Inhibitors of transglutaminases

Abstract

To provide inhibitors of transglutaminases.SOLUTION: The invention relates to compounds of general formula (I) as novel inhibitors of transglutaminases, to methods for producing the compounds, to pharmaceutical compositions containing the compounds, and to their use for the prophylaxis and treatment of diseases associated with transglutaminases, particularly transglutaminase 2. In a further aspect of the invention, the novel compounds according to the general formula (I) are used as pharmaceutically active agents, i.e., the compounds of the formula (I) are used in medicine.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to novel inhibitors of transglutaminase, in particular transglutaminase 2, processes for their synthesis and their use for the prevention and treatment of diseases associated with transglutaminase, in particular transglutaminase 2. [Background technology]

[0002] [Background of the invention] Transglutaminases are part of the class of transferases and, according to EC nomenclature, are precisely designated as "protein-glutamine:amine γ-glutamyltransferases" (EC 2.3.2.13). Transglutaminases link the ε-amino group of the amino acid lysine with the γ-glutamyl group of the amino acid glutamine, forming an isopeptide bond with simultaneous release of ammonia. In the absence of the appropriate amine and / or under certain conditions, deamidation of glutamine can occur, resulting in the generation of the corresponding glutamic acid.

[0003] Furthermore, transglutaminases play an important role in many therapeutic areas, such as cardiovascular diseases (thrombosis and atherosclerosis), autoimmune diseases (celiac disease, Duhring-Brocq-disease, gluten ataxia), neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease), skin diseases (ichthyosis, psoriasis, acne), as well as in wound healing and inflammatory diseases (e.g. tissue fibrosis) (JM Odzinska, Mini-Reviews in medical chemistry, 2005, 5, 279-292).

[0004] However, celiac disease, a gluten intolerance disease, is one of the most important indications. Celiac disease is characterized by chronic inflammation of the mucosa of the small intestine. In susceptible patients, after the ingestion of foods containing gluten, the intestinal epithelium is continuously destroyed, resulting in reduced absorption of nutrients, which again has a great impact on the affected patients and is associated with symptoms such as weight loss, anemia, diarrhea, nausea, vomiting, anorexia, and fatigue. Due to these discoveries, there is a great demand for the development of drugs for the treatment of celiac disease and other diseases associated with tissue transglutaminase (transglutaminase 2, TG2, tTG). Tissue transglutaminase is a central element during pathogenesis. The endogenous enzyme catalyzes the deamidation of gluten / gliadin in the small intestinal mucosa, thus triggering an inflammatory response. Inhibitors of tissue transglutaminase are therefore suitable for use as active agents for drug therapy.

[0005] Another very important group of indications for tissue transglutaminase inhibitors is fibrotic diseases. Fibrotic diseases are characterized by the accumulation of cross-linked extracellular matrix proteins. Diabetic nephropathy, cystic fibrosis, idiopathic pulmonary fibrosis, renal fibrosis, and hepatic fibrosis are among the most important fibrotic diseases that should be addressed with the disclosed compounds.

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

[0007] Tse et al. (J. Med. Chem. 2020, 63, 11585-11601) report the replacement of phenyl residues with non-classical bioisosteres, such as cubane and bicyclo[1.1.1]pentane (BCP), in antimalarial triazolopyrazine compounds to modify the solubility and metabolic stability of the compounds. The authors further evaluated the in vitro antiprotozoal activity of bioisostere-modified triazolopyrazines against the 3D7 strain of P. falciparum. Replacement of the phenyl by a bioisosteric saturated heterocyclic residue resulted in a complete loss of activity. Adamantyl residues, as well as other hydrocarbon-caged derivatives, resulted in up to 2-9 times lower efficacy than the corresponding phenyl triazolopyrazine compounds. In contrast, higher efficacy was achieved by replacing the phenyl with closo-1,2- and 1,7-carborane isomers. The authors concluded that the effect of nonclassical bioisosteric substitutions on biological properties cannot be precisely predicted, and a consideration range of possible bioisosteres must first be tested to identify suitable substitutions to impart the desired properties of a given molecule.

[0008] Subbaiah et al. (J. Med. Chem. 2021, 64, 19, 14046-14128) report on bioisosteres of phenyl rings in lead optimization and drug design. It is noted that replacement of the phenyl ring of bioisosteres with heterocyclic and carbocyclic moieties can lead to improved 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 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 halogenated methyl ketone as a warhead. The inhibitors have activity in the nanomolar and micromolar range (IC 50 ) showed inhibitory activity.

[0010] It is an object of the present invention to provide novel, potentially reversible inhibitors of transglutaminase, in particular transglutaminase 2, as well as methods for the synthesis of said inhibitors and the uses of some of these inhibitors.

[0011] Said object is solved by the technical teachings of the independent items. Further advantageous embodiments, aspects and details of the invention are evident from the dependent items, the description and the examples.

[0012] Surprisingly, the reversible inhibitors having chemical warheads disclosed herein have been shown to effectively inhibit transglutaminases, including tissue transglutaminase, also referred to as transglutaminase 2 or TG2, the terms used interchangeably herein.

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

[0014] In order to prove 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 recognize compound A8 from our patent US9,434,763B2, which we introduce as Ref.3 to highlight 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 (compare A1, A8, A37, A44, A47). In striking contrast, branched alkyl moieties are highly preferred, as shown by the more potent compounds (A28, A29, A59, A61, A63, A67, A68, A79).

[0015] To illustrate the advantage of the branched alkyl moiety over the aromatic moiety, we refer to reference compounds Ref. 2 (ZED1227, US 9,434,763B2) and Ref. 3 (A8, ZED1047). Inhibition data were determined using a classical fluorescent transamidation assay (dansylcadaverine incorporation into methylated casein, DCC-assay) as described [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. IC of Ref. 3 (A8) published in US 9,434,763 B2 50It should be noted that the values ​​are dependent on a fluorogenic isopeptidase assay and cannot be compared with the present data. 50 =53 nM) is 80 times more potent (IC 50 =4,268nM).

[0016] Therefore, those skilled in the art of medicinal chemistry would choose a branched alkyl moiety as the lead structure, excluding aromatic moieties such as phenyl groups. It is a well-known fact that bridged cycloalkyl groups are non-classical bioisosteres of phenyl groups. By replacing the phenyl group in A8 with, for example, an adamantane group, those skilled in the art would expect similar physicochemical or biochemical properties without much effort. Since aromatic moieties are obviously undesirable, bridged cycloalkyl groups would not be expected to improve the compound.

[0017] This is further supported by additional reference compounds: ZED3641 (Ref. 1, disclosed in US11,072,634B2; Ref. 2, a reversibly acting α-ketomethylamide analogue to ZED1227) is about 15 times more potent than Ref.4 (compare Table 1). Ref.4 is similar in scaffold to compound A8 disclosed in US9,434,763B2, again proving the superiority of branched alkyl moieties over aromatic derivatives in combination with reversibly acting warheads.

[0018] Surprisingly, however, replacement of the preferred branched alkyl moieties with bridged cycloalkyl groups further significantly improves the efficacy of the compounds, as shown in Table 1. We therefore appreciate that bridged cycloalkyl groups as disclosed represent an excellent inventive approach. In summary, compounds of the invention rated "A" show approximately 30-fold higher efficacy compared to Ref.3 (A8, compare Table 1). Furthermore, compounds with activities rated "B" or "C" are even more preferred (lower IC 50Peripheric ligands can also be considered inventive because they affect physicochemical or biochemical properties. Thus, depending on the application, compounds with weak effects can be of high value. [Prior art documents] [Patent documents]

[0019] [Patent Document 1] U.S. Pat. No. 11,072,634 [Patent Document 2] U.S. Pat. No. 9,434,763 [Non-patent literature]

[0020] [Non-Patent Document 1] JMWodzinska,Mini-Reviews in medical chemistry,2005,5,279-292 [Non-Patent Document 2] Tse et al. (J. Med. Chem. 2020, 63, 11585-11601) [Non-Patent Document 3] Subbaiah et al. (J.Med.Chem.2021,64,19,14046-14128) [Non-Patent Document 4] 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 Summary of the Invention [Means for solving the problem]

[0021] The present invention therefore relates to a compound of general formula (I) or a diastereomer, an enantiomer, a mixture of diastereomers, a mixture of enantiomers, a racemate, a solvate, a hydrate, or a pharma- ceutically acceptable salt of a compound of general formula (I): [ka]

[0022] During the ceremony, L is -L 1 -L 2 - stands for; L 1 represents -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CO-, or -CH2CH2CO-; L 2 is a bond, -NR N1 -, -NR N1 CH2-, -NR N1 CH2CH2-, or -NR N1 CH(CH3)-; R 1 teeth,

[0023] [ka] represents;

[0024] R 2 teeth,

[0025] [ka]

[0026] [ka]

[0027] [ka]

[0028] [ka]

[0029] [ka]

[0030] [ka] represents;

[0031] wherein the unsubstituted bicyclic residue is one to five substituents R 9 ~R 14 and R N Preferably, one to three substituents R 11 ~R 13 can be substituted with; 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 Replaced by; 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 4 -NR 6 R 7 represents; R 6 represents -CH2CH3, R 7 represents -H;

[0032] R 8 , R 9 , R 10 , R11 , 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, -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, -NHSO2 C(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] [ka] represents;

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

[0035] [ka]

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

[0037] [ka]

[0038] R Nare -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] We propose a bridged bicyclic residue R 3 It has been shown that the reversible inhibitors of formula (I) disclosed herein, having the formula (I) and (II) show increased efficacy over prior art compounds. In particular, the compounds of the present invention contain an aromatic moiety R instead of a bridged bicyclic moiety. 3 It is demonstrated herein that the compound has improved inhibitory activity compared with known compounds having the above structure.To prove the inventiveness of the compound of the present application, the 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) are synthesized and tested as reference compounds to compare with the most similar compound of the present application.

[0040] In the scope of this application, the inhibition data were determined using a classical fluorescent transamination 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 were compared with that of the compounds disclosed in US9,434,763 B2, in particular compound A8, which is referred to herein as reference 3. Of note, the IC of compound A8 published in US9,434,763 B2 and E16 from US11,072,634 B2 were 0.01 to 0.01. 50 The value is that it relies on a fluorogenic isopeptidase assay and cannot be compared with the present data.

[0041] Thus, the compounds of formula (I) of the invention rated "A" showed approximately 100% higher efficacy compared to Ref.3 (A8). The same arguments apply to Ref.4, which also shows that the aromatic moiety of this reference compound strongly reduces the inhibitory activity against TG2.

[0042] Thus, one skilled in the art would exclude aromatic moieties, such as phenyl groups. It is well known that bridged cycloalkyl groups are non-classical bioisosteres of phenyl groups. By replacing the phenyl group in A8 with, for example, an adamantane group, one skilled in the art would expect similar physicochemical or biochemical properties, except for the effort. Since aromatic moieties are clearly undesirable, bridged cycloalkyl groups are not expected to improve the compound.

[0043] Surprisingly, the compounds of the present invention demonstrate that bridged cycloalkyl groups improve the potency of the compounds by orders of magnitude compared to aromatic reference compounds. Accordingly, we believe that the disclosed bridged cycloalkyl groups are an excellent inventive method.

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

[0045] [ka]

[0046] [ka]

[0047] [ka]

[0048] [ka]

[0049] [ka]

[0050] [ka] represents;

[0051] wherein the unsubstituted bicyclic residue is one to five substituents R 9 ~R 14 , and R N and preferably 1 to 3 substituents R 11 ~R 13 The substituent R 9 ~R 14 , and R N has the meaning defined in formula (I); more preferably, R 2 teeth

[0052] [ka]

[0053] [ka]

[0054] [ka]

[0055] [ka]

[0056] [ka]

[0057] [ka] represents;

[0058] wherein the unsubstituted bicyclic residue is one to five substituents R 9 ~R 14 , and R N and preferably 1 to 3 substituents R 11 ~R 13The substituent R 9 ~R 14 , and R N has the meaning defined herein.

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

[0060] [ka]

[0061] [ka]

[0062] [ka]

[0063] [ka]

[0064] [ka]

[0065] [ka]

[0066] [ka]

[0067] [ka] .

[0068] More preferably, the compound is a diastereomer, an enantiomer, a mixture of diastereomers, a mixture of enantiomers, a racemate, a solvate, a hydrate, or a pharma- ceutically acceptable salt of a compound of general formula (I):

[0069] [ka]

[0070] During the ceremony, L is -L 1 -L 2 - stands for; L 1 represents -CH2CO-; L 2 -NR N1 - represents;R 3 represents 1-adamantyl; or L 2 -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 optionally contain one or more R a , R b , R c , R d , and R e Replaced by; R 1 teeth,

[0071] [ka] represents;

[0072] R 2 teeth,

[0073] [ka] represents;

[0074] 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, -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] [ka] represents;

[0076] R N are -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 teeth,

[0078] [ka] represents

[0079] R 8 , R 10 , R 11 , and R N has the meaning 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-homoisotwistyl, adamantyl, diamantyl and hexamethylenetetraminyl each have the following parent structure:

[0080] [ka]

[0081] The foregoing residues optionally contain one or more C=C double bonds and / or one or more R a , R b , R c , R d , and R e is optionally replaced by Preferred are compounds of formula (Ia):

[0082] [ka]

[0083] L, R 2 , R 3 , R 6 has the same meaning as defined in formula (I). Preferably, the present invention relates to a compound of formula (I) or a diastereomer, an enantiomer, a mixture of diastereomers, a mixture of enantiomers, a racemate, a solvate, a hydrate, or a pharma- ceutically acceptable salt of a compound of formula (I):

[0084] [ka]

[0085] During the ceremony, L is -L 1 -L 2 - stands for; L 1 represents -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CO-; L 2 -NR N1 -, or -NR N1 represents CH2-; Preferably, L represents -CH-, -CHCH-, -CHCHCH-, -CHCONH-, -CHCONH-CH-, -CHCON(CH)-CH-, or -CHCONH-CH(CH)-, R 1 teeth,

[0086] [ka] represents;

[0087] R 2 teeth,

[0088] [ka] represents;

[0089] R 3represents 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]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. The 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]heptan-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 residues optionally contain one or more C═C double bonds and / or optionally contain one or more R a , R b , R c , R d , and R e Replaced by; 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 has 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 pharma- ceutically acceptable salt of a compound of formula (I):

[0091] [ka]

[0092] During the ceremony, L is -L 1 -L 2 - stands for; L 1 represents -CH2CO-, L 2 -NR N1 - represents R 3 represents 1-adamantyl; or L 2 -NR N1 CH2-, 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 optionally contain one or more R a , R b , R c , R d , and R e Replaced by; R 1 teeth,

[0093] [ka] represents;

[0094] R 2 teeth,

[0095] [ka] represents;

[0096] R6 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 has 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 pharma- ceutically acceptable salt of a compound of formula (I):

[0098] [ka]

[0099] During the ceremony, L is -L 1 -L 2 - stands for; L 1 represents -CH2CO-, L 2 -NR N1 - represents R 3 represents 1-adamantyl; or L 2 -NR N1 CH2-, 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 optionally contain one or more R a , R b , R c , R d , and R e Replaced by; R 1 teeth,

[0100] [ka] represents;

[0101] R 2 teeth,

[0102] [ka] represents;

[0103] R 6 represents -C2H5; and R 8 , R 10 , R 11 , R a , R b , R c , R d , R e , R N , and R N1 has 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 pharma- ceutically acceptable salt of a compound of formula (Ia):

[0105] [ka]

[0106] During the ceremony, L is -L 1 -L 2 - stands for; L 1 represents -CH2CO-, L 2 -NR N1 - represents R 3 represents 1-adamantyl; or L 2 -NR N1 CH2-, 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 optionally contain one or more R a , R b , R c , R d , and R e Replaced by; R 2 teeth,

[0107] [ka] 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, -NHSO2C2H5, -NHSO2CHF2, -NHSO2CF3, or -NHSO2CH2CF3; 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, -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, -NHSO2 C(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] [ka] represents;

[0110] R N are -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, -CH 2-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 -C2H5.

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

[0112] [ka]

[0113] During the ceremony, L is -L 1 -L 2 - stands for; L 1 represents -CH2CO-, L 2 -NR N1 - represents R 3 represents 1-adamantyl; or L 2 -NR N1 CH2-, 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 optionally contain one or more R a , R b , R c , R d , and R e Replaced by; R 2 teeth,

[0114] [ka] represents;

[0115] R 6 represents -C2H5; R a , R b , R c , R d , and R eare, 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 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,

[0116] [ka] represents;

[0117] R N are -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, -CH 2-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 -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 pharma- ceutically acceptable salt of formula (II):

[0119] [ka]

[0120] During the ceremony, L 2 -NR N1 - represents R 3 represents 1-adamantyl; or L 2 -NR N1 CH2-, R 3 represents 2-bicyclo[3.1.1]heptyl; The adamantyl and 2-bicyclo[3.1.1]heptyl residues mentioned above may optionally contain one or more C=C double bonds and / or may optionally contain one or more R a , R b , R c , R d , and R e Replaced by; R 2 teeth,

[0121] [ka] represents;

[0122] R a , R b , R c , R d , and R eare, 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 are -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-C represents H2I, -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 represents -H, -CH3, or -CH2CH3; R 8 , R 10 , and R 11are each independently -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, -CH 2-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 structure:

[0124] [ka]

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

[0126] [ka] R a and R b has the same meaning 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] [ka]

[0129] [ka]

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

[0131] [ka]

[0132] [ka]

[0133] In the formula, 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 has the same meaning 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 teeth

[0135] [ka] represents;

[0136] More preferably, R 3 teeth

[0137] [ka] represents;

[0138] More preferably, R 3 teeth

[0139] [ka] Represents.

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

[0141] [ka] represents;

[0142] During the ceremony, 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, -NHSO2 C(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] [ka] represents;

[0144] Preferably, R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14are, independently of each other, -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, -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, -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] [ka] represents;

[0148] R N are -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, -CH 2-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 represents -H, -CH3, -C2H5, -CH(CH3)2, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-C5H9, or -COCH3, and more preferably, R N represents -H, -CH3, -C2H5, -CH(CH3)2, -cyclo-C4H7, -cyclo-C5H9, or -COCH3.

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

[0150] [ka]

[0151] [ka] represents;

[0152] More preferably, R 2 teeth

[0153] [ka] Represents.

[0154] Even more preferably, R 2 teeth

[0155] [ka] Represents.

[0156] In a preferred embodiment, the present invention refers to a compound of any one of formulas (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-, or -CH2CONH-CH(CH3)-; Most preferred is a compound of formula (I):

[0157] [ka]

[0158] [ka]

[0159] [ka]

[0160] [ka]

[0161] [ka]

[0162] [ka]

[0163] [ka]

[0164] [ka]

[0165] [ka]

[0166]

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[0178]

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[0179]

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[0180]

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

[0199] [ka]

[0200] As shown in Scheme 1, Methods for preparing compounds of formula (Ia) include: Step 1A: Providing compound 4a

[0201] [ka] ;

[0202] Step 2A: Carry out a coupling reaction between compound 4a and compound 5

[0203] [ka] Obtaining Compound 6a

[0204] [ka] ;

[0205] Step 3A: Amino Protecting Group PG 3 to obtain compound 7a.

[0206] [ka] ;

[0207] Step 4A: Compound 7a and a carboxylic acid (R 2 -CO2H 8) to obtain compound 9a.

[0208] [ka] ;

[0209] Step 5A: Oxidation of compound 9a to produce compound of formula (Ia)

[0210] [ka] ;

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

[0212] [ka]

[0213] Optionally, step 1A' is performed before step 1A: (a) providing a protected aldehyde 1

[0214] [ka] ; (b) Aldehyde 1 and isocyanide (CN-R 6 ) coupling reaction with 2a to obtain intermediate compound 3a

[0215] [ka] ; (c) Protecting group PG of compound 3a 1 and P.G. 2 is deprotected, preferably under acidic conditions, to give the amino protecting group PG 3 to obtain compound 4a

[0216] [ka] ;

[0217] In the formula, R 2 , R 6 has the same meaning as defined in formula (Ia), PG 1 and P.G. 3 is an amino protecting group, PG 2 is a carboxyl protecting group.

[0218] Thus, the following process for the production of compounds of formula (Ia) is preferred: Step 1A': (a) providing a protected aldehyde 1

[0219] [ka] ; (b) Aldehyde 1 and isocyanide (CN-R 6 ) coupling reaction with 2a to obtain intermediate compound 3a

[0220] [ka] ; (c) Protecting group PG of compound 3a 1 and P.G. 2 is deprotected, preferably under acidic conditions, to give the amino protecting group PG 3 to obtain compound 4a

[0221] [ka] ; Step 1A: Providing compound 4a

[0222] [ka] ; Step 2A: carrying out a coupling reaction between compound 4a and compound 5;

[0223] [ka] Obtaining Compound 6a

[0224] [ka] ; Step 3A: Amino Protecting Group PG 3 Deprotection to obtain compound 7a

[0225] [ka] ; Step 4A: Compound 7a and a carboxylic acid (R 2 -CO2H8) to obtain compound 9a.

[0226] [ka] ; Step 5A: Oxidation of compound 9a to produce compound of formula (Ia)

[0227] [ka] ;

[0228] In the formula, L, R 2 , R 3 , and R 6 has the same meaning as defined above in formula (Ia), and PG 1 and P.G. 3 is an amino protecting group, PG 2 is a carboxyl protecting group.

[0229] In an alternative route, first remove all protecting groups PG 1 and P.G. 2At the same time, the protecting group PG is removed. 3 is selectively introduced. Preferably, PG 1 and P.G. 3 is 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. 1 , P.G. 3 , and P.G. 5 is preferably a suitable protecting group for an amino group. 2 and P.G. 4 is preferably a suitable protecting group for a carboxyl group. 1 , P.G. 3 , and P.G. 5 may be selected from the group consisting of or including: acetyl, benzoyl, benzyloxycarbonyl (Cbz), tert-butylcarbonyl, tert-butyloxycarbonyl (Boc), and fluorenylmethylenoxy group (Fmoc). 2 and P.G. 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, an activating reagent is typically used to activate the carboxylic acid to facilitate the coupling reaction with the amino group of the intermediate compound (Ayman El-Faham and Fernando Albericio, "Peptide Coupling Reagents, More than a Letter Soup", Chemical Reviews, 2011, 111(11), p. 6557-6602). Activation may be introduced as a separate reaction or an in situ reaction.Preferably, the following coupling reagents are used: 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-yloxy)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 (tetramethylfluoroformamide hexafluorophosphate), BroP (bromotris(dimethylamino)phosphonium hexafluorophosphate), PyBroP (bromotris(dimethylamino)phosphonium hexafluorophosphate), Either CIP (2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate) and CIP (2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate), or further similar acting reagents, can be used to activate the carboxylic acid group to provide an activated intermediate, or a mixture thereof.

[0232] Pharmaceutical Compositions and Medical Uses Therefore, another aspect of the invention relates to compounds according to general formula (I) as medicaments and their use in medicine, particularly preferably as inhibitors of transglutaminase, in particular transglutaminase 2 (TG2).

[0233] Thus, the compounds of formula (I) described herein or according to the present invention may be administered per se or in the form of a pharma- cologically acceptable salt. The compounds of the present invention may form pharmacologically acceptable salts with organic or inorganic acids or organic or inorganic bases. Examples of acids suitable for forming such acid addition salts include 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, quinic acid (China acid), mandelic acid, o-methylmandelic acid, hydrogen-benzenesulfonic acid, picric acid, adipic acid, do-tolyltartaric acid, tartronic acid, (o, m, p)-toluic 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 with a sufficient amount of the desired acid to produce the salt in a conventional manner. Preferred are the mesylate, hydrochloride, and trifluoroacetate salts, and especially preferred are the trifluoroacetate and hydrochloride salts.

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

[0235] How to use In a further aspect of the present invention the novel compounds according to general formula (I) are used as pharma- ceutical active agents, i.e. the compounds of formula (I) are 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 pharmacologically acceptable salt thereof as an active ingredient, together with at least one pharmacologically 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 associated with 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 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 hepatic fibrosis belong to the most important fibrotic diseases to be addressed with the disclosed compounds.

[0239] In Biological Example B-1, it is demonstrated that the compounds of the present invention as reversible inhibitors effectively inhibit the activity of TG, particularly TG2. The term "inhibit" or "inhibition" as used herein 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] Thus, another aspect of the present invention is the use of the compounds of the present invention of general formula (I) as described, or pharmaceutical compositions 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, skin diseases.

[0241] A further aspect of the present invention relates to the use of compounds 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 embodiment of the present invention there is provided a method for 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, comprising administering in a subject, in particular a human, a pharma- ceutical 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; Vascular diseases include atherosclerosis, thrombosis, and angiosclerosis; Fibrotic diseases affecting the lungs, kidneys, liver, skin or gastrointestinal tract, such as cystic fibrosis, renal fibrosis and diabetic nephropathy, intestinal fibrosis, idiopathic pulmonary fibrosis, hepatic fibrosis, etc.; The liver disease may be alcoholic hepatitis, alcoholic steatohepatitis, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, cirrhosis, autoimmune hepatitis, or liver inflammation; Cholestatic liver diseases include primary biliary cholangitis, and primary sclerosing cholangitis; Cancers include glioblastoma, melanoma, pancreatic cancer, renal cell carcinoma, meningioma, and breast cancer; Neurodegenerative diseases include Parkinson's disease, Huntington's disease, or Alzheimer's disease; The eye disease includes glaucoma, cataracts, macular degeneration, or uveitis; Skin disorders include acne, psoriasis, scarring, and skin aging.

[0244] More preferably, the compounds of formula (I), or pharmaceutical compositions thereof, are useful for the treatment or prevention of coeliac 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 medicaments are prepared in known manner with conventional solid or liquid carriers, or with diluents and conventional pharmaceutically acceptable adjuvants / expedients, in appropriate doses.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 pharma- ceutically 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] Further objects of the present invention also include pharmaceutical formulations for oral, parenteral, dermal, intradermal, intragastric, intracutaneous, intravascular, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, buccal, percutaneous, rectal, subcutaneous, sublingual, topical, transdermal or inhalation application, which, in addition to typical vehicles and excipients, contain as active ingredients a compound of general formula (I) and / or a pharma- ceutically acceptable salt of a compound of general formula (I).

[0247] The pharmaceutical composition of the present invention contains one of the compounds of formula (I) disclosed herein as an active ingredient, and is typically mixed according to conventional pharmaceutical practice with a suitable carrier material selected for the intended administration form, i.e., orally administered tablets, capsules (either filled with solid, semi-solid, or liquid), powders, orally administrable gels, elixirs, dispersible granules, syrups, suspensions, etc. For example, the compound of formula (I) as an active ingredient can be combined with an oral, non-toxic, pharma- ceutically acceptable inert carrier, such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid form), etc., for oral administration in the form of tablets or capsules. In addition, suitable binders, lubricants, disintegrants, and coloring agents can be added to the mixture, if necessary. Powders and tablets consist of the inert carrier to the extent of about 5% to about 95% by weight per weight 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 gum acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes. Possible lubricants for use in the dosage form include boric acid, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrants include starch, methylcellulose, cyclodextrin, guar gum, etc. Optionally, sweeteners and flavoring additives and preservatives can also be included. Some of the terms used above, namely disintegrants, fillers, lubricants, binders, etc., are explained in more detail below.

[0249] Additionally, the compositions of the present invention can be formulated in sustained release form to provide a controlled release rate of any one or more components or active ingredients to optimize the therapeutic effect, i.e., inhibitory activity, etc. Suitable dosage forms for sustained release include layered tablets comprising layers with different dissolution rate or controlled release polymer matrices impregnated with the active ingredient, and tablet or capsule forms comprising said impregnated or encapsulated porous polymer matrix.

[0250] Fluid form preparations include solutions, suspensions, and emulsions. Exemplary mentioned are water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions, and emulsions.

[0251] Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharma- ceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.

[0252] For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides, for example cocoa butter, is first melted and the active ingredient is dispersed homogeneously therein by stirring or similar mixing operations The molten homogeneous mixture is then poured into suitable molds and allowed to cool and thus harden.

[0253] Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such fluid forms include solutions, suspensions, and emulsions.

[0254] Furthermore, the compounds of the present invention may be administered by transdermal application. The transdermal compositions can have the form of creams, lotions, aerosols and / or emulsions.

[0255] The term capsule refers to a special container or casing made of methylcellulose, polyvinyl alcohol, or modified gelatin or starch, in which the active agent can be enclosed. Typically, hard shell capsules are prepared from a mixture of bone and pigskin gelatin, which has relatively high gel strength. The capsule itself can contain small amounts of colorants, opacifiers, softeners, and preservatives.

[0256] Tablet refers to a compressed or molded solid dosage form containing the active ingredient together with a suitable filler. Tablets can be produced by compressing mixtures or granulations obtained by wet granulation, dry granulation, or compaction as known to those skilled in the art.

[0257] Oral gels refer to the active ingredients dispersed or solubilized in a hydrophilic semi-solid matrix. A powder for the composition refers to a powder mixture containing the active ingredient and a suitable bulking agent that can be suspended in water or juice.

[0258] Suitable bulking agents are usually substances that form 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 potato; and celluloses, such as microcrystalline cellulose.The amount of bulking agent in the composition can be in the range of about 5% to about 95% by weight, preferably in the range of about 25% to about 75% by weight, and more preferably in the range of about 30% to about 60% by weight of the total composition.

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

[0260] Binders characterize the substances that bind or "glue" powders together, and thus function as "adhesives" in the formulation. Binders add to the agglomerated starch already available in the bulking agent or disintegrant. Suitable binders include sugars, such as sucrose; starches from wheat, corn, rice, and potato; natural gums, such as gum acacia, gelatin, and tragacanth; seaweed derivatives, such as alginic acid, sodium alginate, and ammonium calcium alginate; cellulose materials, such as methylcellulose, and 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 reduce friction after compression, thereby allowing tablets, granules, etc. to be released from a mold or press. Suitable lubricants include metal stearates, such as magnesium stearate, calcium stearate, or potassium stearate; stearic acid; waxes with high melting points, 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 surfaces of the granules, as well as 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] Lubricant is a material that prevents caking and improves the flow properties of granules, thus making the flow smooth and uniform.Suitable lubricants include silicon dioxide and talc.The amount of lubricant in the composition can be in the range of about 0.1% to about 5% by weight, preferably in the range of about 0.5% to about 2% by weight of the total composition.

[0263] A coloring agent is an adjuvant that colors the composition or dosage form. The adjuvant can include food-quality coloring agents that are adsorbed to a suitable adsorption means, such as 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 "pharmacologically effective amount" of a transglutaminase inhibitor is an amount or activity effective to achieve a desired physiological result in either a cell treated in vitro or a patient treated in vivo. Specifically, a pharmacologic effective amount is that amount sufficient to inhibit one or more clinically defined pathological processes associated with transglutaminase 2 for a specific period of time. The effective amount can vary according to the particular compound of formula (I) and further depends on several 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 age, weight, and health condition of the patient, as well as dose-response curves and toxicity data obtained from preclinical animal studies. When the inhibitor in the form of a compound of formula (I) described herein is contacted with cells in vivo, several preclinical in vitro studies will be designed to determine parameters such as absorption, half-life, dose, toxicity, etc. Determining a pharma- ceutical effective amount for a given pharma- ceutical active ingredient is part of the routine skill of one of ordinary skill in the art.

[0265] [Example] 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 Examples The following examples are intended to illustrate the present invention with selected compounds, without limiting the scope of protection of the present intellectual property right to these specific examples. It is obvious to those skilled in the art that similar compounds and compounds produced according to similar synthesis methods fall within the scope of protection of the present intellectual property right.

[0266] Example I. Synthetic Method I

[0267] [ka]

[0268] Preparation of compound ZED1657

[0269] [ka]

[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 were added and the reaction was stirred at room temperature overnight. 250 mL of HCl (32%) were added and the suspension was stirred at 4° C. for another night. The precipitate was filtered and dried. Yield: 41.2g, 97% ESI-MS: 199.3[M+H] + Preparation of compound ZED3912

[0271] [ka]

[0272] 7.0 g (35.3 mmol) ZED1657, 6.63 g (1 eq) 1-adamantanamine hydrochloride, and 4.77 g (1 eq) HOBt were dissolved in 80 mL DMF and 7.38 mL (1.2 eq) DIPEA. 7.45 g (1.1 eq) 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride were added and the reaction was stirred at room temperature overnight. The solvent was evaporated and the residue was dissolved in 200 mL 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: 10.3g, 88% ESI-MS: 332.4[M+H] + Preparation of compound ZED3913

[0273] [ka]

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

[0275] [ka]

[0276] Preparation of compound ZED788

[0277] [ka]

[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 h. 2.47 ml of iodomethane (39.6 mmol) were added and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was dissolved in ethyl acetate and washed twice with citric acid solution (10%), NaHCO3 solution (10%) and brine respectively. The organic layer was dried over Na2SO4, filtered and the solvent was evaporated. The raw product was used without further purification. Yield: 13.4g, >100% ESI-MS: 318.3 [M+H] + Preparation of compound ZED720

[0279] [ka]

[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 of 17.6 g of di-tert-butyl bicarbonate (77.1 mmol) in 100 ml of acetonitrile was added and the solution was stirred at room temperature overnight. The solvent was evaporated and the residue was dissolved in ethyl acetate and washed twice with citric acid solution (10%), NaHCO3 solution (10%) and brine respectively. The organic layer was dried over Na2SO4, filtered and the solvent was evaporated. The raw product was used without further purification. Yield: 13.7g, 83% ESI-MS: 418.3 [M+H] + Preparation of compound ZED721

[0281] [ka]

[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 min, then quenched with potassium sodium tartrate (Rochelle's salt) solution. The organic layer was separated, dried over Na2SO4, filtered and concentrated to dryness. The crude product was used without further purification. Yield: 13.3g, >100% ESI-MS: 388.3 [M+H] + Preparation of compound ZED3221

[0283] [ka]

[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 was stirred at room temperature overnight. 35 mL of TFA was added and the reaction was stirred for another 3 hours. The solvent was evaporated and the residue was dissolved in 20 mL of DMF. A solution of 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 was stirred at room temperature overnight. The solvent was evaporated and the residue was dissolved in DCM. After extraction with NaHCO3 solution (1.05eq in water), 1.5eq 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: 5.77g, 92% ESI-MS: 347.3 [M+H] + Preparation of Compound I-1a

[0285] [ka]

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

[0287] [ka]

[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 h. 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: 527mg, 87% ESI-MS: 638.5 [M+H] + Preparation of Compound I-1c

[0289] [ka]

[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 h. The solution was diluted with DCM and washed with water. The organic layer was dried over Na2SO4, filtered and the solvent was evaporated. Yield: 469mg, 95% ESI-MS: 596.5 [M+H] + Preparation of Compound I-1

[0291] [ka]

[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 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: 362mg, 77% ESI-MS: 594.5 [M+H] + 1 H-NMR (DMSO-D6, 500MHz, 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 (d dd, 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] 13C-NMR (DMSO-D6, 500MHz, 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-adamantylamide), 170.56 (C=O-NH-pyridinone), 198.43 (C=O-ethylamide).

[0294] Preparation of Compound I-2

[0295] [ka]

[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 deprotection (DCM / TFA) as above and purified by HPLC. Yield: 45 mg, 63% (final step) ESI-MS: 580.4 [M+H] + Preparation of Compound I-3

[0297] [ka]

[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] [ka]

[0300] To a solution of the α-hydroxyester precursor of compound I-4 (382 mg, 0.61 mmol, prepared according to compound ZED3912 using 3,5-dimethyl-1-adamantanamine in step 2) in 10 mL of acetonitrile, 1 mg of TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl, 1 mol%) was added. 88 mg of calcium hypochlorite (1 eq.) was added at 0° C., and the reaction mixture was stirred at 25° C. for 2 h. The suspension was filtered, diluted with ethyl acetate, 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: 176mg, 46% ESI-MS: 622.5 [M+H] + Preparation of Compound I-5

[0301] [ka]

[0302] To a solution of the α-hydroxyester precursor of compound I-5 (162 mg, 0.26 mmol, prepared according to compound ZED3912 using 3-ethyl-1-adamantanamine in step 2) in 5 ml of DMSO, 145 mg of 2-iodoxybenzoic acid (IBX, 2 eq) was added 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] [ka]

[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] [ka]

[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] [ka]

[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] [ka]

[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] [ka]

[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] [ka]

[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: 85mg, 74% (final step) ESI-MS: 652.5 [M+H] + Preparation of Compound I-12

[0315] [ka]

[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: 23mg, 47% (final step) ESI-MS: 630.4 [M+H] + Preparation of Compound I-13

[0317] [ka]

[0318] The synthesis of compound I-13 was carried out according to compound I-1, using (-)-cis-myrtanylamine 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] [ka]

[0320] The synthesis of compound I-14 was carried out according to compound I-1, using (-)-cis-(pinan-2-ylmethyl)amine instead of 1-adamantanamine in step 2 (according to ZED3912). 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] [ka]

[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] [ka]

[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] [ka]

[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 (according to compound I-1b). Yield: 32 mg, 66% (final step) ESI-MS: 662.5 [M+H] + Preparation of Compound I-21

[0333] [ka]

[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 (according to compound I-1b). Yield: 25mg, 56% (final step) ESI-MS: 636.5 [M+H] + Preparation of Compound I-22

[0335] [ka]

[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 (according to compound I-1b). Yield: 45 mg, 77% (final step) ESI-MS: 622.5 [M+H] + Preparation of Compound I-23

[0337] [ka]

[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] [ka]

[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] [ka]

[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] [ka]

[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] [ka]

[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] [ka]

[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] [ka]

[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] [ka]

[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 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] [ka]

[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 in step 6 (according to compound I-1b). Yield: 90 mg, 77% (final step) ESI-MS: 644.5 [M+H] + Preparation of Compound I-32

[0355] [ka]

[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] [ka]

[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] [ka]

[0360] The synthesis of compound I-34 was carried out according to compound I-30, using benzo[b]thiophene-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] [ka]

[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] [ka]

[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] [ka]

[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] [ka]

[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] [ka]

[0370] The synthesis of compound I-39 was carried out according to compound I-30, using 2,3-dihydro-1H-indene-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] [ka]

[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] [ka]

[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] [ka]

[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] [ka]

[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] [ka]

[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] [ka]

[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] [ka]

[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] [ka]

[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] [ka]

[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] [ka]

[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] [ka]

[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] [ka]

[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] [ka]

[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] [ka]

[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] [ka]

[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] [ka]

[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] [ka]

[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] [ka]

[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] [ka]

[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 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] [ka]

[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 (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 deprotection (DCM / TFA) as described above and purified by HPLC. Yield: 35 mg, 83% (final step) ESI-MS: 601.5 [M+H] + Preparation of compound I-60

[0411] [ka]

[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 (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 deprotection (DCM / TFA) as described above and purified by HPLC. Yield: 37 mg, 78% (final step) ESI-MS: 631.4 / 633.4[M+H] + Preparation of Compound I-61

[0413] [ka]

[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 (R)-1-Boc-piperidine-3-in place of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b). The final product was obtained by deprotection (DCM / TFA) as described above and purified by HPLC. Yield: 35 mg, 72% (final step) ESI-MS: 675.3 / 677.3 [M+H] + Preparation of Compound I-62

[0415] [ka]

[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 (R)-4-Boc-morpholine-3- in place of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b). The final product was obtained by deprotection (DCM / TFA) as described above and purified by HPLC. Yield: 31 mg, 80% (final step) ESI-MS: 613.5 [M+H] + Preparation of Compound I-63

[0417] [ka]

[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 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] [ka]

[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 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] [ka]

[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 5-nitronicotinic 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] [ka]

[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 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] [ka]

[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 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] [ka]

[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 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] [ka]

[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 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] [ka]

[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 (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: 94 mg, 79% (final step) ESI-MS: 604.4 [M+H] + Preparation of Compound I-71

[0433] [ka]

[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 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] [ka]

[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 pyridazine-4-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in step 6 (according to compound I-1b). Yield: 44 mg, 61% (final step) ESI-MS: 552.4 [M+H] + Preparation of Compound I-73

[0437] [ka]

[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 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] [ka]

[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] [ka]

[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] [ka]

[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] [ka]

[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 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] [ka]

[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 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] [ka]

[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 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] [ka]

[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 building blocks

[0453] [ka]

[0454] 1. Preparation of compound ZED4893

[0455] [ka]

[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 with 10 mL of DMF and 1.24 mL of DIPEA (2 eq) and stirred at room temperature overnight. 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: 484mg, 47% ESI-MS: 289.3 [M+H] + 2. Preparation of compound ZED4894

[0457] [ka]

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

[0459] [ka]

[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 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] [ka]

[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 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] [ka]

[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 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] [ka]

[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 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 by TFA in the final step. Yield: 15 mg, 68% (final step) ESI-MS: 585.4 [M+H] + Preparation of Compound I-85

[0467] [ka]

[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 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] [ka]

[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] [ka]

[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 using 5-methoxyoxazole-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] [ka]

[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 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] [ka]

[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 2-acetyloxazole-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] + Preparation of compound I-90

[0477] [ka]

[0478] The synthesis of compound I-90 was carried out according to compound I-1, using 1-bicyclo[2.1.1]hexan-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] [ka]

[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 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] [ka]

[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 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] [ka]

[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 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] [ka]

[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] [ka]

[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] [ka]

[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 (following compound I-1b). Yield: 33 mg, 56% (final step) ESI-MS: 650.5 [M+H] + Preparation of Compound I-97

[0491] [ka]

[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] [ka]

[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] [ka]

[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] [ka]

[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 3-cinnolinecarboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b). Yield: 37 mg, 65% (final step) ESI-MS: 574.4 [M+H] + Preparation of Compound I-101

[0499] [ka]

[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 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] [ka]

[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 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] [ka]

[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 2-methyl-1,8-naphthyridine-3-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b). Yield: 40 mg, 64% (final step) ESI-MS: 588.4 [M+H] + Preparation of Compound I-104

[0505] [ka]

[0506] The synthesis of compound I-104 was carried out according to compound I-1, using bicyclo[2.1.1]hexan-1-amine instead of 1-adamantanamine in step 2 (according to ZED3912) and 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 deprotection (DCM / TFA) as described above and purified by HPLC. Yield: 27 mg, 73% (final step) ESI-MS: 591.4 [M+H] + Preparation of Compound I-105

[0507] [ka]

[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 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] [ka]

[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 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] [ka]

[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] [ka]

[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 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 deprotection (DCM / TFA) as described above and purified by HPLC. Yield: 27 mg, 77% (final step) ESI-MS: 529.4 [M+H] + Preparation of Compound I-109

[0515] [ka]

[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 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] + Preparation of Compound I-110

[0517] [ka]

[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 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] [ka]

[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 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] [ka]

[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-sulfamoylfuran-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] [ka]

[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 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] [ka]

[0526] The synthesis of compound I-114 was carried out from compound I-1 using 4-aminoadamantane-1-carboxamide instead of 1-adamantanamine in step 2 (according to ZED3912) and 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] [ka]

[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 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] [ka]

[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 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] [ka]

[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 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] [ka]

[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 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) ESI-MS: 530.3 [M+H] + Preparation of Compound I-119

[0535] [ka]

[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 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] [ka]

[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] [ka]

[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] [ka]

[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 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 compound according to the present invention Transglutaminase assay To determine the effectiveness of inhibitors against tissue transglutaminase, the incorporation of dansylcadaverine into dimethylcasein (Zedira product T036, Lorand et al., Anal Biochem, 1971, 44:221-31) was measured using recombinant human transglutaminase 2 (Zedira product T022).

[0543] Tissue transglutaminase is diluted in 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 stock solution of inhibitor is prepared in DMSO, and from this a series of 1:2 dilutions are prepared also in DMSO. Each initial dilution is then diluted 1:50 with buffer (50 mM Tris-HCl, 7.5 mM CaCl2, 150 mM NaCl, pH=7.4) to produce final working dilutions containing 2% (v / v) DMSO.

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

[0546] Just before starting the assay, 600 μl of 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 per well containing inhibitor.

[0547] The increase in fluorescence was measured at λ for 30 min at 37°C. ex = 330 nm and λ em= 500 nm. The slope of the increase in fluorescence between 20 and 30 minutes is defined as the IC 50 The value (the inhibitor concentration at which 50% of the initial activity is inhibited) is calculated to determine the concentration.

[0548] The enzyme activity is analyzed by calculating the slope of the increase in fluorescence intensity. IC 50 Values ​​are calculated by plotting enzyme activity (as a percentage from a control containing 2% DMSO instead of inhibitor) versus inhibitor concentration. 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 on tissue transglutaminase (TG2) was measured using IC 50 The values ​​used are shown in Table 1 below.

[0550] [Table 1-1]

[0551] [Table 1-2]

[0552] [Table 1-3]

[0553] [Table 1-4]

[0554] Example B-2. logD value of the compound of the present invention To classify the compounds of the invention according to their lipophilicity, LogD values ​​(partition coefficients) were determined using the 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 moderate lipophilicity (LogD values ​​between 0 and 3) usually favor oral absorption, striking a balance between solubility and permeability. However, advanced formulation of the compound may improve 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 compounds of the present invention Permeability coefficient (P app Values ​​were obtained from Caco-2 barrier studies predicting oral / intestinal bioavailability of the tested compounds. The analysis was performed by using CacoReady™ ready-to-use kits from ReadyCell according to the manufacturer's protocol.

[0560] 1x10 -6 P exceeding cm / s app Compounds with a value of 1x10 are classified as permeable, whereas compounds with a -6 P less than cm / s app Compounds having a value are considered to be classified as non-permeating.

[0561] [Table 3-1]

[0562] [Table 3-2]

[0563]

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Claims

1. A compound represented by formula (II): 【Chemistry 12】 During the ceremony, L ２ is -NR Ｎ１ - represents R ３ represents 1-adamantyl; or L ２ is -NR Ｎ１ CH ２ - represents 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 one or more R ａ , R ｂ , R ｃ , R ｄ , and R ｅ optionally replaced by; R ２ teeth 【Chemistry 13】 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 Represents CF3; 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; 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、-C-、-B2、-I、-OH、-CN、-NO ２ 、-CH ３ 、-C ２ H ５ 、-C ３ H ７ ,-EH(EH ３ ) ２ 、-C ４ H ９ 、-CH ２ --H(H) ３ ) ２ ,-EH(EH ３ )-C ２ H ５ 、-シクロ-C ３ H ５ 、-CH ２ -シクロ-C ３ H ５ 、-CH ２ F、-CHF ２ 、-CF ３ 、-CH ２ Cl、-E ２ Br、-EH ２ I、-EH ２ -CH ２ F、-CH ２ -CHF ２ 、-CH ２ -CF ３ 、-CH ２ -CH ２ Cl、-E ２ -CH ２ Br、-EH ２ -CH ２ I, -OCH ３ 、-OC ２ H ５ 、-OC ３ H ７ ,-OCH(CH ３ ) ２ ,-OC(EH 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 represents -C≡CH or -Ph; A compound, or a diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemate, solvate, hydrate, or pharma- ceutically acceptable salt thereof.

2. 10. The compound of claim 1, or a diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemate, solvate, hydrate, or pharma- ceutically acceptable salt thereof, wherein the compound has any one of formulas (II-a), (II-b), (II-b1), (II-b2), (III-a), and (III-b): 【Chemistry 14-1】 【Chemistry 14-2】 In the formula R ２ , R ８ , R １０ , R １１ , R Ｎ , R ａ , R ｂ , R ｃ , R ｄ , and R ｅ has the same meaning as defined in claim 1, A compound, or a diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemate, solvate, hydrate, or pharma- ceutically acceptable salt thereof.

3. A compound according to any one of claims 1 to 2, or a diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemate, solvate, hydrate, or pharma- ceutically acceptable salt thereof, wherein R ３ teeth 【Chemistry 15】 Represents, A compound, or a diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemate, solvate, hydrate, or pharma- ceutically acceptable salt thereof.

4. A compound according to any one of claims 1 to 3, or a diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemate, solvate, hydrate, or pharma- ceutically acceptable salt thereof, wherein R ２ teeth 【Chemistry 16】 Represents, A compound, or a diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemate, solvate, hydrate, or pharma- ceutically acceptable salt thereof.

5. 2. The compound of claim 1 selected from the group consisting of: or a diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemate, solvate, hydrate, or pharma- ceutically acceptable salt thereof. 【Chemistry 17-1】 【Chemistry 17-2】 【Chemistry 17-3】 【Chemistry 17-4】 【Chemistry 17-5】 【Chemistry 17-6】 【Chemistry 17-7】 【Chemistry 17-8】

6. A pharmaceutical composition comprising as an active ingredient a compound according to any one of claims 1 to 5 or a diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemate, solvate, hydrate, or pharma- ceutically acceptable salt thereof, together with at least one pharma- ceutically acceptable carrier, excipient, or diluent, or a combination thereof.

7. 10. A composition comprising a compound according to any one of claims 1 to 5 or a diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemate, solvate, hydrate, or a pharma- ceutically acceptable salt thereof for use in medicine.

8. A composition comprising a compound according to any one of claims 1 to 5 or a diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemate, solvate, hydrate, or pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 6, for use in the treatment or prevention of a disease selected from the group consisting of autoimmune and inflammatory diseases, vascular diseases, fibrotic diseases, liver diseases, cholestatic liver diseases, cancer, neurodegenerative diseases, eye diseases, and skin diseases.

9. A composition for use or a pharmaceutical composition for use according to claim 8, comprising The autoimmune and inflammatory diseases are selected from the group consisting of 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 disease is selected from the group consisting of atherosclerosis, thrombosis, and angiosclerosis; The fibrotic disease affects an organ selected from the group consisting of the lung, kidney, liver, skin, and gastrointestinal tract; The liver disease is selected from the group consisting of alcoholic hepatitis, alcoholic steatohepatitis, nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, liver cirrhosis, autoimmune hepatitis, and liver inflammation; The cholestatic liver disease is selected from the group consisting of primary biliary cholangitis, and primary sclerosing cholangitis; the cancer is selected from the group consisting of glioblastoma, melanoma, pancreatic cancer, renal cell carcinoma, meningioma, and breast cancer; the neurodegenerative disease is selected from the group consisting of Parkinson's disease, Huntington's disease, and Alzheimer's disease; The ocular disease is selected from the group consisting of glaucoma, cataracts, macular degeneration, and uveitis; The skin disease is selected from the group consisting of acne, psoriasis, scarring, and skin aging. A composition for use or a pharmaceutical composition for use.

10. A composition for use, or a pharmaceutical composition for use, as described in any one of claims 8 and 9, wherein the autoimmune and inflammatory diseases include celiac disease.

11. 10. A process for producing a compound of claim 1 or a diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemate, solvate, hydrate, or pharma- ceutically acceptable salt thereof, comprising: Step 1A: Providing Compound 4a Wherein PG3 is an Amino Protecting Group 【Chemistry 17】 Step 2A: Compound 4a is subjected to a coupling reaction with compound 5. 【Chemistry 18】 Obtaining Compound 6a 【Chemistry 19】 Step 3A: The amino protecting group PG ３ to obtain compound 7a. 【Chemistry 20】 Step 4A: Compound 7a and a carboxylic acid (R ２ -CO ２ H8) to obtain compound 9a. 【Chemistry 21】 Step 5A: Oxidation of compound 9a to produce compound of formula (Ia) 【Chemical 22】 wherein R 2 and R 3 have the same meaning as defined in claim 1, L represents L 2 , L 2 has the same meaning as defined in claim 1, and R 6 is ethyl. method.

12. The composition for use or pharmaceutical composition for use described in claim 9, wherein the fibrotic disease is selected from the group consisting of cystic fibrosis, renal fibrosis, diabetic nephropathy, intestinal fibrosis, idiopathic pulmonary fibrosis, and hepatic fibrosis.

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