Transglutaminase inhibitors

Abstract

The present invention relates to compounds of general formula (I) as novel inhibitors of transglutaminase, to processes for the production of the compounds of the invention, to pharmaceutical compositions containing said compounds of the invention, and to their use for the prevention and treatment of diseases associated with transglutaminase, in particular with transglutaminase 2. [Formula 1] TIFF2024524457000501.tif48167

Description

Detailed Description of the Invention

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

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

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

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

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

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

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

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

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

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

[0011] Said object is solved by the technical 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, the reversible inhibitors having chemical warheads disclosed herein have been shown to effectively inhibit transglutaminases, including tissue transglutaminase, also referred to as transglutaminase 2 or TG2, the terms used interchangeably herein.

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

[0014] To prove the inventiveness of the compounds of this application, reference compounds were synthesized and tested in comparison with the most similar compounds in this application. Those skilled in the art may recognize compound A8 from our patent US9,434,763B2, which we introduce as Ref.3 to highlight the inventiveness and preferred features of the compounds claimed. From US9,434,763B2, it is clear that the aromatic moiety (C-terminus) limits the efficacy of these compounds (compare A1, A8, A37, A44, A47). In striking contrast, the efficacy of more potent compounds (A28, A29, A59, A61, A63, A67, A68, A79) is significantly higher than that of the more potent compounds (A28, A29, A59, A61, A63, A67, A68, A79). Branched alkyl moieties are highly preferred, as shown:

[0015] To illustrate the advantage of the branched alkyl moiety over the aromatic moiety, we refer to reference compounds Ref. 2 (ZED1227, US 9,434,763B2) and Ref. 3 (A8, ZED1047). Inhibition data were determined using a classical fluorescent transamidation assay (dansylcadaverine incorporation into methylated casein, DCC-assay) as described [Buchold, C.; Hils, M.; Gerlach, U.; Weber, J.; Pelzer, C.; Heil, A.; Aeschlimann, D.; Pasternack, R. Features of ZED1227: The First-In-Class Tissue Transglutaminase Inhibitor Undergoing Clinical Evaluation for the Treatment of Celiac Disease. of Celiac Disease. Cells 2022, 11, 1667. https: / / doi.org / 10.3390 / cells11101667]. Casein is one of the best-known high molecular weight (24 kDa) protein substrates for transglutaminase. IC of Ref. 3 (A8) published in US 9,434,763 B2 50 It should be noted that the values ​​are dependent on a fluorogenic isopeptidase assay and cannot be compared with the present data. 50 =53 nM) is 80 times more potent (IC 50 =4,268nM).

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

[0017] This is further supported by additional reference compounds: ZED3641 (Ref. 1, disclosed in US11,072,634B2; Ref. 2, a reversibly acting α-ketomethylamide analogue to ZED1227) is about 10 times more potent than Ref.6 (compare Table 1). Ref.6 is similar in scaffold to compound A8 disclosed in US9,434,763B2, again proving the superiority of branched alkyl moieties over aromatic derivatives in combination with reversibly acting warheads.

[0018] Surprisingly, however, replacement of the preferred branched alkyl moieties with bridged cycloalkyl groups further significantly improves the efficacy of the compounds, as shown in Table 1. We therefore appreciate that bridged cycloalkyl groups as disclosed represent an excellent inventive approach.

[0019] In summary, compounds of the invention rated "A" show approximately 100-fold higher efficacy compared to Ref.3 (compare A8, Table 1). Furthermore, compounds with activities rated as "B" or "C" are more preferred (lower IC 50 Peripheric ligands can also be considered inventive because they affect physicochemical or biochemical properties. Thus, depending on the application, compounds with weak effects can be of high value.

[0020] Thus, the present invention relates to a compound of general formula (I), a diastereomeric form of the compound of general formula (I), With respect to a mer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemate, solvate, hydrate, or pharma- ceutically acceptable salt:

[0021] [ka]

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

[0023] [ka] represents;

[0024] R 2 teeth,

[0025] [ka]

[0026] [ka]

[0027] [ka]

[0028] [ka]

[0029] [ka]

[0030] [ka] represents;

[0031] wherein the unsubstituted bicyclic residue is one to five substituents R 9 ~R 14 and R N with preferably 1 to 3 substituents R 11 ~R 13 can 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, hexamethylenetetraminyl, the aforementioned residues optionally containing one or more C=C double bonds and / or optionally containing one or more R a , R b , R c , R d , and R e Replaced by; R a , R b , R c , R d , and R eare, independently of each other, -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -CO2C2H5, -CONH2, -CONHCH3, -CON(CH3)2, -CONHC2H5, -CH2CO2H, -CH2CO2CH3, -CH2CO2C2H5, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2H5, -NHCOCH3, -NHCOC2H5, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C2H5, -NHSO2CHF2, -NHSO2CF3, -NHSO2CH2CF3; R 4 -NR 6 R 7 represents; R 6 and R 7 are each independently -H, -CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2CH=CH2, -CH2CH=CH(CH3), -CH2CH=C(CH3)2, -CH2CH=CHCH2CH3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -cyclo-C6H 11 , -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-C5H9, -CH2-cyclo-C6H 11 , -Ph, -CH2-Ph, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2NHCH3, -CH2CH2N(CH3)2, or -NR 6 R 7 is -N(C2H5)2,

[0032] [ka] and;

[0033] R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14are, independently of each other, -H, -F, -Cl, -Br, -I, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2OH, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2Cl, -CH2-CH2Br, -CH2-CH2I, -OCH3, -OC2H5, -OC3H7, -OCH(CH3)2, -OC(CH3)3, -OC4H9, -OCHF2, -OCF3, -OCH2CF3, -OC2F5, -OCH2OCH3, -O-cyclo-C3H5, -OCH2-cyclo-C3H5, -O-C2H4-cyclo-C3H5, -CHO, -COCH3, -COCF3, -COC2H5, -COC3H7, -COCH(CH3)2, -COC(CH3)3, -COOH, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -OOC-CH3, -OOC-CF3, -OOC-C2H5, -OOC-C3H7, -OOC-CH(CH3)2, -OOC-C(CH3)3, -NH2, -NHCH3, -NHC2H5, -NHC3H7, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC2H5, -NHCOC3H7, -NHCOCH(CH3)2, -NHCOC(CH3)3, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CONHCH(CH3)2, -CONH-cyclo-C3H5, -CONHC(CH3)3, -CON(CH3)2, -CON(C2H5)2, -CON(C3H7)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, -SO2NH2, -SO2NHCH3, -SO2NHC2H5, -SO2NHC3H7, -SO2NHCH(CH3)2, -SO2NH-cyclo-C3H5, -SO2NHC(CH3)3, -SO2N(CH3)2, -SO2N(C2H5)2, -SO2N(C3H7)2,-SO2N[CH(CH3)2]2, -SO2N[C(CH3)3]2, -NHSO2CH3, -NHSO2CF3, -NHSO2C2H5, -NHSO2C3H7, -NHSO2CH(CH3)2, -NHSO2 C(CH3)3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -C≡CH, -C≡C-CH3, -CH2-C≡CH, -Ph, -O-Ph, -O-CH2-Ph,

[0034] [ka] represents;

[0035] Or, R 8 and R 9 , or R 9 and R 10 can together form one of the following five- or six-membered rings:

[0036] [ka]

[0037] Or, R 12 and R 13 , or R 13 and R 14 can together form one of the following five- or six-membered rings:

[0038] [ka]

[0039] R Nare -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-C5H9, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2Cl, -CH2-CH2Br, -CH2-CH2I, -CH2 -CH=CH2, -CH2-C≡CH, -CHO, -COCH3, -COC2H5, -COC3H7, -COCH(CH3)2, -COC(CH3)3, -CO-cyclo-C3H5, -CO-cyclo-C4H7, -CO-cyclo-C5H9, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -SO2CH3, -SO2CF3, -SO2C2H5, -SO2C3H7, -SO2CH(CH3)2, -SO2-cyclo-C3H5, or -SO2C(CH3)3; R N1 represents -H, -CH3, or -CH2CH3.

[0040] We propose a bridged bicyclic residue R 3 It has been shown that the reversible inhibitors of formula (I) disclosed herein, having the formula (I) and (II) show increased efficacy over prior art compounds. In particular, the compounds of the present invention contain an aromatic moiety R instead of a bridged bicyclic moiety. 3 It is demonstrated herein that the compounds have improved inhibitory activity compared to known compounds having the formula: 3 (A8 from US 9,434,763 B2), and known compounds from reference 6) were synthesized and tested as reference compounds to compare with the most similar compounds of the present application.

[0041] Within the scope of this application, the inhibition data are reported in accordance with 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. The inhibition data of the compounds of the present invention were determined using a classical fluorescent transamidation assay (dansylcadaverine incorporation into methylated casein, DCC-assay) as described in [Inhibitor Undergoing Clinical Evaluation for the Treatment of Celiac Disease). Cells 2022, 11, 1667. https: / / doi.org / 10.3390 / cells11101667]. Casein is one of the best known high molecular weight (24 kDa) protein substrates for transglutaminase. The inhibition data of the compounds of the present invention were compared with the inhibition of the compounds disclosed in US 9,434,763 B2, in particular compound A8, which is presented as reference 3 herein. Of note, the IC of compound A8 published in US 9,434,763 B2, and E16 from US 11,072,634 B2 was 1.25 times higher than that of compound A8. 50 The value is that it relies on a fluorogenic isopeptidase assay and cannot be compared with the present data.

[0042] Thus, the compounds of formula (I) of the present invention rated "A" showed approximately 100% higher efficacy compared to Ref.3 (A8). The same argument applies to Ref.6, except for the phenylethyl group, which is identical to compound II-111. Ref.6 is less than 25 times less effective than compound II-111, as is evident from Table 1.

[0043] The improved inhibitory activity of the compounds of the present invention having bridged bicyclic residues over prior art compounds having aromatic residues was unexpected for the skilled person, and this finding is particularly surprising, since it is common knowledge that bridged bicyclic or bridged cycloalkyl groups are non-classical bioisosteres of phenyl groups, and one would only expect to obtain a compound with similar physicochemical and biological properties, including inhibitory activity, if, for example, a phenyl group were replaced by a bridged bicyclic group. The bridged cycloalkyl group is not expected to improve the physicochemical and biological properties of the compound, since the aromatic moiety showed a lower efficacy.

[0044] As used herein, the residues bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, adamantyl, diamantyl and hexamethylenetetraminyl each have the following parent structure:

[0045] [ka]

[0046] The aforementioned residues optionally contain one or more C=C double bonds, such as, for example, bicyclo[2.2.1]hept-5-enyl (s.II-97), and / or one or more R a , R b , R c , R d , and R e is optionally replaced by

[0047] 1 to 5 R substituents 9 ~R 14 and R N The unsubstituted bicyclic residues which can be substituted with have the following structure: 9 ~R 14 and RN has the meaning defined herein:

[0048] [ka]

[0049] [ka]

[0050] [ka]

[0051] [ka]

[0052] [ka]

[0053] [ka]

[0054] [ka]

[0055] [ka] .

[0056] One embodiment is directed to a compound of general formula (I), or a diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemate, solvate, hydrate, or pharma- ceutically acceptable salt of a compound of general formula (I):

[0057] [ka]

[0058] During the ceremony, L is -L 1 - or -L 1 -L 2 -; preferably -L 1 -L 2 - stands for; L 1 is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CO-, or -CH2CH2CO-; R 1 teeth,

[0059] [ka] represents;

[0060] R 2 teeth,

[0061] [ka]

[0062] [ka]

[0063] [ka]

[0064] [ka]

[0065] [ka]

[0066] [ka] represents;

[0067] 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 can be replaced by; i)L 2 is a bond, -NR N1 CH2-, -NR N1 CH2CH2-, or -NR N1 CH(CH3)-; and R 3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, 1-bicyclo[3.1.1]heptyl, 3-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, diamantyl, hexamethylenetetraminyl, wherein the aforementioned residues optionally contain one or more C=C double bonds and / or optionally contain one or more R a , R b , R c , R d , and R e Replaced by; or ii) L 2 is a bond, -NR N1 -, -NR N1 CH2CH2-, or -NR N1 CH(CH3)-; R 3represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]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, 2-adamantyl, diamantyl, hexamethylenetetraminyl, the aforementioned residues optionally containing one or more C=C double bonds and / or optionally containing one or more R a , R b , R c , R d , and R e Replaced by; R a , R b , R c , R d , and R e are, independently of each other, -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -CO2C2H5, -CONH2, -CONHCH3, -CON(CH3)2, -CONHC2H5, -CH2CO2H, -CH2CO2CH3, -CH2CO2C2H5, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2H5, -NHCOCH3, -NHCOC2H5, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C2H5, -NHSO2CHF2, -NHSO2CF3, -NHSO2CH2CF3; R 4 -NR 6 R 7 represents; R 6 and R 7are each independently -H, -CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2CH=CH2, -CH2CH=CH(CH3), -CH2CH=C(CH3)2, -CH2CH=CHCH2CH3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -cyclo-C6H 11 , -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-C5H9, -CH2-cyclo-C6H 11 , -Ph, -CH2-Ph, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2NHCH3, -CH2CH2N(CH3)2, or -NR 6 R 7 is -N(C2H5)2,

[0068] [ka] and;

[0069] R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14are, independently of each other, -H, -F, -Cl, -Br, -I, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2OH, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2Cl, -CH2-CH2Br, -CH2-CH2I, -OCH3, -OC2H5, -OC3H7, -OCH(CH3)2, -OC(CH3)3, -OC4H9, -OCHF2, -OCF3, -OCH2CF3, -OC2F5, -OCH2OCH3, -O-cyclo-C3H5, -OCH2-cyclo-C3H5, -O-C2H4-cyclo-C3H5, -CHO, -COCH3, -COCF3, -COC2H5, -COC3H7, -COCH(CH3)2, -COC(CH3)3, -COOH, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -OOC-CH3, -OOC-CF3, -OOC-C2H5, -OOC-C3H7, -OOC-CH(CH3)2, -OOC-C(CH3)3, -NH2, -NHCH3, -NHC2H5, -NHC3H7, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC2H5, -NHCOC3H7, -NHCOCH(CH3)2, -NHCOC(CH3)3, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CONHCH(CH3)2, -CONH-cyclo-C3H5, -CONHC(CH3)3, -CON(CH3)2, -CON(C2H5)2, -CON(C3H7)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, -SO2NH2, -SO2NHCH3, -SO2NHC2H5, -SO2NHC3H7, -SO2NHCH(CH3)2, -SO2NH-cyclo-C3H5, -SO2NHC(CH3)3, -SO2N(CH3)2, -SO2N(C2H5)2, -SO2N(C3H7)2,-SO2N[CH(CH3)2]2, -SO2N[C(CH3)3]2, -NHSO2CH3, -NHSO2CF3, -NHSO2C2H5, -NHSO2C3H7, -NHSO2CH(CH3)2, -NHSO2 C(CH3)3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -C≡CH, -C≡C-CH3, -CH2-C≡CH, -Ph, -O-Ph, -O-CH2-Ph,

[0070] [ka] represents;

[0071] Or, R 8 and R 9 , or R 9 and R 10 can together form one of the following five- or six-membered rings:

[0072] [ka]

[0073] Or, R 12 and R 13 , or R 13 and R 14 can together form one of the following five- or six-membered rings:

[0074] [ka]

[0075] R Nare -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-C5H9, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2Cl, -CH2-CH2Br, -CH2-CH2I, -CH2 -CH=CH2, -CH2-C≡CH, -CHO, -COCH3, -COC2H5, -COC3H7, -COCH(CH3)2, -COC(CH3)3, -CO-cyclo-C3H5, -CO-cyclo-C4H7, -CO-cyclo-C5H9, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -SO2CH3, -SO2CF3, -SO2C2H5, -SO2C3H7, -SO2CH(CH3)2, -SO2-cyclo-C3H5, or -SO2C(CH3)3; R N1 represents -H, -CH3, or -CH2CH3.

[0076] In one embodiment of the compounds of the invention disclosed herein, the moiety -LR 3 teeth,

[0077] [ka] isn't it.

[0078] In one embodiment of the compounds of the invention disclosed herein, L is -L 1 -L 2 - stands for; L 1 represents -CH2-, or -CH2CO-; and L 2 represents a bond, -NH-, -NHCH2-, -NHCH2CH2-, or -NHCH(CH3)-.

[0079] In one embodiment of the compounds of the invention disclosed herein, L represents -CH2-, -CH2CO-NH-, -CH2CO-NH-CH2-, or -CH2CO-NH-CH(CH3)-.

[0080] In a preferred embodiment of the compounds of the invention in formula (I), R 2 teeth,

[0081] [ka]

[0082] [ka]

[0083] [ka]

[0084] [ka]

[0085] [ka]

[0086] [ka] represents;

[0087] 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 the substituent R 9 ~R 14 and R N3 has the meaning defined herein.

[0088] In an even more preferred embodiment, R 2 teeth:

[0089] [ka]

[0090] [ka] represents

[0091] 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 the substituent R 9 ~R 14 and R N has the meaning defined herein.

[0092] Thus, the present invention relates to a compound of general formula (I), a diastereomer, an enantiomer, a mixture of diastereomers, a mixture of enantiomers, a racemate, a solvate, a hydrate, or a pharma- ceutically acceptable salt of a compound of general formula (I):

[0093] [ka]

[0094] During the ceremony, L is -L 1 - or -L 1 -L 2 -; preferably, -L 1 -L 2 - stands for; L 1 represents -CH2-, or -CH2CO-; L 2 represents a bond, -NH-, -NHCH2-, -NHCH2CH2-, or -NHCH(CH3)-; R 1 teeth,

[0095] [ka] represents;

[0096] R 2 teeth,

[0097] [ka] Represents

[0098] R 3 are 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, hexamethylenetetraminyl, the aforementioned residues optionally containing one or more C=C double bonds and / or optionally one or more R a , R b , R c , R d , and R e Replaced by; R a , R b , R c , R d , and R eare, independently of each other, -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -CO2C2H5, -CONH2, -CONHCH3, -CON(CH3)2, -CONHC2H5, -CH2CO2H, -CH2CO2CH3, -CH2CO2C2H5, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2H5, -NHCOCH3, -NHCOC2H5, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C2H5, -NHSO2CHF2, -NHSO2CF3, -NHSO2CH2CF3; R 4 -NR 6 R 7 represents; R 6 and R 7 are each independently -H, -CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, -CH2CH(CH3)2, -CH2CH=CH2, -CH2CH=CH(CH3), -CH2CH=C(CH3)2, -CH2CH=CHCH2CH3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -cyclo-C6H 11 , -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-C5H9, -CH2-cyclo-C6H 11 , -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2NHCH3, -CH2CH2N(CH3)2, or -NR 6 R 7 is -N(C2H5)2,

[0099] [ka] and;

[0100] R 8 , R9 , R 10 , R 11 , R 12 , R 13 , and R 14 are, independently of one another, -H, -F, -Cl, -Br, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2OH, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2Cl, -CH2-CH2Br, -CH2-CH2I, -OCH3, -OC2H5, -OC3H7, -OCH(CH3)2, -OC(CH3)3, -OC4H9, -OCHF2, -OCF3, -OCH2CF3, -OC2F5, -OCH2OCH3, -O-cyclo-C3H5, -OCH2-cyclo-C3H5, -O-C2H4-cyclo-C3H5, -CHO, -COCH3, -COCF3, -COC2H5, -COC3H7, -COCH(CH3)2, -COC(CH3)3, -COOH, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -OOC-CH3, -OOC-CF3, -OOC-C2H5, -OOC-C3H7, -OOC-CH(CH3)2, -OOC-C(CH3)3, -NH2, -NHCH3, -NHC2H5, -NHC3H7, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC2H5, -NHCOC3H7 , -NHCOCH(CH3)2, -NHCOC(CH3)3, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CONHCH(CH3)2, -CONH-cyclo-C3H5, -CONHC(CH3)3, -CON(CH3)2, -CON (C2H5)2, -CON(C3H7)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, -SO2NH2, -SO2NHCH3, -SO2NHC2H5, -SO2NHC3H7, -SO2NHCH(CH3)2, -SO2NH-cyclo-C3H5, -SO2NHC(CH3)3, -SO2N(CH3)2, -SO2N(C2H5)2, -SO2N(C3H7)2, -SO2N[CH(CH3)2]2, -SO2N[C(CH3)3]2, -NHSO2CH3, -NHSO2CF3, -NHSO2C2H5, -NHSO2 C3H7, -NHSO2CH(CH3)2, -NHSO2C(CH3)3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -C≡CH, -C≡C-CH3, -CH2-C≡CH, -Ph, -O-Ph, -O-CH2-Ph,

[0101] [ka] represents;

[0102] Or, R 8 and R 9 , or R 9 and R 10 can together form one of the following five- or six-membered rings:

[0103] [ka]

[0104] Or, R 12 and R 13 , or R 13 and R 14 can together form one of the following five- or six-membered rings:

[0105] [ka]

[0106] R N are -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-C5H9, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2Cl, -CH2-CH2Br, -CH2-CH2I, -CH2 -CH=CH2, -CH2-C≡CH, -CHO, -COCH3, -COC2H5, -COC3H7, -COCH(CH3)2, -COC(CH3)3, -CO-cyclo-C3H5, -CO-cyclo-C4H7, -CO-cyclo-C5H9, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -SO2CH3, -SO2CF3, -SO2C2H5, -SO2C3H7, -SO2CH(CH3)2, -SO2-cyclo-C3H5, or -SO2C(CH3)3.

[0107] Preferred are compounds of formula (Ib):

[0108] [ka]

[0109] L, R 2 , R 3 , R 6 , R 7 has the same meaning as defined in formula (I). Preferably, a compound of formula (Ib) or a diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemate, solvate, hydrate, or a pharma- ceutically acceptable salt of a compound of formula (Ib):

[0110] [ka]

[0111] During the ceremony, L is -L 1 - or -L 1 -L 2 -; preferably, -L 1 -L 2 - stands for;; L 1 represents -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CO-, or -CH2CH2CO-; L 2 is a bond, -NR N1 -, -NR N1 CH2-, -NR N1 CH2CH2-, or -NR N1 CH(CH3)-; R 2 teeth,

[0112] [ka]

[0113] [ka] represents;

[0114] 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, hexamethylenetetraminyl, the aforementioned residues optionally containing one or more C=C double bonds and / or optionally containing one or more R a , R b, R c , R d , and R e Replaced with; R a , R b , R c , R d , and R e are, independently of each other, -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -CO2C2H5, -CONH2, -CONHCH3, -CON(CH3)2, -CONHC2H5, -CH2CO2H, -CH2CO2CH3, -CH2CO2C2H5, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2H5, -NHCOCH3, -NHCOC2H5, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C2H5, -NHSO2CHF2, -NHSO2CF3, -NHSO2CH2CF3; R 4 -NR 6 R 7 represents; R 6 and R 7 are each independently -H, -CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, -CH2CH(CH3)2, -(CH3)3, -CH2CH=CH2, -CH2CH=CH(CH3), -CH2CH=C(CH3)2, -CH2CH=CHCH2CH3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -cyclo-C6H 11 , -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-C5H9, -CH2-cyclo-C6H 11 , -Ph, -CH2-Ph, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2NHCH3, -CH2CH2N(CH3)2, or -NR 6 R 7is -N(C2H5)2,

[0115] [ka] and;

[0116] R N are -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -CH2-cyclo-C3H5, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2Cl, -CH2-CH2Br, - CH2-CH2I, -CH2-CH=CH2, -CH2-C≡CH, -CHO, -COCH3, -COC2H5, -COC3H7, -COCH(CH3)2, -COC(CH3)3, -COOCH3, -COOC2H5, -COOC 3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -SO2CH3, -SO2CF3, -SO2C2H5, -SO2C3H7, -SO2CH(CH3)2, or -SO2C(CH3)3; R N1 represents -H, -CH3, or -CH2CH3; and R 8 ~R 14 has the meaning previously defined for formula (I).

[0117] Preferably, R 2 teeth

[0118] [ka] Represents.

[0119] Preferably, the —NR 6 R 7are -NH2, -NHCH3, -N(CH3)2, -NHCH(CH3)2, -NHCH2CH2CH3, -NH-CH2CH=CH2, -NHCH2CH2CH2CH3, -NHCH2CH(CH3)2, -NHC(CH3)3, -NHCH2CH2CH2CH2CH3, -NH-cyclo-C3H5, -NH-cyclo-C4H7, -NH-cyclo-C5H9, -NH-cyclo-C6H 11 , -NHCH2-cyclo-C3H5, -NHCH2-cyclo-C4H7, -NHCH2-cyclo-C5H9, -NHCH2-cyclo-C6H 11 , -NHCH2-Ph, -NHCH2OCH3, -NHCH2OCH2CH3, -NHCH2CH2OCH3, -NHCH2CH2NHCH3, -NHCH2CH2N(CH3)2,

[0120] [ka] Represents.

[0121] In some embodiments, the present invention relates to a compound of formula (I):

[0122] [ka]

[0123] During the ceremony, L is -L 1 - or -L 1 -L 2 -; preferably, -L 1 -L 2 - stands for;; L 1 represents -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CO-, or -CH2CH2CO-; L 2 is a bond, -NR N1 -, -NR N1 CH2-, -NR N1 CH2CH2-, or -NR N1 CH(CH3)-; R 1 teeth,

[0124] [ka] represents;

[0125] R 2 teeth,

[0126] [ka]

[0127] [ka] represents;

[0128] R 3 are bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, and bicyclo[1.1.1]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, hexamethylenetetraminyl, optionally containing one or more C=C double bonds and / or one or more R a , R b , R c , R d , and R e Replaced with; R 6 represents -H, -CH3, -CH2CH=CH2, -cyclo-C3H5, -CH2CH2CH2CH2CH3, R 8 ~R 14 , R a , R b , R c , R d , R e , R N , and R N1 has the meaning and preferred meaning defined herein.

[0129] More preferably, it is a compound of general formula (I) or a diastereomer, an enantiomer, a mixture of diastereomers, a mixture of enantiomers, a racemate, a solvate, a hydrate, or a pharma- ceutically acceptable salt of a compound of general formula (I),

[0130] [ka]

[0131] During the ceremony, L is -L 1 - or -L 1 -L 2 - stands for; L 1 represents -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CO-, -CH2CH2CO-; L 2 is a bond, -NR N1 -, -NR N1 CH2-, -NR N1 CH2CH2-, or -NR N1 CH(CH3)-; R 1 teeth,

[0132] [ka] represents;

[0133] R 2 teeth,

[0134] [ka] represents

[0135] R 3represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, adamantyl, diamantyl, hexamethylenetetraminyl, optionally containing one or more C=C double bonds and / or one or more R a , R b , R c , R d , and R e Replaced with; R a , R b , R c , R d , and R e are, independently of each other, -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -CO2C2H5, -CONH2, -CONHCH3, -CON(CH3)2, -CONHC2H5, -CH2CO2H, -CH2CO2CH3, -CH2CO2C2H5, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2H5, -NHCOCH3, -NHCOC2H5, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C2H5, -NHSO2CHF2, -NHSO2CF3, -NHSO2CH2CF3; R 4 -NR 6 R 7 represents; R 6 and R 7 are each independently -H, -CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, -CH2CH(CH3)2, -(CH3)3, -CH2CH=CH2, -CH2CH=CH( CH3), -CH2CH=C(CH3)2, -CH2CH=CHCH2CH3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -cyclo-C6H 11 , -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-C5H9, -CH2-cyclo-C6H 11 , -CH2-Ph, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2NHCH3, -CH2CH2N(CH3)2, or -NR 6 R 7 teeth,

[0136] [ka] represents;

[0137] R N are -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -CH2-cyclo-C3H5, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2Cl, -CH2-CH2Br, - CH2-CH2I, -CH2-CH=CH2, -CH2-C≡CH, -CHO, -COCH3, -COC2H5, -COC3H7, -COCH(CH3)2, -COC(CH3)3, -COOCH3, -COOC2H5, -COOC 3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -SO2CH3, -SO2CF3, -SO2C2H5, -SO2C3H7, -SO2CH(CH3)2, or -SO2C(CH3)3; R N1 represents -H, -CH3, or -CH2CH3.

[0138] More preferred are compounds of formula (I) or (Ib), L1 represents -CH2- or -CH2CO-; L 2 is a bond, -NR N1 -, -NR N1 CH2- or -NR N1 CH(CH3)-; 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, 4-homoisotwistyl, adamantyl or diamantyl, the aforementioned residues optionally containing one or more C=C double bonds and / or one or more R a , R b , R c , R d , and R e is replaced by; and R a , R b , R c , R d , R e , and R N1 has the same meaning as defined herein.

[0139] Preferably, R of formula (I) or formula (Ib) 2 teeth,

[0140] [ka] represents;

[0141] and R 8 ~R 14 , and R N has the same meaning as defined in formula (I) or formula (Ib). Preferably, the compound has any one of formulas (IV-a) to (IV-o) and (Va) to (IV-d):

[0142] [ka]

[0143] [ka]

[0144] [ka]

[0145] R 2 , R 3 , R 6 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R a , R b , R c , R d , and L 2 has the same meaning as defined herein, and preferably as defined in formula (I) or formula (Ib).

[0146] More preferably, it is any compound of formula (IVa-1)

[0147] [ka]

[0148] During the ceremony, R 6 are -H, -CH3, -CH(CH3)2, -CH2CH2CH3, -CH2CH=CH2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2CH2CH2CH2CH3, -cyclo-C3H5, -cyclo-C5H9, -cyclo-C6H 11 or -CH2-cyclo-C3H5, and R 2 , R a , and R b has the same meaning as defined above.

[0149] Preferably, in the compounds of formula (I) or (Ib), R a and R b represent, independently of each other, -H, -F, -Cl, -Br, -OH, -CN, -CH3, -C2H5, or -CO2Me.

[0150] Preferably, in any one of formulas (I) or (Ib), (IV-a) to (IV-o), and (IV-a1), R 2 teeth,

[0151] [ka]

[0152] [ka] represents

[0153] R 6 are -H, -CH3, -CH(CH3)2, -CH2CH2CH3, -CH2CH=CH2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2CH2CH2CH2CH3, -cyclo-C3H5, -cyclo-C5H9, -cyclo-C6H 11 , or -CH2-cyclo-C3H5.

[0154] The specially selected substituent R at the N-terminus of the compounds of the present invention 2 and a specially selected substituent R at the C-terminus 3 allows the stereoscopic dimensions to be adjusted very precisely, so that the binding pocket of a desired target molecule can be addressed with a high degree of fit measurement.

[0155] Preferably, the compound is any one of the compounds represented by formulae (I), (Ib), (IV-a) to (IV-o), and (Va) to (Vd), R 3 teeth

[0156] [ka] Represents.

[0157] Surprisingly, the compounds of the present invention have been shown to reversibly bind to transglutaminase 2 and effectively inhibit transglutaminase. The electrophilic warhead combined with the preferred embodiment specifically reacts with the highly nucleophilic thiol in the active site of transglutaminase 2. Thus, it has been shown to reduce potential non-specific reactions with off-targets.

[0158] In one embodiment, the present invention refers to a compound selected from the group consisting of:

[0159] [ka]

[0160] [ka]

[0161] [ka]

[0162] [ka]

[0163] [ka]

[0164] [ka]

[0165] [ka]

[0166]

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[0167]

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[0193]

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[0199]

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[0200]

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[0201]

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[0211]

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[0240]

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[0250]

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[0251] Particularly preferred are the following compounds, or pharma- ceutically acceptable salts thereof:

[0252] [ka]

[0253] [ka]

[0254] [ka]

[0255] [ka]

[0256] [ka]

[0257] [ka]

[0258] [ka]

[0259] [ka]

[0260] [ka]

[0261] [ka]

[0262]

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[0263]

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[0264]

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[0265]

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[0266]

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[0267]

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[0268]

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[0269]

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[0270]

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[0271]

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[0272] [ka]

[0273] [ka]

[0274] [ka]

[0275] [ka]

[0276] [ka]

[0277] [ka] .

[0278] Methods for preparing the compounds of the present invention In some embodiments, the present invention relates to a method for the synthesis of compounds of formula (I), particularly any compound of formula (Ib):

[0279] [ka]

[0280] A compound of formula (Ib) can be prepared, and the present invention therefore relates to a process for the preparation of a compound of formula (Ib), comprising the following steps in the following order: Step 1B: Providing compound 4b

[0281] [ka] ; Step 2B: Carry out a coupling reaction between compound 4b and compound 5

[0282] [ka] Obtaining compound 6b

[0283] [ka] ; Step 3B: Amino Protecting Group PG 3 to obtain compound 7b.

[0284] [ka] ; Step 4B: Compound 7b and a carboxylic acid (R 2 -CO2H8) to obtain compound 9b.

[0285] [ka] ; Step 5B: Oxidation of compound 9b to produce compound of formula (Ib)

[0286] [ka] ;

[0287] In the formula, L, R 2 , R 3 , R 6 and R 7 has the same meaning as defined above in formula (Ib), and PG 3 is an amino protecting group. In step 5B, a chemical warhead precursor

[0288] [ka] can be treated under basic conditions, for example with K2CO3, to give

[0289] [ka] may be first converted to, and then

[0290] [ka] can be prepared by oxidation methods, preferably using Dess-Martin periodinane (DMP), iodoxybenzoic acid (IBX), or hypochlorite / TEMPO (2,2,6,6-tetramethylphenyl) benzoate (TEMPO) in a polar solvent, as described in the chemical examples. piperidine-1-oxyl) to obtain the corresponding warhead.

[0291] [ka] is converted to.

[0292] In an alternative route, first remove 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.

[0293] As used herein, the term "protecting group" refers to protecting groups commonly used in organic synthesis, preferably protecting groups for amino and carboxyl groups. 1 , P.G. 3 , and P.G. 5 is preferably a suitable protecting group for an amino group. 2 and P.G. 4 is preferably a suitable protecting group for a carboxyl group. 1 , P.G. 3 , and P.G. 5may be selected from the group consisting of or including: acetyl, benzoyl, benzyloxycarbonyl (Cbz), tert-butylcarbonyl, tert-butyloxycarbonyl (Boc), and fluorenylmethylenoxy group (Fmoc). 2 and P.G. 4 may be selected from the group consisting of or including: methoxy, ethoxy, isobutoxy, tert-butoxy, benzyloxy; preferably, it may be a tert-butoxy group.

[0294] In step 2B, an activating reagent is generally used to activate the carboxylic acid to facilitate the coupling reaction with the amino group of the intermediate compound (Ayman El-Faham and Fernando Albericio, "Peptide Coupling Reagents, More than a Letter Soup", Chemical Reviews, 2011, 111(11), p. 6557-6602). The activation may be introduced as a separate reaction or an in situ reaction. Preferably, the following coupling reagents are used: BOP (benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate), PyBOP (benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate), AOP (7-(azabenzotriazol-1-yl)oxytris(dimethylamino)phosphonium hexafluorophosphate), PyBOP (benzotriazol-1-yl-oxy-tris-pyrrolidino- ... hexafluorophosphate), PyAOP ((7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate), TBTU (2-(1H-benzotriazol-1)-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate), EEDQ (N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline), polyphosphoric acid (PPA), DPPA (diphenylphosphoryl azide), HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate), H BTU (O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate), HOBt (1-hydroxybenzotriazole), HOAt (1-hydroxy-7-azabenzotriazole), DCC (N,N'-dicyclohexylcarbodiimide), EDC (or EDAC or EDCI, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), BOP-Cl (bis(2-oxo-3-oxazolidinyl)phosphine chloride), TFFH (tetramethylfluoroformamide hexafluorophosphate), BroP (bromotris(dimethylaminopropyl)carbodiimide), Either phenylamino)phosphonium hexafluorophosphate, PyBroP (bromo-tris-pyrrolidino-phosphonium hexafluorophosphate) and CIP (2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate), or further similar acting reagents, can be used to activate the carboxylic acid group to provide an activated intermediate, or a mixture thereof.

[0295] Pharmaceutical Compositions and Medical Uses Therefore, another aspect of the invention relates to compounds according to general formula (I) as medicaments and their use in medicine, particularly preferably as inhibitors of transglutaminase, in particular transglutaminase 2 (TG2).

[0296] Thus, the compounds of formula (I) described herein or according to the present invention may be administered per se or in the form of a pharma- cologically acceptable salt. The compounds of the present invention may form pharmacologically acceptable salts with organic or inorganic acids or organic or inorganic bases. Examples of acids suitable for forming such acid addition salts include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, p-aminosalicylic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, sulfonic acid, phosphonic acid, perchloric acid, nitric acid, formic acid, propionic acid, gluconic acid, lactic acid, tartaric acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, p-hydroxybenzoic acid, methanesulfonic acid, ethanesulfonic acid, nitrous acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, p-toluenesulfonic acid, naphthylsulfonic acid, sulfanilic acid, camphorsulfonic acid, quinic acid (China acid), mandelic acid, o-methylmandelic acid, hydrogen-benzenesulfonic acid, picric acid, adipic acid, do-tolyltartaric acid, tartronic acid, (o, m, p)-toluic acid, naphthylaminesulfonic acid, trifluoroacetic acid, and other mineral or carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in a conventional manner. Preferred are the mesylate, hydrochloride, and trifluoroacetate salts, with the trifluoroacetate and hydrochloride salts being particularly preferred.

[0297] When the compound of the present invention has an acidic group, it can also use inorganic or organic base to form salt.The examples of suitable inorganic or organic bases are, for example, NaOH, KOH, NH4OH, tetraalkylammonium hydroxide, lysine or arginine, etc.Salts can be prepared in a conventional manner using methods well known in the art, for example, by treating the solution of the compound of general formula (I) with the solution of the acid selected from the above group.

[0298] 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.

[0299] Furthermore, the present invention relates to a pharmaceutical composition comprising at least one compound according to general formula (I) as an active ingredient, or a pharmacologically acceptable salt thereof as an active ingredient, together with at least one pharmacologically acceptable carrier, excipient and / or diluent.

[0300] The compounds according to general formula (I) described herein are particularly suitable for the treatment and prevention of diseases associated with and / or caused by transglutaminase 2.

[0301] Celiac disease, gluten intolerance, is related to tissue transglutaminase (TG2). Another very important group of indications for tissue transglutaminase inhibitors is fibromyalgia. Fibrotic diseases are characterized by the accumulation of cross-linked extracellular matrix proteins. Diabetic nephropathy, cystic fibrosis, idiopathic pulmonary fibrosis, renal fibrosis, and hepatic fibrosis are among the most important fibrotic diseases to be addressed using the disclosed compounds.

[0302] 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 TGs, particularly TG2.

[0303] The term "inhibit" or "inhibition" as used herein refers to the ability of a compound to downregulate, decrease, reduce, suppress, inactivate, or at least partially inhibit the activity of an enzyme or the expression of an enzyme or protein.

[0304] Thus, another aspect of the present invention is the use of the compounds of the present invention of general formula (I) as described, or pharmaceutical compositions thereof, in the treatment or prevention of autoimmune and inflammatory diseases, vascular diseases, fibrotic diseases, liver diseases, cholestatic liver diseases, cancer, neurodegenerative diseases, eye diseases, skin diseases.

[0305] A further aspect of the present invention relates to the use of compounds of general formula (I) for the preparation of a pharmaceutical composition useful for the prevention and / or treatment of autoimmune and inflammatory diseases, vascular diseases, fibrotic diseases, liver diseases, cholestatic liver diseases, cancer, neurodegenerative diseases, eye diseases, and skin diseases.

[0306] In a further embodiment of the present invention there is provided a method for preventing and / or treating autoimmune and inflammatory diseases, vascular diseases, fibrotic diseases, liver diseases, cholestatic liver diseases, cancer, neurodegenerative diseases, eye diseases and skin diseases, comprising administering in a subject, in particular a human, a pharma- ceutical effective amount of at least one compound of general formula (I) for preventing and / or treating said autoimmune and inflammatory diseases, vascular diseases, fibrotic diseases, liver diseases, cholestatic liver diseases, cancer, neurodegenerative diseases, eye diseases and skin diseases.

[0307] Preferably, the autoimmune and inflammatory diseases include multiple sclerosis, celiac disease, Duhring-Brocq-disease (dermatitis herpetiformis), gluten ataxia, gluten neuropathy, diabetes, rheumatoid arthritis, Graves'disease, inflammatory bowel disease, systemic lupus erythematosus, psoriasis, and gingivitis; Vascular diseases include atherosclerosis, thrombosis, and angiosclerosis; Fibrotic diseases affecting the lungs, kidneys, liver, skin or gastrointestinal tract, such as cystic fibrosis, renal fibrosis and diabetic nephropathy, intestinal fibrosis, idiopathic pulmonary fibrosis, hepatic fibrosis, etc.; The liver disease may be alcoholic hepatitis, alcoholic steatohepatitis, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, cirrhosis, autoimmune hepatitis, or liver inflammation; Cholestatic liver diseases include primary biliary cholangitis, and primary sclerosing cholangitis; Cancers include glioblastoma, melanoma, pancreatic cancer, renal cell carcinoma, meningioma, and breast cancer; Neurodegenerative diseases include Parkinson's disease, Huntington's disease, or Alzheimer's disease; The eye disease includes glaucoma, cataracts, macular degeneration, or uveitis; Skin disorders include acne, psoriasis, scarring, and skin aging.

[0308] More preferably, the compounds of formula (I), or pharmaceutical compositions thereof, are useful for the treatment or prevention of coeliac disease. Furthermore, the compounds of general formula (I) can be administered in the form of their pharma- ceutically active salts, optionally using essentially non-toxic pharma- ceutically acceptable carriers, adjuvants or diluents. The drugs can be prepared in known manner in suitable doses with conventional solid or liquid carriers, or with diluents and conventional pharma- ceutically acceptable adjuvants / expedients. Preferred formulations are provided in administrable forms suitable for oral application, such as pills, tablets, film tablets, coated tablets, capsules and powders.

[0309] Tablets, film tablets, coated tablets, gelatin capsules and opaque capsules are preferred pharmaceutical formulations. Any pharmaceutical composition contains at least one compound of general formula (I) and / or its pharma- ceutically acceptable salt in an amount of 5 mg to 500 mg, preferably 10 mg to 250 mg, and most preferably 10 mg to 100 mg per formulation.

[0310] Further objects of the present invention also include pharmaceutical formulations for oral, parenteral, dermal, intradermal, intragastric, intracutaneous, intravascular, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, buccal, percutaneous, rectal, subcutaneous, sublingual, topical, transdermal or inhalation application, which, in addition to typical vehicles and excipients, contain as active ingredients a compound of general formula (I) and / or a pharma- ceutically acceptable salt of a compound of general formula (I).

[0311] The pharmaceutical composition of the present invention contains one of the compounds of formula (I) disclosed herein as an active ingredient, and is typically mixed according to conventional pharmaceutical practice with a suitable carrier material selected for the intended administration form, i.e., orally administered tablets, capsules (either filled with solid, semi-solid, or liquid), powders, orally administrable gels, elixirs, dispersible granules, syrups, suspensions, etc. For example, the compound of formula (I) as an active ingredient can be combined with an oral, non-toxic, pharma- ceutically acceptable inert carrier, such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid form), etc., for oral administration in the form of tablets or capsules. In addition, suitable binders, lubricants, disintegrants, and coloring agents can be added to the mixture, if necessary. Powders and tablets consist of the inert carrier to the extent of about 5% to about 95% by weight per weight of the composition of the present invention.

[0312] Suitable binders include starch, gelatin, natural sugars, sweeteners made from corn, natural and synthetic gums such as gum acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes. Possible lubricants for use in the dosage form include boric acid, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrants include starch, methylcellulose, cyclodextrin, guar gum, etc. Optionally, sweeteners and flavoring additives and preservatives can also be included. Some of the terms used above, namely disintegrants, fillers, lubricants, binders, etc., are explained in more detail below.

[0313] Additionally, the compositions of the present invention can be formulated in sustained release form to provide a controlled release rate of any one or more components or active ingredients to optimize the therapeutic effect, i.e., inhibitory activity, etc. Suitable dosage forms for sustained release include layered tablets comprising layers with different dissolution rate or controlled release polymer matrices impregnated with the active ingredient, and tablet or capsule forms comprising said impregnated or encapsulated porous polymer matrix.

[0314] Fluid form preparations include solutions, suspensions, and emulsions. Exemplary mentioned are water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions, and emulsions.

[0315] Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharma- ceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.

[0316] For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides, for example cocoa butter, is first melted and the active ingredient is dispersed homogeneously therein by stirring or similar mixing operations The molten homogeneous mixture is then poured into suitable molds and allowed to cool and thus harden.

[0317] Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such fluid forms include solutions, suspensions, and emulsions.

[0318] Furthermore, the compounds of the present invention may be administered by transdermal application. The transdermal compositions can have the form of creams, lotions, aerosols and / or emulsions.

[0319] The term capsule refers to a special container or casing made of methylcellulose, polyvinyl alcohol, or modified gelatin or starch, in which the active agent can be enclosed. Typically, hard shell capsules are prepared from a mixture of bone and pigskin gelatin, which has relatively high gel strength. The capsule itself can contain small amounts of colorants, opacifiers, softeners, and preservatives.

[0320] Tablet refers to a compressed or molded solid dosage form containing the active ingredient together with a suitable filler. Tablets can be produced by compressing mixtures or granulations obtained by wet granulation, dry granulation, or compaction as known to those skilled in the art.

[0321] Oral gels refer to the active ingredients dispersed or solubilized in a hydrophilic semi-solid matrix. A powder for the composition refers to a powder mixture containing the active ingredient and a suitable bulking agent that can be suspended in water or juice.

[0322] Suitable bulking agents are usually substances that form the majority of the composition or dosage form.Suitable bulking agents include sugars, such as lactose, sucrose, mannitol, sorbitol, etc.; starches derived from wheat, corn, rice, and potato; and celluloses, such as microcrystalline cellulose.The amount of bulking agent in the composition can range from about 5% to about 95% by weight, preferably from about 25% to about 75% by weight, and more preferably from about 30% to about 60% by weight of the total composition.

[0323] The term disintegrant refers to a material added to the composition to support the disintegration and release of pharmaceutical substances.Suitable disintegrants include starch, modified starch that is soluble in cold water, such as sodium carboxymethyl starch; natural and synthetic gums, such as locust bean gum, karaya, guar gum, tragacanth, and agar; cellulose derivatives, such as methylcellulose and sodium carboxymethylcellulose, microcrystalline cellulose, and crosslinked microcrystalline cellulose, such as croscarmellose sodium; alginates, such as alginic acid and sodium alginate; clays, such as bentonite, and effervescent mixtures.The amount of disintegrant used in the composition can be in the range of about 2% to 20% by weight of the composition, and more preferably in the range of about 5% to about 10% by weight.

[0324] Binders characterize substances that bind or "glue" powders together, and thus function as the "adhesive" in the formulation. Binders add to the cohesive starch already available in the filler or disintegrant. Suitable binders include sugars, e.g., sucrose, glyceryl stearate, sorbitol, sorbitol glycerol ... Examples of binders include starches derived from wheat, corn, rice, and potato, natural gums such as gum acacia, gelatin, and tragacanth, derivatives of seaweed such as alginic acid, sodium alginate, and ammonium calcium alginate, cellulosic materials such as methylcellulose, and sodium carboxymethylcellulose, and hydroxypropylmethylcellulose, polyvinylpyrrolidone, and inorganic compounds such as magnesium aluminum silicate, etc. The amount of binder in the composition can range from about 2% to about 20% by weight of the total composition, preferably from about 3% to about 10% by weight, and more preferably from about 3% to about 6% by weight.

[0325] The term lubricant refers to a substance added to a dosage form to reduce friction after compression, thereby allowing tablets, granules, etc. to be released from a mold or press. Suitable lubricants include metal stearates, such as magnesium stearate, calcium stearate, or potassium stearate; stearic acid; waxes with high melting points, and water-soluble lubricants, such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycol, and D,L-leucine. Due to the fact that the lubricant must be present on the surfaces of the granules, as well as between the granules and the parts of the tablet press, the lubricant is typically added during the last step before compression. The amount of lubricant in the composition can range from about 0.2% to about 5% by weight of the total composition, preferably from about 0.5% to about 2% by weight, and more preferably from about 0.3% to about 1.5% by weight.

[0326] Lubricant is a material that prevents caking and improves the flow properties of granules, thus making the flow smooth and uniform.Suitable lubricants include silicon dioxide and talc.The amount of lubricant in the composition can be in the range of about 0.1% to about 5% by weight, preferably in the range of about 0.5% to about 2% by weight of the total composition.

[0327] A coloring agent is an adjuvant that colors the composition or dosage form. The adjuvant can include food-quality coloring agents that are adsorbed to a suitable adsorption means, such as clay or aluminum oxide. The amount of coloring agent used can vary from about 0.1% to about 5% by weight of the composition, and preferably from about 0.1% to about 1% by weight.

[0328] As used herein, a "pharmacologically effective amount" of a transglutaminase inhibitor is an amount or activity effective to achieve a desired physiological result in either a cell treated in vitro or a patient treated in vivo. Specifically, a pharmacologic effective amount is that amount sufficient to inhibit one or more clinically defined pathological processes associated with transglutaminase 2 for a specific period of time. The effective amount can vary according to the particular compound of formula (I) and further depends on several factors and conditions related to the patient being treated and the severity of the disease. For example, when the inhibitor is administered in vivo, among the data to be considered are factors such as the age, weight, and health condition of the patient, as well as dose-response curves and toxicity data obtained from preclinical animal studies. When the inhibitor in the form of a compound of formula (I) described herein is contacted with cells in vivo, several preclinical in vitro studies will be designed to determine parameters such as absorption, half-life, dose, toxicity, etc. Determining a pharma- ceutical effective amount for a given pharma- ceutical active ingredient is part of the routine skill of one of ordinary skill in the art.

[0329] [Example] The following abbreviations used in the examples have the following meanings: Boc(tert-butoxycarbonyl), BocOSu(N-tert-butoxycarbonyl) bornyloxysuccinimide), DCM (dichloromethane), DMAP (4-(dimethylamino)-pyridine), TEA (triethylamine), DMF (dimethylformamide), DMP (Dess-Martin periodinane), DIPEA (N-ethyldiisopropylamine), Glu (glutamic acid), EDC (1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide), TFA (trifluoroacetic acid), THF (tetrahydrofuran), EtOAc (ethyl acetate), HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate), HOBt (hydroxybenzotriazole), MTBE (methyl tert-butyl ether), tBu (tert-butyl) Chemical Examples The following examples are intended to illustrate the present invention with selected compounds, without limiting the scope of protection of the present intellectual property right to these specific examples. It is obvious to those skilled in the art that similar compounds and compounds produced according to similar synthesis methods fall within the scope of protection of the present intellectual property right.

[0330] Example II. Synthesis Method II

[0331] [ka]

[0332] 1. Preparation of compound ZED1657

[0333] [ka]

[0334] 30.0 g (214 mmol) of 2-hydroxy-3-nitropyridine and 40.5 g (2 eq) of chloroacetic acid were suspended in 600 mL of water. At 40° C., 245 g (3 eq) of trisodium phosphate dodecahydrate were added and the reaction was stirred at room temperature overnight. 250 mL of HCl (32%) were added and the suspension was stirred at 4° C. for another night. The precipitate was filtered and dried. Yield: 41.2 g, 97% ESI-MS: 199.3 [M+H] + 2. Preparation of compound ZED3905

[0335] [ka]

[0336] 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 were 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 washed with 200 mL each of citric acid solution (10%), NaHCO3 solution (10%), and brine. The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated. Yield: 24.1g, 85% ESI-MS: 332.4[M+H] + 3 Preparation of compound ZED3906

[0337] [ka]

[0338] 24.2 g (73.0 mmol) of ZED3905 was suspended in 600 mL of MeOH, then 2.42 g of palladium (10%) on activated carbon (unreduced) was added. The suspension was stirred overnight at room temperature under a hydrogen atmosphere. The catalyst was filtered and the solvent was evaporated. Yield: 1.2 g (73.0 mmol) of ZED3905 was suspended in 600 mL of MeOH, then 2.42 g of palladium (10%) on activated carbon (unreduced) was added. The suspension was stirred overnight at room temperature under a hydrogen atmosphere. The catalyst was filtered and the solvent was evaporated. Amount: 15.7g, 71%ESI-MS:302.4[M+H] +

[0339] [ka]

[0340] Preparation of compound ZED788

[0341] [ka] 12.0 g of Boc-L-Glu-OtBu (39.6 mmol) and 7.09 g of cesium carbonate (21.8 mmol, 0.55 eq) were suspended in 100 ml of DMF. and stirred at room temperature for 1 h. 2.47 ml of iodomethane (39.6 mmol) were added and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was dissolved in ethyl acetate and washed twice with each of citric acid solution (10%), NaHCO3 solution (10%) and brine. The organic layer was dried over Na2SO4, filtered and the solvent was evaporated. The raw product was used without further purification. Yield: 13.4g, >100% ESI-MS: 318.3 [M+H] +

[0342] Preparation of compound ZED720

[0343] [ka]

[0344] 13.4 g of ZED788 (~39.6 mmol) and 986 mg of N,N-dimethyl-4-aminopyridine (DMAP) were dissolved in 30 ml of acetonitrile. A solution of 17.6 g of di-tert-butyl bicarbonate (77.1 mmol) in 100 ml of acetonitrile was added and the solution was stirred at room temperature overnight. The solvent was evaporated and the residue was dissolved in ethyl acetate and washed twice with citric acid solution (10%), NaHCO3 solution (10%) and brine respectively. The organic layer was dried over Na2SO4, filtered and the solvent was evaporated. The raw product was used without further purification. Yield: 13.7g, 83% ESI-MS: 418.3 [M+H] + Preparation of compound ZED721

[0345] [ka]

[0346] 13.7 g of ZED720 (32.8 mmol) was dissolved in 200 ml of dry diethyl ether and cooled to −78° C. under an argon atmosphere. 36.1 ml of diisobutylaluminum hydride (1 M in hexane) was added dropwise and the solution was stirred at −78° C. for 30 min, then quenched with potassium sodium tartrate (Rochelle's salt) solution. The organic layer was separated, dried over Na2SO4, filtered and concentrated to dryness. The crude product was used without further purification. Yield: 13.3g, >100% ESI-MS: 388.3 [M+H] + 4. Preparation of compound ZED3632

[0347] [ka]

[0348] 15.0 g (38.7 mmol) of the aldehyde (S)-tert-butyl 2-(bis(tert-butoxycarbonyl)amino)-5-oxopentanoate (ZED721) was dissolved in 60 mL of DCM. At 0° C., 2.42 mL (1.05 eq) of methyl isocyanide and 2.33 mL (1.05 eq) of acetic acid were added and the reaction was stirred at room temperature overnight. 75 mL of TFA was added and the reaction was stirred for another 3 hours. The solvent was evaporated and the residue was dissolved in 40 mL of DMF. A solution of 13.2 mL (2 eq) of DIPEA and 10.4 g (46.6 mmol) of di-tert-butyl dicarbonate in 10 mL of DMF was added and the reaction was stirred at room temperature overnight. The solvent was evaporated and the residue was dissolved in 40 mL of DMF. A solution of 13.2 mL (2 eq) of DIPEA and 10.4 g (46.6 mmol) of di-tert-butyl dicarbonate in 10 mL of DMF was added and the reaction was stirred at room temperature overnight. and the residue was dissolved in DCM. After extraction with NaHCO3 solution (1.05 eq in water), 1.5 eq of citric acid was added to the aqueous layer, followed by re-extraction with DCM. The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated. The residue was purified by flash chromatography. Yield: 12.5g, 95% ESI-MS: 333.5 [M+H] + 5 Preparation of compound ZED3907

[0349] [ka]

[0350] 19.8 g (59.5 mmol) of ZED3632, 22.6 g (1 eq) of HATU, and 17.9 g (1 eq) of ZED3906 were dissolved in a solution with 400 mL of DMF and 20.8 mL of DIPEA (2 eq) and stirred at 45° C. overnight. The solvent was evaporated; the residue was dissolved in 200 mL of EtOAc and washed twice with 150 mL of citric acid solution (10%), NaHCO3 solution (10%), and brine, respectively. The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated. Yield: 27.4g, 75% ESI-MS: 616.4 [M+H] + 6 Preparation of compound ZED3264

[0351] [ka]

[0352] 480 mg (0.78 mmol) of ZED3907 was dissolved in 4 ml of DCM / TFA (1:1) and stirred at room temperature for 1 h. The solvent was evaporated and the residue was dissolved in 4 ml of DMF. 137 mg (1 eq) of 3-methylbenzo[b]furan-2-carboxylic acid, 296 mg (1 eq) of HATU, and 272 μl (2 eq) of DIPEA were added and the reaction was stirred at room temperature overnight. The solvent was evaporated; the residue was dissolved in 20 mL of EtOAc and washed with 10 mL of citric acid solution (10%), NaHCO3 solution (10%), and brine, respectively. The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated. Yield: 409mg, 78% ESI-MS: 674.4 [M+H] + 7 Preparation of compound ZED3266

[0353] [ka]

[0354] 409 mg (0.61 mmol) ZED3264 was dissolved in 5 ml MeOH. 126 mg (1.5 eq) potassium carbonate was added and the reaction was stirred at room temperature for 1 h. The solution was diluted with DCM and washed with water. The organic layer was dried over Na2SO4, filtered and the solvent was evaporated. Yield: 377mg, 98% ESI-MS: 632.4 [M+H] + 8. Preparation of Compound II-3

[0355] [ka]

[0356] 377 mg (0.60 mmol) of ZED3266 was dissolved in 2 ml of DMF. 405 mg (1.6 eq) of Dess-Martin Periodinane (DMP) was added and the reaction was stirred at room temperature for 2 hours. The precipitate was filtered off and the filtrate was evaporated. The residue was purified by HPLC. Yield: 314mg, 67% ESI-MS: 630.4 [M+H] + 1 H-NMR (DMSO-D6, 500MHz, δ[ppm]): 1.46 / / 1.98(d / / d, 2H / / 2H, adamantyl-C4-H2), 1.68 / / 1.78(m, 4H, adamantyl-C4-H2), 1.71(m, 2H, adamantyl-C1-H), 1.75(m, 2H, adamantyl-C6-H2), 1.78(m, 2H, adamantyl-C5-H), 2.05 / / 2.16(m / / m, 1H / / 1H, β-CH2), 2.53(s, 3H, benzofuran-CH3), 2.64(d, 3H, amide-N-CH3), 2.96(t, 2H, γ-CH2), 3.82(m, 1H, adamantyl- (q,1H,methylamide-NH), 8.54 (q,1H,methylamide-NH), 8.87 (d,1H,α-NH), 9.36 (s,1H,pyridinone-NH).

[0357] 13C-NMR (DMSO-D6, 500MHz, δ[ppm]): 8.62 (benzofuran-CH3), 24.50 (β-CH2), 25.37 (amide-N-CH3), 26.57 / / 26.62 (adamantyl-C5-H), 30.83 (adamantyl-C4-H2), 31.35 (adamantyl-C1-H), 33.61 (γ-CH2), 36.66 (adamantyl-C4'-H2), 37.01 (adamantyl-C6-H2), 51.64 (N-CH2), 52.80 (α-CH2), 53.24 (adamantyl-C2-H), 104.51 (pyridinone-C5-H), 111.55 (benzofuran-CH), 121.09 (benzofuran (C=O-NH-CH3), 121.72 (benzofuran-Cq), 122.53 (pyridinone-C4-H), 123.19 (benzofuran-CH), 127.28 (pyridinone-N-Cq), 127.89 (benzofuran-CH), 129.02 (benzofuran-Cq), 133.27 (pyridinone-C6-H), 142.31 (benzofuran-Cq), 152.68 (benzofuran-Cq), 156.55 (pyridinone-C=O), 159.59 (benzofuran-C=O), 161.32 (C=O-NH-CH3), 165.65 (C=O-adamantylamide), 170.42 (C=O-NH-pyridinone), 198.06 (C=O-methylamide).

[0358] 9. Preparation of Compound II-2

[0359] [ka]

[0360] To a solution of α-hydroxyester precursor of compound II-2 (242 mg, 0.39 mmol, prepared according to compound ZED3264 by using benzofuran-2-carboxylic acid in step 6) in 8 mL of acetonitrile, 1 mg of TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl, 1 mol%) was added. 56 mg of calcium hypochlorite (1 eq) was added at 0° C., and the reaction mixture was stirred at 25° C. for 2 h. The suspension was filtered, diluted with ethyl acetate, washed with NaHCO3 solution (10%) and brine. The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated. The residue was purified by HPLC. Yield: 102mg, 42% ESI-MS: 616.3 [M+H] + 10 Preparation of Compound II-4

[0361] [ka]

[0362] The α-hydroxyester precursor of compound II-4 (124 mg, To a solution of 0.19 mmol, prepared according to compound ZED3264 by using 3-chlorobenzofuran-2-carboxylic acid in step 6) was added 106 mg of 2-iodoxybenzoic acid (IBX, 2 eq) and the reaction mixture was stirred at room temperature for 3 h. A NaHCO3 solution (10%) was added and the suspension was extracted with EtOAc. The organic phase was dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by HPLC. Yield: 37 mg, 30% (final step) ESI-MS: 650.3 / 652.3 [M+H] + 11 Preparation of Compound II-5

[0363] [ka]

[0364] The synthesis of compound II-5 was carried out according to compound II-3, using 4-bromo-1-benzofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 69 mg, 72% (final step) ESI-MS: 694.3 / 696.3 [M+H] + 12 Preparation of Compound II-6

[0365] [ka]

[0366] The synthesis of compound II-6 was carried out according to compound II-3, using benzo[b]thiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 287 mg, 76% (final step) ESI-MS: 632.3 [M+H] + 13 Preparation of Compound II-7

[0367] [ka]

[0368] The synthesis of compound II-7 was carried out according to compound II-3, using 5-bromobenzo[b]thiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 145 mg, 59% (final step) ESI-MS: 710.2 / 712.2 [M+H] + 14 Preparation of Compound II-8

[0369] [ka]

[0370] The synthesis of compound II-8 was carried out according to compound II-3, using 7-fluorobenzo[b]thiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 78 mg, 71% (final step) ESI-MS: 650.3 [M+H] + 15 Preparation of Compound II-9

[0371] [ka]

[0372] The synthesis of compound II-9 was carried out according to compound II-3, using 1H-indole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 57 mg, 69% (final step) ESI-MS: 615.4 [M+H] + 16 Preparation of Compound II-10

[0373] [ka]

[0374] The synthesis of compound II-10 was carried out according to compound II-3, using 4,5-difluoro-1H-indole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 47 mg, 65% (final step) ESI-MS: 651.3 [M+H] + 17 Preparation of Compound II-11

[0375] [ka]

[0376] The synthesis of compound II-11 was carried out according to compound II-3, using 3-methyl-1H-indole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 58 mg, 72% (final step) ESI-MS: 629.4 [M+H] + 18 Preparation of Compound II-12

[0377] [ka]

[0378] The synthesis of compound II-12 was carried out in step 6 by adding 3-methyl The synthesis was carried out according to compound II-3, using 1H-benzo[d]imidazole-2-carboxylic acid instead of benzo[b]furan-2-carboxylic acid. Yield: 27 mg, 48% (final step) ESI-MS: 616.4 [M+H] + 19 Preparation of Compound II-13

[0379] [ka]

[0380] The synthesis of compound II-13 was carried out according to compound II-3, using 2,3-dihydro-1H-indene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 38 mg, 61% (final step) ESI-MS: 616.4 [M+H] + 20 Preparation of Compound II-14

[0381] [ka]

[0382] The synthesis of compound II-14 was carried out according to compound II-3, using 2-bromo-4-methylthiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 98 mg, 70% (final step) ESI-MS: 675.2 / 677.2 [M+H] + 21 Preparation of Compound II-15

[0383] [ka]

[0384] The synthesis of compound II-15 was carried out according to compound II-3, using 4-methyl-2-(trifluoromethyl)thiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 67 mg, 51% (final step) ESI-MS: 665.4 [M+H] + 22 Preparation of Compound II-16

[0385] [ka]

[0386] The synthesis of compound II-16 was carried out according to compound II-3, using 4-bromo-2-(trifluoromethyl)thiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 136 mg, 63% (final step) ESI-MS: 729.3 / 731.3 [M+H] + 23 Preparation of Compound II-17

[0387] [ka]

[0388] The synthesis of compound II-17 was carried out according to compound II-3, using 2,4-dichlorothiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 102 mg, 71% (final step) ESI-MS: 651.2 / 653.2 [M+H] + 24 Preparation of Compound II-18

[0389] [ka]

[0390] The synthesis of compound II-18 was carried out according to compound II-3, using 2-methoxy-4-methylthiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 56 mg, 63% (final step) ESI-MS: 627.3 [M+H] + 25 Preparation of Compound II-19

[0391] [ka]

[0392] The synthesis of compound II-19 was carried out according to compound II-3, using 4-methyl-2-phenylthiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 46 mg, 67% (final step) ESI-MS: 673.4 [M+H] + 26 Preparation of Compound II-20

[0393] [ka]

[0394] The synthesis of compound II-20 was carried out according to compound II-3, using 2,4-dimethylthiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 216 mg, 77% (final step) ESI-MS: 611.4 [M+H] + 27 Preparation of Compound II-21

[0395] [ka]

[0396] The synthesis of compound II-21 was carried out according to compound II-3, using 5-bromo-3-methylthiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 178 mg, 79% (final step) ESI-MS: 674.2 / 676.2.4[M+H] + 28 Preparation of Compound II-22

[0397] [ka] The synthesis of compound II-22 was carried out according to compound II-3, using 3,5-dibromothiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 89 mg, 67% (final step) ESI-MS: 738.2 / 740.2 / 742.2 [M+H] +

[0398] 29 Preparation of Compound II-23

[0399] [ka]

[0400] The synthesis of compound II-23 was carried out according to compound II-3, using 5-bromothiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 141 mg, 72% (final step) ESI-MS: 660.2 / 662.2 [M+H] + 30 Preparation of Compound II-24

[0401] [ka]

[0402] The synthesis of compound II-24 was carried out according to compound II-3, using 5-chlorothiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 117 mg, 78% (final step) ESI-MS: 616.3 / 618.3 [M+H] + 31 Preparation of Compound II-25

[0403] [ka]

[0404] The synthesis of compound II-25 was carried out according to compound II-3, using 5-bromo-3-methylfuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 173 mg, 72% (final step) ESI-MS: 658.2 / 660.2 [M+H] + 32 Preparation of Compound II-26

[0405] [ka]

[0406] The synthesis of compound II-26 was carried out according to compound II-3, using 5-chlorofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 127 mg, 56% (final step) ESI-MS: 600.3 / 602.3 [M+H] + 33 Preparation of Compound II-27

[0407] [ka]

[0408] The synthesis of compound II-27 was carried out by adding 5-chlorothiophene-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). was used according to compound II-3. Yield: 112 mg, 65% (final step) ESI-MS: 616.3 / 618.3 [M+H] + 34 Preparation of Compound II-28

[0409] [ka]

[0410] The synthesis of compound II-28 was carried out according to compound II-3, using 2,5-dichlorothiophene-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 319 mg, 77% (final step) ESI-MS: 650.3 / 652.3 [M+H] + 35 Preparation of Compound II-29

[0411] [ka]

[0412] The synthesis of compound II-29 was carried out according to compound II-3, using 2,5-dibromothiophene-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 98 mg, 52% (final step) ESI-MS: 738.2 / 740.2 / 742.2 [M+H] + 36 Preparation of Compound II-30

[0413] [ka]

[0414] The synthesis of compound II-30 was carried out according to compound II-3, using 5-bromothiophene-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 171 mg, 73% (final step) ESI-MS: 660.2 / 662.2 [M+H] + 37 Preparation of Compound II-31

[0415] [ka]

[0416] The synthesis of compound II-31 was carried out according to compound II-3, using 2-chloro-5-methylthiazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 32 mg, 41% (final step) ESI-MS: 631.3 / 633.3 [M+H] + 38 Preparation of Compound II-32

[0417] [ka]

[0418] The synthesis of compound II-32 was carried out according to compound II-3, using 2,5-dichlorothiazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 41 mg, 35% (final step) ESI-MS: 651.2 / 653.2 [M+H] + 39 Preparation of Compound II-33

[0419] [ka]

[0420] The synthesis of compound II-33 was carried out according to compound II-3, using 2,5-dibromothiazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 21 mg, 32% (final step) ESI-MS: 739.2 / 741.2 / 743.2 [M+H] + 40 Preparation of Compound II-34

[0421] [ka]

[0422] The synthesis of compound II-34 was carried out according to compound II-3, using 2-bromo-5-methylthiazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 42 mg, 57% (final step) ESI-MS: 675.2 / 677.2 [M+H] + 41 Preparation of Compound II-35

[0423] [ka]

[0424] The synthesis of compound II-35 was carried out according to compound II-3, using 2-bromo-5-methylthiazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 66 mg, 46% (final step) ESI-MS: 661.2 / 663.2 [M+H] + 42 Preparation of Compound II-36

[0425] [ka]

[0426] The synthesis of compound II-36 was carried out according to compound II-3, using 2-chlorothiazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 74 mg, 58% (final step) ESI-MS: 617.3 / 619.3 [M+H] + 43 Preparation of Compound II-37

[0427] [ka]

[0428] The synthesis of compound II-37 was carried out by adding 2,5-dimethylfuran-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). The acid was used according to compound II-3. Yield: 152 mg, 73% (final step) ESI-MS: 594.4 [M+H] + 44 Preparation of Compound II-38

[0429] [ka]

[0430] The synthesis of compound II-38 was carried out according to compound II-3, using 4,5-dimethylthiazole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 46 mg, 38% (final step) ESI-MS: 611.4 [M+H] + 45 Preparation of Compound II-39

[0431] [ka]

[0432] The synthesis of compound II-39 was carried out according to compound II-3, using 4-bromothiazole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 84 mg, 68% (final step) ESI-MS: 661.2 / 663.2 [M+H] + 46 Preparation of Compound II-40

[0433] [ka]

[0434] The synthesis of compound II-40 was carried out according to compound II-3, using 4-bromothiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 163 mg, 73% (final step) ESI-MS: 660.2 / 662.2 [M+H] + 47 Preparation of Compound II-41

[0435] [ka]

[0436] The synthesis of compound II-41 was carried out according to compound II-3, using 4-bromo-3-methylthiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 114 mg, 68% (final step) ESI-MS: 674.2 / 676.2 [M+H] + 48 Preparation of Compound II-42

[0437] [ka]

[0438] The synthesis of compound II-42 was carried out according to compound II-3, using 3-bromothiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 149 mg, 76% (final step) ESI-MS: 660.2 / 662.2 [M+H] + 49 Preparation of Compound II-43

[0439] [ka]

[0440] The synthesis of compound II-43 was carried out according to compound II-3, using 3-chloro-4-methylthiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 110 mg, 64% (final step) ESI-MS: 630.3 / 632.3 [M+H] + 50 Preparation of Compound II-44

[0441] [ka]

[0442] The synthesis of compound II-44 was carried out according to compound II-3, using 4-bromo-5-chlorothiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 126 mg, 59% (final step) ESI-MS: 694.2 / 696.2 / 698.2 [M+H] + 51 Preparation of Compound II-45

[0443] [ka]

[0444] The synthesis of compound II-45 was carried out according to compound II-3, using 4,5-dibromothiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 89 mg, 51% (final step) ESI-MS: 738.2 / 740.2 / 742.2 [M+H] + 52 Preparation of Compound II-46

[0445] [ka]

[0446] The synthesis of compound II-46 was carried out according to compound II-3, using 4,5-dibromo-3-methoxythiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 59 mg, 40% (final step) ESI-MS: 768.2 / 770.2 / 772.2 [M+H] + 53 Preparation of Compound II-47

[0447] [ka]

[0448] The synthesis of compound II-47 was carried out according to compound II-3, using 4-bromofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 90 mg, 69% (final step) ESI-MS: 644.3 / 646.3 [M+H] + 54 Preparation of Compound II-48

[0449] [ka]

[0450] The synthesis of compound II-48 was carried out according to compound II-3, using 4,5-dibromofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 72 mg, 56% (final step) ESI-MS: 722.2 / 724.2 / 726.2 [M+H] + 55 Preparation of Compound II-49

[0451] [ka]

[0452] The synthesis of compound II-49 was carried out in step 6 by adding 3-methyl The synthesis was carried out according to compound II-3, using 4,5-dichlorothiophene-2-carboxylic acid instead of benzo[b]furan-2-carboxylic acid. Yield: 55 mg, 48% (final step) ESI-MS: 650.3 / 652.3 [M+H] + 56 Preparation of Compound II-50

[0453] [ka]

[0454] The synthesis of compound II-50 was carried out according to compound II-3, using (S)-1-acetylpyrrolidine-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 190 mg, 78% (final step) ESI-MS: 611.4 [M+H] + 57 Preparation of Compound II-51

[0455] [ka]

[0456] The synthesis of compound II-51 was carried out according to compound II-3, using 1-methyl-1H-1,2,3-triazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 28 mg, 35% (final step) ESI-MS: 581.4 [M+H] + 58 Preparation of Compound II-52

[0457] [ka]

[0458] The synthesis of compound II-52 was carried out according to compound II-3, using 2H-tetrazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 23 mg, 31% (final step) ESI-MS: 568.4 [M+H] + 59 Preparation of Compound II-53

[0459] [ka]

[0460] The synthesis of compound II-53 was carried out according to compound II-3, using pyrazine-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 79 mg, 74% (final step) ESI-MS: 578.3 [M+H] + 60 Preparation of Compound II-54

[0461] [ka]

[0462] The synthesis of compound II-54 was carried out by substituting (S)-1-methylpyrrolidine-2-carboxylic acid for 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). The synthesis was carried out according to compound II-3 using carboxylic acid. Yield: 68 mg, 82% (final step) ESI-MS: 583.4 [M+H] + 61 Preparation of Compound II-55

[0463] [ka]

[0464] The synthesis of compound II-55 was carried out according to compound II-3, using (S)-1-Boc-pyrrolidine-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid (according to ZED3264) in step 6. The final product was obtained by deprotection (DCM / TFA) as described above and purified by HPLC. Yield: 43 mg, 79% (final step) ESI-MS: 569.4 [M+H] + 62 Preparation of Compound II-56

[0465] [ka]

[0466] The synthesis of compound II-56 was carried out according to compound II-3, using (2S,4S)-1-Boc-4-bromopyrrolidine-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid (according to ZED3264) in step 6. The final product was obtained by deprotection (DCM / TFA) as described above and purified by HPLC. Yield: 45 mg, 73% (final step) ESI-MS: 647.3 / 649.3 [M+H] + 63 Preparation of Compound II-58

[0467] [ka]

[0468] The synthesis of compound II-58 was carried out by using (S)-1-Boc-piperidine-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). The carboxylic acid was used according to compound II-3. The final product was obtained by deprotection (DCM / TFA) as described above and purified by HPLC. Yield: 53 mg, 86% (final step) ESI-MS: 583.4 [M+H] + 64 Preparation of Compound II-59

[0469] [ka]

[0470] The synthesis of compound II-59 was carried out according to compound II-3, using (R)-1-Boc-piperidine-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid (according to ZED3264) in step 6. The final product was obtained by deprotection (DCM / TFA) as described above and purified by HPLC. Yield: 43 mg, 77% (final step) ESI-MS: 583.4 [M+H] + 65 Preparation of Compound II-60

[0471] [ka]

[0472] The synthesis of compound II-60 was carried out according to compound II-3, using (R)-4-Boc-morpholine-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid (according to ZED3264) in step 6. The final product was obtained by deprotection (DCM / TFA) as described above and purified by HPLC. Yield: 67 mg, 85% (final step) ESI-MS: 585.4 [M+H] + 66 Preparation of Compound II-61

[0473] [ka]

[0474] The synthesis of compound II-61 was carried out according to compound II-3, using quinuclidine-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 24 mg, 54% (final step) ESI-MS: 609.4 [M+H] + 67 Preparation of Compound II-62

[0475] [ka]

[0476] The synthesis of compound II-62 was carried out according to compound II-3, using mono-methyl 5-nitroisophthalate instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 57 mg, 66% (final step) ESI-MS: 679.3 [M+H] + 68 Preparation of Compound II-63

[0477] [ka]

[0478] The synthesis of compound II-63 was carried out according to compound II-3, using 5-nitronicotinic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 76 mg, 65% (final step) ESI-MS: 622.3 [M+H] + 69 Preparation of Compound II-64

[0479] [ka]

[0480] The synthesis of compound II-64 was carried out according to compound II-3, using 3,5-pyridinedicarboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 16 mg, 52% (final step) ESI-MS: 621.3 [M+H] + 70 Preparation of Compound II-65

[0481] [ka]

[0482] The synthesis of compound II-65 was carried out in step 6 by adding 3-methyl This was done according to compound II-3, using 5-(methoxycarbonyl)nicotinic acid instead of benzo[b]furan-2-carboxylic acid. Yield: 34 mg, 62% (final step) ESI-MS: 635.3 [M+H] + 71 Preparation of Compound II-66

[0483] [ka]

[0484] The synthesis of compound II-66 was carried out according to compound II-3, using 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 45 mg, 37% (final step) ESI-MS: 636.4 [M+H] + 72 Preparation of Compound II-67

[0485] [ka]

[0486] The synthesis of compound II-67 was carried out according to compound II-3, using N-methyl-2-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 66 mg, 45% (final step) ESI-MS: 644.4 [M+H] + 73 Preparation of Compound II-68

[0487] [ka]

[0488] The synthesis of compound II-68 was carried out according to compound II-3, using 5-hydroxy-2-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 21 mg, 34% (final step) ESI-MS: 646.4 [M+H] + 74 Preparation of Compound II-69

[0489] [ka]

[0490] The synthesis of compound II-69 was carried out according to compound II-3, using 5-fluoro-2-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 48 mg, 57% (final step) ESI-MS: 648.4 [M+H] + 75 Preparation of Compound II-70

[0491] [ka]

[0492] The synthesis of compound II-70 was carried out by 2-adamantyl ester (according to ZED3905) in step 2. The reaction was carried out according to compound II-3, using 5-chloro-2-adamantanamine instead of adamantanamine. Yield: 45 mg, 35% (final step) ESI-MS: 664.3 / 666.3 [M+H] + 76 Preparation of Compound II-71

[0493] [ka] The synthesis of compound II-71 was carried out according to compound II-3, using 5-bromo-2-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 31 mg, 34% (final step) ESI-MS: 708.3 / 710.3 [M+H] +

[0494] 77 Preparation of Compound II-72

[0495] [ka]

[0496] The synthesis of compound II-72 was carried out according to compound II-3, using 5-methyl-2-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 68 mg, 54% (final step) ESI-MS: 644.4 [M+H] + 78 Preparation of Compound II-73

[0497] [ka]

[0498] The synthesis of compound II-73 was carried out according to compound II-3, using 2-aminoadamantane-2-carbonitrile instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 26 mg, 46% (final step) ESI-MS: 655.4 [M+H] + 79 Preparation of Compound II-74

[0499] [ka]

[0500] The synthesis of compound II-74 was carried out according to compound II-3, using 2-methyl 2-aminoadamantane-2-carboxylate instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 38 mg, 61% (final step) ESI-MS: 688.4 [M+H] + 80 Preparation of Compound II-87

[0501] [ka]

[0502] The synthesis of compound II-87 was carried out according to compound II-3, using 1-adamantanemethylamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 43 mg, 53% (final step) ESI-MS: 644.4 [M+H] + 81 Preparation of Compound II-88

[0503] [ka]

[0504] The synthesis of compound II-88 was carried out according to compound II-2, using 1-rimantadine instead of 2-adamantanamine (according to ZED3905) in step 2. Yield: 31 mg, 41% (final step). ESI-MS: 644.4[M+H]+ 82 Preparation of Compound II-90

[0505] [ka]

[0506] The synthesis of compound II-90 was carried out according to compound II-3, using (±)-endo-2-norbornylamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 67 mg, 65% (final step) ESI-MS: 590.4 [M+H] + 83 Preparation of Compound II-92

[0507] [ka]

[0508] The synthesis of compound II-92 was carried out according to compound II-3, using (R)-(+)-bornylamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 52 mg, 66% (final step) ESI-MS: 632.5 [M+H] + 84 Preparation of Compound II-94

[0509] [ka]

[0510] The synthesis of compound II-94 was carried out according to compound II-3, using exo-2-aminonorbornane instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 62 mg, 68% (final step) ESI-MS: 590.4 [M+H] + 85 Preparation of Compound II-95

[0511] [ka]

[0512] The synthesis of compound II-95 was carried out according to compound II-3, using bicyclo[2.2.1]heptan-1-ylamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 14 mg, 32% (final step) ESI-MS: 590.4 [M+H] + 86 Preparation of Compound II-96

[0513] [ka]

[0514] The synthesis of compound II-96 was carried out according to compound II-3, using bicyclo[2.2.1]heptan-7-ylamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 36 mg, 53% (final step) ESI-MS: 590.4 [M+H] + 87 Preparation of Compound II-97

[0515] [ka]

[0516] The synthesis of compound II-97 was carried out according to compound II-3, using bicyclo[2.2.1]hept-5-en-2-amine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 21 mg, 44% (final step) ESI-MS: 588.4 [M+H] + 88 Preparation of Compound II-98

[0517] [ka]

[0518] The synthesis of compound II-98 was carried out according to compound II-3, using bicyclo[2.2.2]oct-2-ylamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 25 mg, 41% (final step) ESI-MS: 604.4 [M+H] + 89 Preparation of Compound II-99

[0519] [ka]

[0520] The synthesis of compound II-99 was carried out according to compound II-3, using (R)-(-)-isobornylamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 27 mg, 48% (final step) ESI-MS: 632.5 [M+H] + 90 Preparation of Compound II-100

[0521] [ka]

[0522] The synthesis of compound II-100 was carried out according to compound II-3, using (1R,2R,3R,5S)-(-)-isopinocampheylamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 17 mg, 39% (final step) ESI-MS: 632.5 [M+H] + 91 Preparation of Compound II-101

[0523] [ka]

[0524] The synthesis of compound II-101 was carried out in step 2 by the 2-adduct The synthesis was carried out according to compound II-3, using (1S,2S,3S,5R)-(+)-isopinocampheylamine instead of manthanamine. Yield: 25 mg, 41% (final step) ESI-MS: 632.5 [M+H] + 92 Preparation of Compound II-103

[0525] [ka]

[0526] The synthesis of compound II-103 was carried out according to compound II-3, using 3-amino-4-homoisotwistane instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 12 mg, 28% (final step) ESI-MS: 644.5 [M+H] + 93 Preparation of Compound II-104

[0527] [ka]

[0528] The synthesis of compound II-104 was carried out according to compound II-3, using 1-aminodiamantane instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 17 mg, 35% (final step) ESI-MS: 682.5 [M+H] + 94 Preparation of Compound II-105

[0529] [ka]

[0530] The synthesis of compound II-105 was carried out according to compound II-3, using 4-aminodiamantane instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 8 mg, 26% (final step) ESI-MS: 682.5 [M+H] +

[0531] [ka]

[0532] 95 Preparation of compound ZED4893

[0533] [ka]

[0534] 500 mg (3.57 mmol) of 2-hydroxy-3-nitropyridine and 818 mg (1 eq) of 1-(bromomethyl)adamantane were dissolved in a solution with 10 mL of DMF and 1.24 mL of DIPEA (2 eq) and stirred at room temperature overnight. The solvent was evaporated; the residue was dissolved in 30 mL of EtOAc and washed twice with 10 mL each of citric acid solution (10%), NaHCO3 solution (10%), and brine. The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated. The residue was purified by HPLC. Yield: 484 mg, 47% ESI-MS: 289.3 [M+H] + 96 Preparation of compound ZED4894

[0535] [ka]

[0536] 484 mg (1.68 mmol) of ZED4893 was suspended in 30 mL of MeOH, then 50 mg of palladium (10%) on activated carbon (unreduced) was added. 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] + 97 Preparation of Compound II-107

[0537] [ka]

[0538] The synthesis of compound II-107 was carried out according to compound II-3, using ZED4894 instead of ZED3906 (according to ZED3907) in step 5. Yield: 41 mg, 49% (final step) ESI-MS: 587.4 [M+H] + 98 Preparation of Compound II-108

[0539] [ka]

[0540] The synthesis of compound II-108 was carried out according to compound II-107, using 3-(bromomethyl)-1-adamantanol instead of 1-(bromomethyl)adamantane (according to ZED4893). Yield: 16 mg, 36% (final step) ESI-MS: 603.4 [M+H] + 99 Preparation of Compound II-109

[0541] [ka]

[0542] The synthesis of compound II-109 was carried out according to compound II-107, using 1-bromo-3-(bromomethyl)adamantane instead of 1-(bromomethyl)adamantane (according to ZED4893). Yield: 24 mg, 41% (final step) ESI-MS: 665.3 / 667.3 [M+H] + 100 Preparation of Compound II-110

[0543] [ka]

[0544] The synthesis of compound II-110 was carried out according to compound II-107, using 2-(bromomethyl)adamantane instead of 1-(bromomethyl)adamantane (according to ZED4893). Yield: 46 mg, 62% (final step) ESI-MS: 587.4 [M+H] + 101 Preparation of Compound II-111

[0545] [ka]

[0546] The synthesis of compound II-111 was carried out according to compound II-3, using nicotinic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 65 mg, 46% (final step) ESI-MS: 577.4 [M+H] + 102 Preparation of Compound II-112

[0547] [ka]

[0548] The synthesis of compound II-112 was carried out according to compound II-3, using isonicotinic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 47 mg, 52% (final step) ESI-MS: 577.4 [M+H] + 103 Preparation of Compound II-113

[0549] [ka]

[0550] The synthesis of compound II-113 was carried out according to compound II-3, using pyridazine-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 34 mg, 46% (final step) ESI-MS: 578.4 [M+H] + 104 Preparation of Compound II-114

[0551] [ka]

[0552] The synthesis of compound II-114 was carried out according to compound II-3, using pyridazine-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 43 mg, 56% (final step) ESI-MS: 578.4 [M+H] + 105 Preparation of Compound II-115

[0553] [ka]

[0554] The synthesis of compound II-115 was carried out according to compound II-3, using cyclopropyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632). Yield: 47 mg, 64% (final step) ESI-MS: 656.5 [M+H] + 106 Preparation of Compound II-116

[0555] [ka]

[0556] The synthesis of compound II-116 was carried out according to compound II-3, using pentyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632). Yield: 87 mg, 71% (final step) ESI-MS: 686.5 [M+H] + 107 Preparation of Compound II-117

[0557] [ka]

[0558] The synthesis of compound II-117 was carried out by reacting methyl isopropyl alcohol in step 4 (according to ZED3632). The reaction was carried out according to compound II-3, using allyl isocyanide instead of isocyanide. Yield: 42 mg, 63% (final step) ESI-MS: 656.5 [M+H] +

[0559] [ka]

[0560] Preparation of Compound 10

[0561] [ka]

[0562] 15.0 g (38.7 mmol) of the aldehyde (S)-tert-butyl 2-(bis(tert-butoxycarbonyl)amino)-5-oxopentanoate (ZED721) was dissolved in 150 ml of DCM. 6.42 ml (46.3 mmol) of trimethylamine and 7.37 ml (79.9 mmol) of acetone cyanohydrin were added and the reaction was stirred at room temperature overnight. The solution was washed twice with citric acid solution (10%) and brine respectively. The organic layer was dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography. Yield: 16.2g, >100% ESI-MS: 437.6 [M+Na] + Preparation of compound 11

[0563] [ka]

[0564] 16.2 g (~38.6 mmol) of cyanohydrin 10 was dissolved in 95 ml of MeOH at 4 °C and 1.91 g (45.5 mmol) of lithium hydroxide monohydrate was added. 18.6 ml of hydrogen peroxide (35%) was added dropwise and the reaction was stirred at room temperature for 1.5 h before being quenched with sodium thiosulfate solution (5%). The aqueous layer was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography. Yield: 8.61g, 52% ESI-MS: 455.2 [M+Na] + Preparation of compound 15

[0565] [ka]

[0566] 8.61 g (19.9 mmol) of hydroxyamide 10 was dissolved in 55 ml of DCM. 3.45 ml (24.9 mmol), 1.91 g (45.5 mmol) of trimethylamine, 2.12 ml of acetic anhydride and 62 mg (0.50 mmol) of DMAP were added and the reaction was stirred at room temperature for 3 hours. After washing with water and brine, the organic layer was dried over Na2SO4, filtered and the solvent was evaporated. The product was precipitated from the MTBE solution by the addition of hexane. Yield: 8.08g, 86% ESI-MS: 475.5 [M+H] + Preparation of compound 16

[0567] [ka]

[0568] 8.08 g (17.0 mmol) of 15 was dissolved in 140 ml of DCM / TFA (1:1) and stirred at room temperature for 3 h. The solvent was evaporated and the residue was dissolved in 40 ml of DMF. In 20 ml of DMF, 5.80 ml (2 eq) of DIPEA and 4.55 g (20.4 mmol) of di-tert-butyl dicarbonate were added and the reaction was stirred at room temperature overnight. The solvent was evaporated and the residue was dissolved in 80 ml of EtOAc. After extraction with NaHCO3 solution (1.05 eq in water), the product was precipitated from the aqueous layer by addition of 1.5 eq of citric acid. Yield: 1.64g, 30% ESI-MS: 319.4 [M+H] + 108 Preparation of Compound II-118

[0569] [ka]

[0570] The synthesis of compound II-118 was carried out according to compound II-3, using compound 16 instead of ZED3632 (according to ZED3907) in step 5. Yield: 158 mg, 56% (final step) ESI-MS: 616.4 [M+H] + 109 Preparation of Compound II-119

[0571] [ka]

[0572] The synthesis of compound II-119 was carried out according to compound II-2, using allyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632). Yield: 56 mg, 71% (final step) ESI-MS: 642.4 [M+H] + 110 Preparation of Compound II-120

[0573] [ka]

[0574] The synthesis of compound II-120 was carried out according to compound II-2, using isopropyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632). Yield: 62 mg, 65% (final step) ESI-MS: 644.5 [M+H] + 111 Preparation of Compound II-121

[0575] [ka]

[0576] The synthesis of compound II-121 was carried out according to compound II-2, using cyclopropyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632). Yield: 44 mg, 51% (final step) ESI-MS: 642.4 [M+H] + 112 Preparation of Compound II-122

[0577] [ka]

[0578] The synthesis of compound II-122 was carried out according to compound II-2, using phenyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632). Yield: 37 mg, 56% (final step) ESI-MS: 678.4 [M+H] + 113 Preparation of Compound II-123

[0579] [ka]

[0580] The synthesis of compound II-123 was carried out according to compound II-2, using benzyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632). Yield: 46 mg, 52% (final step) ESI-MS: 692.5 [M+H] + 114 Preparation of Compound II-124

[0581] [ka]

[0582] The synthesis of compound II-124 was carried out according to compound II-118, using benzofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 96 mg, 81% (final step) ESI-MS: 602.4 [M+H] + 115 Preparation of Compound II-125

[0583] [ka]

[0584] The synthesis of compound II-125 was carried out in step 6 by the addition of benzofluorene (according to ZED3264). This was carried out according to compound II-124, using 2,5-dichlorothiophene-3-carboxylic acid instead of ran-2-carboxylic acid. Yield: 78 mg, 71% (final step) ESI-MS: 636.3 / 638.3 [M+H] + 116 Preparation of Compound II-126

[0585] [ka]

[0586] The synthesis of compound II-126 was carried out according to compound II-124, using 4-methyl-2-(trifluoromethyl)thiazole-5-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to ZED3264). Yield: 53 mg, 67% (final step) ESI-MS: 651.3 [M+H] + 117 Preparation of Compound II-127

[0587] [ka]

[0588] The synthesis of compound II-127 was carried out according to compound II-124, using 1-methyl-1H-1,2,3-triazole-5-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to ZED3264). Yield: 26 mg, 49% (final step) ESI-MS: 567.3 [M+H] + 118 Preparation of Compound II-128

[0589] [ka]

[0590] The synthesis of compound II-128 was carried out according to compound II-97, using 2,5-dichlorothiophene-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 53 mg, 73% (final step) ESI-MS: 610.3 / 612.3 [M+H] + 119 Preparation of Compound II-129

[0591] [ka]

[0592] The synthesis of compound II-129 was carried out according to compound II-97, using 4-methyl-2-(trifluoromethyl)thiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 42 mg, 60% (final step) ESI-MS: 625.3 [M+H] + 120 Preparation of Compound II-130

[0593] [ka]

[0594] The synthesis of compound II-130 was carried out according to compound II-97, using 1-methyl-1H-1,2,3-triazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 15 mg, 39% (final step) ESI-MS: 541.3 [M+H] + 121 Preparation of Compound II-131

[0595] [ka]

[0596] The synthesis of compound II-131 was carried out according to compound II-3, using 2H-1,2,3-triazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 28 mg, 56% (final step) ESI-MS: 567.4 [M+H] + 122 Preparation of Compound II-132

[0597] [ka]

[0598] The synthesis of compound II-132 was carried out according to compound II-3, using 1H-1,2,3-triazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 14 mg, 45% (final step) ESI-MS: 567.4 [M+H] + 123 Preparation of Compound II-133

[0599] [ka]

[0600] The synthesis of compound II-133 was carried out according to compound II-3, using 1-methyl-1H-1,2,3-triazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 36 mg, 61% (final step) ESI-MS: 581.4 [M+H] + 124 Preparation of Compound II-134

[0601] [ka]

[0602] The synthesis of compound II-134 was carried out according to compound II-3, using 1H-1,2,4-triazole-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 21 mg, 43% (final step) ESI-MS: 567.4 [M+H] + 125 Preparation of Compound II-135

[0603] [ka]

[0604] The synthesis of compound II-135 was carried out according to compound II-3, using 1-methyl-1H-1,2,4-triazole-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 39 mg, 67% (final step) ESI-MS: 581.4 [M+H] + 126 Preparation of Compound II-136

[0605] [ka]

[0606] The synthesis of compound II-136 was carried out according to compound II-3, using benzofuran-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 56 mg, 71% (final step) ESI-MS: 616.4 [M+H] + 127 Preparation of Compound II-137

[0607] [ka]

[0608] The synthesis of compound II-137 was carried out according to compound II-3, using benzo[b]thiophene-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 49 mg, 64% (final step) ESI-MS: 632.4 [M+H] + 128 Preparation of Compound II-138

[0609] [ka]

[0610] The synthesis of compound II-138 was carried out by adding 1-methyl-1H-pyrazole-3-carboxylate instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Carried out according to compound II-3 using carboxylic acid. Yield: 43 mg, 59% (final step) ESI-MS: 580.4 [M+H] + 129 Preparation of Compound II-139

[0611] [ka]

[0612] The synthesis of compound II-139 was carried out according to compound II-3, using 1-methyl-1H-pyrazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 53 mg, 62% (final step) ESI-MS: 580.4 [M+H] + 130 Preparation of Compound II-140

[0613] [ka]

[0614] The synthesis of compound II-140 was carried out according to compound II-3, using 1-methyl-1H-pyrazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 39 mg, 48% (final step) ESI-MS: 580.4 [M+H] + 131 Preparation of Compound II-141

[0615] [ka]

[0616] The synthesis of compound II-141 was carried out according to compound II-3, using 4-methyl-1,2,3-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 54 mg, 58% (final step) ESI-MS: 598.4 [M+H] + 132 Preparation of Compound II-142

[0617] [ka]

[0618] The synthesis of compound II-142 was carried out according to compound II-3, using 1,2,5-thiadiazole-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 36 mg, 43% (final step) ESI-MS: 584.4 [M+H] + 133 Preparation of Compound II-143

[0619] [ka]

[0620] The synthesis of compound II-143 was carried out according to compound II-3, using 4-iodo-1-methyl-1H-pyrazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 24 mg, 49% (final step) ESI-MS: 706.3 [M+H] + 134 Preparation of Compound II-144

[0621] [ka]

[0622] The synthesis of compound II-144 was carried out according to compound II-118, using 1-methyl-1H-pyrazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 26 mg, 68% (final step) ESI-MS: 566.4 [M+H] + 135 Preparation of Compound II-145

[0623] [ka]

[0624] The synthesis of compound II-145 was carried out according to compound II-118, using 4-methyl-1,2,3-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 35 mg, 62% (final step) ESI-MS: 584.4 [M+H] + 136 Preparation of Compound II-146

[0625] [ka]

[0626] The synthesis of compound II-146 was carried out by using benzofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264) and 2-adamantane-amine in step 2 (according to ZED3905). This was done according to compound II-118, using exo-2-aminonorbornane instead. Yield: 43 mg, 60% (final step) ESI-MS: 562.4 [M+H] + 137 Preparation of Compound II-147

[0627] [ka]

[0628] The synthesis of compound II-147 was carried out according to compound II-118, using exo-2-aminonorbornane instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 56 mg, 67% (final step) ESI-MS: 576.4 [M+H] + 138 Preparation of Compound II-148

[0629] [ka]

[0630] The synthesis of compound II-148 was carried out according to compound II-118, using benzofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264) and (±)-endo-2-aminonorbornane instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 49 mg, 66% (final step) ESI-MS: 562.4 [M+H] + 139 Preparation of Compound II-149

[0631] [ka]

[0632] The synthesis of compound II-149 was carried out in step 2 by the 2-adduct This was done according to compound II-118, using (±)-endo-2-aminonorbornane instead of manthanamine. Yield: 64 mg, 75% (final step) ESI-MS: 576.4 [M+H]+ 140 Preparation of Compound II-150

[0633] [ka]

[0634] The synthesis of compound II-150 was carried out according to compound II-118, using benzofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264) and (R)-(+)-bornylamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 38 mg, 53% (final step) ESI-MS: 604.4 [M+H] + 141 Preparation of Compound II-151

[0635] [ka]

[0636] The synthesis of compound II-151 was carried out according to compound II-118, using (R)-(+)-bornylamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 31 mg, 59% (final step) ESI-MS: 618.5 [M+H] + 142 Preparation of Compound II-152

[0637] [ka]

[0638] The synthesis of compound II-152 was carried out according to compound II-94, using 4-methyl-1,2,3-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 53 mg, 68% (final step) ESI-MS: 558.4 [M+H] + 143 Preparation of Compound II-153

[0639] [ka]

[0640] The synthesis of compound II-153 was carried out according to compound II-94, using 1-methyl-1H-pyrazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 60 mg, 67% (final step) ESI-MS: 540.4 [M+H] + 144 Preparation of Compound II-154

[0641] [ka]

[0642] The synthesis of compound II-154 was carried out in step 6 by the addition of 3-methyl The synthesis was carried out according to compound II-90, using 4-methyl-2-(trifluoromethyl)thiazole-5-carboxylic acid instead of benzo[b]furan-2-carboxylic acid. Yield: 68 mg, 74% (final step) ESI-MS: 625.3 [M+H] + 145 Preparation of Compound II-155

[0643] [ka]

[0644] The synthesis of compound II-155 was carried out according to compound II-90, using 2,5-dichlorothiophene-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 74 mg, 68% (final step) ESI-MS: 610.3 / 612.3 [M+H] + 146 Preparation of Compound II-156

[0645] [ka]

[0646] The synthesis of compound II-156 was carried out according to compound II-90, using 4-methyl-1,2,3-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 56 mg, 61% (final step) ESI-MS: 558.4 [M+H] + 147 Preparation of Compound II-157

[0647] [ka]

[0648] The synthesis of compound II-157 was carried out according to compound II-90, using 1-methyl-1H-1,2,3-triazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 34 mg, 52% (final step) ESI-MS: 541.4 [M+H] + 148 Preparation of Compound II-158

[0649] [ka]

[0650] The synthesis of compound II-158 was carried out according to compound II-90, using 1-methyl-1H-pyrazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 55 mg, 64% (final step) ESI-MS: 540.4 [M+H] + 149 Preparation of Compound II-159

[0651] [ka]

[0652] The synthesis of compound II-159 was carried out by replacing 3-methylbenzo[b]furan-2-carboxylic acid with 4-methyl-2-(trifluoromethyl)benzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). The synthesis was carried out according to Compound II-92 using thiazole-5-carboxylic acid. Yield: 52 mg, 57% (final step) ESI-MS: 667.4 [M+H] + 150 Preparation of Compound II-160

[0653] [ka]

[0654] The synthesis of compound II-160 was carried out according to compound II-92, using 2,5-dichlorothiophene-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 66 mg, 61% (final step) ESI-MS: 652.3 / 654.3 [M+H] + 151 Preparation of Compound II-161

[0655] [ka]

[0656] The synthesis of compound II-161 was carried out according to compound II-92, using 4-methyl-1,2,3-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 41 mg, 51% (final step) ESI-MS: 600.4 [M+H] + 152 Preparation of Compound II-162

[0657] [ka] The synthesis of compound II-162 was carried out by adding 1-methyl-1H-1,2,3-trimethylbenzo[b]furan-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). This was done according to compound II-92 using zole-5-carboxylic acid. Yield: 28 mg, 46% (final step) ESI-MS: 583.5 [M+H] +

[0658] 153 Preparation of Compound II-163

[0659] [ka]

[0660] The synthesis of compound II-163 was carried out according to compound II-92, using 1-methyl-1H-pyrazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 44 mg, 58% (final step) ESI-MS: 582.5 [M+H] + 154 Preparation of Compound II-164

[0661] [ka]

[0662] The synthesis of compound II-164 was carried out according to compound II-107, using 1-(2-bromoethyl)adamantane instead of 1-(bromomethyl)adamantane (according to ZED4893) and 5-tert-butyl-1H-pyrrole-3-carboxylic acid instead of 3-methyl-benzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 32 mg, 56% (final step) ESI-MS: 592.5 [M+H] + 155 Preparation of Compound II-165

[0663] [ka]

[0664] The synthesis of compound II-165 was carried out by using 1-(3-bromopropyl)adamantane instead of 1-(bromomethyl)adamantane (according to ZED4893), and in step 6 (According to ZED3264) Made according to compound II-107 using 4-cyano-1-methyl-1H-pyrrole-2-carboxylic acid instead of 3-methyl-benzo[b]furan-2-carboxylic acid. Yield: 27 mg, 48% (final step) ESI-MS: 589.5 [M+H] + 156 Preparation of Compound II-166

[0665] [ka]

[0666] The synthesis of compound II-166 was carried out according to compound II-3, using 3-chloropropionic acid instead of chloroacetic acid (according to ZED1657) and 5-methoxyoxazole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 31 mg, 59% (final step) ESI-MS: 611.4 [M+H] + 157 Preparation of Compound II-167

[0667] [ka]

[0668] The synthesis of compound II-167 was carried out according to compound II-3, using 1-bicyclo[1.1.1]pentylamine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 45 mg, 67% (final step) ESI-MS: 562.4 [M+H] + 158 Preparation of Compound II-168

[0669] [ka]

[0670] The synthesis of compound II-168 was carried out according to compound II-167, using 2-acetyloxazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 26 mg, 48% (final step) ESI-MS: 541.4 [M+H] + 159 Preparation of Compound II-169

[0671] [ka]

[0672] The synthesis of compound II-169 was carried out according to compound II-3, using bicyclo[2.1.1]hexan-1-amine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 33 mg, 61% (final step) ESI-MS: 576.4 [M+H] + 160 Preparation of Compound II-170

[0673] [ka]

[0674] The synthesis of compound II-170 was carried out in step 6 by the addition of 3-methyl The synthesis was carried out according to compound II-169, using 2-isopropyloxazole-5-carboxylic acid instead of 1-benzo[b]furan-2-carboxylic acid. Yield: 32 mg, 54% (final step) ESI-MS: 555.4 [M+H] + 161 Preparation of Compound II-171

[0675] [ka]

[0676] The synthesis of compound II-171 was carried out according to compound II-2, using bicyclo[3.2.1]octan-8-amine instead of 2-adamantanamine in step 2 (according to ZED3905). Yield: 42 mg, 60% (final step) ESI-MS: 590.4 [M+H] + 162 Preparation of Compound II-172

[0677] [ka]

[0678] The synthesis of compound II-172 was carried out according to compound II-171, using 3,5-dimethylisoxazole-4-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to ZED3264). Yield: 35 mg, 58% (final step) ESI-MS: 569.4 [M+H] + 163 Preparation of Compound II-173

[0679] [ka]

[0680] The synthesis of compound II-173 was carried out according to compound II-3, 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 step 6 (according to ZED3264). Ta. Yield: 25 mg, 49% (final step) ESI-MS: 636.4 [M+H] + 164 Preparation of Compound II-174

[0681] [ka]

[0682] The synthesis of compound II-174 was carried out according to compound II-3 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 step 6 (according to ZED3264). Yield: 33 mg, 56% (final step) ESI-MS: 701.5 [M+H] + 165 Preparation of Compound II-175

[0683] [ka]

[0684] The synthesis of compound II-175 was carried out according to compound II-3, using tert-butyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632) and 1,4-diazabicyclo[2.2.2]octane-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 39 mg, 53% (final step) ESI-MS: 652.5 [M+H] + 166 Preparation of Compound II-176

[0685] [ka]

[0686] The synthesis of compound II-176 was carried out in step 4 by the addition of methyl isopropyl alcohol (according to ZED3632). This was done according to compound II-3, using tert-butyl isocyanide instead of isocyanide and 1H-indole-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 52 mg, 62% (final step) ESI-MS: 657.5 [M+H] + 167 Preparation of Compound II-177

[0687] [ka]

[0688] The synthesis of compound II-177 was carried out according to compound II-3, using tert-butyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632) and 6-methylimidazo[2,1-b][1,3]thiazole-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 42 mg, 53% (final step) ESI-MS: 678.5 [M+H] + 168 Preparation of Compound II-178

[0689] [ka]

[0690] The synthesis of compound II-178 was carried out according to compound II-90, using cyclopentyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632) and 1,3-benzothiazole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 54 mg, 61% (final step) ESI-MS: 647.4 [M+H] + 169 Preparation of Compound II-179

[0691] [ka]

[0692] The synthesis of compound II-179 was carried out by using cyclopentyl isocyanide instead of methyl isocyanide in step 4 (according to ZED 3632) and cyclopentyl isocyanide instead of methyl isocyanide in step 6 (according to ZED 3264) according to compound II-90, using imidazo[2,1-b][1,3]thiazole-6-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid. Yield: 36 mg, 51% (final step) ESI-MS: 636.4 [M+H] + 170 Preparation of Compound II-180

[0693] [ka]

[0694] The synthesis of compound II-180 was carried out according to compound II-90, using cyclopentyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632) and 4-hydroxy-6-(trifluoromethoxy)quinoline-3-carboxylic acid instead of 3-methyl-benzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 19 mg, 41% (final step) ESI-MS: 741.5 [M+H] + 171 Preparation of Compound II-181

[0695] [ka]

[0696] The synthesis of compound II-181 was carried out according to compound II-167, using cyclohexyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632) and 3-cinnoline carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 37 mg, 56% (final step) ESI-MS: 628.5 [M+H] + 172 Preparation of Compound II-182

[0697] [ka]

[0698] The synthesis of compound II-182 was carried out by using cyclohexyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632) and cyclohexyl isocyanide instead of methyl isocyanide in step 6 (according to ZED 3264) according to compound II-167, using 3-ethylbenzofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid. Yield: 53 mg, 68% (final step) ESI-MS: 644.5 [M+H] + 173 Preparation of Compound II-183

[0699] [ka]

[0700] The synthesis of compound II-183 was carried out according to compound II-167 using cyclohexyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632) and 1-ethyl-1H-indole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 41 mg, 57% (final step) ESI-MS: 643.5 [M+H] + 174 Preparation of Compound II-184

[0701] [ka]

[0702] The synthesis of compound II-184 was carried out according to compound II-167, using cyclohexyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632) and 2-methyl-1,8-naphthyridine-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 26 mg, 54% (final step) ESI-MS: 642.5 [M+H] + 175 Preparation of Compound II-185

[0703] [ka]

[0704] The synthesis of compound II-185 was carried out in step 6 by the addition of 3-methyl The synthesis was carried out according to Compound II-169, using N-Boc-1,2,3,4-tetrahydroquinoline-6-carboxylic acid instead of benzo[b]furan-2-carboxylic acid. The final product was obtained by deprotection (DCM / TFA) as described above and purified by HPLC. Yield: 39 mg, 61% (final step) ESI-MS: 577.4 [M+H] + 176 Preparation of Compound II-186

[0705] [ka]

[0706] The synthesis of compound II-186 was carried out according to compound II-3, using 2-amino-5-(trifluoromethyl)adamantane-2-carboxylic acid instead of 2-adamantanamine in step 2 (according to ZED3905) and 3-oxo-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 12 mg, 36% (final step) ESI-MS: 757.4 [M+H] + 177 Preparation of Compound II-187

[0707] [ka]

[0708] The synthesis of compound II-187 was carried out according to compound II-3, using 5-ethyladamantan-2-amine instead of 2-adamantanamine (according to ZED3905) in step 2 and 1,6-naphthyridine-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid (according to ZED3264) in step 6. Yield: 26 mg, 51% (final step). ESI-MS: 656.5 [M+H] + 178 Preparation of Compound II-188

[0709] [ka]

[0710] The synthesis of compound II-188 was carried out in step 6 by adding 3-methyl The synthesis was carried out according to compound II-169, using 2,6-naphthyridine-1-carboxylic acid instead of benzo[b]furan-2-carboxylic acid. Yield: 33 mg, 56% (final step) ESI-MS: 574.4 [M+H] + 179 Preparation of Compound II-189

[0711] [ka]

[0712] The synthesis of compound II-189 was carried out according to compound II-167, using 4-Boc-amino-1,2,5-oxadiazole-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid (according to ZED3264) in step 6. The amine was deprotected by TFA in the final step. Yield: 16 mg, 69% (final step) ESI-MS: 515.3 [M+H] + 180 Preparation of Compound II-190

[0713] [ka]

[0714] The synthesis of compound II-190 was carried out according to compound II-167, using 6-(dimethylamino)benzofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 38 mg, 55% (final step) ESI-MS: 591.4 [M+H] + 181 Preparation of Compound II-191

[0715] [ka]

[0716] The synthesis of compound II-191 was carried out according to compound II-167, using 2-acetylamino-5-thiazole carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 21 mg, 46% (final step) ESI-MS: 572.3 [M+H] + 182 Preparation of Compound II-192

[0717] [ka]

[0718] The synthesis of compound II-192 was carried out according to compound II-167, using 5-carbamoyl-1H-pyrrole-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 13 mg, 38% (final step) ESI-MS: 540.4 [M+H] + 183 Preparation of Compound II-193

[0719] [ka]

[0720] The synthesis of compound II-193 was carried out according to compound II-3, using 1-acetylamino-4-aminoadamantane instead of 2-adamantanamine in step 2 (according to ZED3905) and 5-sulfamoylfuran-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 10 mg, 27% (final step) ESI-MS: 702.4 [M+H] + 184 Preparation of Compound II-194

[0721] [ka]

[0722] The synthesis of compound II-194 was carried out according to compound II-3, using 1-acetylamino-4-aminoadamantane instead of 2-adamantanamine (according to ZED3905) in step 2, and benzofuran-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid (according to ZED3264) in step 6. Yield: 23 mg, 52% (final step). ESI-MS: 673.5 [M+H] + 185 Preparation of Compound II-195

[0723] [ka]

[0724] The synthesis of compound II-195 was carried out according to compound II-3, using 4-aminoadamantane-1-carboxamide instead of 2-adamantanamine (according to ZED3905) in step 2, and benzofuran-6-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid (according to ZED3264) in step 6. Yield: 26 mg, 57% (final step). ESI-MS: 659.4 [M+H] + 186 Preparation of Compound II-196

[0725] [ka]

[0726] The synthesis of compound II-196 was carried out according to compound II-3, using 4-aminoadamantane-1-carboxamide instead of 2-adamantanamine in step 2 (according to ZED3905), and 3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 15 mg, 38% (final step) ESI-MS: 665.5 [M+H] + 187 Preparation of Compound II-197

[0727] [ka]

[0728] The synthesis of compound II-197 was carried out by adding 5-methyl-1,2,4-oxadiazonium chloride instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). The synthesis was carried out according to compound II-167 using zole-3-carboxylic acid. Yield: 36 mg, 58% (final step) ESI-MS: 514.4 [M+H] + 188 Preparation of Compound II-198

[0729] [ka]

[0730] The synthesis of compound II-198 was carried out according to compound II-167, using 1,2,3-thiadiazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 29 mg, 48% (final step) ESI-MS: 516.3 [M+H] + 189 Preparation of Compound II-199

[0731] [ka]

[0732] The synthesis of compound II-199 was carried out according to compound II-167, using 1,2,4-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 35 mg, 56% (final step) ESI-MS: 516.3 [M+H] + 190 Preparation of Compound II-200

[0733] [ka]

[0734] The synthesis of compound II-200 was carried out according to compound II-167, using 1,3,4-thiadiazole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 24 mg, 41% (final step) ESI-MS: 516.3 [M+H] + 191 Preparation of Compound II-201

[0735] [ka]

[0736] The synthesis of compound II-201 was carried out according to compound II-167, using 4-cyclopropyl-[1,2,3]thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 43 mg, 67% (final step) ESI-MS: 556.4 [M+H] + 192 Preparation of Compound II-202

[0737] [ka]

[0738] The synthesis of compound II-202 was carried out according to compound II-3, using 4-cyclopropyl-[1,2,3]thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 42 mg, 56% (final step) ESI-MS: 624.4 [M+H] + 193 Preparation of Compound II-203

[0739] [ka]

[0740] The synthesis of compound II-203 was carried out according to compound II-3, using 4-(propan-2-yl)-1,2,3-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 36 mg, 52% (final step) ESI-MS: 626.4 [M+H] + 194 Preparation of Compound II-204

[0741] [ka]

[0742] The synthesis of compound II-204 was carried out according to compound II-3, using 4-ethyl-1,2,3-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 33 mg, 47% (final step) ESI-MS: 612.4 [M+H] + 195 Preparation of Compound II-205

[0743] [ka]

[0744] The synthesis of compound II-205 was carried out according to compound II-3, using 4-(hydroxymethyl)-1,2,3-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 13 mg, 32% (final step) ESI-MS: 612.4 [M+H] + 196 Preparation of Compound II-206

[0745] [ka]

[0746] The synthesis of compound II-206 was carried out according to compound II-3, using 4-((tetrahydro-2H-pyran-2-yloxy)methyl)-1,2,3-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid (according to ZED3264) in step 6. The tetrahydropyranyl (Thp) protecting group was cleaved by TFA in the final step. Yield: 9 mg, 46% (final step) ESI-MS: 614.4 [M+H] + 197 Preparation of Compound II-207

[0747] [ka]

[0748] The synthesis of compound II-207 was carried out according to compound II-3, using 1-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905) and 1-methyl-1H-imidazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 64 mg, 71% (final step) ESI-MS: 580.4 [M+H] + 198 Preparation of Compound II-208

[0749] [ka]

[0750] The synthesis of compound II-208 was carried out according to compound II-3, using (-)-cis-myrtanylamine instead of 2-adamantanamine in step 2 (according to ZED3905) and 1-methyl-1H-imidazole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 43 mg, 59% (final step) ESI-MS: 582.5 [M+H] + 199 Preparation of Compound II-209

[0751] [ka]

[0752] The synthesis of compound II-209 was carried out according to compound II-3, using (-)-cis-myrtanylamine instead of 2-adamantanamine in step 2 (according to ZED3905) and 1-methyl-1H-imidazole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 31 mg, 55% (final step) ESI-MS: 568.4 [M+H] + 200 Preparation of Compound II-210

[0753] [ka]

[0754] The synthesis of compound II-210 was carried out according to compound II-3, using 3,5-dimethyl-1-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905) and 1-methyl-1H-imidazole-5-carboxylic acid instead of 3-methyl-benzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 46 mg, 66% (final step) ESI-MS: 608.5 [M+H] + 201 Preparation of Compound II-211

[0755] [ka]

[0756] The synthesis of compound II-211 was carried out by using 3,5,7-trimethyl-1-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905) and 3-methyl-benzo[b]furan-2-carbamate in step 6 (according to ZED3264). The synthesis was carried out according to compound II-3, using 1-methyl-1H-imidazole-5-carboxylic acid instead of carboxylic acid. Yield: 53 mg, 70% (final step) ESI-MS: 622.5 [M+H] + 202 Preparation of Reference Compound 6

[0757] [ka]

[0758] The synthesis of reference compound 6 was carried out according to compound II-3, using 2-phenylethylamine instead of 2-adamantanamine in step 2 (according to ZED3905) and nicotinic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). Yield: 89 mg, 79% (final step) ESI-MS: 547.4 [M+H] + [Biological Examples] Example B-1. Inhibitory effect of the compound according to the present invention Transglutaminase assay To determine the effectiveness of inhibitors against tissue transglutaminase, the incorporation of dansylcadaverine into dimethylcasein (Zedira product T036, Lorand et al., Anal Biochem, 1971, 44:221-31) was measured using recombinant human transglutaminase 2 (Zedira product T022).

[0759] Tissue transglutaminase is diluted in buffer (50 mM Tris-HCl, 7.5 mM CaCl2, 150 mM NaCl, pH=7.4). The final concentration of TG2 in the assay is 10 nM.

[0760] A 10 mM stock solution of inhibitor is prepared in DMSO, and from this a series of 1:2 dilutions are prepared also in DMSO. Each initial dilution is then diluted 1:50 with buffer (50 mM Tris-HCl, 7.5 mM CaCl2, 150 mM NaCl, pH=7.4) to produce final working dilutions containing 2% (v / v) DMSO.

[0761] 15 μl of inhibitor working dilution is added per well of a 96-well microtiter plate. As a control, 15 μl of a 2% (v / v) DMSO solution prepared using the above buffer is added per well.

[0762] Just before starting the assay, 600 μl of transglutaminase working solution is added to 11.4 ml of assay buffer (50 mM Tris-HCl, 10 mM CaCl2, 10 mM glutathione, 2.5% glycerol, 16.7 μM dansylcadaverine, 4 μM N,N-dimethylcasein, 200 mM NaCl, pH=8.0). 285 μl of this reaction mixture is added per well containing inhibitor.

[0763] The increase in fluorescence was measured at λ for 30 min at 37°C. ex = 330 nm and λ em = 500 nm. The slope of the increase in fluorescence between 20 and 30 minutes is defined as the IC 50 The value (the inhibitor concentration at which 50% of the initial activity is inhibited) is calculated to determine the concentration.

[0764] The enzyme activity is analyzed by calculating the slope of the increase in fluorescence intensity. IC 50 Values ​​are calculated by plotting enzyme activity (as a percentage from a control containing 2% DMSO instead of inhibitor) versus inhibitor concentration. IC 50 is defined as the inhibitor concentration that inhibits 50% of the initial enzyme activity.

[0765] The inhibitory activity of the compounds of the present invention on tissue transglutaminase (TG2) was measured using IC 50 The values ​​used are shown in Table 1 below.

[0766] [Table 1-1]

[0767] [Table 1-2]

[0768] [Table 1-3]

[0769] [Table 1-4]

[0770] [Table 1-5]

[0771] Example B-2. logD value of the compound of the present invention To classify the compounds of the invention according to their lipophilicity, LogD values ​​(partition coefficients) were determined using the well-established shake flask method and the partitioning of the compounds between octanol and phosphate buffered saline (PBS, pH 7.4) was measured by HPLC.

[0772] LogD is pH dependent and is a "predictor" for in vivo properties. LogD combines lipophilicity (intrinsic structural property of the molecule, logP) and ionizability (pKa).

[0773] Compounds with moderate lipophilicity (LogD values ​​between 0 and 3) usually favor oral absorption, striking a balance between solubility and permeability. However, advanced formulation of the compound may improve oral bioavailability for highly lipophilic compounds.

[0774] [Table 2-1]

[0775] [Table 2-2]

[0776] [Table 2-3]

[0777] [Table 2-4]

[0778] Example B-3. Caco-2 permeability analysis of compounds of the present invention Permeability coefficient (P app Values ​​were obtained from Caco-2 barrier studies predicting oral / intestinal bioavailability of the tested compounds. The analysis was performed by using CacoReady™ ready-to-use kits from ReadyCell according to the manufacturer's protocol.

[0779] 1x10 -6 P exceeding cm / s app Compounds with a value of 1x10 are classified as permeable, whereas compounds with a -6 P less than cm / s app Compounds having a value are considered to be classified as non-permeating.

[0780] [Table 3-1]

[0781] [Table 3-2]

[0782] [Table 3-3]

[0783] [Table 3-4]

[0784] bioavailability studies Promising P appAs estimated from the values ​​(permeability coefficient, see below), we have demonstrated the oral bioavailability of the inhibitors of the present application by representative compounds II-3, II-15, and II-28. For this set of selected representative compounds, the pharmacokinetic profile was determined in male C57BL / 6 mice (N=3 each). Briefly, the compounds were administered at 200 mg / kg as a single dose of soluble oral formulation [20 mg / ml in PBS / (2-hydroxypropyl)-β-cyclodextrin formulation]. Plasma samples were taken (0 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, and 6 h) and analyzed by LC-MS to determine the concentrations of the representative compounds.

[0785] The calculated pharmacokinetic parameters are summarized in the table.

[0786] [Table 4] C max :Maximum plasma concentration. AUCt: area under the plasma concentration-time curve from dose to the last observed concentration at time t, as measured by the trapezoidal rule. K el Kel is estimated by linear regression on the logarithm of the final concentration as a function of time. The points used to calculate Kel are selected using the "Best Fit" option in Winnonlin. MRT:Average dwell time. t 1 / 2 :Formula ln2 / K el It is calculated by applying CL / F: Apparent plasma clearance calculated as: Dose / AUC inf . V d / F (L / kg): apparent volume of distribution after administration. The parameter is V d / F=(CL / F) / K el It is calculated as follows. R 2 :Correlation coefficient.

[0787] [Table 5]

[0788] The corresponding PK profiles showed that plasma levels for all representative compounds were above the IC 90 Over the course of the study (6 hours), IC 50 In summary, the high C max The value is IC 90 Thus, we are occupying all the active TG2 available. I look forward to it.

[0789] Furthermore, in a multiple-dose PK study, II-3 was orally administered twice daily (12-h interval) at a dose of 200 mg / kg (dose volume 10 mL / kg) to three mice. After sacrificing the animals, the liver and lungs were removed. Homogenates of each tissue were analyzed by LC-MS to determine the concentration of the compound. The lung and liver tissue concentrations after the eighth dose (4 days) were 6,800 ng / g and 10,400 ng / g, respectively, indicating that the compound reached the tissues at pharmacologically active concentrations.

Claims

1. A compound of general formula (I) 【Chemical 1】 wherein L is -L １ -, or -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-; L ２ represents a bond, -NR Ｎ１ -, -NR Ｎ１ CH ２ -, -NR Ｎ１ CH ２ CH ２ -, or -NR Ｎ１ CH(CH ３ ); R １ is 【Chemical Formula 2】 represents; R ２ is [Chemical Formula 3-1] [Chemical 3-2] 【Chemical Figure 3-3】 [Chemical Formula 3-4] [Chemical Formula 3-5] [Chemical Formula 3-6] represents; Here, the unsubstituted bicyclic residue can be substituted with one to five substituents R ９ ~R １４ and R Ｎ ; and can be substituted using 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, hexamethylenetetraminyl, and the aforementioned residues optionally contain one or more C═C double bonds and / or are optionally substituted by one or more R ａ , R ｂ , R ｃ , R ｄ , and R ｅ ; R ａ 、R ｂ 、R ｃ 、R ｄ 、and R ｅ are, independently of one another, -H, -F, -Cl, -Br, -CN, -OH, -CH ３ 、-CH ２ CH ３ 、-CH ２ CH ２ CH ３ 、-CH(CH ３ ) ２ 、-CHF ２ 、-CF ３ 、-CH ２ CF ３ 、-COCH ３ 、-COCH ２ CH ３ 、-CO ２ H、-CO ２ CH ３ 、-CO ２ C ２ H ５ 、-CONH ２ 、-CONHCH ３ 、-CON(CH ３ ) ２ 、-CONHC ２ H ５ 、-CH ２ CO ２ H、-CH ２ CO ２ CH ３ 、-CH ２ CO ２ C ２ H ５ 、-CH ２ CONH ２ 、-CH ２ CONHCH ３ 、-CH ２ CON(CH ３ ) ２ 、-CH ２ CONHC ２ H ５ 、-NHCOCH ３ 、-NHCOC ２ H ５ 、-NHCOCF ３ 、-NHCOCH ２ CF ３ 、-NHSO ２ CH ３ , -NHSO ２ C ２ H ５ , -NHSO ２ CHF ２ , -NHSO ２ CF ３ , or -NHSO ２ CH ２ CF ３ , represents; R ４ represents -NR ６ R ７ ; R ６ and R ７ are, independently of one another, -H, -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 -NR ６ R ７ is -N(C ２ H ５ ) ２ , 【Chemical Formula 4】 is; R ８ 、R ９ 、R １０ 、R １１ 、R １２ 、R １３ 、および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 , -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, -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 NHC ３ H ７ 、 -SO ２ NHCH(CH ３ ) ２ 、 -SO ２ NH-cyclo-C ３ H ５ 、 -SO ２ NH C(CH ３ ) ３ 、 -SO ２ N(CH ３ ) ２ 、 -SO ２ N(C ２ H ５ ) ２ 、 -SO ２ N(C ３ H ７ ) ２ 、 -SO ２ N[CH(CH ３ ) ２ ２ 、 -SO ２ N[C(CH ３ ) ３ ) ２ 、 -NHSO ２ CH ３ 、 -NHSO ２ CF ３ 、 -NHSO ２ C ２ H ５ 、 -NHSO ２ C ３ H ７ 、 -NHSO ２ CH(CH ３ ) ２ 、 -NHSO ２ C(CH ３ ) ３ 、 -CH=CH ２ 、 -CH ２ -CH=CH ２ 、 -C(CH ３ )=CH ２ 、 -CH=CH-CH ３ 、 -C≡CH、 -C≡C-CH ３ 、 -CH ２ -C≡CH、 -Ph、 -O-Ph、 -O-CH ２ -Ph、​ 【Chemical Formula 5】 represents; Or, R ８ and R ９ , or R ９ and R １０ can both form one of the following five - or six - membered rings: 【Chemical Formula 6】 Or, R １２ and R １３ , or R １３ and R １４ can both form one of the following five - or six - membered rings: 【Chemical Formula 7】 R Ｎ is -H, -CH ３ , -C ２ H ５ , -C ３ H ７ , -CH(CH ３ ), ２ , -C ４ H9, -CH ２ -CH(CH ３ ), ２ , -CH(CH ３ ), -C ２ H ５ , -C(CH ３ ), ３ , -cyclo-C ３ H ５ , -cyclo-C ４ H ７ , -cyclo-C ５ H ９ , -CH ２ -cyclo-C ３ H ５ , -CH ２ -cyclo-C ４ H ７ , -CH ２ -cyclo-C ５ H ９ , -CH ２ F, -CHF ２ , -CF ３ , -CH ２ Cl, -CH ２ Br, -CH ２ I, -CH ２ -CH ２ F, -CH ２ -CHF ２ , -CH ２ -CF ３ , -CH ２ -CH ２ Cl, -CH ２ -CH ２ 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 ; A compound of general formula (I), or a diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemate, solvate, hydrate, or pharmaceutically acceptable salt of the compound of general formula (I).

2. The compound according to claim 1, or a diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemate, solvate, hydrate, or pharmaceutically acceptable salt thereof, wherein L represents -L1-L2- A compound, or a diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemate, solvate, hydrate, or pharmaceutically acceptable salt thereof.

3. The compound according to claim 1, or a diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemate, solvate, hydrate, or pharmaceutically acceptable salt thereof, wherein the unsubstituted bicyclic residue can be substituted with one to three substituents R11 to R13 A compound, or a diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemate, solvate, hydrate, or pharmaceutically acceptable salt thereof.

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

5. The compound according to claim 4, wherein the unsubstituted bicyclic residue can be substituted with one to three substituents R11 to R13, a compound.

6. The compound according to claim 1, wherein in the formula, R ２ is 【Chemical Formula 9-1】 【Chemical Formula 9-2】 represents, In the formula, the unsubstituted bicyclic residue may be substituted with one to five substituents R ９ to R １４ , and R Ｎ and the substituents R ９ to R １４ , and R Ｎ have the meanings as defined in claim 1, A compound.

7. The compound according to claim 6, wherein the unsubstituted bicyclic residue can be substituted with one to three substituents R11 to R13, a compound.

8. The compound according to claim 1, or a diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemate, solvate, hydrate, or pharmaceutically acceptable salt thereof, wherein the compound has formula (Ib) 【Chemical formula 10】 wherein L is -L １ -, or -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-; 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 ２ is 【Chemical Formula 11-1】 【Chemical Formula 11-2】 represents; 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, hexamethylenetetraminyl, and the foregoing residues optionally contain one or more C═C double bonds and / or are substituted by one or more R ａ , R ｂ , R ｃ , R ｄ , and R ｅ ; R ａ 、R ｂ 、R ｃ 、R ｄ 、and R ｅ are, independently of one another, -H, -F, -Cl, -Br, -CN, -OH, -CH ３ 、-CH ２ CH ３ 、-CH ２ CH ２ CH ３ 、-CH(CH ３ ) ２ 、-CHF ２ 、-CF ３ 、-CH ２ CF ３ 、-COCH ３ 、-COCH ２ CH ３ 、-CO ２ H、-CO ２ CH ３ 、-CO ２ C ２ H ５ 、-CONH ２ 、-CONHCH ３ 、-CON(CH ３ ) ２ 、-CONHC ２ H ５ 、-CH ２ CO ２ H、-CH ２ CO ２ CH ３ 、-CH ２ CO ２ C ２ H ５ 、-CH ２ CONH ２ 、-CH ２ CONHCH ３ 、-CH ２ CON(CH ３ ) ２ 、-CH ２ CONHC ２ H ５ 、-NHCOCH ３ 、-NHCOC ２ H ５ 、-NHCOCF ３ 、-NHCOCH ２ CF ３ 、-NHSO ２ CH ３ , -NHSO ２ C ２ H ５ , -NHSO ２ CHF ２ , -NHSO ２ CF ３ 、 or -NHSO ２ CH ２ CF ３ 、 represents; R ４ represents -NR ６ R ７ ; R ６ and R ７ are, independently of each other, -H, -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 -NR ６ R ７ is -N(C ２ H ５ ) ２ , 【Chemical 12】 is; 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 represents -H, -CH ３ , or -CH ２ CH ３ ; R ８ to R １４ have the meanings as defined in formula (I); A compound, or a diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemate, solvate, hydrate, or pharmaceutically acceptable salt thereof. **Claim 9** The compound according to claim 8, or a diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemate, solvate, hydrate, or pharmaceutically acceptable salt thereof, wherein L represents -L1-L2-. A compound, or a diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemate, solvate, hydrate, or pharmaceutically acceptable salt thereof. **Claim 10** A compound according to any one of claims 1 to 9, wherein L １ represents -CH ２ -, or -CH ２ CO-; L ２ represents a bond, -NR Ｎ１ -, -NR Ｎ１ CH ２ -, or -NR Ｎ１ CH(CH ３ ), and represents 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, 4-homoisotwistyl, adamantyl, or diamantyl, and the aforementioned residues optionally contain one or more C═C double bonds and / or are substituted by one or more ａ R ｂ R ｃ R ｄ , and ｅ R; R ａ 、R ｂ 、R ｃ 、R ｄ 、R ｅ 、 and R Ｎ１ have the same meaning as defined in claim 1, Compound. **Claim 11** A compound according to any one of claims 1 to 10, wherein R ２ is 【Chemical 13】 represents; R ８ ~R １４ 、 and R Ｎ has the meaning as defined in claim 1 or claim 4, Compound. **Claim 12** A compound according to any one of claims 1 to 11, wherein the compound has any one of formulas (IV-a) to (IV-o) and (V-a) to (V-d): 【Chemical Formula 14-1】 【Chemical Formula 14-2】 【Chemical Formula 14-3】 R ２ 、 R ３ 、 R ６ 、 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, Compound. **Claim 13** A compound according to any one of claims 1 to 12, wherein R ２ is 【Chemical Formula 15-1】 [[Chemical 15-2]] 【Chemical Formula 15-3】 represents, R ６ represents -H, -CH ３ , -CH(CH ３ ), ２ , -CH ２ CH ２ CH ３ , -CH ２ CH=CH 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 , -cyclo-C ３ H ５ , -cyclo-C ５ H ９ , -cyclo-C ６ H １１ , or -CH ２ -cyclo-C ３ H ５ . Compound. **Claim 14** The compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of 【Chemical Formula 16-1】 【Chemical Formula 16-2】 【Chemical Formula 16-3】 【Chemical Formula 16-4】 【Chemical Formula 16-5】 【Chemical 16-6】 【Chemical 16-7】 【Chemical Formula 16-8】 【Chemical Formula 16-9】 【Chemical 16-10】 【Chemical 16-11】 【Chemical 16-12】 【Chemical Formula 16-13】 【Chemical Formula 16-14】 【Chemical Formula 16-15】 【Chemical Formula 16-16】 【Chemical 16-17】 【Chemical 16-18】 【Chemical Formula 16-19】 ​ 【Chemical 16-21】 【Chemical 16-22】 【Chemical Formula 16-23】 [Chemical 16-24] 【Chemical 16-25】 【Chemical 16-26】 【Chemical 16-27】 【Chemical 16-28】 【Chemical 16-29】 【Chemical 16 - 30】 【Chemical 16-31】 【Chemical 16-32】 【Chemical 16-33】 **Claim 15** A pharmaceutical composition comprising, as an active ingredient, a compound according to any one of claims 1 to 14, together with at least one pharmaceutically acceptable carrier, excipient and / or diluent. **Claim 16** A compound according to any one of claims 1 to 14 for use in medicine. **Claim 17** A compound according to any one of claims 1 to 14, or the pharmaceutical composition according to claim 15, for use in the treatment or prevention of autoimmune and inflammatory diseases, vascular diseases, fibrotic diseases, liver diseases, cholestatic liver diseases, cancer, neurodegenerative diseases, eye diseases, and skin diseases. **Claim 18** A compound for use according to claim 17, or a pharmaceutical composition for use, wherein The autoimmune and inflammatory diseases include multiple sclerosis, celiac disease, Duhring-Brocq-disease (herpetiform dermatitis), gluten ataxia, gluten neuropathy, diabetes, rheumatoid arthritis, Graves' disease, inflammatory bowel disease, systemic lupus erythematosus psoriasis, and gingivitis; wherein the vascular diseases include atherosclerosis, thrombosis, arteriosclerosis; wherein the fibrotic diseases are diseases affecting the lung, kidney, liver, skin or gastrointestinal tract; wherein the liver diseases include alcoholic hepatitis, alcoholic steatohepatitis, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, cirrhosis, autoimmune hepatitis, or liver inflammation; wherein the cholestatic liver diseases include primary biliary cholangitis, and primary sclerosing cholangitis; wherein the cancers include glioblastoma, melanoma, pancreatic cancer, renal cell carcinoma, meningioma, and breast cancer, wherein the neurodegenerative diseases include Parkinson's disease, Huntington's disease, or Alzheimer's disease, wherein the eye diseases include glaucoma, cataract, macular degeneration, or uveitis; wherein the skin diseases include acne, psoriasis, scarring, and skin aging, A compound for use, or a pharmaceutical composition for use.

19. A compound for use, or a pharmaceutical composition for use according to claim 18, wherein the fibrotic diseases are cystic fibrosis, renal fibrosis and diabetic nephropathy, intestinal fibrosis, idiopathic pulmonary fibrosis, liver fibrosis. A compound for use, or a pharmaceutical composition for use.

20. A compound for use, or a pharmaceutical composition for use according to claim 17 or claim 18 in the treatment or prevention of celiac disease.

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

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