transglutaminase inhibitors

Abstract

This provides a transglutaminase inhibitor. [Solution] The present invention relates to a compound of general formula (I) as a novel inhibitor of transglutaminase, a method for producing the compound of the present invention, a pharmaceutical composition containing the compound of the present invention, and a method for the prevention and treatment of diseases related to transglutaminase, particularly transglutaminase 2. JPEG2026140958000425.jpg56165

Description

[Technical Field]

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

[0002] Transglutaminase is a type of transferase, specifically designated as "protein-glutamine:amine γ-glutamyltransferase" (EC 2.3.2.13) according to EC nomenclature. Transglutaminase links the ε-amino group of the lysine amino acid with the γ-glutamyl group of the glutamine amino acid, releasing ammonia to form an isopeptide bond. In the absence of a suitable amine and / or under certain conditions, deamide of glutamine may occur, producing the corresponding glutamic acid.

[0003] Furthermore, transglutaminase plays an important role in many therapeutic areas, such as cardiovascular diseases (thrombosis and atherosclerosis), autoimmune diseases (celiac disease, Dueling's block, gluten ataxia), neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease), skin diseases (ichthyosis, psoriasis, acne), and wound healing and inflammatory diseases (e.g., histofibrosis) (JMWodzinska, Mini-Reviews in medical chemistry, 2005, 5, 279-292).

[0004] However, one of the most important symptoms is celiac disease, a form of gluten intolerance. Celiac disease is characterized by chronic inflammation of the small intestinal mucosa. In susceptible patients, the intestinal epithelium is progressively destroyed after ingesting gluten-containing foods, resulting in reduced nutrient absorption and further exacerbating the condition, leading to symptoms such as weight loss, anemia, diarrhea, nausea, vomiting, loss of appetite, and fatigue. These findings highlight the strong need for the development of therapeutic drugs for celiac disease and other diseases associated with tissue transglutaminase (transglutaminase 2, TG2, tTG). Tissue transglutaminase is a central component of the disease's etiology. This endogenous enzyme mediates the deamide of gluten / gliadin on the small intestinal mucosa, triggering an inflammatory response. Therefore, tissue transglutaminase inhibitors are well-suited for use as active agents in pharmaceuticals.

[0005] Another important indication for tissue transglutaminase inhibitors is fibrotic disorders. Fibrotic disorders are characterized by the accumulation of cross-linked extracellular matrix proteins. Diabetic nephropathy, cystic fibrosis, idiopathic pulmonary fibrosis, renal fibrosis, and hepatic fibrosis belong to the most important fibrotic disorders addressed by the disclosed compounds.

[0006] US9,434,763B2 discloses pyridinone derivatives having a warhead containing at least one receptor-substituted double bond, such as the Michael system, as irreversible transglutaminase inhibitors. Alkylacetamides and arylacetamidopyridinones have a nanomolar range (IC) against tissue transglutaminase TG2. 50 It showed inhibitory activity against ).

[0007] Tse et al. (J.Med.Chem.2020,63,11585-11601) reported replacing the phenyl residue in antimalarial triazolopyrazine compounds with non-classical bioisosteres, such as cubane and bicyclo[1.1.1]pentane (BCP), to alter the solubility and metabolic stability of the compounds. The authors further evaluated the antiplasmium activity of bioisoster-modified triazolopyrazines against P. falciparum strain 3D7 in vitro. Replacing phenyl with a bioisoster saturated heterocyclic residue resulted in complete loss of activity. Adamantyl residues and other cage hydrocarbon derivatives reduced potency to 1 / 2 to 1 / 9 compared to the corresponding phenyltriazolopyrazine compounds. In contrast, replacing phenyl with closo-1,2- and 1,7-carborane isomers achieved high potency. The authors concluded that it is not possible to accurately predict the effects of non-classical bioisoster substitutions on biological properties, and that a considerable range of possible bioisosters must first be tested in order to identify suitable substitutions that lead to the desired properties of a given molecule. Subbaiah et al. (J.Med.Chem.2021,64,19,14046-14128) reported on phenyl ring bioisosteres in lead optimization and drug design. They showed that replacing the phenyl ring with bioisoster heterocyclic and carbocyclic moies can improve potency, solubility, and metabolic stability while reducing lipophilicity, plasma protein binding, the potential for phospholipidosis, and inhibition of cytochrome P450 enzymes and hERG channels. However, this effect is highly dependent on the properties of the compound itself and the target. US11,072,634B2 discloses a reversible transglutaminase inhibitor comprising as a reactive group an aldehyde, ketone, α-ketaldehyde, α-ketoketone, α-keto acid, α-keto ester, α-ketoamide, or halogenated methyl ketone. This inhibitor exhibits nanomolar and micromolar (IC) reactions against tissue transglutaminase TG2. 50 It showed inhibitory activity against ). [Prior art documents] [Patent Documents]

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

[0009] [Non-Patent Document 1] JMWodzinska,Mini-Reviews in medical chemistry,2005,5,279-292 [Non-Patent Document 2] Tse et al.,J.Med.Chem.2020,63,11585-11601 [Non-Patent Document 3] Subbaiah et al.,J.Med.Chem.2021,64,19,14046-14128 [Overview of the project] [Means for solving the problem]

[0010] The object of the present invention is to provide novel and most likely irreversible inhibitors of transglutaminase, particularly transglutaminase 2, methods for synthesizing such inhibitors, and some uses of these inhibitors.

[0011] This objective is resolved by the technical teachings of the independent claims. Further advantageous embodiments, aspects and details of the present invention are evident from the dependent claims, specification and examples.

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

[0013] Preferably, such chemically reactive group moieties are selected from irreversible reactive groups including, in particular, α,β-unsaturated ketoesters, α,β-unsaturated ketoamides and α,β-unsaturated sulfones. The compounds of the present invention act as selective inhibitors of transglutaminase 2. The present invention provides, for example, the following items. (Item 1) A compound of general formula (I):

Chemical formula

Chemical formula

Chemical formula

Chemical formula

化

化

化

[0014] Therefore, the present invention relates to compound (I) of the general formula: [ka] (In the formula, L is -L) 1 - or -L 1 -L 2 - represents, preferably -L 1 -L 2 - represents, L 1 This represents -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CO-, or -CH2CH2CO-, L 2 is a combination, -NR N1 -, -NR N1 CH2-, -NR N1 CH2CH2-, or -NR N1 Represents CH(CH3)-, R 1 teeth, [ka] This represents, R 2 teeth, [ka] [ka] [ka] [ka] [ka] This represents, Here, the unsubstituted bicyclic residue has 1 to 5 substituents R 9 ~R 14 and R N It may be substituted with, preferably, 1 to 3 substituents R 11 ~R 13 It can be replaced with R 3is represented by bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, adamantyl, diamantyl, or hexamethylenetetraminyl, wherein the aforementioned residues optionally contain one or more C=C double bonds, and / or R a , R b , R c , R d , and R e Replaced by one or more of the following: R a , R b , R c , R d , and R e These 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, - R represents CH2CO2CH3, -CH2CO2C2H5, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2H5, -NHCOCH3, -NHCOC2H5, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C2H5, -NHSO2CHF2, -NHSO2CF3, or -NHSO2CH2CF3. 4 is, -R 5 , -OR 5 or -NR 6 R 7 This represents, R 5-H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2CH2CH2CH2CH3, -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 , represents -Ph, -CH2-Ph, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, or -CH2CH2OCH2CH3, R 6 and R 7 These are mutually independent: -H, -CH3, -CH2CH3, -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 teeth, [ka] This represents, R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14These are -H, -F, -Cl, -Br, -I, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H 5、-C(CH3)3、-シクロ-C3H5、-CH2-シクロ-C3H5、-CH2OH、-CH2F、-CHF2、-CF3、-CH2C l、-CH2Br、-CH2I、-CH2-CH2F、-CH2-CHF2、-CH2-CF3、-CH2-CH2Cl、-CH2-CH2 Br、-CH2-CH2I、-OCH3、-OC2H5、-OC3H7、-OCH(CH3)2、-OC(CH3)3、-OC4H9、- OCHF2、-OCF3、-OCH2CF3、-OC2F5、-OCH2OCH3、-O-シクロ-C3H5、-OCH2-シクロ-C3H 5、-O-C2H4-シクロ-C3H5、-CHO、-COCH3、-COCF3、-COC2H5、-COC3H7、-COCH(CH) 3)2、-COC(CH3)3、-COOH、-COOCH3、-COOC2H5、-COOC3H7、-COOCH(CH3)2、-CO OC(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, -CON H2、-CONHCH3、-CONHC2H5、-CONHC3H7、-CONHCH(CH3)2、-CONH-シクロ-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-CH3-C3H5, -SO2NHC(CH3)3, -SO2N(CH3)2, -SO2N(C2H5)2 -SO2N(C3H7)2, -SO2N[CH(CH3)2]2, -SO2N[C(CH3)3]2, -NHSO2CH3, -NHSO2CF3, -NHSO2C2H5, -NHSO2C3H7, -NHSO2CH(CH3)2, -NHSO2C(CH3)3, -CH=CH2,-CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -C≡CH, -C≡C-CH3, -CH2-C≡CH, -Ph, -O-Ph, -O-CH2-Ph, [ka] Does it represent, or R 8 and R 9 Or R 9 and R 10 Together, they form the following 5-membered or 6-membered rings: [ka] It can form one of the following, or R 12 and R 13 Or R 13 and R 14 Together, they form the following 5-membered or 6-membered rings: [ka] It can form one of the following: R N is -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H 5、-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, -C Represents OC2H5, -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 (This represents -H, -CH3, or -CH2CH3) The invention relates to diastereomers, enantiomers, mixtures of diastereomers, mixtures of enantiomers, racemates, solvates, hydrates, or pharmaceutically acceptable salts thereof.

[0015] The present inventors have identified a cross-linked bicyclic residue R 3 We have found that a reversible inhibitor of formula (I) disclosed herein, having the above, exhibits higher efficacy than prior art compounds. The compound of the present invention has an aromatic moiety R instead of a cross-linked bicyclic residue. 3This specification demonstrates improved inhibitory activity compared to known compounds having [specific characteristic]. To demonstrate the inventive step of the compound of this application, known compounds of US9,434,763B2 (reference substance 2 (ZED1227), reference substance 3 (A8 of US9,434,763B2), and reference substance 5) were synthesized and tested as reference compounds in comparison to the most similar compound of this application. In this regard, the inhibition data were determined using a classic fluorescent amide transfer assay (incorporation of dansyl cadaverine into methylated casein, DCC assay) described in Buchold et al. [Buchold, C.; Hils, M.; Gerlach, U.; Weber, J.; Pelzer, C.; Heil, A.; Aeschlimann, D.; Pasternack, R. Features of ZED1227: The First-In-Class Tissue Transglutaminase Inhibitor Undergoing Clinical Evaluation for the Treatment of Celiac Disease. Cells2022, 11, 1667. https: / / doi.org / 10.3390 / cells11101667]. Casein is one of the most well-known high molecular weight (24 kDa) proteins that serve as substrates for transglutaminase. The inhibition data of the compounds of the present invention were compared with the inhibition of compounds disclosed in US9,434,763B2, particularly compound A8 (referred to herein as reference substance 3). Of particular note is the IC of compound A8 published in US9,434,763B2. 50 The values ​​are based on a fluorescent isopeptidase assay and therefore cannot be compared with this data. When measured by a DCC assay, reference substance 2 (IC) 50 =53nM) is reference substance 3 (IC). 50 It is 80 times more powerful compared to (4,268 nM).

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

[0017] To those skilled in the art, it is common knowledge that cross-linked bicyclic groups or cross-linked cycloalkyl groups are non-classical bioisosteres of phenyl groups, and it is believed that only by replacing the phenyl group with a cross-linked bicyclic group can compounds with similar physicochemical and biological properties, including inhibitory activity, be obtained. Therefore, this discovery was particularly surprising, as it was not predicted that the compounds of the present invention having a cross-linked bicyclic residue would exhibit improved inhibitory activity compared to conventional compounds having an aromatic residue. Because the aromatic moiety showed low potency, the cross-linked cycloalkyl group is not considered to improve the physicochemical and biological properties of the compound.

[0018] The bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, 1-adamantyl, 2-adamantyl, diamantyl, and hexamethylenetetraminyl residues used herein are related to the following parent structures: [ka] The aforementioned residues contain, by choice, one or more C=C double bonds, such as bicyclo[2.2.1]hepta-5-enyl (see III-66), and / or R a , R b , R c , R d , and R e One or more of these will be optionally replaced.

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

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

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

[0022] In one embodiment of the present invention, the compound of formula (I) has an irreversible reactive group such as an α,β-unsaturated ketoester, an α,β-unsaturated ketoamide, and an α,β-unsaturated sulfone. The compound of the present invention acts as a selective inhibitor of transglutaminase 2.

[0023] Therefore, in some embodiments, the present invention relates to the compound of formula (I). [ka] (In the formula, L is -L) 1 - or -L1 -L 2 - represents, preferably -L 1 -L 2 - represents, L 1 This represents -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CO-, or -CH2CH2CO-, L 2 is a combination, -NR N1 -, -NR N1 CH2-, -NR N1 CH2CH2-, or -NR N1 Represents CH(CH3)-, R 1 teeth, [ka] This represents, R 2 teeth, [ka] [ka] [ka] [ka] [ka] This represents, Here, the unsubstituted bicyclic residue has 1 to 5 substituents R 9 ~R 14 and R N It may be substituted with, preferably, 1 to 3 substituents R 11 ~R 13 It can be replaced by, R 3is represented by bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwistyl, adamantyl, diamantyl, or hexamethylenetetraminyl, and the aforementioned residues contain one or more C=C double bonds, and / or R a , R b , R c , R d , and R e Replaced by one or more of the following: R a , R b , R c , R d , and R e These 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, - R represents CH2CO2CH3, -CH2CO2C2H5, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2H5, -NHCOCH3, -NHCOC2H5, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C2H5, -NHSO2CHF2, -NHSO2CF3, or -NHSO2CH2CF3. 4 is, -R 5 , -OR 5 or -NR 6 R 7 This represents, R 5-H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2CH2CH2CH2CH3, -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 , represents -CH2-Ph, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, or -CH2CH2OCH2CH3, R 6 and R 7 These are mutually independent: -H, -CH3, -CH2CH3, -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, or -CH2CH2N(CH3)2, or -NR 6 R 7 teeth, [ka] This represents, R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14These are -H, -F, -Cl, -Br, -I, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H 5、-C(CH3)3、-シクロ-C3H5、-CH2-シクロ-C3H5、-CH2F、-CHF2、-CF3、-CH2Cl、-CH2B r、-CH2I、-CH2-CH2F、-CH2-CHF2、-CH2-CF3、-CH2-CH2Cl、-CH2-CH2Br、-CH 2-CH2I、-OCH3、-OC2H5、-OC3H7、-OCH(CH3)2、-OC(CH3)3、-OC4H9、-OCHF2、 -OCF3、-OCH2CF3、-OC2F5、-OCH2OCH3、-O-シクロ-C3H5、-OCH2-シクロ-C3H5、-O- C2H4-C3H5-CHO-COCH3-COCF3-COC2H5-COC3H7-COCH(CH3)2-COC(CH3)3-COOH-COOCH3-COOC2H5-COOC3H7-COOCH(CH3)2-COOC(C H3)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-シクロ-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-シクロ-C3H5、-SO2NHC(CH3)3、-SO2N(CH3)2、-SO2N(C2H5)2、 -SO2N(C3H7)2、-SO2N[CH(CH3)2]2、-SO2N[C(CH3)3]2、-NHSO2CH3、-NHSO2 CF3、-NHSO2C2H5、-NHSO2C3H7、-NHSO2CH(CH3)2、-NHSO2C(CH3)3、-CH=CH2、-CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -C≡CH, -C≡C-CH3, -CH2-C≡CH, -Ph, -O-Ph, -O-CH2-Ph, [ka] Does it represent, or R 8 and R 9 Or R 9 and R 10 Together, they form the following 5-membered or 6-membered rings: [ka] It can form one of the following, or R 12 and R 13 Or R 13 and R 14 Together, they form the following 5-membered or 6-membered rings: [ka] It can form one of the following: R N is -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H 5、 -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, -C HO, -COCH3, -COC2H5, -COC3H7, -COCH(CH3)2, -COC(CH3)3, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2 , -COOC(CH3)3, -COOCH2Ph, -SO2CH3, -SO2CF3, -SO2C2H5, -SO2C3H7, -SO2CH(CH3)2, or -SO2C(CH3)3, R N1(This represents -H, -CH3, or -CH2CH3) This refers to the diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemates, solvates, hydrates, or pharmaceutically acceptable salts thereof.

[0024] In all general formulas disclosed herein, R 2 Preferably, [ka] [ka] [ka] [ka] [ka] This represents a compound where the unsubstituted bicyclic residue has 1 to 5 substituents R 9 ~R 14 and R N It may be substituted with, preferably, 1 to 3 substituents R 11 ~R 13 Substituent R may be substituted. 9 ~R 14 and R N The terms have the meanings defined herein or in claim 1.

[0025] 1 to 5 substituents R 9 ~R 14 and R N The unsubstituted bicyclic residues that can be substituted have the following structure, with substituent R 9 ~R 14 and R N The terms have the meanings defined herein: [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0026] In one embodiment of the compounds of the present invention disclosed herein, L represents -CH2CO-NH-, -CH2CO-NCH3-, -CH2CO-NH-CH2-, or -CH2CO-NH-CH(CH3)-.

[0027] A preferred compound is one of formula (I), [ka] In the formula, L is -L 1 -L 2 - represents, L 1 This represents -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CO-, or -CH2CH2CO-, L 2 is a combination, -NR N1 -, -NR N1 CH2-, -NR N1 CH2CH2-, or -NR N1 Represents CH(CH3)-, R 1 teeth, [ka] This represents, R 2 , R 3 , R 5 ~R 7 , and R N1This has the meaning defined above.

[0028] A preferred compound is one of formula (I), [ka] In the formula, L is -L 1 - or -L 1 -L 2 - represents, preferably -L 1 -L 2 - represents, L 1 This represents -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CO-, or -CH2CH2CO-, L 2 is a combination, -NR N1 -, -NR N1 CH2-, -NR N1 CH2CH2-, or -NR N1 Represents CH(CH3)-, R 1 teeth, [ka] This represents, R 2 , R 3 , R 5 ~R 7 , and R N1 This has the meaning defined above.

[0029] Even more preferable is one of the compounds of formulas (Ic), (Id), and (Ie): [ka] (In the formula, L, R 2 , R 3 , and R 5 ~R 7 (This has the meaning defined above.)

[0030] Furthermore, a compound of formula (I) is preferred, [ka] In the formula, L is -L 1 - or -L 1 -L 2 - represents, preferably -L 1 -L 2 - represents, L 1 This represents -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CO-, or -CH2CH2CO-, L 2 is a combination, -NR N1 -, -NR N1 CH2-, -NR N1 CH2CH2-, or -NR N1 Represents CH(CH3)-, R 1 teeth, [ka] This represents, R 2 teeth, [ka] [ka] This represents a compound where the unsubstituted bicyclic residue has 1 to 5 substituents R 9 ~R 14 and R N It may be substituted with, preferably, 1 to 3 substituents R 11 ~R 13 It can be replaced with R 5 ~R 14 , R N and R N1 This has the meaning defined above.

[0031] Additionally, any one of the compounds of formulas (Ic) to (Ie) is also preferred: [ka] (In the formula, L is -L) 1 - or -L 1 -L 2- represents, preferably -L 1 -L 2 - represents, L 1 This represents -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CO-, or -CH2CH2CO-, L 2 is a combination, -NR N1 -, -NR N1 CH2-, -NR N1 CH2CH2-, or -NR N1 Represents CH(CH3)-, R 2 teeth, [ka] [ka] This represents a compound where the unsubstituted bicyclic residue has 1 to 5 substituents R 9 ~R 14 and R N It may be substituted with, preferably, 1 to 3 substituents R 11 ~R 13 It can be replaced with R 5 ~R 14 , R N and R N1 (This has the meaning defined above.)

[0032] More preferable is the compound of formula (I), R 1 teeth, [ka] This represents, L is -L 1 -L 2 - represents, L 1 This represents -CH2- or -CH2CO-, L 2 is a combination, -NR N1 -, -NR N1 CH2-, or -NR N1 Represents CH(CH3)-, R 3is represented by 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 R a , R b , R c , R d , and R e Replaced by one or more of the following, R 5 , R 6 , R 7 , R a , R b , R c , R d , R e and R N1 This has the same meaning as defined above.

[0033] More preferable is the compound of formula (I), R 1 teeth, [ka] This represents, L is -L 1 - or -L 1 -L 2 - represents, preferably -L 1 -L 2 - represents, L 1 This represents -CH2- or -CH2CO-, L 2 is a combination, -NR N1 -, -NR N1 CH2-, or -NR N1 Represents CH(CH3)-, R 3 represents 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 R a , R b, R c , R d , and R e Replaced by one or more of the following: R 5 , R 6 , R 7 , R a , R b , R c , R d , R e and R N1 This has the same meaning as defined above.

[0034] Additionally, any one of the compounds of formulas (Ic) to (Ie) is also preferred: [ka] (In the formula, L is -L) 1 - or -L 1 -L 2 - represents, preferably -L 1 -L 2 - represents, L 1 This represents -CH2- or -CH2CO-, L 2 is a combination, -NR N1 -, -NR N1 CH2-, or -NR N1 Represents CH(CH3)-, R 2 teeth, [ka] [ka] This represents a compound where the unsubstituted bicyclic residue has 1 to 5 substituents R 9 ~R 14 , R N It may be substituted with, preferably, 1 to 3 substituents R 11 ~R 13 It can be replaced with R 5 ~R 14 , R N and R N1 (This has the meaning defined above.)

[0035] Preferably, R 2 teeth, [ka] This represents, R 3 represents 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 R a , R b , R c , R d , and R e Replaced by one or more of the following: R 5 ~R 14 , R a , R b , R c , R d , R e , R N and R N1 This has the same meaning as defined above.

[0036] In all general formulas disclosed herein, L is most preferably -L 1 -L 2 - represents, where L 1 preferably represents -CH2CO- or -CH2CH2CO-, more preferably represents -CH2CO-, L 2 -NR N1 -, -NR N1 CH2-, or -NR N1 It represents CH(CH3)-, more preferably -NH-, -N(CH3)-, -NH-CH2-, or -NH-CH(CH3)-, even more preferably -NH-, -NH-CH2-, or -NH-CH(CH3)-, and most preferably -NH-.

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

[0038] Preferably, one compound of any of the formulas (I), (Ic)~(Ie), (VI-a)~(VI-l), (VII-a)~(VII-l), or (VIII-a)~(VIII-l), R 2 teeth, [ka] [ka] This represents, R5 This represents -H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7; -CH2Ph, or -Ph. R 6 and R 7 These are -H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH2CH3, -cyclo-C3H5, -cyclo-C5H9, -cyclo-C6H 11 -CH2CH=CH2, -Ph, or -CH2Ph ​​represent these.

[0039] Preferably, one of the compounds of formulas (IX-a)~(IX-d), (Xa)~(Xd), and (XI-a)~(XI-d) is used. R 5 This represents -H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7; -CH2Ph, or -Ph. R 6 and R 7 These are -H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH2CH3, -cyclo-C3H5, -cyclo-C5H9, -cyclo-C6H 11 -CH2CH=CH2, -Ph, or -CH2Ph ​​represent these.

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

[0041] In a very preferred embodiment, the present invention refers to a compound selected from the group consisting of: [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7] [Table 4-8] [Table 4-9] [Table 4-10] [Table 4-11] [Table 4-12] [Table 4-13] [Table 4-14] [Table 4-15] Table 4-16 Table 4-17 Table 4-18 Table 4-19 Table 4-20 Table 4-21 Table 4-22 Table 4-23 Table 4-24 Table 4-25 Table 4-26 Table 4-27 Table 4-28 Table 4-29 Table 4-30

[0042] In a very preferred embodiment, the present invention is III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-10, III-11, III-12, III-13, III-14, III-15, III-16, I II-17、III-18、III-19、III-20、III-21、III-22、III-23、III-24、III-25、III-26、III-27、III-29、III-30、III-31、III-32、III-33、III-34、III-35、 III-36、III-37、III-38、III-39、III-40、III-41、III-42、III-43、III-44、III-45、III-46、III-48、III-49、III-50、III-51、III-52、III-53、III-54 、III-55、III-56、III-57、III-58、III-59、III-60、III-61、III-62、III-63、III-64、III-65、III-66、III-67、III-68、III-69、III-70、III-71、III-7 2、III-73、III-74、III-75、III-76、III-77、III-83、III-84、III-85、III-86、III-87、III-88、III-89、III-90、III-91、III-92、III-93、III-94、III- 95、III-96、III-97、III-98、III-99、III-100、III-101、III-102、III-103、III-104、III-105、III-106、III-107、III-108、III-109、III-110、III-11 1、III-112、III-113、III-114、III-115、III-116、III-117、III-118、III-119、III-120、III-121、III-122、III-123、III-124、III-125、III-126、III -127、III-128、III-129、III-130、III-134、III-135、III-140、III-142、III-145、III-147、III-148、III-150、III-152、III-153、III-155、III-165、III-166, III-169, III-170, III-171, III-172, and III-173; This refers to a compound selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof.

[0043] Method for producing the compound of the present invention In some embodiments, the present invention relates to a method for synthesizing compounds of formula (I), and in particular any one of the compounds of formulas (Ia) to (Ie): [ka]

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

[0045] As shown in Scheme 1, the method for producing the compound of formula (Ic) includes the following steps in the following order: Step 1C: Provide compound 4c [ka] Step 2C: Compound 4c and Compound 5 [ka] The coupling reaction is carried out to obtain compound 6c. [ka] Step 3C: Amino protecting group PG 3 Deprotect the compound to obtain compound 7c. [ka] Step 4C: Compound 7c and carboxylic acid (R 2 The coupling reaction of -CO2H8 is carried out to produce the compound of formula (Ic). [ka] (Here, L, R 2 , R3 , R 5 This has the same meaning as defined above in equation (Ic), and PG 3 (This is an amino protecting group). Scheme 1 [ka]

[0046] Optionally, step 1C' is performed before step 1C: (a) To provide protected aldehyde 1 [ka] (b) The coupling reaction of aldehyde 1 and triphenylphosphonium ylide 2c is carried out to obtain intermediate compound 3c; [ka] or, (b') The coupling reaction of aldehyde 1 and phosphonate 2c' is carried out to obtain intermediate compound 3c; [ka] (c) Protecting group PG of compound 3c 1 and PG 2 Deprotect the amino protecting group PG 3 By introducing [a certain component], compound 4c is obtained.

[0047] Therefore, the following method is preferred for producing the compound of formula (Ic): Step 1C': (a) To provide protected aldehyde 1 [ka] (b) The coupling reaction of aldehyde 1 and triphenylphosphonium ylide 2c is carried out to obtain intermediate compound 3c; [ka] or, (b') The coupling reaction of aldehyde 1 and phosphonate 2c' is carried out to obtain intermediate compound 3c; [ka] (c) Protecting group PG of compound 3c 1 and PG 2 Deprotect the amino protecting group PG, preferably under acidic conditions. 3 By introducing [a certain element], compound 4c is obtained. [ka] Step 1C: Provide compound 4c [ka] Step 2C: Compound 4c and Compound 5 [ka] The coupling reaction is carried out to obtain compound 6c. [ka] Step 3C: Amino protecting group PG 3 Deprotect the compound to obtain compound 7c. [ka] Step 4C: Compound 7c and carboxylic acid (R 2 The coupling reaction of -CO2H8 is carried out to produce the compound of formula (Ic). [ka] (Here, L, R 2 , R 3 , R 5 In formula (Ic), this has the same meaning as defined above, and PG 1 and PG 3 It is an amino protecting group, and PG 2 (This is a carboxyl protecting group).

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

[0049] As shown in Scheme 2, a method for producing the compound of formula (Id) includes: Step 1D: Provide compound 4d. [ka] Step 2D: Compound 4d and Compound 5 [ka] The coupling reaction is carried out to obtain compound 6d. [ka] Step 3D: Amino Protecting Group PG 3 Deprotect the compound to obtain compound 7d. [ka] Step 4D: Compound 7d and carboxylic acid (R 2 The coupling reaction of -CO2H8) is carried out to produce the compound of formula (Id). [ka] (Here, L, R 2 , R 3 , R 6 , R 7 This has the same meaning as defined above in formula (Id), and PG 3 (This is an amino protecting group).

[0050] Optionally, step 1D' is performed before step 1D: (a) To provide protected aldehyde 1 [ka] (b) The coupling reaction of aldehyde 1 and phosphonate 2d is carried out to obtain intermediate compound 3d; [ka] (c) Protecting group PG of compound 3d 1 and PG 2 Deprotect the amino protecting group PG, preferably under acidic conditions. 3 By introducing [a certain element], compound 4d is obtained. [ka]

[0051] Therefore, the following method is preferred for producing the compound of formula (Id): Step 1D': (a) To provide protected aldehyde 1 [ka] (b) The coupling reaction of aldehyde 1 and phosphonate 2d is carried out to obtain intermediate compound 3d; [ka] (c) Protecting group PG of compound 3d 1 and PG 2 Deprotect the amino protecting group PG, preferably under acidic conditions. 3 By introducing [a certain element], compound 4d is obtained. [ka] Step 1D: Provide compound 4d. [ka] Step 2D: Compound 4d and Compound 5 [ka] The coupling reaction is carried out to obtain compound 6d. [ka] Step 3D: Amino Protecting Group PG 3 Deprotect the compound to obtain compound 7d. [ka] Step 4D: Compound 7d and carboxylic acid (R 2 The coupling reaction of -CO2H8) is carried out to produce the compound of formula (Id). [ka] (Here, L, R 2 , R 3 , R 6 , R 7 This has the same meaning as defined above in formula (Id), and PG 3 (This is an amino protecting group).

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

[0053] As shown in Scheme 3, a method for producing the compound of formula (Ie) includes: Step 1E: Provide compound 4e. [ka] Step 2E: Compound 4e and Compound 5 [ka] The coupling reaction is carried out to obtain compound 6e. [ka] Step 3E: Amino protecting group PG 3Deprotect the compound to obtain compound 7e. [ka] Step 4E: Compound 7e and carboxylic acid (R 2 The coupling reaction of -CO2H8) is carried out to produce the compound of formula (Ie). [ka] (Here, L, R 2 , R 3 , R 5 This has the same meaning as defined above in formula (Ie), and PG 3 (This is an amino protecting group). Scheme 3 [ka]

[0054] Optionally, step 1E' is performed before step 1E: (a) To provide protected aldehyde 1 [ka] (b) The coupling reaction of aldehyde 1 and sulfonylmethylphosphonate 2e is carried out to obtain intermediate compound 3e; [ka] (c) Protecting group PG of compound 3e 1 and PG 2 Deprotect the amino protecting group PG, preferably under acidic conditions. 3 By introducing [a certain element], compound 4e is obtained. [ka]

[0055] (Therefore, the following method is preferred for producing the compound of formula (Ie): Step 1E': (a) To provide protected aldehyde 1 [ka] (b) The coupling reaction of aldehyde 1 and sulfonylmethylphosphonate 2e is carried out. to obtain intermediate compound 3e; [ka] (c) Protecting group PG of compound 3e 1 and PG 2 Deprotect the amino protecting group PG, preferably under acidic conditions. 3 By introducing [a certain element], compound 4e is obtained. [ka] Step 1E: Provide compound 4e. [ka] Step 2E: Compound 4e and Compound 5 [ka] The coupling reaction is carried out to obtain compound 6e. [ka] Step 3E: Amino protecting group PG 3 Deprotect the compound to obtain compound 7e. [ka] Step 4E: Compound 7e and carboxylic acid (R 2 The coupling reaction of -CO2H8) is carried out to produce the compound of formula (Ie). [ka] (Here, L, R 2 , R 3 , R 5 This has the same meaning as defined above in formula (Ie), and PG 3(This is an amino protecting group).

[0056] In the alternative route, all first protected base PGs 1 and PG 2 It is removed at the same time, and protective base PG 3 It is selectively introduced. Preferably, PG 1 and PG 3 They are the same.

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

[0058] In steps 2C, 2D, 2E, 4A, 4B, 4C, 4D, and 4E, activating reagents that activate the carboxylic acid are commonly used to promote the coupling reaction of the intermediate compound with the amino group ("Peptide Coupling Reagents, More than a Letter Soup", Ayman El-Faham and Fernando Albericio, Chemical Reviews, 2011, 111(11), p.6557-6602). Activation is performed in a separate reaction or in It can be introduced by a situ reaction. Preferably, the carboxylic acid group can be activated using one of the following coupling reagents: BOP (benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate), PyBOP (benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate), AOP (7-(azabenzotriazole-1-yl)oxytris(dimethylamino)phosphonium hexafluorophosphate), PyAOP ((7-azabenzotriazole-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate), TBTU (2-(1H-benzotriazole (-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate), EEDQ (N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline), polyphosphate (PPA), DPPA (diphenyl phosphoryl azide), HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate), HBTU (O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate), HOBt (1-hydroxybenzotriazole), HOAt (1-hydroxy-7-azabenzotriazole), DCC (N,N' Reagents of a similar nature, or mixtures thereof, that provide further activation intermediates, such as (-dicyclohexylcarbodiimide), EDC (or EDAC or EDCI, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), BOP-Cl (bis(2-oxo-3-oxazolidinyl)phosphinate chloride), TFFH (tetramethylfluoroformamidinium hexafluorophosphate), BroP (bromotris(dimethylamino)phosphonium hexafluorophosphate), PyBroP (bromotris-pyrrolidino-phosphonium hexafluorophosphate), and CIP (2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate).

[0059] Pharmaceutical compositions and pharmaceutical uses Therefore, another aspect of the present invention relates to compounds according to general formula (I) as pharmaceuticals and their use in pharmaceuticals. Particularly preferred is their use as inhibitors of transglutaminases, and especially transglutaminase 2 (TG2).

[0060] Accordingly, the compounds of formula (I) described herein or according to the present invention may be administered either by themselves or in the form of pharmacopoeia acceptable salts.

[0061] The compounds of the present invention can form pharmaceutically acceptable salts with organic or inorganic acids or bases. Examples of acids suitable for forming such acid addition salts include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, p-aminosalicylic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, sulfonic acid, phosphonic acid, perchloric acid, nitric acid, formic acid, propionic acid, gluconic acid, lactic acid, tartaric acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, p-hydroxybenzoic acid, methanesulfonic acid, and ethanol. These include sulfonic acid, nitrite, hydroxyethanesulfonic acid, ethylenesulfonic acid, p-toluenesulfonic acid, naphthylsulfonic acid, sulfanilic acid, camphorsulfonic acid, quinic acid, mandelic acid, o-methylmandelic acid, hydrogen-benzenesulfonic acid, picric acid, adipic acid, do-tolyltartaric acid, tartonic acid, (o,m,p)-toluic acid, naphthylaminesulfonic acid, trifluoroacetic acid, and other inorganic acids or carboxylic acids well known to those skilled in the art. The salts are prepared by conventional methods by contacting the free base form with a sufficient amount of the desired acid to produce the salt. Preferred are mesylates, hydrochlorides, and trifluoroacetates, with trifluoroacetates and hydrochlorides being particularly preferred.

[0062] If the compound of the present invention has an acidic group, it can also form a salt with an inorganic or organic base. Suitable examples of inorganic or organic bases include, for example, NaOH, KOH, NH4OH, tetraalkylammonium hydroxide, lysine, or arginine. The salt can be prepared conventionally using methods well known in the art, for example, by treating a solution of the compound of general formula (I) with a solution of an acid selected from the group described above.

[0063] How to use In a further embodiment of the present invention, a novel compound according to general formula (I) is used as a pharmaceutically active agent, that is, the compound of formula (I) is used in pharmaceuticals.

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

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

[0066] Celiac disease, a gluten intolerance, is associated with tissue transglutaminase (TG2). Another important indication for tissue transglutaminase inhibitors is fibrotic disorders, characterized by the accumulation of cross-linked extracellular matrix proteins. Diabetic nephropathy, cystic fibrosis, idiopathic pulmonary fibrosis, renal fibrosis, and hepatic fibrosis belong to the most important fibrotic disorders addressed by the disclosed compounds.

[0067] In biological example B-1, it has been demonstrated that the compound of the present invention, as a reversible and irreversible TG inhibitor, effectively inhibits the activity of TG, particularly TG2.

[0068] As used herein, the terms “inhibit” or “inhibit” refer to the ability of a compound to at least partially downregulate, reduce, decrease, suppress, inactivate, or inhibit the activity of an enzyme or the expression of an enzyme or protein.

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

[0070] A further aspect of the present invention relates to the use of compounds of general formula (I) for the preparation of pharmaceutical compositions useful for the prevention and / or treatment of autoimmune diseases, inflammatory diseases, vascular diseases, fibrotic disorders, liver diseases, cholestatic liver diseases, cancer, neurodegenerative diseases, eye diseases, and skin disorders.

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

[0072] Preferably, autoimmune diseases and inflammatory diseases include multiple sclerosis, celiac disease, Dueling's block disease (herpetiform dermatitis), gluten ataxia, gluten peripheral neuropathy, diabetes mellitus, rheumatoid arthritis, Graves' disease, inflammatory bowel disease, systemic lupus erythematosus, and gingivitis; vascular diseases include atherosclerosis, thrombosis, and arteriosclerosis; fibrotic diseases include cystic fibrosis, renal fibrosis and diabetic nephropathy, intestinal fibrosis, idiopathic pulmonary fibrosis, hepatic fibrosis, and other conditions affecting the lungs, kidneys, liver, skin, or intestines; and liver diseases include Cholestatic liver diseases include primary biliary cholangitis and primary sclerosing cholangitis, as well as alcoholic hepatitis, alcoholic steatohepatitis, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, cirrhosis, autoimmune hepatitis, or hepatitis; cancers include glioblastoma, melanoma, pancreatic cancer, renal cell carcinoma, meningioma, and breast cancer; neurodegenerative diseases include Parkinson's disease, Huntington's disease, or Alzheimer's disease; eye diseases include glaucoma, cataracts, macular degeneration, or uveitis; and skin disorders include acne, psoriasis, scarring, and skin aging.

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

[0074] Furthermore, compounds of general formula (I) can be administered, in the form of their pharmaceutically active salts, using, optionally, essentially non-toxic, pharmaceutically acceptable carriers, adjuvants, or expanders. Pharmaceuticals are prepared in suitable doses using conventional solid or liquid carriers or expanders and conventional pharmaceutically acceptable adjuvants / prescriptions by well-known methods. Suitable preparations are provided in administerable forms suitable for oral use, such as pills, tablets, film tablets, coated tablets, capsules, and powders.

[0075] Tablets, film tablets, coated tablets, gelatin capsules, and opaque capsules are preferred pharmaceutical formulations. Any pharmaceutical composition contains at least one compound of general formula (I) and / or a pharmaceutically acceptable salt thereof 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.

[0076] Furthermore, the object of the present invention is also to include pharmaceutical preparations for oral, parenteral, cutaneous, intradermal, gastric, intracutaneous, intravascular, intravenous, intramuscular, intraperitoneal, intranasal, vaginal, intracheek, percutaneous, rectal, subcutaneous, sublingual, topical, transdermal, or inhalation applications, which contain, in addition to typical vehicles and expanders, a compound of general formula (I) and / or a pharmaceutically acceptable salt thereof as an active ingredient.

[0077] The pharmaceutical compositions of the present invention contain one of the compounds of formula (I) disclosed herein as an active ingredient and are typically mixed with a suitable carrier material selected according to conventional pharmaceutical practice for the intended dosage form, i.e., orally administered tablets, capsules (filled with either solid, semi-solid, or liquid), powders, orally administered gels, elixirs, dispersible granules, syrups, suspensions, etc. For example, the compounds of formula (I) can be combined as an active ingredient with any orally administered, non-toxic, pharmaceutically acceptable inert carrier, such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, or ethyl alcohol (in liquid form), to form orally administered tablets or capsules. Furthermore, suitable binders, lubricants, disintegrants, and colorants may be added to the mixture as needed. Powders and tablets may consist of the inert carrier in an amount ranging from about 5% to about 95% by weight of the composition of the present invention.

[0078] Suitable binders include starch, gelatin, natural sugars, sweeteners made from corn, natural and synthetic gums such as gum arabic, sodium alginate, carboxymethylcellulose, polyethylene glycol, and wax. Lubricants usable in this dosage form include boric acid, sodium benzoate, sodium acetate, and sodium chloride. Disintegrants include starch, methylcellulose, cyclodextrin, and guar gum. Sweeteners, flavorings, and preservatives may also be included as needed. Some of the terms used above, namely disintegrants, fillers, lubricants, and binders, will be discussed in more detail below.

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

[0080] Preparations in liquid form include solutions, suspensions, and emulsions. Examples include water or water-propylene glycol solution for parenteral injection, or preparations for oral solutions, suspensions, and emulsions with added sweeteners and opacifiers.

[0081] Suitable aerosol preparations for inhalation include solids in the form of solutions and powders that can be mixed with a pharmaceutically acceptable carrier such as a compressed inert gas, for example, nitrogen.

[0082] When preparing suppositories, a mixture of fatty acid glycerides, such as a low-melting-point wax like cocoa butter, is first melted, and the active ingredient is then uniformly dispersed in it by stirring or a similar mixing operation. The molten, homogeneous mixture is then poured into a suitable mold and cooled to solidify.

[0083] Furthermore, the preparations also include solid forms that are converted into liquid forms immediately before use for either oral or parenteral administration. Such liquid forms include solutions, suspensions, and emulsions.

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

[0085] The term "capsule" refers to a special container or casing made of methylcellulose, polyvinyl alcohol, or modified gelatin or starch, which can contain an activator. Typically, hard-shell capsules are prepared from a mixture of bone and pigskin gelatin, which has relatively high gel strength. The capsule itself may contain small amounts of colorants, opacifiers, softeners, and preservatives.

[0086] A tablet is a compressed or compressed solid dosage form containing an active ingredient together with a suitable bulking agent. Tablets can be manufactured by compressing a mixture or granules obtained by wet granulation, dry granulation, or compression methods known to those skilled in the art.

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

[0088] The powder for composition refers to a powder mixture containing an active ingredient and a suitable bulking agent, which can be suspended in water or juice.

[0089] A suitable bulking agent is typically a substance that forms the majority of the composition or dosage form. Suitable bulking agents include sugars such as lactose, sucrose, mannitol, and sorbitol; starches derived from wheat, corn, rice, and potatoes; and celluloses such as microcrystalline cellulose. The amount of bulking agent in the composition may range from about 5% to about 95% by weight of the total composition, preferably about 25% to about 75% by weight, and more preferably about 30% to about 60% by weight.

[0090] The term "disintegrant" refers to a material added to a composition to assist in the disintegration and release of a pharmaceutical substance. Suitable disintegrants include starch, modified starches such as carboxymethyl starch sodium which is soluble in cold water; natural and synthetic gums such as locust bean gum, karaya, guar gum, tragacanth, and agar; cellulose derivatives such as methylcellulose and carboxymethylcellulose sodium, microcrystalline cellulose and cross-linked microcrystalline cellulose, e.g., croscarmellose sodium; alginates such as sodium alginate; clays such as bentonite, and foaming mixtures. The amount of disintegrant used in a composition may range from about 2 to 20% by weight of the composition, more preferably from about 5 to about 10% by weight.

[0091] A binder is characterized by being a substance that binds or "adheres" powders together, and therefore plays the role of an "adhesive" in the formulation. The binder provides sticky starch that is already available as a bulking agent or disintegrant. Suitable binders include sugars such as sucrose; starches derived from wheat, corn, rice, and potatoes; natural gums such as gum arabic, gelatin, and tragacanth; seaweed derivatives such as alginic acid, sodium alginate, and calcium ammonium alginate; cellulose materials such as methylcellulose, sodium carboxymethylcellulose, and hydroxypropyl methylcellulose; and inorganic compounds such as polyvinylpyrrolidone and magnesium aluminum silicate. The amount of binder in the composition may range from about 2 to about 20% by weight of the total composition, preferably about 3 to about 10% by weight, and more preferably about 3 to about 6% by weight.

[0092] The term lubricant refers to a substance added to a dosage form, such as a tablet or granule, after compression to reduce friction and release it from a mold or press. Suitable lubricants include metal stearates such as magnesium stearate, calcium stearate, or potassium stearate; stearic acid; high-melting-point waxes; and water-soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycol, and D,L-leucine. Because lubricants need to be present not only on the surface of the granules but also between the granules and the parts of the tablet press, they are typically added in the final step before compression. The amount of lubricant in the composition may range from about 0.2% to about 5% by weight of the total composition, preferably about 0.5% to about 2% by weight, and more preferably about 0.3% to about 1.5% by weight.

[0093] Lubricants are materials that prevent granule clumping and improve fluidity, resulting in smooth and uniform flow. Suitable lubricants include silicon dioxide and talc. The amount of lubricant in the composition may be in the range of about 0.1 to about 5% by weight of the total composition, preferably about 0.5 to about 2% by weight.

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

[0095] As used herein, the “pharmaceutically effective amount” of a transglutaminase inhibitor is the amount or activity effective to achieve the desired physiological outcome in either cells treated in vitro or patients treated in vivo. Specifically, the pharmaceutically effective amount is an amount sufficient to inhibit one or more of the clinically defined pathological processes associated with transglutaminase-2 over a specific period of time. The effective amount may vary depending on the particular compound of formula (I) and further depends on several factors and conditions related to the subject being treated and the severity of the disease. For example, when the inhibitor is administered in vivo, factors such as the patient's age, weight, and health status, as well as dose-response curves and toxicity data obtained from preclinical animal studies, are among the data to be considered. When an inhibitor in the form of a compound of formula (I) described herein is brought into contact with cells in vivo, several preclinical in vitro studies are designed to determine parameters such as absorption, half-life, dose, and toxicity. Determining the pharmaceutically effective amount of a given pharmaceutically active ingredient is part of the ordinary art of those skilled in the art. [Examples]

[0096] The following abbreviations used in the examples have the following meanings: Boc (tert-butoxycarbonyl), BocOSu (N-tert-butoxycarbonyloxysuccinimide), DCM (dichloromethane), DMAP (4-(dimethylamino)-pyridine), TEA (triethylamine), DMF (dimethylformamide), DMP (des-martin periodinane), DIPEA (N-ethyldiisopropylamine), Glu (glutamic acid), EDC (1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide), TFA (trifluoroacetic acid), THF (tetrahydrofuran), SiO (ethyl acetate), HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate), HOBt (hydroxybenzotriazole), MTBE (methyl tert-butyl ether), tBu (tert-butyl).

[0097] Chemical Examples The following examples are intended to illustrate the present invention using selected compounds, without limiting the scope of protection of this intellectual property right to these specific examples. It will be apparent to those skilled in the art that similar compounds and compounds produced according to similar synthesis methods are included within the scope of protection of this intellectual property right.

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

[0099] 1. Preparation of compound ZED1657 [ka] 30.0 g (214 mmol) of 2-hydroxy-3-nitropyridine and 40.5 g (2 equivalents) of chloroacetic acid were suspended in 600 mL of water. At 40°C, 245 g (3 equivalents) of trisodium phosphate dodecahydrate was added, and the reaction mixture was stirred overnight at room temperature. 250 mL of HCl (32%) was added, and the suspension was stirred further overnight at 4°C. The precipitate was filtered and dried. Yield: 41.2g, 97% ESI-MS: 199.3 [M+H] +

[0100] 2. Preparation of compound ZED3905 [ka] 17.0 g (85.8 mmol) of ZED1657, 16.1 g (1 equivalent) of 2-adamantanamine hydrochloride, and 11.6 g (1 equivalent) of HOBt were dissolved in 200 mL of DMF and 17.9 mL (1.2 equivalents) of DIPEA. 18.1 g (1.1 equivalents) of 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride was added, and the reaction mixture was stirred overnight at room temperature. The solvent was evaporated, and the residue was dissolved in 500 mL of DCM. The solution was washed with 200 mL of citric acid solution (10%), NaHCO3 solution (10%), and brine, respectively. The organic phase was dried over Na2SO4, filtered, and the solvent was evaporated. Yield: 24.1g, 85% ESI-MS: 332.4 [M+H] +

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

[0102] Scheme III-2 [ka]

[0103] Scheme III-3 [ka]

[0104] Preparation of compound ZED788 [ka] 12.0 g of Boc-L-Glu-OtBu (39.6 mmol) and 7.09 g of cesium carbonate (21.8 mmol, 0.55 equivalents) were suspended in 100 ml of DMF and stirred at room temperature for 1 hour. 2.47 ml of iodomethane (39.6 mmol) was added, and the mixture was stirred at room temperature overnight. The solvent was evaporated, the residue was dissolved in ethyl acetate, and washed twice with citric acid solution (10%), NaHCO3 solution (10%), and brine, respectively. The organic phase was dried over Na2SO4, filtered, and the solvent was evaporated. The product was used without further purification. Yield: 13.4g, >100% ESI-MS: 318.3 [M+H] +

[0105] Preparation of compound ZED720 [ka] 13.4 g of ZED788 (approximately 39.6 mmol) and 986 mg of N,N-dimethyl-4-aminopyridine (DMAP) were dissolved in 30 ml of acetonitrile. 17.6 g of di-tert-butyl bicarbonate (77.1 mmol) was added to 100 ml of acetonitrile, and the solution was stirred overnight at room temperature. The solvent was evaporated, and the residue was dissolved in ethyl acetate and washed twice with citric acid solution (10%), NaHCO3 solution (10%), and brine, respectively. The organic phase was dried over Na2SO4, filtered, and the solvent was evaporated. The product was used without further purification. Yield: 13.7g, 83% ESI-MS: 418.3 [M+H] +

[0106] Preparation of compound ZED721 [ka] 13.7 g of ZED720 (32.8 mmol) was dissolved in 200 ml of anhydrous diethyl ether and cooled to -78°C under an argon atmosphere. 36.1 ml of diisobutylaluminum hydride (1 M in hexane) was added dropwise, and the solution was stirred at -78°C for 30 minutes, then quenched with potassium sodium tartrate (Rochelle salt) solution. The organic layer was separated, dried over Na2SO4, filtered, and concentrated to dryness. The product was used without further purification. Yield: 13.3g, >100% ESI-MS: 388.3 [M+H] +

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

[0108] Preparation of compound Ib [ka] 12.0 g of ZED755 (27.1 mmol) was dissolved in 100 ml of DCM / TFA (1:1) and stirred at room temperature for 1 hour. The solvent was evaporated, and the residue was dissolved in 100 ml of DMF and 9.23 ml of DIPEA (2 equivalents). 7.15 g of N-(tert-butoxycarbonyloxy)succinimide was added, and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was dissolved in ethyl acetate and washed twice with citric acid solution (10%) and brine, respectively. The organic phase was dried over Na2SO4, filtered, and the solvent was evaporated. The residue was purified by flash chromatography. Yield: 5.89g, 76% ESI-MS: 288.3 [M+H] +

[0109] 4. Preparation of compound ZED4198 [ka] 1.67 g (5.80 mmol) of (S,E)-2-(tert-butoxycarbonylamino)-7-methoxy-7-oxohepta-5-enoic acid (Ib), 2.21 g (1 equivalent) of HATU, and 1.75 g (1 equivalent) of ZED3906 were dissolved in 25 mL of DMF and 1.97 mL of DIPEA (2 equivalents), and the mixture was stirred overnight at 45°C. The solvent was evaporated, and the residue was dissolved in 100 mL of siRNA. The mixture was washed twice with 30 mL of citric acid solution (10%), NaHCO3 solution (10%), and brine, respectively. The organic phase was dried over Na2SO4, filtered, and the solvent was evaporated. Yield: 1.65g, 50% ESI-MS: 571.4 [M+H] +

[0110] 5. Preparation of Compound III-1 [ka] 200 mg (0.35 mmol) of ZED4198 was dissolved in 6 ml of DCM / TFA (1:1) and stirred at room temperature for 1 hour. The solvent was evaporated, and the residue was dissolved in 9 ml of DMF. 44.2 mg (1 equivalent) of 1-methyl-1H-imidazole-5-carboxylic acid, 133 mg (1 equivalent) of HATU, and 119 μl (2 equivalents) of DIPEA were added, and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was purified by HPLC. Yield: 165 mg, 81% ESI-MS: 579.4 [M+H] + 1¹H-NMR (DMSO-D6, 500 MHz, δ [ppm]: 1.50 / / 2.00 (d / / d, 2H / / 2H, adamantyl-C4-H2), 1.70 / / 1.80 (m, 4H, adamantyl-C4-H2), 1.78 (m, 2H, adamantyl-C1-H), 1.78 (m, 2H, adamantyl-C6-H2), 1.80 (m, 2H, adamantyl-C5-H), 1.90 / / 2.03 (m / / m, 1H / / 1H, β-CH2), 2.32 (m, 2H, γ-CH2), 3.62 (s, 3H, O-CH3), 3.79 (s, 3H, imidazole-N-CH3), 3.83 (m, 1H, adamantyl-C2-H), 4.58 (ddd, 1H, α-CH2), 4.66 (s, 2H, N-CH2), 5.85 (m, 1H, =CH-), 6.25 (t, 1H, pyridinone-C5-H), 6.92 (m, 1H, =CH-), 7.33 (d, 1H, pyridinone-C6-H), 7.72 (s, 1H, imidazole-CH), 7.77 (s, 1H, imidazole-CH), 8.09 (d, 1H, adamantyl-NH), 8.21 (d, 1H, Pyridinone-C4-H), 8.61 (d, 1H, α-NH), 9.25 (s, 1H, pyridinone-NH). 13 C-NMR (DMSO-D6, 500 MHz, δ [ppm]: 26.70 / / 26.64 (Adamantyl-C5-H), 28.44 (γ-CH2), 29.10 (β-CH2), 30.92 (adamantyl-C4-H2), 31.44 (adamantyl-C1-H), 33.46 (imidazole-N-CH3), 36.74 (adamantyl-C4'-H2), 37.09 (adamantyl-C6-H2), 51.14 (O-CH3), 51.62 (N-CH2), 53.07 (α-CH2), 53.32 (adamantyl-C2-H), 104.59 (pyridinone-C5-H), 121.04 (=CH-), 122.30 (pyridinone-C4-H), 125.06 (imidazole-Cq), 127.90 (pyridinone-N-Cq), 132.78 (imidazole-CH), 133.26 (pyridinone-C6-H), 142.18 (imidazole-CH), 148.54 (=CH-), 156.60 (pyridinone-C=O), 160.24 (imidazole-C=O), 165.71 (C=O-adamantylamide), 165.98 (Cq methyl ester), 170.69 (C=O-NH-pyridinone).

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0137] 32 Preparation of Compound III-28 [ka] Compound III-28 was synthesized according to Compound III-1, using 1-Boc-imidazole-4-carboxylic acid instead of 1-methyl-1H-imidazole-5-carboxylic acid. The final product was obtained by deprotection (DCM / TFA) as described above and purified by HPLC. Yield: 45 mg, 86% (final step) ESI-MS: 565.3 [M+H] +

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0185] Scheme III-4 [ka]

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

[0187] Preparation of 80 ZED4688 [ka] 500 mg (2.24 mmol) of ZED4684 was dissolved in 16 mL of THF. At 0°C, 251 mg (2.24 mmol) of potassium tert-butoxide was added. After 30 minutes, 723 mg (1.87 mmol) of the aldehyde (S)-2-(bis(tert-butoxycarbonyl)amino)-5-oxopentanoate tert-butyl (ZED721) was added in 16 mL of THF. The mixture was stirred at 0°C for 1.5 hours, and then quenched with water (16 mL, 0°C). After extraction with Depositphotos (2 × 32 mL), the combined organic phase was washed with brine (15 mL), dried over Na₂SO₄, filtered, and the solvent was evaporated. The residue was purified by HPLC. Yield: 659 mg, 77% ESI-MS: 457.5 [M+H] +

[0188] 81 Preparation of ZED4690 [ka] 659 mg of ZED4688 (1.44 mmol) was dissolved in 20 ml of DCM / TFA (1:1) and stirred at room temperature for 1 hour. The solvent was evaporated, and the residue was dissolved in 10 ml of DMF and 245 μl of DIPEA (2 equivalents). 310 mg (1 equivalent) of N-(tert-butoxycarbonyloxy)succinimide was added, and the reaction was stirred at room temperature overnight. The solvent was evaporated, and the residue was dissolved in ethyl acetate and washed twice with citric acid solution (10%) and brine, respectively. The organic phase was dried over Na2SO4, filtered, and the solvent was evaporated. The residue was purified by HPLC. Yield: 242 mg, 56% ESI-MS: 301.5 [M+H] +

[0189] Preparation of 82 ZED4692 [ka] 242 mg (0.81 mmol) of ZED4688, 308 mg (1 equivalent) of HATU, and 244 mg (1 equivalent) of ZED3906 were dissolved in 10 mL of DMF and 276 μL of DIPEA (2 equivalents), and stirred overnight at 45°C. The solvent was evaporated, and the residue was dissolved in 50 mL of siRNA. The mixture was washed twice with 15 mL of citric acid solution (10%), NaHCO3 solution (10%), and brine, respectively. The organic phase was dried over Na2SO4, filtered, and the solvent was evaporated. The residue was purified by HPLC. Yield: 288mg, 61% ESI-MS: 584.4 [M+H] +

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

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

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

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

[0194] 86 Preparation of compound ZED4893 [ka] 500 mg (3.57 mmol) of 2-hydroxy-3-nitropyridine and 818 mg (1 equivalent) of 1-(bromomethyl)adamantane were dissolved in 10 mL of DMF and 1.24 mL of DIPEA (2 equivalents), and the mixture was stirred overnight at room temperature. The solvent was evaporated, and the residue was dissolved in 30 mL of siRNA. The mixture was washed twice with 10 mL of citric acid solution (10%), NaHCO3 solution (10%), and brine, respectively. The organic phase was dried over Na2SO4, filtered, and the solvent was evaporated. The residue was purified by HPLC. Yield: 484mg, 47% ESI-MS: 289.3 [M+H] +

[0195] 87 Preparation of compound ZED4894 [ka] 484 mg (1.68 mmol) of ZED4893 was suspended in 30 mL of MeOH, and then 50 mg of palladium (10%) activated carbon (non-reducing) was added. The suspension was stirred at room temperature under a hydrogen atmosphere for 3 hours. The catalyst was filtered, and the solvent was evaporated. Yield: 339mg, 78% ESI-MS: 259.4 [M+H] +

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0294] Biological examples Example B-1. Inhibitory effect of the compound according to the present invention Transglutaminase assay To determine the efficacy of inhibitors against tissue transglutaminase, the incorporation of dansylcadaverine into dimethylcasein (Zedira product T036, Lorand et al.) was investigated. (Al., Analyz Biochem, 1971, 44:221-31) was measured using recombinant human transglutaminase 2 (Zedira product T022).

[0295] Tissue transglutaminase was diluted in buffer solution (50 mM Tris-HCl, 7.5 mM CaCl2, 150 mM NaCl, pH=7.4). The final concentration of TG2 in the assay was 10 nM.

[0296] A 10 mM inhibitor stock solution is prepared with DMSO, and a 1:2 dilution series is prepared from this solution, also with DMSO. Then, each of the initial dilutions is diluted 1:50 with buffer (50 mM Tris-HCl, 7.5 mM CaCl2, 150 mM NaCl, pH=7.4) to obtain a final working dilution containing 2% (v / v) DMSO.

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

[0298] Immediately before starting the assay, add 600 μl of transglutaminase working solution to 11.4 ml of assay buffer (50 mM Tris-HCl, 10 mM CaCl2, 10 mM CaCl2). Add glutathione, 2.5% glycerol, 16.7 μM dansyl cadaverine, 4 μM N,N-dimethylcasein, and 200 mM NaCl (pH=8.0). Add 285 μl of this reaction mixture to each well containing the inhibitor.

[0299] Increase in fluorescence, λ ex =330nm and λ em =Measure using 500nm at 37°C for 30 minutes. IC 50 To determine the value (the inhibitor concentration at which 50% of the initial activity is inhibited), the slope of the fluorescence increase over 20-30 minutes is calculated.

[0300] Enzyme activity is analyzed by calculating the slope of the increase in fluorescence intensity. 50 The value is calculated by plotting the enzyme activity (percentage obtained from a control containing 2% DMSO instead of the inhibitor) against the inhibitor concentration. 50 This is defined as the inhibitor concentration that inhibits 50% of the initial enzyme activity.

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

[0302] Example B-2. logD value of the compound of the present invention To classify the compounds of the present invention according to their lipophilicity, a well-established flask shaking method was used to determine the compounds between octanol and phosphate-buffered saline (PBS, pH 7.4). The distribution was measured by HPLC, and the LogD value (partition coefficient) was determined.

[0303] LogD is pH-dependent and a "predictor" of in vivo properties. LogD combines lipophilicity (the intrinsic structural properties of the molecule, logP) and ionization (pKa).

[0304] Compounds with moderate lipophilicity (LogD value 0-3) are generally favored for oral absorption, offering a good balance between solubility and membrane permeability. However, advanced formulations can improve the oral bioavailability of highly lipophilic compounds. [Table 2-1] [Table 2-2] [Table 2-3]

[0305] Example B-3. Caco-2 membrane permeability assay of the compound of the present invention Permeability coefficient (P app The values ​​were obtained from the Caco-2 barrier test, which predicts the oral / intestinal bioavailability of the test compound. The assay was performed using ReadyCell's ready-to-use CacoReady® kit according to the manufacturer's protocol.

[0306] 1 x 10 -6 P exceeding cm / s app Compounds with a value of 1 × 10 are classified as membrane permeable, -6 P below cm / s app Compounds with a value are considered to be classified as having no membrane permeability. Table 3-1 Table 3-2 Table 3-3

Claims

[Claim 1] The invention described in the present specification.

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