-adamantanamine in Step 2 (according to ZED3912) and using nicotinic acid instead of benzofuran-2-carboxylic acid in Step 6 (according to Compound I-1b). Yield: 68 mg, 77% (final step) ESI-MS: 561.4 [M+H] + Biological Examples Example B-1. Inhibitory Effect of the Compounds According to the Present Invention Transglutaminase Assay To determine the effectiveness of inhibitors against tissue transglutaminase, the incorporation of dansylcadaverine into dimethylcasein (product T036 from Zedira, Lorand et al., Anal Biochem, 1971, 44:221-31) was measured using recombinant human transglutaminase 2 (product T022 from Zedira).

[0543] Tissue transglutaminase is diluted with buffer (50 mM Tris-HCl, 7.5 mM CaCl2, 150 mM NaCl, pH = 7.4). The final concentration of TG2 in the assay is 10 nM.

[0544] A 10 mM inhibitor stock solution is prepared in DMSO, and serial 1:2-fold dilution series are similarly prepared in DMSO. Subsequently, each initial dilution is diluted 1:50-fold with buffer (50 mM Tris-HCl, 7.5 mM CaCl2, 150 mM NaCl, pH = 7.4) to generate the final working dilutions containing 2% (v / v) DMSO.

[0545] 15 μl of the inhibitor working dilution is added to each well of a 96-well microtiter plate. As a control, 15 μl of a 2% (v / v) DMSO solution prepared with the above buffer is added to each well.

[0546] Immediately before starting the assay, 600 μl of the transglutaminase working solution is 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 is added to each well containing the inhibitor.

[0547] The increase in fluorescence is measured at 37 °C for 30 min at λ ex = 330 nm and λem Measure using 500 nm. Calculate the slope of the fluorescence increase between 20 and 30 minutes for the determination of the IC 50 value (the inhibitor concentration at which 50% of the initial activity is inhibited).

[0548] The analysis of enzyme activity is performed by calculating the slope of the increase in fluorescence intensity. The IC 50 value is calculated by plotting the enzyme activity (as a percentage from a control containing 2% DMSO instead of the inhibitor) against the inhibitor concentration. The IC 50 is defined as the inhibitor concentration that inhibits 50% of the initial enzyme activity.

[0549] The inhibitory activity of the compounds of the present invention against tissue transglutaminase (TG2) is shown in Table 1 below using the IC 50 value.

[0550]

Table 1-1

[0551]

Table 1-2

[0552]

Table 1-3

[0553]

Table 1-4

[0554] Example B-2. LogD values of the compounds of the present invention To classify the compounds of the present invention according to their lipophilicity, the LogD value (partition coefficient) was determined using a well-established shake flask method, and the partitioning of the compounds between octanol and phosphate-buffered saline (PBS, pH 7.4) was measured by HPLC.

[0555] Compounds with medium lipophilicity (LogD value of 0 - 3) are usually favorable for oral absorption and have a balance between solubility and permeability. However, advanced formulation of compounds may improve the oral bioavailability for highly lipophilic compounds.

[0556]

Table 2 - 1

[0557]

Table 2 - 2

[0558]

Table 2 - 3

[0559] Example B - 3. Caco - 2 permeability analysis of the compounds of the present invention The permeability coefficient (P app value) was obtained from Caco - 2 barrier studies that predict the oral / enteral bioavailability of the compounds tested. The analysis was performed using a ready - to - use kit, CacoReady (trademark) from ReadyCell, according to the manufacturer's protocol.

[0560] 1x10 -6 cm / s and above have a P app value are classified as permeable, while compounds with a P -6 value less than 1x10 app cm / s are considered to be classified as non - permeable.

[0561]

Table 3 - 1

[0562]

Table 3-2

[0563]

Table 3-3

Claims

1. A compound of general formula (I), 【Chemical Formula 1】 wherein, L is -L １ -L ２ represents -; L １ is -CH ２ -, -CH ２ CH ２ -, -CH ２ CH ２ CH ２ -, -CH ２ CO-, or -CH ２ CH ２ CO- represents; L ２ is a bond, -NR Ｎ１ -, -NR Ｎ１ CH ２ -, -NR Ｎ１ CH ２ CH ２ -, or -NR Ｎ１ CH(CH ３ )- represents; R １ is 【Chemical Formula 2】 represents; R ２ is 【Chemical Formula 3-1】 【Chemical Formula 3-2】 【Chemical Formula 3-3】 【Chemical Formula 3-4】 【Chemical Formula 3-5】 【Chemical Formula 3-6】 represents; Here, the unsubstituted bicyclic residue can be substituted with 1 to 5 substituents R ９ to R １４ and R Ｎ ; R ３represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, adamantyl, diamantyl, or hexamethylenetetraminyl, and the aforementioned residues optionally contain one or more C═C double bonds and / or optionally one or more R ａ , R ｂ , R ｃ , R ｄ , and R ｅ are substituted by; R ａ , R ｂ , R ｃ , R ｄ , and R ｅ are, independently of one another, -H, -F, -Cl, -Br, -CN, -OH, -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , -CH(CH ３ ) ２ , -CHF ２ , -CF ３ , -CH ２ CF ３ , -COCH ３ , -COCH ２ CH ３ , -CO ２ H, -CO ２ CH ３ , -CO ２ C ２ H ５ , -CONH ２ , -CONHCH ３ , -CON(CH ３ ) ２ , -CONHC ２ H ５ , -CH ２ CO ２ H, -CH ２ CO ２ CH ３ , -CH ２ CO ２ C ２ H ５ , -CH ２ CONH ２ , -CH ２ CONHC ３ , -CH ２ CON (CH ３ ) ２ , -CH ２ CONHC ２ H ５ , -NHCOCH ３ , -NHCOC ２ H ５ , -NHCOCF ３ , -NHCOCH ２ CF ３ , -NHSO ２ CH ３ , -NHSO ２ C ２ H ５ , -NHSO ２ CHF ２ , -NHSO ２ CF ３ or -NHSO ２ CH ２ CF ３ , which represents R ４ is -NR ６ R ７ represents; R ６ is -CH ２ CH ３ Represents; R ７ represents -H; R ８ , R ９ , R １０ , R １１ , R １２ , R １３ , and R １４ are, independently of each other, - H, -F, -Cl, -Br, -I, -OH, -CN, -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、 -CH ２ OH、 -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-cyclo-C ３ H ５ 、 -OCH ２ -cyclo-C ３ H ５ 、 -O-C ２ H ４ -cyclo-C ３ H ５ , -CHO, -COCH ３ , -COCF ３ , -COC ２ H ５ , -COC ３ H ７ , -COCH(CH ３ ) ２ , -COC(CH ３ ) ３ , -COOH, -COOCH ３ , -COOC ２ H ５ , -COOC ３ H ７ , -COOCH(CH ３ ) ２ , -COOC(CH ３ ) ３ , -OOCC H ３ , -OOCCF ３ , -OOCC ２ H ５ , -OOCC ３ H ７ , -OOCCH(CH ３ ) ２ , -OOCC(CH ３ ) ３ , -NH ２ , -NHCH ３ , -NHCC ２ H ５ , -NHCC ３ H ７ , -NHCH(CH ３ ) ２ , -NHCC(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 , -CON[C(CH ３ ) ３ ) ２ , -SO ２ NH ２ , -SO ２ NHCH ３ , -SO ２ NH C ２ H ５ , -SO ２ NH C ３ H ７ , -SO ２ NHCH(CH ３ ) ２ , -SO ２ NH - cyclo - C ３ H ５ , -SO ２ NH C(CH ３ ) ３ , -SO ２ N(CH ３ ) ２ , -SO ２ N(C ２ H ５ ) ２ 、 -SO ２ N(C ３ H ７ ) ２ 、 -SO ２ N[CH(CH ３ ) ２ ２ 、 -SO ２ N[C(CH ３ ) ３ ２ 、 -NHSO ２ CH ３ 、 -NHSO ２ CF ３ 、 -NHSO ２ C ２ H ５ 、 -NHSO ２ C ３ H ７ 、 -NHSO ２ CH(CH ３ ) ２ 、 -NHSO ２ C(CH ３ ) ３ 、 -CH=CH ２ 、 -CH ２ -CH=CH ２ 、 -C(CH ３ )=CH ２ 、 -CH=CH-CH ３ 、 -C≡CH、 -C≡C-CH ３ 、 -CH ２ -C≡CH、 -Ph、 -O-Ph、 -O-CH ２ -Ph、 【Chemical Formula 4】 represents; or, R ８ and R ９ 、 or R ９ and R １０ can together form one of the following 5-membered or 6-membered rings: 【Chemical Formula 5】 or, R １２ and R １３ 、 or R １３ and R １４ can together form one of the following 5-membered or 6-membered rings:​​ [Chemical Formula 6] R Ｎ is -H, -CH ３ , -C ２ H ５ , -C ３ H ７ , -CH(CH ３ ) ２ , -C ４ H9, -CH ２ -CH(CH ３ ) ２ , -CH(CH ３ )-C ２ H ５ , -C(CH ３ ) ３ , -cyclo-C ３ H ５ , -cyclo-C ４ H ７ , -cyclo-C ５ H ９ , -CH ２ -cyclo-C ３ H ５ , -CH ２ -cyclo-C ４ H ７ , -CH ２ -cyclo-C ５ H ９ , -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 , -CH ２ -CH ２ , -CH ２ -CH=CH ２ , -CH ２ -C≡CH, -CHO, -COCH ３ , -COC ２ H ５, -COC ３ H ７ , -COCH(CH ３ ) ２ , -COC(CH ３ ) ３ , -CO-cyclo-C ３ H ５ , -CO-cyclo-C ４ H ７ , -CO-cyclo-C ５ H ９ , -COOCH ３ , -COOC ２ H ５ , -COOC ３ H ７ , -COOCH(CH ３ ) ２ , -COOC(CH ３ ) ３ , -COOCH ２ Ph, -SO ２ CH ３ , -SO ２ CF ３ , -SO ２ C ２ H ５ , -SO ２ C ３ H ７ , -SO ２ CH(CH ３ ) ２ , -SO ２ -cyclo-C ３ H ５ , or -SO ２ C(CH ３ ) ３ , represents; R Ｎ１ is, -H, -CH ３ , or -CH ２ CH ３ , represents; The compound of general formula (I), or a diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemate, solvate, hydrate, or pharmaceutically acceptable salt of the compound of general formula (I), However, the following compounds, or diastereomers, enantiomers, mixtures of diastereomers, mixtures of enantiomers, racemates, solvates, hydrates, or pharmaceutically acceptable salts of the following compounds are excluded. In the general formula (I), L ２ represents -NR Ｎ１ -, and R ３ represents 1 - adamantyl; or L ２ represents -NR Ｎ１ CH ２ -, and R ３ represents 2 - bicyclo[3.1.1]heptyl, The aforementioned 1 - adamantyl and 2 - bicyclo[3.1.1]heptyl may optionally contain one or more C = C double bonds and / or be optionally substituted by one or more R ａ , R ｂ , R ｃ , R ｄ , and R ｅ ; R ２ is 【Chemical Formula 7】 represents; R ａ , R ｂ , R ｃ , R ｄ , and R ｅ are, independently of one another, -H, -F, -Cl, -Br, -CN, -OH, -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , -CH(CH ３ ) ２ , -CHF ２ , -CF ３ , -CH ２ CF ３ , -COCH ３ , -COCH ２ CH ３ , -CO ２ H, -CO ２ CH ３ , -CO ２ C ２ H ５ 、 - CONH ２ 、 - CONHCH ３ 、 - CON(CH ３ ) ２ 、 - CONHC ２ H ５ 、 - CH ２ CO ２ H、 - CH ２ CO ２ CH ３ 、 - CH ２ CO ２ C ２ H ５ 、 - CH ２ CONH ２ 、 - CH ２ CONHCH ３ 、 - CH ２ CON(CH ３ ) ２ 、 - CH ２ CONHC ２ H ５ 、 - NHCOCH ３ 、 - NHCOC ２ H ５ 、 - NHCOCF ３ 、 - NHCOCH ２ CF ３ 、 - NHSO ２ CH ３ 、 - NHSO ２ C ２ H ５ 、 - NHSO ２ CHF ２ 、 - NHSO ２ CF ３ 、 or - NHSO ２ CH ２ CF ３ 、 represents; R Ｎ is, - H, - 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 , -cyclo-C ４ H ７ , -cyclo-C ５ H ９ , -CH ２ -Cyclo-C ３ H ５ , -CH ２ -Cyclo-C ４ H ７ , -CH ２ -Cyclo-C ５ H ９ , -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, -CH ２ -CH=CH ２ , -CH ２ -C≡CH, -CHO, -COCH ３ , -COC ２ H ５ , -COC ３ H ７ , -COCH(CH ３ ) ２ , -COC(CH ３ ) ３ , -CO-cyclo-C ３ H ５ , -CO-cyclo-C ４ H ７ , -CO-cyclo-C ５ H ９ , -COOCH ３ , -COOC ２ H ５ , -COOC ３ H ７ , -COOCH(CH ３ ) ２ , -COOC(CH ３ ) ３ , -COOCH ２ Ph, -SO ２ CH ３ , -SO ２ CF ３ , -SO ２ C ２ H ５ , -SO ２ C ３ H ７ , -SO ２ CH (CH ３ ) ２ , or -SO ２ C (CH ３ ) ３ , which represents R Ｎ１ is -H, -CH ３ , or -CH ２ CH ３ represents; R ８ , R １０ , and R １１ are independent of each other, -H, -F, -Cl, -Br, -I, -OH, -CN, -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 , -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-cyclo-C ３ H ５ , -OCH ２ -cyclo-C ３ H ５ , -O-C ２ H ４ -cyclo-C ３ H ５ , -CH=CH ２ , -CH ２ -CH=CH ２ , -C(CH ３ )=CH ２ , -CH=CH-CH ３ , -C≡CH, -C≡C-CH ３ , -CH ２ -C≡CH, or -Ph.

2. The compound according to claim 1, wherein R ２ is 【Chemical Formula 8-1】 【Chemical Formula 8-2】 【Chemical Formula 8-3】 【Chemical Formula 8-4】 【Chemical Formula 8-5】 【Chemical Formula 8-6】 represents; Here, the unsubstituted bicyclic residue can be substituted with one to five substituents R ９ ~R １４ , and R Ｎ ; The substituents R ９ ~R １４ , and R Ｎ have the meanings defined in claim 1, compound.

3. The compound according to claim 1, wherein in the formula, R ２ is 【Chemical Formula 9】 represents, R ８ , R ９ , R １０ , R １１ , R １２ , R １３ , R １４ , and R Ｎ have the meanings defined in claim 1, compound.

4. The compound according to claim 1, wherein in the formula, 【Chemical Formula 10】 In the formula, L represents -L １ -L ２ -; L １ represents -CH ２ CO-, L ２ represents -NR Ｎ１ -, and R ３ represents 1-adamantyl; or L ２ represents -NR Ｎ１ CH ２ -, and R ３ represents 2-bicyclo[3.1.1]heptyl, the aforementioned 1-adamantyl and 2-bicyclo[3.1.1]heptyl optionally contain one or more C=C double bonds, and / or are optionally substituted by one or more R ａ , R ｂ , R ｃ , R ｄ , and R ｅ ; R １ is [Chemical Formula 11] ; R ２ is [Chemical Formula 12] ; R ６ is -C ２ H ５ ; R ８ , R ９ , R １０ , R １１ , R １２ , R １３ , R １４ , R ａ , R ｂ , R ｃ , R ｄ , R ｅ , R Ｎ , and R Ｎ１ have the same meaning as defined in claim 1, a compound, or a diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemate, solvate, hydrate, or pharmaceutically acceptable salt thereof.

5. The compound according to claim 1, wherein the compound has any one of formulas (II-a) to (II-I), (II-b1) to (II-b2), and (III-c) to (III-I): [Chemical Formula 13-1] 【Chemical Formula 13-2】 【Chemical Formula 13-3】 wherein L １ , L ２ , R ２ , R ８ , R １０ , R １１ , R １２ , R １３ , R １４ , R Ｎ , R ａ , R ｂ , R ｃ , R ｄ , and R ｅ have the same meaning as defined in claim 1, compound.

6. The compound according to any one of claims 1 to 4, wherein R ３ is 【Chemical Formula 14】 represents, compound.

7. The compound according to any one of claims 1 to 4, wherein R ２ is 【Chemical Formula 15-1】 【Chemical Formula 15-2】 represents, compound.

8. The compound according to claim 1 selected from the group consisting of, or a pharmaceutically acceptable salt thereof. 【Chemical Formula 16-1】 【Chemical Formula 16-2】 【Chemical Formula 16-3】 【Chemical Formula 16-4】 【Chemical Formula 16-5】 【Chemical Formula 16-6】 【Chemical Formula 16-7】 【Chemical Formula 16-8】 【Chemical Formula 16-9】 【Chemical Formula 16-10】 【Chemical Formula 16-11】 【Chemical Formula 16-12】 【Chemical Formula 16-13】 【Chemical Formula 16-14】 【Chemical Formula 16-15】 【Chemical Formula 16-16】 【Chemical Formula 16-17】 【Chemical Formula 16-18】 【Chemical Formula 16-19】 【Chemical Formula 16-20】 【Chemical Formula 16-21】

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 5 as an active ingredient, together with at least one pharmaceutically acceptable carrier, excipient and / or diluent.

10. The compound according to any one of claims 1 to 5 for use in medicine.

11. The compound according to any one of claims 1 to 5 for use in the treatment or prevention of autoimmune and inflammatory diseases, vascular diseases, fibrotic diseases, liver diseases, cholestatic liver diseases, cancer, neurodegenerative diseases, eye diseases, and skin diseases.

12. A compound for use according to claim 11, wherein The autoimmune and inflammatory diseases include multiple sclerosis, celiac disease, Duhring-Brocq-disease (herpetiform dermatitis), gluten ataxia, gluten neuropathy, diabetes, rheumatoid arthritis, Graves' disease, inflammatory bowel disease, systemic lupus erythematosus psoriasis, and gingivitis; The vascular diseases include atherosclerosis, thrombosis, and arteriosclerosis; The fibrotic diseases affect the lungs, kidneys, liver, skin or gastrointestinal tract and include cystic fibrosis, renal fibrosis and diabetic nephropathy, intestinal fibrosis, idiopathic pulmonary fibrosis, and liver fibrosis; The liver diseases include alcoholic hepatitis, alcoholic steatohepatitis, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, cirrhosis, autoimmune hepatitis, and liver inflammation; The cholestatic liver diseases include primary biliary cholangitis, and primary sclerosing cholangitis; The cancers include glioblastoma, melanoma, pancreatic cancer, renal cell carcinoma, meningioma, and breast cancer, The neurodegenerative diseases include Parkinson's disease, Huntington's disease, and Alzheimer's disease; The eye diseases include glaucoma, cataract, macular degeneration, or uveitis; The skin diseases include acne, psoriasis, scarring, and skin aging. A compound for use.

13. A compound for use according to claim 11 for the treatment or prevention of celiac disease.

14. A pharmaceutical composition according to claim 9 for use in the treatment or prevention of autoimmune and inflammatory diseases, vascular diseases, fibrotic diseases, liver diseases, cholestatic liver diseases, cancers, neurodegenerative diseases, eye diseases, and skin diseases.

15. A pharmaceutical composition for use according to claim 14, The autoimmune and inflammatory diseases include multiple sclerosis, celiac disease, Duhring-Brocq-disease (herpetiform dermatitis), gluten ataxia, gluten neuropathy, diabetes, rheumatoid arthritis, Graves' disease, inflammatory bowel disease, systemic lupus erythematosus psoriasis, and gingivitis; The vascular diseases include atherosclerosis, thrombosis, and arteriosclerosis; The fibrotic diseases affect the lungs, kidneys, liver, skin or gastrointestinal tract and include cystic fibrosis, renal fibrosis and diabetic nephropathy, intestinal fibrosis, idiopathic pulmonary fibrosis, and liver fibrosis; The liver diseases include alcoholic hepatitis, alcoholic steatohepatitis, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, cirrhosis, autoimmune hepatitis, and liver inflammation; The cholestatic liver diseases include primary biliary cholangitis, and primary sclerosing cholangitis; The cancers include glioblastoma, melanoma, pancreatic cancer, renal cell carcinoma, meningioma, and breast cancer, The neurodegenerative diseases include Parkinson's disease, Huntington's disease, and Alzheimer's disease; The eye diseases include glaucoma, cataract, macular degeneration, or uveitis; The skin diseases include acne, psoriasis, scarring, and skin aging, A pharmaceutical composition for use.

16. A pharmaceutical composition for use according to claim 14 for the treatment or prevention of celiac disease.

17. A process for preparing a compound of formula (Ia) according to claim 1, comprising: Step 1A: providing compound 4a 【Chemical Formula 17】 Step 2A: performing a coupling reaction between compound 4a and compound 5 【Chemical Formula 18】 obtaining compound 6a 【Chemical Formula 19】 Step 3A: Deprotect the amino protecting group PG ３ to obtain compound 7a [Chemical Formula 20] Step 4A: Perform a coupling reaction between compound 7a and carboxylic acid 8 (R ２ -CO ２ H) to obtain compound 9a [Chemical Formula 21] Step 5A: Perform an oxidation reaction on compound 9a to produce the compound of formula (Ia) [Chemical Formula 22] wherein L, R ２ , R ３ , and R ６ have the same meanings as defined in claim 1, and PG ３ is an amino protecting group, Method.

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