Transglutaminase Inhibitors

Abstract

The present invention relates to compounds of general formula (I) as novel inhibitors of transglutaminase, to processes for producing the compounds of the invention, to pharmaceutical compositions containing the compounds of the invention, and to methods for the prevention and treatment of diseases associated with transglutaminase, in particular transglutaminase 2. JPEG2024528557000426.jpg56165

Description

[Technical field]

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

[0002] Transglutaminases are a type of transferase, more precisely designated as "protein-glutamine:amine gamma-glutamyltransferase" (EC 2.3.2.13) according to the EC nomenclature. Transglutaminases link the ε-amino group of a lysine amino acid with the γ-glutamyl group of a glutamine amino acid, forming an isopeptide bond with the release of ammonia. In the absence of a suitable amine and / or under certain conditions, deamidation of glutamine may occur, producing the corresponding glutamic acid.

[0003] Furthermore, transglutaminases play an important role in many therapeutic areas, e.g. in cardiovascular diseases (thrombosis and atherosclerosis), autoimmune diseases (celiac disease, Dühring-Brock 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, one of the most important manifestations is celiac disease, which is gluten intolerance. Celiac disease is characterized by chronic inflammation of the small intestinal mucosa. In susceptible patients, the intestinal epithelium is destroyed in turn after ingestion of gluten-containing foods, resulting in reduced absorption of nutrients, which further affects affected patients, with symptoms such as weight loss, anemia, diarrhea, nausea, vomiting, appetite and fatigue. These findings have led to a strong demand for the development of medicines for the treatment of celiac disease and other diseases related to tissue transglutaminase (transglutaminase 2, TG2, tTG). Tissue transglutaminase is a central element in the pathogenesis. This endogenous enzyme mediates the deamidation of gluten / gliadin on the small intestinal mucosa, which induces an inflammatory response. Therefore, tissue transglutaminase inhibitors are suitable for use as active agents in pharmaceuticals.

[0005] Another important indication of tissue transglutaminase inhibitors is fibrotic disorders. Fibrotic disorders 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 disorders that are addressed by the disclosed compounds.

[0006] US9,434,763B2 discloses pyridinone derivatives having a warhead containing at least one acceptor-substituted double bond, such as a Michael system, as irreversible transglutaminase inhibitors. Alkylacetamido and arylacetamido pyridinones have been shown to have activity in the nanomolar range (IC) against tissue transglutaminase TG2. 50 ) inhibitory activity.

[0007] Tse et al. (J. Med. Chem. 2020, 63, 11585-11601) reported replacing the phenyl residue of antimalarial triazolopyrazine compounds with nonclassical bioisosteres, e.g., cubane and bicyclo[1.1.1]pentane (BCP), to alter the solubility and metabolic stability of the compounds. The authors further evaluated the antiplasmodial activity of bioisostere-modified triazolopyrazines against the 3D7 strain of P. falciparum in vitro. Replacement of the phenyl with bioisostere saturated heterocyclic residues resulted in a complete loss of activity. Adamantyl residues and other caged hydrocarbon derivatives were 2- to 9-fold less potent than the corresponding phenyl triazolopyrazine compounds. In contrast, high potency was achieved when the phenyl was replaced with closo-1,2- and 1,7-carborane isomers. The authors concluded that the impact of nonclassical bioisostere substitutions on biological properties cannot be accurately predicted, and a significant range of possible bioisosteres must first be tested to identify appropriate substitutions that lead to the desired properties of a given molecule. Subbaiah et al. (J. Med. Chem. 2021, 64, 19, 14046-14128) report on bioisosteres of phenyl rings in lead optimization and drug design. They show that replacement of phenyl rings with bioisosteric heterocyclic and carbocyclic moieties can result in improved potency, solubility, and metabolic stability while reducing lipophilicity, plasma protein binding, phospholipidosis potential, and inhibition of cytochrome P450 enzymes and hERG channels. However, this effect is highly dependent on the properties of the compound itself and the target of interest. US11,072,634B2 discloses reversible transglutaminase inhibitors containing an aldehyde, ketone, α-ketoaldehyde, α-ketoketone, α-ketoacid, α-ketoester, α-ketoamide or halogenated methyl ketone as a reactive group. The inhibitors have activity in the nanomolar and micromolar range (IC) against tissue transglutaminase TG2. 50 ) inhibitory activity. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] US9,434,763B2 [Patent Document 2] US11,072,634B2 [Non-patent literature]

[0009] [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 Summary of the Invention [Means for solving the problem]

[0010] It is an object of the present invention to provide novel and most likely irreversible 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] This object is solved by the technical teaching of the independent claims. Further advantageous embodiments, aspects and details of the invention are evident from the dependent claims, the description and the examples.

[0012] Surprisingly, it has been found that the chemically reactive irreversible inhibitors disclosed herein effectively inhibit transglutaminases, including tissue transglutaminase, also referred to as transglutaminase 2 or TG2, the terms being used interchangeably herein.

[0013] Preferably, such chemically reactive moieties are selected from irreversibly reactive groups such as α,β-unsaturated ketoesters, α,β-unsaturated ketoamides and α,β-unsaturated sulfones, among others. The compounds of the present invention act as selective inhibitors of transglutaminase 2. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] Thus, the present invention relates to compounds of the general formula (I): [ka] (Wherein, L is -L 1 -or-L 1 -L 2 -, preferably -L 1 -L 2 - represents L 1 -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CO-, or -CH 2 CH 2 CO-, L 2 is a bond, -NR N1 -, -NR N1 CH 2 -, -NR N1 CH 2 CH 2 -, or -NR N1 CH(CH 3 )-, R 1 teeth, [ka] represents R 2 teeth, [ka] [ka] [ka] [ka] [ka] represents 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 and R 3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, adamantyl, diamantyl, or hexamethylenetetraminyl, the aforementioned residues optionally containing one or more C=C double bond(s), and / or R a , R b , R c , R d , and R e and optionally replaced by one or more of R a , R b , R c , R d , and R e are, independently of each other, -H, -F, -Cl, -Br, -CN, -OH, -CH 3 , -CH 2CH 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 、または-NHSO2 CH 2 CF 3 represents R 4 -R 5 , -OR 5 or -NR 6 R 7 represents R 5 -H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 CH 2 CH 2 CH 2 CH 3 , -CH 2 CH=CH 2 , -CH 2 CH=CH(CH 3 ), -CH 2 CH=C(CH 3 ) 2 , -CH 2 CH=CHCH 2 CH 3 , -cyclo-C 3 H 5 , -cyclo-C 4 H 7 , -cyclo-C 5 H 9 , -cyclo-C 6 H 11 , -CH 2 -Cyclo-C 3 H 5 , -CH 2 -Cyclo-C 4 H 7 , -CH 2 -Cyclo-C 5 H 9 , -CH2 -Cyclo-C 6 H 11 , -Ph, -CH 2 -Ph, -CH 2 OCH 3 , -CH 2 OCH 2 CH 3 , -CH 2 CH 2 OCH 3 , or -CH 2 CH 2 OCH 2 CH 3 represents R 6 and R 7 are, independently of each other, -H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 CH=CH 2 , -CH 2 CH=CH(CH 3 ), -CH 2 CH=C(CH 3 ) 2 , -CH 2 CH=CHCH 2 CH 3 , -cyclo-C 3 H 5 , -cyclo-C 4 H 7 , -cyclo-C 5 H 9 , -cyclo-C 6 H 11 , -CH 2-Cyclo-C 3 H 5 , -CH 2 -Cyclo-C 4 H 7 , -CH 2 -Cyclo-C 5 H 9 , -CH 2 -Cyclo-C 6 H 11 , -Ph, -CH 2 -Ph, -CH 2 OCH 3 , -CH 2 OCH 2 CH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 3 , -CH 2 CH 2 NHCH 3 , -CH 2 CH 2 N(CH 3 ) 2 represents or or -NR 6 R 7 teeth, [ka] represents R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 are, independently of each other, -H, -F, -Cl, -Br, -I, -OH, -CN, -NO 2 , -CH 3 , -C 2 H 5 , -C 3 H 7 , -CH(CH 3 ) 2 , -C 4 H 9 , -CH 2 -CH(CH 3 ) 2、-CH(CH 3 )-C 2 H 5、 -C(CH 3 ) 3 、-シクロ-C 3 H 5 、-CH 2 -シクロ-C 3 H 5 、-CH 2 OH、-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、-AND 3 、-OC 2 H 5 、-OC 3 H 7 、-OCH(CH 3 ) 2 、-OC(CH 3 ) 3 、-OC 4 H 9 ,-OCHF 2 、-OCF 3 ,-AND 2 CF 3 、-OC 2 F 5 ,-AND 2 AND 3 、-O-シクロ-C 3 H 5 ,-AND 2 -シクロ-C 3 H 5 、-OC 2 H 4 -シクロ-C 3 H 5 、-CHO、-COCH 3 、-COCF3 、-COC 2 H 5 、-COC 3 H 7 、-COCH(CH 3 ) 2 、-COC(CH 3 ) 3 、-COOH、-COOCH 3 、-COOC 2 H 5 、-COOC 3 H 7 、-COOCH(CH 3 ) 2 、-COOC(CH 3 ) 3 、-OOC-CH 3 、-OOC-CF 3 、-OOC-C 2 H 5 、-OOC-C 3 H 7 、-OOC-CH(CH 3 ) 2 、-OOC-C(CH 3 ) 3 、-NH 2 -NHCH 3 、-NHC 2 H 5 、-NHC 3 H 7 、-NHCH(CH 3 ) 2 、-NHC(CH 3 ) 3 、-N(CH 3 ) 2 、-N(C 2 H 5 ) 2 、-N(C 3 H 7 ) 2 、-N[CH(CH 3 ) 2 ] 2 、-N[C(CH 3 ) 3 ] 2 、-NHCOCH 3 、-NHCOCF 3 、-NHCOC 2 H 5 、-NHCOC 3 H 7、-NHCOCH(CH 3 ) 2 、-NHCOC(CH 3 ) 3 、-CONH 2 、-CONHCH 3 、-CONHC 2 H 5 、-CONHC 3 H 7 、-CONHCH(CH 3 ) 2 、-CONH-シクロ-C 3 H 5 、-CONHC(CH 3 ) 3 、-CON(CH 3 ) 2 、-CON(C 2 H 5 ) 2 、-CON(C 3 H 7 ) 2 、-CON[CH(CH 3 ) 2 ] 2 、-CON[C(CH 3 ) 3 ] 2 、-SO 2 NH 2 、-SO 2 NHCH 3 、-SO 2 NHC 2 H 5 、-SO 2 NHC 3 H 7 、-SO 2 NHCH(CH 3 ) 2 、-SO 2 NH-シクロ-C 3 H 5 、-SO 2 NHC(CH 3 ) 3 、-SO 2 N(CH 3 ) 2 、-SO 2 N(C 2 H 5 ) 2 、-SO 2 N(C 3 H 7 )2 , -SO 2 N[CH(CH 3 ) 2 ] 2 , -SO 2 N[C(CH 3 ) 3 ] 2 , -NHSO 2 CH 3 , -NHSO 2 CF 3 , -NHSO 2 C 2 H 5 , -NHSO 2 C 3 H 7 , -NHSO 2 CH(CH 3 ) 2 , -NHSO 2 C(CH 3 ) 3 , -CH=CH 2 , -CH 2 -CH=CH 2 , -C(CH 3 )=CH 2 , -CH=CH-CH 3 , -C≡CH, -C≡C-CH 3 , -CH 2 -C≡CH, -Ph, -O-Ph, -O-CH 2 -Ph, [ka] represents or or R 8 and R 9 Or R 9 and R 10 together form the following five- or six-membered ring: [ka] or or R 12 and R 13 Or R 13 and R 14 together form the following five- or six-membered ring: [ka] may form one of R N -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 , -COC2 H 5 , -COC 3 H 7 , -COCH(CH 3 ) 2 , -COC(CH 3 ) 3 , -CO-cyclo-C 3 H 5 , -CO-cyclo-C 4 H 7 , -CO-cyclo-C 5 H 9 , -COOCH 3 , -COOC 2 H 5 , -COOC 3 H 7 , -COOCH(CH 3 ) 2 , -COOC(CH 3 ) 3 , -COOCH 2 Ph, -SO 2 CH 3 , -SO 2 CF 3 , -SO 2 C 2 H 5 , -SO 2 C 3 H 7 , -SO 2 CH(CH 3 ) 2 , -SO 2 -Cyclo-C 3 H 5 , or -SO 2 C(CH 3 ) 3 represents R N1 -H, -CH 3 , or -CH 2 CH 3 (represents or a diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemate, solvate, hydrate, or pharma- ceutically acceptable salt thereof.

[0015] We propose a bridged bicyclic residue R 3It has been found that the reversible inhibitors of formula (I) disclosed herein, having the formula: 3 It is shown herein that the compounds have improved inhibitory activity compared to known compounds having the formula: In order to prove the inventive step of the compounds of the present application, the known compounds of US9,434,763B2 (Reference 2 (ZED1227), Reference 3 (A8 of US9,434,763B2), and Reference 5) were synthesized and tested as reference compounds in comparison with the most similar compounds of the present application. In this regard, inhibition data were determined using a classical fluorescent transamidation 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) proteins as a substrate for transglutaminase. The inhibition data of the compounds of the present invention were compared to that of the compounds disclosed in US 9,434,763 B2, in particular compound A8 (referred to herein as Reference 3). Of note, the IC 50 The values ​​are based on a fluorescent isopeptidase assay and therefore cannot be compared with the present data. 50 = 53 nM) was compared with reference substance 3 (IC 50 =4,268 nM), which is 80 times more potent than

[0016] Thus, the compound of formula (I) of the present invention, ranked as "A", showed approximately 250 times higher efficacy compared to reference substance 3 (A8). The same argument applies to reference substance 5, which is identical to compound III-83 except for the phenylethyl group. As is evident from Table 1, reference substance 5 is 25 times less potent than compound III-83.

[0017] This finding was particularly surprising since it is common knowledge for the skilled artisan that bridged bicyclic or bridged cycloalkyl groups are non-classical bioisosteres of the phenyl group, and it was believed that only replacing the phenyl group with a bridged bicyclic group would result in a compound with similar physicochemical and biological properties, including inhibitory activity, and it was not expected that the compounds of the present invention having a bridged bicyclic residue would have improved inhibitory activity over prior art compounds having aromatic residues. The bridged cycloalkyl group is not considered to improve the physicochemical and biological properties of the compound, since the aromatic moiety showed low potency.

[0018] As used herein, the 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, 1-adamantyl, 2-adamantyl, diamantyl, and hexamethylenetetraminyl residues are each independently selected from the group consisting of the parent structures: [ka] and / or R a , R b , R c , R d , and R e is optionally replaced by one or more of:

[0019] In particular, the terms "1-adamantyl", "2-adamantyl" and "2-bicyclo[3.1.1]heptyl" have the following structure: [ka] (In the formula, R a , R b , R c , R d and R e have the same meaning as defined herein).

[0020] Preferably, the 2-bicyclo[3.1.1]heptyl has the following structure: [ka] (In the formula, R a and R b have the same meaning as defined herein).

[0021] Compounds of formula (Ic) are preferred: [ka] (L, R 2 , R 3 , R 5 , R 6 , R 7 has the same meaning as defined herein for formula (I).

[0022] In one embodiment of the present invention, the compounds of formula (I) have irreversible reactive groups such as α,β-unsaturated ketoesters, α,β-unsaturated ketoamides and α,β-unsaturated sulfones. The compounds of the present invention act as selective inhibitors of transglutaminase 2.

[0023] Thus, in some embodiments, the present invention provides a compound of formula (I) [ka] (Wherein, L is -L 1 -or-L1 -L 2 -, preferably -L 1 -L 2 - represents L 1 -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CO-, or -CH 2 CH 2 CO-, L 2 is a bond, -NR N1 -, -NR N1 CH 2 -, -NR N1 CH 2 CH 2 -, or -NR N1 CH(CH 3 )-, R 1 teeth, [ka] represents R 2 teeth, [ka] [ka] [ka] [ka] [ka] represents 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 13may be substituted with R 3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, adamantyl, diamantyl, or hexamethylenetetraminyl, the aforementioned residues containing one or more C=C double bond(s), and / or R a , R b , R c , R d , and R e is replaced by one or more of R a , R b , R c , R d , and R e are, independently of each other, -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 CH3 , -CH 2 CO 2 C 2 H 5 , -CH 2 CONH 2 , -CH 2 CONHCH 3 , -CH 2 CON(CH 3 ) 2 , -CH 2 CONHC 2 H 5 , -NHCOCH 3 , -NHCOC 2 H 5 , -NHCOCF 3 , -NHCOCH 2 CF 3 , -NHSO 2 CH 3 , -NHSO 2 C 2 H 5 , -NHSO 2 CHF 2 , -NHSO 2 CF 3 , or -NHSO 2 CH 2 CF 3 represents R 4 -R 5 , -OR 5 or -NR 6 R 7 represents R 5 -H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 CH 2 CH2 CH 2 CH 3 , -CH 2 CH=CH 2 , -CH 2 CH=CH(CH 3 ), -CH 2 CH=C(CH 3 ) 2 , -CH 2 CH=CHCH 2 CH 3 , -cyclo-C 3 H 5 , -cyclo-C 4 H 7 , -cyclo-C 5 H 9 , -cyclo-C 6 H 11 , -CH 2 -Cyclo-C 3 H 5 , -CH 2 -Cyclo-C 4 H 7 , -CH 2 -Cyclo-C 5 H 9 , -CH 2 -Cyclo-C 6 H 11 , -CH 2 -Ph, -CH 2 OCH 3 , -CH 2 OCH 2 CH 3 , -CH 2 CH 2 OCH 3 , or -CH 2 CH 2 OCH 2 CH 3 represents R 6 and R 7 are, independently of each other, -H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH2 CH 3 , -CH 2 CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 CH=CH 2 , -CH 2 CH=CH(CH 3 ), -CH 2 CH=C(CH 3 ) 2 , -CH 2 CH=CHCH 2 CH 3 , -cyclo-C 3 H 5 , -cyclo-C 4 H 7 , -cyclo-C 5 H 9 , -cyclo-C 6 H 11 , -CH 2 -Cyclo-C 3 H 5 , -CH 2 -Cyclo-C 4 H 7 , -CH 2 -Cyclo-C 5 H 9 , -CH 2 -Cyclo-C 6 H 11 , -Ph, -CH 2 -Ph, -CH 2 OCH 3 , -CH 2 OCH 2 CH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 3 , -CH 2 CH 2 NHCH 3 , or -CH 2 CH 2N(CH 3 ) 2 represents or or -NR 6 R 7 teeth, [ka] represents R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 are, independently of each other, -H, -F, -Cl, -Br, -I, -OH, -CN, -NO 2 , -CH 3 , -C 2 H 5 , -C 3 H 7 , -CH(CH 3 ) 2 , -C 4 H 9 , -CH 2 -CH(CH 3 ) 2 , -CH(CH 3 )-C 2 H 5、 -C(CH 3 ) 3 , -cyclo-C 3 H 5 , -CH 2 -Cyclo-C 3 H 5 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 Cl, -CH 2 Br, -CH 2 I, -CH 2 -CH 2 F, -CH 2 -CHF 2 , -CH 2 -CF 3 , -CH 2 -CH 2 Cl, -CH 2 -CH 2 Br, -CH 2 -CH 2I、-AND 3 、-OC 2 H 5 、-OC 3 H 7 、-OCH(CH 3 ) 2 、-OC(CH 3 ) 3 、-OC 4 H 9 ,-OCHF 2 、-OCF 3 ,-AND 2 CF 3 、-OC 2 F 5 ,-AND 2 AND 3 、-O-シクロ-C 3 H 5 ,-AND 2 -シクロ-C 3 H 5 、-OC 2 H 4 -シクロ-C 3 H 5 、-CHO、-COCH 3 、-COCF 3 、-COC 2 H 5 、-COC 3 H 7 、-COCH(CH 3 ) 2 、-COC(CH 3 ) 3 、-COOH、-COOCH 3 、-COOC 2 H 5 、-COOC 3 H 7 、-COOCH(CH 3 ) 2 、-COOC(CH 3 ) 3 、-OOC-CH 3 、-OOC-CF 3 、-OOC-C 2 H 5 、-OOC-C 3 H 7 、-OOC-CH(CH 3 ) 2 、-OOC-C(CH 3 ) 3 、-NH2 -NHCH 3 、-NHC 2 H 5 、-NHC 3 H 7 、-NHCH(CH 3 ) 2 、-NHC(CH 3 ) 3 、-N(CH 3 ) 2 、-N(C 2 H 5 ) 2 、-N(C 3 H 7 ) 2 、-N[CH(CH 3 ) 2 ] 2 、-N[C(CH 3 ) 3 ] 2 、-NHCOCH 3 、-NHCOCF 3 、-NHCOC 2 H 5 、-NHCOC 3 H 7 、-NHCOCH(CH 3 ) 2 、-NHCOC(CH 3 ) 3 、-CONH 2 、-CONHCH 3 、-CONHC 2 H 5 、-CONHC 3 H 7 、-CONHCH(CH 3 ) 2 、-CONH-シクロ-C 3 H 5 、-CONHC(CH 3 ) 3 、-CON(CH 3 ) 2 、-CON(C 2 H 5 ) 2 、-CON(C 3 H 7 ) 2 、-CON[CH(CH 3 ) 2 ] 2 、-CON[C(CH 3) 3 ] 2 、-SO 2 NH 2 、-SO 2 NHCH 3 、-SO 2 NHC 2 H 5 、-SO 2 NHC 3 H 7 、-SO 2 NHCH(CH 3 ) 2 、-SO 2 NH-シクロ-C 3 H 5 、-SO 2 NHC(CH 3 ) 3 、-SO 2 N(CH 3 ) 2 、-SO 2 N(C 2 H 5 ) 2 、-SO 2 N(C 3 H 7 ) 2 、-SO 2 N[CH(CH 3 ) 2 ] 2 、-SO 2 N[C(CH 3 ) 3 ] 2 、-NHSO 2 CH 3 、-NHSO 2 CF 3 、-NHSO 2 C 2 H 5 、-NHSO 2 C 3 H 7 、-NHSO 2 CH(CH 3 ) 2 、-NHSO 2 C(CH 3 ) 3 、-CH=CH 2 、-CH 2 -CH=CH 2 、-C(CH 3 )=CH 2, -CH=CH-CH 3 , -C≡CH, -C≡C-CH 3 , -CH 2 -C≡CH, -Ph, -O-Ph, -O-CH 2 -Ph, [ka] represents or or R 8 and R 9 Or R 9 and R 10 together form the following five- or six-membered ring: [ka] or or R 12 and R 13 Or R 13 and R 14 together form the following five- or six-membered ring: [ka] may form one of R N -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 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 , -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 , -SO 3 ) 2 , or -SO 2 C(CH 3 ) 3 represents R N1-H, -CH 3 , or -CH 2 CH 3 (represents or a diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemate, solvate, hydrate, or pharma- ceutically acceptable salt thereof.

[0024] In all general formulas disclosed herein, R 2 is preferably [ka] [ka] [ka] [ka] [ka] where the unsubstituted bicyclic residue is represented by 1 to 5 substituents R 9 ~R 14 and R N and preferably 1 to 3 substituents R 11 ~R 13 and the substituent R 9 ~R 14 and R N has the meaning defined herein or in claim 1.

[0025] 1 to 5 R substituents 9 ~R 14 and R N The unsubstituted bicyclic residues which may be substituted with have the following structure: 9 ~R 14 and R N has the meaning defined herein: [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0026] In one embodiment of the compounds of the invention disclosed herein, L is -CH 2 CO-NH-, -CH 2 CO-NCH 3 -, -CH 2 CO-NH-CH 2 -, or -CH 2 CO-NH-CH(CH 3 )-represents

[0027] Preferred are compounds of formula (I) [ka] In the formula, L is -L 1 -L 2 - represents L 1 -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CO-, or -CH 2 CH 2 CO-, L 2 is a bond, -NR N1 -, -NRN1 CH 2 -, -NR N1 CH 2 CH 2 -, or -NR N1 CH(CH 3 )-, R 1 teeth, [ka] represents R 2 , R 3 , R 5 ~R 7 , and R N1 has the meaning defined above.

[0028] Preferred are compounds of formula (I) [ka] In the formula, L is -L 1 -or-L 1 -L 2 -, preferably -L 1 -L 2 - represents L 1 -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CO-, or -CH 2 CH 2 CO-, L 2 is a bond, -NR N1 -, -NR N1 CH 2 -, -NR N1 CH 2 CH 2 -, or -NR N1 CH(CH 3 )-, R 1 teeth, [ka] represents R 2 , R 3 , R 5 ~R 7 , and R N1 has the meaning defined above.

[0029] Even more preferred is a compound of any one of formulae (Ic), (Id), and (Ie): [ka] (In the formula, L, R 2 , R 3 , and R 5 ~R 7 has the meaning defined above).

[0030] Also preferred are compounds of formula (I) [ka] In the formula, L is -L 1 -or-L 1 -L 2 -, preferably -L 1 -L 2 - represents L 1 -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CO-, or -CH 2 CH 2 CO-, L 2 is a bond, -NR N1 -, -NR N1 CH 2 -, -NR N1 CH 2 CH 2 -, or -NR N1 CH(CH 3 )-, R 1 teeth, [ka] represents R 2 teeth, [ka] [ka] where the unsubstituted bicyclic residue is represented by 1 to 5 substituents R 9 ~R 14 and R N and preferably 1 to 3 substituents R 11 ~R 13 and R 5 ~R 14 , R N and R N1 has the meaning defined above.

[0031] Also preferred is a compound of any one of formulae (Ic) to (Ie): [ka] (Wherein, L is -L 1 -or-L 1 -L 2 -, preferably -L 1 -L 2 - represents L 1 -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CO-, or -CH 2 CH 2 CO-, L 2 is a bond, -NR N1 -, -NR N1 CH 2 -, -NR N1 CH 2 CH 2-, or -NR N1 CH(CH 3 )-, R 2 teeth, [ka] [ka] where the unsubstituted bicyclic residue is represented by 1 to 5 substituents R 9 ~R 14 and R N and preferably 1 to 3 substituents R 11 ~R 13 and R 5 ~R 14 , R N and R N1 has the meaning defined above).

[0032] More preferred are compounds of formula (I) R 1 teeth, [ka] represents L is -L 1 -L 2 - represents L 1 -CH 2 -, or -CH 2 CO-, L 2 is a bond, -NR N1 -, -NR N1 CH 2 -, or -NR N1 CH(CH 3 )-, R 3 represents bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 4-homoisotwistyl, adamantyl or diamantyl, the aforementioned residues optionally containing one or more C=C double bond(s), and / or Ra , R b , R c , R d , and R e and optionally replaced by one or more of R 5 , R 6 , R 7 , R a , R b , R c , R d , R e and R N1 has the same meaning as defined above.

[0033] More preferred are compounds of formula (I) R 1 teeth, [ka] represents L is -L 1 -or-L 1 -L 2 -, preferably -L 1 -L 2 - represents L 1 -CH 2 -, or -CH 2 CO-, L 2 is a bond, -NR N1 -, -NR N1 CH 2 -, or -NR N1 CH(CH 3 )-, R 3 represents bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 4-homoisotwistyl, adamantyl, or diamantyl, the aforementioned residues optionally containing one or more C═C double bond(s), and / or R a , R b , R c , R d , and R e and optionally replaced by one or more of R 5 , R 6 , R 7 , R a , R b , R c , R d , R e and R N1 has the same meaning as defined above.

[0034] Also preferred is a compound of any one of formulae (Ic) to (Ie): [ka] (Wherein, L is -L 1 -or-L 1 -L 2 -, preferably -L 1 -L 2 - represents L 1 -CH 2 -, or -CH 2 CO-, L 2 is a bond, -NR N1 -, -NR N1 CH 2 -, or -NR N1 CH(CH 3 )-, R 2 teeth, [ka] [ka] where the unsubstituted bicyclic residue is represented by 1 to 5 substituents R 9 ~R 14 , R N and preferably 1 to 3 substituents R 11 ~R 13 and R 5 ~R 14 , R N and R N1 has the meaning defined above).

[0035] Preferably, R 2 teeth, [ka] represents R 3 represents bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 4-homoisotwistyl, adamantyl, or diamantyl, the aforementioned residues optionally containing one or more C═C double bond(s), and / or R a , R b , R c , R d , and R e and optionally replaced by one or more of R 5 ~R 14 , R a , R b , R c , R d , R e , R N and R N1 has the same meaning as defined above.

[0036] In all general formulae disclosed herein, L is most preferably -L 1 -L 2 -, where L 1 is preferably -CH 2 CO- or -CH 2 CH 2 CO-, more preferably -CH 2 CO-, L 2 -NR N1 -, -NR N1 CH 2 -, or -NR N1 CH(CH 3 )-, and more preferably -NH-, -N(CH 3 )-, -NH-CH 2 - or -NH-CH(CH 3 )-, and even more preferably -NH-, -NH-CH2 - or -NH-CH(CH 3 )-, and most preferably -NH-.

[0037] More preferred is a compound of any one of formulas (VI-a) to (VI-l), (VII-a) to (VII-l), (VIII-a) to (VIII-l), (IX-a) to (IX-d), (Xa) to (Xd), and (XI-a) to (XI-d): [ka] [ka] [ka] [ka] [ka] [ka] (R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R a , R b , R c , R d and L 2 have the same meaning as defined above).

[0038] Preferred are compounds of any one of formulae (I), (Ic) to (Ie), (VI-a) to (VI-l), (VII-a) to (VII-l), (VIII-a) to (VIII-l), in which R 2 teeth, [ka] [ka] represents R 5 -H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -C(CH 3 ) 3 , -cyclo-C 3 H 5 , -cyclo-C 4 H 7 , -CH 2 -Cyclo-C 3 H 5 , -CH 2 -Cyclo-C 4 H 7 ;-CH 2 Ph or -Ph, R 6 and R 7 are, independently of each other, -H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 2 CH 3 , -cyclo-C 3 H 5 , -cyclo-C 5 H 9 , -cyclo-C 6 H 11 , -CH 2 CH=CH2 , -Ph, or -CH 2 It represents Ph.

[0039] Preferred is a compound represented by any one of formulae (IX-a) to (IX-d), (Xa) to (Xd), and (XI-a) to (XI-d), R 5 -H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -C(CH 3 ) 3 , -cyclo-C 3 H 5 , -cyclo-C 4 H 7 , -CH 2 -Cyclo-C 3 H 5 , -CH 2 -Cyclo-C 4 H 7 ;-CH 2 Ph or -Ph, R 6 and R 7 are, independently of each other, -H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 2 CH 3 , -cyclo-C 3 H 5 , -cyclo-C 5 H 9 , -cyclo-C 6H 11 , -CH 2 CH=CH 2 , -Ph, or -CH 2 It represents Ph.

[0040] Preferred are compounds of any of formulae (I), (Ic) to (Ie), (VI-a) to (VI-l), (VII-a) to (VII-l), (VIII-a) to (VIII-l), (IX-a) to (IX-d), (Xa) to (Xd), and (XI-a) to (XI-d), wherein R 3 teeth, [ka] It represents.

[0041] In a highly preferred embodiment, the present invention refers to a compound selected from the group consisting of: [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7] [Table 4-8] [Table 4-9]

Table 4-10

Table 4-11

Table 4-12

Table 4-13

Table 4-14

Table 4-15

Table 4-16

Table 4-17

Table 4-18

Table 4-19

Table 4-20

Table 4-21

Table 4-22

Table 4-23

Table 4-24

Table 4-25

Table 4-26

Table 4-27

Table 4-28

Table 4-29

Table 4-30

[0042] In a very preferred embodiment, the invention is II-17、III-18、III-19、III-20、III-21、III-22、III-23、III-24、III-25、III-26、III-27、III-29、III-30、III-31、III-32、III-33、III-34、III-35、 III-36、III-37、III-38、III-39、III-40、III-41、III-42、III-43、III-44、III-45、III-46、III-48、III-49、III-50、III-51、III-52、III-53、III-54 、III-55、III-56、III-57、III-58、III-59、III-60、III-61、III-62、III-63、III-64、III-65、III-66、III-67、III-68、III-69、III-70、III-71、III-7 2、III-73、III-74、III-75、III-76、III-77、III-83、III-84、III-85、III-86、III-87、III-88、III-89、III-90、III-91、III-92、III-93、III-94、III- 95、III-96、III-97、III-98、III-99、III-100、III-101、III-102、III-103、III-104、III-105、III-106、III-107、III-108、III-109、III-110、III-11 1、III-112、III-113、III-114、III-115、III-116、III-117、III-118、III-119、III-120、III-121、III-122、III-123、III-124、III-125、III-126、III -127、III-128、III-129、III-130、III-134、III-135、III-140、III-142、III-145、III-147、III-148、III-150、III-152、III-153、III-155、III-165、III-166, III-169, III-170, III-171, III-172, and III-173; or a pharma- ceutically acceptable salt thereof.

[0043] Methods for Producing the Compounds of the Invention In some embodiments, the present invention relates to a method of synthesis of a compound of formula (I), particularly any compound of any one of formulas (Ia)-(Ie): [ka]

[0044] A further aspect of the present invention relates to the production of compounds of formula (Ic).

[0045] As shown in Scheme 1, the process for preparing a compound of formula (Ic) comprises the following steps in the following order: Step 1C: Providing Compound 4c [ka] Step 2C: Compound 4c and Compound 5 [ka] to obtain compound 6c. [ka] Step 3C: Amino Protecting Group PG 3 to obtain compound 7c. [ka] Step 4C: Compound 7c and a carboxylic acid (R 2 -CO 2 H8) to carry out a coupling reaction to produce a compound of formula (Ic) [ka] (Here, L, R 2 , R 3 , R 5 has the same meaning as defined above in formula (Ic), and PG 3 is an amino protecting group). Scheme 1 [ka]

[0046] Optionally, step 1C' is performed before step 1C: (a) providing a protected aldehyde 1 [ka] (b) carrying out a coupling reaction of aldehyde 1 with triphenylphosphonium ylide 2c to give intermediate compound 3c; [ka] or, (b') carrying out a coupling reaction of aldehyde 1 with phosphonate 2c' to give intermediate compound 3c; [ka] (c) Protecting group PG of compound 3c 1 and P.G. 2 is deprotected to form an amino protecting group PG 3 is introduced to give compound 4c.

[0047] Therefore, the following method is preferred for the production of compounds of formula (Ic): Step 1C': (a) providing a protected aldehyde 1 [ka] (b) carrying out a coupling reaction of aldehyde 1 with triphenylphosphonium ylide 2c to give intermediate compound 3c; [ka] or, (b') carrying out a coupling reaction of aldehyde 1 with phosphonate 2c' to give intermediate compound 3c; [ka] (c) Protecting group PG of compound 3c 1 and P.G. 2 is deprotected, preferably under acidic conditions, to give the amino protecting group PG 3 to obtain compound 4c. [ka] Step 1C: Providing Compound 4c [ka] Step 2C: Compound 4c and Compound 5 [ka] to obtain compound 6c. [ka] Step 3C: Amino Protecting Group PG 3 to obtain compound 7c. [ka] Step 4C: Compound 7c and a carboxylic acid (R 2 -CO 2 H8) to carry out a coupling reaction to produce a compound of formula (Ic) [ka] (Here, L, R 2 , R 3 , R5 has the same meaning as defined above in formula (Ic), and PG 1 and P.G. 3 is an amino protecting group, PG 2 is a carboxyl protecting group).

[0048] Scheme 2 [ka] A further aspect of the present invention relates to the production of compounds of formula (Id).

[0049] As shown in Scheme 2, a method for producing a compound of formula (Id) includes: Step 1D: Providing compound 4d [ka] Step 2D: Compound 4d and Compound 5 [ka] to obtain compound 6d. [ka] Step 3D: Amino Protecting Group PG 3 to obtain compound 7d. [ka] Step 4D: Compound 7d and carboxylic acid (R 2 -CO 2 H8) coupling reaction to produce a compound of formula (Id) [ka] (Here, L, R 2 , R 3 , R 6 , R 7 has the same meaning as defined above in formula (Id), and PG3 is an amino protecting group).

[0050] Optionally, step 1D' is performed before step 1D: (a) providing a protected aldehyde 1 [ka] (b) carrying out a coupling reaction of aldehyde 1 with phosphonate 2d to give intermediate compound 3d; [ka] (c) Protecting group PG of compound 3d 1 and P.G. 2 is deprotected, preferably under acidic conditions, to give the amino protecting group PG 3 to obtain compound 4d. [ka]

[0051] Thus, the following method is preferred for the production of compounds of formula (Id): Step 1D': (a) providing a protected aldehyde 1 [ka] (b) carrying out a coupling reaction of aldehyde 1 with phosphonate 2d to give intermediate compound 3d; [ka] (c) Protecting group PG of compound 3d 1 and P.G. 2 is deprotected, preferably under acidic conditions, to give the amino protecting group PG 3 to obtain compound 4d. [ka] Step 1D: Providing compound 4d [ka] Step 2D: Compound 4d and Compound 5 [ka] to obtain compound 6d. [ka] Step 3D: Amino Protecting Group PG 3 to obtain compound 7d. [ka] Step 4D: Compound 7d and carboxylic acid (R 2 -CO 2 H8) coupling reaction to produce a compound of formula (Id) [ka] (Here, L, R 2 , R 3 , R 6 , R 7 has the same meaning as defined above in formula (Id), and PG 3 is an amino protecting group).

[0052] A further aspect of the present invention relates to the production of compounds of formula (Ie). [ka]

[0053] As shown in Scheme 3, a method for producing a compound of formula (Ie) includes: Step 1E: Providing compound 4e [ka] Step 2E: Compound 4e and Compound 5 [ka] to obtain compound 6e. [ka] Step 3E: Amino Protecting Group PG 3 to obtain compound 7e. [ka] Step 4E: Compound 7e and a carboxylic acid (R 2 -CO 2 H8) to carry out a coupling reaction to produce a compound of formula (Ie) [ka] (Here, L, R 2 , R 3 , R 5 has the same meaning as defined above for formula (Ie), and PG 3 is an amino protecting group). Scheme 3 [ka]

[0054] Optionally, step 1E' is performed before step 1E: (a) providing a protected aldehyde 1 [ka] (b) carrying out a coupling reaction of aldehyde 1 with sulfonylmethylphosphonate 2e to give intermediate compound 3e; [ka] (c) Protecting group PG of compound 3e 1 and P.G. 2 is deprotected, preferably under acidic conditions, to give the amino protecting group PG 3 to obtain compound 4e. [ka]

[0055] (Thus, the following method is preferred for producing compounds of formula (Ie): Step 1E': (a) providing a protected aldehyde 1 [ka] (b) carrying out a coupling reaction of aldehyde 1 with sulfonylmethylphosphonate 2e to give intermediate compound 3e; [ka] (c) Protecting group PG of compound 3e 1 and P.G. 2 is deprotected, preferably under acidic conditions, to give the amino protecting group PG 3 to obtain compound 4e. [ka] Step 1E: Providing compound 4e [ka] Step 2E: Compound 4e and Compound 5 [ka] to obtain compound 6e. [ka] Step 3E: Amino Protecting Group PG 3 to obtain compound 7e. [ka] Step 4E: Compound 7e and a carboxylic acid (R 2 -CO 2 H8) to carry out a coupling reaction to produce a compound of formula (Ie) [ka] (Here, L, R 2 , R 3 , R 5 has the same meaning as defined above for formula (Ie), and PG 3 is an amino protecting group).

[0056] In an alternative route, all protecting groups PG 1 and P.G. 2 is simultaneously removed, and the protecting group PG 3 is selectively introduced. Preferably, PG 1 and P.G. 3 is the same.

[0057] The term "protecting group" as used herein refers to protecting groups commonly used in organic synthesis, preferably 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 protecting group for a carboxyl group. 1 , P.G. 3 , and P.G. 5 may be selected from the group consisting of an acetyl group, a benzoyl group, a benzyloxycarbonyl group (Cbz), a tert-butylcarbonyl group, a tert-butyloxycarbonyl group (Boc), and a fluorenylmethylenoxy group (Fmoc). 2 and P.G. 4 may be selected from the group consisting of methoxy, ethoxy, isobutoxy, tert-butoxy, benzyloxy, and is preferably a tert-butoxy group.

[0058] In steps 2C, 2D, 2E, 4A, 4B, 4C, 4D, and 4E, an activating reagent is generally used to activate a carboxylic acid to promote coupling reactions with the amino group of an intermediate compound ("Peptide Coupling Reagents, More than a Letter Soup", Ayman El-Faham and Fernando Albericio, Chemical Reviews, 2011, 111(11), p.6557-6602). Activation can be introduced in a separate reaction or in situ reaction.Preferably, any of the following coupling reagents can be used to activate the carboxylic acid group: 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-yloxy)tripyrrolidinophosphonium hexafluorophosphate), -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)phosphinic chloride), TFFH (tetramethylfluoroformamidinium hexafluorophosphate), BroP (bromotris(dimethylamino)phosphonium hexafluorophosphate), PyBroP (bromo-tris-pyrrolidino-phosphonium hexafluorophosphate) and CIP (2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate), or reagents of similar action which provide further activated intermediates, or mixtures thereof.

[0059] Pharmaceutical compositions and pharmaceutical uses Another aspect of the invention therefore relates to compounds according to general formula (I) as medicaments and their use in medicine. The use as inhibitors of transglutaminase, in particular transglutaminase 2 (TG2), is particularly preferred.

[0060] 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 pharmacologically acceptable salt.

[0061] The compounds of the present invention can form pharmacologically acceptable salts with organic or inorganic acids or 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, ethanol, and the like. Examples of suitable salts include benzenesulfonic acid, nitrous acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, p-toluenesulfonic acid, naphthylsulfonic acid, sulfanilic acid, camphorsulfonic acid, quinic 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 inorganic 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, with the trifluoroacetate and hydrochloride salts being particularly preferred.

[0062] When the compound of the present invention has an acidic group, it can form a salt with an inorganic or organic base. Examples of suitable inorganic or organic bases include NaOH, KOH, NH 4OH, tetraalkylammonium hydroxide, lysine or arginine, etc. The salts can be prepared conventionally using methods well known in the art, for example by treating a solution of a compound of general formula (I) with a solution of an acid selected from the group mentioned above.

[0063] 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.

[0064] Furthermore, the present invention relates to a pharmaceutical composition comprising at least one compound according to general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient together with at least one pharmacologically acceptable carrier, excipient and / or diluent.

[0065] The compounds according to general formula (I) described herein are particularly suitable for the treatment and prevention of diseases associated with and / or mediated by transglutaminase 2.

[0066] Celiac disease, which is gluten intolerance, is associated with tissue transglutaminase (TG2). Another important indication for tissue transglutaminase inhibitors is fibrotic disorders. Fibrotic disorders 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 disorders that are addressed by the disclosed compounds.

[0067] In Biological Example B-1, it is demonstrated that the compounds of the present invention as reversible and irreversible TG inhibitors effectively inhibit the activity of TG, especially TG2.

[0068] As used herein, the term "inhibiting" or "inhibition" refers to the ability of a compound to at least partially downregulate, decrease, reduce, suppress, inactivate, or inhibit the activity of an enzyme or the expression of an enzyme or protein.

[0069] Therefore, another aspect of the present invention is the use of the compounds of the present invention of general formula (I) as described or a pharmaceutical composition thereof in the treatment or prevention of autoimmune diseases, inflammatory diseases, vascular diseases, fibrotic disorders, liver diseases, cholestatic liver diseases, cancer, neurodegenerative diseases, eye diseases, and skin disorders.

[0070] 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 diseases, inflammatory diseases, vascular diseases, fibrotic disorders, liver diseases, cholestatic liver diseases, cancer, neurodegenerative diseases, eye diseases and skin disorders.

[0071] In a further aspect of the present invention there is provided a method for preventing and / or treating autoimmune diseases, inflammatory diseases, vascular diseases, fibrotic disorders, liver diseases, cholestatic liver diseases, cancer, neurodegenerative diseases, eye diseases and skin disorders, comprising administering to a subject, in particular a human, a pharma- ceutically effective amount of at least one compound of general formula (I).

[0072] Preferably, the autoimmune and inflammatory diseases include multiple sclerosis, celiac disease, Dühring-Brock disease (dermatitis herpetiformis), gluten ataxia, gluten peripheral neuropathy, diabetes, rheumatoid arthritis, Graves' disease, inflammatory bowel disease, systemic lupus erythematosus, and gingivitis; the vascular diseases include atherosclerosis, thrombosis, angiosclerosis; the fibrotic diseases include those affecting the lungs, kidneys, liver, skin or intestines, such as cystic fibrosis, renal fibrosis and diabetic nephropathy, intestinal fibrosis, idiopathic pulmonary fibrosis, hepatic fibrosis; the liver diseases include , alcoholic hepatitis, alcoholic steatohepatitis, nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, cirrhosis, autoimmune hepatitis or hepatitis, 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, eye diseases include glaucoma, cataracts, macular degeneration, or uveitis, and skin disorders include acne, psoriasis, scarring, and skin aging.

[0073] More preferably, the compound of formula (I) or a pharmaceutical composition thereof is useful for the treatment or prevention of coeliac disease.

[0074] Furthermore, the compound of general formula (I) can be administered in the form of its pharmaceutically active salt, optionally using essentially non-toxic pharmaceutically acceptable carriers, adjuvants or diluents.The pharmaceutical preparations are prepared in a suitable dosage with conventional solid or liquid carriers or diluents and conventional pharmaceutically acceptable adjuvants / drugs in a well-known manner.The suitable preparations are provided in suitable administrable forms for oral use, such as pills, tablets, film tablets, coated tablets, capsules and powders.

[0075] 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- ceutical acceptable salt in an amount of 5 mg to 500 mg, preferably 10 mg to 250 mg, most preferably 10 to 100 mg per formulation.

[0076] Furthermore, the subject of the present invention also includes pharmaceutical preparations for oral, parenteral, dermal, intradermal, intragastric, intracutaneous, intravascular, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, buccal, percutaneous, rectal, subcutaneous, sublingual, topical, transdermal or inhalation application, which contain, in addition to typical vehicles and excipients, a compound of general formula (I) and / or a pharma- ceutically acceptable salt thereof as active ingredient.

[0077] The pharmaceutical compositions of the present invention contain one of the compounds of formula (I) disclosed herein as an active ingredient, and are typically mixed with a suitable carrier material selected according to conventional pharmaceutical practice for the intended dosage form, i.e., orally administered tablets, capsules (filled with either solid, semisolid or liquid), powders, orally administrable gels, elixirs, dispersible granules, syrups, suspensions, etc. For example, the compound of formula (I) can be combined as the active ingredient with any 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., to form a tablet or capsule for oral administration. In addition, suitable binders, lubricants, disintegrants and coloring agents can be added to the mixture as necessary. Powders and tablets can be composed of the inert carrier in the range of about 5% to about 95% by weight of the composition of the present invention.

[0078] Suitable binders include starch, gelatin, natural sugars, sweeteners made from corn, natural and synthetic gums such as gum arabic, sodium alginate, carboxymethylcellulose, polyethylene glycol and wax. Lubricants that can be used 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 flavor additives and preservatives can also be included. Some of the terms used above, namely disintegrants, fillers, lubricants, binders, etc., are discussed in more detail below.

[0079] In addition, the compositions of the present invention can be formulated in a sustained release form to provide a controlled release rate of any one or more components or active ingredients in order to optimize the therapeutic effect, i.e., inhibitory activity, etc. Suitable dosage forms for sustained release include layered tablets containing layers with different degrading rates or a controlled release polymer matrix impregnated with the active ingredient, and tablet or capsule forms containing such impregnated or encapsulated porous polymer matrices.

[0080] Liquid form preparations include solutions, suspensions and emulsions, exemplified by water or water-propylene glycol solutions for parenteral injection or with the addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions.

[0081] Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be mixed with a pharma- ceutically acceptable carrier, such as a compressed inert gas, e.g., nitrogen.

[0082] 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, The molten homogeneous mixture is then poured into suitable molds and allowed to cool and solidify.

[0083] Also included are solid form preparations that are converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions, and emulsions.

[0084] Furthermore, the compounds of the present invention can be administered via transdermal application. The transdermal composition can have the form of a cream, lotion, aerosol and / or emulsion.

[0085] 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 may contain small amounts of colorants, opacifiers, softeners, and preservatives.

[0086] By tablet is meant a compressed or tableted solid dosage form containing the active ingredient together with a suitable filler. Tablets can be prepared by compressing mixtures or granulations obtained by wet granulation, dry granulation or compression methods known to those skilled in the art.

[0087] Oral gels refer to the active ingredients dispersed or solubilized in a hydrophilic semi-solid matrix.

[0088] A powder composition refers to a powder mixture containing the active ingredients and a suitable bulking agent, which can be suspended in water or juice.

[0089] Suitable bulking agents are materials that usually form the majority of the composition or dosage form. Suitable bulking agents include sugars such as lactose, sucrose, mannitol and sorbitol; starches derived from wheat, corn, rice and potato; and celluloses such as microcrystalline cellulose. The amount of bulking agent in the composition can range from about 5 to about 95% by weight of the total composition, preferably from about 25 to about 75% by weight, more preferably from about 30 to about 60% by weight.

[0090] The term disintegrant refers to a material added to the composition to aid in the disintegration and release of the pharmaceutical substance. Suitable disintegrants include starch, modified starches such as sodium carboxymethyl starch that are soluble in cold water; 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, e.g., croscarmellose sodium; alginates such as sodium alginate; clays such as bentonite, and effervescent mixtures. The amount of disintegrant used in the composition can range from about 2 to 20% by weight of the composition, more preferably from about 5 to about 10% by weight.

[0091] Binders are characterized as substances that bind or "glue" powders together, and therefore act as the "adhesive" in the formulation. Binders provide sticky starches that are already available as fillers or disintegrants. Suitable binders include sugars such as sucrose; starches derived from wheat, corn, rice and potato; natural gums such as gum arabic, gelatin and tragacanth; alginic acid, derivatives of seaweed such as sodium alginate and calcium ammonium 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, more preferably from about 3 to about 6% by weight.

[0092] The term lubricant refers to a substance added to a dosage form to reduce friction after compression of tablets, granules, etc., to facilitate release from the mold or press. Suitable lubricants include metal stearates such as magnesium stearate, calcium stearate, or potassium stearate; stearic acid; high melting point waxes, and water-soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycol, and D,L-leucine. Lubricants are typically added at the last step before compression due to the fact that they need to be present not only on the surfaces of the granules, but also between the granules and the parts of the tablet press. 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, more preferably from about 0.3 to about 1.5% by weight.

[0093] A lubricant is a material that prevents granules from caking and improves flowability so that the flow is smooth and uniform. Suitable lubricants include silicon dioxide and talc. The amount of lubricant in the composition can range from about 0.1 to about 5% by weight of the total composition, preferably from about 0.5 to about 2% by weight.

[0094] Colorants are adjuvants that impart color to the composition or dosage form. Such adjuvants may include food-quality colorants adsorbed to a suitable adsorption means, such as clay or aluminum oxide. The amount of colorant used may vary from about 0.1 to about 5% by weight of the composition, preferably from about 0.1 to about 1% by weight.

[0095] As used herein, a "pharmacologically effective amount" of a transglutaminase inhibitor is an amount or activity effective to achieve a desired physiological result, either in cells treated in vitro or in patients treated in vivo. Specifically, a pharmacologic effective amount is an amount sufficient to inhibit one or more of the clinically defined pathological processes associated with transglutaminase 2 for a particular period of time. The effective amount may vary depending on the particular compound of formula (I) and further depends on several factors and conditions related to the subject being treated and the severity of the disease. For example, when the inhibitor is administered in vivo, factors such as the age, weight and health of the patient, as well as dose-response curves and toxicity data obtained from preclinical animal studies are among the data to be considered. 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 are designed to determine parameters such as absorption, half-life, dose, toxicity, etc. It is part of the ordinary skill of one of ordinary skill in the art to determine the pharmacologic effective amount of a given pharmacologic active ingredient. EXAMPLES

[0096] The following abbreviations used in the examples have the following meanings: Boc (tert-butoxycarbonyl), BocOSu (N-tert-butoxycarbonyloxy-succinimide) 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).

[0097] Chemical Examples The following examples are intended to illustrate the present invention with selected compounds, without limiting the scope of protection of the intellectual property right to these specific examples. It is obvious to those skilled in the art that similar compounds and compounds prepared according to similar synthetic methods are included in the scope of protection of the intellectual property right.

[0098] Example III. Synthesis Method III Scheme III-1 [ka]

[0099] 1. Preparation of compound ZED1657 [ka] 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%) was 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] +

[0100] 2. Preparation of compound ZED3905 [ka] 17.0 g (85.8 mmol) of ZED1657, 16.1 g (1 eq.) of 2-adamantanamine hydrochloride and 11.6 g (1 eq.) of HOBt were dissolved in 200 mL of DMF and 17.9 mL (1.2 eq.) of DIPEA. 18.1 g (1.1 eq.) of 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride was added and the reaction was stirred at room temperature overnight. The solvent was evaporated and the residue was dissolved in 500 mL of DCM. The solution was diluted with 200 mL of citric acid solution (10%), NaHCO 3 The organic phase was washed with NaCl solution (10%) and brine. 2 SO 4 It was dried at 40° C., filtered and the solvent was evaporated. Yield: 24.1g, 85% ESI-MS: 332.4 [M+H] +

[0101] 3 Preparation of compound ZED3906 [ka] 24.2 g (73.0 mmol) of ZED3905 was suspended in 600 mL of MeOH, followed by the addition of 2.42 g of palladium (10%) on activated carbon (non-reduced). The suspension was stirred overnight at room temperature under a hydrogen atmosphere. The catalyst was filtered and the solvent was evaporated. Yield: 15.7g, 71% ESI-MS: 302.4 [M+H] +

[0102] Scheme III-2 [ka]

[0103] Scheme III-3 [ka]

[0104] Preparation of compound ZED788 [ka] 12.0 g of Boc-L-Glu-OtBu (39.6 mmol) and 7.09 g of cesium carbonate (21.8 mmol, 0.55 equiv.) 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 diluted with citric acid solution (10%), NaHCO 3 The organic phase was washed twice with NaCl solution (10%) and brine. 2 SO 4 It was dried at 40° C., filtered and the solvent was evaporated, the product was used as is without further purification. Yield: 13.4g, >100% ESI-MS: 318.3 [M+H] +

[0105] Preparation of compound ZED720 [ka] 13.4 g of ZED788 (approximately 39.6 mmol) and 986 mg of N,N-dimethyl-4-aminopyridine (DMAP) were dissolved in 30 ml of acetonitrile. 17.6 g of di-tert-butyl bicarbonate (77.1 mmol) in 100 ml of acetonitrile were added and the solution was stirred at room temperature overnight. The solvent was evaporated and the residue was dissolved in ethyl acetate and diluted with citric acid solution (10%), NaHCO 3 The organic phase was washed twice with NaCl solution (10%) and brine. 2 SO 4 It was dried at 40° C., filtered and the solvent was evaporated, the product was used as is without further purification. Yield: 13.7g, 83% ESI-MS: 418.3 [M+H] +

[0106] Preparation of compound ZED721 [ka] 13.7 g of ZED720 (32.8 mmol) was dissolved in 200 ml of anhydrous diethyl ether and cooled to -78°C under an argon atmosphere. 36.1 ml of diisobutylaluminum hydride (1M in hexane) was added dropwise and the solution was stirred at -78°C for 30 min before being quenched with potassium sodium tartrate (Rochelle's salt) solution. The organic layer was separated and the Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to dryness. The product was used as is without further purification. Yield: 13.3g, >100% ESI-MS: 388.3 [M+H] +

[0107] Preparation of compound ZED755 [ka] 13.3 g of ZED721 (approximately 32.8 mmol) was dissolved in 60 ml of benzene and 11.2 g of (carbomethoxymethylene)triphenylphosphorane (1 eq.) was added in portions. After stirring overnight, the solvent was evaporated. The residue was purified by flash chromatography. Yield: 12.0g, 83% ESI-MS: 444.3 [M+H] +

[0108] Preparation of compound Ib [ka] 12.0 g of ZED755 (27.1 mmol) was dissolved in 100 ml of DCM / TFA (1:1) and stirred at room temperature for 1 h. The solvent was evaporated and the residue was dissolved in 100 ml of DMF and 9.23 ml of DIPEA (2 eq.). 7.15 g of N-(tert-butoxycarbonyloxy)succinimide was added and the reaction 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%) and brine respectively. The organic phase was washed with Na 2 SO4 It was dried at 40° C., filtered and the solvent was evaporated, and the residue was purified by flash chromatography. Yield: 5.89g, 76% ESI-MS: 288.3 [M+H] +

[0109] 4. Preparation of compound ZED4198 [ka] 1.67 g (5.80 mmol) of (S,E)-2-(tert-butoxycarbonylamino)-7-methoxy-7-oxohept-5-enoic acid (Ib), 2.21 g (1 eq.) HATU and 1.75 g (1 eq.) ZED3906 were dissolved in 25 mL of DMF and 1.97 mL of DIPEA (2 eq.) and stirred overnight at 45° C. The solvent was evaporated and the residue was dissolved in 100 mL of EtOAc and 30 mL of a solution of citric acid (10%), NaHCO 3 The organic phase was washed twice with NaCl solution (10%) and brine. 2 SO 4 It was dried at 40° C., filtered and the solvent was evaporated. Yield: 1.65g, 50% ESI-MS: 571.4 [M+H] +

[0110] 5. Preparation of Compound III-1 [ka] 200 mg (0.35 mmol) of ZED4198 was dissolved in 6 ml of DCM / TFA (1:1) and stirred at room temperature for 1 h. The solvent was evaporated and the residue was dissolved in 9 ml of DMF. 44.2 mg (1 eq.) of 1-methyl-1H-imidazole-5-carboxylic acid, 133 mg (1 eq.) of HATU and 119 μl (2 eq.) of DIPEA were added and the reaction was stirred at room temperature overnight. The solvent was evaporated and the residue was purified by HPLC. Yield: 165mg, 81% ESI-MS: 579.4 [M+H] + 1 H-NMR (DMSO-D6, 500 MHz, δ [ppm]: 1.50 / / 2.00 (d / / d, 2H / / 2H, adamantyl-C4-H 2 ), 1.70 / / 1.80 (m, 4H, adamantyl-C4-H 2 ), 1.78 (m, 2H, adamantyl-C1-H), 1.78 (m, 2H, adamantyl-C6-H 2 ), 1.80 (m, 2H, adamantyl-C5-H), 1.90 / / 2.03 (m / / m, 1H / / 1H, β-CH 2 ), 2.32 (m, 2H, γ-CH 2 ), 3.62 (s, 3H, O-CH 3 ), 3.79 (s, 3H, imidazole-N-CH 3 ), 3.83 (m, 1H, adamantyl-C2-H), 4.58 (ddd, 1H, α-CH 2 ), 4.66 (s, 2H, N-CH 2 ), 5.85 (m, 1H, =CH-), 6.25 (t, 1H, pyridinone-C5-H), 6.92 (m, 1H, =CH-), 7.33 (d, 1H, pyridinone-C6-H), 7.72 (s, 1H, imidazole-CH), 7.77 (s, 1H, imidazole-CH), 8.09 (d, 1H, adamantyl-NH), 8.21 (d, 1H, pyridinone-C4-H), 8.61 (d, 1H, α-NH), 9.25 (s, 1H, pyridinone-NH). 13 C-NMR (DMSO-D6, 500 MHz, δ [ppm]: 26.70 / / 26.64 (Adamantyl-C5-H), 28.44 (γ-CH 2 ), 29.10 (β-CH 2 ), 30.92 (adamantyl-C4-H 2 ), 31.44 (adamantyl-C1-H), 33.46 (imidazole-N-CH 3 ), 36.74 (adamantyl-C4'-H 2), 37.09 (adamantyl-C6-H 2 ), 51.14 (O-CH 3 ), 51.62 (N-CH 2 ), 53.07 (α-CH 2 ), 53.32 (adamantyl-C2-H), 104.59 (pyridinone-C5-H), 121.04 (=CH-), 122.30 (pyridinone-C4-H), 125.06 (imidazole-Cq), 127.90 (pyridinone-N-Cq), 132.78 (imidazole-CH), 133.26 (pyridinone-C6-H), 142.18 (imidazole-CH), 148.54 (=CH-), 156.60 (pyridinone-C=O), 160.24 (imidazole-C=O), 165.71 (C=O-adamantyl amide), 165.98 (Cq methyl ester), 170.69 (C=O-NH-pyridinone).

[0111] 6 Preparation of Compound III-2 [ka] The synthesis of compound III-2 was carried out according to compound III-1, using 3-methylbenzo[b]furan-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 101 mg, 75% (final step) ESI-MS: 629.4 [M+H] +

[0112] 7 Preparation of Compound III-3 [ka] The synthesis of compound III-3 was carried out according to compound III-1 using 3-chlorobenzofuran-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 214 mg, 82% (final step) ESI-MS: 649.3 / 651.3 [M+H] +

[0113] 8. Preparation of Compound III-4 [ka] The synthesis of compound III-4 was carried out according to compound III-1 using 4-bromo-1-benzofuran-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 104 mg, 76% (final step) ESI-MS: 693.3 / 695.3 [M+H] +

[0114] 9. Preparation of Compound III-5 [ka] The synthesis of compound III-5 was carried out according to compound III-1 using benzo[b]thiophene-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 356 mg, 85% (final step) ESI-MS: 631.3 [M+H] +

[0115] 10 Preparation of Compound III-6 [ka] The synthesis of compound III-6 was carried out according to compound III-1 using 5-bromobenzo[b]thiophene-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 102 mg, 70% (final step) ESI-MS: 709.2 / 711.2 [M+H] +

[0116] 11 Preparation of Compound III-7 [ka] The synthesis of compound III-7 was carried out according to compound III-1 using 7-fluorobenzo[b]thiophene-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 56 mg, 68% (final step) ESI-MS: 649.3 [M+H] +

[0117] 12 Preparation of compound III-8 [ka] The synthesis of compound III-8 was carried out according to compound III-1 using 1H-indole-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 79 mg, 76% (final step) ESI-MS: 614.4 [M+H] +

[0118] 13 Preparation of Compound III-9 [ka] The synthesis of compound III-9 was carried out according to compound III-1 using 4,5-difluoro-1H-indole-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 43 mg, 76% (final step) ESI-MS: 650.3 [M+H] +

[0119] 14 Preparation of Compound III-10 [ka] The synthesis of compound III-10 was carried out according to compound III-1 using 3-methyl-1H-indole-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 73 mg, 82% (final step) ESI-MS: 628.4 [M+H] +

[0120] 15 Preparation of Compound III-11 [ka] The synthesis of compound III-11 was carried out according to compound III-1 using 1H-benzo[d]imidazole-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 22 mg, 41% (final step) ESI-MS: 615.4 [M+H] +

[0121] 16 Preparation of Compound III-12 [ka] The synthesis of compound III-12 was carried out according to compound III-1 using 2,3-dihydro-1H-indene-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 51 mg, 75% (final step) ESI-MS: 615.4 [M+H] +

[0122] 17 Preparation of Compound III-13 [ka] The synthesis of compound III-13 was carried out according to compound III-1 using 2,5-dichlorothiophene-3-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 78 mg, 71% (final step) ESI-MS: 649.3 / 651.3 [M+H] +

[0123] 18 Preparation of Compound III-14 [ka] The synthesis of compound III-14 was carried out according to compound III-1 using 4-methyl-2-(trifluoromethyl)thiazole-5-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 52 mg, 67% (final step) ESI-MS: 664.4 [M+H] +

[0124] 19 Preparation of Compound III-15 [ka] The synthesis of compound III-15 was carried out according to compound III-1 using 3,5-dibromothiophene-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 143 mg, 86% (final step) ESI-MS: 737.2 / 739.2 / 741.2 [M+H] +

[0125] 20 Preparation of Compound III-16 [ka] The synthesis of compound III-16 was carried out according to compound III-1 using 2,5-dibromothiophene-3-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 107 mg, 65% (final step) ESI-MS: 737.2 / 739.2 / 741.2 [M+H] +

[0126] 21 Preparation of Compound III-17 [ka] The synthesis of compound III-17 was carried out according to compound III-1 using 5-bromothiophene-3-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 89 mg, 80% (final step) ESI-MS: 659.2 / 661.2 [M+H] +

[0127] 22 Preparation of Compound III-18 [ka] The synthesis of compound III-18 was carried out according to compound III-1 using 4-bromothiophene-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 143 mg, 76% (final step) ESI-MS: 659.2 / 661.2 [M+H] +

[0128] 23 Preparation of Compound III-19 [ka] The synthesis of compound III-19 was carried out according to compound III-1 using 4,5-dibromothiophene-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 57 mg, 64% (final step) ESI-MS: 737.2 / 739.2 / 741.2 [M+H] +

[0129] 24 Preparation of Compound III-20 [ka] The synthesis of compound III-20 was carried out according to compound III-1 using 4,5-dichlorothiophene-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 78 mg, 73% (final step) ESI-MS: 649.3 / 651.3 [M+H] +

[0130] 25 Preparation of Compound III-21 [ka] The synthesis of compound III-21 was carried out according to compound III-1 using (S)-1-acetylpyrrolidine-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 114 mg, 86% (final step) ESI-MS: 610.4 [M+H] +

[0131] 26 Preparation of Compound III-22 [ka] The synthesis of compound III-22 was carried out according to compound III-1 using 1-methyl-1H-1,2,3-triazole-5-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 45 mg, 59% (final step) ESI-MS: 580.4 [M+H] +

[0132] 27 Preparation of Compound III-23 [ka] The synthesis of compound III-23 was carried out according to compound III-1 using 2H-tetrazole-5-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 42 mg, 57% (final step) ESI-MS: 567.4 [M+H] +

[0133] 28 Preparation of Compound III-24 [ka] The synthesis of compound III-24 was carried out according to compound III-1 using pyrazine-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 54 mg, 68% (final step) ESI-MS: 577.3 [M+H] +

[0134] 29 Preparation of Compound III-25 [ka] The synthesis of compound III-25 was carried out according to compound III-1 using (S)-1-methylpyrrolidine-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 85 mg, 79% (final step) ESI-MS: 582.4 [M+H] +

[0135] 30 Preparation of Compound III-26 [ka] The synthesis of compound III-26 was carried out according to compound III-1, using (S)-1-Boc-pyrrolidine-3-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid. The final product was obtained by deprotection (DCM / TFA) as described above and purified by HPLC. Yield: 78 mg, 93% (final step) ESI-MS: 568.4 [M+H] +

[0136] 31 Preparation of Compound III-27 [ka] The synthesis of compound III-27 was carried out according to compound III-1, using (2S,4S)-1-Boc-4-bromopyrrolidine-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid. The final product was obtained by deprotection (DCM / TFA) as described above and purified by HPLC. Yield: 56 mg, 89% (final step) ESI-MS: 646.3 / 648.3 [M+H] +

[0137] 32 Preparation of Compound III-28 [ka] The synthesis of compound III-28 was carried out according to compound III-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 described above and purified by HPLC. Yield: 45 mg, 86% (final step) ESI-MS: 565.3 [M+H] +

[0138] 33 Preparation of Compound III-29 [ka] The synthesis of compound III-29 was carried out according to compound III-1, using (S)-1-Boc-piperidine-2-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid. The final product was obtained by deprotection (DCM / TFA) as described above and purified by HPLC. Yield: 108 mg, 94% (final step) ESI-MS: 582.4 [M+H] +

[0139] 34 Preparation of Compound III-30 [ka] The synthesis of compound III-30 was carried out according to compound III-1, using (R)-1-Boc-piperidine-3-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid. The final product was obtained by deprotection (DCM / TFA) as described above and purified by HPLC. Yield: 68 mg, 87% (final step) ESI-MS: 582.4 [M+H] +

[0140] 35 Preparation of Compound III-31 [ka] The synthesis of compound III-31 was carried out according to compound III-1, using (R)-4-Boc-morpholine-3-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid. The final product was obtained by deprotection (DCM / TFA) as described above and purified by HPLC. Yield: 73 mg, 90% (final step) ESI-MS: 584.4 [M+H] +

[0141] 36 Preparation of Compound III-32 [ka] The synthesis of compound III-32 was carried out according to compound III-1 using quinuclidine-3-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 23 mg, 71% (final step) ESI-MS: 608.4 [M+H] +

[0142] 37 Preparation of Compound III-33 [ka] The synthesis of compound III-33 was carried out according to compound III-1 using mono-methyl 5-nitroisophthalate instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 68 mg, 86% (final step) ESI-MS: 678.3 [M+H] +

[0143] 38 Preparation of Compound III-34 [ka] The synthesis of compound III-34 was carried out according to compound III-1 using 5-nitronicotinic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 54 mg, 75% (final step) ESI-MS: 621.3 [M+H] +

[0144] 39 Preparation of Compound III-35 [ka] The synthesis of compound III-35 was carried out according to compound III-1 using 3,5-pyridinedicarboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 28 mg, 63% (final step) ESI-MS: 620.3 [M+H] +

[0145] 40 Preparation of Compound III-36 [ka] The synthesis of compound III-36 was carried out according to compound III-1 using 5-(methoxycarbonyl)nicotinic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 48 mg, 77% (final step) ESI-MS: 634.3 [M+H] +

[0146] 41 Preparation of Compound III-37 [ka] The synthesis of compound III-37 was carried out according to compound III-2 using N-methyl-2-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 42 mg, 47% (final step) ESI-MS: 643.4 [M+H] +

[0147] 42 Preparation of Compound III-38 [ka] The synthesis of compound III-38 was carried out according to compound III-2, using 5-hydroxy-2-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 35 mg, 24% (final step) ESI-MS: 645.4 [M+H] +

[0148] 43 Preparation of Compound III-39 [ka] The synthesis of compound III-39 was carried out according to compound III-2 using 5-fluoro-2-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 64 mg, 68% (final step) ESI-MS: 647.4 [M+H] +

[0149] 44 Preparation of Compound III-40 [ka] The synthesis of compound III-40 was carried out according to compound III-2 using 5-chloro-2-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 32 mg, 27% (final step) ESI-MS: 663.3 / 665.3 [M+H] +

[0150] 45 Preparation of Compound III-41 [ka] The synthesis of compound III-41 was carried out according to compound III-2 using 5-bromo-2-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 41 mg, 57% (final step) ESI-MS: 707.3 / 709.3 [M+H] +

[0151] 46 Preparation of Compound III-42 [ka] The synthesis of compound III-42 was carried out according to compound III-2, using 5-methyl-2-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 51 mg, 47% (final step) ESI-MS: 643.4 [M+H] +

[0152] 47 Preparation of Compound III-43 [ka] The synthesis of compound III-43 was carried out according to compound III-2 using 2-aminoadamantane-2-carbonitrile instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 36 mg, 52% (final step) ESI-MS: 654.4 [M+H] +

[0153] 48 Preparation of Compound III-44 [ka] The synthesis of compound III-44 was carried out according to compound III-2 using 2-methyl 2-aminoadamantane-2-carboxylate instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 49 mg, 68% (final step) ESI-MS: 687.4 [M+H] +

[0154] 49 Preparation of Compound III-45 [ka] The synthesis of compound III-45 was carried out according to compound III-2 using 1-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 214 mg, 77% (final step) ESI-MS: 629.4 [M+H] +

[0155] 50 Preparation of Compound III-46 [ka] The synthesis of compound III-46 was carried out according to compound III-2 using 3,5-dimethyl-1-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 67 mg, 77% (final step) ESI-MS: 657.4 [M+H] +

[0156] 51 Preparation of Compound III-47 [ka] The synthesis of compound III-47 was carried out according to compound III-2, using N-methyl-1-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 36 mg, 41% (final step) ESI-MS: 643.4 [M+H] +

[0157] 52 Preparation of Compound III-48 [ka] The synthesis of compound III-48 was carried out according to compound III-2, using 3-ethyl-1-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 78 mg, 54% (final step) ESI-MS: 657.4 [M+H] +

[0158] 53 Preparation of Compound III-49 [ka] The synthesis of compound III-49 was carried out according to compound III-2, using 3-trifluoromethyl-1-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 29 mg, 45% (final step) ESI-MS: 697.4 [M+H] +

[0159] 54 Preparation of Compound III-50 [ka] The synthesis of compound III-50 was carried out according to compound III-2, using 3-hydroxy-1-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 23 mg, 37% (final step) ESI-MS: 645.4 [M+H] +

[0160] 55 Preparation of Compound III-51 [ka] The synthesis of compound III-51 was carried out according to compound III-2 using 3-fluoro-1-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 56 mg, 62% (final step) ESI-MS: 647.4 [M+H] +

[0161] 56 Preparation of Compound III-52 [ka] The synthesis of compound III-52 was carried out according to compound III-2 using 3-chloro-1-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 24 mg, 32% (final step) ESI-MS: 663.3 / 665.3 [M+H] +

[0162] 57 Preparation of Compound III-53 [ka] The synthesis of compound III-53 was carried out according to compound III-2, using 3-bromo-1-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 25 mg, 42% (final step) ESI-MS: 707.3 / 709.3 [M+H] +

[0163] 58 Preparation of Compound III-54 [ka] The synthesis of compound III-54 was carried out according to compound III-2 using methyl 3-aminoadamantane-1-carboxylate instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 38 mg, 52% (final step) ESI-MS: 687.4 [M+H] +

[0164] 59 Preparation of Compound III-55 [ka] The synthesis of compound III-55 was carried out according to compound III-2 using 4,4-difluoro-1-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 11 mg, 36% (final step) ESI-MS: 665.4 [M+H] +

[0165] 60 Preparation of Compound III-56 [ka] The synthesis of compound III-56 was carried out according to compound III-2 using 1-adamantanemethylamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 47 mg, 68% (final step) ESI-MS: 643.4 [M+H] +

[0166] 61 Preparation of Compound III-57 [ka]

[0167] The synthesis of compound III-57 was carried out according to compound III-2, using 1-rimantadine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 23 mg, 35% (final step) ESI-MS: 657.5 [M+H] +

[0168] 62 Preparation of Compound III-58 [ka] The synthesis of compound III-58 was carried out according to compound III-1 using (±)-endo-2-norbornylamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 36 mg, 53% (final step) ESI-MS: 539.4 [M+H] +

[0169] 63 Preparation of Compound III-59 [ka] The synthesis of compound III-59 was carried out according to compound III-2 using (±)-endo-2-norbornylamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 56 mg, 69% (final step) ESI-MS: 589.4 [M+H] +

[0170] 64 Preparation of Compound III-60 [ka] The synthesis of compound III-60 was carried out according to compound III-1 using (R)-(+)-bornylamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 25 mg, 49% (final step) ESI-MS: 581.5 [M+H] +

[0171] 65 Preparation of Compound III-61 [ka] The synthesis of compound III-61 was carried out according to compound III-2 using (R)-(+)-bornylamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 42 mg, 63% (final step) ESI-MS: 631.5 [M+H] +

[0172] 66 Preparation of Compound III-62 [ka] The synthesis of compound III-62 was carried out according to compound III-1 using exo-2-aminonorbornane instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 56 mg, 64% (final step) ESI-MS: 539.4 [M+H] +

[0173] 67 Preparation of Compound III-63 [ka] The synthesis of compound III-63 was carried out according to compound III-2 using exo-2-aminonorbornane instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 78 mg, 71% (final step) ESI-MS: 589.4 [M+H] +

[0174] 68 Preparation of Compound III-64 [ka] The synthesis of compound III-64 was carried out according to compound III-2 using bicyclo[2.2.1]heptan-1-ylamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 27 mg, 52% (final step) ESI-MS: 589.4 [M+H] +

[0175] 69 Preparation of Compound III-65 [ka] The synthesis of compound III-65 was carried out according to compound III-2 using bicyclo[2.2.1]heptan-7-ylamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 52 mg, 75% (final step) ESI-MS: 589.4 [M+H] +

[0176] 70 Preparation of Compound III-66 [ka] The synthesis of compound III-66 was carried out according to compound III-2 using bicyclo[2.2.1]hept-5-en-2-amine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 36 mg, 54% (final step) ESI-MS: 587.4 [M+H] +

[0177] 71 Preparation of Compound III-67 [ka] The synthesis of compound III-67 was carried out according to compound III-2 using bicyclo[2.2.2]oct-2-ylamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 42 mg, 51% (final step) ESI-MS: 603.4 [M+H] +

[0178] 72 Preparation of Compound III-68 [ka] The synthesis of compound III-68 was carried out according to compound III-2 using (R)-(-)-isobornylamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 26 mg, 56% (final step) ESI-MS: 631.5 [M+H] +

[0179] 73 Preparation of Compound III-69 [ka] The synthesis of compound III-69 was carried out according to compound III-2 using (1R,2R,3R,5S)-(-)-isopinocampheylamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 15 mg, 48% (final step) ESI-MS: 631.5 [M+H] +

[0180] 74 Preparation of Compound III-70 [ka] The synthesis of compound III-70 was carried out according to compound III-2 using (1S,2S,3S,5R)-(+)-isopinocampheylamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 21 mg, 58% (final step) ESI-MS: 631.5 [M+H] +

[0181] 75 Preparation of Compound III-71 [ka] The synthesis of compound III-71 was carried out according to compound III-2 using (-)-cis-myrtanylamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 12 mg, 45% (final step) ESI-MS: 631.5 [M+H] +

[0182] 76 Preparation of Compound III-72 [ka] The synthesis of compound III-72 was carried out according to compound III-2, using 3-amino-4-homoisotwistane instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 23 mg, 59% (final step) ESI-MS: 643.5 [M+H] +

[0183] 77 Preparation of Compound III-73 [ka] The synthesis of compound III-73 was carried out according to compound III-2 using 1-aminodiamantane instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 26 mg, 62% (final step) ESI-MS: 681.5 [M+H] +

[0184] 78 Preparation of Compound III-74 [ka] The synthesis of compound III-74 was carried out according to compound III-2 using 4-aminodiamantane instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 17 mg, 53% (final step) ESI-MS: 681.5 [M+H] +

[0185] Scheme III-4 [ka]

[0186] 79 Preparation of ZED4684 [ka] 2.5 mL (24.3 mmol) of 2-chloro-N,N-dimethylacetamide and 4.2 mL (1 eq.) of triethyl phosphite were stirred for 8 h at 160° C. The mixture was purified by HPLC. Yield: 2.50g, 46% ESI-MS: 224.4 [M+H] +

[0187] 80 Preparation of ZED4688 [ka] 500 mg (2.24 mmol) of ZED4684 was dissolved in 16 mL of THF. At 0° C., 251 mg (2.24 mmol) of potassium tert-butoxide was added. After 30 min, 723 mg (1.87 mmol) of the aldehyde (S)-2-(bis(tert-butoxycarbonyl)amino)-5-oxopentanoate tert-butyl (ZED721) in 16 mL of THF was added and the mixture was stirred at 0° C. for 1.5 h before being quenched with water (16 mL, 0° C.). After extraction with EtOAc (2×32 mL), the combined organic phase was washed with brine (15 mL) and diluted with Na 2 SO 4 It was dried at 40° C., filtered and the solvent was evaporated, and the residue was purified by HPLC. Yield: 659 mg, 77% ESI-MS: 457.5 [M+H] +

[0188] 81 Preparation of ZED4690 [ka] 659 mg of ZED4688 (1.44 mmol) was dissolved in 20 ml of DCM / TFA (1:1) and stirred at room temperature for 1 h. The solvent was evaporated and the residue was dissolved in 10 ml of DMF and 245 μl of DIPEA (2 eq.). 310 mg (1 eq.) of N-(tert-butoxycarbonyloxy)succinimide was added and the reaction 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%) and with brine respectively. The organic phase was washed with Na2 SO 4 It was dried at 40° C., filtered and the solvent was evaporated, and the residue was purified by HPLC. Yield: 242mg, 56% ESI-MS: 301.5 [M+H] +

[0189] 82 Preparation of ZED4692 [ka] 242 mg (0.81 mmol) of ZED4688, 308 mg (1 eq.) of HATU and 244 mg (1 eq.) of ZED3906 were dissolved in 10 mL of DMF and 276 μL of DIPEA (2 eq.) and stirred overnight at 45° C. The solvent was evaporated and the residue was dissolved in 50 mL of EtOAc and diluted with 15 mL of citric acid solution (10%), NaHCO 3 The organic phase was washed twice with NaCl solution (10%) and brine. 2 SO 4 It was dried at 40° C., filtered and the solvent was evaporated, and the residue was purified by HPLC. Yield: 288mg, 61% ESI-MS: 584.4 [M+H] +

[0190] 83 Preparation of Compound III-75 [ka] 100 mg (0.17 mmol) of ZED4692 was dissolved in 6 ml of DCM / TFA (1:1) and stirred at room temperature for 1 h. The solvent was evaporated and the residue was dissolved in 15 ml of DMF and 58 μl of DIPEA (2 eq.). 30 mg (1 eq.) of 3-methylbenzo[b]furan-2-carboxylic acid and 65 mg (1 eq.) of HATU were added and the reaction was stirred at room temperature overnight. The solvent was evaporated and the residue was purified by HPLC. Yield: 78 mg, 71% ESI-MS: 642.5 [M+H] +

[0191] 84 Preparation of Compound III-76 [ka] The synthesis of compound III-76 was carried out according to compound III-75 using 1-methyl-1H-imidazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in the final step. Yield: 70 mg, 69% (final step) ESI-MS: 592.5 [M+H] +

[0192] 85 Preparation of Compound III-77 [ka] The synthesis of compound III-77 was carried out according to compound III-75 using 3,5-dimethyl-1-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 45 mg, 57% (final step) ESI-MS: 670.5 [M+H] +

[0193] Scheme III-5 New Building Blocks [ka]

[0194] 86 Preparation of compound ZED4893 [ka] 500 mg (3.57 mmol) of 2-hydroxy-3-nitropyridine and 818 mg (1 eq.) of 1-(bromomethyl)adamantane were dissolved in 10 mL of DMF and 1.24 mL of DIPEA (2 eq.) and stirred at room temperature overnight. The solvent was evaporated and the residue was dissolved in 30 mL of EtOAc and 10 mL of a solution of citric acid (10%), NaHCO 3 The organic phase was washed twice with NaCl solution (10%) and brine. 2SO 4 It was dried at 40° C., filtered and the solvent was evaporated, and the residue was purified by HPLC. Yield: 484mg, 47% ESI-MS: 289.3 [M+H] +

[0195] 87 Preparation of compound ZED4894 [ka] 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 (non-reduced). 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] +

[0196] 88 Preparation of Compound III-78 [ka] The synthesis of compound III-78 was carried out according to compound III-1 using ZED4894 instead of ZED3906 in step 5 (according to ZED3907). Yield: 43 mg, 59% (final step) ESI-MS: 536.4 [M+H] +

[0197] 89 Preparation of Compound III-79 [ka] The synthesis of compound III-79 was carried out according to compound III-2 using ZED4894 instead of ZED3906 in step 5 (according to ZED3907). Yield: 56 mg, 69% (final step) ESI-MS: 586.4 [M+H] +

[0198] 90 Preparation of Compound III-80 [ka] The synthesis of compound III-80 was carried out according to compound III-79, using 3-(bromomethyl)-1-adamantanol instead of 1-(bromomethyl)adamantane (according to ZED4893). Yield: 29 mg, 51% (final step) ESI-MS: 602.4 [M+H] +

[0199] 91 Preparation of Compound III-81 [ka] The synthesis of compound III-81 was carried out according to compound III-79, using 1-bromo-3-(bromomethyl)adamantane instead of 1-(bromomethyl)adamantane (according to ZED4893). Yield: 37 mg, 61% (final step) ESI-MS: 664.3 / 666.3 [M+H] +

[0200] 92 Preparation of Compound III-82 [ka] The synthesis of compound III-82 was carried out according to compound III-79 using 2-(bromomethyl)adamantane instead of 1-(bromomethyl)adamantane (according to ZED4893). Yield: 58 mg, 77% (final step) ESI-MS: 586.4 [M+H] +

[0201] 93 Preparation of Compound III-83 [ka] The synthesis of compound III-83 was carried out according to compound III-1 using nicotinic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in the final step. Yield: 59 mg, 79% (final step) ESI-MS: 576.4 [M+H] +

[0202] 94 Preparation of Compound III-84 [ka] The synthesis of compound III-84 was carried out according to compound III-1 using isonicotinic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in the final step. Yield: 73 mg, 85% (final step) ESI-MS: 576.4 [M+H] +

[0203] 95 Preparation of Compound III-85 [ka] The synthesis of compound III-85 was carried out according to compound III-1 using pyridazine-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in the final step. Yield: 54 mg, 78% (final step) ESI-MS: 577.4 [M+H] +

[0204] 96 Preparation of Compound III-86 [ka] The synthesis of compound III-86 was carried out according to compound III-1 using pyridazine-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in the final step. Yield: 47 mg, 82% (final step) ESI-MS: 577.4 [M+H]+

[0205] 97 Preparation of Compound III-87 [ka] The synthesis of compound III-87 was carried out according to compound III-1 using 1-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 117 mg, 78% (final step) ESI-MS: 579.5 [M+H] +

[0206] 98 Preparation of Compound III-88 [ka] The synthesis of compound III-88 was carried out according to compound III-1 using 3,5-dimethyl-1-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 132 mg, 83% (final step) ESI-MS: 607.5 [M+H] +

[0207] 99 Preparation of Compound III-89 [ka] The synthesis of compound III-89 was carried out according to compound III-2, using (carboethoxyethylidene)triphenylphosphorane instead of (carbomethoxymethylene)triphenylphosphorane (according to ZED755). Yield: 57 mg, 85% (final step) ESI-MS: 643.5 [M+H] +

[0208] 100 Preparation of Compound III-90 [ka] The synthesis of compound III-90 was carried out according to compound III-2 using diethyl (methanesulfonylmethyl)phosphonate instead of (carbomethoxymethylene)triphenylphosphorane (according to ZED755). Yield: 79 mg, 72% (final step) ESI-MS: 649.4 [M+H] +

[0209] 101 Preparation of Compound III-91 [ka] The synthesis of compound III-91 was carried out according to compound III-1, using 3,5,7-trimethyl-1-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 41 mg, 69% (final step) ESI-MS: 621.5 [M+H] +

[0210] 102 Preparation of Compound III-92 [ka] The synthesis of compound III-92 was carried out according to compound III-2, using 3,5,7-trimethyl-1-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 67 mg, 75% (final step) ESI-MS: 671.5 [M+H] +

[0211] 103 Preparation of Compound III-93 [ka] The synthesis of compound III-93 was carried out according to compound III-22, using 3,5,7-trimethyl-1-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 34 mg, 68% (final step) ESI-MS: 622.5 [M+H] +

[0212] 104 Preparation of Compound III-94 [ka] The synthesis of compound III-94 was carried out according to compound III-13 using 3,5,7-trimethyl-1-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 69 mg, 88% (final step) ESI-MS: 691.3 / 693.3 [M+H] +

[0213] 105 Preparation of Compound III-95 [ka] The synthesis of compound III-95 was carried out according to compound III-14 using 3,5,7-trimethyl-1-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 35 mg, 64% (final step) ESI-MS: 706.4 [M+H] +

[0214] 106 Preparation of Compound III-96 [ka] The synthesis of compound III-96 was carried out according to compound III-22 using exo-2-aminonorbornane instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 24 mg, 64% (final step) ESI-MS: 540.4 [M+H] +

[0215] 107 Preparation of Compound III-97 [ka] The synthesis of compound III-97 was carried out according to compound III-13 using exo-2-aminonorbornane instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 78 mg, 84% (final step) ESI-MS: 609.3 / 611.3 [M+H] +

[0216] 108 Preparation of Compound III-98 [ka] The synthesis of compound III-98 was carried out according to compound III-14 using exo-2-aminonorbornane instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 48 mg, 68% (final step) ESI-MS: 624.3 [M+H] +

[0217] 109 Preparation of Compound III-99 [ka] The synthesis of compound III-99 was carried out according to compound III-89 using 1-methyl-1H-imidazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in the final step. Yield: 68 mg, 79% (final step) ESI-MS: 593.5 [M+H] +

[0218] 110 Preparation of Compound III-100 [ka] The synthesis of compound III-100 was carried out according to compound III-90 using 1-methyl-1H-imidazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in the final step. Yield: 46 mg, 73% (final step) ESI-MS: 599.4 [M+H] +

[0219] 111 Preparation of Compound III-101 [ka] The synthesis of compound III-101 was carried out according to compound III-1 using 2H-1,2,3-triazole-4-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 28 mg, 63% (final step) ESI-MS: 566.4 [M+H] +

[0220] 112 Preparation of Compound III-102 [ka] The synthesis of compound III-102 was carried out according to compound III-1 using 1H-1,2,3-triazole-4-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 37 mg, 70% (final step) ESI-MS: 566.4 [M+H] +

[0221] 113 Preparation of Compound III-103 [ka] The synthesis of compound III-103 was carried out according to compound III-1 using 1-methyl-1H-1,2,3-triazole-4-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 52 mg, 76% (final step) ESI-MS: 580.4 [M+H] +

[0222] 114 Preparation of Compound III-104 [ka] The synthesis of compound III-104 was carried out according to compound III-1 using 1H-1,2,4-triazole-3-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 31 mg, 59% (final step) ESI-MS: 566.4 [M+H] +

[0223] 115 Preparation of Compound III-105 [ka] The synthesis of compound III-105 was carried out according to compound III-1 using 1-methyl-1H-1,2,4-triazole-3-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 42 mg, 72% (final step) ESI-MS: 580.4 [M+H] +

[0224] 116 Preparation of Compound III-106 [ka] The synthesis of compound III-106 was carried out according to compound III-1 using benzofuran-3-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 56 mg, 77% (final step) ESI-MS: 615.4 [M+H] +

[0225] 117 Preparation of Compound III-107 [ka] The synthesis of compound III-107 was carried out according to compound III-1 using benzo[b]thiophene-3-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 61 mg, 82% (final step) ESI-MS: 631.4 [M+H] +

[0226] 118 Preparation of Compound III-108 [ka] The synthesis of compound III-108 was carried out according to compound III-91 using 4-methyl-1,2,3-thiadiazole-5-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 25 mg, 43% (final step) ESI-MS: 639.4 [M+H] +

[0227] 119 Preparation of Compound III-109 [ka] The synthesis of compound III-109 was carried out according to compound III-91 using 1-methyl-1H-pyrazole-5-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 39 mg, 62% (final step) ESI-MS: 621.5 [M+H] +

[0228] 120 Preparation of Compound III-110 [ka] The synthesis of compound III-110 was carried out according to compound III-62 using 4-methyl-1,2,3-thiadiazole-5-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 19 mg, 36% (final step) ESI-MS: 557.4 [M+H] +

[0229] 121 Preparation of Compound III-111 [ka] The synthesis of compound III-111 was carried out according to compound III-62 using 1-methyl-1H-pyrazole-5-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 32 mg, 69% (final step) ESI-MS: 539.4 [M+H] +

[0230] 122 Preparation of Compound III-112 [ka] The synthesis of compound III-112 was carried out according to compound III-46 using 4-methyl-1,2,3-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in the final step. Yield: 24 mg, 43% (final step) ESI-MS: 625.4 [M+H] +

[0231] 123 Preparation of Compound III-113 [ka] The synthesis of compound III-113 was carried out according to compound III-46 using 1-methyl-1H-pyrazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in the final step. Yield: 31 mg, 56% (final step) ESI-MS: 607.5 [M+H] +

[0232] 124 Preparation of Compound III-114 [ka] The synthesis of compound III-114 was carried out according to compound III-46 using 1-methyl-1H-1,2,3-triazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in the final step. Yield: 14 mg, 42% (final step) ESI-MS: 608.5 [M+H] +

[0233] 125 Preparation of Compound III-115 [ka] The synthesis of compound III-115 was carried out according to compound III-58 using 4-methyl-1,2,3-thiadiazole-5-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 26 mg, 48% (final step) ESI-MS: 557.4 [M+H] +

[0234] 126 Preparation of Compound III-116 [ka] The synthesis of compound III-116 was carried out according to compound III-58 using 1-methyl-1H-1,2,3-triazole-5-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 20 mg, 39% (final step) ESI-MS: 540.4 [M+H] +

[0235] 127 Preparation of Compound III-117 [ka] The synthesis of compound III-117 was carried out according to compound III-58 using 1-methyl-1H-pyrazole-5-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 23 mg, 53% (final step) ESI-MS: 539.4 [M+H] +

[0236] 128 Preparation of Compound III-118 [ka] The synthesis of compound III-118 was carried out according to compound III-1 using 4-methyl-1,2,3-thiadiazole-5-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 31 mg, 49% (final step) ESI-MS: 597.4 [M+H] +

[0237] 129 Preparation of Compound III-119 [ka] The synthesis of compound III-119 was carried out according to compound III-1 using 1-methyl-1H-pyrazole-5-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 39 mg, 62% (final step) ESI-MS: 579.4 [M+H] +

[0238] 130 Preparation of Compound III-120 [ka] The synthesis of compound III-120 was carried out according to compound III-60 using 4-methyl-1,2,3-thiadiazole-5-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 12 mg, 33% (final step) ESI-MS: 631.4 [M+H] +

[0239] 131 Preparation of Compound III-121 [ka] The synthesis of compound III-121 was carried out according to compound III-60 using 1-methyl-1H-1,2,3-triazole-5-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 15 mg, 29% (final step) ESI-MS: 582.5 [M+H] +

[0240] 132 Preparation of Compound III-122 [ka] The synthesis of compound III-122 was carried out according to compound III-60 using 1-methyl-1H-pyrazole-5-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 23 mg, 46% (final step) ESI-MS: 581.5 [M+H] +

[0241] 133 Preparation of Compound III-123 [ka] The synthesis of compound III-123 was carried out according to compound III-46 using 4-methyl-2-(trifluoromethyl)thiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in the final step. Yield: 35 mg, 71% (final step) ESI-MS: 692.4 [M+H] +

[0242] 134 Preparation of Compound III-124 [ka] The synthesis of compound III-124 was carried out according to compound III-46 using 2,5-dichlorothiophene-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in the final step. Yield: 52 mg, 78% (final step) ESI-MS: 677.4 / 679.4 [M+H] +

[0243] 135 Preparation of Compound III-125 [ka] The synthesis of compound III-125 was carried out according to compound III-58 using 4-methyl-2-(trifluoromethyl)thiazole-5-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 34 mg, 67% (final step) ESI-MS: 624.4 [M+H] +

[0244] 136 Preparation of Compound III-126 [ka] The synthesis of compound III-126 was carried out according to compound III-58 using 2,5-dichlorothiophene-3-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 56 mg, 74% (final step) ESI-MS: 609.3 / 611.3 [M+H] +

[0245] 137 Preparation of Compound III-127 [ka] The synthesis of compound III-127 was carried out according to compound III-60 using 4-methyl-2-(trifluoromethyl)thiazole-5-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 27 mg, 46% (final step) ESI-MS: 666.4 [M+H] +

[0246] 138 Preparation of Compound III-128 [ka] The synthesis of compound III-128 was carried out according to compound III-60 using 2,5-dichlorothiophene-3-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 76 mg, 70% (final step) ESI-MS: 651.3 / 653.3 [M+H] +

[0247] 139 Preparation of Compound III-129 [ka] The synthesis of compound III-129 was carried out according to compound III-1 using 1-methyl-1H-pyrazole-3-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 56 mg, 75% (final step) ESI-MS: 579.4 [M+H] +

[0248] 140 Preparation of Compound III-130 [ka] The synthesis of compound III-130 was carried out according to compound III-1 using 1-methyl-1H-pyrazole-4-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid in the final step. Yield: 73 mg, 78% (final step) ESI-MS: 579.4 [M+H] +

[0249] 141 Preparation of Compound III-131 [ka] The synthesis of compound III-131 was carried out according to compound III-79, using 1-(2-bromoethyl)adamantane instead of 1-(bromomethyl)adamantane in the final step (according to ZED4893) and 5-tert-butyl-1H-pyrrole-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid. Yield: 18 mg, 42% (final step) ESI-MS: 591.5 [M+H] +

[0250] 142 Preparation of Compound III-132 [ka] The synthesis of compound III-132 was carried out according to compound III-79, using 1-(3-bromopropyl)adamantane instead of 1-(bromomethyl)adamantane in the final step (according to ZED4893) and 4-cyano-1-methyl-1H-pyrrole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid. Yield: 13 mg, 36% (final step) ESI-MS: 588.5 [M+H] +

[0251] 143 Preparation of Compound III-133 [ka] The synthesis of compound III-133 was carried out according to compound III-2, using 3-chloropropionic acid instead of chloroacetic acid in the final step (according to ZED1657) and 5-methoxyoxazole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid. Yield: 46 mg, 72% (final step) ESI-MS: 610.4 [M+H] +

[0252] 144 Preparation of Compound III-134 [ka] The synthesis of compound III-134 was carried out according to compound III-2, using bicyclo[2.1.1]hexane-1-amine instead of 2-adamantanamine in step 2 (according to ZED3905) and 2-isopropyloxazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in the final step. Yield: 52 mg, 70% (final step) ESI-MS: 554.4 [M+H] +

[0253] 145 Preparation of Compound III-135 [ka] The synthesis of compound III-135 was carried out according to compound III-2, using bicyclo[3.2.1]octan-8-amine instead of 2-adamantanamine in step 2 (according to ZED3905) and 3,5-dimethylisoxazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in the final step. Yield: 41 mg, 68% (final step) ESI-MS: 568.4 [M+H] +

[0254] 146 Preparation of Compound III-136 [ka] The synthesis of compound III-136 was carried out according to compound III-2, using 4-aminoadamantane-1-carboxylic acid instead of 2-adamantanamine in step 2 (according to ZED3905) and 4-methylpyrimidine-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in the final step. Yield: 16 mg, 34% (final step) ESI-MS: 635.4 [M+H]+

[0255] 147 Preparation of Compound III-137 [ka] The synthesis of compound III-137 was carried out according to compound III-2, using 4-aminoadamantane-N,N-dimethyl-1-carboxamide instead of 2-adamantanamine in step 2 (according to ZED3905) and 1,2,3,4-tetrahydronaphthalene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in the final step. Yield: 38 mg, 53% (final step) ESI-MS: 646.5 [M+H] +

[0256] 148 Preparation of Compound III-138 [ka] The synthesis of compound III-138 was carried out according to compound III-75 using N,N-diethylchloroacetamide instead of 2-chloro-N,N-dimethylacetamide in step 2 (according to ZED4684), 1-bicyclo[1.1.1]pentylamine instead of 2-adamantanamine (according to ZED3905), and 2-acetyloxazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in the final step. Yield: 25 mg, 63% (final step) ESI-MS: 581.4 [M+H] +

[0257] 149 Preparation of Compound III-139 [ka] The synthesis of compound III-139 was carried out according to compound III-138 using 1,4-diazabicyclo[2.2.2]octane-2-carboxylic acid instead of 2-acetyloxazole-4-carboxylic acid in the final step. Yield: 16 mg, 54% (final step) ESI-MS: 582.5 [M+H] +

[0258] 150 Preparation of Compound III-140 [ka] The synthesis of compound III-140 was carried out according to compound III-75 using 2-chloro-N-isopropylacetamide instead of 2-chloro-N,N-dimethylacetamide in step 2 (according to ZED4684), 1-bicyclo[1.1.1]pentylamine instead of 2-adamantanamine (according to ZED3905), and 1H-indole-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in the final step. Yield: 36 mg, 68% (final step) ESI-MS: 573.4 [M+H] +

[0259] 151 Preparation of Compound III-141 [ka] The synthesis of compound III-141 was carried out according to compound III-140 using 6-methylimidazo[2,1-b][1,3]thiazole-3-carboxylic acid instead of 1H-indole-3-carboxylic acid in the final step. Yield: 29 mg, 54% (final step) ESI-MS: 594.4 [M+H] +

[0260] 152 Preparation of Compound III-142 [ka] The synthesis of compound III-142 was carried out according to compound III-75 using 2-chloro-N-pentylacetamide instead of 2-chloro-N,N-dimethylacetamide in step 2 (according to ZED4684), 1-bicyclo[1.1.1]pentylamine instead of 2-adamantanamine (according to ZED3905), and 1,3-benzothiazole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in the final step. Yield: 42 mg, 65% (final step) ESI-MS: 619.4 [M+H] +

[0261] 153 Preparation of Compound III-143 [ka] The synthesis of compound III-143 was carried out according to compound III-142 using imidazo[2,1-b][1,3]thiazole-6-carboxylic acid instead of 1,3-benzothiazole-2-carboxylic acid in the final step. Yield: 23 mg, 59% (final step) ESI-MS: 608.4 [M+H] +

[0262] 154 Preparation of Compound III-144 [ka] The synthesis of compound III-144 was carried out according to compound III-75 using 2-chloro-N-cyclopropylacetamide instead of 2-chloro-N,N-dimethylacetamide in step 2 (according to ZED4684), 1-bicyclo[1.1.1]pentylamine instead of 2-adamantanamine (according to ZED3905), and 4-hydroxy-6-(trifluoromethoxy)quinoline-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in the final step. Yield: 12 mg, 36% (final step) ESI-MS: 683.4 [M+H] +

[0263] 155 Preparation of Compound III-145 [ka] The synthesis of compound III-145 was carried out according to compound III-144 using 3-cinnoline carboxylic acid instead of 4-hydroxy-6-(trifluoromethoxy)quinoline-3-carboxylic acid in the final step. Yield: 32 mg, 66% (final step) ESI-MS: 584.4 [M+H] +

[0264] 156 Preparation of Compound III-146 [ka] The synthesis of compound III-146 was carried out according to compound III-75, using 2-chloro-N-cyclopentylacetamide instead of 2-chloro-N,N-dimethylacetamide in step 2 (according to ZED4684), 1-bicyclo[1.1.1]pentylamine instead of 2-adamantanamine (according to ZED3905), and 2-methyl-1,8-naphthyridine-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in the final step. Yield: 28 mg, 68% (final step) ESI-MS: 626.5 [M+H] +

[0265] 157 Preparation of Compound III-147 [ka] The synthesis of compound III-147 was carried out according to compound III-146 using 3-ethyl-1-benzofuran-2-carboxylic acid instead of 2-methyl-1,8-naphthyridine-3-carboxylic acid in the final step. Yield: 54 mg, 72% (final step) ESI-MS: 628.5 [M+H] +

[0266] 158 Preparation of Compound III-148 [ka] The synthesis of compound III-148 was carried out according to compound III-75 using 2-chloro-N-cyclohexylacetamide instead of 2-chloro-N,N-dimethylacetamide in step 2 (according to ZED4684), 1-bicyclo[1.1.1]pentylamine instead of 2-adamantanamine (according to ZED3905), and 1-ethyl-1H-indole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in the final step. Yield: 62 mg, 67% (final step) ESI-MS: 641.5 [M+H] +

[0267] 159 Preparation of Compound III-149 [ka] The synthesis of compound III-149 was carried out according to compound III-148, using N-Boc-1,2,3,4-tetrahydroquinoline-7-carboxylic acid instead of 1-ethyl-1H-indole-2-carboxylic acid in the final step. The final product was obtained by deprotection (DCM / TFA) as described above and purified by HPLC. Yield: 24 mg, 53% (final step) ESI-MS: 629.5 [M+H] +

[0268] 160 Preparation of Compound III-150 [ka] The synthesis of compound III-150 was carried out according to compound III-75 using N-allyl-2-chloroacetamide instead of 2-chloro-N,N-dimethylacetamide in step 2 (according to ZED4684), 1-bicyclo[1.1.1]pentylamine instead of 2-adamantanamine (according to ZED3905), and 1,6-naphthyridine-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in the final step. Yield: 26 mg, 52% (final step) ESI-MS: 584.4 [M+H] +

[0269] 161 Preparation of Compound III-151 [ka] The synthesis of compound III-151 was carried out according to compound III-150 using 2,6-naphthyridine-1-carboxylic acid instead of 1,6-naphthyridine-2-carboxylic acid in the final step. Yield: 29 mg, 55% (final step) ESI-MS: 584.4 [M+H] +

[0270] 162 Preparation of Compound III-152 [ka] The synthesis of compound III-152 was carried out according to compound III-75 using 2-chloro-N-phenylacetamide instead of 2-chloro-N,N-dimethylacetamide in step 2 (according to ZED4684), 1-bicyclo[1.1.1]pentylamine instead of 2-adamantanamine (according to ZED3905), and 5-bromo-2-methylfuran-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in the final step. Yield: 43 mg, 75% (final step) ESI-MS: 650.3 / 652.3 [M+H] +

[0271] 163 Preparation of Compound III-153 [ka] The synthesis of compound III-153 was carried out according to compound III-152 using 2,5-dimethylfuran-3-carboxylic acid instead of 5-bromo-2-methylfuran-3-carboxylic acid in the final step. Yield: 57 mg, 82% (final step) ESI-MS: 586.4 [M+H] +

[0272] 164 Preparation of Compound III-154 [ka] The synthesis of compound III-154 was carried out according to compound III-75 using N-benzyl-2-chloroacetamide instead of 2-chloro-N,N-dimethylacetamide in step 2 (according to ZED4684), 1-bicyclo[1.1.1]pentylamine instead of 2-adamantanamine (according to ZED3905), and 2,5-dichlorothiazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in the final step. Yield: 22 mg, 46% (final step) ESI-MS: 657.2 / 659.2 [M+H] +

[0273] 165 Preparation of Compound III-155 [ka] The synthesis of compound III-155 was carried out according to compound III-154 using 4-bromothiazole-2-carboxylic acid instead of 2,5-dichlorothiazole-4-carboxylic acid in the final step. Yield: 42 mg, 73% (final step) ESI-MS: 667.2 / 669.2 [M+H] +

[0274] 166 Preparation of Compound III-156 [ka] The synthesis of compound III-156 was carried out according to compound III-2, using (benzyloxycarbonylmethylene)triphenylphosphorane instead of (carbomethoxymethylene)triphenylphosphorane in step 2 (according to ZED755), 1-bicyclo[1.1.1]pentylamine instead of 2-adamantanamine (according to ZED3905), and 4-methyl-2-phenylthiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in the final step. Yield: 26 mg, 72% (final step) ESI-MS: 680.4 [M+H] +

[0275] 167 Preparation of Compound III-157 [ka] The synthesis of compound III-157 was carried out according to compound III-2, using (benzoylmethylene)triphenylphosphorane instead of (carbomethoxymethylene)triphenylphosphorane in step 2 (according to ZED755), 1-bicyclo[1.1.1]pentylamine instead of 2-adamantanamine (according to ZED3905), and 1-methyl-1H-imidazole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in the final step. Yield: 39 mg, 68% (final step) ESI-MS: 557.4 [M+H] +

[0276] 168 Preparation of Compound III-158 [ka] The synthesis of compound III-158 was carried out according to compound III-2, using (isopropyloxycarbonylmethylene)triphenylphosphorane instead of (carbomethoxymethylene)triphenylphosphorane in step 2 (according to ZED755), bicyclo[2.1.1]hexane-1-amine instead of 2-adamantanamine (according to ZED3905), and 2H-1,2,3-triazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in the final step. Yield: 11 mg, 44% (final step) ESI-MS: 540.4 [M+H] +

[0277] 169 Preparation of Compound III-159 [ka] The synthesis of compound III-159 was carried out according to compound III-2, using (acetylmethylene)triphenylphosphorane instead of (carbomethoxymethylene)triphenylphosphorane in step 2 (according to ZED755), bicyclo[3.2.1]octan-8-amine (according to ZED3905), and 1-methyl-1H-1,2,4-triazole-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in the final step. Yield: 26 mg, 53% (final step) ESI-MS: 538.4 [M+H] +

[0278] 170 Preparation of Compound III-160 [ka] The synthesis of compound III-160 was carried out according to compound III-2 using 1-bicyclo[1.1.1]pentylamine in step 2 (according to ZED3905) and 4-Boc-amino-1,2,5-oxadiazole-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in the final step, followed by deprotection with TFA. Yield: 42 mg, 61% (final step) ESI-MS: 514.4 [M+H] +

[0279] 171 Preparation of Compound III-161 [ka] The synthesis of compound III-161 was carried out according to compound III-160 using 6-(dimethylamino)benzofuran-2-carboxylic acid instead of 4-Boc-amino-1,2,5-oxadiazole-3-carboxylic acid in the final step. Yield: 24 mg, 58% (final step) ESI-MS: 590.4 [M+H] +

[0280] 172 Preparation of Compound III-162 [ka] The synthesis of compound III-162 was carried out according to compound III-160 using 2-acetylamino-5-thiazolecarboxylic acid instead of 4-Boc-amino-1,2,5-oxadiazole-3-carboxylic acid in the final step. Yield: 33 mg, 68% (final step) ESI-MS: 571.3 [M+H] +

[0281] 173 Preparation of Compound III-163 [ka] The synthesis of compound III-163 was carried out according to compound III-160 using 5-carbamoyl-1H-pyrrole-3-carboxylic acid instead of 4-Boc-amino-1,2,5-oxadiazole-3-carboxylic acid in the final step. Yield: 41 mg, 62% (final step) ESI-MS: 539.4 [M+H] +

[0282] 174 Preparation of Compound III-164 [ka] The synthesis of compound III-164 was carried out according to compound III-2, using 1-acetylamino-4-aminoadamantane in step 2 (according to ZED3905) and 5-sulfamoylfuran-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in the final step. Yield: 35 mg, 58% (final step) ESI-MS: 701.4 [M+H] +

[0283] 175 Preparation of Compound III-165 [ka] The synthesis of compound III-165 was carried out according to compound III-164 using benzofuran-5-carboxylic acid instead of 5-sulfamoylfuran-3-carboxylic acid in the final step. Yield: 53 mg, 61% (final step) ESI-MS: 672.5 [M+H] +

[0284] 176 Preparation of Compound III-166 [ka] The synthesis of compound III-166 was carried out according to compound III-2, using 4-aminoadamantane-1-carboxamide in step 2 (according to ZED3905) and benzofuran-6-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in the final step. Yield: 43 mg, 66% (final step) ESI-MS: 658.4 [M+H] +

[0285] 177 Preparation of Compound III-167 [ka] The synthesis of compound III-167 was carried out according to compound III-166 using 3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxylic acid instead of benzofuran-6-carboxylic acid in the final step. Yield: 28 mg, 49% (final step) ESI-MS: 664.5 [M+H] +

[0286] 178 Preparation of Compound III-168 [ka] The synthesis of compound III-168 was carried out according to compound III-160 using 5-methyl-1,2,4-oxadiazole-3-carboxylic acid instead of 4-Boc-amino-1,2,5-oxadiazole-3-carboxylic acid in the final step. Yield: 55 mg, 68% (final step) ESI-MS: 513.4 [M+H] +

[0287] 179 Preparation of Compound III-169 [ka] The synthesis of compound III-169 was carried out according to compound III-160 using 1,2,3-thiadiazole-4-carboxylic acid instead of 4-Boc-amino-1,2,5-oxadiazole-3-carboxylic acid in the final step. Yield: 38 mg, 53% (final step) ESI-MS: 515.3 [M+H] +

[0288] 180 Preparation of Compound III-170 [ka] The synthesis of compound III-170 was carried out according to compound III-160 using 1,2,4-thiadiazole-5-carboxylic acid instead of 4-Boc-amino-1,2,5-oxadiazole-3-carboxylic acid in the final step. Yield: 25 mg, 46% (final step) ESI-MS: 515.3 [M+H] +

[0289] 181 Preparation of Compound III-171 [ka] The synthesis of compound III-171 was carried out according to compound III-160 using 1,3,4-thiadiazole-2-carboxylic acid instead of 4-Boc-amino-1,2,5-oxadiazole-3-carboxylic acid in the final step. Yield: 36 mg, 57% (final step) ESI-MS: 515.3 [M+H] +

[0290] 182 Preparation of Compound III-172 [ka] The synthesis of compound III-172 was carried out according to compound III-160 using 4-cyclopropyl-[1,2,3]thiadiazole-5-carboxylic acid instead of 4-Boc-amino-1,2,5-oxadiazole-3-carboxylic acid in the final step. Yield: 57 mg, 71% (final step) ESI-MS: 555.3 [M+H] +

[0291] 183 Preparation of Compound III-173 [ka] The synthesis of compound III-173 was carried out according to compound III-160 using 1,2,5-thiadiazole-3-carboxylic acid instead of 4-Boc-amino-1,2,5-oxadiazole-3-carboxylic acid in the final step. Yield: 23 mg, 42% (final step) ESI-MS: 515.3 [M+H] +

[0292] 184 Preparation of Compound III-174 [ka] The synthesis of compound III-174 was carried out according to compound III-2, using 1-acetylamino-4-aminoadamantane in step 2 (according to ZED3905) and 4-(hydroxymethyl)-1,2,3-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in the final step. Yield: 15 mg, 34% (final step) ESI-MS: 723.4 [M+H] +

[0293] 185 Preparation of Compound III-175 [ka] The synthesis of compound III-175 was carried out according to compound III-2 using 4-((tetrahydro-2H-pyran-2-yloxy)methyl)-1,2,3-thiadiazole-5-carboxylic acid in the final step, followed by cleavage of the tetrahydropyranyl (Thp) protecting group by TFA. Yield: 23 mg, 42% (final step) ESI-MS: 613.4 [M+H] +

[0294] Biological Examples Example B-1. Inhibitory effect of the compounds according to the present invention Transglutaminase assay To determine inhibitor potency 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).

[0295] Tissue transglutaminase was incubated in a buffer (50 mM Tris-HCl, 7.5 mM CaCl 2 , 150 mM NaCl, pH=7.4). The final concentration of TG2 in the assay is 10 nM.

[0296] A 10 mM stock solution of inhibitor is prepared in DMSO, and a 1:2 dilution series is prepared from this solution, also in DMSO. Each initial dilution is then diluted in buffer (50 mM Tris-HCl, 7.5 mM CaCl 2 Dilute 1:50 in 100 mM NaCl, pH = 7.4) to obtain the final working dilution containing 2% (v / v) DMSO.

[0297] 15 μl of inhibitor working solution is added to each well of a 96-well microtiter plate. As a control, 15 μl of a 2% (v / v) DMSO solution prepared using the above buffer is added to each well.

[0298] Immediately before starting the assay, dissolve 600 μl of transglutaminase working solution in 11.4 ml of assay buffer (50 mM Tris-HCl, 10 mM CaCl 2 , 10 mM glutathione, 2.5% glycerol, 16.7 μM dansylcadaverine, 4 μM N,N-dimethylcasein, 200 mM NaCl, pH=8.0) is added to each well containing inhibitor. 285 μl of this reaction mixture is added to each well containing inhibitor.

[0299] The increase in fluorescence is denoted as λ ex = 330 nm and λ em Measure at 37°C for 30 min using IC = 500 nm. 50 To determine the value (the inhibitor concentration at which 50% of the initial activity is inhibited), calculate the slope of the increase in fluorescence between 20 and 30 min.

[0300] The enzyme activity is analyzed by calculating the slope of the increase in fluorescence intensity. IC 50 Values ​​are calculated by plotting enzyme activity (percentage obtained 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.

[0301] The inhibitory activity of the compounds of the present invention against tissue transglutaminase (TG2) was measured using IC 50 The values ​​used are shown in Table 1 below. [Table 1-1] [Table 1-2] [Table 1-3] [ka]

[0302] Example B-2. logD value of the compound of the present invention To classify the compounds of the present invention according to their lipid solubility, the partitioning of the compounds between octanol and phosphate buffered saline (PBS, pH 7.4) was measured by HPLC using the well-established shake flask method to determine the LogD values ​​(partition coefficients).

[0303] LogD is pH dependent and is a "predictor" of in vivo properties. LogD combines lipophilicity (an inherent structural property of the molecule, logP) and ionizability (pKa).

[0304] Compounds with moderate lipid solubility (LogD values ​​between 0 and 3) are usually favored for oral absorption, with a good balance between solubility and membrane permeability. However, advanced formulation of the compound can improve the oral bioavailability of highly lipid-soluble compounds. [Table 2-1] [Table 2-2] [Table 2-3]

[0305] Example B-3. Caco-2 membrane permeability assay of the compound of the present invention Permeability coefficient (P app Values ​​were obtained from a Caco-2 barrier study predicting oral / intestinal bioavailability of test compounds. The assay was performed using ReadyCell's ready-to-use CacoReady™ kits according to the manufacturer's protocol.

[0306] 1×10 -6 P greater than cm / s app Compounds with a value of 1 × 10 are classified as membrane permeable. -6 P below cm / s app Compounds having a value are considered to be classified as not membrane permeable. [Table 3-1] [Table 3-2] [Table 3-3]

Claims

1. A compound of general formula (I): 【Chemical 289】 (wherein, L is -L １ - or -L １ -L ２ - represents, preferably, -L １ -L ２ - represents, L １ represents -CH ２ -, -CH ２ CH ２ -, -CH ２ CH ２ CH ２ -, -CH ２ CO-, or -CH ２ CH ２ CO- and L ２ represents a bond, -NR Ｎ１ -, -NR Ｎ１ CH ２ -, -NR Ｎ１ CH ２ CH ２ -, or -NR Ｎ１ CH(CH ３ ), and represents R １ is 【Chemical 290】 wherein R ２ is 【Chemical 291-1】 【Chemical 291-2】 【Chemical 291-3】 【Chemical 291-4】 [[Chemical 291-5]] wherein Here, the unsubstituted bicyclic residue may be substituted with 1 to 5 substituents R ９ ~R １４ 、R Ｎ and preferably may be substituted with 1 to 3 substituents R １１ ~R １３ and may be substituted R ３ represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisostilbene, adamantyl, diamantyl, hexamethylenetetraminyl, and the aforementioned residues contain one or more C═C double bonds (multiple possible) and / or R ａ , R ｂ , R ｃ , R ｄ , and R ｅ is substituted by one or more of them. 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 , -CH ２ CO ２ CH ３ , -CH ２ CO ２ C ２ H ５ , -CH ２ CONH ２ , -CH ２ CONHCH ３ , -CH ２ CON(CH ３ ) ２ , -CH ２ CONHC ２ H ５ , -NHCOCH ３ , -NHCOC ２ H ５ , -NHCOCF ３ , -NHCOCH ２ CF ３ , -NHSO ２ CH ３ , -NHSO ２ C ２ H ５ , -NHSO ２ CHF ２ , -NHSO ２ CF ３ , or -NHSO ２ CH ２ CF ３ represents, R ４ is, -R ５ , -OR ５ or -NR ６ R ７ represents, R ５ is -H, -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , -CH(CH ３ ), ２ , -CH ２ CH ２ CH ２ CH ３ , -CH ２ CH(CH ３ ), ２ , -C(CH ３ ), ３ , -CH ２ CH ２ CH ２ CH ２ CH ３ , -CH ２ CH=CH ２ , -CH ２ CH=CH(CH ３ ), -CH ２ CH=C(CH ３ ), ２ , -CH ２ CH=CHCH ２ CH ３ , -cyclo -C ３ H ５ , -cyclo -C ４ H ７ , -cyclo -C ５ H ９ , -cyclo -C ６ H １１ , -CH ２ -cyclo -C ３ H ５ , -CH ２ -cyclo -C ４ H ７ , -CH ２ -cyclo -C ５ H ９ , -CH ２ -cyclo -C ６ H １１ , -Ph, -CH ２ -Ph, -CH ２ OCH ３ , -CH ２ OCH ２ CH ３ , -CH ２ CH ２ OCH ３ 、 or -CH ２ CH ２ OCH ２ CH ３ represents, R ６ and R ７ are, independently of each other, -H, -CH ３ -, -CH ２ CH ３ -, -CH ２ CH ２ CH ３ -, -CH(CH ３ ) ２ -, -CH ２ CH ２ CH ２ CH ３ -, -CH ２ CH ２ CH ２ CH ２ CH ３ -, -CH ２ CH(CH ３ ) ２ -, -C(CH ３ ) ３ -, -CH ２ CH=CH ２ -, -CH ２ CH=CH(CH ３ ), -CH ２ CH=C(CH ３ ) ２ -, -CH ２ CH=CHCH ２ CH ３ -, -cyclo-C ３ H ５ -, -cyclo-C ４ H ７ -, -cyclo-C ５ H ９ -, -cyclo-C ６ H １１ -, -CH ２ -cyclo-C ３ H ５ -, -CH ２ -cyclo-C ４ H ７ -, -CH ２ -cyclo-C ５ H ９ -, -CH ２ -cyclo-C ６ H １１ -, -Ph, -CH ２ -Ph, -CH ２ OCH ３ -, -CH ２ OCH ２ CH ３ 、 -CH ２ CH ２ OCH ３ 、 -CH ２ CH ２ OCH ２ CH ３ 、 -CH ２ CH ２ NHCH ３ 、 or -CH ２ CH ２ N(CH ３ ) ２ represents, or or -NR ６ R ７ is 【Chemical 292】 wherein R ８ 、R ９ 、R １０ 、R １１ 、R １２ 、R １３ 、and R １４ are, independently of one another, -H, -F, -Cl, -Br, -I, -OH, -CN, -NO ２ 、-CH ３ 、-C ２ H ５ 、-C ３ H ７ 、-CH(CH ３ ) ２ 、-C ４ H ９ 、-CH ２ -CH(CH ３ ) ２ 、-CH(CH ３ )-C ２ H ５、 -C(CH ３ ) ３ 、-cyclo-C ３ H ５ 、-CH ２ -cyclo-C ３ H ５ 、-CH ２ OH、-CH ２ F、-CHF ２ 、-CF ３ 、-CH ２ Cl、-CH ２ Br、-CH ２ I、-CH ２ -CH ２ F、-CH ２ -CHF ２ 、-CH ２ -CF ３ 、-CH ２ -CH ２ Cl、-CH ２ -CH ２ Br、-CH ２ -CH ２ I、-OCH ３ 、-OC ２ H ５ 、-OC ３ H ７ 、-OCH(CH ３ ) ２ 、-OC(CH ３ ) ３ , -OC ４ H ９ , -OCHF ２ , -OCF ３ , -OCH ２ CF ３ , -OC ２ F ５ , -OCH ２ OCH ３ , -O-cyclo-C ３ H ５ , -OCH ２ -cyclo-C ３ H ５ , -O-C ２ H ４ -cyclo-C ３ H ５ , -CHO, -COCH ３ , -COCF ３ , -COC ２ H ５ , -COC ３ H ７ , -COCH(CH ３ ) ２ , -COC(CH ３ ) ３ , -COOH, -COOCH ３ , -COOC ２ H ５ , -COOC ３ H ７ , -COOCH(CH ３ ) ２ , -COOC(CH ３ ) ３ , -OOC-CH ３ , -OOC-CF ３ , -OOC-C ２ H ５ , -OOC-C ３ H ７ , -OOC-CH(CH ３ ) ２ , -OOC-C(CH ３ ) ３ , -NH ２ , -NHCH ３ , -NHC ２ H ５ , -NHC ３ H ７ , -NHCH(CH ３ ) ２ , -NHC(CH ３ ) ３ , -N(CH ３ ) ２ , -N( C ２ H ５ ) ２ , -N(C ３ H ７ ) ２ , -N[CH(CH ３ ) ２ ２ , -N[C(CH ３ ) ３ ２ , -NHCOCH ３ , -NHCOCF ３ , -NHCOC ２ H ５ , -NHCOC ３ H ７ , -NHCOCH(CH ３ ) ２ , -NHCOC(CH ３ ) ３ , -CONH ２ , -CONHCH ３ , -CONHC ２ H ５ , -CONHC ３ H ７ , -CONHCH(CH ３ ) ２ , -CONH-cyclo-C ３ H ５ , -CONHC(CH ３ ) ３ , -CON(CH ３ ) ２ , -CON(C ２ H ５ ) ２ , -CON(C ３ H ７ ) ２ , -CON[CH(CH ３ ) ２ ) ２ , -CON[C(CH ３ ) ３ ) ２ , -SO ２ NH ２ , -SO ２ NHCH ３ , -SO ２ NH C ２ H ５ , -SO ２ NH C ３ H ７ , -SO​​ ２ NHCH(CH ３ ) ２ 、-SO ２ NH-cyclo-C ３ H ５ 、-SO ２ NH C(CH ３ ) ３ 、-SO ２ N(CH ３ ) ２ 、-SO ２ N(C ２ H ５ ) ２ 、-SO ２ N(C ３ H ７ ) ２ 、-SO ２ N[CH(CH ３ ) ２ ２ 、-SO ２ N[C(CH ３ ) ３ ) ２ 、-NHSO ２ CH ３ 、-NHSO ２ CF ３ 、-NHSO ２ C ２ H ５ 、-NHSO ２ C ３ H ７ 、-NHSO ２ CH(CH ３ ) ２ 、-NHSO ２ C(CH ３ ) ３ 、-CH=CH ２ 、-CH ２ -CH=CH ２ 、-C(CH ３ )=CH ２ 、-CH=CH-CH ３ 、-C≡CH、-C≡C-CH ３ 、-CH ２ -C≡CH、-Ph、-O-Ph、-O-CH ２ -Ph,​ 【Chemical 293】 represents, or or R ８ and R ９ or R ９ and R １０ together form the following 5- or 6-membered ring: 【Chemical Formula 294】 is capable of forming one of or R １２ and R １３ or R １３ and R １４ together form the following 5- or 6-membered ring: 【Chemical 295】 is capable of forming one of 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 RO-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 , -SO ２ - cyclo - C ３ H ５ , or -SO ２ C(CH ３ ) ３ represents R Ｎ１ represents -H, -CH ３ , or -CH ２ CH ３ ). or a diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemate, solvate, hydrate, or pharmaceutically acceptable salt thereof.

2. Said compound is of formula (I): 【Chemical 296】 (wherein, L represents -L １ - or -L １ -L ２ - represents, preferably, -L １ -L ２ - represents, L １ represents -CH ２ -, -CH ２ CH ２ -, -CH ２ CH ２ CH ２ -, -CH ２ CO-, or -CH ２ CH ２ CO- and L ２ represents a bond, -NR Ｎ１ -, -NR Ｎ１ CH ２ -, -NR Ｎ１ CH ２ CH ２ -, or -NR Ｎ１ CH(CH ３ ), and represents R １ is 【Chemical 297】 wherein R ２ is 【Chemical 298-1】 【Chemical 298-2】 【Chemical 298-3】 【Chemical 298-4】 【Chemical 298-5】 wherein R ３ represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisostilbene, adamantyl, diamantyl, or hexamethylenetetraminyl, and the foregoing residues optionally contain one or more C═C double bonds (multiple possible), and / or R ａ , R ｂ , R ｃ , R ｄ , and R ｅ is optionally substituted by one or more of the foregoing, R ａ 、R ｂ 、R ｃ 、R ｄ 、and R ｅ are, independently of one another, -H, -F, -Cl, -Br, -CN, -OH, -CH ３ 、-CH ２ CH ３ 、-CH ２ CH ２ CH ３ 、-CH(CH ３ ) ２ 、-CHF ２ 、-CF ３ 、-CH ２ CF ３ 、-COCH ３ 、-COCH ２ CH ３ 、-CO ２ H、-CO ２ CH ３ 、-CO ２ C ２ H ５ 、-CONH ２ 、-CONHCH ３ 、-CON(CH ３ ) ２ 、-CONHC ２ H ５ 、-CH ２ CO ２ H、-CH ２ CO ２ CH ３ 、-CH ２ CO ２ C ２ H ５ 、-CH ２ CONH ２ 、-CH ２ CONHCH ３ 、-CH ２ CON(CH ３ ) ２ 、-CH ２ CONHC ２ H ５ 、-NHCOCH ３ 、-NHCOC ２ H ５ 、-NHCOCF ３ 、-NHCOCH ２ CF ３ 、-NHSO ２ CH ３ 、 - NHSO ２ C ２ H ５ 、 - NHSO ２ CHF ２ 、 - NHSO ２ CF ３ 、 or - NHSO ２ CH ２ CF ３ represents, and R ４ is - R ５ 、 - OR ５ or - NR ６ R ７ represents, R ５ is -H, -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , -CH(CH ３ ) ２ , -CH ２ CH ２ CH ２ CH ３ , -CH ２ CH(CH ３ ) ２ , -C(CH ３ ) ３ , -CH ２ CH ２ CH ２ CH ２ CH ３ , -CH ２ CH=CH ２ , -CH ２ CH=CH(CH ３ ), -CH ２ CH=C(CH ３ ) ２ , -CH ２ CH=CHCH ２ CH ３ , -cyclo-C ３ H ５ , -cyclo-C ４ H ７ , -cyclo-C ５ H ９ , -cyclo-C ６ H １１ , -CH ２ -cyclo-C ３ H ５ , -CH ２ -cyclo-C ４ H ７ , -CH ２ -cyclo-C ５ H ９ , -CH ２ -cyclo-C ６ H １１ , -CH ２ -Ph, -CH ２ OCH ３ , -CH ２ OCH ２ CH ３ , -CH ２ CH ２ OCH ３ , or -CH ２ CH ２ OCH ２ CH ３ represents R ６ and R ７ are, independently of each other, -H, -CH ３ -, -CH ２ CH ３ -, -CH ２ CH ２ CH ３ -, -CH(CH ３ ) ２ -, -CH ２ CH ２ CH ２ CH ３ -, -CH ２ CH ２ CH ２ CH ２ CH ３ -, -CH ２ CH(CH ３ ) ２ -, -C(CH ３ ) ３ -, -CH ２ CH=CH ２ -, -CH ２ CH=CH(CH ３ ), -CH ２ CH=C(CH ３ ) ２ -, -CH ２ CH=CHCH ２ CH ３ -, -cyclo-CH ３ H ５ -, -cyclo-CH ４ H ７ -, -cyclo-CH ５ H ９ -, -cyclo-CH ６ H １１ -, -CH ２ -cyclo-CH ３ H ５ -, -CH ２ -cyclo-CH ４ H ７ -, -CH ２ -cyclo-CH ５ H ９ -, -CH ２ -cyclo-CH ６ H １１ -, -Ph, -CH ２ -Ph, -CH ２ OCH ３ -, -CH ２ OCH ２ CH ３ , -CH ２ CH ２ OCH ３ , -CH ２ CH ２ OCH ２ CH ３ , -CH ２ CH ２ NHCH ３ , or -CH ２ CH ２ N(CH ３ ) ２ represents, or or -NR ６ R ７ is 【Chemical 299】 wherein R ８ 、R ９ 、R １０ 、R １１ 、R １２ 、R １３ 、and R １４ are, independently of each other, -H, -F, -Cl, -Br, -I, -OH, -CN, -NO ２ 、-CH ３ 、-C ２ H ５ 、-C ３ H ７ 、-CH(CH ３ ) ２ 、-C ４ H ９ 、-CH ２ -CH(CH ３ ) ２ 、-CH(CH ３ )-C ２ H ５、 -C(CH ３ ) ３ 、-cyclo-C ３ H ５ 、-CH ２ -cyclo-C ３ H ５ 、-CH ２ F、-CHF ２ 、-CF ３ 、-CH ２ Cl、-CH ２ Br、-CH ２ I、-CH ２ -CH ２ F、-CH ２ -CHF ２ 、-CH ２ -CF ３ 、-CH ２ -CH ２ Cl、-CH ２ -CH ２ Br、-CH ２ -CH ２ I、-OCH ３ 、-OC ２ H ５ 、-OC ３ H ７ 、-OCH(CH ３ ) ２ 、-OC(CH ３ ) ３ 、-OC ４ H ９ , -OCHF ２ , -OCF ３ , -OCH ２ CF ３ , -OC ２ F ５ , -OCH ２ OCH ３ , -O-cyclo-C ３ H ５ , -OCH ２ -cyclo-C ３ H ５ , -O-C ２ H ４ -cyclo-C ３ H ５ , -CHO, -COCH ３ , -COCF ３ , -COC ２ H ５ , -COC ３ H ７ , -COCH(CH ３ ) ２ , -COC(CH ３ ) ３ , -COOH, -COOCH ３ , -COOC ２ H ５ , -COOC ３ H ７ , -COOCH(CH ３ ) ２ , -COOC(CH ３ ) ３ , -OOC-CH ３ , -OOC-CF ３ , -OOC-C ２ H ５ , -OOC-C ３ H ７ , -OOC-CH(CH ３ ) ２ , -OOC-C(CH ３ ) ３ , -NH ２ , -NHCH ３ , -NHC ２ H ５ , -NHC ３ H ７ , -NHCH(CH ３ ) ２ , -NHC(CH ３ ) ３ , -N(CH ３ ) ２ , -N(C ２ H ５ ) ２ , -N(C ３ H ７ ) ２ , -N[CH(CH ３ ) ２ ２ , -N[C(CH ３ ) ３ ２ , -NHCOCH ３ , -NHCOCF ３ , -NHCOC ２ H ５ , -NHCOC ３ H ７ , -NHCOCH(CH ３ ) ２ , -NHCOC(CH ３ ) ３ , -CONH ２ , -CONHCH ３ , -CONHC ２ H ５ , -CONHC ３ H ７ , -CONHCH(CH ３ ) ２ , -CONH-cyclo-C ３ H ５ , -CONHC(CH ３ ) ３ , -CON(CH ３ ) ２ , -CON(C ２ H ５ ) ２ , -CON(C ３ H ７ ) ２ , -CON[CH(CH ３ ) ２ ) ２ , -CON[C(CH ３ ) ３ ) ２ , -SO ２ NH ２ , -SO ２ NHCH ３ , -SO ２ NH-C ２ H ５ , -SO ２ NH-C​​ ３ H ７ 、 - SO ２ NHCH(CH ３ ) ２ 、 - SO ２ NH - cyclo - C ３ H ５ 、 - SO ２ NH C(CH ３ ) ３ 、 - SO ２ N(CH ３ ) ２ 、 - SO ２ N(C ２ H ５ ) ２ 、 - SO ２ N(C ３ H ７ ) ２ 、 - SO ２ N[CH(CH ３ ) ２ ２ 、 - SO ２ N[C(CH ３ ) ３ ​​ ２ , -NHSO ２ CH ３ , -NHSO ２ CF ３ , -NHSO ２ C ２ H ５ , -NHSO ２ C ３ H ７ , -NHSO ２ CH(CH ３ ) ２ , -NHSO ２ C(CH ３ ) ３ , -CH=CH ２ , -CH ２ -CH=CH ２ , -C(CH ３ )=CH ２ , -CH=CH-CH ３ , -C≡CH, -C≡C-CH ３ , -CH ２ -C≡CH, -Ph, -O-Ph, -O-CH ２ -Ph, 【Chemical 300】 represents, or or R ８ and R ９ or R ９ and R １０ together form the following 5- or 6-membered ring: 【Chemical 301】 is capable of forming one of or R １２ and R １３ or R １３ and R １４ together form the following 5- or 6-membered ring: 【Chemical 302】 is capable of forming one of 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 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 , -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 represents R Ｎ１ is -H, -CH ３ , or -CH ２ CH ３ (as represented by), according to claim 1 a compound, or a diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemate, solvate, hydrate, or pharmaceutically acceptable salt thereof.

3. R １ is 【Chemical 303】 wherein R ２ is 【Chemical 304-1】 【Chemical 304-2】 represents, wherein the unsubstituted bicyclic residue is 1 to 5 of said substituents R ９ ~R １４ and R Ｎ may be substituted, preferably 1 to 3 of said substituents R １１ ~R １３ may be substituted, R ５ ~R １４ and R Ｎ have the meanings defined in claim 1, the compound according to claim 1.

4. R ２ is 【Chemical 305-1】 【Chemical 305-2】 [Chemical 305-3] 【Chemical 305-4】 【Chemical 305-5】 wherein Here, the unsubstituted bicyclic residue may be substituted with 1 to 5 of the substituents R ９ ~R １４ , R Ｎ and preferably may be substituted with 1 to 3 of the substituents R １１ ~R １３ . The substituents R ９ ~R １４ and R Ｎ have the meanings defined in claim 1, and the compound according to claim 1.

5. R １ is 【Chemical 306】 wherein L １ represents -CH ２ -, or -CH ２ CO-, and L ２ is a bond, -NR Ｎ１ -, -NR Ｎ１ CH ２ -, or -NR Ｎ１ CH(CH ３ ), and represents R ３ is 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, 4-homoisostyryl, adamantyl, or diamantyl, and the foregoing residues optionally contain one or more C═C double bond(s) and / or are substituted by one or more of R ａ , R ｂ , R ｃ , R ｄ , and R ｅ ; R ５ , R ６ , R ７ , R ａ , R ｂ , R ｃ , R ｄ , R ｅ and R Ｎ１ is a compound according to any one of claims 1, 3 and 4, having the same meaning as defined in claim 1.

6. Said compound is of formulas (VI-a) to (VI-l), (VII-a) to (VII-l), (VIII-a) to (VIII-l), (IX-a) to (IX-d), (X-a) to (X-d), and (XI-a) to (XI-d): 【Chemical 307-1】 【Chemical 307-2】 [Chemical 307-3] 【Chemical 307-4】 【Chemical 307-5】 【Chemical 307-6】 (R ２ , R ３ , R ５ , R ６ , R ７ , R ８ , R ９ , R １０ , R １１ , R １２ , R １３ , R ａ , R ｂ , R ｃ , R ｄ and L ２ have the same meaning as defined in claim 1), a compound according to any one of claims 1, 3 and 4 having any one of them.

7. R ２ is 【Chemical 308-1】 【Chemical 308-2】 A compound according to any one of claims 1, 3, and 4, wherein

8. R ３ is 【Chemical 309】 A compound according to any one of claims 1, 3, and 4, wherein

9. A compound according to claim 1, selected from the group consisting of: 【Table 5-1】 【Table 5-2】 【Table 5-3】 【Table 5-4】 【Table 5-5】 【Table 5-6】 【Table 5-7】 【Table 5-8】 【Table 5-9】 【Table 5-10】 【Table 5-11】 【Table 5-12】 【Table 5-13】 【Table 5-14】 【Table 5-15】

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4 and 9 as an active ingredient, together with at least one pharmaceutically acceptable carrier, excipient, and / or diluent.

11. A pharmaceutical composition for use in the treatment or prevention of an autoimmune disease, inflammatory disease, vascular disease, fibrotic disorder, liver disease, cancer, neurodegenerative disease, eye disease, or skin disorder, comprising a compound according to any one of claims 1 to 4 and 9.

12. wherein said autoimmune and inflammatory diseases are multiple sclerosis, celiac disease, Duhring's disease (dermatitis herpetiformis), gluten ataxia, gluten peripheral neuropathy, diabetes, rheumatoid arthritis, Graves' disease, inflammatory bowel disease, systemic lupus erythematosus, or gingivitis, wherein said vascular diseases are atherosclerosis, thrombosis, or arteriosclerosis, wherein said liver diseases are alcoholic hepatitis, alcoholic steatohepatitis, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, cirrhosis, autoimmune hepatitis, hepatitis, primary biliary cholangitis, or primary sclerosing cholangitis, The cancer is glioblastoma, melanoma, pancreatic cancer, renal cell carcinoma, meningioma, or breast cancer, The neurodegenerative disease is Parkinson's disease, Huntington's disease, or Alzheimer's disease, The eye disease is glaucoma, cataract, macular degeneration, or uveitis, The skin disorder is acne, psoriasis, scar, or skin aging, A pharmaceutical composition for use according to claim 11.

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

14. A method for producing the compound according to claim 1, comprising: Step 1C: Providing compound 4c 【Chemical 310】 (wherein PG3 is an amino protecting group) Step 2C: Performing a coupling reaction of the compound 4c with compound 5 【Chemical 311】 to obtain compound 6c 【Chemical 312】 Step 3C: Deprotect the amino protecting group PG ３ to obtain compound 7c 【Chemical 313】 Step 4C: Performing a coupling reaction of the compound 7c with a carboxylic acid (R ２ -CO ２ H8) to produce a compound of formula (Ic) 【Chemical 314】 (where L, R ２ , R ３ , R ５ have the same meaning as defined in claim 1), the method comprising; or Step 1D: Providing compound 4d 【Chemical 315】 (wherein PG3 is an amino protecting group) Step 2D: Performing a coupling reaction of the compound 4d with compound 5 【Chemical 316】 to obtain compound 6d 【Chemical 317】 Step 3D: Deprotect the amino protecting group PG ３ to obtain compound 7d 【Chemical 318】 Step 4D: Performing a coupling reaction of the compound 7d with a carboxylic acid (R ２ -CO ２ H8) to produce a compound of formula (Id) 【Chemical 319】 (where L, R ２ , R ３ , R ６ , R ７ have the same meaning as defined above in formula (Id)), the method comprising; or Step 1E: Providing compound 4e 【Chemical 320】 (wherein PG3 is an amino protecting group) Step 2E: Performing a coupling reaction of the compound 4e with compound 5 【Chemical 321】 to obtain compound 6e 【Chemical 322】 Step 3E: Deprotect the amino protecting group PG ３ to obtain compound 7e 【Chemical 323】 Step 4E: Performing a coupling reaction of the compound 7e with a carboxylic acid (R ２ -CO ２ H8) to produce a compound of formula (Ie) 【Chemical 324】 (where L, R ２ , R ３ , R ５ have the same meaning as those defined above in formula (Ie)), the method comprising).

15. R1 is 【Chemical 306】 representing L1 represents -CH2-, or -CH2CO-, L2 represents a bond, -NRN1-, -NRN1CH2-, or -NRN1CH(CH3)-, R3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, 4-homoisostilbene, adamantyl, or diamantyl, and the aforementioned residues may optionally contain one or more C=C double bonds (multiple possible) and / or be substituted by one or more of Ra, Rb, Rc, Rd, and Re, The compound according to claim 5, wherein R5, R6, R7, Ra, Rb, Rc, Rd, Re, and Rn1 have the same meanings as defined in claim 1.

16. The compound is of formula (VI-a) to (VI-l), (VII-a) to (VII-l), (VIII-a) to (VIII-l), (IX-a) to (IX-d), (X-a) to (X-d), and (XI-a) to (XI-d): 【Chemical 307-1】 【Chemical 307-2】 [Chemical 307-3] [Chemical 307-4] 【Chemical 307-5】 [Chemical 307-6] (wherein R2, R3, R5, R6, R7, R8, R9, R10, R11, R12, R13, Ra, Rb, Rc, Rd and L2 have the same meanings as defined in claim 1), the compound according to claim 5 having any one of them.

17. R2 is 【Chemical 308-1】 【Chemical 308-2】 representing, the compound according to claim 5.

18. R2 is 【Chemical 308-1】 【Chemical 308-2】 representing, the compound according to claim 6.

19. R3 is 【Chemical 309】 representing, the compound according to claim 5.

20. R3 is 【Chemical 309】 representing, the compound according to claim 6.

21. R3 is 【Chemical 309】 representing, the compound according to claim 7.

22. The pharmaceutical composition for the use according to claim 11, wherein the use is for the treatment or prevention of a fibrotic disease affecting an organ selected from the group consisting of the lung, kidney, liver, skin and intestine.

23. The pharmaceutical composition for the use according to claim 22, wherein the fibrotic disease is selected from the group consisting of cystic fibrosis, renal fibrosis, diabetic nephropathy, intestinal fibrosis, idiopathic pulmonary fibrosis, and liver fibrosis.

Images