Transglutaminase inhibitors

Abstract

The present invention relates to compounds of general formula (I) as novel inhibitors of transglutaminase, methods for producing the compounds of the present invention, pharmaceutical compositions containing the compounds of the present invention, and their use in preventing and treating diseases associated with transglutaminase, particularly transglutaminase 2. #imgabs0#

Description

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

[0003] Transglutaminases are part of the transferase class and, according to EC nomenclature, are appropriately named "protein-glutamine:amine gamma-glutamyltransferases" (EC 2.3.2.13). They link the epsilon-amino group of the amino acid lysine and the gamma-glutamyl group of the amino acid glutamine, forming an isopeptide bond with the release of ammonia. In the absence of a suitable amine and / or under certain conditions, deamidation of glutamine can occur, yielding the corresponding glutamic acid.

[0004] In addition, transglutaminases play an important role in many therapeutic areas such as cardiovascular diseases (thrombosis and atherosclerosis), autoimmune diseases (diarrheal celiac disease, Duhring-Brocq disease, gluten ataxia), neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease), skin diseases (ichthyosis, psoriasis, acne), as well as wound healing and inflammatory diseases (e.g. tissue fibrosis) (JM Woodzinska, Mini-Reviews inmedical chemistry, 2005, 5, 279-292).

[0005] However, diarrhoeal celiac disease, gluten intolerance, is one of the most important indications. Diarrhoeal celiac disease is characterized by chronic inflammation of the small intestinal mucosa. In susceptible patients, after ingesting gluten-containing foods, the intestinal epithelium is subsequently destroyed, resulting in reduced absorption of nutrients, which again has a huge impact on the 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 great need for the development of drugs for the treatment of diarrhoeal celiac disease and other diseases related to tissue transglutaminase (transglutaminase 2, TG2, tTG). Tissue transglutaminase is a key factor during the onset of disease. The endogenous enzyme catalyzes the deamidation of gluten / gliadin in the small intestinal mucosa and thereby triggers an inflammatory response. Therefore, inhibitors of tissue transglutaminase are suitable for use as active agents in 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 hepatic fibrosis are among the most important fibrotic disorders to be addressed with the disclosed compounds.

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

[0008] Tse et al. (J.Med.Chem.2020,63,11585-11601) reported on the replacement of phenyl residues by non-classical bioisosteres such as cubanes and bicyclo[1.1.1]pentane (BCP) in antimalarial triazolopyrazine compounds in order to change the solubility and metabolic stability of the compound. The authors further evaluated the in vitro anti-malarial activity of bioisosterically modified triazolopyrazines against the 3D7 strain of Plasmodium falciparum (P.falciparum). The replacement of phenyl by bioisosteric saturated heterocyclic residues resulted in a complete loss of activity. Adamantyl residues and other hydrocarbon caged derivatives resulted in efficacy that was up to 2-9 times lower than that of the corresponding phenyltriazolopyrazine compounds. In contrast, higher efficacy was obtained by replacing phenyl with closed-1,2-(closo-1,2-) and 1,7-carborane isomers. The authors conclude that the effects of non-classical bioisostere substitutions on biological properties cannot be accurately predicted, and that a considerable range of possible bioisosteres must first be tested in order to identify suitable substitutions that lead to the desired properties of a given molecule.

[0009] Subbaiah et al. (J.Med.Chem.2021,64,19,14046-14128) reported on the bioisostere of the phenyl ring in the dominant optimization and drug design. It is worth noting that the bioisostere phenyl ring replacement with heterocyclic and carbocyclic moieties can lead to enhanced efficacy, solubility and metabolic stability, while reducing lipophilicity, plasma protein binding, phospholipid disease potential and cytochrome P450 enzymes and hERG channels. However, the effect strongly depends on the characteristics of the compound itself and the addressing target.

[0010] US 11,072,634 B2 discloses a reversible glutaminase inhibitor comprising an aldehyde, ketone, α-ketoaldehyde, α-ketoketone, α-ketoacid, α-ketoester, α-ketoamide or halogen methylketone as a warhead. The inhibitor shows inhibitory activity (IC) against tissue transglutaminase TG2 in the nanomolar and micromolar range. 50 ).

[0011] The object of the present invention is to provide novel, most likely reversible inhibitors of transglutaminases, in particular transglutaminase 2, and methods for the synthesis of said inhibitors as well as several uses of these inhibitors.

[0012] Said object is achieved by the technical teaching of the independent claims. Further advantageous embodiments, aspects and details of the invention are apparent from the dependent claims, the description and the examples.

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

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

[0015] In order to prove the creativity of the compound of the present application, the reference compound is synthesized and tested with the most similar compound compared to the present application. The technician may notice compound A8 from our patent US 9,434,763 B2, which we introduce as Ref.3 to highlight the creativity and preferred features of the claimed compound. From US 9,434,763 B2, it is obvious that the aromatic part (C-terminal) limits the efficacy of these compounds (compared with A1, A8, A37, A44, A47). In sharp contrast, as indicated by more potent compounds (A28, A29, A59, A61, A63, A67, A68, A79), the branched alkyl part is highly preferred.

[0016] To illustrate the advantages of branched alkyl moieties over aromatic moieties, we refer to reference compounds Ref. 2 (ZED1227, US 9,434,763 B2) and Ref. 3 (A8, ZED1047). Inhibition data were determined using a classical fluorescent transamidation assay (dansylcadaverine incorporation into methylated casein, DCC-assay) as described [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]. Casein is one of the most well-known high molecular weight (24 kDa) protein substrates for transglutaminase. Note that the IC of Ref. 3 (A8) published in US 9,434,763 B2 50 The values ​​are not comparable to the present data, which rely on fluorescent isopeptidase assays. 50 =53 nM) compared to Ref.3 (IC 50 =4,268 nM) was 80-fold more potent.

[0017] Therefore, those skilled in the art of medicinal chemistry would select 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 adamantane group, one would expect similar physicochemical or biochemical properties without further effort. Since aromatic moieties are clearly not preferred, bridged cycloalkyl groups would not be considered improved compounds.

[0018] This is further supported by additional reference compounds. ZED3641 (Ref. 1, as disclosed in US Pat. No. 11,072,634 B2; Ref. 2, a reversibly acting α-ketomethylamide analog of ZED1227) is approximately 10 times more potent than Ref. 6 (compare Table 1). Ref. 6 is similar to Compound A8 disclosed in US Pat. No. 9,434,763 B2 regarding the backbone, again demonstrating the superiority of the branched alkyl moiety over aromatic derivatives combined with reversibly acting warheads.

[0019] However, surprisingly, replacing the preferred branched alkyl moiety with a bridged cycloalkyl further significantly improved the potency of the compound, as shown in Table 1. Therefore, we believe that the bridged cycloalkyl is disclosed in an excellent inventive manner.

[0020] In conclusion, the compounds of the present invention rated "A" showed approximately 100-fold higher efficacy compared to Ref. 3 (A8, compared to Table 1).

[0021] Furthermore, compounds with activities rated "B" or "C" are still preferred (lower IC 50 These compounds may also be considered inventive because the peripheral ligands affect physicochemical or biochemical properties. Therefore, depending on the application, less potent compounds may also be of high value.

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

[0023]

[0024] in

[0025] L stands for -L 1 -or-L 1 -L 2 -; preferably -L 1 -L 2 -;;

[0026] L 1 represents -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CO-, or -CH2CH2CO-;

[0027] L 2 Indicates a 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 residue may be substituted by a substituent R 9 -R 14 and R N 1 to 5 of substituted; and preferably substituted by R 11 -R 13 1 to 3 substitutions in;

[0036] R 3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwisted alkyl, adamantyl, diadamantyl, hexamethylenetetraminyl, and the above residues optionally contain one or more C=C double bonds and / or are optionally replaced by 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 represent -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, -N HCOC2H5, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C2H5, -NHSO2CHF2, -NHSO2CF3, -NHSO2CH2CF3;

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

[0039] R 6 and R 7 Each independently represents -H, -CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2CH=CH2, -CH2CH=CH(CH3), -CH2CH=C(CH3)2, -CH2CH=CHCH2CH3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -cyclo-C6H 11 , -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-C5H9, -CH2-cyclo-C6H 11 , -Ph, -CH2-Ph, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2NHCH3, -CH2CH2N(CH3)2,

[0040] or -NR 6 R 7 It is -N(C2H5)2,

[0041] R 8 、R 9 、R 10 、R 11 、R 12 、R 13 and R 14represents independently of one another -H, -F, -Cl, -Br, -I, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2OH, -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, -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,

[0042]

[0043] or R 8 and R 9 or R 9 and R 10 Together they can form one of the following five-membered or six-membered rings:

[0044]

[0045] or R 12 and R 13 or R 13 and R 14 Together they can form one of the following five-membered or six-membered rings:

[0046]

[0047] R Nrepresents -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;

[0048] R N1 represents -H, -CH3, or -CH2CH3;

[0049] or a diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemate, solvate, hydrate, or pharmaceutically acceptable salt thereof.

[0050] The inventors have found that the bicyclic residues R 3 The reversible inhibitors of formula (I) exhibit increased potency over prior art compounds. In particular, it is demonstrated herein that 3Compared with known compounds containing bicyclic residues rather than bridged residues, the compounds of the present invention have improved inhibitory activity. In order to prove the creativity of the compounds of the present application, known compounds from US 9,434,763 B2 and US11,072,634 B2 (reference 1 (E16 from US11,072,634 B2), reference 3 (A8 from US 9,434,763 B2) and reference 6) were synthesized and tested as reference compounds compared with the most similar compounds of the present application. To this extent, the inhibition data were determined using a classical fluorescent transamidation assay (dansylcadaverine incorporation into methylated casein, DCC-assay) as described in 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]. Casein is one of the best-known high molecular weight (24 kDa) protein substrates for transglutaminases. The inhibition data of the compounds of the present invention were compared with the inhibition of compounds disclosed in US 9,434,763 B2 (indicated herein as reference 3), in particular compound A8. It is noteworthy that the IC values ​​of compound A8 disclosed in US 9,434,763 B2 and E16 from US 11,072,634 B2 were 0.1% and 0.2% respectively, relying on the fluorescent isopeptidase assay. 50 The values ​​cannot be compared with the data of the present invention.

[0051] Thus, the compound of the present invention of Formula (I), rated "A," exhibited approximately 100-fold greater efficacy compared to Ref.3 (A8). The same reasoning applies to Ref.6, which is identical to compound II-111 except for the phenylethyl moiety. As is apparent from Table 1, Ref.6 is more than 25-fold less potent than compound II-111.

[0052] This finding is particularly surprising because one would not expect that the compounds of the present invention with a bridged bicyclic residue would have improved inhibitory activity compared to prior art compounds with an aromatic residue, since it is well known that bridged bicyclic groups or bridged cycloalkyl groups are non-classical bioisosteres of phenyl groups, so that when replacing phenyl groups with bridged bicyclic groups, one would only expect to obtain compounds with similar physicochemical and biological properties (including inhibitory activity). Since the aromatic moiety shows lower potency, the bridged cycloalkyl group would not be expected to improve the physicochemical and biological properties of the compound.

[0053] As used herein, the residues bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwisted alkyl, adamantyl, diadamantyl, and hexamethylenetetraminyl have the following parent structures, respectively:

[0054]

[0055]

[0056] The above residues optionally contain one or more C=C double bonds, such as bicyclo[2.2.1]hept-5-enyl (see II-97) and / or are optionally replaced by R a 、R b 、R c 、R d and R e One or more substitutions in .

[0057] Can be substituted by R 9 -R 14 and R N 1 to 5 substituted unsubstituted bicyclic residues in; having the following structure and the substituent R 9 -R 14 and R N has the meaning as defined herein:

[0058]

[0059]

[0060]

[0061]

[0062]

[0063]

[0064]

[0065] One embodiment relates to compounds of the general formula (I):

[0066]

[0067] in

[0068] L stands for -L 1 -or-L 1 -L 2 -; preferably -L 1 -L 2 -;

[0069] L 1 represents -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CO-, or -CH2CH2CO-;

[0070] R 1 express

[0071] R 2 express

[0072]

[0073]

[0074]

[0075]

[0076]

[0077] The unsubstituted bicyclic residue may be substituted by a substituent R 9 -R 14 and R N 1 to 5 of substituted; and preferably substituted by R 11 -R 13 1 to 3 substitutions in;

[0078] in

[0079] i)L 2 Indicates a key, -NR N1 CH2-、-NR N1 CH2CH2-, or -NR N1 CH(CH3)-; and

[0080] R 3represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, 1-bicyclo[3.1.1]heptyl, 3-bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwisted alkyl, diadamantyl, hexamethylenetetraminyl, and the above residues optionally contain one or more C=C double bonds and / or are optionally replaced by R a 、R b 、R c 、R d and R e one or more substitutions in ; or

[0081] ii)L 2 Indicates a key, -NR N1 -、-NR N1 CH2CH2-, or -NR N1 CH(CH3)-; and

[0082] R 3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwisted alkyl, 2-adamantyl, diadamantyl, hexamethylenetetraminyl, and the above residues optionally contain one or more C=C double bonds and / or are optionally replaced by R a 、R b 、R c 、R d and R e One or more substitutions in ;

[0083] R a 、R b 、R c 、R d and R eindependently represent -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, -N HCOC2H5, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C2H5, -NHSO2CHF2, -NHSO2CF3, -NHSO2CH2CF3;

[0084] R 4 Indicates -NR 6 R 7 ;

[0085] R 6 and R 7 Each independently represents -H, -CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2CH=CH2, -CH2CH=CH(CH3), -CH2CH=C(CH3)2, -CH2CH=CHCH2CH3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -cyclo-C6H 11 , -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-C5H9, -CH2-cyclo-C6H 11 , -Ph, -CH2-Ph, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2NHCH3, -CH2CH2N(CH3)2,

[0086] or -NR 6 R 7 It is -N(C2H5)2,

[0087] R 8 、R 9 、R 10 、R 11 、R 12 、R 13 and R14represents independently of one another -H, -F, -Cl, -Br, -I, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2OH, -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, -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,

[0088]

[0089] or R 8 and R 9 or R 9 and R 10 Together they can form one of the following five-membered or six-membered rings:

[0090]

[0091] or R 12 and R 13 or R 13 and R 14 Together they can form one of the following five-membered or six-membered rings:

[0092]

[0093] R Nrepresents -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;

[0094] R N1 represents -H, -CH3, or -CH2CH3;

[0095] or a diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemate, solvate, hydrate, or pharmaceutically acceptable salt thereof.

[0096] In one embodiment of the compounds of the invention disclosed herein, the moiety -LR 3 no

[0097]

[0098] In one embodiment of the compounds of the invention disclosed herein, L represents -L 1 -L 2 -;

[0099] L 1 represents -CH2-, or -CH2CO-; and

[0100] L 2 It represents a bond, -NH-, -NHCH2-, -NHCH2CH2-, or -NHCH(CH3)-.

[0101] In one embodiment of the compounds of the invention disclosed herein, L represents -CH2-, -CH2CO-NH-, -CH2CO-NH-CH2-, or -CH2CO-NH-CH(CH3)-.

[0102] In a preferred embodiment of the compounds of the invention of formula (I), R 2 express

[0103]

[0104]

[0105]

[0106]

[0107]

[0108] The unsubstituted bicyclic residue may be substituted by a substituent R 9 -R 14 and R N 1 to 5 of substituted; and preferably substituted by R 11 -R 13 1 to 3 substitutions in 9 -R 14 and R N3 has the meaning as defined herein.

[0109] In an even more preferred embodiment, R 2 express:

[0110]

[0111]

[0112] The unsubstituted bicyclic residue may be substituted by a substituent R 9 -R 14 and R N 1 to 5 of substituted; and preferably substituted by R 11 -R 13 1 to 3 substitutions in 9 -R 14 and R N has the meaning as defined herein.

[0113] Therefore, the present invention relates to compounds of general formula (I):

[0114]

[0115] in

[0116] L stands for -L 1 -or-L 1 -L 2 -; preferably -L 1 -L 2 -;

[0117] L 1 represents -CH2-, or -CH2CO-;

[0118] L 2 represents a bond, -NH-, -NHCH2-, -NHCH2CH2-, or -NHCH(CH3)-, R 1 express

[0119] R 2 express

[0120]

[0121]

[0122] R 3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwisted alkyl, adamantyl, diadamantyl, hexamethylenetetraminyl, and the above residues optionally contain one or more C=C double bonds and / or are optionally replaced by R a 、R b 、R c 、R d and R e One or more substitutions in ;

[0123] R a 、R b 、R c 、R d and R eindependently represent -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, -N HCOC2H5, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C2H5, -NHSO2CHF2, -NHSO2CF3, -NHSO2CH2CF3;

[0124] R 4 Indicates -NR 6 R 7 ;

[0125] R 6 and R 7 Each independently represents -H, -CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, -CH2CH(CH3)2, -CH2CH=CH2, -CH2CH=CH(CH3), -CH2CH=C(CH3)2, -CH2CH=CHCH2CH3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -cyclo-C6H 11 , -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-C5H9, -CH2-cyclo-C6H 11 , -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2NHCH3, -CH2CH2N(CH3)2,

[0126] or -NR 6 R 7 It is -N(C2H5)2,

[0127] R 8 、R 9 、R 10 、R 11 、R 12 、R 13 and R 14represents independently of one another -H, -F, -Cl, -Br, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2OH, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2Cl, -CH2-CH2Br, -CH2-CH2I, -OCH3, -OC2H5, -OC3H7, - OCH(CH3)2, -OC(CH3)3, -OC4H9, -OCHF2, -OCF3, -OCH2CF3, -OC2F5, -OCH2OCH3, -O-ring-C3H5, -OCH2-ring-C3H5, -O-C2H4-ring-C3H5, -CHO, -COCH3, -COCF3, -C OC2H5, -COC3H7, -COCH(CH3)2, -COC(CH3)3, -COOH, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -OOC-CH3, -OOC-CF3, -OOC-C2H5, -OO C-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(C H3)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,

[0128]

[0129] or R 8 and R 9 or R 9 and R 10 Together they can form one of the following five-membered or six-membered rings:

[0130]

[0131] or R 12 and R 13 or R 13 and R 14 Together they can form one of the following five-membered or six-membered rings:

[0132]

[0133] R N represents -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;

[0134] or a diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemate, solvate, hydrate, or pharmaceutically acceptable salt thereof.

[0135] Preferred are compounds of formula (Ib):

[0136]

[0137] And L, R 2 、R 3 、R 6 、R 7 has the same meaning as defined in formula (I)

[0138] Preferred are compounds of formula (Ib):

[0139]

[0140] in

[0141] L stands for -L 1 -or-L 1 -L 2 -; preferably -L 1 -L 2 -;

[0142] L 1 represents -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CO-, or -CH2CH2CO-;

[0143] L 2 Indicates a key, -NR N1 -、-NR N1 CH2-、-NR N1 CH2CH2-, or -NR N1 CH(CH3)-;

[0144] R 2 express

[0145]

[0146]

[0147] R 3represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwisted alkyl, adamantyl, diadamantyl, hexamethylenetetraminyl, and the above residues optionally contain one or more C=C double bonds and / or are optionally replaced by R a 、R b 、R c 、R d and R e One or more substitutions in ;

[0148] R a 、R b 、R c 、R d and R e independently represent -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, -N HCOC2H5, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C2H5, -NHSO2CHF2, -NHSO2CF3, -NHSO2CH2CF3;

[0149] R 4 Indicates -NR 6 R 7 ;

[0150] R 6 and R 7 Each independently represents -H, -CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2CH=CH2, -CH2CH=CH(CH3), -CH2CH=C(CH3)2, -CH2CH=CHCH2CH3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -cyclo-C6H11 , -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-C5H9, -CH2-cyclo-C6H 11 , -Ph, -CH2-Ph, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2NHCH3, -CH2CH2N(CH3)2,

[0151] or -NR 6 R 7 It is -N(C2H5)2,

[0152] R N represents -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -CH2-cyclo-C3H5, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2Cl, -CH2-CH2Br, -C H2-CH2I, -CH2-CH=CH2, -CH2-C≡CH, -CHO, -COCH3, -COC2H5, -COC3H7, -COCH(CH3)2, -COC(CH3)3, -COOCH3, -COOC2H5, -CO OC3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -SO2CH3, -SO2CF3, -SO2C2H5, -SO2C3H7, -SO2CH(CH3)2, or -SO2C(CH3)3;

[0153] R N1 represents -H, -CH3, or -CH2CH3;

[0154] And R 8 -R 14 has the meaning as defined above for formula (I);

[0155] or a diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemate, solvate, hydrate, or pharmaceutically acceptable salt thereof.

[0156] Preferably, R 2 express

[0157]

[0158]

[0159] Preferably, -NR of formula (Ib) 6 R 7 represents -NH2, -NHCH3, -N(CH3)2, -NHCH(CH3)2, -NHCH2CH2CH3, -NH-CH2CH=CH2, -NHCH2CH2CH2CH3, -NHCH2CH(CH3)2, -NHC(CH3)3, -NHCH2CH2CH2CH2CH3, -NH-cyclo-C3H5, -NH-cyclo-C4H7, -NH-cyclo-C5H9, -NH-cyclo-C6H 11 , -NHCH2-cyclo-C3H5, -NHCH2-cyclo-C4H7, -NHCH2-cyclo-C5H9, -NHCH2-cyclo-C6H 11 , -NHCH2-Ph, -NHCH2OCH3, -NHCH2OCH2CH3, -NHCH2CH2OCH3, -NHCH2CH2NHCH3, -NHCH2CH2N(CH3)2,

[0160] In some embodiments, the present invention relates to compounds of formula (I),

[0161]

[0162] in

[0163] L stands for -L 1 -or-L 1 -L 2 -; preferably -L 1 -L 2 -;

[0164] L 1 represents -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CO-, or -CH2CH2CO-;

[0165] L 2 Indicates a key, -NR N1 -、-NR N1 CH2-、-NR N1 CH2CH2-, or -NR N1 CH(CH3)-;

[0166] R 1 express

[0167] R 2 express

[0168]

[0169]

[0170] R 3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwisted alkyl, adamantyl, diadamantyl, hexamethylenetetraminyl, and the above residues optionally contain one or more C=C double bonds and / or are replaced by R a 、R b 、R c 、R d and R e One or more substitutions in ;

[0171] R 6 Represents -H, -CH3, -CH2CH=CH2, -cyclo-C3H5, -

[0172] CH2CH2CH2CH2CH3;

[0173] And R 8 -R 14 、R a 、R b 、R c 、R d 、R e 、R N and R N1 has the meaning and preferred meanings as defined herein.

[0174] Also preferred are compounds of the general formula (I),

[0175]

[0176] in

[0177] L stands for -L 1 -or-L 1 -L 2 -;

[0178] L 1 represents -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CO-, -CH2CH2CO-;

[0179] L 2 Yes key, -NR N1 -、-NR N1CH2-、-NR N1 CH2CH2-, or -NR N1 CH(CH3)-;

[0180] R 1 express

[0181] R 2 express

[0182]

[0183]

[0184] R 3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwisted alkyl, adamantyl, diadamantyl, hexamethylenetetraminyl, and the above residues optionally contain one or more C=C double bonds and / or are replaced by R a 、R b 、R c 、R d and R e One or more substitutions in ;

[0185] R a 、R b 、R c 、R d and R e independently represent -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, -N HCOC2H5, -NHCOCF3, -NHCOCH2CF3, -NHSO2CH3, -NHSO2C2H5, -NHSO2CHF2, -NHSO2CF3, -NHSO2CH2CF3;

[0186] R 4 Indicates -NR6 R 7 ;

[0187] R 6 and R 7 Each independently represents -H, -CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2CH=CH2, -CH2CH=CH(CH3), -CH2CH=C(CH3)2, -CH2CH=CHCH2CH3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -cyclo-C6H 11 , -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-C5H9, -CH2-cyclo-C6H 11 , -CH2-Ph, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2NHCH3, -CH2CH2N(CH3)2,

[0188] or -NR 6 R 7 express

[0189] R N represents -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -CH2-cyclo-C3H5, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2Cl, -CH2-CH2Br, -C H2-CH2I, -CH2-CH=CH2, -CH2-C≡CH, -CHO, -COCH3, -COC2H5, -COC3H7, -COCH(CH3)2, -COC(CH3)3, -COOCH3, -COOC2H5, -CO OC3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -SO2CH3, -SO2CF3, -SO2C2H5, -SO2C3H7, -SO2CH(CH3)2, or -SO2C(CH3)3;

[0190] R N1 represents -H, -CH3, or -CH2CH3;

[0191] or a diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemate, solvate, hydrate, or pharmaceutically acceptable salt thereof.

[0192] Also preferred are compounds of formula (I) or (Ib) wherein

[0193] L 1 represents -CH2-, or -CH2CO-;

[0194] L 2 Indicates a key, -NR N1 -、-NR N1 CH2-, or -NR N1 CH(CH3)-;

[0195] R 3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 4-homoisotwisted alkyl, adamantyl, or diadamantyl, and the above residues optionally contain one or more C=C double bonds and / or are replaced by R a 、R b 、R c 、R d and R e One or more substitutions in ; and

[0196] R a 、R b 、R c 、R d 、R e and R N1 have the same meaning as defined herein.

[0197] Preferably, R of formula (I) or (Ib) 2 express

[0198]

[0199] And R 8 -R 14 and R N has the meanings as defined in formula (I) or (Ib).

[0200] Preferred are compounds having any one of formulae (IV-a)-(IV-o) and (Va)-(Vd):

[0201]

[0202]

[0203]

[0204] And R 2 、R 3 、R 6 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R a 、R b 、R c 、R d and L 2 has the same meaning as defined herein, preferably as defined in formula (I) or (Ib).

[0205] Also preferred are compounds of any one of formula (IVa-1),

[0206]

[0207] in

[0208] R 6 represents -H, -CH3, -CH(CH3)2, -CH2CH2CH3, -CH2CH=CH2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2CH2CH2CH2CH3, -cyclo-C3H5, -cyclo-C5H9, -cyclo-C6H 11 Or -CH2-cyclo-C3H5.

[0209] And R 2 、R a and R b have the same meaning as defined above.

[0210] Preferably, in the compounds of formula (I) or (Ib), R a and R b Each independently represents -H, -F, -Cl, -Br, -OH, -CN, -CH3, -C2H5, or -CO2Me.

[0211] Preferably, in any one of formula (I), (Ib), (IV-a)-(IV-o), or (IVa-1):

[0212] R 2 express

[0213]

[0214] and

[0215] R 6 represents -H, -CH3, -CH(CH3)2, -CH2CH2CH3, -CH2CH=CH2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2CH2CH2CH2CH3, -cyclo-C3H5, -cyclo-C5H9, -cyclo-C6H 11 Or -CH2-cyclo-C3H5.

[0216] Due to the specially selected substituent R on the N-terminal side 2 and a substituent R on the C-terminal side 3 As well as the compounds according to the invention, the spatial dimensions can be adjusted very precisely so that the binding pocket of a desired target molecule can be addressed with a highly matched measurement.

[0217] Preferred are compounds of any one of formulae (I), (Ib), (IV-a)-(IV-o) and (Va)-(Vd), wherein

[0218] R 3 express

[0219]

[0220] Unexpectedly, the compounds of the present invention were found to reversibly bind to and effectively inhibit transglutaminase 2. The combination of the electrophilic warhead and the preferred embodiment reacts specifically with highly nucleophilic thiols in the active site of transglutaminase 2. As a result, potential off-target nonspecific reactions were found to be reduced.

[0221] In one embodiment, the present invention relates to a compound selected from the group consisting of:

[0222]

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251] or a pharmaceutically acceptable salt thereof.

[0252] Especially preferred are the following compounds:

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265] or a pharmaceutically acceptable salt thereof.

[0266] Method for producing the compound of the present invention

[0267] In some embodiments, the present invention relates to methods for synthesizing compounds of formula (I), in particular any compound of formula (Ib):

[0268]

[0269] The compound of formula (Ib) can be prepared, and therefore the present invention relates to a process for preparing the compound of formula (Ib) comprising the following steps in the following order:

[0270] Step 1B: Providing compound 4b

[0271]

[0272] Step 2B: Coupling reaction of compound 4b with compound 5

[0273]

[0274] To obtain compound 6b

[0275]

[0276] Step 3B: Make the amino protecting group PG 3 Deprotection to obtain compound 7b

[0277]

[0278] Step 4B: Compound 7b is reacted with a carboxylic acid (R2 -CO2H 8) to obtain compound 9b

[0279]

[0280] Step 5B: Oxidation of compound 9b to produce a compound of formula (Ib)

[0281]

[0282] Among them, L, R 2 、R 3 、R 6 and R 7 has the same meaning as defined in formula (Ib) above, and PG 3 It is an amino protecting group.

[0283] In step 5B, chemical warhead precursors It can be first converted to And then Conversion to the corresponding chemical warhead by oxidation, preferably by using Dess-Martin periodinane (DMP), iodobenzoic acid (IBX), or hypochlorite / TEMPO (2,2,6,6-tetramethylpiperidin-1-oxyl) in a polar solvent As described in Chemical Examples.

[0284] In the alternative route, all protecting groups PG are first removed simultaneously. 1 and PG 2 , and selectively introduce the protecting group PG 3 Preferably, PG 1 and PG 3 same.

[0285] As used herein, the term "protecting group" refers to a protecting group commonly used in organic synthesis, preferably amino and carboxyl groups. 1 PG 3 and PG 5 Preferably a suitable protecting group for the amino group. PG 2 and PG 4 Preferably, PG is a suitable protecting group for the carboxyl group. 1 PG 3 and PG 5 The PG may be selected from the group consisting of or comprising: acetyl, benzoyl, benzyloxycarbonyl (Cbz), tert-butylcarbonyl, tert-butyloxycarbonyl (Boc) and fluorenylmethyleneoxy (Fmoc). 2 and PG4 It may be selected from the group consisting of or comprising: methoxy, ethoxy, isobutoxy, tert-butoxy, benzyloxy; preferably, tert-butoxy.

[0286] In step 2B, in order to promote the coupling reaction with the amino group of the intermediate compound, an activating reagent is generally 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). The activation can be introduced into a separate reaction or an in situ reaction. Preferably, any of the following coupling reagents can be used to activate the carboxylic acid group: BOP (benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate), PYBOP (benzotriazol-1-yl-oxy-tris-pyrrolidinyl-phosphonium hexafluorophosphate), AOP (7-(azabenzotriazol-1-yl) tris(dimethylamino)phosphonium hexafluorophosphate), PYAOP ((7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate), TBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylammonium tetrafluoroborate), EEDQ (N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline), polyphosphoric acid (PPA), DPPA (diphenylphosphoryl azide), HATU (1-[bis(dimethylamino)phosphonium] [4,5-B]pyridinium 3-oxide hexafluorophosphate), HBTU (O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate), HOBT (1-hydroxybenzotriazole), HOAT (1-hydroxy-7-azabenzotriazole), DCC (N,N'-dicyclohexylcarbodiimide), EDC (or EDAC or EDCI, 1-ethyl-3-( 3-dimethylaminopropyl)carbodiimide), BOP-CL (bis(2-oxo-3-oxazolidinyl)phosphine chloride), TFFH (tetramethylfluoroformamidinium hexafluorophosphate), BROP (bromotris(dimethylamino)phosphonium hexafluorophosphate), PYBROP (bromo-tris-pyrrolidinyl-phosphonium hexafluorophosphate) and CIP (2-chloro-1,3-dimethylimidazolinium hexafluorophosphate), or further, similar reagents that provide activated intermediates, or mixtures thereof.

[0287] Pharmaceutical compositions and medical uses

[0288] Therefore, another aspect of the present invention relates to the compounds according to general formula (I) as medicaments and their use in medicine. Particularly preferred is their use as inhibitors of transglutaminases, in particular transglutaminase 2 (TG2).

[0289] Thus, the compounds of formula (I) described herein or according to the present invention may be administered per se or in the form of a pharmacologically acceptable salt.

[0290] 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, p-aminosalicylic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, sulfonic acid, phosphonic acid, perchloric acid, nitric acid, formic acid, propionic acid, gluconic acid, lactic acid, tartaric acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, p-hydroxybenzoic acid, methanesulfonic acid, ethanesulfonic acid, nitrous acid, hydroxyethanesulfonic acid, 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, tartronic acid, (o,m,p)-methylformic acid, naphthylaminesulfonic acid, trifluoroacetic acid, and other mineral acids or carboxylic acids familiar to those skilled in the art. The salts are prepared by contacting the free base form with an amount of the desired acid sufficient to produce the salt in a conventional manner. Preferred are the methanesulfonate, hydrochloride and trifluoroacetate salts, with the trifluoroacetate and hydrochloride salts being especially preferred.

[0291] In the case where the compounds of the present invention carry acidic groups, salts may also be formed with inorganic or organic bases. Examples of suitable inorganic or organic bases are, for example, NaOH, KOH, NH OH, tetraalkylammonium hydroxide, lysine or arginine. Salts may be prepared in a conventional manner using methods well known in the art, for example by treating a solution of a compound of formula (I) with a solution of an acid selected from the groups mentioned above.

[0292] How to use

[0293] In a further aspect of the invention, the novel compounds according to general formula (I) are used as pharmaceutically active agents, ie the compounds of formula (I) are used in medicine.

[0294] Furthermore, the present invention relates to a pharmaceutical composition comprising at least one compound according to general formula (I) as active ingredient or a pharmacologically acceptable salt thereof as active ingredient, and at least one pharmacologically acceptable carrier, excipient and / or diluent.

[0295] The compounds according to general formula (I) described herein are particularly suitable for the treatment and prevention of diseases which are associated with and / or caused by transglutaminase 2.

[0296] Celiac disease 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 hepatic fibrosis are among the most important fibrotic disorders addressed with the disclosed compounds.

[0297] In Biological Example B-1, it was demonstrated that the compounds of the present invention effectively inhibit the activity of TG, especially TG2, as reversible and irreversible TG inhibitors.

[0298] 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 inhibit the activity of an enzyme, or the expression of an enzyme or protein.

[0299] Therefore, another aspect of the present invention is the use of a compound of the present invention of general formula (I) as described, or a pharmaceutical composition 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.

[0300] Another aspect of the present invention relates to the use of compounds of general formula (I) for the preparation of pharmaceutical compositions useful for the prevention and / or treatment of autoimmune and inflammatory diseases, vascular diseases, fibrotic diseases, liver diseases, cholestatic liver diseases, cancer, neurodegenerative diseases, eye diseases and skin disorders.

[0301] In another aspect of the present 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, which comprises administering to a subject, in particular a human, a pharmaceutically effective amount of at least one compound of general formula (I) to prevent and / or treat the autoimmune and inflammatory diseases, vascular diseases, fibrotic diseases, liver diseases, cholestatic liver diseases, cancer, neurodegenerative diseases, eye diseases and skin disorders.

[0302] Preferred autoimmune and inflammatory diseases include multiple sclerosis, celiac disease with diarrhea, Duhring-Brocq disease (dermatitis herpetiformis), gluten ataxia, gluten neuropathy, diabetes, rheumatoid arthritis, Graves' disease, inflammatory bowel disease, systemic lupus erythematosus, psoriasis, and gingivitis;

[0303] Vascular diseases include atherosclerosis, thrombosis, and vascular sclerosis;

[0304] fibrotic diseases that affect the lungs, kidneys, liver, skin, or intestines, such as cystic fibrosis, renal fibrosis and diabetic nephropathy, intestinal fibrosis, idiopathic pulmonary fibrosis, and hepatic fibrosis;

[0305] Liver disease such as alcoholic hepatitis, alcoholic steatohepatitis, nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, cirrhosis, autoimmune hepatitis, or hepatitis;

[0306] Cholestatic liver diseases include primary biliary cholangitis and primary sclerosing cholangitis;

[0307] Cancers include glioblastoma, melanoma, pancreatic cancer, renal cell carcinoma, meningioma, and breast cancer.

[0308] Neurodegenerative diseases include Parkinson's disease, Huntington's disease, or Alzheimer's disease.

[0309] Eye diseases including glaucoma, cataracts, macular degeneration, or uveitis;

[0310] Skin disorders include acne, psoriasis, scarring and skin aging.

[0311] More preferably, the compound of formula (I) or its pharmaceutical composition can be used for the treatment or prevention of diarrheal celiac disease.

[0312] In addition, the compound of general formula (I) can be given in the form of its pharmaceutically active salt, optionally using substantially nontoxic pharmaceutically acceptable carrier, adjuvant or extender. The medicine is prepared in a known manner in conventional solid or fluid carriers or in extenders and conventional pharmaceutically acceptable adjuvants / excipients with suitable dosage. Preferred preparations are provided in an administrable form suitable for oral administration, such as pills, tablets, film-coated tablets, coated tablets, capsules and powders.

[0313] Tablets, film-coated tablets, coated tablets, gelatin capsules and opaque capsules are preferred pharmaceutical formulations. Any pharmaceutical composition contains at least one compound of 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 in an amount of 10 to 100 mg per formulation.

[0314] Furthermore, the present invention also includes pharmaceutical preparations for oral, parenteral, cutaneous, intradermal, intragastric, intradermal, intravascular, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, intrabuccal, transdermal, rectal, subcutaneous, sublingual, topical, transdermal or inhalation administration, which contain, in addition to typical vehicles and bulking agents, a compound of the general formula (I) and / or a pharmaceutically acceptable salt thereof as active ingredient.

[0315] The pharmaceutical compositions of the present invention contain one of the compounds of formula (I) disclosed herein as the active ingredient, typically mixed with a suitable carrier material selected with respect to the intended form of administration (i.e., tablets to be administered orally, capsules (filled with solid, semi-solid or liquid), powders, orally administrable gels, elixirs, dispersible granules, syrups, suspensions, etc.). For example, the compound of formula (I) can be combined as the active ingredient with any oral, non-toxic, 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 the form of tablets or capsules. In addition, if desired, suitable binders, lubricants, disintegrants, and colorants can be added to the mixture. Powders and tablets can be composed of the inert carrier in an amount of about 5% to about 95% by weight of the composition of the present invention.

[0316] Suitable binding agents include starch, gelatin, natural sugars, sweeteners made from corn, natural and synthetic gums such as gum arabic, sodium alginate, carboxymethyl cellulose, polyethylene glycol and wax. Possible lubricants used in the dosage form include boric acid, sodium benzoate, sodium acetate, sodium chloride etc. Disintegrants include starch, methyl cellulose, cyclodextrin, guar gum etc. If necessary, sweeteners and flavor additives and preservatives can also be included. Below, some terms used above are discussed in more detail, i.e. disintegrants, extenders, lubricants, binding agents etc.

[0317] Additionally, the compositions of the present invention may be formulated in a sustained release form to provide a controlled rate of release of any one or more components or active ingredients in order to optimize the therapeutic effect, i.e., inhibitory activity, etc. Suitable dosage forms for sustained release include layered tablets containing layers having different degradation rates or controlled release polymer matrices impregnated with the active ingredient, and in the form of tablets or capsules containing such impregnated or encapsulated porous polymer matrices.

[0318] Preparations in fluid form include solutions, suspensions and emulsions. Water or water propylene glycol solutions for parenteral injection or the addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions are exemplified.

[0319] Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as compressed inert gas, eg nitrogen.

[0320] For preparing suppositories, a low melting point wax, such as a mixture of fatty acid glycerides (e.g., cocoa butter), is first melted and the active ingredient is uniformly dispersed therein by stirring or similar mixing operation. The molten homogeneous mixture is then poured into the appropriate form, cooled, and thereby hardened.

[0321] Also included are additional preparations that are in solid form and are intended to be converted shortly before use to a fluid form for oral or parenteral administration.Such fluid forms include solutions, suspensions, and emulsions.

[0322] Additionally, the compounds of the present invention may be administered via transdermal application. Transdermal compositions may be in the form of creams, lotions, aerosols, and / or emulsions.

[0323] The term capsule refers to a specialized container or shell composed of methylcellulose, polyvinyl alcohol, or modified gelatin or starch, within which the active agent can be encapsulated. Typically, hard-shell capsules are made from a mixture of bone and porcine skin gelatin, which have relatively high gel strength. The capsule itself may contain small amounts of colorants, opacifiers, softeners, and preservatives.

[0324] Tablets are intended to be compressed or cast solid dosage forms containing the active ingredient with suitable bulking agents. Tablets can be produced by compressing mixtures or granules obtained by wet granulation, dry granulation or compaction, as is known to those skilled in the art.

[0325] Oral gels are active ingredients dispersed or dissolved in a hydrophilic semisolid matrix.

[0326] Dusts for use in compositions refer to a powder mix containing the active ingredient and suitable extenders which can be suspended in water or juice.

[0327] Suitable bulking agents are substances that typically form the largest portion of a composition or dosage form. Suitable bulking agents include sugars such as lactose, sucrose, mannitol, and sorbitol; starches derived from wheat, corn, rice, and potatoes; and celluloses such as microcrystalline cellulose. The amount of bulking agent in the composition 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.

[0328] 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, modified starches soluble in cold water, such as sodium starch glycolate; natural and synthetic gums, such as locust bean gum, caraya, guar gum, tragacanth, and agar; cellulose derivatives, such as methylcellulose and sodium carboxymethylcellulose, microcrystalline cellulose, and cross-linked microcrystalline cellulose, such as sodium croscarmellose; alginates, such as alginic acid and sodium alginate; and clays, such as bentonite and foaming mixtures. The amount of disintegrant used in the composition may range from about 2% to 20% by weight of the composition, and more preferably from about 5% to about 10% by weight.

[0329] Binders characterize substances that bind or "adhere" powders to each other, and thus they act as "glue" in the formulation. Binders add cohesive starches that are already available in bulking agents or disintegrants. Suitable binders include sugars such as sucrose; starches derived from wheat, corn, rice, and potato; natural gums such as gum arabic, gelatin, and tragacanth; derivatives of seaweed such as alginic acid, sodium alginate, and calcium ammonium alginate, cellulosic materials such as methylcellulose and sodium carboxymethylcellulose and hydroxypropyl methylcellulose, polyvinylpyrrolidone, and inorganic compounds such as magnesium aluminum silicate. The amount of binder in the composition may range from about 2% to about 20% by weight of the total composition, preferably from about 3% to about 10% by weight, and further preferably from about 3% to about 6% by weight.

[0330] The term lubricant refers to a substance added to a dosage form to reduce friction and allow tablets, granules, etc. to release from the casting or compression mold after compression. 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 tablet press, 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 from about 0.5% to about 2% by weight, and more preferably from about 0.3% to about 1.5% by weight.

[0331] Lubricants are materials that prevent caking and improve the flow characteristics of the granules, making the flow smooth and uniform. 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.

[0332] Colorants are adjuvants that impart color to a composition or dosage form. Such adjuvants may include food-quality colorants adsorbed onto a suitable adsorption means, such as clay or alumina. The amount of colorant used may vary from about 0.1% to 5% by weight of the composition, and preferably from about 0.1% to about 1% by weight.

[0333] As used herein, a "pharmaceutically effective amount" of a transglutaminase inhibitor is an amount or activity effective to achieve the desired physiological outcome in cells treated in vitro or in patients treated in vivo. Specifically, a pharmaceutically effective amount is an amount sufficient to inhibit one or more of the clinically defined pathological processes associated with transglutaminase 2 for a period of time. The effective amount may vary depending on the specific compound of formula (I) and, in addition, depends on a number of factors and conditions associated with the subject to be treated and the severity of the disease. For example, if an 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) as described herein is contacted with cells in vivo, a number of preclinical in vitro studies will be designed to determine parameters such as absorption, half-life, dosage, toxicity, etc. Determining a pharmaceutically effective amount for a given pharmaceutically active ingredient is part of the ordinary skill of those skilled in the art. Example

[0334] The following abbreviations used in the examples have the following meanings.

[0335] Boc (tert-butoxycarbonyl), BocOSu (N-tert-butoxycarbonyloxy-succinimide), DCM (dichloromethane), DMAP (4-(dimethylamino)-pyridine), TEA (triethylamine), DMF (dimethylformamide), DMP (Dess-Martin periodinane), DIPEA (N-ethyldiisopropylamine), Glu (glutamic acid), EDC (1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide), TFA (trifluoroacetic acid), THF (tetrahydrofuran), EtOAc (ethyl acetate), HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate), HOBt (hydroxybenzotriazole), MTBE (methyl tert-butyl ether), tBu (tert-butyl),

[0336] Chemical Examples

[0337] The following examples are intended to illustrate the present invention with selected compounds, without limiting the scope of protection of this intellectual property to these specific examples. 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.

[0338] Example II. Synthesis Method II

[0339] Scheme II-1

[0340]

[0341] 1. Preparation of compound ZED1657

[0342]

[0343] 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 were added at 40° C., and the reaction was stirred at room temperature overnight. 250 mL of 32% HCl was added, and the suspension was stirred at 4° C. for another overnight. The precipitate was filtered and dried. Yield: 41.2 g, 97% ESI-MS: 199.3 [M+H] +

[0344] 2. Preparation of compound ZED3905

[0345]

[0346] 17.0 g (85.8 mmol) of ZED1657, 16.1 g (1 equivalent) of 2-adamantanamine hydrochloride and 11.6 g (1 equivalent) of HOBt were dissolved in 200 mL of DMF and 17.9 mL (1.2 equivalents) of DIPEA. 18.1 g (1.1 equivalents) of 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride were added and the reaction was stirred at room temperature overnight. The solvent was evaporated and the residue was dissolved in 500 mL of DCM. The solution was washed with 200 mL each of citric acid solution (10%), NaHCO solution (10%) and salt water. The organic phase was dried over NaSO, filtered and the solvent was evaporated.

[0347] Yield: 24.1 g, 85% ESI-MS: 332.4 [M+H] +

[0348] 3. Preparation of compound ZED3906

[0349]

[0350] 24.2 g (73.0 mmol) of ZED3905 were suspended in 600 mL of MeOH, and then 2.42 g of palladium on activated carbon (10%) (unreduced) were added. The suspension was stirred at room temperature under a hydrogen atmosphere overnight. The catalyst was filtered and the solvent was evaporated. Yield: 15.7 g, 71% ESI-MS: 302.4 [M+H] +

[0351] Scheme II-2

[0352]

[0353] Preparation of compound ZED788

[0354]

[0355] 12.0g of Boc-L-Glu-OtBu (39.6mmol) and 7.09g of cesium carbonate (21.8mmol, 0.55 equivalent) are suspended in 100ml of DMF and stirred at room temperature for 1h. 2.47ml of iodomethane (39.6mmol) are added and the mixture is stirred at room temperature overnight. The solvent is evaporated, and the residue is dissolved in ethyl acetate and washed twice with each citric acid solution (10%), NaHCO solution (10%) and salt water. The organic phase is dried over Na SO, filtered and the solvent is evaporated. The crude product is used without further purification.

[0356] Yield: 13.4 g, >100%

[0357] ESI-MS: 318.3[M+H] +

[0358] Preparation of compound ZED720

[0359]

[0360] 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) in 100 ml of acetonitrile were added and the solution was stirred at room temperature overnight. The solvent was evaporated, and the residue was dissolved in ethyl acetate and washed twice with citric acid solution (10%), NaHCO solution (10%), and brine. The organic phase was dried over NaSO, filtered, and the solvent was evaporated. The crude product was used without further purification.

[0361] Yield: 13.7 g, 83%

[0362] ESI-MS: 418.3[M+H] +

[0363] Preparation of compound ZED721

[0364]

[0365] 13.7 g of ZED720 (32.8 mmol) was dissolved in 200 ml of dry 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 and 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.

[0366] Yield: 13.3 g, >100%

[0367] ESI-MS: 388.3[M+H] +

[0368] 4. Preparation of compound ZED3632

[0369]

[0370] 15.0g (38.7mmol) of aldehyde (S)-tert-butyl 2-(bis(tert-butoxycarbonyl)amino)-5-oxopentanoate (ZED721) is dissolved in 60mL DCM. At 0°C, 2.42mL (1.05 equivalents) of methyl isocyanide and 2.33mL (1.05 equivalents) of acetic acid are added, and the reaction is stirred at room temperature overnight. 75mL of TFA is added, and the reaction is stirred for another 3h. The solvent is evaporated, and the residue is dissolved in 40mL of DMF. 13.2mL (2 equivalents) of DIPEA and 10.4g (46.6mmol) of di-tert-butyl dicarbonate in 10mL of DMF are added, and the reaction is stirred at room temperature overnight. The solvent is evaporated, and the residue is dissolved in DCM. After extraction with NaHCO solution (1.05 equivalents in water), 1.5 equivalents of citric acid are added to the aqueous phase, then extracted again with DCM. The organic phase was dried over Na2SO4, filtered and the solvent was evaporated.The residue was purified by flash chromatography.

[0371] Yield: 12.5 g, 95%

[0372] ESI-MS: 333.5[M+H] +

[0373] 5. Preparation of compound ZED3907

[0374]

[0375] 19.8 g (59.5 mmol) of ZED3632, 22.6 g (1 equivalent) of HATU and 17.9 g (1 equivalent) of ZED3906 were dissolved in 400 mL of DMF and 20.8 mL of DIPEA (2 equivalents) and stirred at 45° C. overnight. The solvent was evaporated; the residue was dissolved in 200 mL of EtOAc and washed twice with 150 mL each of 10% citric acid solution, 10% NaHCO solution and brine. The organic phase was dried over Na SO, filtered and the solvent was evaporated.

[0376] Yield: 27.4 g, 75%

[0377] ESI-MS: 616.4[M+H] +

[0378] 6 Preparation of compound ZED3264

[0379]

[0380] 480mg (0.78mmol) of ZED3907 was dissolved in 4ml of DCM / TFA (1:1) and stirred at room temperature for 1h. The solvent was evaporated and the residue was dissolved in 4ml of DMF. 137mg (1 equivalent) of 3-methylbenzo[b]furan-2-carboxylic acid, 296mg (1 equivalent) of HATU and 272μl (2 equivalents) of DIPEA were added and the reaction was stirred at room temperature overnight. The solvent was evaporated; the residue was dissolved in 20mL of EtOAc and washed with 10mL each of citric acid solution (10%), NaHCO solution (10%) and brine. The organic phase was dried over NaSO, filtered and the solvent was evaporated.

[0381] Yield: 409 mg, 78%

[0382] ESI-MS: 674.4[M+H] +

[0383] 7 Preparation of compound ZED3266

[0384]

[0385] 409 mg (0.61 mmol) of ZED3264 was dissolved in 5 ml of MeOH. 126 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 evaporated.

[0386] Yield: 377 mg, 98%

[0387] ESI-MS: 632.4[M+H] +

[0388] 8 Preparation of Compound II-3

[0389]

[0390] 377 mg (0.60 mmol) of ZED3266 was dissolved in 2 ml of DMF. 405 mg (1.6 equivalents) of Dess-Martin periodinane (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.

[0391] Yield: 314 mg, 67%

[0392] ESI-MS: 630.4[M+H] +

[0393] 1 H-NMR (DMSO-D6, 500 MHz, δ [ppm]): 1.46 / / 1.98 (d / / d, 2H / / 2H, adamantyl-C4-H2), 1.68 / / 1.78 (m, 4H, adamantyl-C4-H2), 1.71 (m, 2H, adamantyl-C1-H), 1.75 (m, 2H, adamantyl-C6-H2), 1.78 (m, 2H, adamantyl-C5-H), 2.05 / / 2.16 (m / / m, 1H / / 1H, β-CH2), 2.53 (s, 3H, benzofuran-CH3), 2.64 (d, 3H, amide-N-CH3), 2.96 (t, 2H, γ-CH2), 3.82 (m, 1H, gold d, 1H, benzofuran-CH), 7.63 (d, 1H, benzofuran-CH), 7.76 (d, 1H, benzofuran-CH), 8.06 (d, 1H, adamantyl-NH), 8.21 (d, 1H, pyridinone-C4-H), 8.54 (q, 1H, methylamide-NH), 8.87 (d, 1H, α-NH), 9.36 (s, 1H, pyridinone-NH).

[0394] 13C-NMR (DMSO-D6, 500 MHz, δ [ppm]: 8.62 (benzofuran-CH3), 24.50 (β-CH2), 25.37 (amide-N-CH3), 26.57 / / 26.62 (adamantyl-C5-H), 30.83 (adamantyl-C4-H2), 31.35 (adamantyl-C1-H), 33.61 (γ-CH2), 36.66 (adamantyl-C4'-H2), 37.01 (adamantyl-C6-H2), 51.64 (N-CH2), 52.80 (α-CH2), 53.24 (adamantyl-C2-H), 104.51 (pyridone-C5-H), 111.55 (benzofuran-CH3), 121.09 (Benzofuran-CH), 121.72 (Benzofuran-Cq), 122.53 (Pyridone-C4-H), 123.19 (Benzofuran-CH), 127.28 (Pyridone-N-Cq), 127.89 (Benzofuran-CH), 129.02 (Benzofuran-Cq), 133.27 (Pyridone-C6-H), 142.31 (Benzofuran-Cq), 152.68 (Benzofuran-Cq), 156.55 (Pyridone-C=O), 159.59 (Benzofuran-C=O), 161.32 (C=O-NH-CH3), 165.65 (C=O-adamantylamide), 170.42 (C=O-NH-pyridone), 198.06 (C=O-methylamide).

[0395] 9 Preparation of Compound II-2

[0396]

[0397] To the α-hydroxy ester precursor of compound II-2 (242 mg, 0.39 mmol, prepared by using benzofuran-2-carboxylic acid in step 6 according to compound ZED3264) in 8 mL of acetonitrile was added 1 mg of TEMPO (2,2,6,6-tetramethylpiperidin-1-oxyl, 1 mol%). 56 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.

[0398] Yield: 102 mg, 42%

[0399] ESI-MS: 616.3[M+H] +

[0400] 10 Preparation of Compound II-4

[0401]

[0402] To the α-hydroxyester precursor of compound II-4 (124 mg, 0.19 mmol, prepared by using 3-chlorobenzofuran-2-carboxylic acid in step 6 according to compound ZED3264) in 4 ml of DMSO was added 106 mg of 2-iodobenzoic acid (IBX, 2 equivalents), and the reaction mixture was stirred at room temperature for 3 h. NaHCO solution (10%) was added and the suspension was extracted with EtOAc. The organic phase was dried over NaSO, filtered, and the solvent was evaporated. The residue was purified by HPLC.

[0403] Yield: 37 mg, 30% (last step)

[0404] ESI-MS: 650.3 / 652.3[M+H] +

[0405] 11 Preparation of Compound II-5

[0406]

[0407] The synthesis of compound II-5 was carried out according to compound II-3, using 4-bromo-1-benzofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0408] Yield: 69 mg, 72% (last step)

[0409] ESI-MS: 694.3 / 696.3[M+H] +

[0410] 12 Preparation of Compound II-6

[0411]

[0412] The synthesis of compound II-6 was carried out according to compound II-3, using benzo[b]thiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0413] Yield: 287 mg, 76% (last step)

[0414] ESI-MS: 632.3[M+H] +

[0415] 13 Preparation of Compound II-7

[0416]

[0417] The synthesis of compound II-7 was carried out according to compound II-3, using 5-bromobenzo[b]thiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0418] Yield: 145 mg, 59% (last step)

[0419] ESI-MS: 710.2 / 712.2[M+H] +

[0420] 14 Preparation of Compound II-8

[0421]

[0422] The synthesis of compound II-8 was carried out according to compound II-3, using 7-fluorobenzo[b]thiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0423] Yield: 78 mg, 71% (last step)

[0424] ESI-MS: 650.3[M+H] +

[0425] 15 Preparation of Compound II-9

[0426]

[0427] The synthesis of compound II-9 was carried out according to compound II-3, using 1H-indole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0428] Yield: 57 mg, 69% (last step)

[0429] ESI-MS: 615.4[M+H] +

[0430] 16 Preparation of Compound II-10

[0431]

[0432] The synthesis of compound II-10 was carried out according to compound II-3, using 4,5-difluoro-1H-indole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0433] Yield: 47 mg, 65% (last step)

[0434] ESI-MS: 651.3[M+H] +

[0435] 17 Preparation of Compound II-11

[0436]

[0437] The synthesis of compound II-11 was carried out according to compound II-3, using 3-methyl-1H-indole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0438] Yield: 58 mg, 72% (last step)

[0439] ESI-MS: 629.4[M+H] +

[0440] 18 Preparation of Compound II-12

[0441]

[0442] The synthesis of compound II-12 was carried out according to compound II-3, using 1H-benzo[d]imidazole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0443] Yield: 27 mg, 48% (last step)

[0444] ESI-MS: 616.4[M+H] +

[0445] 19 Preparation of Compound II-13

[0446]

[0447] The synthesis of compound II-13 was carried out according to compound II-3, using 2,3-dihydro-1H-indene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0448] Yield: 38 mg, 61% (last step)

[0449] ESI-MS: 616.4[M+H] +

[0450] 20 Preparation of Compound II-14

[0451]

[0452] The synthesis of compound II-14 was carried out according to compound II-3, using 2-bromo-4-methylthiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0453] Yield: 98 mg, 70% (last step)

[0454] ESI-MS: 675.2 / 677.2[M+H] +

[0455] 21 Preparation of Compound II-15

[0456]

[0457] The synthesis of compound II-15 was carried out according to compound II-3, using 4-methyl-2-(trifluoromethyl)thiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0458] Yield: 67 mg, 51% (last step)

[0459] ESI-MS: 665.4[M+H] +

[0460] 22 Preparation of Compound II-16

[0461]

[0462] The synthesis of compound II-16 was carried out according to compound II-3, using 4-bromo-2-(trifluoromethyl)thiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0463] Yield: 136 mg, 63% (last step)

[0464] ESI-MS: 729.3 / 731.3[M+H] +

[0465] 23 Preparation of Compound II-17

[0466]

[0467] The synthesis of compound II-17 was carried out according to compound II-3, using 2,4-dichlorothiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0468] Yield: 102 mg, 71% (last step)

[0469] ESI-MS: 651.2 / 653.2[M+H] +

[0470] 24 Preparation of Compound II-18

[0471]

[0472] The synthesis of compound II-18 was carried out according to compound II-3, using 2-methoxy-4-methylthiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0473] Yield: 56 mg, 63% (last step)

[0474] ESI-MS: 627.3[M+H] +

[0475] 25 Preparation of Compound II-19

[0476]

[0477] The synthesis of compound II-19 was carried out according to compound II-3, using 4-methyl-2-phenylthiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0478] Yield: 46 mg, 67% (last step)

[0479] ESI-MS: 673.4[M+H] +

[0480] 26 Preparation of Compound II-20

[0481]

[0482] The synthesis of compound II-20 was carried out according to compound II-3, using 2,4-dimethylthiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0483] Yield: 216 mg, 77% (last step)

[0484] ESI-MS: 611.4[M+H] +

[0485] 27 Preparation of Compound II-21

[0486]

[0487] The synthesis of compound II-21 was carried out according to compound II-3, using 5-bromo-3-methylthiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0488] Yield: 178 mg, 79% (last step)

[0489] ESI-MS: 674.2 / 676.2.4[M+H] +

[0490] 28 Preparation of Compound II-22

[0491]

[0492] The synthesis of compound II-22 was carried out according to compound II-3, using 3,5-dibromothiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0493] Yield: 89 mg, 67% (last step)

[0494] ESI-MS:738.2 / 740.2 / 742.2[M+H] +

[0495] 29 Preparation of Compound II-23

[0496]

[0497] The synthesis of compound II-23 was carried out according to compound II-3, using 5-bromothiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0498] Yield: 141 mg, 72% (last step)

[0499] ESI-MS: 660.2 / 662.2[M+H] +

[0500] 30 Preparation of Compound II-24

[0501]

[0502] The synthesis of compound II-24 was carried out according to compound II-3, using 5-chlorothiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0503] Yield: 117 mg, 78% (last step)

[0504] ESI-MS: 616.3 / 618.3[M+H] +

[0505] 31 Preparation of Compound II-25

[0506]

[0507] The synthesis of compound II-25 was carried out according to compound II-3, using 5-bromo-3-methylfuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0508] Yield: 173 mg, 72% (last step)

[0509] ESI-MS: 658.2 / 660.2[M+H] +

[0510] 32 Preparation of Compound II-26

[0511]

[0512] The synthesis of compound II-26 was carried out according to compound II-3, using 5-chlorofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0513] Yield: 127 mg, 56% (last step)

[0514] ESI-MS: 600.3 / 602.3[M+H] +

[0515] 33 Preparation of Compound II-27

[0516]

[0517] The synthesis of compound II-27 was carried out according to compound II-3, using 5-chlorothiophene-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0518] Yield: 112 mg, 65% (last step)

[0519] ESI-MS: 616.3 / 618.3[M+H] +

[0520] 34 Preparation of Compound II-28

[0521]

[0522] The synthesis of compound II-28 was carried out according to compound II-3, using 2,5-dichlorothiophene-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0523] Yield: 319 mg, 77% (last step)

[0524] ESI-MS: 650.3 / 652.3[M+H] +

[0525] 35 Preparation of Compound II-29

[0526]

[0527] The synthesis of compound II-29 was carried out according to compound II-3, using 2,5-dibromothiophene-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0528] Yield: 98 mg, 52% (last step)

[0529] ESI-MS:738.2 / 740.2 / 742.2[M+H] +

[0530] 36 Preparation of Compound II-30

[0531]

[0532] The synthesis of compound II-30 was carried out according to compound II-3, using 5-bromothiophene-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0533] Yield: 171 mg, 73% (last step)

[0534] ESI-MS: 660.2 / 662.2[M+H] +

[0535] 37 Preparation of Compound II-31

[0536]

[0537] The synthesis of compound II-31 was carried out according to compound II-3, using 2-chloro-5-methylthiazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0538] Yield: 32 mg, 41% (last step)

[0539] ESI-MS: 631.3 / 633.3[M+H] +

[0540] 38 Preparation of Compound II-32

[0541]

[0542] The synthesis of compound II-32 was carried out according to compound II-3, using 2,5-dichlorothiazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0543] Yield: 41 mg, 35% (last step)

[0544] ESI-MS: 651.2 / 653.2[M+H] +

[0545] 39 Preparation of Compound II-33

[0546]

[0547] The synthesis of compound II-33 was carried out according to compound II-3, using 2,5-dibromothiazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0548] Yield: 21 mg, 32% (last step)

[0549] ESI-MS:739.2 / 741.2 / 743.2[M+H] +

[0550] 40 Preparation of Compound II-34

[0551]

[0552] The synthesis of compound II-34 was carried out according to compound II-3, using 2-bromo-5-methylthiazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0553] Yield: 42 mg, 57% (last step)

[0554] ESI-MS: 675.2 / 677.2[M+H] +

[0555] 41 Preparation of Compound II-35

[0556]

[0557] The synthesis of compound II-35 was carried out according to compound II-3, using 2-bromothiazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0558] Yield: 66 mg, 46% (last step)

[0559] ESI-MS: 661.2 / 663.2[M+H] +

[0560] 42 Preparation of Compound II-36

[0561]

[0562] The synthesis of compound II-36 was carried out according to compound II-3, using 2-chlorothiazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0563] Yield: 74 mg, 58% (last step)

[0564] ESI-MS: 617.3 / 619.3[M+H] +

[0565] 43 Preparation of Compound II-37

[0566]

[0567] The synthesis of compound II-37 was carried out according to compound II-3, using 2,5-dimethylfuran-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0568] Yield: 152 mg, 73% (last step)

[0569] ESI-MS: 594.4[M+H] +

[0570] 44 Preparation of Compound II-38

[0571]

[0572] The synthesis of compound II-38 was carried out according to compound II-3, using 4,5-dimethylthiazole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0573] Yield: 46 mg, 38% (last step)

[0574] ESI-MS: 611.4[M+H]+

[0575] 45 Preparation of Compound II-39

[0576]

[0577] The synthesis of compound II-39 was carried out according to compound II-3, using 4-bromothiazole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0578] Yield: 84 mg, 68% (last step)

[0579] ESI-MS: 661.2 / 663.2[M+H] +

[0580] 46 Preparation of Compound II-40

[0581]

[0582] The synthesis of compound II-40 was carried out according to compound II-3, using 4-bromothiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0583] Yield: 163 mg, 73% (last step)

[0584] ESI-MS: 660.2 / 662.2[M+H] +

[0585] 47 Preparation of Compound II-41

[0586]

[0587] The synthesis of compound II-41 was carried out according to compound II-3, using 4-bromo-3-methylthiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0588] Yield: 114 mg, 68% (last step)

[0589] ESI-MS: 674.2 / 676.2[M+H] +

[0590] 48 Preparation of Compound II-42

[0591]

[0592] The synthesis of compound II-42 was carried out according to compound II-3, using 3-bromothiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0593] Yield: 149 mg, 76% (last step)

[0594] ESI-MS: 660.2 / 662.2[M+H] +

[0595] 49 Preparation of Compound II-43

[0596]

[0597] The synthesis of compound II-43 was carried out according to compound II-3, using 3-chloro-4-methylthiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0598] Yield: 110 mg, 64% (last step)

[0599] ESI-MS: 630.3 / 632.3[M+H] +

[0600] 50 Preparation of Compound II-44

[0601]

[0602] The synthesis of compound II-44 was carried out according to compound II-3, using 4-bromo-5-chlorothiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0603] Yield: 126 mg, 59% (last step)

[0604] ESI-MS: 694.2 / 696.2 / 698.2[M+H] +

[0605] 51 Preparation of Compound II-45

[0606]

[0607] The synthesis of compound II-45 was carried out according to compound II-3, using 4,5-dibromothiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0608] Yield: 89 mg, 51% (last step)

[0609] ESI-MS:738.2 / 740.2 / 742.2[M+H] +

[0610] 52 Preparation of Compound II-46

[0611]

[0612] The synthesis of compound II-46 was carried out according to compound II-3, using 4,5-dibromo-3-methoxythiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0613] Yield: 59 mg, 40% (last step)

[0614] ESI-MS:768.2 / 770.2 / 772.2[M+H] +

[0615] 53 Preparation of Compound II-47

[0616]

[0617] The synthesis of compound II-47 was carried out according to compound II-3, using 4-bromofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0618] Yield: 90 mg, 69% (last step)

[0619] ESI-MS: 644.3 / 646.3[M+H] +

[0620] 54 Preparation of Compound II-48

[0621]

[0622] The synthesis of compound II-48 was carried out according to compound II-3, using 4,5-dibromofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0623] Yield: 72 mg, 56% (last step)

[0624] ESI-MS:722.2 / 724.2 / 726.2[M+H] +

[0625] 55 Preparation of Compound II-49

[0626]

[0627] The synthesis of compound II-49 was carried out according to compound II-3, using 4,5-dichlorothiophene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0628] Yield: 55 mg, 48% (last step)

[0629] ESI-MS: 650.3 / 652.3[M+H] +

[0630] 56 Preparation of Compound II-50

[0631]

[0632] The synthesis of compound II-50 was carried out according to compound II-3, using (S)-1-acetylpyrrolidine-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0633] Yield: 190 mg, 78% (last step)

[0634] ESI-MS: 611.4[M+H] +

[0635] 57 Preparation of Compound II-51

[0636]

[0637] The synthesis of compound II-51 was carried out according to compound II-3, using 1-methyl-1H-1,2,3-triazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0638] Yield: 28 mg, 35% (last step)

[0639] ESI-MS: 581.4[M+H] +

[0640] 58 Preparation of Compound II-52

[0641]

[0642] The synthesis of compound II-52 was carried out according to compound II-3, using 2H-tetrazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0643] Yield: 23 mg, 31% (last step)

[0644] ESI-MS: 568.4[M+H] +

[0645] 59 Preparation of Compound II-53

[0646]

[0647] The synthesis of compound II-53 was carried out according to compound II-3, using pyrazine-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0648] Yield: 79 mg, 74% (last step)

[0649] ESI-MS: 578.3[M+H] +

[0650] 60 Preparation of Compound II-54

[0651]

[0652] The synthesis of compound II-54 was carried out according to compound II-3, using (S)-1-methylpyrrolidine-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0653] Yield: 68 mg, 82% (last step)

[0654] ESI-MS: 583.4[M+H] +

[0655] 61 Preparation of Compound II-55

[0656]

[0657] The synthesis of compound II-55 was carried out according to compound II-3, using (S)-1-Boc-pyrrolidine-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). The final product was obtained by deprotection (DCM / TFA) as described above and purified by HPLC.

[0658] Yield: 43 mg, 79% (last step)

[0659] ESI-MS: 569.4[M+H] +

[0660] 62 Preparation of Compound II-56

[0661]

[0662] The synthesis of compound II-56 was carried out according to compound II-3, using (2S, 4S)-1-Boc-4-bromopyrrolidine-2-carboxylic acid instead of 3-methylbenzo [b] furan-2-carboxylic acid in step 6 (according to ZED3264). The final product was obtained by deprotection (DCM / TFA) as described above and purified by HPLC.

[0663] Yield: 45 mg, 73% (last step)

[0664] ESI-MS: 647.3 / 649.3[M+H] +

[0665] 63 Preparation of Compound II-58

[0666]

[0667] The synthesis of compound II-58 was carried out according to compound II-3, using (S)-1-Boc-piperidine-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). The final product was obtained by deprotection (DCM / TFA) as described above and purified by HPLC.

[0668] Yield: 53 mg, 86% (last step)

[0669] ESI-MS: 583.4[M+H] +

[0670] 64 Preparation of Compound II-59

[0671]

[0672] The synthesis of compound II-59 was carried out according to compound II-3, using (R)-1-Boc-piperidine-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). The final product was obtained by deprotection (DCM / TFA) as described above and purified by HPLC.

[0673] Yield: 43 mg, 77% (last step)

[0674] ESI-MS: 583.4[M+H] +

[0675] 65 Preparation of Compound II-60

[0676]

[0677] The synthesis of compound II-60 was carried out according to compound II-3, using (R)-4-Boc-morpholine-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). The final product was obtained by deprotection (DCM / TFA) as described above and purified by HPLC.

[0678] Yield: 67 mg, 85% (last step)

[0679] ESI-MS: 585.4[M+H] +

[0680] 66 Preparation of Compound II-61

[0681]

[0682] The synthesis of compound II-61 was carried out according to compound II-3, using quinuclidine-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0683] Yield: 24 mg, 54% (last step)

[0684] ESI-MS: 609.4[M+H] +

[0685] 67 Preparation of Compound II-62

[0686]

[0687] The synthesis of compound II-62 was carried out according to compound II-3, using 5-nitroisophthalic acid monomethyl ester instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0688] Yield: 57 mg, 66% (last step)

[0689] ESI-MS: 679.3[M+H] +

[0690] 68 Preparation of Compound II-63

[0691]

[0692] The synthesis of compound II-63 was carried out according to compound II-3, using 5-nitronicotinic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0693] Yield: 76 mg, 65% (last step)

[0694] ESI-MS: 622.3[M+H] +

[0695] 69 Preparation of Compound II-64

[0696]

[0697] The synthesis of compound II-64 was carried out according to compound II-3, using 3,5-pyridinedicarboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0698] Yield: 16 mg, 52% (last step)

[0699] ESI-MS: 621.3[M+H] +

[0700] 70 Preparation of Compound II-65

[0701]

[0702] The synthesis of compound II-65 was carried out according to compound II-3, using 5-(methoxycarbonyl)nicotinic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0703] Yield: 34 mg, 62% (last step)

[0704] ESI-MS: 635.3[M+H] +

[0705] 71 Preparation of Compound II-66

[0706]

[0707] The synthesis of compound II-66 was carried out according to compound II-3, using 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0708] Yield: 45 mg, 37% (last step)

[0709] ESI-MS: 636.4[M+H] +

[0710] 72 Preparation of Compound II-67

[0711]

[0712] The synthesis of compound II-67 was carried out according to compound II-3, except that N-methyl-2-adamantanamine was used instead of 2-adamantanamine in step 2 (according to ZED3905).

[0713] Yield: 66 mg, 45% (last step)

[0714] ESI-MS: 644.4[M+H] +

[0715] 73 Preparation of Compound II-68

[0716]

[0717] The synthesis of compound II-68 was carried out according to compound II-3, except that 5-hydroxy-2-adamantanamine was used instead of 2-adamantanamine in step 2 (according to ZED3905).

[0718] Yield: 21 mg, 34% (last step)

[0719] ESI-MS: 646.4[M+H] +

[0720] 74 Preparation of Compound II-69

[0721]

[0722] The synthesis of compound II-69 was carried out according to compound II-3, except that 5-fluoro-2-adamantanamine was used instead of 2-adamantanamine in step 2 (according to ZED3905).

[0723] Yield: 48 mg, 57% (last step)

[0724] ESI-MS: 648.4[M+H] +

[0725] 75 Preparation of Compound II-70

[0726]

[0727] The synthesis of compound II-70 was carried out according to compound II-3, using 5-chloro-2-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905).

[0728] Yield: 45 mg, 35% (last step)

[0729] ESI-MS: 664.3 / 666.3[M+H] +

[0730] 76 Preparation of Compound II-71

[0731]

[0732] The synthesis of compound II-71 was carried out according to compound II-3, using 5-bromo-2-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905).

[0733] Yield: 31 mg, 34% (last step)

[0734] ESI-MS: 708.3 / 710.3 [M+H] +

[0735] 77 Preparation of Compound II-72

[0736]

[0737] The synthesis of compound II-72 was carried out according to compound II-3, using 5-methyl-2-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905).

[0738] Yield: 68 mg, 54% (last step)

[0739] ESI-MS: 644.4[M+H] +

[0740] 78 Preparation of Compound II-73

[0741]

[0742] The synthesis of compound II-73 was carried out according to compound II-3, using 2-aminoadamantane-2-carbonitrile instead of 2-adamantanamine in step 2 (according to ZED3905).

[0743] Yield: 26 mg, 46% (last step)

[0744] ESI-MS: 655.4[M+H] +

[0745] 79 Preparation of Compound II-74

[0746]

[0747] The synthesis of compound II-74 was carried out according to compound II-3, using 2-aminoadamantane-2-carboxylic acid 2-methyl ester instead of 2-adamantanamine in step 2 (according to ZED3905).

[0748] Yield: 38 mg, 61% (last step)

[0749] ESI-MS: 688.4[M+H] +

[0750] 80 Preparation of Compound II-87

[0751]

[0752] The synthesis of compound II-87 was carried out according to compound II-3, using 1-adamantanylmethylamine instead of 2-adamantanamine in step 2 (according to ZED3905).

[0753] Yield: 43 mg, 53% (last step)

[0754] ESI-MS: 644.4[M+H] +

[0755] 81 Preparation of Compound II-88

[0756]

[0757] The synthesis of compound II-88 was carried out according to compound II-2, using 1-adamantanethamine instead of 2-adamantanamine in step 2 (according to ZED3905).

[0758] Yield: 31 mg, 41% (last step)

[0759] ESI-MS: 644.4[M+H] +

[0760] 82 Preparation of Compound II-90

[0761]

[0762] The synthesis of compound II-90 was carried out according to compound II-3, using (±)-endo-2-norbornylamine instead of 2-adamantanamine in step 2 (according to ZED3905).

[0763] Yield: 67 mg, 65% (last step)

[0764] ESI-MS: 590.4[M+H] +

[0765] 83 Preparation of Compound II-92

[0766]

[0767] The synthesis of compound II-92 was carried out according to compound II-3, using (R)-(+)-bornylamine instead of 2-adamantanamine in step 2 (according to ZED3905).

[0768] Yield: 52 mg, 66% (last step)

[0769] ESI-MS: 632.5[M+H] +

[0770] 84 Preparation of Compound II-94

[0771]

[0772] The synthesis of compound II-94 was carried out according to compound II-3, using exo-2-aminonorbornane instead of 2-adamantanamine in step 2 (according to ZED3905).

[0773] Yield: 62 mg, 68% (last step)

[0774] ESI-MS: 590.4[M+H] +

[0775] 85 Preparation of Compound II-95

[0776]

[0777] The synthesis of compound II-95 was carried out according to compound II-3, using bicyclo[2.2.1]heptan-1-ylamine instead of 2-adamantanamine in step 2 (based on ZED3905).

[0778] Yield: 14 mg, 32% (last step)

[0779] ESI-MS: 590.4[M+H] +

[0780] 86 Preparation of Compound II-96

[0781]

[0782] The synthesis of compound II-96 was carried out according to compound II-3, using bicyclo[2.2.1]heptan-7-ylamine instead of 2-adamantanamine in step 2 (according to ZED3905).

[0783] Yield: 36 mg, 53% (last step)

[0784] ESI-MS: 590.4[M+H] +

[0785] 87 Preparation of Compound II-97

[0786]

[0787] The synthesis of compound II-97 was carried out according to compound II-3, using bicyclo[2.2.1]hept-5-en-2-amine instead of 2-adamantanamine in step 2 (according to ZED3905).

[0788] Yield: 21 mg, 44% (last step)

[0789] ESI-MS: 588.4[M+H] +

[0790] 88 Preparation of Compound II-98

[0791]

[0792] The synthesis of compound II-98 was carried out according to compound II-3, using bicyclo[2.2.2]octan-2-ylamine instead of 2-adamantanamine in step 2 (according to ZED3905).

[0793] Yield: 25 mg, 41% (last step)

[0794] ESI-MS: 604.4[M+H] +

[0795] 89 Preparation of Compound II-99

[0796]

[0797] The synthesis of compound II-99 was carried out according to compound II-3, using (R)-(-)-isobornylamine instead of 2-adamantanamine in step 2 (according to ZED3905).

[0798] Yield: 27 mg, 48% (last step)

[0799] ESI-MS: 632.5[M+H] +

[0800] 90 Preparation of Compound II-100

[0801]

[0802] The synthesis of compound II-100 was carried out according to compound II-3, except that (1R,2R,3R,5S)-(-)-isopinocamphetamine was used in step 2 (according to ZED3905) instead of 2-adamantanamine.

[0803] Yield: 17 mg, 39% (last step)

[0804] ESI-MS: 632.5[M+H] +

[0805] 91 Preparation of Compound II-101

[0806]

[0807] The synthesis of compound II-101 was carried out according to compound II-3, except that (1S,2S,3S,5R)-(+)-isopinocamphetamine was used instead of 2-adamantanamine in step 2 (according to ZED3905).

[0808] Yield: 25 mg, 41% (last step)

[0809] ESI-MS: 632.5[M+H] +

[0810] 92 Preparation of Compound II-103

[0811]

[0812] The synthesis of compound II-103 was carried out according to compound II-3, except that 3-amino-4-homoisotruncatane was used instead of 2-adamantanamine in step 2 (according to ZED3905).

[0813] Yield: 12 mg, 28% (last step)

[0814] ESI-MS: 644.5[M+H] +

[0815] 93 Preparation of Compound II-104

[0816]

[0817] The synthesis of compound II-104 was carried out according to compound II-3, using 1-aminobisadamantane instead of 2-adamantanamine in step 2 (according to ZED3905).

[0818] Yield: 17 mg, 35% (last step)

[0819] ESI-MS: 682.5[M+H] +

[0820] 94 Preparation of Compound II-105

[0821]

[0822] The synthesis of compound II-105 was carried out according to compound II-3, using 4-aminobisadamantane instead of 2-adamantanamine in step 2 (according to ZED3905).

[0823] Yield: 8 mg, 26% (last step)

[0824] ESI-MS: 682.5[M+H] +

[0825] Scheme II-3 New building blocks

[0826]

[0827] 95 Preparation of compound ZED4893

[0828]

[0829] 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 at room temperature overnight. The solvent was evaporated; the residue was dissolved in 30 mL of EtOAc and washed twice with 10 mL each of 10% citric acid solution, 10% NaHCO solution, and brine. The organic phase was dried over NaSO, filtered, and the solvent was evaporated. The residue was purified by HPLC.

[0830] Yield: 484 mg, 47% ESI-MS: 289.3 [M+H] +

[0831] Preparation of compound ZED4894

[0832]

[0833] 484 mg (1.68 mmol) of ZED4893 were suspended in 30 mL of MeOH, and then 50 mg of palladium on activated carbon (10%) (unreduced) were added. The suspension was stirred at room temperature under a hydrogen atmosphere for 3 h. The catalyst was filtered and the solvent was evaporated.

[0834] Yield: 339 mg, 78%

[0835] ESI-MS: 259.4[M+H] +

[0836] 97 Preparation of Compound II-107

[0837]

[0838] The synthesis of compound II-107 was carried out according to compound II-3, using ZED4894 instead of ZED3906 in step 5 (based on ZED3907).

[0839] Yield: 41 mg, 49% (last step)

[0840] ESI-MS: 587.4[M+H] +

[0841] 98 Preparation of Compound II-108

[0842]

[0843] The synthesis of compound II-108 was carried out according to compound II-107, using 3-(bromomethyl)-1-adamantanol instead of 1-(bromomethyl)adamantane (according to ZED4893).

[0844] Yield: 16 mg, 36% (last step)

[0845] ESI-MS: 603.4[M+H] +

[0846] 99 Preparation of Compound II-109

[0847]

[0848] The synthesis of compound II-109 was carried out according to compound II-107, using 1-bromo-3-(bromomethyl)adamantane instead of 1-(bromomethyl)adamantane (according to ZED4893).

[0849] Yield: 24 mg, 41% (last step)

[0850] ESI-MS: 665.3 / 667.3[M+H] +

[0851] 100 Preparation of Compound II-110

[0852]

[0853] The synthesis of compound II-110 was carried out according to compound II-107, using 2-(bromomethyl)adamantane instead of 1-(bromomethyl)adamantane (according to ZED4893).

[0854] Yield: 46 mg, 62% (last step)

[0855] ESI-MS: 587.4[M+H] +

[0856] 101 Preparation of Compound II-111

[0857]

[0858] The synthesis of compound II-111 was carried out according to compound II-3, using nicotinic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0859] Yield: 65 mg, 46% (last step)

[0860] ESI-MS: 577.4[M+H] +

[0861] 102 Preparation of Compound II-112

[0862]

[0863] The synthesis of compound II-112 was carried out according to compound II-3, using isonicotinic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0864] Yield: 47 mg, 52% (last step)

[0865] ESI-MS: 577.4[M+H] +

[0866] 103 Preparation of Compound II-113

[0867]

[0868] The synthesis of compound II-113 was carried out according to compound II-3, using pyridazine-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0869] Yield: 34 mg, 46% (last step)

[0870] ESI-MS: 578.4[M+H] +

[0871] 104 Preparation of Compound II-114

[0872]

[0873] The synthesis of compound II-114 was carried out according to compound II-3, using pyridazine-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0874] Yield: 43 mg, 56% (last step)

[0875] ESI-MS: 578.4[M+H] +

[0876] 105 Preparation of Compound II-115

[0877]

[0878] The synthesis of compound II-115 was carried out according to compound II-3, using cyclopropyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632).

[0879] Yield: 47 mg, 64% (last step)

[0880] ESI-MS: 656.5[M+H] +

[0881] 106 Preparation of Compound II-116

[0882]

[0883] The synthesis of compound II-116 was carried out according to compound II-3, using amyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632).

[0884] Yield: 87 mg, 71% (last step)

[0885] ESI-MS: 686.5[M+H] +

[0886] 107 Preparation of Compound II-117

[0887]

[0888] The synthesis of compound II-117 was carried out according to compound II-3, using allyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632).

[0889] Yield: 42 mg, 63% (last step)

[0890] ESI-MS: 656.5[M+H] +

[0891] Scheme II-4

[0892]

[0893] Preparation of compound 10

[0894]

[0895] 15.0 g (38.7 mmol) of aldehyde (S)-2-(bis(tert-butoxycarbonyl)amino)-5-oxopentanoic acid tert-butyl ester (ZED721) was dissolved in 150 ml of DCM. 6.42 ml (46.3 mmol) of trimethylamine and 7.37 ml (79.9 mmol) of acetone cyanohydrin were added and the reaction was stirred at room temperature overnight. The solution was washed twice with citric acid solution (10%) and brine. The organic phase was dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography.

[0896] Yield: 16.2 g, >100%

[0897] ESI-MS: 437.6[M+Na] +

[0898] Preparation of compound 11

[0899]

[0900] At 4 ℃, 16.2g (~38.6mmol) of cyanohydrin 10 was dissolved in 95ml MeOH and 1.91g (45.5mmol) of lithium hydroxide monohydrate was added. 18.6ml hydrogen peroxide (35%) was added dropwise and the reaction was stirred at room temperature for 1.5h, then quenched with sodium thiosulfate solution (5%). The aqueous phase was extracted with DCM. The combined organic phases were dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography.

[0901] Yield: 8.61 g, 52%

[0902] ESI-MS: 455.2[M+Na] +

[0903] Preparation of compound 15

[0904]

[0905] 8.61 g (19.9 mmol) of hydroxyamide 10 was dissolved in 55 ml of DCM. 3.45 ml (24.9 mmol), 1.91 g (45.5 mmol) of trimethylamine, 2.12 ml of acetic anhydride and 62 mg (0.50 mmol) of DMAP were added and the reaction was stirred at room temperature for 3 h. After washing with water and salt water, the organic phase was dried over Na SO , filtered and the solvent was evaporated. The product was precipitated from the MTBE solution by adding hexane.

[0906] Yield: 8.08 g, 86%

[0907] ESI-MS: 475.5[M+H]+

[0908] Preparation of compound 16

[0909]

[0910] 15 of 8.08g (17.0mmol) is dissolved among the 140ml DCM / TFA (1: 1) and at room temperature stirs 3h.With solvent evaporation, and resistates is dissolved among the 40ml DMF.Add 5.80ml (2 equivalents) DIPEA and 4.55g (20.4mmol) ditert-Butyl dicarbonate in 20ml DMF, and reaction is stirred at room temperature overnight.With solvent evaporation, and resistates is dissolved among the 80ml EtOAc.Use NaHCO After solution (1.05 equivalents, in water) extraction, product is precipitated from aqueous phase by adding 1.5 equivalents of citric acid.

[0911] Yield: 1.64 g, 30%

[0912] ESI-MS: 319.4[M+H] +

[0913] 108 Preparation of Compound II-118

[0914]

[0915] The synthesis of compound II-118 was carried out according to compound II-3, using compound 16 instead of ZED3632 in step 5 (based on ZED3907).

[0916] Yield: 158 mg, 56% (last step)

[0917] ESI-MS: 616.4[M+H] +

[0918] 109 Preparation of Compound II-119

[0919]

[0920] The synthesis of compound II-119 was carried out according to compound II-2, except that allyl isocyanide was used instead of methyl isocyanide in step 4 (according to ZED3632).

[0921] Yield: 56 mg, 71% (last step)

[0922] ESI-MS: 642.4[M+H] +

[0923] 110 Preparation of Compound II-120

[0924]

[0925] The synthesis of compound II-120 was carried out according to compound II-2, using isopropyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632).

[0926] Yield: 62 mg, 65% (last step)

[0927] ESI-MS: 644.5[M+H] +

[0928] 111 Preparation of Compound II-121

[0929]

[0930] The synthesis of compound II-121 was carried out according to compound II-2, using cyclopropyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632).

[0931] Yield: 44 mg, 51% (last step)

[0932] ESI-MS: 642.4[M+H] +

[0933] 112 Preparation of Compound II-122

[0934]

[0935] The synthesis of compound II-122 was carried out according to compound II-2, using phenyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632).

[0936] Yield: 37 mg, 56% (last step)

[0937] ESI-MS: 678.4[M+H] +

[0938] 113 Preparation of Compound II-123

[0939]

[0940] The synthesis of compound II-123 was carried out according to compound II-2, except that benzyl isocyanide was used instead of methyl isocyanide in step 4 (according to ZED3632).

[0941] Yield: 46 mg, 52% (last step)

[0942] ESI-MS: 692.5[M+H]+

[0943] 114 Preparation of Compound II-124

[0944]

[0945] The synthesis of compound II-124 was carried out according to compound II-118, using benzofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0946] Yield: 96 mg, 81% (last step)

[0947] ESI-MS: 602.4[M+H] +

[0948] 115 Preparation of Compound II-125

[0949]

[0950] The synthesis of compound II-125 was carried out according to compound II-124, using 2,5-dichlorothiophene-3-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to ZED3264).

[0951] Yield: 78 mg, 71% (last step)

[0952] ESI-MS: 636.3 / 638.3[M+H] +

[0953] 116 Preparation of Compound II-126

[0954]

[0955] The synthesis of compound II-126 was carried out according to compound II-124, using 4-methyl-2-(trifluoromethyl)thiazole-5-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to ZED3264).

[0956] Yield: 53 mg, 67% (last step)

[0957] ESI-MS: 651.3[M+H] +

[0958] 117 Preparation of Compound II-127

[0959]

[0960] The synthesis of compound II-127 was carried out according to compound II-124, using 1-methyl-1H-1,2,3-triazole-5-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to ZED3264).

[0961] Yield: 26 mg, 49% (last step)

[0962] ESI-MS: 567.3[M+H] +

[0963] 118 Preparation of Compound II-128

[0964]

[0965] The synthesis of compound II-128 was carried out according to compound II-97, using 2,5-dichlorothiophene-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0966] Yield: 53 mg, 73% (last step)

[0967] ESI-MS: 610.3 / 612.3[M+H] +

[0968] 119 Preparation of Compound II-129

[0969]

[0970] The synthesis of compound II-129 was carried out according to compound II-97, using 4-methyl-2-(trifluoromethyl)thiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0971] Yield: 42 mg, 60% (last step)

[0972] ESI-MS: 625.3[M+H] +

[0973] 120 Preparation of Compound II-130

[0974]

[0975] The synthesis of compound II-130 was carried out according to compound II-97, using 1-methyl-1H-1,2,3-triazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0976] Yield: 15 mg, 39% (last step)

[0977] ESI-MS: 541.3[M+H] +

[0978] 121 Preparation of Compound II-131

[0979]

[0980] The synthesis of compound II-131 was carried out according to compound II-3, using 2H-1,2,3-triazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0981] Yield: 28 mg, 56% (last step)

[0982] ESI-MS: 567.4[M+H] +

[0983] 122 Preparation of Compound II-132

[0984]

[0985] The synthesis of compound II-132 was carried out according to compound II-3, using 1H-1,2,3-triazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0986] Yield: 14 mg, 45% (last step)

[0987] ESI-MS: 567.4[M+H] +

[0988] 123 Preparation of Compound II-133

[0989]

[0990] The synthesis of compound II-133 was carried out according to compound II-3, using 1-methyl-1H-1,2,3-triazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0991] Yield: 36 mg, 61% (last step)

[0992] ESI-MS: 581.4[M+H] +

[0993] 124 Preparation of Compound II-134

[0994]

[0995] The synthesis of compound II-134 was carried out according to compound II-3, using 1H-1,2,4-triazole-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[0996] Yield: 21 mg, 43% (last step)

[0997] ESI-MS: 567.4[M+H] +

[0998] 125 Preparation of Compound II-135

[0999]

[1000] The synthesis of compound II-135 was carried out according to compound II-3, using 1-methyl-1H-1,2,4-triazole-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1001] Yield: 39 mg, 67% (last step)

[1002] ESI-MS: 581.4[M+H] +

[1003] 126 Preparation of Compound II-136

[1004]

[1005] The synthesis of compound II-136 was carried out according to compound II-3, using benzofuran-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1006] Yield: 56 mg, 71% (last step)

[1007] ESI-MS: 616.4[M+H] +

[1008] 127 Preparation of Compound II-137

[1009]

[1010] The synthesis of compound II-137 was carried out according to compound II-3, using benzo[b]thiophene-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1011] Yield: 49 mg, 64% (last step)

[1012] ESI-MS: 632.4[M+H] +

[1013] 128 Preparation of Compound II-138

[1014]

[1015] The synthesis of compound II-138 was carried out according to compound II-3, using 1-methyl-1H-pyrazole-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1016] Yield: 43 mg, 59% (last step)

[1017] ESI-MS: 580.4[M+H] +

[1018] 129 Preparation of Compound II-139

[1019]

[1020] The synthesis of compound II-139 was carried out according to compound II-3, using 1-methyl-1H-pyrazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1021] Yield: 53 mg, 62% (last step)

[1022] ESI-MS: 580.4[M+H] +

[1023] 130 Preparation of Compound II-140

[1024]

[1025] The synthesis of compound II-140 was carried out according to compound II-3, using 1-methyl-1H-pyrazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1026] Yield: 39 mg, 48% (last step)

[1027] ESI-MS: 580.4[M+H] +

[1028] 131 Preparation of Compound II-141

[1029]

[1030] The synthesis of compound II-141 was carried out according to compound II-3, using 4-methyl-1,2,3-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1031] Yield: 54 mg, 58% (last step)

[1032] ESI-MS: 598.4[M+H] +

[1033] 132 Preparation of Compound II-142

[1034]

[1035] The synthesis of compound II-142 was carried out according to compound II-3, using 1,2,5-thiadiazole-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1036] Yield: 36 mg, 43% (last step)

[1037] ESI-MS: 584.4[M+H] +

[1038] 133 Preparation of Compound II-143

[1039]

[1040] The synthesis of compound II-143 was carried out according to compound II-3, using 4-iodo-1-methyl-1H-pyrazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1041] Yield: 24 mg, 49% (last step)

[1042] ESI-MS: 706.3[M+H] +

[1043] 134 Preparation of Compound II-144

[1044]

[1045] The synthesis of compound II-144 was carried out according to compound II-118, using 1-methyl-1H-pyrazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1046] Yield: 26 mg, 68% (last step)

[1047] ESI-MS: 566.4[M+H] +

[1048] 135 Preparation of Compound II-145

[1049]

[1050] The synthesis of compound II-145 was carried out according to compound II-118, using 4-methyl-1,2,3-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1051] Yield: 35 mg, 62% (last step)

[1052] ESI-MS: 584.4[M+H] +

[1053] 136 Preparation of Compound II-146

[1054]

[1055] The synthesis of compound II-146 was carried out according to compound II-118, using benzofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264) and exo-2-aminonorbornane instead of 2-adamantanamine in step 2 (according to ZED3905).

[1056] Yield: 43 mg, 60% (last step)

[1057] ESI-MS: 562.4[M+H] +

[1058] 137 Preparation of Compound II-147

[1059]

[1060] The synthesis of compound II-147 was carried out according to compound II-118, using exo-2-aminonorbornane instead of 2-adamantanamine in step 2 (according to ZED3905).

[1061] Yield: 56 mg, 67% (last step)

[1062] ESI-MS: 576.4[M+H] +

[1063] 138 Preparation of Compound II-148

[1064]

[1065] The synthesis of compound II-148 was carried out according to compound II-118, using benzofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264) and using (±)-endo-2-aminonorbornane instead of 2-adamantanamine in step 2 (according to ZED3905).

[1066] Yield: 49 mg, 66% (last step)

[1067] ESI-MS: 562.4[M+H] +

[1068] 139 Preparation of Compound II-149

[1069]

[1070] The synthesis of compound II-149 was carried out according to compound II-118, using (±)-endo-2-aminonorbornane instead of 2-adamantanamine in step 2 (according to ZED3905).

[1071] Yield: 64 mg, 75% (last step)

[1072] ESI-MS: 576.4[M+H] +

[1073] 140 Preparation of Compound II-150

[1074]

[1075] The synthesis of compound II-150 was carried out according to compound II-118, using benzofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264) and (R)-(+)-bornylamine instead of 2-adamantanamine in step 2 (according to ZED3905).

[1076] Yield: 38 mg, 53% (last step)

[1077] ESI-MS: 604.4[M+H] +

[1078] 141 Preparation of Compound II-151

[1079]

[1080] The synthesis of compound II-151 was carried out according to compound II-118, using (R)-(+)-bornylamine instead of 2-adamantanamine in step 2 (according to ZED3905).

[1081] Yield: 31 mg, 59% (last step)

[1082] ESI-MS: 618.5[M+H] +

[1083] 142 Preparation of Compound II-152

[1084]

[1085] The synthesis of compound II-152 was carried out according to compound II-94, using 4-methyl-1,2,3-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1086] Yield: 53 mg, 68% (last step)

[1087] ESI-MS: 558.4[M+H] +

[1088] 143 Preparation of Compound II-153

[1089]

[1090] The synthesis of compound II-153 was carried out according to compound II-94, using 1-methyl-1H-pyrazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1091] Yield: 60 mg, 67% (last step)

[1092] ESI-MS: 540.4[M+H] +

[1093] 144 Preparation of Compound II-154

[1094]

[1095] The synthesis of compound II-154 was carried out according to compound II-90, using 4-methyl-2-(trifluoromethyl)thiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1096] Yield: 68 mg, 74% (last step)

[1097] ESI-MS: 625.3[M+H] +

[1098] 145 Preparation of Compound II-155

[1099]

[1100] The synthesis of compound II-155 was carried out according to compound II-90, using 2,5-dichlorothiophene-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1101] Yield: 74 mg, 68% (last step)

[1102] ESI-MS: 610.3 / 612.3[M+H] +

[1103] 146 Preparation of Compound II-156

[1104]

[1105] The synthesis of compound II-156 was carried out according to compound II-90, using 4-methyl-1,2,3-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1106] Yield: 56 mg, 61% (last step)

[1107] ESI-MS: 558.4[M+H] +

[1108] 147 Preparation of Compound II-157

[1109]

[1110] The synthesis of compound II-157 was carried out according to compound II-90, using 1-methyl-1H-1,2,3-triazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1111] Yield: 34 mg, 52% (last step)

[1112] ESI-MS: 541.4[M+H] +

[1113] 148 Preparation of Compound II-158

[1114]

[1115] The synthesis of compound II-158 was carried out according to compound II-90, using 1-methyl-1H-pyrazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1116] Yield: 55 mg, 64% (last step)

[1117] ESI-MS: 540.4[M+H] +

[1118] 149 Preparation of Compound II-159

[1119]

[1120] The synthesis of compound II-159 was carried out according to compound II-92, using 4-methyl-2-(trifluoromethyl)thiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1121] Yield: 52 mg, 57% (last step)

[1122] ESI-MS: 667.4[M+H] +

[1123] 150 Preparation of Compound II-160

[1124]

[1125] The synthesis of compound II-160 was carried out according to compound II-92, using 2,5-dichlorothiophene-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1126] Yield: 66 mg, 61% (last step)

[1127] ESI-MS: 652.3 / 654.3[M+H] +

[1128] 151 Preparation of Compound II-161

[1129]

[1130] The synthesis of compound II-161 was carried out according to compound II-92, using 4-methyl-1,2,3-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1131] Yield: 41 mg, 51% (last step)

[1132] ESI-MS: 600.4[M+H] +

[1133] 152 Preparation of Compound II-162

[1134]

[1135] The synthesis of compound II-162 was carried out according to compound II-92, using 1-methyl-1H-1,2,3-triazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1136] Yield: 28 mg, 46% (last step)

[1137] ESI-MS: 583.5[M+H] +

[1138] 153 Preparation of Compound II-163

[1139]

[1140] The synthesis of compound II-163 was carried out according to compound II-92, using 1-methyl-1H-pyrazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1141] Yield: 44 mg, 58% (last step)

[1142] ESI-MS: 582.5[M+H] +

[1143] 154 Preparation of Compound II-164

[1144]

[1145] The synthesis of compound II-164 was carried out according to compound II-107, using 1-(2-bromoethyl)adamantane instead of 1-(bromomethyl)adamantane (according to ZED4893) and using 5-tert-butyl-1H-pyrrole-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1146] Yield: 32 mg, 56% (last step)

[1147] ESI-MS: 592.5[M+H] +

[1148] 155 Preparation of Compound II-165

[1149]

[1150] The synthesis of compound II-165 was carried out according to compound II-107, using 1-(3-bromopropyl)adamantane instead of 1-(bromomethyl)adamantane (according to ZED4893) and using 4-cyano-1-methyl-1H-pyrrole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1151] Yield: 27 mg, 48% (last step)

[1152] ESI-MS: 589.5[M+H] +

[1153] 156 Preparation of Compound II-166

[1154]

[1155] The synthesis of compound II-166 was carried out according to compound II-3, using 3-chloropropionic acid instead of chloroacetic acid (according to ZED1657) and using 5-methoxyoxazole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1156] Yield: 31 mg, 59% (last step)

[1157] ESI-MS: 611.4[M+H] +

[1158] 157 Preparation of Compound II-167

[1159]

[1160] The synthesis of compound II-167 was carried out according to compound II-3, using 1-bicyclo[1.1.1]pentylamine instead of 2-adamantanamine in step 2 (according to ZED3905).

[1161] Yield: 45 mg, 67% (last step)

[1162] ESI-MS: 562.4[M+H] +

[1163] 158 Preparation of Compound II-168

[1164]

[1165] The synthesis of compound II-168 was carried out according to compound II-167, using 2-acetyloxazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1166] Yield: 26 mg, 48% (last step)

[1167] ESI-MS: 541.4[M+H] +

[1168] 159 Preparation of Compound II-169

[1169]

[1170] The synthesis of compound II-169 was carried out according to compound II-3, using bicyclo[2.1.1]hexane-1-amine instead of 2-adamantanamine in step 2 (based on ZED3905).

[1171] Yield: 33 mg, 61% (last step)

[1172] ESI-MS: 576.4[M+H] +

[1173] 160 Preparation of Compound II-170

[1174]

[1175] The synthesis of compound II-170 was carried out according to compound II-169, using 2-isopropyloxazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1176] Yield: 32 mg, 54% (last step)

[1177] ESI-MS: 555.4[M+H] +

[1178] 161 Preparation of Compound II-171

[1179]

[1180] The synthesis of compound II-171 was carried out according to compound II-2, using bicyclo[3.2.1]octan-8-amine instead of 2-adamantanamine in step 2 (according to ZED3905).

[1181] Yield: 42 mg, 60% (last step)

[1182] ESI-MS: 590.4[M+H] +

[1183] 162 Preparation of Compound II-172

[1184]

[1185] The synthesis of compound II-172 was carried out according to compound II-171, using 3,5-dimethylisoxazole-4-carboxylic acid instead of benzofuran-2-carboxylic acid in step 6 (according to ZED3264).

[1186] Yield: 35 mg, 58% (last step)

[1187] ESI-MS: 569.4[M+H] +

[1188] 163 Preparation of Compound II-173

[1189]

[1190] The synthesis of compound II-173 was carried out according to compound II-3, using 4-aminoadamantane-1-carboxylic acid instead of 2-adamantanamine in step 2 (according to ZED3905) and using 4-methylpyrimidine-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1191] Yield: 25 mg, 49% (last step)

[1192] ESI-MS: 636.4[M+H] +

[1193] 164 Preparation of Compound II-174

[1194]

[1195] The synthesis of compound II-174 was carried out according to compound II-3, using 4-aminoadamantane-N,N-dimethyl-1-carboxamide instead of 2-adamantaneamine in step 2 (according to ZED3905) and using 1,2,3,4-tetrahydronaphthalene-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1196] Yield: 33 mg, 56% (last step)

[1197] ESI-MS: 701.5[M+H] +

[1198] 165 Preparation of Compound II-175

[1199]

[1200] The synthesis of compound II-175 was carried out according to compound II-3, using tert-butyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632) and using 1,4-diazabicyclo[2.2.2]octane-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1201] Yield: 39 mg, 53% (last step)

[1202] ESI-MS: 652.5[M+H] +

[1203] 166 Preparation of Compound II-176

[1204]

[1205] The synthesis of compound II-176 was carried out according to compound II-3, using tert-butyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632) and using 1H-indole-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1206] Yield: 52 mg, 62% (last step)

[1207] ESI-MS: 657.5[M+H] +

[1208] 167 Preparation of Compound II-177

[1209]

[1210] The synthesis of compound II-177 was carried out according to compound II-3, using tert-butyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632) and using 6-methylimidazo[2,1-b][1,3]thiazole-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1211] Yield: 42 mg, 53% (last step)

[1212] ESI-MS: 678.5[M+H] +

[1213] 168 Preparation of Compound II-178

[1214]

[1215] The synthesis of compound II-178 was carried out according to compound II-90, using cyclopentyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632) and using 1,3-benzothiazole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1216] Yield: 54 mg, 61% (last step)

[1217] ESI-MS: 647.4[M+H] +

[1218] 169 Preparation of Compound II-179

[1219]

[1220] The synthesis of compound II-179 was carried out according to compound II-90, using cyclopentyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632) and using imidazo[2,1-b][1,3]thiazole-6-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1221] Yield: 36 mg, 51% (last step)

[1222] ESI-MS: 636.4[M+H] +

[1223] 170 Preparation of Compound II-180

[1224]

[1225] The synthesis of compound II-180 was carried out according to compound II-90, using cyclopentyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632) and using 4-hydroxy-6-(trifluoromethoxy)quinoline-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1226] Yield: 19 mg, 41% (last step)

[1227] ESI-MS: 741.5[M+H] +

[1228] 171 Preparation of Compound II-181

[1229]

[1230] The synthesis of compound II-181 was carried out according to compound II-167, using cyclohexyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632) and using 3-cinnolinecarboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1231] Yield: 37 mg, 56% (last step)

[1232] ESI-MS: 628.5[M+H] +

[1233] 172 Preparation of Compound II-182

[1234]

[1235] The synthesis of compound II-182 was carried out according to compound II-167, using cyclohexyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632) and using 3-ethylbenzofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1236] Yield: 53 mg, 68% (last step)

[1237] ESI-MS: 644.5[M+H] +

[1238] 173 Preparation of Compound II-183

[1239]

[1240] The synthesis of compound II-183 was carried out according to compound II-167, using cyclohexyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632) and using 1-ethyl-1H-indole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1241] Yield: 41 mg, 57% (last step)

[1242] ESI-MS: 643.5[M+H] +

[1243] 174 Preparation of Compound II-184

[1244]

[1245] The synthesis of compound II-184 was carried out according to compound II-167, using cyclohexyl isocyanide instead of methyl isocyanide in step 4 (according to ZED3632) and using 2-methyl-1,8-naphthyridine-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1246] Yield: 26 mg, 54% (last step)

[1247] ESI-MS: 642.5[M+H] +

[1248] 175 Preparation of Compound II-185

[1249]

[1250] The synthesis of compound II-185 was carried out according to compound II-169, using N-Boc-1,2,3,4-tetrahydroquinoline-6-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). The final product was obtained by deprotection (DCM / TFA) as described above and purified by HPLC.

[1251] Yield: 39 mg, 61% (last step)

[1252] ESI-MS: 577.4[M+H] +

[1253] 176 Preparation of Compound II-186

[1254]

[1255] The synthesis of compound II-186 was carried out according to compound II-3, using 2-amino-5-(trifluoromethyl)adamantane-2-carboxylic acid instead of 2-adamantaneamine in step 2 (according to ZED3905) and using 3-oxo-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1256] Yield: 12 mg, 36% (last step)

[1257] ESI-MS: 757.4[M+H] +

[1258] 177 Preparation of Compound II-187

[1259]

[1260] The synthesis of compound II-187 was carried out according to compound II-3, using 5-ethyladamantan-2-amine instead of 2-adamantanamine in step 2 (according to ZED3905) and using 1,6-naphthyridine-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1261] Yield: 26 mg, 51% (last step)

[1262] ESI-MS: 656.5[M+H] +

[1263] 178 Preparation of Compound II-188

[1264]

[1265] The synthesis of compound II-188 was carried out according to compound II-169, using 2,6-naphthyridine-1-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1266] Yield: 33 mg, 56% (last step)

[1267] ESI-MS: 574.4[M+H] +

[1268] 179 Preparation of Compound II-189

[1269]

[1270] The synthesis of compound II-189 was carried out according to compound II-167, using 4-Boc-amino-1,2,5-oxadiazole-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). The amine was deprotected with TFA in the final step.

[1271] Yield: 16 mg, 69% (last step)

[1272] ESI-MS: 515.3[M+H] +

[1273] 180 Preparation of Compound II-190

[1274]

[1275] The synthesis of compound II-190 was carried out according to compound II-167, using 6-(dimethylamino)benzofuran-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1276] Yield: 38 mg, 55% (last step)

[1277] ESI-MS: 591.4[M+H] +

[1278] 181 Preparation of Compound II-191

[1279]

[1280] The synthesis of compound II-191 was carried out according to compound II-167, using 2-acetylamino-5-thiazolecarboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1281] Yield: 21 mg, 46% (last step)

[1282] ESI-MS: 572.3[M+H] +

[1283] 182 Preparation of Compound II-192

[1284]

[1285] The synthesis of compound II-192 was carried out according to compound II-167, using 5-carbamoyl-1H-pyrrole-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1286] Yield: 13 mg, 38% (last step)

[1287] ESI-MS: 540.4[M+H] +

[1288] 183 Preparation of Compound II-193

[1289]

[1290] The synthesis of compound II-193 was carried out according to compound II-3, using 1-acetylamino-4-aminoadamantane instead of 2-adamantaneamine in step 2 (according to ZED3905) and using 5-sulfamoylfuran-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1291] Yield: 10 mg, 27% (last step)

[1292] ESI-MS: 702.4[M+H] +

[1293] 184 Preparation of Compound II-194

[1294]

[1295] The synthesis of compound II-194 was carried out according to compound II-3, using 1-acetylamino-4-aminoadamantane instead of 2-adamantanamine in step 2 (according to ZED3905) and using benzofuran-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1296] Yield: 23 mg, 52% (last step)

[1297] ESI-MS: 673.5[M+H] +

[1298] 185 Preparation of Compound II-195

[1299]

[1300] The synthesis of compound II-195 was carried out according to compound II-3, using 4-aminoadamantane-1-carboxamide instead of 2-adamantaneamine in step 2 (according to ZED3905) and using benzofuran-6-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1301] Yield: 26 mg, 57% (last step)

[1302] ESI-MS: 659.4[M+H] +

[1303] 186 Preparation of Compound II-196

[1304]

[1305] The synthesis of compound II-196 was carried out according to compound II-3, using 4-aminoadamantane-1-carboxamide instead of 2-adamantaneamine in step 2 (according to ZED3905) and using 3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1306] Yield: 15 mg, 38% (last step)

[1307] ESI-MS: 665.5[M+H] +

[1308] 187 Preparation of Compound II-197

[1309]

[1310] The synthesis of compound II-197 was carried out according to compound II-167, using 5-methyl-1,2,4-oxadiazole-3-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1311] Yield: 36 mg, 58% (last step)

[1312] ESI-MS: 514.4[M+H] +

[1313] 188 Preparation of Compound II-198

[1314]

[1315] The synthesis of compound II-198 was carried out according to compound II-167, using 1,2,3-thiadiazole-4-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1316] Yield: 29 mg, 48% (last step)

[1317] ESI-MS: 516.3[M+H] +

[1318] 189 Preparation of Compound II-199

[1319]

[1320] The synthesis of compound II-199 was carried out according to compound II-167, using 1,2,4-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1321] Yield: 35 mg, 56% (last step)

[1322] ESI-MS: 516.3[M+H] +

[1323] 190 Preparation of Compound II-200

[1324]

[1325] The synthesis of compound II-200 was carried out according to compound II-167, using 1,3,4-thiadiazole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1326] Yield: 24 mg, 41% (last step)

[1327] ESI-MS: 516.3[M+H] +

[1328] 191 Preparation of Compound II-201

[1329]

[1330] The synthesis of compound II-201 was carried out according to compound II-167, using 4-cyclopropyl-[1,2,3]thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1331] Yield: 43 mg, 67% (last step)

[1332] ESI-MS: 556.4[M+H] +

[1333] 192 Preparation of Compound II-202

[1334]

[1335] The synthesis of compound II-202 was carried out according to compound II-3, using 4-cyclopropyl-[1,2,3]thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1336] Yield: 42 mg, 56% (last step)

[1337] ESI-MS: 624.4[M+H] +

[1338] 193 Preparation of Compound II-203

[1339]

[1340] The synthesis of compound II-203 was carried out according to compound II-3, using 4-(propan-2-yl)-1,2,3-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1341] Yield: 36 mg, 52% (last step)

[1342] ESI-MS: 626.4[M+H] +

[1343] 194 Preparation of Compound II-204

[1344]

[1345] The synthesis of compound II-204 was carried out according to compound II-3, using 4-ethyl-1,2,3-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1346] Yield: 33 mg, 47% (last step)

[1347] ESI-MS: 612.4[M+H] +

[1348] 195 Preparation of Compound II-205

[1349]

[1350] The synthesis of compound II-205 was carried out according to compound II-3, using 4-(hydroxymethyl)-1,2,3-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1351] Yield: 13 mg, 32% (last step)

[1352] ESI-MS: 612.4[M+H] +

[1353] 196 Preparation of Compound II-206

[1354]

[1355] The synthesis of compound II-206 was carried out according to compound II-3, using 4-((tetrahydro-2H-pyran-2-yloxy)methyl)-1,2,3-thiadiazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264). The tetrahydropyranyl (Thp) protecting group was cleaved with TFA in the final step.

[1356] Yield: 9 mg, 46% (last step)

[1357] ESI-MS: 614.4[M+H] +

[1358] 197 Preparation of Compound II-207

[1359]

[1360] The synthesis of compound II-207 was carried out according to compound II-3, using 1-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905) and using 1-methyl-1H-imidazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1361] Yield: 64 mg, 71% (last step)

[1362] ESI-MS: 580.4[M+H] +

[1363] 198 Preparation of Compound II-208

[1364]

[1365] The synthesis of compound II-208 was carried out according to compound II-3, using (-)-cis-myrtanylamine instead of 2-adamantanamine in step 2 (according to ZED3905) and using 1-methyl-1H-imidazole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1366] Yield: 43 mg, 59% (last step)

[1367] ESI-MS: 582.5[M+H] +

[1368] 199 Preparation of Compound II-209

[1369]

[1370] The synthesis of compound II-209 was carried out according to compound II-3, using (-)-cis-myrtylamine instead of 2-adamantanamine in step 2 (according to ZED3905) and using 1-methyl-1H-imidazole-2-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1371] Yield: 31 mg, 55% (last step)

[1372] ESI-MS: 568.4[M+H] +

[1373] 200 Preparation of Compound II-210

[1374]

[1375] The synthesis of compound II-210 was carried out according to compound II-3, using 3,5-dimethyl-1-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905) and using 1-methyl-1H-imidazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1376] Yield: 46 mg, 66% (last step)

[1377] ESI-MS: 608.5[M+H] +

[1378] 201 Preparation of Compound II-211

[1379]

[1380] The synthesis of compound II-211 was carried out according to compound II-3, using 3,5,7-trimethyl-1-adamantanamine instead of 2-adamantanamine in step 2 (according to ZED3905) and using 1-methyl-1H-imidazole-5-carboxylic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1381] Yield: 53 mg, 70% (last step)

[1382] ESI-MS: 622.5[M+H] +

[1383] 202 Preparation of Reference Compound 6

[1384]

[1385] The synthesis of reference compound 6 was carried out according to compound II-3, using 2-phenylethylamine instead of 2-adamantanamine in step 2 (according to ZED3905) and nicotinic acid instead of 3-methylbenzo[b]furan-2-carboxylic acid in step 6 (according to ZED3264).

[1386] Yield: 89 mg, 79% (last step)

[1387] ESI-MS: 547.4[M+H] +

[1388] Biological Examples

[1389] Example B-1. Inhibitory effect of the compound according to the present invention

[1390] Transglutaminase assay

[1391] To determine the potency of the inhibitors against tissue transglutaminase, the incorporation of dansylcadaverine into dimethylcasein (Zedira product T036, Lorand et al., Anal Biochem, 1971, 44:221-31) was measured using recombinant human transglutaminase 2 (Zedira product T022).

[1392] 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.

[1393] A 10 mM inhibitor stock solution was prepared in DMSO, and a 1:2 dilution series was prepared from this 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 give a final working dilution containing 2% (v / v) DMSO.

[1394] 15 μl of the inhibitor working dilution was added to each well of a 96-well microtiter plate. As a control, 15 μl of a 2% (v / v) DMSO solution prepared using the above-mentioned buffer was added to each well.

[1395] Immediately 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 dansylcadaverine, 4 μM N,N-dimethylcasein, 200 mM NaCl, pH = 8.0). 285 μl of this reaction mixture was added to each well containing inhibitor.

[1396] Use λ at 37℃ ex =330nm and λ em =500 nm was used to measure the increase in fluorescence for 30 min. The slope of the fluorescence increase between 20 and 30 min was calculated to determine the IC 50 The inhibitor concentration at which 50% of the initial activity is blocked is expressed as the inhibitor concentration.

[1397] Enzyme activity was analyzed by calculating the slope of the increase in fluorescence intensity. 50 IC values ​​were calculated by plotting enzyme activity against inhibitor concentration (as a percentage relative to a control containing 2% DMSO instead of inhibitor). 50 It is defined as the inhibitor concentration that blocks 50% of the initial enzyme activity.

[1398] The inhibitory activity of the compounds of the present invention on tissue transglutaminase (TG2) was determined using IC 50 - Values ​​are shown in Table 1 below.

[1399] Table 1. Efficacy of reversible TG2 inhibitors

[1400] A:IC 50 <40nM, B: 40nM≤IC 50 <400nM, C: 400nM≤IC 50 <2,500nM,

[1401] D: 2,500nM≤IC 50 <10,000nM

[1402]

[1403]

[1404]

[1405]

[1406]

[1407]

[1408] Example B-2. logD values ​​of compounds of the present invention

[1409] In order to classify the compounds according to their lipophilicity, the LogD values ​​(partition coefficients) were determined with the aid of an established shake flask method, and the partitioning of the compounds between octanol and phosphate-buffered saline (PBS, pH 7.4) was measured by HPLC.

[1410] LogD is pH dependent and is a "predictor" of in vivo properties. LogD combines lipophilicity (an intrinsic structural property of the molecule, logP) and ionizability (pKa).

[1411] Compounds with moderate lipophilicity (LogD values ​​from 0 to 3) are generally favored for oral absorption, maintaining a balance between solubility and permeability. However, complex formulations of compounds can improve the oral bioavailability of highly lipophilic compounds.

[1412] Table 2. LogD values ​​of reversible TG2 inhibitors

[1413] A: logD<1, B: 1≤logD<3, C: 3≤logD<5

[1414]

[1415]

[1416]

[1417]

[1418] Example B-3. Caco-2 permeability measurement of compounds of the present invention

[1419] Permeability coefficients (P app The assay was performed using the CacoReady from ReadyCell according to the manufacturer's protocol. TM Ready-to-use kit.

[1420] Considered to have a value higher than 1x10 -6 P in cm / s app Compounds with values ​​below 1x10 -6 P in cm / s app Compounds with values ​​of 1000 nm are classified as impermeable.

[1421] Table 3. Caco2 permeability assay of reversible TG2 inhibitors

[1422] A:P app <1x10 -6 cm / s, B:P app ≥1x10 -6 cm / s≤P app <10x10 -6 cm / s

[1423] C:P app ≥10x10 -6 cm / s

[1424]

[1425]

[1426]

[1427]

[1428] Bioavailability studies

[1429] From the promising P appThe value (permeability coefficient, see below) is speculated that the inventors have demonstrated the oral bioavailability of the inhibitor of the present application by representative compounds II-3, II-15 and II-28. For the representative compound of this selected group, pharmacokinetic properties are determined in male C57BL / 6 mice (N=3, each group). In brief, the compound is administered with a single dose of 200 mg / kg soluble oral formulation [20 mg / ml in PBS / (2-hydroxypropyl)-β-cyclodextrin formulation]. At (0, 0.25, 0.5, 1, 2, 4 and 6 hours) plasma samples are collected and analyzed by LC-MS to determine the concentration of the representative compound.

[1430] The calculated pharmacokinetic parameters are summarized in the table.

[1431]

[1432] C max : Maximum plasma concentration.

[1433] AUCt: Area under the plasma concentration time curve from dosing to the last observed concentration at time t, measured by the trapezoidal rule.

[1434] K el : estimated by linear regression of the logarithm of the final concentration as a function of time. The points used to calculate Kel were chosen using the "best fit" option of Winnonlin.

[1435] MRT: mean residence time.

[1436] t 1 / 2 : By applying the equation ln2 / K el To calculate.

[1437] CL / F: Apparent plasma clearance is calculated as follows: dose / AUCinf.

[1438] V d / F (L / kg): Apparent volume of distribution after administration. The parameter is calculated as V d / F=(CL / F) / K el .

[1439] R 2 : correlation coefficient.

[1440]

[1441] The corresponding PK characteristics revealed that the plasma levels of all representative compounds exceeded the IC for 3.5 hours. 90 and exceeded IC throughout the study period (6 hours) 50 In conclusion, the high c maxValue exceeds IC 90 The levels were >100-fold higher. Therefore, we expect to occupy all accessible active TG2.

[1442] In addition, in a multiple dose PK study, II-3 was orally administered to 3 mice twice a day (12 hour intervals) at 200 mg / kg dosage (dose volume 10 mL / kg). After the animals were killed, the liver and lungs were taken out. The homogenate of the corresponding tissues was analyzed by LC-MS to determine the concentration of the compound. After the eighth administration (four days), the tissue concentrations in the lungs and liver were 6,800 and 10,400 ng / g, respectively, indicating that the compound arrived at the tissue with pharmacologically active concentrations.

Claims

1. A compound of general formula (I): in L stands for -L 1 -or-L 1 -L 2 -; L 1 represents -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CO-, or -CH2CH2CO-; L 2 Indicates a key, -NR N1 -、-NR N1 CH2-、-NR N1 CH2CH2-, or -NR N1 CH(CH3)-; R 1 express R 2 express The unsubstituted bicyclic residue may be substituted by a substituent R 9 -R 14 and R N 1 to 5 substitutions in; R 3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwisted alkyl, adamantyl, diadamantyl, hexamethylenetetraminyl, and the above residues optionally contain one or more C=C double bonds and / or are optionally replaced by 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 -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 and R 7 Each independently represents -H, -CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2CH=CH2, -CH2CH=CH(CH3), -CH2CH=C(CH3)2, -CH2CH=CHCH2CH3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -cyclo-C6H 11 , -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-C5H9, -CH2-cyclo-C6H 11 , -Ph, -CH2-Ph, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2NHCH3, or -CH2CH2N(CH3)2, or -NR 6 R 7 It is -N(C2H5)2, R 8 、R 9 、R 10 、R 11 、R 12 、R 13 and R 14 represents independently of one another -H, -F, -Cl, -Br, -I, -OH, -CN, -NO2, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -CH2-cyclo-C3H5, -CH2OH, -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, -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 Together they can form one of the following five-membered or six-membered rings: or R 12 and R 13 or R 13 and R 14 Together they can form one of the following five-membered or six-membered rings: R N represents -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-C5H9, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2Cl, -CH2-CH2Br, -CH2-CH2I, -CH 2-CH=CH2, -CH2-C≡CH, -CHO, -COCH3, -COC2H5, -COC3H7, -COCH(CH3)2, -COC(CH3)3, -CO-cyclo-C3H5, -CO-cyclo-C4H7, -CO-cyclo-C5H9, -COOCH3, -COOC2H5, -COOC3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -SO2CH3, -SO2CF3, -SO2C2H5, -SO2C3H7, -SO2CH(CH3)2, -SO2-cyclo-C3H5, or -SO2C(CH3)3; R N1 represents -H, -CH3, or -CH2CH3; or a diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemate, or pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein R 2 express wherein the unsubstituted bicyclic residue may be substituted by a substituent R 9 -R 14 and R N 1 to 5 substitutions in; and the substituent R 9 -R 14 and R N has the meaning as defined in claim 1.

3. The compound according to claim 1, wherein R 2 express wherein the unsubstituted bicyclic residue may be substituted by a substituent R 9 -R 14 and R N 1 to 5 substitutions in; and the substituent R 9 -R 14 and R N has the meaning as defined in claim 1.

4. The compound according to claim 1, wherein the compound has formula (Ib) in L stands for -L 1 -or-L 1 -L 2 -; L 1 represents -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CO-, or -CH2CH2CO-; L 2 Indicates a key, -NR N1 -、-NR N1 CH2-、-NR N1 CH2CH2-, or -NR N1 CH(CH3)-; R 2 express R 3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, bicyclo[3.3.3]undecyl, 4-homoisotwisted alkyl, adamantyl, diadamantyl, hexamethylenetetraminyl, and the above residues optionally contain one or more C=C double bonds and / or are replaced by 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 -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 and R 7 Each independently represents -H, -CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2CH=CH2, -CH2CH=CH(CH3), -CH2CH=C(CH3)2, -CH2CH=CHCH2CH3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -cyclo-C6H 11 , -CH2-cyclo-C3H5, -CH2-cyclo-C4H7, -CH2-cyclo-C5H9, -CH2-cyclo-C6H 11 , -Ph, -CH2-Ph, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2NHCH3, -CH2CH2N(CH3)2, or -NR 6 R 7 It is -N(C2H5)2, R N represents -H, -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -CH2-cyclo-C3H5, -CH2F, -CHF2, -CF3, -CH2Cl, -CH2Br, -CH2I, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2-CH2Cl, -CH2-CH2Br, -C H2-CH2I, -CH2-CH=CH2, -CH2-C≡CH, -CHO, -COCH3, -COC2H5, -COC3H7, -COCH(CH3)2, -COC(CH3)3, -COOCH3, -COOC2H5, -CO OC3H7, -COOCH(CH3)2, -COOC(CH3)3, -COOCH2Ph, -SO2CH3, -SO2CF3, -SO2C2H5, -SO2C3H7, -SO2CH(CH3)2, or -SO2C(CH3)3; R N1 represents -H, -CH3, or -CH2CH3; And R 8 -R 14 has the meaning as defined in formula (I); or a diastereomer, enantiomer, mixture of diastereomers, mixture of enantiomers, racemate, or pharmaceutically acceptable salt thereof.

5. The compound according to any one of claims 1 to 4, wherein L 1 represents -CH2-, or -CH2CO-; L 2 Indicates a key, -NR N1 -、-NR N1 CH2-, or -NR N1 CH(CH3)-; R 3 represents bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 4-homoisotwisted alkyl, adamantyl, or diadamantyl, and the above residues optionally contain one or more C=C double bonds and / or are replaced by R a 、R b 、R c 、R d and R e One or more substitutions in ; And R a 、R b 、R c 、R d 、R e and R N1 has the same meaning as defined in claim 1.

6. The compound according to claim 1, wherein R 2 express And R 8 -R 14 and R N has the meaning as defined in claim 1 or 2.

7. The compound according to claim 1, wherein the compound has any one of formulas (IV-a)-(IV-o) and (Va)-(Vd): And R 2 、R 3 、R 6 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R a 、R b 、R c 、R d and L 2 has the same meaning as defined in claim 1.

8. The compound according to claim 1, wherein R 2 express and R 6 Indicates -H, -CH3, -CH(CH3)2, -CH2CH2CH3, -CH2CH=CH2, -CH2CH2CH2CH3、-CH2CH(CH3)2、-C(CH3)3、-CH2CH2CH2CH2CH3、-cyclo-C3H5、-cyclo-C5H9、-cyclo-C6H 11 Or -CH2-cyclo-C3H5.

9. The compound according to claim 1 or 4, wherein L represents -L 1 -L 2 -, and L 1 and L 2 has the meaning as defined in claim 1 or 4.

10. The compound according to claim 1, wherein R 2 express wherein the unsubstituted bicyclic residue may be substituted by a substituent R 11 -R 13 1 to 3 substitutions in; and the substituent R 9 -R 14 and R N has the meaning as defined in claim 1.

11. The compound according to claim 2, wherein R 2 express wherein the unsubstituted bicyclic residue may be substituted by a substituent R 11 -R 13 1 to 3 substitutions in; and the substituent R 9 -R 14 and R N has the meaning as defined in claim 1.

12. The compound according to claim 1, wherein R 2 express wherein the unsubstituted bicyclic residue may be substituted by a substituent R 11 -R 13 1 to 3 substitutions in the 9 -R 14 and R N has the meaning as defined in claim 1.

13. The compound according to claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising the compound according to any one of claims 1 to 13 as an active ingredient, and at least one pharmaceutically acceptable carrier, excipient and / or diluent.

15. Use of a compound according to any one of claims 1 to 13 or use of a pharmaceutical composition according to claim 14 in the preparation of a medicament for treating or preventing a disease associated with and / or caused by transglutaminase 2, wherein the disease is selected from autoimmune and inflammatory diseases, vascular diseases, fibrotic diseases, liver diseases, cancer, neurodegenerative diseases, eye diseases and skin disorders.

16. The use of a compound or a pharmaceutical composition according to claim 15, wherein The autoimmune and inflammatory diseases include multiple sclerosis, celiac disease with diarrhea, Duhring-Brocq disease, gluten ataxia, gluten neuropathy, diabetes, rheumatoid arthritis, Graves' disease, inflammatory bowel disease, systemic lupus erythematosus, psoriasis and gingivitis; the vascular diseases include atherosclerosis, thrombosis, and vascular sclerosis; the fibrotic diseases affect the lungs, kidneys, liver, skin or intestines and include cystic fibrosis, renal fibrosis and diabetic nephropathy, intestinal fibrosis, idiopathic pulmonary fibrosis, and hepatic fibrosis; wherein the liver disease comprises alcoholic steatohepatitis, nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, cirrhosis or autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis; wherein the cancer comprises glioblastoma, melanoma, pancreatic cancer, renal cell carcinoma, meningioma, and breast cancer; wherein the neurodegenerative disease comprises Parkinson's disease, Huntington's disease, or Alzheimer's disease; wherein the eye disease comprises glaucoma, cataracts, macular degeneration, or uveitis; and wherein the skin disorder comprises acne, psoriasis, scarring, and skin aging.

17. Use of a compound or use of a pharmaceutical composition according to claim 15, wherein the liver disease comprises alcoholic hepatitis.

18. Use of a compound or use of a pharmaceutical composition according to claim 15, wherein the liver disease comprises hepatitis.

19. Use of a compound or use of a pharmaceutical composition according to claim 15 or 16 for the treatment or prevention of diarrhoeal celiac disease.

20. A method for producing a compound of formula (Ib), comprising: Step 1B: Providing compound 4b Step 2B: Coupling reaction of compound 4b with compound 5 To obtain compound 6b Step 3B: Make the amino protecting group PG 3 Deprotection to obtain compound 7b Step 4B: Compound 7b is reacted with carboxylic acid 8(R 2 -CO2H) coupling reaction to obtain compound 9b Step 5B: Oxidation of compound 9b to produce the compound of formula (Ib) Among them, L, R 2 、R 3 、R 6 and R 7 has the same meaning as defined in claim 1, and PG 3 It is an amino protecting group.

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