Inhibitors of transglutaminase

Abstract

This invention relates to compounds of general formula (I) as novel inhibitors of transglutaminase, methods for producing the compounds of the invention, pharmaceutical compositions containing the compounds of the invention, and their use for the prevention and treatment of diseases associated with transglutaminase, particularly transglutaminase 2.

Description

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

[0003] Transglutaminases are part of the class of transferases and, according to EC nomenclature, are appropriately named “protein-glutamine:amine γ-glutamyltransferases” (EC 2.3.2.13). They link the ε-amino group of the amino acid lysine to the γ-glutamyl group of the amino acid glutamine, forming an isopeptide bond and releasing ammonia in the process. In the absence of a suitable amine and / or under certain conditions, deamidation of glutamine can occur, resulting in the production of the corresponding glutamate.

[0004] In addition, transglutaminase plays an important role in many therapeutic areas such as cardiovascular diseases (thrombosis and atherosclerosis), autoimmune diseases (celiac diarrhea, Duhring-Brocq disease, glutamate 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., tissue fibrosis) (JMWodzinska, Mini-Reviews in Medical Chemistry, 2005, 5, 279-292).

[0005] However, celiac disease with diarrhea, gluten intolerance, is one of the most important indications. Celiac disease with diarrhea is characterized by chronic inflammation of the small intestinal mucosa. In susceptible patients, the intestinal epithelium is subsequently damaged after ingestion of gluten-containing foods, leading to reduced nutrient absorption, which again has a significant impact on affected patients and is associated with symptoms such as weight loss, anemia, diarrhea, nausea, vomiting, loss of appetite, and fatigue. Due to these findings, there is a significant need for the development of drugs to treat celiac disease with diarrhea and other conditions related to tissue transglutaminase (transglutaminase 2, TG2, tTG). Tissue transglutaminase is a central element during the course of the disease. The endogenous enzyme catalyzes the deamidation of gluten / prolamins in the small intestinal mucosa, thereby triggering an inflammatory response. Therefore, inhibitors of tissue transglutaminase are suitable as active agents for drugs.

[0006] Another very important group of indications 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 liver fibrosis are among the most important fibrotic disorders that the disclosed compounds aim to address.

[0007] US 9,434,763 B2 discloses pyridone derivatives as irreversible glutaminase inhibitors, having a warhead comprising at least one receptor-substituted double bond, such as the Michael system. Alkylacetamido and arylacetamidopyridones exhibit inhibitory activity (IC50) against tissue transglutaminase TG2 in the nanomolar range. 50 ).

[0008] Tse et al. (J.Med.Chem.2020,63,11585-11601) reported on the substitution of phenyl residues 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 in vitro antimalarial activity of bioisostere-modified triazolopyrazines against the 3D7 strain of *Plasmodium falciparum*. Substitution of the phenyl residue with a bioisostere-saturated heterocyclic residue resulted in complete loss of activity. Adamantyl residues and other hydrocarbon cage-like derivatives resulted in potency up to 2-9 times lower than the corresponding phenyltriazolopyrazine compounds. In contrast, higher potency was obtained by substituting the phenyl residue with closed-form -1,2-(closo-1,2-) and 1,7-carborane isomers. The authors conclude that the effects of nonclassical bioisosteric substitutions on biological properties cannot be accurately predicted, and a considerable range of possible bioisosteres must first be tested to identify suitable substitutions that result in the desired properties of a given molecule.

[0009] Subbaiah et al. (J.Med.Chem.2021,64,19,14046-14128) reported on bioelectroisosterry of phenyl rings in dominant optimization and drug design. Notably, substitution of the phenyl ring with heterocyclic and carbocyclic moieties for bioelectroisosterry can lead to enhanced potency, solubility, and metabolic stability, while reducing lipophilicity, plasma protein binding, phospholipid disease potential, and inhibition of cytochrome P450 enzymes and hERG channels. However, this effect is strongly dependent on the characteristics of the compound itself and the addressing target.

[0010] US11,072,634B2 discloses a reversible glutaminase inhibitor comprising, as a warhead, an aldehyde, ketone, α-ketoaldehyde, α-ketoketone, α-ketoamino acid, α-keto ester, α-ketoamide, or halogenated methyl ketone. The inhibitor exhibits inhibitory activity (IC50) against tissue transglutaminase TG2 in the nanomolar and micromolar ranges. 50 ).

[0011] The object of this invention is to provide novel, most likely reversible inhibitors of transglutaminase, particularly transglutaminase 2, methods for synthesizing said inhibitors, and several uses of these inhibitors.

[0012] The stated objective is achieved by the technical teachings of the independent claims. Further advantageous embodiments, aspects, and details of the invention will become apparent from the dependent claims, the description, and the examples.

[0013] Surprisingly, reversible inhibitors with chemical warheads as disclosed herein have been found to effectively inhibit transglutaminases, including tissue transglutaminases known as transglutaminase 2 or TG2. These terms are used synonymously herein.

[0014] Preferably, this chemical warhead portion is particularly selected from reversible warheads, such as α-ketoamides. The compounds of the present invention are used as selective inhibitors of transglutaminase 2.

[0015] To demonstrate the inventive step of the compounds in this application, the reference compounds will be synthesized and tested against the most similar compounds compared to those in this application. Those skilled in the art may notice compound A8 from our patent US 9,434,763B2, which we introduce as Ref. 3 to highlight the inventive step and preferred features of the claimed compounds. It is evident from US 9,434,763B2 that the aromatic moiety (C-terminus) limits the potency of these compounds (compared to A1, A8, A37, A44, A47). In stark contrast, the branched alkyl moiety is highly preferred, as indicated by the more potent compounds (A28, A29, A59, A61, A63, A67, A68, A79).

[0016] To illustrate the advantage of the branched alkyl moiety over the aromatic moiety, we refer to reference compounds Ref. 2 (ZED1227, US 9,434,763 B2) and Ref. 3 (A8, ZED1047). As described in [Büchold, C.; Hils, M.; Gerlach, U.; Weber, J.; Pelzer, C.; Heil, A.; Aeschlimann, D.; Pasternack, R. Features of ZED1227: The First-In-Class Tissue Transglutaminase Inhibitor Undergoing Clinical Evaluation for the Treatment of Celiac Disease. Cells 2022, 11, 1667. https: / / doi.org / 10.3390 / cells11101667], inhibition data were determined using a classic fluorescent transamidit assay (danstanyl cadaverine incorporated into methylated casein, DCC-assay). Casein is one of the most well-known high-molecular-weight (24 kDa) protein substrates for transglutaminase. Note the IC50 data in Ref. 3 (A8) of US 9,434,763 B2. 50 The values ​​cannot be compared with the data of this invention, as this relies on the fluorescent isopeptidase assay. Ref. 2 (IC) was measured in the DCC assay. 50 =53nM) compared to Ref.3 (IC 50 =4,268nM) has more than 80 times the efficacy.

[0017] Therefore, those skilled in medicinal chemistry will choose branched alkyl moieties as lead structures, excluding aromatic moieties such as phenyl. It is well known that bridged cycloalkyl groups are non-classical bioisosteres of phenyl. By replacing the phenyl group in A8 with, for example, an adamantyl group, those skilled in the art will expect similar physicochemical or biochemical properties without much effort. Since aromatic moieties are clearly not preferred, bridged cycloalkyl groups will not be considered an improvement to the compound.

[0018] This is further supported by other reference compounds. ZED3641 (Ref. 1, as disclosed in US 11,072,634B2; Ref. 2, a reversible α-ketomethylamide analog of ZED1227) has approximately 15 times more potency than Ref. 4 (compare Table 1). Ref. 4 is similar to compound A8 with the skeleton disclosed in US 9,434,763B2, further demonstrating the superiority of the branched alkyl moiety over aromatic derivatives combined with reversible warheads.

[0019] However, surprisingly, replacing the preferred branched alkyl moiety with a bridged cycloalkyl group further significantly improves the potency of the compound, as shown in Table 1. Therefore, we consider the bridged cycloalkyl group to be disclosed in an excellent inventive manner.

[0020] In summary, the compounds of the present invention, rated "A", exhibit approximately 30 times higher efficacy compared to Ref. 3 (A8, compared to Table 1).

[0021] Furthermore, compounds with an activity rating of "B" or "C" are still preferred (lower IC50 values). 50 These compounds can also be considered creative because the peripheral ligands influence the physicochemical or biochemical properties. Therefore, depending on the application, compounds with lower potency may also have high value.

[0022] Therefore, this invention relates to compounds of general formula (I):

[0023]

[0024] in

[0025] L represents -L 1 -L 2 -;

[0026] L 1 It can represent -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CO-, or -CH2CH2CO-;

[0027] L 2 Indicates key, -NR N1 -、-NR N1 CH2-, -NR N1 CH2CH2- or -NR N1 CH(CH3)-,

[0028] R 1 express

[0029] R 2 express

[0030]

[0031]

[0032]

[0033]

[0034]

[0035] The unsubstituted bicyclic residues can be replaced by the substituent R. 9 -R 14 and R N One to five substitutions, preferably by substituent R 11 -R 13 One to three substitutions in;

[0036] R 3 The residues described herein represent 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, diadamantyl, or hexamethylenetetramine, and optionally contain one or more C=C double bonds and / or optionally R a R b R c R d and R e One or more substitutions in;

[0037] R a R b R c R d and R e Independently representing -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -CO2C2H5, -CONH2, -CONHCH3, -CON(CH3)2, -CONHC2H5, -CH2CO2H, -CH2CO2CH3, -CH2CO2C2H5, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2H5, -NHCOCH3, -NHCOC2H5, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C2H5, -NHSO2CHF2, -NHSO2CF3, or -NHSO2CH2CF3;

[0038] R 4 Indicates -NR 6 R 7 ;

[0039] R 6 It represents -CH2CH3, and R7 Indicates -H;

[0040] R 8 R 9 R 10 R 11 R 12 R 13 and R 14Independently representing -H, -F, -Cl, -Br, -I, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclic-C3H5, -CH2-cyclic-C3H5, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2Cl, -CH2-CH2Br, -CH2-CH2I, -CH2OH, -OCH3, -OC2H5, -O C3H7, -OCH(CH3)2, -OC(CH3)3, -OC4H9, -OCHF2, -OCF3, -OCH2CF3, -OC2F5, -OCH2OCH3, -O-ring-C3H5, -OCH2-ring-C3H5, -O-C2H4-ring-C3H5, -CHO, -COCH3,- COCF3, -COC2H5, -COC3H7, -COCH(CH3)2, -COC(CH3)3, -COOH, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -OOC-CH3, -OOC-CF3, -OOC -C2H5, -OOC-C3H7, -OOC-CH(CH3)2, -OOC-C(CH3)3, -NH2, -NHCH3, -NHC2H5, -NHC3H7, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC2H5, -NHCOC3H7, -NHCOCH(CH3)2, -NHCOC(CH3)3, -CONH2, -CONHCH3, -CONHC2H5, -CONHC 3H7, -CONHCH(CH3)2, -CONH-cyclo-C3H5, -CONHC(CH3)3, -CON(CH3)2, -CON(C2H5)2, -CON(C3H7)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, -SO2NH2, -SO2NH CH3、-SO2NHC2H5、-SO2NHC3H7、-SO2NHCH(CH3)2、-SO2NH-cyclo-C3H5、-SO2NHC(CH3)3、-SO2N(CH3)2、-SO2N(C2H5)2、-SO2N(C3H7)2、-SO2N[CH(CH3)2]2-SO2N[C(CH3)3]2, -NHSO2CH3, -NHSO2CF3, -NHSO2C2H5, -NHSO2C3H7, -NHSO2CH(CH3)2, -NHSO2C(CH3)3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -C≡CH, -C≡C-CH3, -CH2-C≡CH, -Ph, -O-Ph, -O-CH2-Ph,

[0041]

[0042] Or R 8 and R 9 Or R 9 and R 10 They can form one of the following quinary or hexacyclic rings:

[0043]

[0044] Or R 12 and R 13 Or R 13 and R 14 They can form one of the following quinary or hexacyclic rings:

[0045]

[0046] R NThis indicates -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-C5H9, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2Cl, -CH2-CH2Br, -CH2-CH2I, -CH 2-CH=CH2, -CH2-C≡CH, -CHO, -COCH3, -COC2H5, -COC3H7, -COCH(CH3)2, -COC(CH3)3, -CO-cyclo-C3H5, -CO-cyclo-C4H7, -CO-cyclo-C5H9, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -SO2CH3, -SO2CF3, -SO2C2H5, -SO2C3H7, -SO2CH(CH3)2, -SO2-cyclo-C3H5, or -SO2C(CH3)3;

[0047] R N1 It represents -H, -CH3, or -CH2CH3;

[0048] Or its diastereomers, enantiomers, mixtures of diastereomers, mixtures of enantiomers, racemic mixtures, solvates, hydrates, or pharmaceutically acceptable salts.

[0049] The inventors have discovered that the bridging bicyclic residue R disclosed herein... 3 The reversible inhibitor of formula (I) exhibits increased potency compared to compounds of the prior art. In particular, this paper demonstrates that, with the aromatic moiety R… 3Compared to known compounds that do not bridge bicyclic residues, the compounds of the present invention exhibit enhanced inhibitory activity. To demonstrate the inventiveness of the compounds of this application, known compounds from US 9,434,763 B2 and US 11,072,634 B2 (Reference 1 (E16 of US 11,072,634 B2), Reference 3 (A8 of US 9,434,763 B2), and Reference 4) were synthesized and tested as reference compounds compared to the most similar compounds of this application. To this extent, as described by Büchold et al. [Büchold, C.; Hils, M.; Gerlach, U.; Weber, J.; Pelzer, C.; Heil, A.; Aeschlimann, D.; Pasternack, R. Features of ZED1227: The First-In-Class Tissue Transglutaminase Inhibitor Undergoing Clinical Evaluation for the Treatment of Celiac Disease. Cells 2022, 11, 1667. https: / / doi.org / 10.3390 / cells11101667], inhibition data were determined using a classic fluorescent transaminasing assay (dansyl cadaverine incorporated into methylated casein, DCC-assay). Casein is one of the most well-known high molecular weight (24 kDa) protein substrates for transglutaminase. The inhibition data of the compounds of the present invention were compared with those of compounds disclosed in US 9,434,763 B2 (referred to herein as reference 3), particularly compound A8. It is noteworthy that the IC50 data of compound A8 in US 9,434,763 B2 and E16 from US 11,072,634 B2 are significantly different. 50 The values ​​cannot be compared with the data of this invention and depend on the fluorescence isopeptidase assay.

[0050] Therefore, the compound of formula (I) of the present invention, rated "A", exhibits approximately 100 times higher efficacy compared to Ref. 3 (A8). The same argument applies to Ref. 4. Ref. 4 also shows that the aromatic moiety of this reference compound strongly reduces inhibitory activity against TG2.

[0051] Therefore, those skilled in the art would exclude aromatic moieties, such as phenyl. It is well known that bridged cycloalkyl groups are non-classical bioisosteres of phenyl. By replacing the phenyl group in A8 with, for example, an adamantyl group, those skilled in the art would expect similar physicochemical or biochemical properties without much effort. Since aromatic moieties are clearly not preferred, bridged cycloalkyl groups would not be considered an improvement to the compound.

[0052] Surprisingly, the compounds of this invention demonstrate that bridging cycloalkyl groups enhance the potency of the compounds by several orders of magnitude compared to aromatic reference compounds. Therefore, we consider bridging cycloalkyl groups to be disclosed in an excellent inventive manner.

[0053] In another group of preferred compounds

[0054] R 2 express

[0055]

[0056]

[0057]

[0058]

[0059]

[0060]

[0061] The unsubstituted bicyclic residues can be replaced by the substituent R. 9 -R 14 and R N One to five substitutions; and preferably the substituent R 11 -R 13 One to three substitutions in; and substituent R 9 -R 14 and R N It has the meaning as defined in equation (I); and more preferably, R 2 express

[0062]

[0063]

[0064]

[0065]

[0066] The unsubstituted bicyclic residues can be replaced by the substituent R. 9 -R 14 and R N One to five substitutions; and preferably the substituent R 11 -R 13 One to three substitutions in; and substituent R 9 -R 14 and RN It has the meaning as defined in this article.

[0067] Preferably, it can be substituted by R 9 -R 14 and R N One to five substituted unsubstituted bicyclic residues; having the following structure and substituent R 9 -R 14 and R N It has the meaning as defined in this article:

[0068]

[0069]

[0070]

[0071]

[0072]

[0073]

[0074]

[0075] Compounds of general formula (I) are also preferred.

[0076]

[0077] in

[0078] L represents -L 1 -L 2 -;

[0079] L 1 It represents -CH2CO-;

[0080] L 2 Indicates -NR N1 - and R 3 Indicates 1-adamantyl; or

[0081] L 2 Indicates -NR N1 CH2-, and R 3 It represents 2-bicyclo[3.1.1]heptyl,

[0082] Furthermore, the aforementioned 1-adamantyl and 2-bicyclo[3.1.1]heptyl residues optionally contain one or more C=C double bonds and / or optionally are R a R b R c R d and Re One or more substitutions in;

[0083] R 1 express

[0084] R 2 express

[0085] R 6 It represents -C2H5;

[0086] R a R b R c R d and R e Independently representing -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -CO2C2H5, -CONH2, -CONHCH3, -CON(CH3)2, -CONHC2H5, -CH2CO2H, -CH2CO2CH3, -CH2CO2C2H5, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2H5, -NHCOCH3, -NHCOC2H5, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C2H5, -NHSO2CHF2, -NHSO2CF3, or -NHSO2CH2CF3;

[0087] R 8 R 10 and R 11Independently representing -H, -F, -Cl, -Br, -I, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclic-C3H5, -CH2-cyclic-C3H5, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2Cl, -CH2-CH2Br, -CH2-CH2I, -OCH3, -OC2H5, -OC3H7, -OCH (CH3)2, -OC(CH3)3, -OC4H9, -OCHF2, -OCF3, -OCH2CF3, -OC2F5, -OCH2OCH3, -O-ring-C3H5, -OCH2-ring-C3H5, -O-C2H4-ring-C3H5, -CHO, -COCH3, -COCF3, -COC2 H5, -COC3H7, -COCH(CH3)2, -COC(CH3)3, -COOH, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -OOC-CH3, -OOC-CF3, -OOC-C2H5, -OOC-C 3H7, -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(CH 3)2, -CONH-ring-C3H5, -CONHC(CH3)3, -CON(CH3)2, -CON(C2H5)2, -CON(C3H7)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, -SO2NH2, -SO2NHCH3, -SO2NHC2H5, -SO2NHC3H7, -SO2NHCH(CH3)2, -SO2NH-cyclo-C3H5, -SO2NHC(CH3)3, -SO2N(CH3)2, -SO2N(C2H5)2, -SO2N(C3H7)2, -SO2N[CH(CH3)2]2, -SO2N[C(CH3)3]2,-NHSO2CH3, -NHSO2CF3, -NHSO2C2H5, -NHSO2C3H7, -NHSO2CH(CH3)2, -NHSO2C(CH3)3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -C≡CH, -C≡C-CH3, -CH2-C≡CH, -Ph, -O-Ph, -O-CH2-Ph,

[0088]

[0089] R N This indicates -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-C5H9, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2Cl, -CH2-CH2Br, -CH2-CH2I, -CH 2-CH=CH2, -CH2-C≡CH, -CHO, -COCH3, -COC2H5, -COC3H7, -COCH(CH3)2, -COC(CH3)3, -CO-cyclo-C3H5, -CO-cyclo-C4H7, -CO-cyclo-C5H9, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -SO2CH3, -SO2CF3, -SO2C2H5, -SO2C3H7, -SO2CH(CH3)2, -SO2-cyclo-C3H5, or -SO2C(CH3)3;

[0090] R N1 It represents -H, -CH3, or -CH2CH3;

[0091] Or its diastereomers, enantiomers, mixtures of diastereomers, mixtures of enantiomers, racemic mixtures, solvates, hydrates, or pharmaceutically acceptable salts.

[0092] Among the compounds in the preferred group

[0093] R 2 express

[0094] And R 8 R 10R 11 and R N It has the meaning as defined in this article.

[0095] The residues used in this paper, namely 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-highly iso-twisted alkyl, adamantyl, diadamantyl, and hexamethylenetetramine, have the following parent structures:

[0096]

[0097]

[0098] Furthermore, the aforementioned residues optionally contain one or more C=C double bonds and / or optionally are R a R b R c R d and R e One or more substitutions in.

[0099] The preferred compound is that of formula (Ia):

[0100]

[0101] And L, R 2 R 3 R 6 It has the same meaning as defined in equation (I).

[0102] Preferably, the present invention relates to compounds of formula (I).

[0103]

[0104] in

[0105] L represents -L 1 -L 2 -;

[0106] L 1 It represents -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CO-.

[0107] L 2 Indicates -NR N1 - or -NR N1 CH2;

[0108] And preferably, L represents -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CONH-, -CH2CONH-CH2-, -CH2CON(CH3)-CH2-, or -CH2CONH-CH(CH3)-.

[0109] R 1 express

[0110] R 2 express

[0111]

[0112] R 3 The terms [1.1.1]pentan-1-yl, [2.1.1]hexan-1-yl, [3.1.1]heptan-3-yl, [2.2.1]heptan-2-yl, [2.2.1]heptan-5-en-2-yl, [2.2.1]heptan-7-yl, [2.2.1]heptan-2-yl, [2.2.2]octane-2-yl, 1-adamantyl, 2-adamantyl, 4-highly iso-twisted alkyl, 1-diadamantyl, or 4-diadamantyl, and the above-mentioned bicyclo[1.1.1] The pentanyl-1-yl, bicyclo[2.1.1]hexanyl-1-yl, bicyclo[3.1.1]heptane-3-yl, bicyclo[2.2.1]heptane-2-yl, bicyclo[2.2.1]heptane-5-en-2-yl, bicyclo[2.2.1]heptane-7-yl, bicyclo[2.2.1]heptane-2-yl, bicyclo[2.2.2]octane-2-yl, 1-adamantyl, 2-adamantyl, 4-highly iso-twisted alkyl, 1-diadamantyl, or 4-diadamantyl residues optionally contain one or more C=C double bonds and / or optionally are R a R b R c R d and R e One or more substitutions in;

[0113] R 6 It represents -C2H5;

[0114] And R 8 R 9 R 10 R 11 R 12 R 13 R 14 R a R b R c R d R e R N and RN1 It has the same meaning as defined in formula (I), or its diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemic mixture, solvate, hydrate, or pharmaceutically acceptable salt.

[0115] In some embodiments, the present invention relates to compounds of formula (I).

[0116]

[0117] in

[0118] L represents -L 1 -L 2 -;

[0119] L 1 It represents -CH2CO-,

[0120] L 2 Indicates -NR N1 - and R 3 Indicates 1-adamantyl; or

[0121] L 2 Indicates -NR N1 CH2-, and R 3 It represents 2-bicyclo[3.1.1]heptyl,

[0122] Furthermore, the aforementioned 1-adamantyl and 2-bicyclo[3.1.1]heptyl residues optionally contain one or more C=C double bonds and / or optionally are R a R b R c R d and R e One or more substitutions in;

[0123] R 1 express

[0124] R 2 express

[0125]

[0126]

[0127] R 6 It represents -C2H5;

[0128] And R 8 R 9 R 10 R 11 R 12 R 13 R14 R a R b R c R d R e R N and R N1 It has the same meaning as defined in formula (I), or its diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemic mixture, solvate, hydrate, or pharmaceutically acceptable salt.

[0129] In some embodiments, the present invention relates to compounds of formula (I).

[0130]

[0131] in

[0132] L represents -L 1 -L 2 -;

[0133] L 1 It represents -CH2CO-,

[0134] L 2 Indicates -NR N1 - and R 3 Indicates 1-adamantyl; or

[0135] L 2 Indicates -NR N1 CH2-, and R 3 It represents 2-bicyclo[3.1.1]heptyl,

[0136] Furthermore, the aforementioned 1-adamantyl and 2-bicyclo[3.1.1]heptyl residues optionally contain one or more C=C double bonds and / or optionally are R a R b R c R d and R e One or more substitutions in;

[0137] R 1 express

[0138] R 2 express

[0139]

[0140] R 6 It represents -C2H5;

[0141] And R 8 R 10 R11 R a R b R c R d R e R N and R N1 It has the same meaning as defined in formula (I), or its diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemic mixture, solvate, hydrate, or pharmaceutically acceptable salt.

[0142] In some embodiments, the present invention relates to compounds of formula (Ia):

[0143]

[0144] in

[0145] L represents -L 1 -L 2 -;

[0146] L 1 It represents -CH2CO-,

[0147] L 2 Indicates -NR N1 - and R 3 Indicates 1-adamantyl; or

[0148] L 2 Indicates -NR N1 CH2-, and R 3 It represents 2-bicyclo[3.1.1]heptyl,

[0149] Furthermore, the aforementioned 1-adamantyl and 2-bicyclo[3.1.1]heptyl residues optionally contain one or more C=C double bonds and / or optionally are R a R b R c R d and R e One or more substitutions in;

[0150] R 2 express

[0151]

[0152]

[0153] R 6 It represents -C2H5;

[0154] R a R b R c Rd and R e Independently representing -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -CO2C2H5, -CONH2, -CONHCH3, -CON(CH3)2, -CONHC2H5, -CH2CO2H, -CH2CO2CH3, -CH2CO2C2H5, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2H5, -NHCOCH3, -NHCOC2H5, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C2H5, -NHSO2CHF2, -NHSO2CF3, or -NHSO2CH2CF3;

[0155] R 8 R 9 R 10 R 11 R 12 R 13 and R 14Independently representing -H, -F, -Cl, -Br, -I, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclic-C3H5, -CH2-cyclic-C3H5, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2Cl, -CH2-CH2Br, -CH2-CH2I, -CH2OH, -OCH3, -OC2H5, -O C3H7, -OCH(CH3)2, -OC(CH3)3, -OC4H9, -OCHF2, -OCF3, -OCH2CF3, -OC2F5, -OCH2OCH3, -O-ring-C3H5, -OCH2-ring-C3H5, -O-C2H4-ring-C3H5, -CHO, -COCH3,- COCF3, -COC2H5, -COC3H7, -COCH(CH3)2, -COC(CH3)3, -COOH, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -OOC-CH3, -OOC-CF3, -OOC -C2H5, -OOC-C3H7, -OOC-CH(CH3)2, -OOC-C(CH3)3, -NH2, -NHCH3, -NHC2H5, -NHC3H7, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC2H5, -NHCOC3H7, -NHCOCH(CH3)2, -NHCOC(CH3)3, -CONH2, -CONHCH3, -CONHC2H5, -CONHC 3H7, -CONHCH(CH3)2, -CONH-cyclo-C3H5, -CONHC(CH3)3, -CON(CH3)2, -CON(C2H5)2, -CON(C3H7)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, -SO2NH2, -SO2NH CH3、-SO2NHC2H5、-SO2NHC3H7、-SO2NHCH(CH3)2、-SO2NH-cyclo-C3H5、-SO2NHC(CH3)3、-SO2N(CH3)2、-SO2N(C2H5)2、-SO2N(C3H7)2、-SO2N[CH(CH3)2]2-SO2N[C(CH3)3]2, -NHSO2CH3, -NHSO2CF3, -NHSO2C2H5, -NHSO2C3H7, -NHSO2CH(CH3)2, -NHSO2C(CH3)3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -C≡CH, -C≡C-CH3, -CH2-C≡CH, -Ph, -O-Ph, -O-CH2-Ph,

[0156]

[0157] R N This indicates -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-C5H9, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2Cl, -CH2-CH2Br, -CH2-CH2I, -CH 2-CH=CH2, -CH2-C≡CH, -CHO, -COCH3, -COC2H5, -COC3H7, -COCH(CH3)2, -COC(CH3)3, -CO-cyclo-C3H5, -CO-cyclo-C4H7, -CO-cyclo-C5H9, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -SO2CH3, -SO2CF3, -SO2C2H5, -SO2C3H7, -SO2CH(CH3)2, -SO2-cyclo-C3H5, or -SO2C(CH3)3;

[0158] R N1 It represents -H, -CH3, or -C2H5;

[0159] Or its diastereomers, enantiomers, mixtures of diastereomers, mixtures of enantiomers, racemic mixtures, solvates, hydrates, or pharmaceutically acceptable salts.

[0160] Preferably, the present invention relates to compounds of formula (Ia):

[0161]

[0162] in

[0163] L represents -L 1 -L 2 -;

[0164] L 1 It represents -CH2CO-,

[0165] L 2 Indicates -NR N1 - and R 3 Indicates 1-adamantyl; or

[0166] L 2 Indicates -NR N1 CH2-, and R 3 It represents 2-bicyclo[3.1.1]heptyl,

[0167] Furthermore, the aforementioned 1-adamantyl and 2-bicyclo[3.1.1]heptyl residues optionally contain one or more C=C double bonds and / or optionally are R a R b R c R d and R e One or more substitutions in;

[0168] R 2 express

[0169]

[0170] R 6 It represents -C2H5;

[0171] R a R b R c R d and R e Independently representing -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -CO2C2H5, -CONH2, -CONHCH3, -CON(CH3)2, -CONHC2H5, -CH2CO2H, -CH2CO2CH3, -CH2CO2C2H5, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2H5, -NHCOCH3, -NHCOC2H5, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C2H5, -NHSO2CHF2, -NHSO2CF3, or -NHSO2CH2CF3;

[0172] R 8 R 10 and R 11Independently representing -H, -F, -Cl, -Br, -I, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclic-C3H5, -CH2-cyclic-C3H5, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2Cl, -CH2-CH2Br, -CH2-CH2I, -OCH3, -OC2H5, -O C3H7, -OCH(CH3)2, -OC(CH3)3, -OC4H9, -OCHF2, -OCF3, -OCH2CF3, -OC2F5, -OCH2OCH3, -O-ring-C3H5, -OCH2-ring-C3H5, -O-C2H4-ring-C3H5, -CHO, -COCH 3. -COCF3, -COC2H5, -COC3H7, -COCH(CH3)2, -COC(CH3)3, -COOH, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -OOC-CH3, -OOC-CF 3. -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, -CON HC2H5, -CONHC3H7, -CONHCH(CH3)2, -CONH-ring-C3H5, -CONHC(CH3)3, -CON(CH3)2, -CON(C2H5)2, -CON(C3H7)2, -CON[CH(CH3)2]2, -CON[C(CH3)3] 2. -SO2NH2, -SO2NHCH3, -SO2NHC2H5, -SO2NHC3H7, -SO2NHCH(CH3)2, -SO2NH-cyclo-C3H5, -SO2NHC(CH3)3, -SO2N(CH3)2, -SO2N(C2H5)2, -SO2N(C3H7) 2、-SO2N[CH(CH3)2]2, -SO2N[C(CH3)3]2, -NHSO2CH3, -NHSO2CF3, -NHSO2C2H5, -NHSO2C3H7, -NHSO2CH(CH3)2, -NHSO2 C(CH3)3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -C≡CH, -C≡C-CH3, -CH2-C≡CH, -Ph, -O-Ph, -O-CH2-Ph,

[0173]

[0174]

[0175] R N This indicates -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-C5H9, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2Cl, -CH2-CH2Br, -CH2-CH2I, -CH 2-CH=CH2, -CH2-C≡CH, -CHO, -COCH3, -COC2H5, -COC3H7, -COCH(CH3)2, -COC(CH3)3, -CO-cyclo-C3H5, -CO-cyclo-C4H7, -CO-cyclo-C5H9, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -SO2CH3, -SO2CF3, -SO2C2H5, -SO2C3H7, -SO2CH(CH3)2, -SO2-cyclo-C3H5, or -SO2C(CH3)3;

[0176] R N1 It represents -H, -CH3, or -C2H5;

[0177] Or its diastereomers, enantiomers, mixtures of diastereomers, mixtures of enantiomers, racemic mixtures, solvates, hydrates, or pharmaceutically acceptable salts.

[0178] Preferably, the compound of the present invention has formula (II):

[0179]

[0180] in

[0181] L 2 Indicates -NR N1 - and R 3 Indicates 1-adamantyl; or

[0182] L 2 Indicates -NR N1 CH2-, and R 3 It represents 2-bicyclo[3.1.1]heptyl,

[0183] Furthermore, the aforementioned adamantyl and bicyclic [3.1.1]heptyl residues optionally contain one or more C=C double bonds and / or optionally are R a R b R c R d and R e One or more substitutions in;

[0184] R 2 express

[0185]

[0186] R a R b R c R d and R e Independently representing -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -CO2C2H5, -CONH2, -CONHCH3, -CON(CH3)2, -CONHC2H5, -CH2CO2H, -CH2CO2CH3, -CH2CO2C2H5, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2H5, -NHCOCH3, -NHCOC2H5, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C2H5, -NHSO2CHF2, -NHSO2CF3, or -NHSO2CH2CF3;

[0187] R NThis indicates -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-C5H9, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2Cl, -CH2-CH2Br, -CH2-CH 2I, -CH2-CH=CH2, -CH2-C≡CH, -CHO, -COCH3, -COC2H5, -COC3H7, -COCH(CH3)2, -COC(CH3)3, -CO-cyclo-C3H5, -CO-cyclo-C4H7, -CO-cyclo-C5H9, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -SO2CH3, -SO2CF3, -SO2C2H5, -SO2C3H7, -SO2CH(CH3)2, or -SO2C(CH3)3;

[0188] R N1 It represents -H, -CH3, or -CH2CH3;

[0189] R 8 R 10 and R 11 Representing each other independently

[0190] -H, -F, -Cl, -Br, -I, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -cyclo-C3H5, -C H2-ring-C3H5, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2Cl, -CH2-CH2Br, -CH2 -CH2I, -OCH3, -OC2H5, -OC3H7, -OCH(CH3)2, -OC(CH3)3, -OC4H9, -OCHF2, -OCF3, -OCH2CF3, -OC2F5, -OCH2OCH3, -O-cyclo-C3H5, -OCH2-cyclo-C3H5, -O-C2H4-cyclo-C3H5, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -C≡CH, -C≡C-CH3, -CH2-C≡CH, or -Ph;

[0191] Or its diastereomers, enantiomers, mixtures of diastereomers, mixtures of enantiomers, racemic mixtures, solvates, hydrates, or pharmaceutically acceptable salts.

[0192] The terms “1-adamantyl” and “2-bicyclo[3.1.1]heptyl” have the following structures respectively:

[0193]

[0194] And R a R b R c R d and R e It has the same meaning as defined in this article.

[0195] Preferably, the 2-bicyclo[3.1.1]heptyl group has the following structure:

[0196]

[0197] And R a and R b It has the same meaning as defined in this article.

[0198] More preferably, the compound has any one of the formulas (II-a)-(II-l), (II-b1)-(II-b2), and (III-a)-(III-l):

[0199]

[0200]

[0201]

[0202] Where L 1 L 2 R 2 R N R a R b R c R d and R e It has the same meaning as defined in formula (I), preferably formula (Ia), and more preferably formula (II).

[0203]

[0204]

[0205] Where L 1 L 2 R 8 R 10 R 11 R 12 R 13 R 11 R N R a R b R c R d and R e It has the same meaning as defined in formula (I) and preferably in formula (Ia).

[0206] In a preferred embodiment, the present invention relates to compounds of formulas (I), (Ia), and (II), wherein

[0207] R 3 express

[0208]

[0209]

[0210] Furthermore, R 3 express

[0211]

[0212] More preferably, R 3 express

[0213] In a preferred embodiment, the present invention relates to compounds of any one of formulas (I), (Ia), (II), (II-a)-(II-l), (II-b1)-(II-b2), wherein

[0214] R 2 express

[0215]

[0216]

[0217] in

[0218] R 8 R 9 R 10 R 11 R 12 R 13 and R 14Independently representing -H, -F, -Cl, -Br, -I, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclic-C3H5, -CH2-cyclic-C3H5, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2Cl, -CH2-CH2Br, -CH2-CH2I, -CH2OH, -OCH3, -OC2H5, -O C3H7, -OCH(CH3)2, -OC(CH3)3, -OC4H9, -OCHF2, -OCF3, -OCH2CF3, -OC2F5, -OCH2OCH3, -O-ring-C3H5, -OCH2-ring-C3H5, -O-C2H4-ring-C3H5, -CHO, -COCH3,- COCF3, -COC2H5, -COC3H7, -COCH(CH3)2, -COC(CH3)3, -COOH, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -OOC-CH3, -OOC-CF3, -OOC -C2H5, -OOC-C3H7, -OOC-CH(CH3)2, -OOC-C(CH3)3, -NH2, -NHCH3, -NHC2H5, -NHC3H7, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC2H5, -NHCOC3H7, -NHCOCH(CH3)2, -NHCOC(CH3)3, -CONH2, -CONHCH3, -CONHC2H5, -CONHC 3H7, -CONHCH(CH3)2, -CONH-cyclo-C3H5, -CONHC(CH3)3, -CON(CH3)2, -CON(C2H5)2, -CON(C3H7)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, -SO2NH2, -SO2NH CH3、-SO2NHC2H5、-SO2NHC3H7、-SO2NHCH(CH3)2、-SO2NH-cyclo-C3H5、-SO2NHC(CH3)3、-SO2N(CH3)2、-SO2N(C2H5)2、-SO2N(C3H7)2、-SO2N[CH(CH3)2]2-SO2N[C(CH3)3]2, -NHSO2CH3, -NHSO2CF3, -NHSO2C2H5, -NHSO2C3H7, -NHSO2CH(CH3)2, -NHSO2C(CH3)3, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -C≡CH, -C≡C-CH3, -CH2-C≡CH, -Ph, -O-Ph, -O-CH2-Ph,

[0219]

[0220] Preferably, R 8 R 9 R 10 R 11 R 12 R 13 and R 14 Independently representing -H, -F, -Cl, -Br, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclic-C3H5, -CH2-cyclic-C3H5, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, - CH2-CF3, -CH2-CH2Cl, -CH2-CH2Br, -CH2-CH2I, -CH2OH, -OCH3, -OC2H5, -OC3H7, -OCH(CH3)2, -OC(CH3)3, -OC 4H9, -OCHF2, -OCF3, -OCH2CF3, -OC2F5, -OCH2OCH3, -O-ring-C3H5, -OCH2-ring-C3H5, -O-C2H4-ring-C3H5, -CHO, -COCH 3、 -COCF 3、-COC2H5, -COC3H7, -COCH(CH3)2, -COC(CH3)3, -COOH, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -OOC-CH3, -OOC-CF3, -OOC-C2H5, -OOC-C3H7, -OOC-CH(CH3)2, -OOC-C(CH3)3, -NH2, -NHCH3, -NHC2H5, -NHC3H7, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC2H5, -NHCOC3H7, -NHCOCH(CH3)2, -NHCOC(CH3)3, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CONHCH(CH3)2, -CONH-ring-C3H5, -CONHC or

[0221] More preferably, R 8 R 9 R 10 R 11 R 12 R 13 and R 14 Independently representing -H, -F, -Cl, -Br, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C(CH3)3, -cyclic -C3H5, -CF3, -CH2OH, -OCH3, -OCF3, -CHO, -COCH3, -COOH, -COOCH3, -NH2, -N(CH3)2, -CONH2, -SO2NH2, -Ph, or

[0222] R NThis indicates -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-C5H9, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2Cl, -CH2-CH2Br, -CH2-CH2I, -CH 2-CH=CH2, -CH2-C≡CH, -CHO, -COCH3, -COC2H5, -COC3H7, -COCH(CH3)2, -COC(CH3)3, -CO-cyclo-C3H5, -CO-cyclo-C4H7, -CO-cyclo-C5H9, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -SO2CH3, -SO2CF3, -SO2C2H5, -SO2C3H7, -SO2CH(CH3)2, -SO2-cyclo-C3H5, or -SO2C(CH3)3;

[0223] Preferably, R N Representing -H, -CH3, -C2H5, -CH(CH3)2, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-C5H9, or -COCH3, more preferably, R N It represents -H, -CH3, -C2H5, -CH(CH3)2, -cyclic-C4H7, -cyclic-C5H9, or -COCH3.

[0224] In a preferred embodiment, the present invention relates to compounds of any one of formulas (I), (Ia), (II), (II-a)-(II-l), (II-b1)-(II-b2), R 2 express

[0225]

[0226] Furthermore, R 2 express

[0227]

[0228] Even more preferably, R2 express

[0229]

[0230] In a preferred embodiment, the present invention relates to compounds of any one of formulas (I), (Ia), (II), (II-a)-(II-l), (II-b1)-(II-b2), wherein

[0231] L represents -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CONH-,

[0232] -CH2CONH-CH2-, -CH2CON(CH3)-CH2-, -CH2CONH-CH(CH3)-,

[0233] The most preferred compound is the one of formula (I):

[0234]

[0235]

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254] Method for producing the compound of the present invention

[0255] In some embodiments, the present invention relates to methods for synthesizing compounds of formula (I), and in particular any compound of formula (Ia):

[0256]

[0257] As shown in Scheme 1,

[0258] A method for preparing a compound of formula (Ia), comprising:

[0259] Step 1A: Provide compound 4a

[0260]

[0261] Step 2A: Perform the coupling reaction between compound 4a and compound 5.

[0262]

[0263] To obtain compound 6a

[0264]

[0265] Step 3A: Protect the amino group PG 3 Deprotection to obtain compound 7a

[0266]

[0267] Step 4A: React compound 7a with carboxylic acid (R) 2 The coupling reaction of -CO2H 8) yields compound 9a.

[0268]

[0269] Step 5A: Oxidize compound 9a to produce compound (Ia).

[0270]

[0271] Among them, L and R 2 R 3 and R 6 It has the same meaning as defined in equation (Ia) above, and PG3 It is an amino protecting group.

[0272] Solution 1

[0273]

[0274] Optionally, step 1A' is performed before step 1A:

[0275] (a) Provides protected aldehyde 1

[0276]

[0277] (b) Reacting aldehyde 1 with isocyanate (CN-R) 6 The coupling reaction of 2a yields intermediate compound 3a.

[0278]

[0279] (c) Protecting group PG of compound 3a 1 and PG 2 Preferably, deprotection is performed under acidic conditions and an amino protecting group PG is introduced. 3 To obtain compound 4a

[0280]

[0281] Where R 2 R 6 It has the same meaning as defined in equation (Ia).

[0282] PG 1 and PG 3 It is an amino protecting group.

[0283] PG 2 It is a carboxyl protecting group.

[0284] Therefore, the following method is preferred for preparing compounds of formula (Ia):

[0285] Step 1A′:

[0286] (a) Provides protected aldehyde 1

[0287]

[0288] (b) Reacting aldehyde 1 with isocyanate (CN-R) 6 The coupling reaction of 2a yields intermediate compound 3a.

[0289]

[0290] (c) Protecting group PG of compound 3a 1 and PG2 Preferably, deprotection is performed under acidic conditions and an amino protecting group PG is introduced. 3 To obtain compound 4a

[0291]

[0292] Step 1A: Provide compound 4a

[0293]

[0294] Step 2A: Perform the coupling reaction between compound 4a and compound 5.

[0295]

[0296] To obtain compound 6a

[0297]

[0298] Step 3A: Protect the amino group PG 3 Deprotection to obtain compound 7a

[0299]

[0300] Step 4A: React compound 7a with carboxylic acid (R) 2 The coupling reaction of -CO2H 8) yields compound 9a.

[0301]

[0302] Step 5A: Oxidize compound 9a to produce compound (Ia).

[0303]

[0304] Among them, L and R 2 R 3 and R 6 It has the same meaning as defined in equation (Ia) above, and PG 1 and PG 3 It is an amino protecting group.

[0305] PG 2 It is a carboxyl protecting group.

[0306] In the alternative pathway, all protecting groups PG are removed simultaneously first. 1 and PG 2 And selectively introduce the protecting group PG. 3 Preferably, PG 1 and PG 3 same.

[0307] As used herein, the term "protecting group" refers to a protecting group commonly used in organic synthesis, preferably for amino and carboxyl groups. PG 1 PG 3 and PG 5 Preferably, it is a suitable protecting group for the amino group. PG 2 and PG 4 Preferably, it is a suitable protecting group for the carboxyl group. Preferably, PG 1 PG 3 and PG 5 It can be selected from or include the following groups: acetyl, benzoyl, benzyloxycarbonyl (Cbz), tert-butylcarbonyl, tert-butoxycarbonyl (Boc), and fluorenylmethyleneoxy (Fmoc). PG 2 and PG 4 It may be selected from or include the group consisting of: methoxy, ethoxy, isobutoxy, tert-butoxy, benzyloxy; preferably, tert-butoxy.

[0308] In step 2A, to facilitate the coupling reaction with the amino group of the intermediate compound, an activating agent is typically used to activate the carboxylic acid ("PEPTIDE COUPLING REAGENTS, MORE THAN A LETTER SOUP", AYMAN EL-FAHAM and FERNANDO ALBERICIO, CHEMICAL REVIEWS, 2011, 111(11), pp. 6557-6602). Activation can be introduced as a standalone reaction or an in-situ reaction. Preferably, any of the following coupling agents can be used to activate the carboxylic acid group: BOP (benzotriazol-1-yl-oxy-tris(dimethylamino)-phosphonium hexafluorophosphate), PYBOP (benzotriazol-1-yl-oxy-tris(dimethylamino)-phosphonium hexafluorophosphate), AOP (7-(azabenzotriazol-1-yl)oxy-tris(dimethylamino)-phosphonium hexafluorophosphate), PYAOP ((7-azabenzotriazol-1-yl-oxy-tris(dimethylamino)-phosphonium hexafluorophosphate), PYAOP ((7-azabenzotriazol-1-yl-oxy-tris(dimethylamino)-phosphonium hexafluorophosphate)). Tripyrrolidinyl phosphonium hexafluorophosphate), TBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyltetrafluoroborate), EEDQ (N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline), polyphosphoric acid (PPA), DPPA (diphenylphosphoazide), 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'-tetramethylureonium hexafluorophosphate), HOBT (1-hydroxybenzotriazole), HOAT (1-hydroxy-7-azabenzotriazole), DCC (N,N′-dicyclohexylcarbodiimide), EDC (or EDAC or EDCI, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), BOP-CL (bis(2-oxo-3-oxazolidinyl)phosphine chloride), TFFH (tetramethylfluoroformamidinium hexafluorophosphate), BROP (bromotris(dimethylamino)phosphonium hexafluorophosphate), PYBROP (bromotri-pyrrolidinyl-phosphonium hexafluorophosphate), and CIP (2-chloro-1,3-dimethylimidazolineonium hexafluorophosphate), or further, a similar agent for activating intermediates, or a mixture thereof.

[0309] Pharmaceutical Compositions and Medical Uses

[0310] Therefore, another aspect of the invention relates to compounds according to general formula (I) as pharmaceuticals and their use in medicine. Particularly preferred are their use as inhibitors of transglutaminases, particularly transglutaminase 2 (TG2).

[0311] Therefore, compounds of formula (I) described herein or according to the present invention may be administered either on their own or as pharmacologically acceptable salts.

[0312] The compounds of the present invention can form pharmacologically acceptable salts with organic or inorganic acids or bases. Examples of suitable acids for the formation of such acid addition salts are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, para-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, para-aminobenzoic acid, para-hydroxybenzoic acid, methanesulfonic acid, ethanesulfonic acid, nitrous acid, hydroxyethanesulfonic acid, vinylsulfonic acid, p-toluenesulfonic acid, naphthylsulfonic acid, sulfanilic acid, camphorsulfonic acid, china acid, mandelic acid, o-methylmandelic acid, hydrobenzenesulfonic acid, picric acid, adipic acid, d-o-tolyltartaric acid, malonic acid, (o, m, p)-methylformic acid, naphthylaminesulfonic acid, trifluoroacetic acid, and other mineral acids or carboxylic acids well known to those skilled in the art. Salts are prepared by contacting a free base with a desired amount of acid sufficient to produce salt in a conventional manner. Methanesulfonates, hydrochlorides, and trifluoroacetates are preferred, with trifluoroacetates and hydrochlorides being particularly preferred.

[0313] When the compounds of the present invention contain acidic groups, they can also form salts with inorganic or organic bases. Examples of suitable inorganic or organic bases are, for example, NaOH, KOH, NH4OH, tetraalkylammonium hydroxide, lysine, or arginine. The salts can be prepared in a conventional manner using methods well known in the art, for example by treating a solution of a compound of general formula (I) with a solution of an acid selected from the groups mentioned above.

[0314] How to use

[0315] In another aspect of the invention, novel compounds according to general formula (I) are used as pharmaceutically active agents, i.e., compounds of formula (I) are used in medicine.

[0316] Furthermore, the present invention relates to pharmaceutical compositions comprising at least one compound according to general formula (I) as an active ingredient or a pharmacologically acceptable salt thereof as an active ingredient, and at least one pharmacologically acceptable carrier, excipient and / or diluent.

[0317] The compounds described herein according to general formula (I) are particularly suitable for the treatment and prevention of diseases associated with and / or caused by gamma-glutamyl transferase 2.

[0318] Celiac diarrhea and gluten intolerance are associated with tissue transglutaminase (TG2). Another very important group of indications 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 liver fibrosis are among the most important fibrotic disorders to be addressed with the disclosed compounds.

[0319] In biological example B-1, the compounds of the present invention were demonstrated to effectively inhibit the activity of TG, especially TG2, as reversible inhibitors.

[0320] As used herein, the term “inhibiting” or “inhibition” refers to the ability of a compound to at least partially downregulate, reduce, decrease, inhibit, inactivate, or suppress the activity of an enzyme or the expression of an enzyme or protein.

[0321] Therefore, another aspect of the invention is the use of compounds of the invention of general formula (I) as described herein, or pharmaceutical compositions thereof, in the treatment or prevention of autoimmune and inflammatory diseases, vascular diseases, fibrotic diseases, liver diseases, cholestatic liver diseases, cancer, neurodegenerative diseases, eye diseases, and skin disorders.

[0322] Another aspect of the invention relates to the use of compounds of general formula (I) in the preparation of pharmaceutical compositions for the prevention and / or treatment of autoimmune and inflammatory diseases, vascular diseases, fibrotic diseases, liver diseases, cholestatic liver diseases, cancer, neurodegenerative diseases, eye diseases and skin disorders.

[0323] In another aspect of the invention, a method for preventing and / or treating autoimmune and inflammatory diseases, vascular diseases, fibrotic diseases, liver diseases, cholestatic liver diseases, cancer, neurodegenerative diseases, eye diseases, and skin disorders, comprising administering to a subject, particularly a human, a pharmaceutically effective amount of at least one compound of general formula (I) to prevent and / or treat said autoimmune and inflammatory diseases, vascular diseases, fibrotic diseases, liver diseases, cholestatic liver diseases, cancer, neurodegenerative diseases, eye diseases, and skin disorders.

[0324] Preferred autoimmune and inflammatory diseases include multiple sclerosis, celiac disease, Duhring-Brocq disease (dermatitis herpetiformis), glutamate ataxia, glutamate neuropathy, diabetes, rheumatoid arthritis, Graves' disease, inflammatory bowel disease, systemic lupus erythematosus, psoriasis, and gingivitis;

[0325] Vascular diseases include atherosclerosis, thrombosis, and arteriosclerosis;

[0326] Fibrotic diseases affecting the lungs, kidneys, liver, skin, or intestines, such as cystic fibrosis, renal fibrosis and diabetic nephropathy, intestinal fibrosis, idiopathic pulmonary fibrosis, and liver fibrosis;

[0327] Liver diseases such as alcoholic hepatitis, alcoholic steatohepatitis, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, cirrhosis, autoimmune hepatitis or hepatitis;

[0328] Cholestatic liver disease includes primary biliary cholangitis and primary sclerosing cholangitis;

[0329] Cancers include glioblastoma, melanoma, pancreatic cancer, renal cell carcinoma, meningioma, and breast cancer.

[0330] Neurodegenerative diseases include Parkinson's disease, Huntington's disease, or Alzheimer's disease.

[0331] Eye diseases include glaucoma, cataracts, macular degeneration, or uveitis;

[0332] Skin disorders include acne, psoriasis, scarring, and skin aging.

[0333] More preferably, the compound of formula (I), or a pharmaceutical composition thereof, can be used in the treatment or prevention of celiac disease.

[0334] Furthermore, compounds of general formula (I) may be administered as their pharmaceutically active salts, optionally using substantially non-toxic, pharmaceutically acceptable carriers, excipients, or extenders. The drug is prepared in a known manner in a suitable dose in a conventional solid or fluid carrier or in an extender and a conventional pharmaceutically acceptable excipient / formula. Preferred formulations are provided in dossier forms suitable for oral administration, such as pills, tablets, film-coated tablets, coated tablets, capsules, and powders.

[0335] Tablets, film-coated 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 to 100 mg per formulation.

[0336] Furthermore, the present invention also includes pharmaceutical preparations for oral, parenteral, skin, intradermal, gastric, intradermal, intravascular, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, buccal, transdermal, rectal, subcutaneous, sublingual, topical, transdermal, or inhalation administration, which, in addition to typical mediators and extenders, contain a compound of general formula (I) and / or a pharmaceutically acceptable salt thereof as an active ingredient.

[0337] The pharmaceutical compositions of the present invention contain one of the compounds of formula (I) disclosed herein as an active ingredient, typically mixed with suitable carrier materials selected relative to the intended form of administration (i.e., tablets, capsules (filled with solid, semi-solid, or liquid), powders, orally administerable gels, elixirs, dispersible granules, syrups, suspensions, etc.). For example, the compound of formula (I) can be combined as the 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, ethanol (in liquid form), etc., for oral administration in tablet or capsule form. Furthermore, suitable binders, lubricants, disintegrants, and colorants can be added to the mixture if desired. Powders and tablets can consist of said inert carrier in amounts from about 5% to about 95% by weight of the composition of the present invention.

[0338] Suitable binders include starch, gelatin, natural sugars, sweeteners derived from corn, natural and synthetic gums such as gum arabic, sodium alginate, carboxymethyl cellulose, polyethylene glycol, and waxes. Possible lubricants used in these dosage forms include boric acid, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrants include starch, methyl cellulose, cyclodextrin, guar gum, etc. Sweeteners, flavor additives, and preservatives may also be included, if desired. Some of the terms used above, namely disintegrants, extenders, lubricants, binders, etc., are discussed in more detail below.

[0339] Furthermore, the compositions of the present invention can be formulated in a sustained-release form to provide a controlled release rate of any one or more components or active ingredients in order to optimize therapeutic effects, i.e., inhibitory activity, etc. Suitable dosage forms for sustained release include layered tablets containing layers with different degradation rates or controlled-release polymer matrices impregnated with active ingredients, and are in the form of tablets or capsules containing such impregnated or encapsulated porous polymer matrices.

[0340] Formulations in fluid form include solutions, suspensions, and emulsions. Exemplary examples include the addition of water or propylene glycol aqueous solutions for parenteral injection or sweeteners and emulsifiers for oral solutions, suspensions, and emulsions.

[0341] Aerosol formulations suitable for inhalation may include solutions and solids in powder form, which may be combined with pharmaceutically acceptable carriers, such as compressed inert gases, for example, nitrogen.

[0342] For the preparation of suppositories, a mixture of low-melting-point waxes, such as fatty acid glycerides (e.g., cocoa butter), is first melted, and the active ingredient is uniformly dispersed therein by stirring or similar mixing operations. The molten homogeneous mixture is then poured out in the appropriate form, cooled, and thus hardened.

[0343] This also includes additional formulations in solid form that will be converted into a fluid form for oral or parenteral administration shortly before use. Such fluid forms include solutions, suspensions, and emulsions.

[0344] Furthermore, the compounds of the present invention can be administered via transdermal application. The transdermal compositions can be in the form of creams, lotions, aerosols, and / or emulsions.

[0345] The term "capsule" refers to a special container or shell made of methylcellulose, polyvinyl alcohol, or modified gelatin or starch, into which active agents can be encapsulated. Typically, hard-shell capsules are prepared from a mixture of bone and porcine skin gelatin, which has relatively high gel strength. The capsule itself may contain small amounts of colorants, opacifiers, softeners, and preservatives.

[0346] Tablets refer to a compressed or cast solid dosage form containing an active ingredient and a suitable extender. Tablets can be produced by compressing mixtures or granules obtained through wet granulation, dry granulation, or compaction, as is known to those skilled in the art.

[0347] Oral gels refer to active components dispersed or dissolved in a hydrophilic semi-solid matrix.

[0348] Powders used in compositions refer to powder mixtures containing active ingredients and suitable extenders that can be suspended in water or juice.

[0349] Suitable extenders are substances that typically form the largest portion of a composition or dosage form. Suitable extenders 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 extender in the composition can range from about 5% to about 95% by weight of the total composition, preferably from about 25% to about 75% by weight, and more preferably from about 30% to about 60% by weight.

[0350] The term disintegrant refers to a material added to a composition to support the disintegration and release of a pharmaceutical substance. Suitable disintegrants include starch, water-soluble modified starch such as sodium carboxymethyl starch; natural and synthetic gums such as locust bean gum, caraya, guar gum, astragalus gum, and agar; cellulose derivatives such as methylcellulose and sodium carboxymethyl cellulose, microcrystalline cellulose and cross-linked microcrystalline cellulose such as sodium cross-linked carboxymethyl cellulose; alginates such as alginic acid and sodium alginate; and clays such as bentonite and foaming mixtures. The amount of disintegrant used in the composition can range from about 2% to 20% by weight of the composition, and more preferably from about 5% to about 10% by weight.

[0351] Binders characterize substances that bind or “adhere” powders together, and thus they are used as “glue” in formulations. Binder additions have been used in the addition of intracellular starches as expanders or disintegrants. Suitable binders include sugars such as sucrose; starches derived from wheat, corn, rice, and potatoes; natural gums such as gum arabic, gelatin, and astragalus gum; seaweed derivatives such as alginate, sodium alginate, and calcium ammonium alginate; cellulosic materials such as methylcellulose and sodium carboxymethylcellulose, as well as hydroxypropyl methylcellulose; polyvinylpyrrolidone; and inorganic compounds such as magnesium aluminum silicate. The amount of binder in the composition can range from about 2% to about 20% by weight of the total composition, preferably from about 3% to about 10% by weight, and more preferably from about 3% to about 6% by weight.

[0352] The term lubricant refers to a substance added to a dosage form to allow tablets, granules, etc., to be released from a casting or compression mold after compression by reducing friction. Suitable lubricants include metal stearates, such as magnesium stearate, calcium stearate, or potassium stearate; stearic acid; waxes with high melting points; and water-soluble lubricants, such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycol, and D,L-leucine. Because lubricants must be present on the surface of the granules and between the granules and the parts of the tableting machine, they are typically added during the final step before compression. The amount of lubricant in the composition can range from about 0.2% to about 5% by weight of the total composition, preferably about 0.5% to about 2% by weight, and more preferably about 0.3% to about 1.5% by weight.

[0353] Lubricants are materials that prevent agglomeration and improve the flow properties of particles, resulting in smooth and uniform flow. Suitable lubricants include silica and talc. The amount of lubricant in the composition can range from about 0.1% to 5% by weight of the total composition, preferably from about 0.5% to about 2% by weight.

[0354] Colorants are auxiliary agents used to color a composition or dosage form. Such auxiliary agents may include food-grade colorants that are adsorbed onto a suitable adsorption medium, such as clay or alumina. The amount of colorant used can vary from about 0.1% to 5% by weight of the composition, and preferably from about 0.1% to about 1% by weight.

[0355] As used herein, a “pharmaceutically effective amount” of a transglutaminase inhibitor is an effective amount or activity for achieving the desired physiological outcome in cells treated in vitro or in a patient treated in vivo. Specifically, a pharmaceutically effective amount is an amount sufficient to inhibit one or more clinically defined pathological processes associated with transglutaminase 2 for a sustained period of time. The effective amount can vary depending on the specific compound of formula (I) and additionally depends on multiple factors and conditions associated with the subject being treated and the severity of the disease. For example, if the inhibitor is to be administered in vivo, factors such as the patient’s age, weight, and health status, as well as dose-response curves and data on toxicity obtained from preclinical animal studies, will be considered. If an inhibitor in the form of a compound of formula (I) described herein is brought into contact with cells in vivo, multiple preclinical in vitro studies will be designed to determine parameters such as absorption, half-life, dose, toxicity, etc. Determining a pharmaceutically effective amount of a given pharmaceutically active ingredient is part of the ordinary skill of those skilled in the art. Example

[0356] The following abbreviations used in the embodiments have the following meanings.

[0357] Boc (tert-butoxycarbonyl), BocOSu (N-tert-butoxycarbonyloxy-succinimide), DCM (dichloromethane), DMAP (4-(dimethylamino)-pyridine), TEA (triethylamine), DMF (dimethylformamide), DMP (Diesel-Martin oxidant), DIPEA (N-ethyldiisopropylamine), Glu (glutamic acid), EDC (1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide), TFA (trifluoroacetic acid), THF (tetrahydrofuran), EtOAc (ethyl acetate), HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate), HOBt (hydroxybenzotriazole), MTBE (methyl tert-butyl ether), tBu (tert-butyl),

[0358] Chemical Examples

[0359] The following examples are intended to illustrate the invention using selected compounds, and do not limit the scope of protection of these specific embodiments by this intellectual property. It will be apparent to those skilled in the art that similar compounds and compounds produced according to similar synthetic methods fall within the scope of protection of this intellectual property.

[0360] Example I. Synthesis Method I

[0361] Plan I-1

[0362]

[0363] Preparation of compound ZED1657

[0364]

[0365] 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. 245 g (3 equivalents) of trisodium phosphate dodecahydrate was added at 40 °C, and the reaction was stirred overnight at room temperature. 250 mL of HCl (32%) was added, and the suspension was stirred again overnight at 4 °C. The precipitate was filtered and dried.

[0366] Yield: 41.2 g, 97%; ESI-MS: 199.3 [M+H] +

[0367] Preparation of compound ZED3912

[0368]

[0369] 7.0 g (35.3 mmol) of ZED1657, 6.63 g (1 equivalent) of 1-adamantaneamine hydrochloride, and 4.77 g (1 equivalent) of HOBt were dissolved in 80 mL of DMF and 7.38 mL (1.2 equivalent) of DIPEA. 7.45 g (1.1 equivalent) of 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride was added, and the reaction was stirred overnight at room temperature. The solvent was evaporated, and the residue was dissolved in 200 mL of DCM. The solution was washed with 100 mL each of 10% citric acid solution, 10% NaHCO3 solution, and brine. The organic phase was dried over Na2SO4, filtered, and the solvent was evaporated.

[0370] Yield: 10.3 g, 88%; ESI-MS: 332.4 [M+H] +

[0371] Preparation of compound ZED3913

[0372]

[0373] 10.3 g (31.0 mmol) of ZED3912 was suspended in 200 mL of MeOH, and then 1.0 g of palladium supported on activated carbon (10%) (unreduced) was added. The suspension was stirred overnight at room temperature under a hydrogen atmosphere. The catalyst was filtered and the solvent was evaporated.

[0374] Yield: 7.51g, 78%

[0375] ESI-MS: 302.3 [M+H] +

[0376] Plan I-2

[0377]

[0378] Preparation of compound ZED788

[0379]

[0380] 12.0 g of Boc-L-Glu-OtBu (39.6 mmol) and 7.09 g of cesium carbonate (21.8 mmol, 0.55 equivalent) were suspended in 100 mL of DMF and stirred at room temperature for 1 h. 2.47 mL of iodomethane (39.6 mmol) was added, and the mixture was stirred overnight at room temperature. The solvent was evaporated, and the residue was dissolved in ethyl acetate and washed twice with citric acid solution (10%), NaHCO3 solution (10%), and brine. The organic phase was dried over Na2SO4, filtered, and the solvent was evaporated. The crude product was used without further purification.

[0381] Yield: 13.4g, >100%

[0382] ESI-MS: 318.3 [M+H] +

[0383] Preparation of compound ZED720

[0384]

[0385] 13.4 g of ZED788 (~39.6 mmol) and 986 mg of N,N-dimethyl-4-aminopyridine (DMAP) were dissolved in 30 mL of acetonitrile. 17.6 g of di-tert-butyl dicarbonate (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 10% citric acid solution, 10% NaHCO3 solution, and brine. The organic phase was dried over Na2SO4, filtered, and the solvent was evaporated. The crude product was used without further purification.

[0386] Yield: 13.7g, 83%

[0387] ESI-MS: 418.3 [M+H] +

[0388] Preparation of compound ZED721

[0389]

[0390] 13.7 g of ZED720 (32.8 mmol) was dissolved in 200 mL of dry diethyl ether and cooled to -78 °C under an argon atmosphere. 36.1 mL of diisobutylaluminum hydride (1 M, in hexane) was added dropwise, and the solution was stirred at -78 °C for 30 min, then quenched with potassium sodium tartrate (Rochelle salt) solution. The organic layer was separated, dried over Na₂SO₄, filtered, and concentrated to dryness. The crude product was used without further purification.

[0391] Yield: 13.3g, >100%

[0392] ESI-MS: 388.3 [M+H] +

[0393] Preparation of compound ZED3221

[0394]

[0395] 7.0 g (18.1 mmol) of tert-butyl (S)-2-(bis(tert-butoxycarbonyl)amino)-5-oxovalerate (ZED721) was dissolved in 30 mL of DCM. At 0 °C, 1.04 g (1.05 equivalents) of ethyl isocyanate and 1.09 mL (1.05 equivalents) of acetic acid were added, and the reaction was stirred overnight at room temperature. 35 mL of TFA was added, and the reaction was stirred for another 3 h. The solvent was evaporated, and the residue was dissolved in 20 mL of DMF. 6.29 mL (2 equivalents) of DIPEA and 4.73 g (1.2 equivalents) of ditert-butyl dicarbonate in 5 mL of DMF were added, and the reaction was stirred overnight at room temperature. The solvent was evaporated, and the residue was dissolved in DCM. After extraction with NaHCO3 solution (1.05 equivalents in water), 1.5 equivalents of citric acid were added to the aqueous phase, followed by re-extraction with DCM. The organic phase was dried over Na2SO4, filtered, and the solvent was evaporated. The residue was purified by rapid chromatography.

[0396] Yield: 5.77g, 92%

[0397] ESI-MS: 347.3 [M+H] +

[0398] Preparation of compound I-1a

[0399]

[0400] 5.77 g (16.7 mmol) of ZED3221, 6.33 g (1 equivalent) of HATU, and 5.02 g (1 equivalent) of ZED3913 were dissolved in 100 mL of DMF and 5.80 mL of DIPEA (2 equivalents) and stirred overnight at 45 °C. The solvent was evaporated; the residue was dissolved in 50 mL of EtOAc and washed twice with 35 mL each of 10% citric acid solution, 10% NaHCO3 solution, and brine. The organic phase was dried over Na2SO4, filtered, and the solvent was evaporated.

[0401] Yield: 7.41g, 71%

[0402] ESI-MS: 630.5 [M+H] +

[0403] Preparation of compound I-1b

[0404]

[0405] 600 mg (0.95 mmol) of I-1a was dissolved in 5 mL of DCM / TFA (1:1) and stirred at room temperature for 1 h. The solvent was evaporated, and the residue was dissolved in 5 mL of DMF. 120 mg (1 equivalent) of 1-methyl-1H-imidazol-5-carboxylic acid, 362 mg (1 equivalent) of HATU, and 332 μl (2 equivalent) of DIPEA were added, and the reaction was stirred overnight at room temperature. The solvent was evaporated; the residue was dissolved in 25 mL of EtOAc and washed with 15 mL each of 10% citric acid solution, 10% NaHCO3 solution, and brine. The organic phase was dried over Na2SO4, filtered, and the solvent was evaporated.

[0406] Yield: 527 mg, 87%

[0407] ESI-MS: 638.5 [M+H] +

[0408] Preparation of compound I-1c

[0409]

[0410] 527 mg (0.83 mmol) of I-1b was dissolved in 7 mL of MeOH. 171 mg (1.5 equivalents) of potassium carbonate was added, and the reaction was stirred at room temperature for 1 h. The solution was diluted with DCM and washed with water. The organic phase was dried over Na2SO4, filtered, and the solvent was evaporated.

[0411] Yield: 469 mg, 95%

[0412] ESI-MS: 596.5 [M+H] +

[0413] Preparation of compound I-1

[0414]

[0415] 469 mg (0.60 mmol) of I-1c was dissolved in 5 mL of DMF. 534 mg (1.6 equivalents) of Des Martin oxidant (DMP) was added, and the reaction was stirred at room temperature for more than 2 h. The precipitate was filtered off, and the filtrate was evaporated. The residue was purified by HPLC.

[0416] Yield: 362 mg, 77%

[0417] ESI-MS: 594.5 [M+H] +

[0418] 1 ¹H NMR (DMSO-D6, 500MHz, δ [ppm]: 1.27 (t, 3H, ethyl-CH₃), 1.74 (m, 6H, adamantyl-C₄-H₂), 1.97 / / 2.15 (m / / m, 1H / / 1H, β-CH₂), 2.09 (m, 3H, adamantyl-C₃-H), 2.17 (m, 6H, adamantyl-C₂-H₂), 3.23 (m, 2H, ethyl-CH₂), 2.91 (t, 2H, γ-CH₂), 3.74 (s, 3H, imidazole-N-CH₃), 4.5 4(ddd,1H,a-CH2), 4.61(s,2H,N-CH2), 6.26(t,1H,pyridone-C5-H), 7.31(d,1H,pyridone-C6-H), 7.69(s,1H,imidazol-CH), 7.77(s,1H,imidazol-CH), 8.04(d,1H,adamantyl-NH), 8.17(d,1H,pyridone-C4-H), 8.44(q,1H,ethylamide-NH), 8.56(d,1H,α-NH), 9.16(s,1H,pyridone-NH).

[0419] 13C-NMR (DMSO-D6, 500MHz, δ [ppm]: 15.14 (ethyl-CH3), 24.54 (β-CH2), 29.19 (adamantyl-C3-H), 33.54 (imidazolium-N-CH3), 33.71 (γ-CH2), 34.41 (ethyl-CH2), 35.89 (adamantyl-C4-H2), 40.77 (adamantyl-C2-H2), 44.12 (adamantyl-C1), 51.74 (N-CH2), 52.42 (α-CH2), 104.66 (pyridone-C5) -H), 122.39 (pyridone-C4-H), 125.22 (imidazolium-Cq), 127.92 (pyridone-N-Cq), 132.85 (imidazolium-CH), 133.27 (pyridone-C6-H), 142.23 (imidazolium-CH), 156.63 (pyridone-C=O), 160.32 (imidazolium-C=O), 161.10 (C=O-NH-CH2CH3), 165.75 (C=O-adamantylamide), 170.56 (C=O-NH-pyridone), 198.43 (C=O-ethylamide).

[0420] Preparation of compound I-2

[0421]

[0422] The synthesis of compound I-2 was carried out according to compound I-1, using 1-Boc-imidazol-4-carboxylic acid instead of 1-methyl-1H-imidazol-5-carboxylic acid. The final product was obtained by deprotection (DCM / TFA) as described above and purified by HPLC.

[0423] Yield: 45 mg, 63% (final step)

[0424] ESI-MS: 580.4 [M+H] +

[0425] Preparation of compound I-3

[0426]

[0427] The synthesis of compound I-3 was carried out according to compound I-1, with N-methyl-1-adamantaneamine used instead of 1-adamantaneamine in step 2 (according to ZED3912).

[0428] Yield: 26 mg, 52% (final step)

[0429] ESI-MS: 608.5 [M+H] +

[0430] Preparation of compound I-4

[0431]

[0432] 1 mg of TEMPO (2,2,6,6-tetramethylpiperidin-1-oxy, 1 mol%) was added to the α-hydroxy ester precursor of compound I-4 (382 mg, 0.61 mmol, prepared by step 2 of compound ZED3912 using 3,5-dimethyl-1-adamantaneamine) in 10 mL of acetonitrile. 88 mg of calcium hypochlorite (1 equivalent) was added at 0 °C, and the reaction mixture was stirred at 25 °C for 2 h. The suspension was filtered, diluted with ethyl acetate, and washed with NaHCO3 solution (10%) and brine. The organic phase was dried over Na2SO4, filtered, and the solvent was evaporated. The residue was purified by HPLC.

[0433] Yield: 176 mg, 46%

[0434] ESI-MS: 622.5 [M+H] +

[0435] Preparation of compound I-5

[0436]

[0437] 145 mg of 2-iodobenzoic acid (IBX, 2 equivalents) was added to the α-hydroxy ester precursor of compound I-5 (162 mg, 0.26 mmol, prepared by using 3-ethyl-1-adamantaneamine in step 2 according to compound ZED3912) in 5 mL DMSO, and the reaction mixture was stirred at room temperature for 3 h. A 10% NaHCO3 solution was added, and the suspension was extracted with EtOAc. The organic phase was dried over Na2SO4, filtered, and the solvent was evaporated. The residue was purified by HPLC.

[0438] Yield: 59 mg, 37% (final step)

[0439] ESI-MS: 622.5 [M+H] +

[0440] Preparation of compound I-6

[0441]

[0442] The synthesis of compound I-6 was carried out according to compound I-1, with 3-trifluoromethyl-1-adamantaneamine used instead of 1-adamantaneamine in step 2 (according to ZED3912).

[0443] Yield: 36 mg, 51% (final step)

[0444] ESI-MS: 662.4 [M+H] +

[0445] Preparation of compound I-7

[0446]

[0447] The synthesis of compound I-7 was carried out according to compound I-1, with 3-hydroxy-1-adamantaneamine used instead of 1-adamantaneamine in step 2 (according to ZED3912).

[0448] Yield: 21 mg, 45% (final step)

[0449] ESI-MS: 610.5 [M+H] +

[0450] Preparation of compound I-8

[0451]

[0452] The synthesis of compound I-8 was carried out according to compound I-1, with 3-fluoro-1-adamantaneamine used instead of 1-adamantaneamine in step 2 (according to ZED3912).

[0453] Yield: 52 mg, 61% (final step) ESI-MS: 612.5 [M+H] +

[0454] Preparation of compound I-9

[0455]

[0456] The synthesis of compound I-9 was carried out according to compound I-1, with 3-chloro-1-adamantaneamine used instead of 1-adamantaneamine in step 2 (according to ZED3912).

[0457] Yield: 49 mg, 68% (final step) ESI-MS: 628.3 / 630.3 [M+H] +

[0458] Preparation of compound I-10

[0459]

[0460] The synthesis of compound I-10 was carried out according to compound I-1, with 3-bromo-1-adamantaneamine used instead of 1-adamantaneamine in step 2 (according to ZED3912).

[0461] Yield: 59 mg, 71% (final step)

[0462] ESI-MS: 672.3 / 674.3 [M+H] +

[0463] Preparation of compound I-11

[0464]

[0465] The synthesis of compound I-11 was carried out according to compound I-1, with methyl 3-aminoadamantane-1-carboxylate used instead of 1-adamantaneamine in step 2 (according to ZED3912).

[0466] Yield: 85 mg, 74% (final step)

[0467] ESI-MS: 652.5 [M+H] +

[0468] Preparation of compound I-12

[0469]

[0470] The synthesis of compound I-12 was carried out according to compound I-1, with 4,4-difluoro-1-adamantaneamine used instead of 1-adamantaneamine in step 2 (according to ZED3912).

[0471] Yield: 23 mg, 47% (final step)

[0472] ESI-MS: 630.4 [M+H] +

[0473] Preparation of compound I-13

[0474]

[0475] The synthesis of compound I-13 was carried out according to compound I-1, with (-)-cis-myrtle alkylamine used instead of 1-adamantaneamine in step 2 (according to ZED3912).

[0476] Yield: 74 mg, 68% (final step) ESI-MS: 596.5 [M+H] +

[0477] Preparation of compound I-14

[0478]

[0479] The synthesis of compound I-14 was carried out according to compound I-1, with (-)-cis-(pine-2-ylmethyl)amine used instead of 1-adamantaneamine in step 2 (according to ZED3912).

[0480] Yield: 52 mg, 63% (final step) ESI-MS: 596.5 [M+H] +

[0481] Preparation of compound I-15

[0482]

[0483] The synthesis of compound I-15 is carried out according to compound I-5, with 1-methyl-1H-imidazol-4-carboxylic acid used instead of 1-methyl-1H-imidazol-5-carboxylic acid in step 6 (according to compound I-1b).

[0484] Yield: 26 mg, 67% (final step)

[0485] ESI-MS: 622.5 [M+H] +

[0486] Preparation of compound I-16

[0487]

[0488] The synthesis of compound I-16 was carried out according to compound I-5, in which 1-methyl-1H-imidazol-2-carboxylic acid was used instead of 1-methyl-1H-imidazol-5-carboxylic acid in step 6 (according to compound I-1b).

[0489] Yield: 46 mg, 71% (final step)

[0490] ESI-MS: 622.5 [M+H] +

[0491] Preparation of compound I-17

[0492]

[0493] The synthesis of compound I-17 was carried out according to compound I-5, in which 1,4-dimethyl-1H-imidazol-5-carboxylic acid was used instead of 1-methyl-1H-imidazol-5-carboxylic acid in step 6 (according to compound I-1b).

[0494] Yield: 69 mg, 75% (final step)

[0495] ESI-MS: 636.5 [M+H] +

[0496] Preparation of compound I-18

[0497]

[0498] The synthesis of compound I-18 was carried out according to compound I-5, in which 1-isobutyl-1H-imidazol-4-carboxylic acid was used instead of 1-methyl-1H-imidazol-5-carboxylic acid in step 6 (according to compound I-1b).

[0499] Yield: 38 mg, 62% (final step) ESI-MS: 664.5 [M+H] +

[0500] Preparation of compound I-19

[0501]

[0502] The synthesis of compound I-19 was carried out according to compound I-5, in which 1-cyclopentyl-1H-imidazol-4-carboxylic acid was used instead of 1-methyl-1H-imidazol-5-carboxylic acid in step 6 (according to compound I-1b).

[0503] Yield: 24 mg, 57% (final step) ESI-MS: 676.5 [M+H] +

[0504] Preparation of compound I-20

[0505]

[0506] The synthesis of compound I-20 was carried out according to compound I-5, in which 1-cyclobutyl-1H-imidazol-4-carboxylic acid was used instead of 1-methyl-1H-imidazol-5-carboxylic acid in step 6 (according to compound I-1b).

[0507] Yield: 32 mg, 66% (final step)

[0508] ESI-MS: 662.5 [M+H] +

[0509] Preparation of compound I-21

[0510]

[0511] The synthesis of compound I-21 was carried out according to compound I-4, with 1,4-dimethyl-1H-imidazol-5-carboxylic acid used instead of 1-methyl-1H-imidazol-5-carboxylic acid in step 6 (according to compound I-1b).

[0512] Yield: 25 mg, 56% (final step)

[0513] ESI-MS: 636.5 [M+H] +

[0514] Preparation of compound I-22

[0515]

[0516] The synthesis of compound I-22 was carried out according to compound I-4, in which 1-methyl-1H-imidazol-4-carboxylic acid was used instead of 1-methyl-1H-imidazol-5-carboxylic acid in step 6 (according to compound I-1b).

[0517] Yield: 45 mg, 77% (final step)

[0518] ESI-MS: 622.5 [M+H] +

[0519] Preparation of compound I-23

[0520]

[0521] The synthesis of compound I-23 was carried out according to compound I-4, in which 1-methyl-1H-imidazol-2-carboxylic acid was used instead of 1-methyl-1H-imidazol-5-carboxylic acid in step 6 (according to compound I-1b).

[0522] Yield: 18 mg, 50% (final step)

[0523] ESI-MS: 622.5 [M+H] +

[0524] Preparation of compound I-24

[0525]

[0526] The synthesis of compound I-24 was carried out according to compound I-4, in which 1,2-dimethyl-1H-imidazol-5-carboxylic acid was used instead of 1-methyl-1H-imidazol-5-carboxylic acid in step 6 (according to compound I-1b).

[0527] Yield: 44 mg, 72% (final step)

[0528] ESI-MS: 636.5 [M+H] +

[0529] Preparation of compound I-25

[0530]

[0531] The synthesis of compound I-25 was carried out according to compound I-1, with 3-methyl-1-adamantaneamine used instead of 1-adamantaneamine in step 2 (according to ZED 3912). Yield: 37 mg, 59% (final step). ESI-MS: 608.5 [M+H] +

[0532] Preparation of compound I-26

[0533]

[0534] The synthesis of compound I-26 was carried out according to compound I-4, in which 2-chloro-1-methyl-1H-imidazol-5-carboxylic acid was used instead of 1-methyl-1H-imidazol-5-carboxylic acid in step 6 (according to compound I-1b).

[0535] Yield: 57 mg, 71% (final step) ESI-MS: 656.5 / 658.5 [M+H] +

[0536] Preparation of compound I-27

[0537]

[0538] The synthesis of compound I-27 was carried out according to compound I-25, in which 1,2-dimethyl-1H-imidazol-5-carboxylic acid was used instead of 1-methyl-1H-imidazol-5-carboxylic acid in step 6 (according to compound I-1b).

[0539] Yield: 29 mg, 52% (final step)

[0540] ESI-MS: 622.5 [M+H] +

[0541] Preparation of compound I-28

[0542]

[0543] The synthesis of compound I-28 was carried out according to compound I-1, with 3,5,7-trimethyl-1-adamantaneamine used instead of 1-adamantaneamine in step 2 (according to ZED3912).

[0544] Yield: 48 mg, 63% (final step)

[0545] ESI-MS: 636.5 [M+H] +

[0546] Preparation of compound I-29

[0547]

[0548] The synthesis of compound I-29 was carried out according to compound I-28, in which 2-chloro-1-methyl-1H-imidazol-5-carboxylic acid was used instead of 1-methyl-1H-imidazol-5-carboxylic acid in step 6 (according to compound I-1b).

[0549] Yield: 23 mg, 52% (final step)

[0550] ESI-MS: 670.5 / 672.5 [M+H] +

[0551] Preparation of compound I-30

[0552]

[0553] The synthesis of compound I-30 was carried out according to compound I-1, with 1-adamantanamine used instead of 1-adamantanamine in step 2 (according to ZED3912) and benzofuran-2-carboxylic acid used instead of 1-methyl-1H-imidazol-5-carboxylic acid in step 6 (according to compound I-1b).

[0554] Yield: 73 mg, 68% (final step)

[0555] ESI-MS: 630.4 [M+H] +

[0556] Preparation of compound I-31

[0557]

[0558] The synthesis of compound I-31 was carried out according to compound I-30, with 3-methylbenzo[b]furan-2-carboxylic acid used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[0559] Yield: 90 mg, 77% (final step)

[0560] ESI-MS: 644.5 [M+H] +

[0561] Preparation of compound I-32

[0562]

[0563] The synthesis of compound I-32 was carried out according to compound I-30, in which 3-chlorobenzofuran-2-carboxylic acid was used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[0564] Yield: 56 mg, 72% (final step)

[0565] ESI-MS: 664.4 / 666.4 [M+H] +

[0566] Preparation of compound I-33

[0567]

[0568] The synthesis of compound I-33 was carried out according to compound I-30, with 4-bromo-1-benzofuran-2-carboxylic acid used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[0569] Yield: 64 mg, 69% (final step)

[0570] ESI-MS: 708.3 / 710.3 [M+H] +

[0571] Preparation of compound I-34

[0572]

[0573] The synthesis of compound I-34 was carried out according to compound I-30, in which benzo[b]thiophene-2-carboxylic acid was used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[0574] Yield: 51 mg, 67% (final step)

[0575] ESI-MS: 646.4 [M+H] +

[0576] Preparation of compound I-35

[0577]

[0578] The synthesis of compound I-35 was carried out according to compound I-30, with 7-fluorobenzo[b]thiophene-2-carboxylic acid used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[0579] Yield: 36 mg, 64% (final step)

[0580] ESI-MS: 664.4 [M+H] +

[0581] Preparation of compound I-36

[0582]

[0583] The synthesis of compound I-36 was carried out according to compound I-30, in step 6 (according to compound I-1b) using 4,5-difluoro-1H-indole-2-carboxylic acid instead of benzofuran-2-carboxylic acid.

[0584] Yield: 48 mg, 67% (final step)

[0585] ESI-MS: 665.4 [M+H] +

[0586] Preparation of compound I-37

[0587]

[0588] The synthesis of compound I-37 was carried out according to compound I-30, in which 3-methyl-1H-indole-2-carboxylic acid was used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[0589] Yield: 42 mg, 64% (final step)

[0590] ESI-MS: 643.5 [M+H] +

[0591] Preparation of compound I-38

[0592]

[0593] The synthesis of compound I-38 was carried out according to compound I-30, with 1H-benzo[d]imidazol-2-carboxylic acid used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[0594] Yield: 26 mg, 55% (final step)

[0595] ESI-MS: 630.5 [M+H] +

[0596] Preparation of compound I-39

[0597]

[0598] The synthesis of compound I-39 was carried out according to compound I-30, with 2,3-dihydro-1H-indene-2-carboxylic acid used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[0599] Yield: 19 mg, 46% (final step)

[0600] ESI-MS: 630.5 [M+H] +

[0601] Preparation of compound I-40

[0602]

[0603] The synthesis of compound I-40 was carried out according to compound I-30, in which 4-methyl-2-(trifluoromethyl)thiazol-5-carboxylic acid was used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[0604] Yield: 34 mg, 61% (final step)

[0605] ESI-MS: 679.4 [M+H] +

[0606] Preparation of compound I-41

[0607]

[0608] The synthesis of compound I-41 was carried out according to compound I-30, in which 4-bromo-2-(trifluoromethyl)thiazol-5-carboxylic acid was used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[0609] Yield: 39 mg, 56% (final step)

[0610] ESI-MS: 743.3 / 745.3 [M+H] +

[0611] Preparation of compound I-42

[0612]

[0613] The synthesis of compound I-42 was carried out according to compound I-30, in which 4-methyl-2-phenylthiazol-5-carboxylic acid was used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[0614] Yield: 43 mg, 69% (final step)

[0615] ESI-MS: 687.5 [M+H] +

[0616] Preparation of compound I-43

[0617]

[0618] The synthesis of compound I-43 was carried out according to compound I-30, in which 5-bromo-3-methylthiophene-2-carboxylic acid was used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[0619] Yield: 55 mg, 67% (final step)

[0620] ESI-MS: 688.3 / 690.3 [M+H] +

[0621] Preparation of compound I-44

[0622]

[0623] The synthesis of compound I-44 was carried out according to compound I-30, with 3,5-dibromothiophene-2-carboxylic acid used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[0624] Yield: 43 mg, 60% (final step)

[0625] ESI-MS:752.2 / 754.2 / 756.2[M+H] +

[0626] Preparation of compound I-45

[0627]

[0628] The synthesis of compound I-45 was carried out according to compound I-30, in which 5-bromo-3-methylfuran-2-carboxylic acid was used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[0629] Yield: 52 mg, 71% (final step)

[0630] ESI-MS: 672.3 / 674.3 [M+H] +

[0631] Preparation of compound I-46

[0632]

[0633] The synthesis of compound I-46 was carried out according to compound I-30, in which 2,5-dichlorothiophene-3-carboxylic acid was used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[0634] Yield: 85 mg, 72% (final step)

[0635] ESI-MS: 664.3 / 666.3 [M+H] +

[0636] Preparation of compound I-47

[0637]

[0638] The synthesis of compound I-47 was carried out according to compound I-30, in which 2,5-dibromothiophene-3-carboxylic acid was used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[0639] Yield: 64 mg, 68% (final step)

[0640] ESI-MS:752.2 / 754.2 / 756.2[M+H] +

[0641] Preparation of compound I-48

[0642]

[0643] The synthesis of compound I-48 was carried out according to compound I-30, with 2,5-dichlorothiazol-4-carboxylic acid used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[0644] Yield: 26 mg, 48% (final step)

[0645] ESI-MS: 665.3 / 667.3 [M+H] +

[0646] Preparation of compound I-49

[0647]

[0648] The synthesis of compound I-49 was carried out according to compound I-30, in which 2,5-dimethylfuran-3-carboxylic acid was used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[0649] Yield: 53 mg, 74% (final step)

[0650] ESI-MS: 608.5 [M+H] +

[0651] Preparation of compound I-50

[0652]

[0653] The synthesis of compound I-50 was carried out according to compound I-30, with 4-bromothiazol-2-carboxylic acid used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[0654] Yield: 37 mg, 59% (final step)

[0655] ESI-MS: 675.3 / 677.3 [M+H] +

[0656] Preparation of compound I-51

[0657]

[0658] The synthesis of compound I-51 was carried out according to compound I-30, with 4-bromothiophene-2-carboxylic acid used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[0659] Yield: 52 mg, 66% (final step)

[0660] ESI-MS: 674.3 / 676.3 [M+H] +

[0661] Preparation of compound I-52

[0662]

[0663] The synthesis of compound I-52 was carried out according to compound I-30, in which 4-bromo-5-chlorothiophene-2-carboxylic acid was used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[0664] Yield: 48 mg, 65% (final step)

[0665] ESI-MS: 708.2 / 710.2 [M+H] +

[0666] Preparation of compound I-53

[0667]

[0668] The synthesis of compound I-53 was carried out according to compound I-30, in which 4,5-dibromothiophene-2-carboxylic acid was used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[0669] Yield: 52 mg, 63% (final step)

[0670] ESI-MS:752.2 / 754.2 / 756.2[M+H] +

[0671] Preparation of compound I-54

[0672]

[0673] The synthesis of compound I-54 was carried out according to compound I-30, in which 4,5-dichlorothiophene-2-carboxylic acid was used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[0674] Yield: 63 mg, 68% (final step)

[0675] ESI-MS: 664.2 / 666.2 [M+H] +

[0676] Preparation of compound I-55

[0677]

[0678] The synthesis of compound I-55 was carried out according to compound I-30, in which (S)-1-acetylpyrrolidine-2-carboxylic acid was used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[0679] Yield: 76 mg, 73% (final step)

[0680] ESI-MS: 625.5 [M+H] +

[0681] Preparation of compound I-56

[0682]

[0683] The synthesis of compound I-56 was carried out according to compound I-30, in which 1-methyl-1H-1,2,3-triazol-5-carboxylic acid was used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[0684] Yield: 50 mg, 61% (final step)

[0685] ESI-MS: 595.5 [M+H] +

[0686] Preparation of compound I-57

[0687]

[0688] The synthesis of compound I-57 was carried out according to compound I-30, with 2H-tetrazole-5-carboxylic acid used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[0689] Yield: 32 mg, 48% (final step)

[0690] ESI-MS: 582.4 [M+H] +

[0691] Preparation of compound I-58

[0692]

[0693] The synthesis of compound I-58 was carried out according to compound I-1, with 5-hydroxy-2-adamantaneamine used instead of 1-adamantaneamine in step 2 (according to ZED3912) and pyrazine-2-carboxylic acid used instead of 1-methyl-1H-imidazol-5-carboxylic acid in step 6 (according to compound I-1b).

[0694] Yield: 26 mg, 53% (final step)

[0695] ESI-MS: 608.5 [M+H]+

[0696] Preparation of compound I-59

[0697]

[0698] The synthesis of compound I-59 was carried out according to compound I-1, with 5-fluoro-2-adamantaneamine used instead of 1-adamantaneamine in step 2 (according to ZED3912) and (S)-1-Boc-pyrrolidine-3-carboxylic acid used instead of 1-methyl-1H-imidazol-5-carboxylic acid in step 6 (according to compound I-1b). The final product was obtained by deprotection (DCM / TFA) as described above and purified by HPLC.

[0699] Yield: 35 mg, 83% (final step)

[0700] ESI-MS: 601.5 [M+H] +

[0701] Preparation of compound I-60

[0702]

[0703] The synthesis of compound I-60 was carried out according to compound I-1, with 5-chloro-2-adamantaneamine used instead of 1-adamantaneamine in step 2 (according to ZED3912) and (S)-1-Boc-piperidine-2-carboxylic acid used instead of 1-methyl-1H-imidazol-5-carboxylic acid in step 6 (according to compound I-1b). The final product was obtained by deprotection (DCM / TFA) as described above and purified by HPLC.

[0704] Yield: 37 mg, 78% (final step)

[0705] ESI-MS: 631.4 / 633.4 [M+H] +

[0706] Preparation of compound I-61

[0707]

[0708] The synthesis of compound I-61 was carried out according to compound I-1, with 5-bromo-2-adamantaneamine used instead of 1-adamantaneamine in step 2 (according to ZED3912) and (R)-1-Boc-piperidine-3-carboxylic acid used instead of 1-methyl-1H-imidazol-5-carboxylic acid in step 6 (according to compound I-1b). The final product was obtained by deprotection (DCM / TFA) as described above and purified by HPLC.

[0709] Yield: 35 mg, 72% (final step)

[0710] ESI-MS: 675.3 / 677.3 [M+H] +

[0711] Preparation of compound I-62

[0712]

[0713] The synthesis of compound I-62 was carried out according to compound I-1, with 5-methyl-2-adamantaneamine used instead of 1-adamantaneamine in step 2 (according to ZED3912) and (R)-4-Boc-morpholino-3-carboxylic acid used instead of 1-methyl-1H-imidazol-5-carboxylic acid in step 6 (according to compound I-1b). The final product was obtained by deprotection (DCM / TFA) as described above and purified by HPLC.

[0714] Yield: 31 mg, 80% (final step)

[0715] ESI-MS: 613.5 [M+H] +

[0716] Preparation of compound I-63

[0717]

[0718] The synthesis of compound I-63 was carried out according to compound I-1, with 2-aminoadamantane-2-carboxynitrile used instead of 1-adamantaneamine in step 2 (according to ZED3912) and quinine-3-carboxylic acid used instead of 1-methyl-1H-imidazol-5-carboxylic acid in step 6 (according to compound I-1b).

[0719] Yield: 24 mg, 56% (final step)

[0720] ESI-MS: 648.5 [M+H] +

[0721] Preparation of compound I-64

[0722]

[0723] The synthesis of compound I-64 was carried out according to compound I-1, in step 2 (according to ZED3912) 2-methyl 2-aminoadamantane-2-carboxylic acid was used instead of 1-adamantaneamine and in step 6 (according to compound I-1b) 5-nitroisophthalic acid monomethyl ester was used instead of 1-methyl-1H-imidazol-5-carboxylic acid.

[0724] Yield: 46 mg, 71% (final step)

[0725] ESI-MS: 751.5 [M+H] +

[0726] Preparation of compound I-65

[0727]

[0728] The synthesis of compound I-65 was carried out according to compound I-1, with 1-adamantanemethylamine used instead of 1-adamantaneamine in step 2 (according to ZED3912) and 5-nicotinic acid used instead of 1-methyl-1H-imidazol-5-carboxylic acid in step 6 (according to compound I-1b).

[0729] Yield: 61 mg, 74% (final step)

[0730] ESI-MS: 650.5 [M+H] +

[0731] Preparation of compound I-66

[0732]

[0733] The synthesis of compound I-66 was carried out according to compound I-1, with 1-adamantaneethylamine used instead of 1-adamantaneamine in step 2 (according to ZED3912) and 3,5-pyridinedicarboxylic acid used instead of 1-methyl-1H-imidazol-5-carboxylic acid in step 6 (according to compound I-1b).

[0734] Yield: 31 mg, 56% (final step)

[0735] ESI-MS: 663.5 [M+H] +

[0736] Preparation of compound I-67

[0737]

[0738] The synthesis of compound I-67 was carried out according to compound I-1, with N-methyl-2-adamantaneamine used instead of 1-adamantaneamine in step 2 (according to ZED3912) and 6-methylimidazo[2,1-b]thiazol-5-carboxylic acid used instead of 1-methyl-1H-imidazo-5-carboxylic acid in step 6 (according to compound I-1b).

[0739] Yield: 23 mg, 52% (final step)

[0740] ESI-MS: 664.5 [M+H] +

[0741] Preparation of compound I-68

[0742]

[0743] The synthesis of compound I-68 was carried out according to compound I-1, with (±)-endo-2-norbornylamine used instead of 1-adamantanamine in step 2 (according to ZED3912) and 3-methylbenzo[b]furan-2-carboxylic acid used instead of 1-methyl-1H-imidazol-5-carboxylic acid in step 6 (according to compound I-1b).

[0744] Yield: 106 mg, 78% (final step)

[0745] ESI-MS: 604.4 [M+H] +

[0746] Preparation of compound I-69

[0747]

[0748] The synthesis of compound I-69 was carried out according to compound I-1, with (R)-(+)-borneolamine used instead of 1-adamantanamine in step 2 (according to ZED3912) and 3-methylbenzo[b]furan-2-carboxylic acid used instead of 1-methyl-1H-imidazol-5-carboxylic acid in step 6 (according to compound I-1b).

[0749] Yield: 86 mg, 72% (final step)

[0750] ESI-MS: 646.5 [M+H] +

[0751] Preparation of compound I-70

[0752]

[0753] The synthesis of compound I-70 was carried out according to compound I-1, with 1-adamantanamine replaced by exo-2-aminonorbornene in step 2 (according to ZED3912) and 1-methyl-1H-imidazol-5-carboxylic acid replaced by 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to compound I-1b).

[0754] Yield: 94 mg, 79% (final step)

[0755] ESI-MS: 604.4 [M+H] +

[0756] Preparation of compound I-71

[0757]

[0758] The synthesis of compound I-71 was carried out according to compound I-1, with bicyclo[2.2.1]heptane-1-ylamine used instead of 1-adamantanamine in step 2 (according to ZED3912) and isonicotinic acid used instead of 1-methyl-1H-imidazol-5-carboxylic acid in step 6 (according to compound I-1b).

[0759] Yield: 77 mg, 72% (final step)

[0760] ESI-MS: 551.4 [M+H] +

[0761] Preparation of compound I-72

[0762]

[0763] The synthesis of compound I-72 was carried out according to compound I-1, with bicyclo[2.2.1]heptane-7-ylamine used instead of 1-adamantanamine in step 2 (according to ZED3912) and pyridazine-4-carboxylic acid used instead of 1-methyl-1H-imidazol-5-carboxylic acid in step 6 (according to compound I-1b).

[0764] Yield: 44 mg, 61% (final step)

[0765] ESI-MS: 552.4 [M+H] +

[0766] Preparation of compound I-73

[0767]

[0768] The synthesis of compound I-73 was carried out according to compound I-1, with bicyclo[2.2.1]hept-5-en-2-amine used instead of 1-adamantanamine in step 2 (according to ZED3912) and pyridazine-3-carboxylic acid used instead of 1-methyl-1H-imidazol-5-carboxylic acid in step 6 (according to compound I-1b).

[0769] Yield: 31 mg, 52% (final step)

[0770] ESI-MS: 550.4 [M+H] +

[0771] Preparation of compound I-74

[0772]

[0773] The synthesis of compound I-74 was carried out according to compound I-1, with bicyclo[2.2.2]octyl-2-ylamine used instead of 1-adamantanamine in step 2 (according to ZED3912) and 2H-1,2,3-triazol-4-carboxylic acid used instead of 1-methyl-1H-imidazol-5-carboxylic acid in step 6 (according to compound I-1b).

[0774] Yield: 35 mg, 57% (final step)

[0775] ESI-MS: 555.4 [M+H] +

[0776] Preparation of compound I-75

[0777]

[0778] The synthesis of compound I-75 was carried out according to compound I-1, with (R)-(-)-isobornylamine used instead of 1-adamantanamine in step 2 (according to ZED3912) and 1-methyl-1H-1,2,3-triazol-4-carboxylic acid used instead of 1-methyl-1H-imidazol-5-carboxylic acid in step 6 (according to compound I-1b).

[0779] Yield: 44 mg, 68% (final step)

[0780] ESI-MS: 597.5 [M+H] +

[0781] Preparation of compound I-76

[0782]

[0783] The synthesis of compound I-76 was carried out according to compound I-1, with (1R,2R,3R,5S)-(-)-isopinepineamine used instead of 1-adamantanamine in step 2 (according to ZED3912) and 1-methyl-1H-1,2,4-triazol-3-carboxylic acid used instead of 1-methyl-1H-imidazol-5-carboxylic acid in step 6 (according to compound I-1b).

[0784] Yield: 51 mg, 72% (final step)

[0785] ESI-MS: 597.5 [M+H] +

[0786] Preparation of compound I-77

[0787]

[0788] The synthesis of compound I-77 was carried out according to compound I-1, with (1S,2S,3S,5R)-(+)-isopinepineamine used instead of 1-adamantanamine in step 2 (according to ZED3912) and benzofuran-3-carboxylic acid used instead of 1-methyl-1H-imidazol-5-carboxylic acid in step 6 (according to compound I-1b).

[0789] Yield: 66 mg, 75% (final step)

[0790] ESI-MS: 632.5 [M+H] +

[0791] Preparation of compound I-78

[0792]

[0793] The synthesis of compound I-78 was carried out according to compound I-1, with 3-amino-4-homoisotwisted alkyl instead of 1-adamantanamine in step 2 (according to ZED3912) and benzo[b]thiophene-3-carboxylic acid instead of 1-methyl-1H-imidazol-5-carboxylic acid in step 6 (according to compound I-1b).

[0794] Yield: 42 mg, 59% (final step)

[0795] ESI-MS: 660.4 [M+H] +

[0796] Preparation of compound I-79

[0797]

[0798] The synthesis of compound I-79 was carried out according to compound I-1, with 1-aminobisadamantane used instead of 1-adamantaneamine in step 2 (according to ZED3912) and 1-methyl-1H-pyrazole-4-carboxylic acid used instead of 1-methyl-1H-imidazol-5-carboxylic acid in step 6 (according to compound I-1b).

[0799] Yield: 28 mg, 53% (final step)

[0800] ESI-MS: 646.5 [M+H] +

[0801] Preparation of compound I-80

[0802]

[0803] The synthesis of compound I-80 was carried out according to compound I-1, with 4-aminobisadamantane used instead of 1-adamantaneamine in step 2 (according to ZED3912) and 1-methyl-1H-pyrazole-3-carboxylic acid used instead of 1-methyl-1H-imidazol-5-carboxylic acid in step 6 (according to compound I-1b).

[0804] Yield: 36 mg, 59% (final step)

[0805] ESI-MS: 646.5 [M+H] +

[0806] Scheme I-3 New Building Block

[0807]

[0808] 1. Preparation of compound ZED4893

[0809]

[0810] 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 stirred overnight at room temperature. The solvent was evaporated; the residue was dissolved in 30 mL of EtOAc and washed twice with 10 mL each of 10% citric acid solution, 10% NaHCO3 solution, and brine. The organic phase was dried over Na2SO4, filtered, and the solvent was evaporated. The residue was purified by HPLC.

[0811] Yield: 484 mg, 47%

[0812] ESI-MS: 289.3 [M+H] +

[0813] 2. Preparation of compound ZED4894

[0814]

[0815] 484 mg (1.68 mmol) of ZED4893 was suspended in 30 mL of MeOH, and then 50 mg of palladium supported on activated carbon (10%) (unreduced) was added. The suspension was stirred at room temperature under a hydrogen atmosphere for 3 h. The catalyst was filtered and the solvent was evaporated.

[0816] Yield: 339 mg, 78%

[0817] ESI-MS: 259.4 [M+H] +

[0818] Preparation of compound I-81

[0819]

[0820] The synthesis of compound I-81 was carried out according to compound I-1, with ZED4894 used instead of ZED3913 in step 5 (according to I-1a) and 1-methyl-1H-pyrazole-5-carboxylic acid used instead of 1-methyl-1H-imidazol-5-carboxylic acid in step 6 (according to compound I-1b).

[0821] Yield: 43 mg, 65% (final step)

[0822] ESI-MS: 551.5 [M+H] +

[0823] Preparation of compound I-82

[0824]

[0825] The synthesis of compound I-82 was carried out according to compound I-81, with 3-(bromomethyl)-1-adamantanol used instead of 1-(bromomethyl)adamantane (according to ZED4893) and 4-cyclopropyl-[1,2,3]thiadiazole-5-carboxylic acid used instead of 1-methyl-1H-pyrazole-5-carboxylic acid.

[0826] Yield: 26 mg, 46% (final step)

[0827] ESI-MS: 611.4 [M+H] +

[0828] Preparation of compound I-83

[0829]

[0830] The synthesis of compound I-83 was carried out according to compound I-81, with 1-bromo-3-(bromomethyl)adamantane replaced by 1-(bromomethyl)adamantane (according to ZED4893) and 1,2,5-thiadiazole-3-carboxylic acid replaced by 1-methyl-1H-pyrazole-5-carboxylic acid.

[0831] Yield: 42 mg, 61% (final step)

[0832] ESI-MS: 633.3 / 635.3 [M+H] +

[0833] Preparation of compound I-84

[0834]

[0835] The synthesis of compound I-84 was carried out according to compound I-81, using 2-(bromomethyl)adamantane instead of 1-(bromomethyl)adamantane (according to ZED4893) and 4-((tetrahydro-2H-pyran-2-yloxy)methyl)-1,2,3-thiadiazole-5-carboxylic acid instead of 1-methyl-1H-pyrazole-5-carboxylic acid. In the final step, the tetrahydropyranyl (Thp) protecting group was cleaved using TFA.

[0836] Yield: 15 mg, 68% (final step)

[0837] ESI-MS: 585.4 [M+H] +

[0838] Preparation of compound I-85

[0839]

[0840] The synthesis of compound I-85 was carried out according to compound I-81, with 1-(2-bromoethyl)adamantane replaced by 1-(bromomethyl)adamantane (according to ZED4893) and 5-tert-butyl-1H-pyrrole-3-carboxylic acid replaced by 1-methyl-1H-pyrazole-5-carboxylic acid in the final step.

[0841] Yield: 32 mg, 58% (final step)

[0842] ESI-MS: 606.5 [M+H] +

[0843] Preparation of compound I-86

[0844]

[0845] The synthesis of compound I-86 was carried out according to compound I-81, with 1-(3-bromopropyl)adamantane replaced by 1-(bromomethyl)adamantane (according to ZED4893) and 4-cyano-1-methyl-1H-pyrrole-2-carboxylic acid replaced by 1-methyl-1H-pyrazole-5-carboxylic acid in the final step.

[0846] Yield: 28 mg, 51% (final step)

[0847] ESI-MS: 603.5 [M+H] +

[0848] Preparation of compound I-87

[0849]

[0850] The synthesis of compound I-87 was carried out according to compound I-1, with 3-chloropropionic acid used instead of chloroacetic acid (according to ZED1657) and 5-methoxyoxazol-2-carboxylic acid used instead of 1-methyl-1H-pyrazole-5-carboxylic acid in step 6 (according to compound I-1b).

[0851] Yield: 39 mg, 64% (final step)

[0852] ESI-MS: 625.5 [M+H] +

[0853] Preparation of compound I-88

[0854]

[0855] The synthesis of compound I-88 was carried out according to compound I-1, with 1-bicyclo[1.1.1]pentylamine used instead of 1-adamantanamine in step 2 (according to ZED3912) and 3-methylbenzo[b]furan-2-carboxylic acid used instead of 1-methyl-1H-imidazol-5-carboxylic acid in step 6 (according to compound I-1b).

[0856] Yield: 107 mg, 81% (final step)

[0857] ESI-MS: 576.4 [M+H] +

[0858] Preparation of compound I-89

[0859]

[0860] The synthesis of compound I-89 was carried out according to compound I-1, with 1-bicyclo[1.1.1]pentylamine used instead of 1-adamantanamine in step 2 (according to ZED3912) and 2-acetyloxazol-4-carboxylic acid used instead of 1-methyl-1H-imidazol-5-carboxylic acid in step 6 (according to compound I-1b).

[0861] Yield: 68 mg, 75% (final step)

[0862] ESI-MS: 555.4 [M+H] +

[0863] Preparation of compound I-90

[0864]

[0865] The synthesis of compound I-90 was carried out according to compound I-1, with 1-bicyclo[2.1.1]hexane-1-amine used instead of 1-adamantanamine in step 2 (according to ZED3912) and 2-isopropyloxazol-5-carboxylic acid used instead of 1-methyl-1H-imidazol-5-carboxylic acid in step 6 (according to compound I-1b).

[0866] Yield: 46 mg, 60% (final step)

[0867] ESI-MS: 569.4 [M+H] +

[0868] Preparation of compound I-91

[0869]

[0870] The synthesis of compound I-91 was carried out according to compound I-1, with 1-bicyclo[3.2.1]octane-8-amine used instead of 1-adamantanamine in step 2 (according to ZED3912) and 3,5-dimethylisoxazole-4-carboxylic acid used instead of 1-methyl-1H-imidazol-5-carboxylic acid in step 6 (according to compound I-1b).

[0871] Yield: 32 mg, 54% (final step)

[0872] ESI-MS: 583.4 [M+H] +

[0873] Preparation of compound I-92

[0874]

[0875] The synthesis of compound I-92 was carried out according to compound I-1, with 4-aminoadamantane-1-carboxylic acid used instead of 1-adamantaneamine in step 2 (according to ZED3912) and 4-methylpyrimidine-5-carboxylic acid used instead of 1-methyl-1H-imidazol-5-carboxylic acid in step 6 (according to compound I-1b).

[0876] Yield: 35 mg, 46% (final step)

[0877] ESI-MS: 650.5 [M+H] +

[0878] Preparation of compound I-93

[0879]

[0880] The synthesis of compound I-93 was carried out according to compound I-1, with 4-aminoadamantane-N,N-dimethyl-1-carboxamide used instead of 1-adamantaneamine in step 2 (according to ZED3912) and 1,2,3,4-tetrahydronaphthalene-2-carboxylic acid used instead of 1-methyl-1H-imidazol-5-carboxylic acid in step 6 (according to compound I-1b).

[0881] Yield: 31 mg, 55% (final step)

[0882] ESI-MS: 672.5 [M+H] +

[0883] Preparation of compound I-94

[0884]

[0885] The synthesis of compound I-94 was carried out according to compound I-30, in which 1,4-diazabicyclo[2.2.2]octane-2-carboxylic acid was used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[0886] Yield: 39 mg, 58% (final step)

[0887] ESI-MS: 624.5 [M+H] +

[0888] Preparation of compound I-95

[0889]

[0890] The synthesis of compound I-95 was carried out according to compound I-30, with 1H-indole-3-carboxylic acid used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[0891] Yield: 56 mg, 74% (final step)

[0892] ESI-MS: 629.5 [M+H] +

[0893] Preparation of compound I-96

[0894]

[0895] The synthesis of compound I-96 was carried out according to compound I-30, in which 6-methylimidazo[2,1-b][1,3]thiazo-3-carboxylic acid was used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[0896] Yield: 33 mg, 56% (final step)

[0897] ESI-MS: 650.5 [M+H] +

[0898] Preparation of compound I-97

[0899]

[0900] The synthesis of compound I-97 was carried out according to compound I-1, with (±)-endo-2-norbornylamine used instead of 1-adamantanamine in step 2 (according to ZED3912) and 1,3-benzothiazol-2-carboxylic acid used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[0901] Yield: 45 mg, 73% (final step)

[0902] ESI-MS: 607.4 [M+H] +

[0903] Preparation of compound I-98

[0904]

[0905] The synthesis of compound I-98 was carried out according to compound I-1, with (±)-endo-2-norborneolamine replaced by 1-adamantanamine in step 2 (according to ZED3912) and imidazo[2,1-b][1,3]thiazo-6-carboxylic acid replaced by benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[0906] Yield: 26 mg, 50% (final step)

[0907] ESI-MS: 596.4 [M+H] +

[0908] Preparation of compound I-99

[0909]

[0910] The synthesis of compound I-99 was carried out according to compound I-1, with (±)-endo-2-norborneolamine replaced by 1-adamantanamine in step 2 (according to ZED3912) and 4-hydroxy-6-(trifluoromethoxy)quinoline-3-carboxylic acid replaced by benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[0911] Yield: 15 mg, 42% (final step)

[0912] ESI-MS: 701.4 [M+H] +

[0913] Preparation of compound I-100

[0914]

[0915] The synthesis of compound I-100 was carried out according to compound I-1, with 1-bicyclo[1.1.1]pentylamine used instead of 1-adamantanamine in step 2 (according to ZED3912) and 3-oxolinecarboxylic acid used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[0916] Yield: 37 mg, 65% (final step)

[0917] ESI-MS: 574.4 [M+H] +

[0918] Preparation of compound I-101

[0919]

[0920] The synthesis of compound I-101 was carried out according to compound I-1, with 1-bicyclo[1.1.1]pentylamine used instead of 1-adamantanamine in step 2 (according to ZED3912) and 3-ethylbenzofuran-2-carboxylic acid used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[0921] Yield: 55 mg, 73% (final step)

[0922] ESI-MS: 590.4 [M+H] +

[0923] Preparation of compound I-102

[0924]

[0925] The synthesis of compound I-102 was carried out according to compound I-1, with 1-bicyclo[1.1.1]pentylamine used instead of 1-adamantanamine in step 2 (according to ZED3912) and 1-ethyl-1H-indole-2-carboxylic acid used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[0926] Yield: 43 mg, 68% (final step)

[0927] ESI-MS: 589.4 [M+H] +

[0928] Preparation of compound I-103

[0929]

[0930] The synthesis of compound I-103 was carried out according to compound I-1, with 1-bicyclo[1.1.1]pentylamine used instead of 1-adamantanamine in step 2 (according to ZED3912) and 2-methyl-1,8-naphthidine-3-carboxylic acid used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[0931] Yield: 40 mg, 64% (final step)

[0932] ESI-MS: 588.4 [M+H] +

[0933] Preparation of compound I-104

[0934]

[0935] The synthesis of compound I-104 was carried out according to compound I-1, with bicyclo[2.1.1]hexane-1-amine used instead of 1-adamantanamine in step 2 (according to ZED3912) and N-Boc-1,2,3,4-tetrahydroquinoline-6-carboxylic acid used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b). The final product was obtained by deprotection (DCM / TFA) as described above and purified by HPLC.

[0936] Yield: 27 mg, 73% (final step)

[0937] ESI-MS: 591.4 [M+H] +

[0938] Preparation of compound I-105

[0939]

[0940] The synthesis of compound I-105 was carried out according to compound I-1, with 2-amino-5-(trifluoromethyl)adamantane-2-carboxylic acid used instead of 1-adamantaneamine in step 2 (according to ZED3912) and 3-oxo-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[0941] Yield: 19 mg, 44% (final step)

[0942] ESI-MS: 771.5 [M+H] +

[0943] Preparation of compound I-106

[0944]

[0945] The synthesis of compound I-106 was carried out according to compound I-1, with 5-ethyladamantane-2-amine used instead of 1-adamantaneamine in step 2 (according to ZED3912) and 1,6-naphthidine-2-carboxylic acid used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[0946] Yield: 25 mg, 54% (final step)

[0947] ESI-MS: 670.5 [M+H] +

[0948] Preparation of compound I-107

[0949]

[0950] The synthesis of compound I-107 was carried out according to compound I-1, with bicyclo[2.1.1]hexane-1-amine used instead of 1-adamantanamine in step 2 (according to ZED3912) and 2,6-naphthidine-1-carboxylic acid used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[0951] Yield: 58 mg, 74% (final step)

[0952] ESI-MS: 588.4 [M+H] +

[0953] Preparation of compound I-108

[0954]

[0955] The synthesis of compound I-108 was carried out according to compound I-1, with 1-bicyclo[1.1.1]pentylamine used instead of 1-adamantanamine in step 2 (according to ZED3912) and 4-Boc-amino-1,2,5-oxadiazol-3-carboxylic acid used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b). The final product was obtained by deprotection (DCM / TFA) as described above and purified by HPLC.

[0956] Yield: 27 mg, 77% (final step)

[0957] ESI-MS: 529.4 [M+H] +

[0958] Preparation of compound I-109

[0959]

[0960] The synthesis of compound I-109 was carried out according to compound I-1, with 1-bicyclo[1.1.1]pentylamine used instead of 1-adamantanamine in step 2 (according to ZED3912) and 6-(dimethylamino)benzofuran-2-carboxylic acid used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[0961] Yield: 35 mg, 57% (final step)

[0962] ESI-MS: 605.4 [M+H] +

[0963] Preparation of compound I-110

[0964]

[0965] The synthesis of compound I-110 was carried out according to compound I-1, with 1-bicyclo[1.1.1]pentylamine used instead of 1-adamantanamine in step 2 (according to ZED3912) and 2-acetylamino-5-thiazocarboxylic acid used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[0966] Yield: 25 mg, 49% (final step)

[0967] ESI-MS: 586.4 [M+H] +

[0968] Preparation of compound I-111

[0969]

[0970] The synthesis of compound I-111 was carried out according to compound I-1, with 1-bicyclo[1.1.1]pentylamine used instead of 1-adamantanamine in step 2 (according to ZED3912) and 5-carbamoyl-1H-pyrrole-3-carboxylic acid used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[0971] Yield: 19 mg, 42% (final step)

[0972] ESI-MS: 554.4 [M+H] +

[0973] Preparation of compound I-112

[0974]

[0975] The synthesis of compound I-112 was carried out according to compound I-1, with 1-acetylamino-4-aminoadamantane used instead of 1-adamantaneamine in step 2 (according to ZED3912) and 5-aminosulfonylfuran-3-carboxylic acid used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[0976] Yield: 24 mg, 53% (final step)

[0977] ESI-MS: 716.4 [M+H] +

[0978] Preparation of compound I-113

[0979]

[0980] The synthesis of compound I-113 was carried out according to compound I-1, with 1-acetylamino-4-aminoadamantane used instead of 1-adamantaneamine in step 2 (according to ZED3912) and benzofuran-5-carboxylic acid used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[0981] Yield: 30 mg, 58% (final step)

[0982] ESI-MS: 687.5 [M+H] +

[0983] Preparation of compound I-114

[0984]

[0985] The synthesis of compound I-114 was carried out according to compound I-1, with 4-aminoadamantane-1-carboxamide used instead of 1-adamantaneamine in step 2 (according to ZED3912) and benzofuran-6-carboxylic acid used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[0986] Yield: 37 mg, 65% (final step)

[0987] ESI-MS: 673.5 [M+H] +

[0988] Preparation of compound I-115

[0989]

[0990] The synthesis of compound I-115 was carried out according to compound I-1, with 4-aminoadamantane-1-carboxamide used instead of 1-adamantaneamine in step 2 (according to ZED3912) and 3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxylic acid used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[0991] Yield: 23 mg, 47% (final step)

[0992] ESI-MS: 679.5 [M+H] +

[0993] Preparation of compound I-116

[0994]

[0995] The synthesis of compound I-116 was carried out according to compound I-1, with 1-bicyclo[1.1.1]pentylamine used instead of 1-adamantanamine in step 2 (according to ZED3912) and 5-methyl-1,2,4-oxadiazole-3-carboxylic acid used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[0996] Yield: 36 mg, 62% (final step)

[0997] ESI-MS: 528.4 [M+H] +

[0998] Preparation of compound I-117

[0999]

[1000] The synthesis of compound I-117 was carried out according to compound I-1, with 1-bicyclo[1.1.1]pentylamine used instead of 1-adamantanamine in step 2 (according to ZED3912) and 1,2,3-thiadiazole-4-carboxylic acid used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[1001] Yield: 31 mg, 57% (final step)

[1002] ESI-MS: 530.3 [M+H] +

[1003] Preparation of compound I-118

[1004]

[1005] The synthesis of compound I-118 was carried out according to compound I-1, with 1-bicyclo[1.1.1]pentylamine used instead of 1-adamantanamine in step 2 (according to ZED3912) and 1,2,4-thiadiazole-4-carboxylic acid used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[1006] Yield: 39 mg, 63% (final step)

[1007] ESI-MS: 530.3 [M+H] +

[1008] Preparation of compound I-119

[1009]

[1010] The synthesis of compound I-119 was carried out according to compound I-1, with 1-bicyclo[1.1.1]pentylamine used instead of 1-adamantanamine in step 2 (according to ZED3912) and 1,3,4-thiadiazole-5-carboxylic acid used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[1011] Yield: 28 mg, 52% (final step)

[1012] ESI-MS: 530.3 [M+H] +

[1013] Preparation of compound I-120

[1014]

[1015] The synthesis of compound I-120 was carried out according to compound I-30, in which 4-(hydroxymethyl)-1,2,3-thiadiazole-5-carboxylic acid was used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[1016] Yield: 17 mg, 41% (final step)

[1017] ESI-MS: 626.4 [M+H] +

[1018] Preparation of compound I-121

[1019]

[1020] The synthesis of compound I-120 was carried out according to compound I-1, with nicotinic acid used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[1021] Yield: 56 mg, 60% (final step)

[1022] ESI-MS: 591.5 [M+H] +

[1023] Preparation of reference compound Ref. 4

[1024]

[1025] The synthesis of reference compound Ref.4 was carried out according to compound I-1, with 2-phenylethylamine used instead of 1-adamantanamine in step 2 (according to ZED3912) and nicotinic acid used instead of benzofuran-2-carboxylic acid in step 6 (according to compound I-1b).

[1026] Yield: 68 mg, 77% (final step)

[1027] ESI-MS: 561.4 [M+H] +

[1028] Biological Examples

[1029] Example B-1. Inhibitory effect of the compound according to the present invention

[1030] Transglutaminase assay

[1031] To determine the efficacy of the inhibitor against tissue transglutaminase, the incorporation of dansylcadaverine into dimethylcasein was measured using recombinant human transglutaminase 2 (Zedira product T022) (Zedira product T036, Lorand et al., Anal Biochem, 1971, 44:221-31).

[1032] Tissue transglutaminase was diluted in buffer (50 mM Tris-HCl, 7.5 mM CaCl2, 150 mM NaCl, pH 7.4). The final concentration of TG2 in the assay was 10 nM.

[1033] A 10 mM inhibitor stock solution was prepared in DMSO, and a series of 1:2 dilutions were then prepared in DMSO. Each initial dilution was then 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.

[1034] Add 15 μl of inhibitor working dilution 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 mentioned above to each well.

[1035] Shortly before starting the assay, 600 μl of transglutaminase working solution was added to 11.4 mL of assay buffer (50 mM Tris-HCl, 10 mM CaCl2, 10 mM glutathione, 2.5% glycerol, 16.7 μM tansyl cadaverine, 4 μM N,N-dimethylcasein, 200 mM NaCl, pH 8.0). 285 μl of this reaction mixture was then added to each well containing the inhibitor.

[1036] Using λ at 37℃ ex =330nm and λ em The increase in fluorescence was measured at 500 nm over 30 minutes. The slope of the fluorescence increase between 20 and 30 minutes was calculated to determine the IC50. 50 Value (inhibitor concentration at which 50% of the initial activity is blocked).

[1037] Enzyme activity was analyzed by calculating the slope of the increase in fluorescence intensity. IC50 50 The values ​​were calculated by plotting enzyme activity against inhibitor concentration (as a percentage relative to a control containing 2% DMSO, rather than the inhibitor). IC50 was calculated. 50 The inhibitor concentration is defined as the concentration that blocks 50% of the initial enzyme activity.

[1038] The compounds of this invention exhibit inhibitory activity against tissue transglutaminase (TG2) using IC50 assay. 50 The values ​​are shown in Table 1 below.

[1039] Table 1. Efficacy of reversible TG2 inhibitors

[1040] A: IC 50 <150nM, B: 150nM≤IC 50 <600nM, C: 600nM≤IC 50 <3,500 nM,

[1041] D: 3,500 nM ≤ IC 50 <10,000nM

[1042]

[1043]

[1044]

[1045]

[1046] Example B-2. LogD value of the compound of the present invention

[1047] In order to classify the compounds of the present invention according to their lipophilicity, the LogD value (partition coefficient) was determined by means of the established shake flask method, and the partition of the compounds between octanol and phosphate-buffered saline (PBS, pH 7.4) was measured by HPLC.

[1048] Compounds with moderate lipophilicity (LogD values ​​from 0 to 3) are generally advantageous for oral absorption, maintaining a balance between solubility and permeability. However, complex formulations can improve the oral bioavailability of highly lipophilic compounds.

[1049] Table 2. LogD values ​​of reversible TG2 inhibitors. A: logD < 1, B: 1 ≤ logD < 3, C: 3 ≤ logD < 5

[1050]

[1051]

[1052]

[1053] Example B-3. Caco-2 permeability determination of the compounds of the present invention

[1054] The permeability coefficient (P) was obtained from the Caco-2 barrier study predicting the oral / gut bioavailability of the tested compounds. app (Value). Measurements were taken according to the manufacturer's specifications using CacoReady from ReadyCell. TM Use ready-to-use kits.

[1055] It is considered to have a value higher than 1x10 -6 P cm / s app Compounds with values ​​below 1x10 are classified as permeable, while those with values ​​below 1x10 are classified as permeable. -6 P cm / s app The compounds with the value were classified as impermeable.

[1056] Table 3. Caco2 permeability assay of reversible TG2 inhibitors A:P app <1x10 -6 cm / s, B:P app ≥1x10 -6 cm / s≤P app <10x10 -6 cm / s

[1057]

[1058]

[1059]

Claims

1. A compound of general formula (I): in L represents -L 1 -L 2 -; L 1 It can represent -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CO-, or -CH2CH2CO-; L 2 Indicates key, -NR N1 -、-NR N1 CH2-, -NR N1 CH2CH2- or -NR N1 CH(CH3)-; R 1 express R 2 express The unsubstituted bicyclic residues can be replaced by the substituent R. 9 -R 14 and R N One to five substitutions in the middle; R 3 The residues described herein represent 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-highly iso-twisted alkyl, adamantyl, diadamantyl, or hexamethylenetetramine, and optionally contain one or more C=C double bonds and / or optionally R a 、R b 、R c 、R d and R e One or more substitutions in; R a 、R b 、R c 、R d and R e Independently representing -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -CO2C2H5, -CONH2, -CONHCH3, -CON(CH3)2, -CONHC2H5, -CH2CO2H, -CH2CO2CH3, -CH2CO2C2H5, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2H5, -NHCOCH3, -NHCOC2H5, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C2H5, -NHSO2CHF2, -NHSO2CF3, or -NHSO2CH2CF3; R 4 Indicates -NR 6 R 7 ; R 6 It represents -CH2CH3; and R 7 Indicates -H; R 8 、R 9 、R 10 、R 11 、R 12 、R 13 and R 14 Independently representing -H, -F, -Cl, -Br, -I, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclic-C3H5, -CH2-cyclic-C3H5, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2Cl, -CH2-CH2Br, -CH2-CH2I, -CH2OH, -OCH3, -OC2H5, -O C3H7, -OCH(CH3)2, -OC(CH3)3, -OC4H9, -OCHF2, -OCF3, -OCH2CF3, -OC2F5, -OCH2OCH3, -O-ring-C3H5, -OCH2-ring-C3H5, -O-C2H4-ring-C3H5, -CHO, -COCH3,- COCF3, -COC2H5, -COC3H7, -COCH(CH3)2, -COC(CH3)3, -COOH, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -OOC-CH3, -OOC-CF3, -OOC -C2H5, -OOC-C3H7, -OOC-CH(CH3)2, -OOC-C(CH3)3, -NH2, -NHCH3, -NHC2H5, -NHC3H7, -NHCH(CH3)2, -NHC(CH3)3, -N(CH3)2, -N(C2H5)2, -N(C3H7)2, -N[CH(CH3)2]2, -N[C(CH3)3]2, -NHCOCH3, -NHCOCF3, -NHCOC2H5, -NHCOC3H7, -NHCOCH(CH3)2, -NHCOC(CH3)3, -CONH2, -CONHCH3, -CONHC2H5, -CONHC 3H7, -CONHCH(CH3)2, -CONH-cyclo-C3H5, -CONHC(CH3)3, -CON(CH3)2, -CON(C2H5)2, -CON(C3H7)2, -CON[CH(CH3)2]2, -CON[C(CH3)3]2, -SO2NH2, -SO2NH CH3、-SO2NHC2H5、-SO2NHC3H7、-SO2NHCH(CH3)2、-SO2NH-cyclo-C3H5、-SO2NHC(CH3)3、-SO2N(CH3)2、-SO2N(C2H5)2、-SO2N(C3H7)2、-SO2N[CH(CH3)2]2-SO2N[C(CH3)3]2、-NHSO2CH3、-NHSO2CF3、-NHSO2C2H5、-NHSO2C3H7、-NHSO2CH(CH3)2、-NHSO2C(CH3)3、-CH=CH2、-CH2-CH=CH2、-C(CH3)=CH2、-CH=CH-CH3、-C≡CH、-C≡C-CH3、-CH2-C≡CH、-Ph、-O-Ph、-O-CH2-Ph、 Or R 8 and R 9 Or R 9 and R 10 They can form one of the following quinary or hexacyclic rings: Or R 12 and R 13 Or R 13 and R 14 They can form one of the following quinary or hexacyclic rings: R N This indicates -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-C5H9, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2Cl, -CH2-CH2Br, -CH2-CH2I, -CH 2-CH=CH2, -CH2-C≡CH, -CHO, -COCH3, -COC2H5, -COC3H7, -COCH(CH3)2, -COC(CH3)3, -CO-cyclo-C3H5, -CO-cyclo-C4H7, -CO-cyclo-C5H9, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -SO2CH3, -SO2CF3, -SO2C2H5, -SO2C3H7, -SO2CH(CH3)2, -SO2-cyclo-C3H5, or -SO2C(CH3)3; R N1 It represents -H, -CH3, or -CH2CH3; Or its diastereomers, enantiomers, mixtures of diastereomers, mixtures of enantiomers, racemic mixtures, or pharmaceutically acceptable salts.

2. The compound according to claim 1, wherein... R 2 express The unsubstituted bicyclic residues can be replaced by the substituent R. 9 -R 14 and R N One to five substitutions in the middle; And the substituent R 9 -R 14 and R N It has the meaning as defined in claim 1.

3. The compound according to claim 1, wherein... R 2 express And R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 and R N It has the meaning as defined in claim 1.

4. The compound according to claim 1, wherein... in L represents -L 1 -L 2 -; L 1 It represents -CH2CO-, L 2 Indicates -NR N1 - and R 3 Indicates 1-adamantyl; or L 2 Indicates -NR N1 CH2-, and R 3 It represents 2-bicyclo[3.1.1]heptyl, Furthermore, the aforementioned 1-adamantyl and 2-bicyclo[3.1.1]heptyl residues optionally contain one or more C=C double bonds and / or optionally are R a 、R b 、R c 、R d and R e One or more substitutions in; R 1 express R 2 express R 6 It represents -C2H5; And R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R a 、R b 、R c 、R d 、R e 、R N and R N1 It has the same meaning as defined in claim 1, or its diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemic mixture, or pharmaceutically acceptable salt.

5. The compound according to claim 1 or 4, represented by formula (II): in L 2 Indicates -NR N1 - and R 3 Indicates 1-adamantyl; or L 2 Indicates -NR N1 CH2-, and R 3 It represents 2-bicyclo[3.1.1]heptyl, Furthermore, the aforementioned 1-adamantyl and 2-bicyclo[3.1.1]heptyl residues optionally contain one or more C=C double bonds and / or optionally are R a 、R b 、R c 、R d and R e One or more substitutions in; R 2 express R a 、R b 、R c 、R d and R e Independently representing -H, -F, -Cl, -Br, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2CF3, -COCH3, -COCH2CH3, -CO2H, -CO2CH3, -CO2C2H5, -CONH2, -CONHCH3, -CON(CH3)2, -CONHC2H5, -CH2CO2H, -CH2CO2CH3, -CH2CO2C2H5, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2, -CH2CONHC2H5, -NHCOCH3, -NHCOC2H5, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C2H5, -NHSO2CHF2, -NHSO2CF3, or -NHSO2CH2CF3; R N This indicates -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-C5H9, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2Cl, -CH2-CH2Br, -CH2-CH 2I, -CH2-CH=CH2, -CH2-C≡CH, -CHO, -COCH3, -COC2H5, -COC3H7, -COCH(CH3)2, -COC(CH3)3, -CO-cyclo-C3H5, -CO-cyclo-C4H7, -CO-cyclo-C5H9, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -SO2CH3, -SO2CF3, -SO2C2H5, -SO2C3H7, -SO2CH(CH3)2, or -SO2C(CH3)3; R N1 It represents -H, -CH3, or -CH2CH3; R 8 、R 10 and R 11 Representing each other independently -H, -F, -Cl, -Br, -I, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -cyclo-C3H5, -C H2-ring-C3H5, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2Cl, -CH2-CH2Br, -CH2 -CH2I, -OCH3, -OC2H5, -OC3H7, -OCH(CH3)2, -OC(CH3)3, -OC4H9, -OCHF2, -OCF3, -OCH2CF3, -OC2F5, -OCH2OCH3, -O-cyclo-C3H5, -OCH2-cyclo-C3H5, -O-C2H4-cyclo-C3H5, -CH=CH2, -CH2-CH=CH2, -C(CH3)=CH2, -CH=CH-CH3, -C≡CH, -C≡C-CH3, -CH2-C≡CH, or -Ph, Or its diastereomers, enantiomers, mixtures of diastereomers, mixtures of enantiomers, racemic mixtures, or pharmaceutically acceptable salts.

6. The compound according to claim 1, wherein the compound has any one of the formulas (II-a)-(II-l), (II-b1)-(II-b2), and (III-a)-(III-l): Where L 1 L 2 、R 2 、R 8 、R 10 、R 11 、R 12 、R 13 、R 14 、R N 、R a 、R b 、R c 、R d and R e It has the same meaning as defined in claim 1.

7. The compound according to any one of claims 1-5, wherein R 3 express 8. The compound according to claim 1, wherein, R 2 express 9. The compound according to claim 1, wherein the compound is selected from the group consisting of: Or its pharmaceutically acceptable salt.

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

11. Use of the compound according to any one of claims 1-9 or the pharmaceutical composition according to claim 10 in the preparation of a medicament, wherein the medicament is an inhibitor of transglutaminase 2.

12. The use according to claim 11, wherein the drug is used to treat or prevent diseases selected from autoimmune and inflammatory diseases, fibrotic diseases, and liver diseases. The autoimmune and inflammatory diseases mentioned therein are selected from celiac disease, Duhring-Brocq disease, gluten ataxia, and gluten neuropathy; The fibrotic diseases affecting the lungs, kidneys, liver, skin, or intestines are selected from cystic fibrosis, renal fibrosis and diabetic nephropathy, intestinal fibrosis, idiopathic pulmonary fibrosis, and liver fibrosis; The liver diseases mentioned are selected from alcoholic steatohepatitis, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, cirrhosis, autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis.

13. Use of the compound according to claim 11 or use of the pharmaceutical composition, wherein the pharmaceutical composition is used to treat or prevent alcoholic hepatitis.

14. Use of the compound according to claim 11 or use of the pharmaceutical composition, wherein the pharmaceutical composition is used to treat or prevent hepatitis.

15. The use according to claim 11, wherein the drug is used to treat or prevent celiac disease.

16. A method for preparing a compound of formula (Ia) according to claim 1, comprising: Step 1A: Provide compound 4a Step 2A: Perform the coupling reaction between compound 4a and compound 5. To obtain compound 6a Step 3A: Protect the amino group PG 3 Deprotection to obtain compound 7a Step 4A: React compound 7a with carboxylic acid (R) 2 The coupling reaction of -CO2H 8) yields compound 9a. Step 5A: Perform the oxidation reaction of compound 9a to produce the compound of formula (Ia). Among them, L and R 2 、R 3 and R 6 It has the same meaning as defined in claim 1, and PG 3 It is an amino protecting group.

17. The compound according to claim 1, wherein... R 2 express The unsubstituted bicyclic residues can be replaced by the substituent R. 11 -R 13 One to three substitutions in, of which R 9 -R 14 and R N It has the meaning as defined in claim 1.

18. The compound according to claim 1, wherein... R 2 express The unsubstituted bicyclic residues can be replaced by the substituent R. 11 -R 13 One to three substitutions in; And the substituent R 9 -R 14 and R N It has the meaning as defined in claim 1.

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