Composition for preventing or treating inflammatory bowel disease containing a novel compound

Abstract

The compound according to the present invention or its pharmacologic acceptable salt selectively and specifically acts as an agonist of GPR39, promotes the proliferation and enterohepatic connection of intestinal tissue cells, promotes cell differentiation, and alleviates inflammation of inflamed intestinal tissue.Therefore, the compound can be used in a composition for alleviating, alleviating, preventing, or treating inflammatory bowel disease.

Description

Detailed Description of the Invention

[0001] Technical Field The present invention relates to a novel compound and a composition for preventing or treating inflammatory bowel disease, which comprises the novel compound as an active ingredient.

[0002] Background technology Approximately 880 G protein-coupled receptors (GPCRs), the most abundant membrane proteins in all mammals, are currently known. Of these, approximately 60% are involved in vision, olfaction, taste, etc., while the remaining approximately 400 GPCRs, including orphan GPCRs, are regulated by various ligands in the body (e.g., proteins, peptide hormones, amino acids, amines, and lipids) and are involved in various biological phenomena. In particular, GPCRs are associated with diseases such as metabolic diseases, cardiovascular diseases, degenerative diseases, and carcinogenesis. Therefore, they are important targets for drug discovery, and more than 50% of drugs developed so far are directly or indirectly related to the activity of GPCRs.

[0003] On the other hand, GPR39 (G protein-coupled receptor 39) is one of the orphan GPCRs, and no endogenous ligand has been found so far. GPR39 belongs to the ghrelin receptor (GHSR, growth hormone secretagogue receptor) family and is known to be distributed in the stomach, intestine, pancreas, liver, kidney, reproductive and adipose tissues (Cell. Mol. Life Sci. 2011, 68: 85-95). GPR39, also known as the zinc-sensing receptor, is mainly expressed in gastrointestinal tissues and is known to promote gastric emptying and enhance gastric juice secretion through studies of GPR39-deficient mice (Gastroenterology, 2006, 131: 1131-1141). GPR39 is also known to promote the expression of factors for tight junctions in a model of ulcerative colitis, one of the inflammatory bowel diseases (IBD) (Phil. Trans. R. Soc. B., 2016, 371: 20150420).

[0004] These results suggest that GPR39 plays an important role in gastrointestinal function in the body, and GPR39 modulators are expected to be new drug candidates for the treatment of inflammatory bowel disease.

[0005] Detailed Description of the Invention technical challenges The present inventors have completed the present invention by confirming that a peptide consisting of a specific amino acid sequence or a variant thereof activates the intestinal function of GPR39 and effectively regulates the activity exhibiting anti-inflammatory effects.

[0006] Therefore, an object of the present invention is to provide a compound represented by the following formula 1 or a pharma- ceutically acceptable salt thereof. [Formula 1] [ka]

[0007] Means for solving the problem In order to achieve the above object, in one aspect of the present invention, a compound represented by the following formula 1: [Formula 1] [ka] (In formula 1, A is -C(-R0)-, -N= or -N(-R1)-, Cy is C 6~14 aryl or 5- to 6-membered heteroaryl; R1 and R3 each independently represent hydrogen, Ra, an amine protecting group, or C substituted with 1 to 3 Ra. 1~6 Alkyl, C 3~10 cycloalkyl, or 5- to 6-membered heterocyclyl, said heterocyclyl having or having 1 to 3 substituents selected from phenylethyl and cyclohexylethyl; R2 is hydrogen, Ra, or a 5- to 6-membered heterocyclyl; R0 is hydrogen, or R0 and R2 are joined together to form a benzene ring together with the two carbon atoms to which they are attached; Ra is independently C 3~10 Cycloalkyl or C 6~14 aryl, wherein the aryl is a C substituted with halogen, -OH, or 5-6 membered heteroaryl; 6~14 Aryl, C 1~6 Alkyl and C 1~6 with or without one or more substituents selected from the group consisting of alkoxy, n is 1 to 10; R4 is hydrogen, C 1~10 Alkyl or C1-C 20 is an alkylcarbonyl; R5 is hydrogen, halogen, CF3 or C 1~6 is alkyl, R6 is hydrogen, C 1~10 alkyl or -S(=O)2OH; R7 and R8 are each independently hydrogen, halogen, nitro, amine or C 1~6 is alkyl, R9 is -OH or -NH2; R 10 is hydrogen, an amine protecting group, or biotin, and the heterocyclyl and heteroaryl each independently contain at least one heteroatom selected from the group consisting of N, S, and O, or a pharma- ceutically acceptable salt thereof.

[0008] In another aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating inflammatory bowel disease, comprising the above compound or a pharma- ceutically acceptable salt thereof as an active ingredient. In another aspect of the present invention, there is provided a health functional food composition for preventing or alleviating inflammatory bowel disease, comprising the above-mentioned compound or a pharma- ceutically acceptable salt thereof as an active ingredient.

[0009] Effect of the Invention The compound according to the present invention or its pharma- ceutical acceptable salt selectively and specifically acts as an agonist of GPR39, promotes the proliferation and tight junction of intestinal tissue cells, promotes cell differentiation, and alleviates inflammation of inflamed intestinal tissue.Therefore, the compound can be used in a composition for alleviating, alleviating, preventing, or treating inflammatory bowel disease. [Brief description of the drawings]

[0010] [Figure 1] FIG. 1 shows the results obtained by confirming the purity of HKFY-1 prepared according to one embodiment of the present invention by HPLC. [Diagram 2] FIG. 1 shows the results obtained by confirming the purity of HKFY-2 prepared according to one embodiment of the present invention by HPLC. [Diagram 3] FIG. 1 shows the results obtained by confirming the purity of HKFY-3 prepared according to one embodiment of the present invention by HPLC. [Figure 4] FIG. 1 shows the results obtained by confirming the purity of HKFY-4 prepared according to one embodiment of the present invention by HPLC. [Diagram 5] FIG. 1 shows the results obtained by confirming the purity of HKFY-5 prepared according to one embodiment of the present invention by HPLC. [Figure 6] FIG. 1 shows the results obtained by confirming the purity of HKFY-6 prepared according to one embodiment of the present invention by HPLC. [Figure 7] FIG. 1 shows the results obtained by confirming the purity of HKFY-7 prepared according to one embodiment of the present invention by HPLC. [Figure 8] FIG. 1 shows the results obtained by confirming the purity of HKFY-8 prepared according to one embodiment of the present invention by HPLC. [Figure 9] FIG. 1 shows the results obtained by confirming the purity of HKFY-9 prepared according to one embodiment of the present invention by HPLC. [Figure 10] FIG. 1 shows the results obtained by confirming the purity of HKFY-10 prepared according to one embodiment of the present invention by HPLC. [Figure 11] FIG. 1 shows the results obtained by confirming the purity of HKFY-11 prepared according to one embodiment of the present invention by HPLC. [Figure 12] FIG. 1 shows the results obtained by confirming the purity of HKFY-12 prepared according to one embodiment of the present invention by HPLC. [Figure 13] FIG. 1 shows the results obtained by confirming the purity of HKFY-13 prepared according to one embodiment of the present invention by HPLC. [Figure 14] FIG. 1 shows the results obtained by confirming the purity of HKFY-14 prepared according to one embodiment of the present invention by HPLC. [Figure 15] FIG. 1 shows the results obtained by confirming the purity of HKFY-15 prepared according to one embodiment of the present invention by HPLC. [Figure 16] FIG. 1 shows the results obtained by confirming the purity of HKFY-16 prepared according to one embodiment of the present invention by HPLC. [Figure 17] FIG. 1 shows the results obtained by confirming the purity of HKFY-17 prepared according to one embodiment of the present invention by HPLC. [Figure 18] FIG. 1 shows the results obtained by confirming the purity of HKFY-18 prepared according to one embodiment of the present invention by HPLC. [Figure 19] FIG. 1 shows the results obtained by confirming the purity of HKFY-19 prepared according to one embodiment of the present invention by HPLC. [Figure 20] FIG. 1 shows the results obtained by confirming the purity of HKFY-20 prepared according to one embodiment of the present invention by HPLC. [Figure 21]FIG. 1 shows the results obtained by confirming the purity of HKFY-21 prepared according to one embodiment of the present invention by HPLC. [Figure 22] FIG. 1 shows the results obtained by confirming the purity of HKFY-22 prepared according to one embodiment of the present invention by HPLC. [Diagram 23] FIG. 1 shows the results obtained by confirming the purity of HKFY-23 prepared according to one embodiment of the present invention by HPLC. [Figure 24] FIG. 1 shows the results obtained by confirming the purity of HKFY-24 prepared according to one embodiment of the present invention by HPLC. [Diagram 25] FIG. 1 shows the results obtained by confirming the purity of HKFY-25 prepared according to one embodiment of the present invention by HPLC. [Figure 26] FIG. 1 shows the results obtained by confirming the purity of HKFY-26 prepared according to one embodiment of the present invention by HPLC. [Figure 27] FIG. 1 shows the results obtained by confirming the purity of HKFY-27 prepared according to one embodiment of the present invention by HPLC. [Figure 28] FIG. 1 shows the results obtained by confirming the purity of HKFY-28 prepared according to one embodiment of the present invention by HPLC. [Figure 29] FIG. 1 shows the results obtained by confirming the purity of HKFY-29 prepared according to one embodiment of the present invention by HPLC. [Diagram 30] FIG. 1 shows the results obtained by confirming the purity of HKFY-30 prepared according to one embodiment of the present invention by HPLC. [Diagram 31] FIG. 1 shows the results obtained by confirming the purity of HKFY-31 prepared according to one embodiment of the present invention by HPLC. [Diagram 32]FIG. 1 shows the results obtained by confirming the purity of HKFY-32 prepared according to one embodiment of the present invention by HPLC. [Diagram 33] FIG. 1 shows the results obtained by confirming the purity of HKFY-33 prepared according to one embodiment of the present invention by HPLC. [Diagram 34] FIG. 1 shows the results obtained by confirming the purity of HKFY-34 prepared according to one embodiment of the present invention by HPLC. [Diagram 35] FIG. 1 shows the results obtained by confirming the purity of HKFY-35 prepared according to one embodiment of the present invention by HPLC. [Diagram 36] FIG. 1 shows the results obtained by confirming the purity of HKFY-36 prepared according to one embodiment of the present invention by HPLC. [Figure 37] FIG. 1 shows the results obtained by confirming the molecular weight of HKFY-1 prepared according to one embodiment of the present invention by Ion-Mass. [Figure 38] FIG. 1 shows the results obtained by confirming the molecular weight of HKFY-2 prepared according to one embodiment of the present invention by Ion-Mass. [Figure 39] FIG. 1 shows the results obtained by confirming the molecular weight of HKFY-3 prepared according to one embodiment of the present invention by Ion-Mass. [Diagram 40] FIG. 1 shows the results obtained by confirming the molecular weight of HKFY-4 prepared according to one embodiment of the present invention by Ion-Mass. [Diagram 41] FIG. 1 shows the results obtained by confirming the molecular weight of HKFY-5 prepared according to one embodiment of the present invention by Ion-Mass. [Diagram 42] FIG. 1 shows the results obtained by confirming the molecular weight of HKFY-6 prepared according to one embodiment of the present invention by Ion-Mass. [Diagram 43]FIG. 1 shows the results obtained by confirming the molecular weight of HKFY-7 prepared according to one embodiment of the present invention by Ion-Mass. [Diagram 44] FIG. 1 shows the results obtained by confirming the molecular weight of HKFY-8 prepared according to one embodiment of the present invention by Ion-Mass. [Diagram 45] FIG. 1 shows the results obtained by confirming the molecular weight of HKFY-9 prepared according to one embodiment of the present invention by Ion-Mass. [Figure 46] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-10 prepared according to one embodiment of the present invention by Ion-Mass. [Figure 47] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-11 prepared according to one embodiment of the present invention by Ion-Mass. [Figure 48] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-12 prepared according to one embodiment of the present invention by Ion-Mass. [Figure 49] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-13 prepared according to one embodiment of the present invention by Ion-Mass. [Figure 50] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-14 prepared according to one embodiment of the present invention by Ion-Mass. [Figure 51] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-15 prepared according to one embodiment of the present invention by Ion-Mass. [Figure 52] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-16 prepared according to one embodiment of the present invention by Ion-Mass. [Diagram 53] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-17 prepared according to one embodiment of the present invention by Ion-Mass. [Figure 54]FIG. 1 shows the results obtained by checking the molecular weight of HKFY-18 prepared according to one embodiment of the present invention by Ion-Mass. [Figure 55] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-19 prepared according to one embodiment of the present invention by Ion-Mass. [Figure 56] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-20 prepared according to one embodiment of the present invention by Ion-Mass. [Figure 57] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-21 prepared according to one embodiment of the present invention by Ion-Mass. [Figure 58] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-22 prepared according to one embodiment of the present invention by Ion-Mass. [Figure 59] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-23 prepared according to one embodiment of the present invention by Ion-Mass. [Figure 60] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-24 prepared according to one embodiment of the present invention by Ion-Mass. [Figure 61] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-25 prepared according to one embodiment of the present invention by Ion-Mass. [Figure 62] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-26 prepared according to one embodiment of the present invention by Ion-Mass. [Figure 63] FIG. 1 shows the results obtained by confirming the molecular weight of HKFY-27 prepared according to one embodiment of the present invention by Ion-Mass. [Figure 64] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-28 prepared according to one embodiment of the present invention by Ion-Mass. [Figure 65]FIG. 1 shows the results obtained by checking the molecular weight of HKFY-29 prepared according to one embodiment of the present invention by Ion-Mass. [Figure 66] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-30 prepared according to one embodiment of the present invention by Ion-Mass. [Figure 67] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-31 prepared according to one embodiment of the present invention by Ion-Mass. [Figure 68] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-32 prepared according to one embodiment of the present invention by Ion-Mass. [Figure 69] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-33 prepared according to one embodiment of the present invention by Ion-Mass. [Figure 70] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-34 prepared according to one embodiment of the present invention by Ion-Mass. [Figure 71] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-35 prepared according to one embodiment of the present invention by Ion-Mass. [Figure 72] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-36 prepared according to one embodiment of the present invention by Ion-Mass. [Figure 73] FIG. 1 shows the results of analyzing the specific binding of HKFY-34 to the GPR39 receptor using a luciferase assay system (top) and a calcium influx assay system (bottom). [Figure 74] The results of analyzing the binding ability of each endogenous ligand to NTSR1, NTSR2, GHSR, MTLR, NMUR1, NMUR2 and TRHR belonging to the GHSR family, as well as to HKFY-34, an HKFY derivative, using a luciferase assay system are shown. [Figure 75]1 is a graph showing the results of measuring cell proliferation in HT-29 cells, an intestinal epithelial cell line, after treatment with different concentrations of HKFY-34. [Figure 76] 1 is a graph showing the results of treating HT-29 cells, an intestinal epithelial cell line, with HKFY-34 (10 μM) and measuring the intracellular calcium concentration by Fluo-8 staining. [Figure 77] 1 is a graph showing the results of quantitative RT-PCR of mRNA expression levels of occludin and ZO-1 in HT-29 cells, an intestinal epithelial cell line, which were treated with different concentrations of HKFY-34. *p indicates significant difference (*p<0.05 and ***p<0.001) between the HKFY-34-treated group and the untreated group (vehicle). [Figure 78] These are graphs and figures showing the results of Western blot analysis of the protein expression levels of occludin and ZO-1 in HT-29 cells, an intestinal epithelial cell line, which were treated with different concentrations of HKFY-34. *p indicates a significant difference (*p<0.05) between the HKFY-34-treated group and the untreated group (vehicle). [Figure 79] Graphs and figures showing the results of Western blot analysis of AMPK phosphorylation in HT-29 cells, an intestinal epithelial cell line, after treatment with different concentrations of HKFY-34. *p indicates significant difference (***p<0.001) between the HKFY-34-treated group and the untreated group (vehicle). [Figure 80] Graphs and figures showing the results of Western blot analysis of AMPK phosphorylation in HT-29 cells, an intestinal epithelial cell line, by treatment with HKFY-34 after pretreatment with an AMPK inhibitor (STO-609, 1 μM). *p indicates significant difference between the group treated with HKFY-34 and the group treated with STO-609 alone (***p<0.001), and ###p indicates significant difference between the group treated with a combination of HKFY-34 and STO-609 and the group treated with STO-609 alone (###p<0.001). [Figure 81]This is a graph showing the results of quantitative RT-PCR to confirm the expression levels of pro-inflammatory cytokines (interleukin (IL)-1β, IL-6, IL-8, and TNF-α) associated with ulcerative colitis by treatment with different concentrations of HKFY-34 after inducing inflammation in HT-29 cells, an intestinal epithelial cell line, with 1 μg / mL LPS (lipopolysaccharide). *p indicates significant difference from the untreated group (vehicle) (*p<0.05 and ***p<0.001), and #p indicates significant difference from the group treated with LPS alone (#p<0.05 and ###p<0.001). [Figure 82] This is a graph showing the results of confirming the extracellular secretion of ulcerative colitis-related proinflammatory cytokines (IL-1β, IL-6, IL-8, and TNF-α) by treatment with different concentrations of HKFY-34 after inducing inflammation in HT-29 cells, an intestinal epithelial cell line, with 1 μg / mL LPS. *p indicates significant difference from the untreated group (vehicle) (***p<0.001), #p indicates significant difference from the group treated with LPS alone (#p<0.05, ##p<0.01, and ###p<0.001). [Figure 83] This graph shows the results of measuring the changes in body weight during (left) or after (right) intraperitoneal administration of HKFY-34 at doses of 0.1 mg / kg, 1 mg / kg, and 10 mg / kg for 5 days to a mouse model in which ulcerative colitis was induced by DSS intake (left: daily cumulative body weight loss (%), right: final body weight loss (%)). *p indicates significant difference from the control group (vehicle) (***p<0.001), #p indicates significant difference from the negative control group (treated with DSS alone) (#p<0.05 and ##p<0.01). [Figure 84] These are graphs and figures showing the results of measuring the length of the colon in model mice in which ulcerative colitis was induced by DSS ingestion, after intraperitoneally administering HKFY-34 at doses of 0.1 mg / kg, 1 mg / kg, and 10 mg / kg for 5 days to the model mice in which ulcerative colitis was induced by DSS ingestion. *p indicates significant difference from the control group (vehicle) (***p<0.001), #p indicates significant difference from the negative control group (treated with DSS alone) (###p<0.001). [Figure 85] This is a graph showing the degree of stool consistency (diarrhea) as a score when HKFY-34 was administered intraperitoneally at doses of 0.1 mg / kg, 1 mg / kg, and 10 mg / kg to model mice in which ulcerative colitis was induced by DSS intake. *p indicates significant difference from the control group (vehicle) (***p<0.001), #p indicates significant difference from the negative control group (treated with DSS alone) (#p<0.05). [Figure 86] This graph shows the degree of blood in the stools of mice modeled after ulcerative colitis was induced by DSS ingestion and intraperitoneally administered HKFY-34 at doses of 0.1 mg / kg, 1 mg / kg, and 10 mg / kg. *p indicates significant difference from the control group (vehicle) (***p<0.001), #p indicates significant difference from the negative control group (treated with DSS alone) (#p<0.05). [Figure 87] Graph showing the results of quantitative RT-PCR of mRNA expression levels of IL-1β, IL-6, IL-8 and TNF-α in colonic tissues of DSS-induced ulcerative colitis model mice after intraperitoneal administration of HKFY-34 at doses of 0.1 mg / kg, 1 mg / kg and 10 mg / kg for 5 days to DSS-induced ulcerative colitis model mice. *p indicates significant difference from the control group (vehicle) (*p<0.05, **p<0.01 and ***p<0.001), #p indicates significant difference from the negative control group (treated with DSS alone) (#p<0.05, ##p<0.01 and ###p<0.001). [Figure 88] 1 is a graph showing the results of ELISA for the blood IL-1β and TNF-α concentrations in model mice in which ulcerative colitis was induced by DSS intake, after intraperitoneal administration of HKFY-34 at doses of 0.1 mg / kg, 1 mg / kg, and 10 mg / kg for 5 days to model mice in which ulcerative colitis was induced by DSS intake. *p indicates significant difference from the control group (vehicle) (*p<0.05, **p<0.01, and ***p<0.001), and #p indicates significant difference from the negative control group (treated with DSS alone) (##p<0.01, and ###p<0.001). [Figure 89]The left graph shows the results of H&E staining of colonic tissues from model mice in which ulcerative colitis was induced by DSS intake after intraperitoneal administration of HKFY-34 at doses of 0.1 mg / kg, 1 mg / kg, and 10 mg / kg for 5 days, and the right graph shows the results of analysis and quantification of the degree of inflammatory damage (macrophage infiltration rate, mucus-secreting cell loss rate, villus structure collapse rate, and secretory gland loss rate) compared with the control group. #p indicates significant difference (##p<0.01 and ###p<0.001) from the negative control group (treated with DSS alone). [Figure 90] Graph showing the results of quantitative RT-PCR of mRNA expression levels of occludin and ZO-1 in colon tissues of DSS-induced colitis model mice after intraperitoneal administration of HKFY-34 at doses of 0.1 mg / kg, 1 mg / kg, and 10 mg / kg for 5 days to DSS-induced ulcerative colitis model mice. *p indicates significant difference from the control group (vehicle) (*p<0.05, **p<0.01, and ***p<0.001), and #p indicates significant difference from the negative control group (treated with DSS alone) (##p<0.01, and ###p<0.001). [Figure 91] This graph shows the results of measuring the weight change during (left) and after (right) intraperitoneal administration of HKFY-34 at a dose of 10 mg / kg to wild-type and GPR39 gene-deficient (Gpr39- / -) model mice in which ulcerative colitis was induced by DSS intake (left: daily cumulative weight loss (%), right: final weight loss (%)). *p indicates significant difference from the control group (vehicle) (**p<0.01 and ***p<0.001), #p indicates significant difference from the negative control group (treated with DSS alone) (##p<0.01). [Figure 92]Graphs and figures showing the results obtained by measuring the length of the colon in wild-type and GPR39 gene-deficient (Gpr39- / -) model mice in which ulcerative colitis was induced by DSS intake, after intraperitoneal administration of HKFY-34 at a dose of 10 mg / kg for 5 days. *p indicates significant difference from the control group (vehicle) (***p<0.001), #p indicates significant difference from the negative control group (treated with DSS alone) (##p<0.01). [Figure 93] This graph shows the degree of stool consistency (diarrhea) as a score when HKFY-34 was administered intraperitoneally at a dose of 10 mg / kg to wild-type and GPR39 gene-deficient (Gpr39- / -) model mice in which ulcerative colitis was induced by DSS intake. #p indicates a significant difference (#p<0.05) from the negative control group (treated with DSS alone). [Figure 94] 1 is a graph showing the degree of blood in the stool observed in wild-type and GPR39 gene-deficient (Gpr39- / -) model mice in which ulcerative colitis was induced by DSS intake and HKFY-34 was administered intraperitoneally at a dose of 10 mg / kg. [Figure 95] Wild-type and GPR39 gene (Gpr39- / -) knockout model mice in which ulcerative colitis was induced by DSS intake were intraperitoneally administered HKFY-34 at a dose of 10 mg / kg for 5 days, and the results of H&E staining of colon tissue from the model mice in which ulcerative colitis was induced by DSS (left) and the results of analysis and quantification of the degree of inflammatory damage (macrophage infiltration rate, mucus-secreting cell loss rate, villus structure collapse rate, and secretory gland loss rate) compared to the control group (right) are shown in the graphs and figures. [Figure 96] FIG. 1 shows the results obtained by checking the 1H NMR of HKFY-1 prepared according to one embodiment of the present invention. [Figure 97] FIG. 1 shows the results obtained by checking the 1H NMR of HKFY-2 prepared according to one embodiment of the present invention. [Figure 98]FIG. 1 shows the results obtained by checking the 1H NMR of HKFY-34 prepared according to one embodiment of the present invention. [Figure 99] FIG. 1 shows the results obtained by confirming the purity of HKFY-37 prepared according to one embodiment of the present invention by HPLC. [Figure 100] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-37 prepared according to one embodiment of the present invention by Ion-Mass. [Figure 101] FIG. 1 shows the results obtained by confirming the purity of HKFY-38 prepared according to one embodiment of the present invention by HPLC. [Figure 102] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-38 prepared according to one embodiment of the present invention by Ion-Mass. [Figure 103] FIG. 1 shows the results obtained by confirming the purity of HKFY-39 prepared according to one embodiment of the present invention by HPLC. [Figure 104] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-39 prepared according to one embodiment of the present invention by Ion-Mass. [Figure 105] FIG. 1 shows the results obtained by confirming the purity of HKFY-40 prepared according to one embodiment of the present invention by HPLC. [Figure 106] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-40 prepared according to one embodiment of the present invention by Ion-Mass. [Figure 107] FIG. 1 shows the results obtained by confirming the purity of HKFY-41 prepared according to one embodiment of the present invention by HPLC. [Figure 108] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-41 prepared according to one embodiment of the present invention by Ion-Mass. [Fig. 109]FIG. 1 shows the results obtained by confirming the purity of HKFY-42 prepared according to one embodiment of the present invention by HPLC. [Figure 110] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-42 prepared according to one embodiment of the present invention by Ion-Mass. [Figure 111] FIG. 1 shows the results obtained by confirming the purity of HKFY-43 prepared according to one embodiment of the present invention by HPLC. [Figure 112] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-43 prepared according to one embodiment of the present invention by Ion-Mass. [Figure 113] FIG. 1 shows the results obtained by confirming the purity of HKFY-44 prepared according to one embodiment of the present invention by HPLC. [Fig. 114] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-44 prepared according to one embodiment of the present invention by Ion-Mass. [Figure 115] FIG. 1 shows the results obtained by confirming the purity of HKFY-45 prepared according to one embodiment of the present invention by HPLC. [Fig. 116] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-45 prepared according to one embodiment of the present invention by Ion-Mass. [Figure 117] FIG. 1 shows the results obtained by confirming the purity of HKFY-46 prepared according to one embodiment of the present invention by HPLC. [Fig. 118] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-46 prepared according to one embodiment of the present invention by Ion-Mass. [Figure 119] FIG. 1 shows the results obtained by confirming the purity of HKFY-47 prepared according to one embodiment of the present invention by HPLC. [Figure 120]FIG. 1 shows the results obtained by checking the molecular weight of HKFY-47 prepared according to one embodiment of the present invention by Ion-Mass. [Figure 121] FIG. 1 shows the results obtained by confirming the purity of HKFY-48 prepared according to one embodiment of the present invention by HPLC. [Figure 122] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-48 prepared according to one embodiment of the present invention by Ion-Mass. [Figure 123] FIG. 1 shows the results obtained by confirming the purity of HKFY-49 prepared according to one embodiment of the present invention by HPLC. [Figure 124] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-49 prepared according to one embodiment of the present invention by Ion-Mass. [Fig. 125] FIG. 1 shows the results obtained by confirming the purity of HKFY-50 prepared according to one embodiment of the present invention by HPLC. [Fig. 126] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-50 prepared according to one embodiment of the present invention by Ion-Mass. [Figure 127] FIG. 1 shows the results obtained by confirming the purity of HKFY-51 prepared according to one embodiment of the present invention by HPLC. [Figure 128] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-51 prepared according to one embodiment of the present invention by Ion-Mass. [Figure 129] FIG. 1 shows the results obtained by confirming the purity of HKFY-52 prepared according to one embodiment of the present invention by HPLC. [Fig. 130] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-52 prepared according to one embodiment of the present invention by Ion-Mass. [Fig. 131]FIG. 1 shows the results obtained by confirming the purity of HKFY-53 prepared according to one embodiment of the present invention by HPLC. [Fig. 132] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-53 prepared according to one embodiment of the present invention by Ion-Mass. [Fig. 133] FIG. 1 shows the results obtained by confirming the purity of HKFY-54 prepared according to one embodiment of the present invention by HPLC. [Fig. 134] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-54 prepared according to one embodiment of the present invention by Ion-Mass. [Fig. 135] FIG. 1 shows the results obtained by confirming the purity of HKFY-55 prepared according to one embodiment of the present invention by HPLC. [Fig. 136] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-55 prepared according to one embodiment of the present invention by Ion-Mass. [Fig. 137] FIG. 1 shows the results obtained by confirming the purity of HKFY-56 prepared according to one embodiment of the present invention by HPLC. [Figure 138] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-56 prepared according to one embodiment of the present invention by Ion-Mass. [Figure 139] FIG. 1 shows the results obtained by confirming the purity of HKFY-57 prepared according to one embodiment of the present invention by HPLC. [Fig. 140] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-57 prepared according to one embodiment of the present invention by Ion-Mass. [Fig. 141] FIG. 1 shows the results obtained by confirming the purity of HKFY-58 prepared according to one embodiment of the present invention by HPLC. [Fig. 142]FIG. 1 shows the results obtained by checking the molecular weight of HKFY-58 prepared according to one embodiment of the present invention by Ion-Mass. [Fig. 143] FIG. 1 shows the results obtained by confirming the purity of HKFY-59 prepared according to one embodiment of the present invention by HPLC. [Fig. 144] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-59 prepared according to one embodiment of the present invention by Ion-Mass. [Fig. 145] FIG. 1 shows the results obtained by confirming the purity of HKFY-60 prepared according to one embodiment of the present invention by HPLC. [Fig. 146] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-60 prepared according to one embodiment of the present invention by Ion-Mass. [Fig. 147] FIG. 1 shows the results obtained by confirming the purity of HKFY-61 prepared according to one embodiment of the present invention by HPLC. [Fig. 148] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-61 prepared according to one embodiment of the present invention by Ion-Mass. [Figure 149] FIG. 1 shows the results obtained by confirming the purity of HKFY-62 prepared according to one embodiment of the present invention by HPLC. [Fig. 150] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-62 prepared according to one embodiment of the present invention by Ion-Mass. [Fig. 151] FIG. 1 shows the results obtained by confirming the purity of HKFY-63 prepared according to one embodiment of the present invention by HPLC. [Fig. 152] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-63 prepared according to one embodiment of the present invention by Ion-Mass. [Fig. 153]FIG. 1 shows the results obtained by confirming the purity of HKFY-64 prepared according to one embodiment of the present invention by HPLC. [Fig. 154] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-64 prepared according to one embodiment of the present invention by Ion-Mass. [Fig. 155] FIG. 1 shows the results obtained by confirming the purity of HKFY-65 prepared according to one embodiment of the present invention by HPLC. [Fig. 156] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-65 prepared according to one embodiment of the present invention by Ion-Mass. [Fig. 157] FIG. 1 shows the results obtained by confirming the purity of HKFY-66 prepared according to one embodiment of the present invention by HPLC. [Fig. 158] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-66 prepared according to one embodiment of the present invention by Ion-Mass. [Fig. 159] FIG. 1 shows the results obtained by confirming the purity of HKFY-67 prepared according to one embodiment of the present invention by HPLC. [Fig. 160] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-67 prepared according to one embodiment of the present invention by Ion-Mass. [Fig. 161] FIG. 1 shows the results obtained by confirming the purity of HKFY-68 prepared according to one embodiment of the present invention by HPLC. [Fig. 162] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-68 prepared according to one embodiment of the present invention by Ion-Mass. [Fig. 163] FIG. 1 shows the results obtained by confirming the purity of HKFY-69 prepared according to one embodiment of the present invention by HPLC. [Fig. 164]FIG. 1 shows the results obtained by checking the molecular weight of HKFY-69 prepared according to one embodiment of the present invention by Ion-Mass. [Fig. 165] FIG. 1 shows the results obtained by confirming the purity of HKFY-70 prepared according to one embodiment of the present invention by HPLC. [Fig. 166] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-70 prepared according to one embodiment of the present invention by Ion-Mass. [Fig. 167] FIG. 1 shows the results obtained by confirming the purity of HKFY-71 prepared according to one embodiment of the present invention by HPLC. [Fig. 168] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-71 prepared according to one embodiment of the present invention by Ion-Mass. [Fig. 169] FIG. 1 shows the results obtained by confirming the purity of HKFY-72 prepared according to one embodiment of the present invention by HPLC. [Fig. 170] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-72 prepared according to one embodiment of the present invention by Ion-Mass. [Fig. 171] FIG. 1 shows the results obtained by confirming the purity of HKFY-73 prepared according to one embodiment of the present invention by HPLC. [Fig. 172] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-73 prepared according to one embodiment of the present invention by Ion-Mass. [Fig. 173] FIG. 1 shows the results obtained by confirming the purity of HKFY-74 prepared according to one embodiment of the present invention by HPLC. [Fig. 174] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-74 prepared according to one embodiment of the present invention by Ion-Mass. [Fig. 175]FIG. 1 shows the results obtained by confirming the purity of HKFY-75 prepared according to one embodiment of the present invention by HPLC. [Fig. 176] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-75 prepared according to one embodiment of the present invention by Ion-Mass. [Fig. 177] FIG. 1 shows the results obtained by confirming the purity of HKFY-76 prepared according to one embodiment of the present invention by HPLC. [Fig. 178] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-76 prepared according to one embodiment of the present invention by Ion-Mass. [Fig. 179] FIG. 1 shows the results obtained by confirming the purity of HKFY-77 prepared according to one embodiment of the present invention by HPLC. [Fig. 180] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-77 prepared according to one embodiment of the present invention by Ion-Mass. [Fig. 181] FIG. 1 shows the results obtained by confirming the purity of HKFY-78 prepared according to one embodiment of the present invention by HPLC. [Fig. 182] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-78 prepared according to one embodiment of the present invention by Ion-Mass. [Fig. 183] FIG. 1 shows the results obtained by confirming the purity of HKFY-79 prepared according to one embodiment of the present invention by HPLC. [Fig. 184] FIG. 1 shows the results obtained by checking the molecular weight of HKFY-79 prepared according to one embodiment of the present invention by Ion-Mass.

[0011] Best Mode for Carrying Out the Invention The present invention will now be described in more detail.

[0012] In one aspect of the present invention, there is provided a compound represented by the following formula 1 or a pharma- ceutically acceptable salt thereof: [Formula 1] [ka] (In formula 1, A is -C(-R0)-, -N= or -N(-R1)-, Cy is C 6~14 aryl or 5- to 6-membered heteroaryl; R1 and R3 each independently represent hydrogen, Ra, an amine protecting group, or C substituted with 1 to 3 Ra. 1~6 Alkyl, C 3~10 cycloalkyl, or 5- to 6-membered heterocyclyl, said heterocyclyl having or having 1 to 3 substituents selected from phenylethyl and cyclohexylethyl; R2 is hydrogen, Ra, or 5- to 6-membered heterocyclyl; R0 is hydrogen, or R0 and R2 are linked together to form a benzene ring together with the two carbon atoms to which they are attached; Ra is independently C 3~10 Cycloalkyl or C 6~14 aryl, wherein the aryl is a C substituted with halogen, -OH, or 5-6 membered heteroaryl; 6~14 Aryl, C 1~6 Alkyl and C 1~6 with or without one or more substituents selected from the group consisting of alkoxy, n is 1 to 10; R4 is hydrogen, C 1~10 Alkyl or C1-C 20 is an alkylcarbonyl; R5 is hydrogen, halogen, CF3 or C 1~6 is alkyl, R6 is hydrogen, C 1~10 alkyl or -S(=O)2OH; R7 and R8 are each independently hydrogen, halogen, nitro, amine or C 1~6 is alkyl, R9 is -OH or -NH2; R 10 is hydrogen, an amine protecting group, or biotin; The heterocyclyl and heteroaryl each independently contain at least one heteroatom selected from the group consisting of N, S and O.

[0013] In one embodiment of the invention, the compound may be a peptide, which may be a derivative of a peptide having a sequence of four amino acids, which may be His-Lys-Phe-Tyr (SEQ ID NO:1).

[0014] According to conventional usage in the art, in the formulas herein: [ka] is used to indicate the bond that is the point of attachment of a moiety or substituent to a core or backbone structure.

[0015] As used herein, the term "alkyl" refers to a hydrocarbon having primary, secondary, tertiary, or cyclic carbon atoms. For example, an alkyl group can be any group having 1 to 20 carbon atoms (i.e., C1 to C4). 20 alkyl), 1 to 10 carbon atoms (i.e., C1 to C 10Examples of suitable alkyl groups include (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)C H2CH3), 2-Methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2C H(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4- Examples include, but are not limited to, methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3, and octyl (-(CH2)7CH3).

[0016] As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic ring containing only carbon atoms in the ring. Cycloalkyls can have 3-7 carbon atoms as monocyclic rings, 7-12 carbon atoms as bicyclic cycloalkyls, and up to about 20 carbon atoms as polycyclic rings. Monocyclic cycloalkyls have 3-6 ring atoms, more typically 5 or 6 ring atoms. Bicyclic cycloalkyls have 7-12 ring atoms arranged in a bicyclo[4,5], [5,5], [5,6], or [6,6] system, or 9-10 ring atoms arranged in a bicyclo[5,6] or [6,6] system or spiro-fused ring. Non-limiting examples of monocyclic cycloalkyls can include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, each of which may be substituted or unsubstituted.

[0017] As used herein, the term "heterocyclyl" includes, but is not limited to, the heterocyclic radicals described in the literature [Paquette, Leo A.; Principles of Modern Heterocyclic Chemistry (WA Benjamin, New York, 1968), specifically Chapters 1, 3, 4, 6, 7, and 9; The Chemistry of Heterocyclic Compounds, A Series of Monographs (John Wiley & Sons, New York, 1950-present), specifically Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566]. The term "heterocyclyl" refers to an aromatic or non-aromatic ring radical formed as a saturated or unsaturated monocyclic or polycyclic ring and having one or more heteroatoms. For example, "5-6 membered heterocyclyl" may refer to a heterocyclyl having a total of 5-6 heteroatoms and / or carbon atoms. As used herein, when "heterocyclyl" is described as a substituent, it may be used as a term that encompasses "heterocycloalkyl" and "heteroaryl". As used herein, "heterocycloalkyl" refers to a saturated ring radical formed as a monocyclic or polycyclic ring and having one or more heteroatoms, and "heteroaryl" refers to an aromatic ring radical formed as a monocyclic or polycyclic ring and having one or more heteroatoms, and the "heteroatoms" may be selected from N, O, and S. Non-limiting examples of heteroaryl rings include all those listed in the definition of "heterocyclyl," including pyridinyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, purinyl, furanyl, thienyl, benzofuranyl, benzothiophenyl, carbazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolyl, isoquinolyl, pyridazyl, pyrimidyl, pyrazyl (which may be substituted or unsubstituted), and the like.

[0018] As used herein, the term "heteroaryl" refers to an aromatic heterocyclyl having one or more heteroatoms in the ring. Non-limiting examples of suitable heteroatoms that may be included in the aromatic ring include oxygen, sulfur and nitrogen. Non-limiting examples of heteroaryl rings include all those listed in the definition of "heterocyclyl", including pyridinyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, purinyl, furanyl, thienyl, benzofuranyl, benzothiophenyl, carbazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolyl, isoquinolyl, pyridazyl, pyrimidyl, pyrazyl (which may be substituted or unsubstituted), etc.

[0019] As used herein, the term "alkoxy" refers to a group having the formula -O-alkyl, where an alkyl group, as defined above, is attached to the parent compound through an oxygen atom. The alkyl portion of the alkoxy group can have 1 to 20 carbon atoms (i.e., C1 to C6). 20 alkoxy), 1 to 12 carbon atoms (i.e., C1 to C 12 alkoxy), or 1 to 6 carbon atoms (i.e., C1-C6 alkoxy). Examples of suitable alkoxy groups include, but are not limited to, methoxy (-O-CH3 or -OMe), ethoxy (-OCH2CH3 or -OEt), t-butoxy (-OC(CH3)3 or -O-tBu), and the like.

[0020] As used herein, the term "alkylcarbonyl" refers to a group having the formula -C(=O)-alkyl, where the alkyl group, as defined above, is attached to the parent compound through a carbon atom. The alkyl portion of the alkylcarbonyl group can have 1 to 20 carbon atoms (i.e., C1 to C2). 20 alkylcarbonyl) or 5 to 17 carbon atoms (i.e., C5 to C 17 Examples of suitable alkylcarbonyl groups include caprylic acid (-C(=O)(CH2)6CH3), capric acid (-C(=O)(CH2)8CH3), lauric acid (-C(=O)(CH2)10 CH3), myristic acid (-C(=O)(CH2) 12 CH3), palmitic acid (-C(=O)(CH2) 14 CH3), but are not limited to these.

[0021] The term "substituted" with respect to alkyl, aryl, heteroaryl, heterocyclyl, carbocyclyl (e.g., cycloalkyl), etc., such as "substituted alkyl," "substituted aryl," "substituted heteroaryl," "substituted heterocyclyl," and "substituted carbocyclyl (e.g., cycloalkyl)," refers to an alkyl, aryl, heteroaryl, heterocyclyl, carbocyclyl (e.g., cycloalkyl) in which one or more hydrogen atoms are each independently replaced with a non-hydrogen substituent. Typical substituents include -X, -R, -O-, =O, -OR, -SR, -S-, -NR2, -N+R3, =NR, -C(X)3, -CN, -OCN, -SCN, -N=C=O, -NCS, -NO, -NO2, =N-OH, =N2, -N3, -NHC(=O)R, -C(=O)R, -C(=O)NRR-S(=O)2O-, -S(=O)2OH, -S(=O)2R, -OS(=O)2OR, -S(=O)2NR, -S(=O)R, -OP(=O)(OR)2, -C(=O)R, alkylene- Examples include, but are not limited to, C(=O)R, -C(S)R, -C(=O)OR, alkylene-C(=O)OR, -C(=O)O-, alkylene-C(=O)O-, -C(=S)OR, -C(=O)SR, -C(=S)SR, -C(=O)NRR, alkylene-C(=O)NRR, -C(=S)NRR, -C(-NR)NRR, where each X is independently a halogen: F, Cl, Br, or I, and R is independently H, alkyl, aryl, arylalkyl, or heterocycle. Alkylene, alkenylene, and alkynylene groups may also be substituted.

[0022] Furthermore, the present invention includes pharma- ceutically acceptable salts and addition salts of the compounds of the present invention, such as, but not limited to, hydrochloride, hydrobromide or trifluoroacetate addition salts, as well as sodium, potassium and magnesium salts.

[0023] It will be understood by those of skill in the art that when an "alkyl", "aryl", "heterocyclyl", etc. moiety is substituted with one or more substituents, it may be optionally referred to as an "alkylene", "arylene", "heterocyclylene", etc. moiety (i.e., meaning that one or more hydrogen atoms of the parent "alkyl", "aryl", "heterocyclyl" moiety have been replaced with a substituent as described above). When an "alkyl", "aryl", "heterocyclyl", etc. moiety is referred to as "substituted" herein or shown as substituted in the drawings (which may be optionally substituted, e.g., where the number of substituents is from 0 to a positive number), the "alkyl", "aryl", "heterocyclyl", etc. terms should be understood to be interchangeable with "alkylene", "arylene", "heterocyclylene", etc.

[0024] It will be understood by those skilled in the art that the substituents and other moieties of the compounds of formula 1 should be selected to provide a compound that is sufficiently stable to provide a pharma- ceutical useful compound that can be formulated into an acceptably stable pharmaceutical composition. Compounds of formula 1 having such stability are considered to be within the scope of the present invention.

[0025] As used herein, the term "optionally substituted" refers to certain moieties of a compound of Formula 1 that bear one, two or more substituents.

[0026] In the present invention, the compound represented by formula 1 may be an L- or D-optical isomer.

[0027] In the compounds of formula 1 according to the present invention, A may be -C(-R0)- or -N(-R1)-, where R1 is hydrogen, [ka] or [ka] In addition, R0 may be hydrogen, R2 may be hydrogen, [ka] Or [ka] or R0 and R2 may be linked together to form a benzene ring with the two carbon atoms to which they are attached, but are not limited thereto. [ka] and [ka] and preferably selected from the group consisting of [ka] may be, but is not limited to.

[0028] Further, n may be 3 or 4, R4 may be heptylcarbonyl, R5 may be methyl or CF3, R6 may be hydrogen or S(=O)2OH, and R7 and R8 may each independently be hydrogen or an amine. Further, R7 and R8 may each independently be hydrogen, R9 may be -OH, and R 10 may be, but is not limited to, hydrogen, p-toluenesulfonyl (p-Ts), t-butoxycarbonyl (t-Boc) or biotin. In addition, R5, R7 and R8 are not particularly limited in the positions at which they are substituted on the benzene ring. For example, R5 may be substituted at the ortho (o-), meta (m-) or para (p-) position.

[0029] It may be any one selected from the group consisting of: 1) His(trt)-Lys(caprylic acid)-Phe-Tyr, 2) Biotin-His(trt)-Lys(caprylic acid)-Phe-Tyr; 3) His(benzyl)-Lys(caprylic acid)-Phe-Tyr, 4) d-His(trt)-Lys(caprylic acid)-Phe-Tyr, 5) His(4-methyltrityl)-Lys(caprylic acid)-Phe-Tyr; 6) His(DAMP-3)-Lys(caprylic acid)-Phe-Tyr; 7) His(DAMP-5)-Lys(caprylic acid)-Phe-Tyr, 8) His(DAMP-2)-Lys(caprylic acid)-Phe-Tyr, 9) His(2-phenylethyl)-Lys(caprylic acid)-Phe-Tyr; 10) His(2-naphthalene-1-ethyl)-Lys(caprylic acid)-Phe-Tyr, 11) His(2-cyclohexylethyl)-Lys(caprylate)-Phe-Tyr; 12) His(trt)-Lys(caprylic acid)-d-Phe-Tyr, 13) His(trt)-Lys(caprylic acid)-d-Phe(4-Cl)-Tyr; 14) d-His(trt)-Lys(caprylic acid)-d-Phe(4-Cl)-d-Tyr; 15) His(trt)-Lys(caprylic acid)-d-Phe(4-Cl)-d-Tyr; 16) His(trt)-d-Lys(caprylic acid)-d-Phe(4-Cl)-Tyr; 17) His(3,3-diphenylpropyl)-Lys(caprylic acid)-Phe-Tyr; 18) His(Fm)-Lys(caprylic acid)-Phe-Tyr; 19) His(phenylpropyl)-Lys(caprylic acid)-Phe-Tyr; 20) His(4-methoxybenzhydryl)-Lys(caprylic acid)-Phe-Tyr, 21) His(4-chlorobenzhydryl)-Lys(caprylic acid)-Phe-Tyr; 22) His(4-methylbenzhydryl)-Lys(caprylic acid)-Phe-Tyr; 23) His(adamantanemethyl)-Lys(caprylate)-Phe-Tyr, 24) His(trt)-Lys(capric acid)-Phe-Tyr, 25) His(trt)-Lys(lauric acid)-Phe-Tyr, 26) His(trt)-Lys(myristic acid)-Phe-Tyr, 27) His(trt)-Lys(palmitic acid)-Phe-Tyr, 28) His(trt)-Lys(caprylic acid)-d-Phe(F)-Tyr; 29) His(trt)-Lys(caprylic acid)-d-Phe(Br)-Tyr; 30) His(trt)-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr; 31) d-His(trt)-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr; 32) His(1,3-difluorobenzhydryl)-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr; 33) His(benzhydryl)-Lys(caprylic acid)-Phe-Tyr; 34) His(benzhydryl)-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr; 35) His(benzhydryl)-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr(SO3H), 36) His(benzhydryl)-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr(2,6-dimethyl), 57) His(2-phenyl)-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr; 58) His(1-phenyl)-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr; 59) His(1,2-diphenyl)-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr; 60) His(2-(4-tert-butyl)phenyl)-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr; 61) His(1-(4-tert-butyl)phenyl)-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr; 62) d-His(benzhydryl)-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr; 63) His(thiophene)-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr; 64) His(4-methoxybenzhydryl)-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr, and 65)His(4-hydroxybenzhydryl)-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr 66)His(benzhydryl)-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr-NH2 67)His(benzhydryl)-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr(3-chloro) 68)His(benzhydryl)-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr(3-nitro) 69) His(benzhydryl)-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr(3,5-nitro) 70)His(benzhydryl)-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr(3-amino) 71)His(benzhydryl)-Orn(caprylic acid)-d-Phe(4-methyl)-Tyr 72) Biotin-His(benzhydryl)-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr 73) His(trt)-Lys(caprylic acid)-d-3Pal-Tyr 74) His(trt)-Lys(caprylic acid)-d-2Nal-Tyr 75) His(tosyl)-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr 76)His(trt)-Lys(caprylic acid)-d-Phe(4-CF3)-Tyr 77) His(tbm)-Lys(caprylic acid)-d-Phe(4-CF3)-Tyr 78) Boc-Trp-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr and 79)His(benzhydryl)Lys(caprylic acid).

[0030] In the present invention, the compound is (X1)-(X2)-[His(trt)-Lys(caprylic acid)-Phe-Tyr] (wherein X1 and X2 may each independently be any one amino acid selected from 20 amino acids or derivatives thereof), and specifically, 37) Gly-Ser-His(trt)-Lys(caprylic acid)-Phe-Tyr (SEQ ID NO: 2).

[0031] In the compound of the present invention represented by formula 1, 1 to 10 amino acids or derivatives thereof may be further bound to the C-terminus of the compound. Specifically, the compound is [His(trt)-Lys(caprylic acid)-Phe-Tyr]-(X3) a -(X4) b -(X5) c -(X6) d -(X7) e -(X8) f -(X9) g(wherein X3 to X9 may each independently be any one amino acid selected from 20 amino acids or derivatives thereof, a to g may be 0 or 1, and at least one of them may be 1). More specifically, the compound may be 38) His(trt)-Lys(caprylic acid)-Phe-Tyr-Ser-Asp-Gln-Gln-Ala-Arg-Phe (SEQ ID NO: 3), 39) His(trt)-Lys(caprylic acid)-Phe-Tyr-Ser-Gln-Asn-Gly-Ala-Arg-Phe (SEQ ID NO: 4), 40) His(trt)-Lys(caprylic acid)-Phe-Tyr-Ser-His-Gln-Gln-Ala-Arg-Phe (SEQ ID NO: 5), 41) His(trt)-Lys(caprylic acid) 41) His(trt)-Lys(caprylic acid)-Phe-Tyr-Gln-Asn-Gly-Ala-Arg-Phe (SEQ ID NO: 6), 42) His(trt)-Lys(caprylic acid)-Phe-Tyr-His-Gln-Gln-Ala-Arg-Phe (SEQ ID NO: 7), 43) His(trt)-Lys(caprylic acid)-Phe-Tyr-Gln-Asn-Gln-Ala-Arg-Phe (SEQ ID NO: 8), and 44) ​​His(trt)-Lys(caprylic acid)-Phe-Tyr-Trp (SEQ ID NO: 9).

[0032] In another aspect of the present invention, there is provided a compound or a pharma- ceutically acceptable salt thereof, the compound being [His(trt)-Lys(caprylic acid)]-(X 10 ) h -(X 11 ) i (In the formula, X 10 and X 11may each independently be any one amino acid selected from 20 amino acids or derivatives thereof, and h and i may be 0 or 1, and at least one of them may be 1). Specifically, the compound may be any one selected from the group consisting of 45) Biotin-His(trt)-Lys(caprylic acid)-Bip-Tyr (SEQ ID NO: 10), 46) His(trt)-Lys(caprylic acid)-Phe-Trp (SEQ ID NO: 11), 47) His(trt)-Lys(caprylic acid)-Tyr-Phe (SEQ ID NO: 12), 48) His(trt)-Lys(caprylic acid)-Tyr-Tyr (SEQ ID NO: 13), 49) His(trt)-Lys(caprylic acid)-Phe, 50) His(trt)-Lys(caprylic acid)-Phe-Ser (SEQ ID NO: 14), and 51) His(trt)-Lys(caprylic acid)-Leu-Tyr (SEQ ID NO: 15).

[0033] In another aspect of the present invention, there is provided any one selected from the group consisting of 52) His(trt)-Phe-Tyr-Asp-Gln-Gln-Ala-Arg-Phe (SEQ ID NO: 16), 53) His(trt)-Gly-Ser-Lys(caprylic acid)-Phe-Tyr (SEQ ID NO: 17), 54) Lys(caprylic acid)-Phe-Tyr, 55) Lys(caprylic acid)-His(trt)-Phe-Tyr (SEQ ID NO: 18), 56) His(trt)-Lys(caproic acid)-Phe-Tyr-Asp-Gln-Gln-Ala-Arg-Phe (SEQ ID NO: 19), and 79) His(benzhydryl)Lys(caprylic acid).

[0034] In the present invention, the compounds may be present as a mixture of L- and D-amino acids (e.g., but not limited to, any one amino acid selected from the group consisting of His, Lys, Phe, Tyr, Ser, Asp, Gln, Ala, Arg, and Asn), and "d" refers to a D-amino acid.

[0035] In the present invention, "trt" is triphenylmethyl, "Boc" is t-butyloxycarbonyl, "tBu" is t-butyl, "Fmoc" is 9-fluorenylmethyloxycarbonyl, "dde" is 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl, and "Bip" is biphenylalanine.

[0036] In the present invention, "biotin" refers to a type of vitamin B group necessary for the growth of animals and plants. The natural form is the D-isomer in which the bonds between the two pentagonal rings are in a cis configuration. The other seven isomers, such as cis-type L-biotin or trans-type allobiotin, do not exhibit coenzyme activity.

[0037] In the present invention, the "amine protecting group" may be a protecting group selected from the group consisting of t-butyloxycarbonyl (Boc), p-toluenesulfonyl (Ts), fluorenylmethyloxycarbonyl, benzyl, triphenylmethyl and carboxybenzyl, and may be preferably p-toluenesulfonyl or t-butyloxycarbonyl.

[0038] In the present invention, R in the compound represented by formula 1 10 When is biotin, the biotin may be a compound represented by the following formula 2: [Formula 2] [ka]

[0039] In formula 2, n may be 1 to 10, and preferably 4, but is not limited thereto.

[0040] In addition, the compound represented by formula 1 according to the present invention can be further represented by the following formula 3, in which A is -N=, R2 is hydrogen, and R3 is [ka] wherein n is 4, R4 is heptylcarbonyl, Cy is phenyl, R5 is methyl, R6 is S(=O)2OH, and R7, R8 and R 10 are each independently hydrogen and R9 is -OH, the amino acid of SEQ ID NO: 1 may be a substitute such as His(benzhydryl)-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr. The IUPAC name of the compound represented by the following formula 3 is ((R)-2-((S)-2-((S)-2-amino-3-(1-benzhydryl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanoyl)-L-tyrosine, and in one embodiment of the present invention, it is named HKFY-34. [Formula 3] [ka]

[0041] In an embodiment of the present invention, it has been confirmed that a peptide derivative, which is a compound having the structure of formula 1 according to the present invention, selectively and specifically binds to GPR39 (G protein-coupled receptor 39), which is an orphan G protein-coupled receptor (orphan GPCR) that is a membrane protein (Tables 3 to 5, Figures 73 and 74).

[0042] In another aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating inflammatory bowel disease, comprising the above compound or a pharma- ceutically acceptable salt thereof as an active ingredient.

[0043] As used herein, the term "inflammation" refers to a response to protect the body from harmful factors and includes a series of processes involving immune cells, blood vessels, and inflammatory mediators to inhibit cell damage, remove damaged tissue and necrotic cells, and regenerate tissue.

[0044] As used herein, the term "inflammatory bowel disease (IBD)" refers to diseases that cause chronic inflammation in the gastrointestinal tract and may include both infectious enteritis, such as bacterial, viral, amoebic and tuberculous enteritis, and inflammatory diseases that occur in the entire intestine, such as ischemic enteropathy and radiation enteritis. The cause of inflammatory bowel disease has not been clearly identified, but it is known to be influenced by genetic and environmental factors and mediated by immunological abnormalities. Inflammatory bowel disease may be, but is not limited to, Crohn's disease, ulcerative colitis, intestinal Behcet's disease and enteritis.

[0045] "Crohn's disease" is a chronic inflammatory bowel disease that affects the entire digestive tract from the mouth to the anus. Crohn's disease is an autoimmune disease that occurs mostly in the ileocecal area, which is the boundary between the small intestine and the large intestine, and frequently in the large intestine, the terminal ileum, and the small intestine. Crohn's disease is characterized by repeated symptomatic and asymptomatic phases that show symptoms such as abdominal pain and diarrhea. The cause of the disease is unclear, but it is speculated that mycobacterial infection, measles virus infection, and an excessive immune response to normal bacteria in the digestive tract are involved. "Ulcerative colitis" is a type of diffuse nonspecific inflammatory disease that mainly infiltrates the mucous membrane and causes putrefaction or ulceration. The cause of ulcerative colitis is not clearly identified, and it causes various systemic symptoms such as bloody diarrhea. "Behçet's disease" is a disease in which oral and genital ulcers and eye inflammation occur repeatedly, and is a systemic and chronic disease that affects the cardiovascular system, nervous system, digestive tract, liver, spleen, kidneys, and lungs. When Behcet's disease affects the intestinal tract, it is called "intestinal Behcet's disease." Intestinal Behcet's disease is a nonspecific, relapsing, chronic inflammatory disease with symptoms such as abdominal pain and diarrhea, and may be accompanied by complications such as bleeding and perforation.

[0046] In one embodiment of the present invention, when HT-29 cells were treated with the peptide derivative according to the present invention, cell proliferation and binding were enhanced (Figures 75 to 78). Furthermore, inflammation was alleviated in a cell model of inflammatory bowel disease (IBD) (Figure 81). When a mouse model of ulcerative colitis was treated with the peptide derivative of the present invention, weight loss and contraction of intestinal length, which are symptoms of ulcerative colitis, were inhibited, and diarrhea, bloody stool, and inflammatory reactions in the intestinal tissue were alleviated. Thus, it was confirmed that the peptide derivative of the present invention has an excellent therapeutic effect on inflammatory bowel disease (Figures 83 to 89). Furthermore, when GPR39-deficient mice in which ulcerative colitis was induced were treated with the peptide derivative of the present invention, no significant alleviating effect was observed (Figures 91 to 95). Thus, it was confirmed that the peptide derivative of the present invention acts specifically on GPR39 against inflammatory bowel disease.

[0047] As used herein, the term "prevention" refers to any action of administration of a composition that inhibits or delays the onset, spread, and recurrence of a target disease. As used herein, the term "treatment" refers to any action of administration of a composition that improves or beneficially alters the symptoms of a target disease. Specifically, it includes curing, alleviating, avoiding, preventing, delaying, or reducing symptoms caused by inflammatory bowel disease.

[0048] The pharmaceutical composition may further comprise suitable carriers, excipients and diluents that are generally used in the preparation of pharmaceutical compositions. In addition, it may be formulated and used in the form of oral preparations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, and sterile injections according to conventional methods. Suitable preparations known in the art may be those disclosed in the literature (Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA).

[0049] In addition, the pharmaceutical composition may contain carriers, excipients and diluents including lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, mineral oil, etc. When formulating the composition, it may be prepared using diluents or excipients, such as commonly used fillers, extenders, binders, wetting agents, disintegrants and surfactants.

[0050] The solid preparation for oral administration of the "pharmaceutical composition" of the present invention includes tablets, pills, powders, granules, capsules, etc. Such solid preparations can be prepared by mixing the composition with at least one or more excipients, such as starch, calcium carbonate, sucrose, lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc may be used. Liquid preparations for oral administration may include suspensions, oral solutions, emulsions, syrups, etc., and may contain various excipients such as wetting agents, sweeteners, flavoring agents, and preservatives in addition to water and liquid paraffin, which are commonly used simple diluents.

[0051] Preparations for parenteral administration may include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, and suppositories. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspending agents. As the base for suppositories, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin, etc. may be used.

[0052] The compositions are preferably formulated into dosage forms specific for a particular patient.

[0053] Each unit dose for oral administration preferably contains the compound of formula 1 or a pharma- ceutically acceptable salt thereof in an amount of 0.1 mg / kg to 500 mg / kg, 1 mg / kg to 100 mg / kg, or 10 mg / kg to 50 mg / kg.

[0054] A preferred dosage of the pharmaceutical composition varies depending on the condition and weight of the patient, the severity of the disease, the type of drug, the administration route and administration period, but can be appropriately selected by one skilled in the art.

[0055] A suitable daily dosage for oral administration is about 0.01 to 40 mg / kg of the compound of formula 1 or a pharma- ceutically acceptable salt thereof, which may be administered 1 to 6 times a day depending on the condition of the patient.

[0056] Additionally, the pharmaceutical compositions may be used alone or in combination with methods using surgery, hormone therapy, chemotherapy, and biological response modifiers for the prevention and treatment of inflammatory bowel disease.

[0057] In another aspect of the invention, there is provided a method for preventing or treating inflammatory bowel disease, comprising administering to a mammal a compound or a pharma- ceutically acceptable salt thereof, wherein the compound or salt thereof, inflammatory bowel disease, administration, prevention and treatment are as described above.

[0058] In another aspect of the present invention, there is provided a use of a compound or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for preventing or treating inflammatory bowel disease, in which the compound or salt thereof, inflammatory bowel disease, prevention and treatment are as described above.

[0059] In another aspect of the present invention, there is provided a health functional food composition for preventing or alleviating inflammatory bowel disease, comprising the above-mentioned compound or a biologically acceptable salt thereof as an active ingredient. In this case, the compound or its salt, inflammatory bowel disease and prevention are the same as those described above.

[0060] The health functional food of the present invention may be in the form of powder, granules, tablets, capsules, or beverages, and may also be candy, chocolate, gum, tea, vitamin complex, dietary supplement, etc. The health functional food may be prepared in various forms, such as, but not limited to, tablets, capsules, powders, granules, liquids, pills, etc., to obtain useful effects in alleviating inflammatory bowel disease.

[0061] In this case, the content of the compound of the present invention or its biologically acceptable salt contained in the health functional food may be usually 0.01 to 50% by weight, or 0.1 to 20% by weight, based on the total weight of the food, and in the case of a health drink composition, it may be 0.02 to 10 g, or 0.3 to 1 g, based on 100 mL of the health drink composition.

[0062] The food product may further comprise a biologically acceptable food supplement additive in addition to the compound according to the invention or a biologically acceptable salt thereof.

[0063] The health functional food of the present invention may contain additives commonly used in food compositions to improve odor, taste, appearance, etc. For example, vitamins A, C, D, E, B1, B2, B6, B12, niacin, biotin, folic acid, pantothenic acid, etc. may be included. Furthermore, minerals such as zinc (Zn), iron (Fe), calcium (Ca), chromium (Cr), magnesium (Mg), manganese (Mn), and copper (Cu) may be included. Furthermore, amino acids such as lysine, tryptophan, cysteine, and valine may be included.

[0064] In addition, food additives such as preservatives (potassium sorbate, sodium benzoate, salicylic acid, sodium dehydroacetate, etc.), bactericides (bleaching powder, high bleaching powder, sodium hypochlorite, etc.), antioxidants (butyl hydroxyanisole (BHA), butyl hydroxytoluene (BHT), etc.), colorants (tar dyes, etc.), color formers (sodium nitrite, sodium nitrite, etc.), bleaching agents (sodium sulfite), seasonings (MSG monosodium glutamate, etc.), sweeteners (dulcin, cyclamate, saccharin, sodium, etc.), flavors (vanillin, lactone, etc.), foaming agents (alum, potassium D-hydrogen tartrate, etc.), strengthening agents, emulsifiers, thickeners, coating agents, gum bases, antifoaming agents, solvents, and denaturants may be added. The additives may be selected according to the type of food and used in an appropriate amount.

[0065] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described in detail below with reference to examples. However, the following examples are for the purpose of illustrating the present invention, and the present invention is not limited to the following examples.

[0066] Example 1. Preparation of HKFY derivatives Example 1.1. Preparation of HKFY-1 To prepare His(trt)-Lys(caprylic acid)-Phe-Tyr (N6-octanoyl-N2-(Nt-trityl-L-histidyl)-L-lysyl-L-phenylalanyl-L-tyrosine, HKFY-1), Fmoc-Tyr(tBu) and DMF (dimethylformamide) were loaded onto a trityl resin to prepare Fmoc-Tyr(tBu)-trityl resin. DMF containing 20% ​​piperidine, Fmoc-Phe-OH and HOBt (hydroxyl-benzotriazole) were added to the Fmoc-Tyr(tBu)-trityl resin to prepare Fmoc-Phe-Tyr(tBu)-trityl resin. Fmoc-Lys-OH was prepared by removing dde by adding DMF containing 2% NH2NH2·H2O to Fmoc-Lys(dde)-OH. Fmoc-Lys(caprylic acid)-OH was prepared by adding DMF containing caprylic acid, HOBt, and DIC to Fmoc-Lys-OH. Fmoc-Lys(caprylic acid)-Phe-Tyr(tBu)-trityl resin was prepared by adding 20% ​​piperidine in DMF to Fmoc-Lys(caprylic acid)-OH and adding HOBt (hydroxyl-benzotriazole). Boc-His(trt)-Lys(caprylic acid)-Phe-Tyr(tBu)-trityl resin was prepared by adding 20% ​​piperidine in DMF to Fmoc-Lys(caprylic acid)-Phe-Tyr(tBu)-trityl resin, followed by addition of Boc-His(trt)-OH and HOBt (hydroxyl-benzotriazole). His(trt)-Lys(caprylic acid)-Phe-Tyr(tBu)-trityl resin was deprotected and purified to prepare His(trt)-Lys(caprylic acid)-Phe-Tyr. Purity, molecular weight and 1 The H NMR spectra are shown in Figures 1, 37 and 96, respectively.

[0067] Example 1.2. Preparation of HKFY-2 To prepare biotin ((S)-3-([1,1'-biphenyl]-4-yl)-2-((S)-6-octanamido-2-((S)-2-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)-3-(1-trityl-1H-imidazol-4-yl)propanamido)hexanamido)propanoyl)-L-tyrosine, DMF containing 20% ​​piperidine was added to the Fmoc-Lys(caprylic acid)-Phe-Tyr(tBu)-trityl resin obtained in Example 1.1, and Fmoc-His(trt)-OH was added to prepare Fmoc-His(trt)-Lys(caprylic acid)-Phe-Tyr(tBu)-trityl resin. Similarly, D-biotin was added to prepare D-biotin-His(trt)-Lys(caprylic acid)-Phe-Tyr(tBu)-trityl resin. After cleavage of the protecting group of the resin and purification, biotin-His(trt)-Lys(caprylic acid)-Phe-Tyr (N6-octanoyl-N2-(Na-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoyl)-Nt-trityl-L-histidyl)-L-lysyl-L-phenylalanyl-L-tyrosine) was prepared.

[0068] Purity, molecular weight, and 1 The H NMR spectra are shown in Figures 2, 38, and 97, respectively.

[0069] Example 1.3. Preparation of HKFY-3 His(benzyl)-Lys(caprylic acid)-Phe-Tyr (N2-(Nt-benzyl-L-histidyl)-N6-octanoyl-L-lysyl-L-phenylalanyl-L-tyrosine) was prepared in the same manner as in Example 1.1, except that Boc-His(benzyl)-OH was used instead of Boc-His(trt)-OH obtained in the preparation process of Example 1.1. The purity and molecular weight of HKFY-3 are shown in Figures 3 and 39, respectively.

[0070] Example 1.4. Preparation of HKFY-4 In the same manner as in Example 1.1, except that Boc-d-His(trt) was used instead of Boc-His(trt)-OH obtained in the preparation process of Example 1.1, d-His(trt)-Lys(caprylic acid)-Phe-Tyr (N6-octanoyl-N2-(Nt-trityl-D-histidyl)-L-lysyl-L-phenylalanyl-L-tyrosine) was prepared. The purity and molecular weight of HKFY-4 are shown in Figures 4 and 40, respectively.

[0071] Example 1.5. Preparation of HKFY-5 His(4-methyltrityl)-Lys(caprylic acid)-Phe-Tyr(N2-(Nt-(diphenyl(p-tolyl)methyl)-L-histidyl)-N6-octanoyl-L-lysyl-L-phenylalanyl-L-tyrosine) was prepared in the same manner as in Example 1.1, except that Boc-His(4-methyltrityl)-OH was used instead of Boc-His(trt)-OH obtained in the preparation process of Example 1.1. The purity and molecular weight of HKFY-5 are shown in Figures 5 and 41, respectively.

[0072] Example 1.6. Preparation of HKFY-6 His(DAMP-3)-Lys(caprylic acid)-Phe-Tyr (N2-((S)-2-amino-3-(1,3-diphenethyl-2,3-dihydro-1H-imidazol-4-yl)propanoyl)-N6-octanoyl-L-lysyl-L-phenylalanyl-L-tyrosine) was prepared in the same manner, except that Boc-His(DAMP-3)-OH was used instead of Boc-His(trt)-OH obtained in the preparation process of Example 1.1. The purity and molecular weight of HKFY-6 are shown in Figures 6 and 42, respectively.

[0073] Example 1.7. Preparation of HKFY-7 His(DAMP-5)-Lys(caprylic acid)-Phe-Tyr(N2-((S)-2-amino-3-(3-(2-cyclohexylethyl)-2,3-dihydro-1H-imidazol-4-yl)propanoyl)-N6-octanoyl-L-lysyl-L-phenylalanyl-L-tyrosine) was prepared in the same manner, except that Boc-His(DAMP-5)-OH was used instead of Boc-His(trt)-OH obtained in the preparation process of Example 1.1. The purity and molecular weight of HKFY-7 are shown in Figures 7 and 43, respectively.

[0074] Example 1.8. Preparation of HKFY-8 His(DAMP-2)-Lys(caprylic acid)-Phe-Tyr(N2-((S)-2-amino-3-(1,3-bis(2-cyclohexylethyl)-2,3-dihydro-1H-imidazol-4-yl)propanoyl)-N6-octanoyl-L-lysyl-L-phenylalanyl-L-tyrosine) was prepared in the same manner, except that Boc-His(DAMP-2)-OH was used instead of Boc-His(trt)-OH obtained in the preparation process of Example 1.1. The purity and molecular weight of HKFY-8 are shown in Figures 8 and 44, respectively.

[0075] Example 1.9. Preparation of HKFY-9 His(DAMP-2)-Lys(caprylic acid)-Phe-Tyr (N6-octanoyl-N2-(Nt-phenethyl-L-histidyl)-L-lysyl-L-phenylalanyl-L-tyrosine) was prepared in the same manner as in Example 1.1, except that Boc-His(2-phenylethyl)-OH was used instead of Boc-His(trt)-OH obtained in the preparation process of Example 1.1. The purity and molecular weight of HKFY-9 are shown in Figures 9 and 45, respectively.

[0076] Example 1.10. Preparation of HKFY-10 His(2-naphthalene-1-ethyl)-Lys(caprylic acid)-Phe-Tyr(N2-(Nt-(naphthalene-1-ylmethyl)-L-histidyl)-N6-octanoyl-L-lysyl-L-phenylalanyl-L-tyrosine) was prepared in the same manner as in Example 1.1, except that Boc-His(2-naphthalene-1-ethyl)-OH was used instead of Boc-His(trt)-OH obtained in the preparation process of Example 1.1. The purity and molecular weight of HKFY-10 are shown in Figures 10 and 46, respectively.

[0077] Example 1.11. Preparation of HKFY-11 His(2-cyclohexylethyl)-Lys(caprylic acid)-Phe-Tyr (N2-(Nt-(2-cyclohexylethyl)-L-histidyl)-N6-octanoyl-L-lysyl-L-phenylalanyl-L-tyrosine) was prepared in the same manner as in Example 1.1, except that Boc-His(2-cyclohexylethyl)-OH was used instead of Boc-His(trt)-OH obtained in the preparation process of Example 1.1. The purity and molecular weight of HKFY-11 are shown in Figure 11 and Figure 47, respectively.

[0078] Example 1.12. Preparation of HKFY-12 To prepare His(trt)-Lys(caprylic acid)-d-Phe-Tyr (N6-decanoyl-N2-(Nt-trityl-L-histidyl)-L-lysyl-D-phenylalanyl-L-tyrosine, HKFY-12), Fmoc-Tyr(tBu) and DMF (dimethylformamide) were loaded onto a trityl resin to prepare Fmoc-Tyr(tBu)-trityl resin. DMF containing 20% ​​piperidine and Fmoc-d-Phe-OH of formula 8, and HOBt (hydroxyl-benzotriazole) were added to the Fmoc-Tyr(tBu)-trityl resin to prepare Fmoc-d-Phe-Tyr(tBu)-trityl resin. Fmoc-Lys(caprylic acid)-d-Phe-Tyr(tBu)-trityl resin was prepared by adding Fmoc-Lys(caprylic acid)-OH and HOBt (hydroxyl-benzotriazole) to Fmoc-Lys(caprylic acid)-d-Phe-Tyr(tBu)-trityl resin. Boc-His(trt)-Lys(caprylic acid)-d-Phe-Tyr(tBu)-trityl resin was prepared by adding DMF containing 20% ​​piperidine to Fmoc-Lys(caprylic acid)-d-Phe-Tyr(tBu)-trityl resin, and adding Boc-His(trt)-OH and HOBt (hydroxyl-benzotriazole). His(trt)-Lys(caprylic acid)-d-Phe-Tyr(tBu)-trityl resin was deprotected and purified to prepare His(trt)-Lys(caprylic acid)-d-Phe-Tyr. The purity and molecular weight of HKFY-12 are shown in Figures 12 and 48, respectively.

[0079] Example 1.13. Preparation of HKFY-13 His(trt)-Lys(caprylic acid)-d-Phe(4-Cl)-Tyr(((R)-2-((S)-2-((S)-2-amino-3-(1-trityl-1H-imidazol-4-yl)propanamido)-6-(non-1-en-2-ylamino)hexanamido)-3-(4-chlorophenyl)propanoyl)-L-tyrosine, HKFY-13) was prepared in the same manner, except that Fmoc-d-Phe(4-Cl)-OH was used instead of Fmoc-d-Phe-OH obtained in the preparation process of Example 1.6. The purity and molecular weight of HKFY-13 are shown in Figures 13 and 49, respectively.

[0080] Example 1.14. Preparation of HKFY-14 Fmoc-d-Tyr(tBu)-trityl resin was prepared in the same manner, except that Fmoc-d-Tyr(tBu)-OH was used instead of Fmoc-Tyr(tBu)-OH obtained in the preparation process of Example 1.13. In the subsequent process, Boc-His(trt)-OH was changed to Boc-d-His(trt)-OH to prepare d-His(trt)-Lys(caprylic acid)-d-Phe(4-Cl)-d-Tyr(((R)-2-((S)-2-((R)-2-amino-3-(1-trityl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(4-chlorophenyl)propanoyl)-D-tyrosine). The purity and molecular weight of HKFY-14 are shown in Figures 14 and 50, respectively.

[0081] Example 1.15. Preparation of HKFY-15 His(trt)-Lys(caprylic acid)-d-Phe(4-Cl)-d-Tyr(((R)-2-((S)-2-((S)-2-amino-3-(1-trityl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(4-chlorophenyl)propanoyl)-D-tyrosine) was prepared in the same manner, except that Boc-His(trt)-OH was used instead of Boc-d-His(trt)-OH obtained during the preparation process of Example 1.14. The purity and molecular weight of HKFY-15 are shown in Figures 15 and 51, respectively.

[0082] Example 1.16. Preparation of HKFY-16 His(trt)-d-Lys(caprylic acid)-d-Phe(4-Cl)-Tyr(((R)-2-((R)-2-((S)-2-amino-3-(1-trityl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(4-chlorophenyl)propanoyl)-L-tyrosine) was prepared in the same manner as in Example 1.13, except that in the preparation process using Fmoc-Lys(caprylic acid)-OH instead of Fmoc-Lys(dde)-OH obtained in the preparation process of Example 1.13, Fmoc-d-Lys(caprylic acid)-OH was used by replacing Fmoc-Lys(dde)-OH with Fmoc-d-Lys(dde)-OH. The purity and molecular weight of HKFY-16 are shown in Figures 16 and 52, respectively.

[0083] Example 1.17. Preparation of HKFY-17 His(3,3-diphenylpropyl)-Lys(caprylic acid)-Phe-Tyr (N2-(Nt-(2,2-diphenylethyl)-L-histidyl)-N6-octanoyl-L-lysyl-L-phenylalanyl-L-tyrosine) was prepared in the same manner as in Example 1.1, except that Boc-His(3,3-diphenylpropyl)-OH was used instead of Boc-His(trt)-OH obtained in the preparation process of Example 1.1. The purity and molecular weight of HKFY-17 are shown in Figures 17 and 53, respectively.

[0084] Example 1.18. Preparation of HKFY-18 His(Fm)-Lys(caprylic acid)-Phe-Tyr (N2-(Nt-(9H-fluoren-9-yl)-L-histidyl)-N6-octanoyl-L-lysyl-L-phenylalanyl-L-tyrosine) was prepared in the same manner as in Example 1.1, except that Boc-His(Fm)-OH was used instead of Boc-His(trt)-OH obtained in the preparation process of Example 1.1. The purity and molecular weight of HKFY-18 are shown in Figures 18 and 54, respectively.

[0085] Example 1.19. Preparation of HKFY-19 His(phenylpropyl)-Lys(caprylic acid)-Phe-Tyr (N6-octanoyl-N2-(Nt-phenethyl-L-histidyl)-L-lysyl-L-phenylalanyl-L-tyrosine) was prepared in the same manner as in Example 1.1, except that Boc-His(phenylpropyl)-OH was used instead of Boc-His(trt)-OH obtained in the preparation process of Example 1.1. The purity and molecular weight of HKFY-19 are shown in Figures 19 and 55, respectively.

[0086] Example 1.20. Preparation of HKFY-20 His(methoxybenzhydryl)-Lys(caprylic acid)-Phe-Tyr(N2-(Nt-((4-methoxyphenyl)(phenyl)methyl)-L-histidyl)-N6-octanoyl-L-lysyl-L-phenylalanyl-L-tyrosine) was prepared in the same manner as in Example 1.1, except that Boc-His(methoxybenzhydryl)-OH was used instead of Boc-His(trt)-OH obtained in the preparation process of Example 1.1. The purity and molecular weight of HKFY-20 are shown in Figure 20 and Figure 56, respectively.

[0087] Example 1.21. Preparation of HKFY-21 His(4-chlorobenzhydryl)-Lys(caprylic acid)-Phe-Tyr(N2-(Nt-((R)-(4-chlorophenyl)(phenyl)methyl)-L-histidyl)-N6-octanoyl-L-lysyl-L-phenylalanyl-L-tyrosine) was prepared in the same manner as in Example 1.1, except that Boc-His(4-chlorobenzhydryl)-OH was used instead of Boc-His(trt)-OH obtained in the preparation process of Example 1.1. The purity and molecular weight of HKFY-21 are shown in Figures 21 and 57, respectively.

[0088] Example 1.22. Preparation of HKFY-22 His(methylbenzhydryl)-Lys(caprylic acid)-Phe-Tyr (N6-octanoyl-N2-(Nt-((R)-phenyl(p-tolyl)methyl)-L-histidyl)-L-lysyl-L-phenylalanyl-L-tyrosine) was prepared in the same manner as in Example 1.1, except that Boc-His(methylbenzhydryl)-OH was used instead of Boc-His(trt)-OH obtained in the preparation process of Example 1.1. The purity and molecular weight of HKFY-22 are shown in Figures 22 and 58, respectively.

[0089] Example 1.23. Preparation of HKFY-23 His(adamantanemethyl)-Lys(caprylic acid)-Phe-Tyr (N2-(Nt-(adamantane-1-yl)-L-histidyl)-N6-octanoyl-L-lysyl-L-phenylalanyl-L-tyrosine) was prepared in the same manner as in Example 1.1, except that Boc-His(adamantanemethyl)-OH was used instead of Boc-His(trt)-OH obtained in the preparation process of Example 1.1. The purity and molecular weight of HKFY-23 are shown in Figures 23 and 59, respectively.

[0090] Example 1.24. Preparation of HKFY-24 His(trt)-Lys(capric acid)-Phe-Tyr (N6-decanoyl-N2-(Nt-trityl-L-histidyl)-L-lysyl-L-phenylalanyl-L-tyrosine, HKFY-24) was prepared in the same manner as in Example 1.1, except that capric acid was added instead of caprylic acid to Fmoc-Lys-OH obtained in the preparation process of Example 1.1. The purity and molecular weight of HKFY-24 are shown in Figures 24 and 60, respectively.

[0091] Example 1.25. Preparation of HKFY-25 His(trt)-Lys(lauric acid)-Phe-Tyr (N6-dodecanoyl-N2-(Nt-trityl-L-histidyl)-L-lysyl-L-phenylalanyl-L-tyrosine, HKFY-25) was prepared in the same manner as in Example 1.1, except that lauric acid was added instead of caprylic acid to Fmoc-Lys-OH obtained in the preparation process of Example 1.1. The purity and molecular weight of HKFY-25 are shown in Figures 25 and 61, respectively.

[0092] Example 1.26. Preparation of HKFY-26 His(trt)-Lys(myristic acid)-Phe-Tyr (N6-tetradecanoyl-N2-(Nt-trityl-L-histidyl)-L-lysyl-L-phenylalanyl-L-tyrosine, HKFY-26) was prepared in the same manner as in Example 1.1, except that myristic acid was added instead of caprylic acid to the Fmoc-Lys-OH obtained in the preparation process of Example 1.1. The purity and molecular weight of HKFY-26 are shown in Figures 26 and 62, respectively.

[0093] Example 1.27. Preparation of HKFY-27 His(trt)-Lys(palmitic acid)-Phe-Tyr (N6-palmitoyl-N2-(Nt-trityl-L-histidyl)-L-lysyl-L-phenylalanyl-L-tyrosine, HKFY-27) was prepared in the same manner as in Example 1.1, except that palmitic acid was added instead of caprylic acid to Fmoc-Lys-OH obtained in the preparation process of Example 1.1. The purity and molecular weight of HKFY-27 are shown in Figures 27 and 63, respectively.

[0094] Example 1.28. Preparation of HKFY-28 His(trt)-Lys(caprylic acid)-d-Phe(4-F)-Tyr(((R)-2-((S)-2-((S)-2-amino-3-(1-trityl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(4-fluorophenyl)propanoyl)-L-tyrosine, HKFY-28) was prepared in the same manner, except that Fmoc-d-Phe(4-F)-OH was used instead of Fmoc-d-Phe-OH obtained in the preparation process of Example 1.6. The purity and molecular weight of HKFY-28 are shown in Figures 28 and 64, respectively.

[0095] Example 1.29. Preparation of HKFY-29 His(trt)-Lys(caprylic acid)-d-Phe(4-Br)-Tyr(((R)-2-((S)-2-((S)-2-amino-3-(1-trityl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(4-bromophenyl)propanoyl)-L-tyrosine, HKFY-29) was prepared in the same manner, except that Fmoc-d-Phe(4-Br)-OH was used instead of Fmoc-d-Phe-OH obtained in the preparation process of Example 1.6. The purity and molecular weight of HKFY-29 are shown in Figures 29 and 65, respectively.

[0096] Example 1.30. Preparation of HKFY-30 His(trt)-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr(((R)-2-((S)-2-((S)-2-amino-3-(1-trityl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanoyl)-L-tyrosine, HKFY-30) was prepared in the same manner, except that Fmoc-d-Phe(4-methyl)-OH was used instead of Fmoc-d-Phe-OH obtained in the preparation process of Example 1.6. The purity and molecular weight of HKFY-30 are shown in Figures 30 and 66, respectively.

[0097] Example 1.31. Preparation of HKFY-31 D-His(trt)-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr((R)-2-((S)-2-((R)-2-amino-3-(1-trityl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanoyl)-L-tyrosine) was prepared in the same manner, except that Boc-d-His(trt)-OH obtained during the preparation process of Example 1.30 was used instead of Boc-His(trt)-OH. The purity and molecular weight of HKFY-31 are shown in Figures 31 and 67, respectively.

[0098] Example 1.32. Preparation of HKFY-32 His(1,3-difluorobenzhydryl)-Lys(caprylic acid)-d-Phe(methyl)-Tyr(((2R)-2-((2S)-2-((2S)-2-amino-3-(1-((2,4-difluorophenyl)(phenyl)methyl)-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanoyl)-L-tyrosine) was prepared in the same manner as in Example 1.34 below, except that Boc-His(1,3-difluorobenzhydryl)-OH was used instead of Boc-His(benzhydryl)-OH. The purity and molecular weight of HKFY-32 are shown in Figures 32 and 68, respectively.

[0099] Example 1.33. Preparation of HKFY-33 His(benzhydryl)-Lys(caprylic acid)-Phe-Tyr (N2-(Nt-benzhydryl-L-histidyl)-N6-octanoyl-L-lysyl-L-phenylalanyl-L-tyrosine) was prepared in the same manner as in Example 1.1, except that Boc-His(benzhydryl)-OH was used instead of Boc-His(trt)-OH obtained in the preparation process of Example 1.1. The purity and molecular weight of HKFY-33 are shown in Figures 33 and 69, respectively.

[0100] Example 1.34. Preparation of HKFY-34 To prepare His(benzhydryl)-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr(((R)-2-((S)-2-((S)-2-amino-3-(1-benzhydryl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanoyl)-L-tyrosine, HKFY-34, Fmoc-Tyr(tBu) and DMF (dimethylformamide) were loaded onto a trityl resin to prepare Fmoc-Tyr(tBu)-trityl resin. Fmoc-d-Phe(4-methyl)-Tyr(tBu)-trityl resin was prepared by adding 20% ​​piperidine in DMF, Fmoc-d-Phe(4-methyl)-OH and HOBt (hydroxyl-benzotriazole) to the Fmoc-Tyr(tBu)-trityl resin. Fmoc-Lys-OH was prepared by removing dde by adding DMF containing 2% NH2NH2·H2O to Fmoc-Lys-OH. Fmoc-Lys(caprylic acid)-OH was prepared by adding DMF containing caprylic acid, HOBt, and DIC to Fmoc-Lys-OH, and Boc-His(benzhydryl)-OH was prepared by using Boc-His(trt)-OH. Fmoc-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr(tBu)-trityl resin was prepared by adding 20% ​​piperidine in DMF to Fmoc-Lys(caprylic acid)-OH and HOBt (hydroxyl-benzotriazole). Boc-His(benzhydryl)-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr(tBu)-trityl resin was prepared by adding 20% ​​piperidine in DMF to Fmoc-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr(tBu)-trityl resin and adding Boc-His(benzhydryl)-OH and HOBt (hydroxyl-benzotriazole). His(benzhydryl)-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr(tBu)-trityl resin was purified after cleavage of the protecting groups, to prepare His(benzhydryl)-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr-OH. Purity, molecular weight and 1 The H NMR spectra are shown in Figures 34, 70 and 98, respectively.

[0101] Example 1.35. Preparation of HKFY-35 His(benzhydryl)-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr((SOH)-OH(S)-2-((R)-2-((S)-2-((S)-2-amino-3-(1-benzhydryl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanamido)-3-(4-(sulfoxy)phenyl)propanoic acid) was prepared in the same manner, except that Fmoc-Tyr(SOH)-OH was used instead of Fmoc-Tyr(tBu)-OH obtained during the preparation process of Example 1.34. The purity and molecular weight of HKFY-35 are shown in Figures 35 and 71, respectively.

[0102] Example 1.36. Preparation of HKFY-36 His(benzhydryl)-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr((2.6-dimethyl)-OH(S)-2-((R)-2-((S)-2-((S)-2-amino-3-(1-benzhydryl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanamido)-3-(4-hydroxy-2,6-dimethylphenyl)propanoic acid) was prepared in the same manner, except that Fmoc-Tyr(tBu)-OH obtained in the preparation process of Example 1.34 was replaced with Fmoc-Tyr(2.6-dimethyl)-OH. The purity and molecular weight of HKFY-36 are shown in Figures 36 and 72, respectively.

[0103] Example 1.37. Preparation of HKFY-37 The Fmoc-His(trt)-Lys(caprylic acid)-Phe-Tyr-OH-trityl resin obtained in the preparation process of Example 1.1 was added with DMF containing 20% ​​piperidine, and HOBt (hydroxyl-benzotriazole) was added to Fmoc-Ser(tBu)-OH to prepare Fmoc-Ser(tBu)-His(trt)-Lys(caprylic acid)-Phe-Tyr-OH-trityl resin. The DMF containing 20% ​​piperidine was added to the resin, and HOBt (hydroxyl-benzotriazole) was added to Fmoc-Gly-OH to prepare Fmoc-Gly-Ser(tBu)-His(trt)-Lys(caprylic acid)-Phe-Tyr-OH-trityl resin. Gly-Ser-His(trt)-Lys(caprylate)-Phe-Tyr-OH-trityl resin was prepared by cleavage of the protecting groups and subsequent purification of the resin: Gly-Ser-His(trt)-Lys(caprylate)-Phe-Tyr (N2-(Na-glycyl-L-seryl-Nt-trityl-L-histidyl)-N6-octanoyl-L-lysyl-L-phenylalanyl-L-tyrosine). The purity and molecular weight of HKFY-37 are shown in Figures 99 and 100, respectively.

[0104] Example 1.38. Preparation of HKFY-38 HKFY-38 ((3S,6S,9S,12S,15S)-15-((S)-2-amino-3-(1-trityl-1H-imidazol-4-yl)propanamide)-12-benzyl-3-(((6S,9S,12S,15S)-1,18-diamino-6-(((S)-1-amino-1-oxo-3-phenylpropan-2-yl)carbamoyl)-12-(3-amino-3-oxopropyl)-1-imino-9-methyl-8,11,14,18-tetrahydrofuran-2-yl)carbamoyl) To prepare tetraoxo-2,7,10,13-tetraazaoctadecan-15-yl)carbamoyl)-9-(4-hydroxybenzyl)-6-(hydroxymethyl)-5,8,11,14,21-pentaoxo-4,7,10,13,20-pentaazaoctacosanoic acid, Fmoc-Phe-trityl resin was prepared by loading Fmoc-Phe-OH and DMF (dimethylformamide) onto a trityl resin. Fmoc-Phe-trityl resin To the Fmoc-Arg(pbf)-Phe-trityl resin, 20% piperidine in DMF, Fmoc-Arg(pbf)-OH and HOBt (hydroxyl-benzotriazole) were added to prepare Fmoc-Arg(pbf)-Phe-trityl resin. To the Fmoc-Arg(pbf)-Phe-trityl resin, 20% piperidine in DMF, Fmoc-Ala-OH and HOBt (hydroxyl-benzotriazole) were added to prepare Fmoc-Ala-Arg(pbf)-Phe-trityl resin. He-trityl resin was prepared. Fmoc-Gln(trt)-OH, Fmoc-Gln(trt)-OH, Fmoc-Asp(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Tyr(tbu)-OH, and Fmoc-Phe-OH were added in sequence in the same manner as above to prepare Fmoc-Phe-Tyr(tBu)-Ser(tBu)-Asp(tBu)-Gln(trt)-Ala-Arg(pbf)-Phe-trityl resin. Fmoc-Lys(caprylate)-Phe-Tyr(tBu)-Ser(tBu)-Asp(tBu)-Gln(trt)-Gln(trt)-Ala-Arg(pbf)-Phe-trityl resin was prepared by adding DMF containing 20% ​​piperidine and Fmoc-Lys(caprylate)-OH obtained in Example 1.1 and HOBt (hydroxyl-benzotriazole) to the resin. Fmoc-His(trt)-Lys(caprylate)-Phe-Tyr(tBu)-Ser(tBu)-Asp(tBu)-Gln(trt)-Gln(trt)-Ala-Arg(pbf)-Phe-trityl resin was prepared by adding DMF containing 20% ​​piperidine and Fmoc-His(trt)-OH obtained in Example 1.1 and HOBt (hydroxyl-benzotriazole) to the resin. The protecting groups were cleaved from the Fmoc-His(trt)-Lys(caprylate)-Phe-Tyr(tBu)-Ser(tBu)-Asp(tBu)-Gln(trt)-Gln(trt)-Ala-Arg(pbf)-Phe-trityl resin and the resin was then purified to prepare His(trt)-Lys(caprylate)-Phe-Tyr-Ser-Asp-Gln-Gln-Ala-Arg-Phe. The purity and molecular weight of HKFY-38 are shown in Figures 101 and 102, respectively.

[0105] Example 1.39. Preparation of HKFY-39 HKFY-39((3S,6S,9S,12S,15S,18S)-3-((2-(((S)-1-(((S)-1-(((S)-1-amino-1-oxo-3-phenylpropan-2-yl)amino)-5-guanidino-1-oxopentan-2-yl)amino)-1-oxopropan-2-yl)amino)-2-oxoethyl)carbamoyl)-18-((S)-2-amino-3-(1-trityl-1H-imidazol-4-yl)propanamido)-6-(3-amino-3-oxopropyl)-15-benzyl To prepare Fmoc-Gly-Ala-Arg(pbf)-Phe-trityl resin (Fmoc-Gly-Ala-Arg(pbf)-Phe-trityl resin), 20% piperidine in DMF, Fmoc-Gly-OH and HOBt (hydroxyl-benzotriazole) were added to the Fmoc-Ala-Arg(pbf)-Phe-trityl resin obtained in Example 1.38 to prepare Fmoc-Gly-Ala-Arg(pbf)-Phe-trityl resin. Fmoc-Asn(trt)-Gly-Ala-Arg(pbf)-Phe-trityl resin was prepared by adding 20% ​​piperidine in DMF, Fmoc-Asn(trt)-OH and HOBt (hydroxyl-benzotriazole) to Fmoc-Gly-Ala-Arg(pbf)-Phe-trityl resin. Similarly, Fmoc-Phe-Tyr(tBu)-Ser(tBu)-Gly-Ala-Arg(pbf)-Phe-trityl resin was prepared by sequentially adding Fmoc-Gln(trt)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Tyr(tbu)-OH and Fmoc-Phe-OH. Fmoc-Lys(caprylate)-OH obtained in Example 1.1 and HOBt (hydroxyl-benzotriazole) were added to the resin to prepare Fmoc-Lys(caprylate)-Phe-Tyr(tBu)-Ser(tBu)-Gly-Ala-Arg(pbf)-Phe-trityl resin. Fmoc-His(trt)-Lys(caprylate)-Phe-Tyr(tBu)-Ser(tBu)-Gly-Ala-Arg(pbf)-Phe-trityl resin was prepared by adding 20% ​​piperidine in DMF and Fmoc-His(trt)-OH obtained in Example 1.1 and HOBt (hydroxyl-benzotriazole) to the resin. The protecting groups were cleaved from the Fmoc-His(trt)-Lys(caprylate)-Phe-Tyr(tBu)-Ser(tBu)-Gly-Ala-Arg(pbf)-Phe-trityl resin and the resin was then purified to prepare His(trt)-Lys(caprylate)-Phe-Tyr-Ser-Gly-Ala-Arg-Phe. The purity and molecular weight of HKFY-39 are shown in Figures 103 and 104, respectively.

[0106] Example 1.40. Preparation of HKFY-40 Fmoc-Gln(trt)-Ala-Arg(pbf)-Phe-trityl resin was prepared by adding 20% ​​piperidine in DMF, Fmoc-Gln(trt)-OH and HOBt (hydroxyl-benzotriazole) to the Fmoc-Ala-Arg(pbf)-Phe-trityl resin obtained in Example 1.39. Similarly, Fmoc-Phe-Tyr(tBu)-Ser(tBu)-His(trt)-Gln(trt)-Gln(trt)-Ala-Arg(pbf)-Phe-trityl resin was prepared by sequential addition of Fmoc-Gln(trt)-OH, Fmoc-His(trt)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Tyr(tBu)-OH, and Fmoc-Phe-OH. Similarly, Fmoc-Lys(caprylic acid)-OH and Fmoc-His(trt)-OH obtained in Example 1.1 were successively added to the resin to prepare Fmoc-His(trt)-Lys(caprylic acid)-Phe-Tyr(tBu)-Ser(tBu)-His(trt)-Gln(trt)-Gln(trt)-Ala-Arg(pbf)-Phe-trityl resin. The protecting groups were cleaved from the Fmoc-His(trt)-Lys(caprylate)-Phe-Tyr(tBu)-Ser(tBu)-His(trt)-Gln(trt)-Gln(trt)-Ala-Arg(pbf)-Phe-trityl resin and the resin was then purified to give His(trt)-Lys(caprylate)-Phe-Tyr-Ser-His-Gln-Gln-Ala-Arg-Phe((S)-2-((2S,5S,8S,11S,14S)-2-((1H-imidazol-4-yl)methyl)-14-((S)-2-amino-3-(1-trityl- ... A mixture of (S)-5-amino-1-(((S)-1-(((S)-1-(((S)-1-amino-1-oxo-3-phenylpropan-2-yl)amino)-5-guanidino-1-oxopentan-2-yl)amino)-1-oxopropan-2-yl)amino)-1,5-dioxopentan-2-yl)pentanediamide) was prepared. The purity and molecular weight of HKFY-40 are shown in Figures 105 and 106, respectively.

[0107] Example 1.41. Preparation of HKFY-41 Fmoc-Gly-Ala-Arg(pbf)-Phe-trityl resin was prepared by adding 20% ​​piperidine in DMF, Fmoc-Gly-OH and HOBt (hydroxyl-benzotriazole) to the Fmoc-Ala-Arg(pbf)-Phe-trityl resin obtained in Example 1.39. Similarly, Fmoc-His(trt)-Lys(caprylic acid)-Phe-Tyr(tBu)-Gln(trt)-Asn(trt)-Gly-Ala-Arg(pbf)-Phe-trityl resin was prepared by sequentially adding Fmoc-Asn(trt)-OH, Fmoc-Gln(trt)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Phe-OH, Fmoc-Lys(caprylic acid)-OH obtained in Example 1.1, and Fmoc-His(trt)-OH to the resin. The protecting groups on the resin were cleaved to give His(trt)-Lys(caprylic acid)-Phe-Tyr-Gln-Asn-Gly-Ala-Arg-Phe((3S,6S,9S,12S,15S,18S)-3-((2-(((S)-1-(((S)-1-(((S)-1-amino-1-oxo-3-phenylpropan-2-yl)amino)-5-guanidino-1-oxopentan-2-yl)amino)-1-oxopropan-2-yl )amino)-2-oxoethyl)carbamoyl)-18-((S)-2-amino-3-(1-trityl-1H-imidazol-4-yl)propanamido)-6-(3-amino-3-oxopropyl)-15-benzyl-12-(4-hydroxybenzyl)-9-(hydroxymethyl)-5,8,11,14,17,24-hexaoxo-4,7,10,13,16,23-hexaazahentriacontanoic acid) was prepared. The purity and molecular weight of HKFY-41 are shown in Figures 107 and 108, respectively.

[0108] Example 1.42. Preparation of HKFY-42 Fmoc-Gly-Ala-Arg(pbf)-Phe-trityl resin was prepared by adding 20% ​​piperidine in DMF, Fmoc-Gln(trt) and HOBt (hydroxyl-benzotriazole) to the Fmoc-Ala-Arg(pbf)-Phe-trityl resin obtained in Example 1.39. Similarly, Fmoc-His(trt)-Lys(caprylic acid)-Phe-Tyr(tBu)-His(trt)-Gln(trt)-Gln(trt)-Ala-Arg(pbf)-Phe-trityl resin was prepared by sequential addition of Fmoc-Gln(trt)-OH, Fmoc-His(trt)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Phe-OH, Fmoc-Lys(caprylic acid)-OH obtained in Example 1.1, and Fmoc-His(trt)-OH. The protecting groups on the resin were cleaved to give His(trt)-Lys(caprylic acid)-Phe-Tyr-His-Gln-Gln-Ala-Arg-Phe((S)-2-((2S,5S,8S,11S)-2-((1H-imidazol-4-yl)methyl)-11-((S)-2-amino-3-(1-trityl-1H-imidazol-4-yl)propanamido)-8-benzyl-5-(4-hydroxybenzyl)-4,7,10 ,17-tetraoxo-3,6,9,16-tetraazatetracosanamide)-N1-((S)-5-amino-1-(((S)-1-(((S)-1-(((S)-1-amino-1-oxo-3-phenylpropan-2-yl)amino)-5-guanidino-1-oxopentan-2-yl)amino)-1-oxopropan-2-yl)amino)-1,5-dioxopentan-2-yl)pentanediamide) was prepared. The purity and molecular weight of HKFY-42 are shown in Figures 109 and 110, respectively.

[0109] Example 1.43. Preparation of HKFY-43 Fmoc-His(trt)-Lys(caprylic acid)-Phe-Tyr(tBu)-Gln(trt)-Asn(trt)-Gln(trt)-Ala-Arg(pbf)-Phe-trityl resin was prepared in the same manner as in Example 1.41, except that Fmoc-Gln(trt)-OH was used instead of Fmoc-Gly-OH among the constituent amino acids. The protecting groups on the resin were cleaved to give His(trt)-Lys(caprylate)-Phe-Tyr-Gln-Asn-Gln-Ala-Arg-Phe((S)-N1-((S)-1-(((S)-1-(((S)-1-amino-1-oxo-3-phenylpropan-2-yl)amino)-5-guanidino-1-oxopentan-2-yl)amino)-1-oxopropan-2-yl)-2-((2S,5S,8S, 11S,14S)-2-(2-amino-2-oxoethyl)-14-((S)-2-amino-3-(1-trityl-1H-imidazol-4-yl)propanamide)-5-(3-amino-3-oxopropyl)-11-benzyl-8-(4-hydroxybenzyl)-4,7,10,13,20-pentaoxo-3,6,9,12,19-pentaazaheptacosanamide) pentanediamide) was prepared. The purity and molecular weight of HKFY-43 are shown in Figures 111 and 112, respectively.

[0110] Example 1.44. Preparation of HKFY-44 To prepare His(trt)-Lys(caprylic acid)-Phe-Tyr-Trp, Fmoc-Trp(Boc)-OH and DMF were loaded onto trityl resin to prepare Fmoc-Trp(Boc)-trityl resin. Fmoc-Tyr(tBu)-OH and HOBt (hydroxyl-benzotriazole) were added to Fmoc-Trp(Boc)-trityl resin to prepare Fmoc-Tyr(tBu)-Trp(Boc)-trityl resin. Similarly, Fmoc-Phe-OH, Fmoc-Lys(caprylic acid)-OH obtained in Example 1.1, and Fmoc-His(trt)-OH were added to the resin in that order to prepare Fmoc-His(trt)-Lys(caprylic acid)-Phe-Tyr(tBu)-Trp(Boc)-trityl resin. The protecting group of the resin was cleaved to prepare His(trt)-Lys(caprylic acid)-Phe-Tyr-Trp (N6-octanoyl-N2-(Nt-trityl-L-histidyl)-L-lysyl-L-phenylalanyl-L-tyrosyl-L-tryptophan). The purity and molecular weight of HKFY-44 are shown in Figures 113 and 114, respectively.

[0111] Example 1.45. Preparation of HKFY-45 D-Biotin-His(trt)-K(caprylate)-Bip-Tyr(Boc)-trityl resin was prepared in the same manner as in Example 1.2, except that Fmoc-Phe-OH was replaced with Fmoc-Bip-OH during the preparation process. The protecting group of the resin was cleaved to prepare Biotin-His(trt)-K(caprylic acid)-Bip-Tyr(((S)-3-([1,1'-biphenyl]-4-yl)-2-((S)-6-octanamido-2-((S)-2-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)-3-(1-trityl-1H-imidazol-4-yl)propanamido)hexanamido)propanoyl)-L-tyrosine). The purity and molecular weight of HKFY-45 are shown in Figures 115 and 116, respectively.

[0112] Example 1.46. Preparation of HKFY-46 Fmoc-Trp(Boc)-trityl resin was prepared by loading Fmoc-Phe-OH and DMF onto the Fmoc-Trp(Boc)-trityl resin obtained in Example 1.44. Similarly, Fmoc-Lys(caprylic acid)-OH and Fmoc-His(trt)-OH obtained in Example 1.1 were added in sequence to prepare Fmoc-His(trt)-Lys(caprylic acid)-Phe-Trp(Boc)-trityl resin. The protecting group of the resin was cleaved to prepare His(trt)-Lys(caprylic acid)-Phe-Trp (N6-octanoyl-N2-(Nt-trityl-L-histidyl)-L-lysyl-L-phenylalanyl-L-tryptophan). The purity and molecular weight of HKFY-46 are shown in Figures 117 and 118, respectively.

[0113] Example 1.47. Preparation of HKFY-47 To prepare N6-octanoyl-N2-(Nt-trityl-L-histidyl)-L-lysyl-L-tyrosyl-L-phenylalanine, Fmoc-Phe-trityl resin was prepared by loading Fmoc-Phe-OH and DMF onto a trityl resin. Similarly, Fmoc-Tyr(Boc)-OH, Fmoc-Lys(caprylic acid)-OH obtained in Example 1.1, and Fmoc-His(trt)-OH were added to the resin in sequence to prepare Fmoc-His(trt)-Lys(caprylic acid)-Tyr(Boc)-Phe-trityl resin. The protecting groups on the resin were cleaved to prepare His(trt)-Lys(caprylic acid)-Tyr-Phe (N6-octanoyl-N2-(Nt-trityl-L-histidyl)-L-lysyl-L-tyrosyl-L-phenylalanine). The purity and molecular weight of HKFY-47 are shown in Figures 119 and 120, respectively.

[0114] Example 1.48. Preparation of HKFY-48 To prepare HKFY-48 (N6-octanoyl-N2-(Nt-trityl-L-histidyl)-L-lysyl-L-tyrosyl-L-tyrosine), Fmoc-Tyr(Boc)-OH and DMF were loaded onto a trityl resin to prepare Fmoc-Tyr(Boc)-trityl resin. Similarly, Fmoc-Tyr(Boc)-OH, Fmoc-Lys(caprylic acid)-OH obtained in Example 1.1, and Fmoc-His(trt)-OH were added to the resin in sequence to prepare Fmoc-His(trt)-Lys(caprylic acid)-Tyr(Boc)-Tyr(Boc)-trityl resin. The protecting groups on the resin were cleaved to prepare His(trt)-Lys(caprylic acid)-Tyr-Tyr (N6-octanoyl-N2-(Nt-trityl-L-histidyl)-L-lysyl-L-tyrosyl-L-tyrosine). The purity and molecular weight of HKFY-48 are shown in Figures 121 and 122, respectively.

[0115] Example 1.49. Preparation of HKFY-49 Similarly, to prepare HKFY-49 (N6-octanoyl-N2-(Nt-trityl-L-histidyl)-L-lysyl-L-phenylalanine), Fmoc-Lys(caprylic acid)-OH and Fmoc-His(trt)-OH obtained in Example 1.1 were added sequentially to the Fmoc-Phe-trityl resin obtained in Example 1.47 to prepare Fmoc-His(trt)-Lys(caprylic acid)-Phe-trityl resin. The protecting group of the resin was cleaved to prepare His(trt)-Lys(caprylic acid)-Phe. The purity and molecular weight of HKFY-49 are shown in Figures 123 and 124, respectively.

[0116] Example 1.50. Preparation of HKFY-50 To prepare HKFY-50 (N6-octanoyl-N2-(Nt-trityl-L-histidyl)-L-lysyl-L-phenylalanyl-L-serine), Fmoc-Ser(tBu)-OH and DMF were loaded onto a trityl resin to prepare Fmoc-Ser(tBu)-trityl resin. Similarly, Fmoc-Phe-OH, Fmoc-Lys(caprylic acid)-OH obtained in Example 1.1, and Fmoc-His(trt)-OH were added to the resin in sequence to prepare Fmoc-His(trt)-Lys(caprylic acid)-Phe-Ser-trityl resin. The protecting group of the resin was cleaved to prepare His(trt)-Lys(caprylic acid)-Phe-Ser. The purity and molecular weight of HKFY-50 are shown in Figures 125 and 126, respectively.

[0117] Example 1.51. Preparation of HKFY-51 His(trt)-Lys(caprylic acid)-Leu-Tyr (N6-octanoyl-N2-(Nt-trityl-L-histidyl)-L-lysyl-L-leucyl-L-tyrosine) was prepared in the same manner as in Example 1.48, except that Fmoc-Leu-OH was used instead of Fmoc-Tyr(Boc)-OH among the constituent amino acids. The purity and molecular weight of HKFY-51 are shown in Figures 127 and 128, respectively.

[0118] Example 1.52. Preparation of HKFY-52 Similarly, Fmoc-Asp(tBu)-OH, Fmoc-Tyr(Boc)-OH, Fmoc-Phe-OH, and Fmoc-His(trt)-OH were added sequentially to the Fmoc-Gln(trt)-Gln(trt)-Ala-Arg(pbf)-Phe-trityl resin obtained in Example 1.38 to prepare Fmoc-His(trt)-Phe-Tyr(Boc)-Asp(tBu)-Gln(trt)-Ala-Arg(pbf)-Phe-trityl resin. The protecting groups on the resin were cleaved to give His(trt)-Phe-Tyr-Asp-Gln-Gln-Ala-Arg-Phe((6S,9S,12S,15S,18S)-1-amino-6-(((S)-1-amino-1-oxo-3-phenylpropan-2-yl)carbamoyl)-18-((S)-2-((S)-2-amino-3-(1-triphenylpropan-2-yl)carbamoyl). Lithyl-1H-imidazol-4-yl)propanamido)-3-phenylpropanamido)-3-(4-hydroxyphenyl)propanamido)-12,15-bis(3-amino-3-oxopropyl)-1-imino-9-methyl-8,11,14,17-tetraoxo-2,7,10,13,16-pentaazaicosan-20-oic acid) was prepared. The purity and molecular weight of HKFY-52 are shown in Figure 129 and Figure 130, respectively.

[0119] Example 1.53. Preparation of HKFY-53 Similarly, Fmoc-Lys(caprylic acid)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Gly-OH, and Fmoc-His(trt)-OH obtained in Example 1.1 were added to the Fmoc-Phe-Tyr(Boc)-trityl resin obtained in Example 1.47 in order to prepare Fmoc-His(trt)-Gly-Ser(tBu)-Lys(caprylic acid)-Phe-Tyr(Boc)-trityl resin. The protecting group of the resin was cleaved to prepare His(trt)-Gly-Ser-Lys(caprylic acid)-Phe-Tyr (N6-octanoyl-N2-(Nt-trityl-L-histidylglycyl-L-seryl)-L-lysyl-L-phenylalanyl-L-tyrosine). The purity and molecular weight of HKFY-53 are shown in Figures 131 and 132, respectively.

[0120] Example 1.54. Preparation of HKFY-54 Fmoc-Lys(caprylic acid)-OH obtained in Example 1.1, DMF and HOBt were added to the Fmoc-Phe-Tyr(Boc)-trityl resin obtained in Example 1.47 to prepare Fmoc-Lys(caprylic acid)-Phe-Tyr(Boc)-trityl resin. The protecting group of the resin was cleaved to prepare Lys(caprylic acid)-Phe-Tyr(N6-octanoyl-L-lysyl-L-phenylalanyl-L-tyrosine). The purity and molecular weight of HKFY-54 are shown in Figures 133 and 134, respectively.

[0121] Example 1.55. Preparation of HKFY-55 Similarly, Fmoc-Lys(caprylic acid)-His(trt)-Phe-Tyr(Boc)-trityl resin was prepared by sequentially adding Fmoc-His(trt)-OH and Fmoc-Lys(caprylic acid)-OH obtained in Example 1.1 to the Fmoc-Phe-Tyr(Boc)-trityl resin obtained in Example 1.47. The protecting group of the resin was cleaved to prepare Lys(caprylic acid)-His(trt)-Phe-Tyr (Na-(N6-octanoyl-L-lysyl)-Nt-trityl-L-histidyl-L-phenylalanyl-L-tyrosine). The purity and molecular weight of HKFY-55 are shown in Figures 135 and 136, respectively.

[0122] Example 1.56. Preparation of HKFY-56 Fmoc-Asp(tBu)-Gln(trt)-Gln(trt)-Ala-Arg(pbf)-Phe-trityl resin was prepared in the same manner as in Example 1.38, except that Fmoc-Asp(tBu)-OH was used instead of Fmoc-Ser(tBu)-OH. Fmoc-Lys-OH was prepared by adding DMF containing 2% NH2NH2·H2O to Fmoc-Lys(dde)-OH and removing dde. Fmoc-Lys(caproic acid)-OH was prepared by adding DMF containing caproic acid, HOBt and DIC to Fmoc-Lys-OH. Similarly, Fmoc-Lys(caproic acid)-OH and Fmoc-His(trt)-OH were added sequentially to prepare Fmoc-His(trt)-Lys(caproic acid)-Phe-Tyr(Boc)-Asp(tBu)-Gln(trt)-Gln(trt)-Ala-Arg(pbf)-Phe-trityl resin. The protecting groups on the resin were cleaved to obtain His(trt)-Lys(caproic acid)-Phe-Tyr-Asp-Gln-Gln-Ala-Arg-Phe((6S,9S,12S,15S,18S)-1-amino-6-(((S)-1-amino-1-oxo-3-phenylpropan-2-yl)carbamoyl)-18-((S)-2-((S)-2-((S)-2-amino-3-(1-trityl-1 H-imidazol-4-yl)propanamido)-6-(non-1-en-2-ylamino)hexanamido)-3-phenylpropanamido)-3-(4-hydroxyphenyl)propanamido)-12,15-bis(3-amino-3-oxopropyl)-1-imino-9-methyl-8,11,14,17-tetraoxo-2,7,10,13,16-pentaazaicosan-20-oic acid) was prepared. The purity and molecular weight of HKFY-56 are shown in Figures 137 and 138, respectively.

[0123] Example 1.57. Preparation of HKFY-57 His(2-phenyl)-Lys(caprylic acid)-d-Phe(methyl)-Tyr(((R)-2-((S)-2-((S)-2-amino-3-(2-phenyl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanoyl)-L-tyrosine) was prepared in the same manner as in Example 1.34, except that Boc-His(2-phenyl)-OH was used instead of Boc-His(benzhydryl)-OH. The purity and molecular weight of HKFY-57 are shown in Figure 139 and Figure 140, respectively.

[0124] Example 1.58. Preparation of HKFY-58 His(1-phenyl)-Lys(caprylic acid)-d-Phe(methyl)-Tyr(((R)-2-((S)-2-((S)-2-amino-3-(1-phenyl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanoyl)-L-tyrosine) was prepared in the same manner as in Example 1.34, except that Boc-His(1-phenyl)-OH was used instead of Boc-His(benzhydryl)-OH. The purity and molecular weight of HKFY-58 are shown in Figures 141 and 142, respectively.

[0125] Example 1.59. Preparation of HKFY-59 His(1,2-diphenyl)-Lys(caprylic acid)-d-Phe(methyl)-Tyr(((R)-2-((S)-2-((S)-2-amino-3-(1,2-diphenyl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanoyl)-L-tyrosine) was prepared in the same manner as in Example 1.34, except that Boc-His(1,2-diphenyl)-OH was used instead of Boc-His(benzhydryl)-OH. The purity and molecular weight of HKFY-59 are shown in Figures 143 and 144, respectively.

[0126] Example 1.60. Preparation of HKFY-60 His(2-(4-tert-butyl)phenyl)-Lys(caprylic acid)-d-Phe(methyl)-Tyr(((R)-2-((S)-2-((S)-2-amino-3-(2-(4-(tert-butyl)phenyl)-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanoyl)-L-tyrosine) was prepared in the same manner as in Example 1.34, except that Boc-His(2-(4-tert-butyl)phenyl)-OH was used instead of Boc-His(benzhydryl)-OH. The purity and molecular weight of HKFY-60 are shown in Figures 145 and 146, respectively.

[0127] Example 1.61. Preparation of HKFY-61 His(1-(4-tert-butyl)phenyl)-Lys(caprylic acid)-d-Phe(methyl)-Tyr(((R)-2-((S)-2-((S)-2-amino-3-(1-(4-(tert-butyl)phenyl)-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanoyl)-L-tyrosine) was prepared in the same manner as in Example 1.34, except that Boc-His(1-(4-tert-butyl)phenyl)-OH was used instead of Boc-His(benzhydryl)-OH. The purity and molecular weight of HKFY-61 are shown in Figures 147 and 148, respectively.

[0128] Example 1.62. Preparation of HKFY-62 D-His(benzhydryl)-Lys(caprylic acid)-d-Phe(methyl)-Tyr(((R)-2-((S)-2-((R)-2-amino-3-(1-benzhydryl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanoyl)-L-tyrosine) was prepared in the same manner as in Example 1.34, except that Boc-d-His(benzhydryl)-OH was used instead of Boc-His(benzhydryl)-OH. The purity and molecular weight of HKFY-62 are shown in the figure: 149 and 150, respectively.

[0129] Example 1.63. Preparation of HKFY-63 His(thiophene)-Lys(caprylic acid)-d-Phe(methyl)-Tyr(((R)-2-((S)-2-((S)-2-amino-3-(2-(thiophen-2-yl)-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanoyl)-L-tyrosine) was prepared in the same manner as in Example 1.34, except that Boc-His(thiophene)-OH was used instead of Boc-His(benzhydryl)-OH. The purity and molecular weight of HKFY-63 are shown in Figures 151 and 152, respectively.

[0130] Example 1.64. Preparation of HKFY-64 His(4-methoxybenzhydryl)-Lys(caprylic acid)-d-Phe(methyl)-Tyr(((2R)-2-((2S)-2-((2S)-2-amino-3-(1-((4-methoxyphenyl)(phenyl)methyl)-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanoyl)-L-tyrosine) was prepared in the same manner as in Example 1.34, except that Boc-His(4-methoxybenzhydryl)-OH was used instead of Boc-His(benzhydryl)-OH. The purity and molecular weight of HKFY-64 are shown in Figures 153 and 154, respectively.

[0131] Example 1.65. Preparation of HKFY-65 His(4-hydroxybenzhydryl)-Lys(caprylic acid)-d-Phe(methyl)-Tyr(((2R)-2-((2S)-2-((2S)-2-amino-3-(1-((4-hydroxyphenyl)(phenyl)methyl)-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanoyl)-L-tyrosine) was prepared in the same manner as in Example 1.34, except that Boc-His(4-hydroxybenzhydryl)-OH was used instead of Boc-His(benzhydryl)-OH. The purity and molecular weight of HKFY-65 are shown in Figure 155 and Figure 156, respectively.

[0132] Example 1.66. Preparation of HKFY-66 His(benzhydryl)-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr-NH2, (N-((S)-5-((S)-2-amino-3-(1-benzhydryl-1H-imidazol-4-yl)propanamide)-6-(((R)-1-(((S)-1-amino-3-(4-hydroxyphenyl)-1-oxopropan-2-yl)amino)-1-oxo-3-(p-tolyl)propan-2-yl)amino)-6-oxohexyl)octanamide) was prepared in the same manner as in Example 1.34, except that Fmoc-Tyr-wang resin was used instead of trityl resin. The purity and molecular weight of HKFY-66 are shown in Figures 157 and 158, respectively.

[0133] Example 1.67. Preparation of HKFY-67 His(benzhydryl)-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr(3-chloro)((S)-2-((R)-2-((S)-2-((S)-2-amino-3-(1-benzhydryl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanamido)-3-(3-chloro-4-hydroxyphenyl)propanoic acid) was prepared in the same manner as in Example 1.34, except that Fmoc-Tyr(3-chloro) was used instead of Fmoc-Tyr(tBu). The purity and molecular weight of HKFY-67 are shown in Figures 159 and 160, respectively.

[0134] Example 1.68. Preparation of HKFY-68 His(benzhydryl)-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr(3-nitro)((S)-2-((R)-2-((S)-2-((S)-2-amino-3-(1-benzhydryl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanamido)-3-(4-hydroxy-3-nitrophenyl)propanoic acid) was prepared in the same manner as in Example 1.34, except that Fmoc-Tyr(3-nitro) was used instead of Fmoc-Tyr(tBu). The purity and molecular weight of HKFY-68 are shown in Figures 161 and 162, respectively.

[0135] Example 1.69. Preparation of HKFY-69 His(benzhydryl)-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr(3,5-nitro)((S)-2-((R)-2-((S)-2-((S)-2-amino-3-(1-benzhydryl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanamido)-3-(4-hydroxy-3,5-dinitrophenyl)propanoic acid) was prepared in the same manner as in Example 1.34, except that Fmoc-Tyr(3,5-nitro) was used instead of Fmoc-Tyr(tBu). The purity and molecular weight of HKFY-69 are shown in Figures 163 and 164, respectively.

[0136] Example 1.70. Preparation of HKFY-70 His(benzhydryl)-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr(3-amino)((S)-2-((R)-2-((S)-2-((S)-2-amino-3-(1-benzhydryl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanamido)-3-(3-amino-4-hydroxyphenyl)propanoic acid) was prepared in the same manner as in Example 1.34, except that Fmoc-Tyr(3-amino) was used instead of Fmoc-Tyr(tBu). The purity and molecular weight of HKFY-70 are shown in Figure 165 and Figure 166, respectively.

[0137] Example 1.71. Preparation of HKFY-71 His(benzhydryl)-Orn(caprylic acid)-d-Phe(4-methyl)-Tyr(((R)-2-((S)-2-((S)-2-amino-3-(1-benzhydryl-1H-imidazol-4-yl)propanamido)-5-octanamidopentanamido)-3-(p-tolyl)propanoyl)-L-tyrosine) was prepared in the same manner as in Example 1.34, except that Fmoc-Orn(dde) was used instead of Fmoc-Lys(dde). The purity and molecular weight of HKFY-71 are shown in Figures 167 and 168, respectively.

[0138] Example 1.72. Preparation of HKFY-72 Similar to the synthesis process of D-biotin in Example 1.2, biotin-His(benzhydryl)-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr(((S)-2-((S)-2-((S)-3-(1-benzhydryl-1H-imidazol-4-yl)-2-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanoyl)-L-tyrosine) was prepared using His(benzhydryl)-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr-OH in Example 1.34. The purity and molecular weight of HKFY-72 are shown in Figure 169 and Figure 170, respectively.

[0139] Example 1.73. Preparation of HKFY-73 H(trt)Lys(caprylic acid)-d-3Pal-Tyr(((R)-2-((S)-2-((S)-2-amino-3-(1-trityl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(pyridin-3-yl)propanoyl)-L-tyrosine) was prepared in the same manner as in Example 1.12, except that Fmoc-d-3Pal was used instead of Fmoc-d-Phe-OH. The purity and molecular weight of HKFY-73 are shown in Figures 171 and 172, respectively.

[0140] Example 1.74. Preparation of HKFY-74 H(trt)Lys(caprylic acid)-d-2Nal-Tyr(((R)-2-((S)-2-((S)-2-amino-3-(1-trityl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(naphthalen-2-yl)propanoyl)-L-tyrosine) was prepared in the same manner as in Example 1.73, except that Fmoc-d-2Nal was used instead of Fmoc-d-3Pal among the constituent amino acids. The purity and molecular weight of HKFY-74 are shown in the figure, 173 and 174, respectively.

[0141] Example 1.75. Preparation of HKFY-75 His(tosyl)-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr(((R)-2-((S)-2-((S)-2-amino-3-(1-tosyl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanoyl)-L-tyrosine) was prepared in the same manner as in Example 1.34, except that Boc-His(tosyl)-OH was used instead of Boc-His(benzhydryl)-OH among the constituent amino acids. The purity and molecular weight of HKFY-75 are shown in Figures 175 and 176, respectively.

[0142] Example 1.76. Preparation of HKFY-76 His(trityl)-Lys(caprylic acid)-d-Phe(4-CF3)-Tyr(((R)-2-((S)-2-((S)-2-amino-3-(1-trityl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(4-(trifluoromethyl)phenyl)propanoyl)-L-tyrosine) was prepared in the same manner as in Example 1.73, except that Fmoc-d-Phe(4-CF3) was used instead of Fmoc-d-3Pal. The purity and molecular weight of HKFY-76 are shown in Figures 177 and 178, respectively.

[0143] Example 1.77. Preparation of HKFY-77 His(tbm)-Lys(caprylic acid)-d-Phe(4-CF3)-Tyr(((R)-2-((S)-2-((S)-3-(1-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-1H-imidazol-4-yl)-2-aminopropanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanoyl)-L-tyrosine) was prepared in the same manner as in Example 1.34, except that Boc-His(tbm)-OH was used instead of Boc-His(benzhydryl)-OH. The purity and molecular weight of HKFY-77 are shown in Figure 179 and Figure 180, respectively.

[0144] Example 1.78. Preparation of HKFY-78 Boc-Trp-Lys(caprylic acid)-d-Phe(4-methyl)-Tyr(((R)-2-((S)-2-((S)-2-((tert-butoxycarbonyl)amino)-3-(1H-indol-3-yl)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanoyl)-L-tyrosine) was prepared in the same manner as in Example 1.34, except that Boc-Trp-OH was used instead of Boc-His(benzhydryl)-OH. The purity and molecular weight of HKFY-78 are shown in Figures 181 and 182, respectively.

[0145] Example 1.79. Preparation of HKFY-79 Fmoc-Lys(dde) and DMF (dimethylformamide) were loaded onto trityl resin to prepare Fmoc-Lys(dde)-trityl resin. Fmoc-Lys(caprylic acid)-trityl resin was prepared in the same manner as in the synthesis process of Example 1.1. Then, His(benzhydryl)-Lys(caprylic acid) (N2-(Nt-benzhydryl-L-histidyl)-N6-octanoyl-L-lysine) was prepared using Boc-His(benzhydryl)-OH.

[0146] The HKFY peptide derivatives prepared by the above-mentioned preparation method are shown in Table 1 below. [Table 1] JPEG0007627783000016.jpg193149 JPEG0007627783000017.jpg199149 JPEG0007627783000018.jpg176149 JPEG0007627783000019.jpg191149 JPEG0007627783000020.jpg203149 JPEG0007627783000021.jpg203149 JPEG0007627783000022.jpg198149 JPEG0007627783000023.jpg198149 JPEG0007627783000024.jpg187149

[0147] Experimental Example 1. Analysis of HKFY derivatives The HKFY derivatives prepared in Examples 1.1 to 1.79 were analyzed for purity and molecular weight using HPLC and ion mass. The results are shown in Table 2 below, and the HPLC analysis results of the HKFY derivatives are shown in Figures 1 to 36, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, 167, 169, 171, 173, 175, 177, 179, 181 and 182. 3, the results of ion-mass spectrometry of the HKFY derivatives are shown in Figures 37 to 72, 100, 102, 104, 106, 108, 110, 112, 114, 117, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182 and 184. [Table 2] JPEG0007627783000026.jpg225149 JPEG0007627783000027.jpg68149

[0148] Experimental Example 2. Confirmation of the binding ability of HKFY derivatives to the GPR39 receptor A luciferase assay system was used to examine the binding ability of the HKFY derivatives prepared in the above Examples 1.1 to 1.79 to GPR39. The luciferase assay system is a method for confirming the degree of activity of a receptor in a cell by binding a ligand to the receptor in the cell. Specifically, the fibroblast cell line CV-1 (1 × 10 5 After culturing for 24 hours in a 96-well cell culture plate, the cells were treated with 50 MOI (multiplicity of infection) and 25 MOI of adenovirus-inserted GPR39 and SRE (serum response element) luciferase, respectively, for 3 hours and then cultured for 24 hours. After 24 hours, the medium was replaced with serum-free medium and cultured for 16 hours to provide a fasting process. After that, the cells were treated with each HKFY and HKFY derivative for 6 hours and cultured, and the expression level of the reporter gene luciferase was quantified by activated GPR39 using a luminometer (Table 3). [Table 3] JPEG0007627783000029.jpg225149 JPEG0007627783000030.jpg68149

[0149] As a result, referring to Table 3, it was confirmed that all HKFY derivatives had high activity against GPR39 at the nM to μM level. In addition, among the analogs in which various fatty acids were conjugated to Lys, the analog bound to caprylic acid showed the most excellent activity. Derivatives showing activity at the nM level are considered to have highly selective and specific activity against GPR39. On the other hand, the HKFY-30, HKFY-34, HKFY-63, HKFY-64 and HKFY-65 derivatives showed higher activity levels than the other HKFY derivatives. In particular, HKFY-30 and HKFY-34, which are composed of d-Phe (methyl), showed the highest activity and high ECmax value.

[0150] Experimental Example 3. Confirmation of selectivity and specificity of HKFY derivatives for GPR39 To confirm the selectivity and specificity of the HKFY derivatives to GPR39, the degree of activity was confirmed by a luciferase assay system and a calcium influx assay system (FIG. 73 and Table 4). Specifically, the activity of HKFY-34, one of the HKFY derivatives in Experimental Example 2, was analyzed by luciferase assay (Figure 73, upper part). In the calcium influx assay, the fibroblast cell line CV-1 (1 x 10 5 73 cells / mL) were transfected with a mixture of human GPR39 (pCDNA3.1_hGPR39, American Type Culture Collection), Gαq (pCDNA3.1_Gαq, American Type Culture Collection), Aequorin (pCDNA3.1_aequrin, American Type Culture Collection), and Lipofectamine (American Type Culture Collection). The medium was then replaced with serum-free medium, and after fasting for 16 hours, the cells were treated with HKFY-34 for 6 hours and cultured. After the culture, the degree of binding of calcium activated by activated GPR39 to aequorin was quantified using a luminometer (lower part of Figure 73). [Table 4]

[0151] As a result, referring to FIG. 73 and Table 4, it was confirmed that treatment with HKFY-34 resulted in superior binding ability and activity to the GPR39 receptor. Furthermore, activity tests of HKFY derivatives against receptors similar to GPR39, the ghrelin receptor family (ghrelin receptor (GHSR), motilin receptor (MTLR), neurotensin receptor (NTSR1 and NTSR2), neuromedin U receptor (NMU1 and NMU2), and TRH (thyrotropin-releasing hormone) receptor (TRHR)) confirmed selectivity and specificity for the GPR39 receptor. Specifically, the degree of activity between endogenous ligands for each receptor and HKFY-34 was analyzed using a luciferase assay system (FIG. 74). As a result, referring to FIG. 74, it was confirmed that HKFY-34 had very low activity against GHSR, MTLR, NTSR1 and NTSR2, NMU1 and NMU2, and TRHR. These results suggested that the HKFY derivatives could be used as agonists that selectively and specifically bind to the GPR39 receptor.

[0152] Experimental Example 4. Evaluation of the promoting activity of HKFY-34 on intestinal tissue cell growth From a study using GPR39-deficient mice, it is known that GPR39 is involved in the growth and differentiation of intestinal tissue cells (Phil. Trans. R. Soc. B., 2016, 371: 20150420). Therefore, to confirm the effect of HKFY-34 on the growth of intestinal tissue cells, we measured the degree of cell proliferation induced by HKFY-34 using HT-29 cells (Korea Cell Line Bank), which are intestinal epithelial cells. Specifically, HT-29 cells were cultured in 96-well plates and then treated with different concentrations of HKFY-34 for 24, 48 and 72 hours. The cell proliferation of the cultured cells was measured using a Cellvia kit (AB frontier) and a BrdU cell proliferation kit (abcam). As a result, the proliferation of HT-29 cells was increased by HKFY-34 in a dose-dependent manner (Figure 75). Studies using GPR39-deficient mice have shown that calcium signaling is involved in GPR39-induced intestinal cell growth (Phil. Trans. R. Soc. B. 2016, 371: 20150420). Therefore, we investigated whether calcium signaling is involved in cell growth promoted by HKFY-34. Specifically, HT-29 cells were cultured in 96-well black culture plates, then treated with HKFY-34, and the intracellular calcium ion concentration was measured using Fluo-8 direct™ calcium assay kit (Thermo Fisher Scientific). As a result, the calcium ion concentration in HT-29 cells was increased by HKFY-34 compared to the untreated group (vehicle) (Figure 76).

[0153] Experimental Example 5. Evaluation of the promoting activity of HKFY-34 on tight junctions GPR39 is known to be involved in gastrointestinal protection (Phil. Trans. R. Soc. B., 2016, 371: 20150420). To confirm the effect of HKFY-34 on the gastrointestinal protective function of GPR39, we evaluated the promoting activity of HKFY-34 on tight junctions using HT-29 cells, which are important for intestinal tissue formation. Specifically, after treating HT-29 cells with different concentrations of HKFY-34, the expression levels of ZO-1 and occludin, which are important factors in tight junctions in the intestinal barrier function, mRNA (Figure 77) and protein (Figure 78) were confirmed by quantitative RT-PCR (qPCR) and Western blot. As a result, the expression levels of ZO-1 and occludin mRNA and protein were significantly increased by HKFY-34 in a dose-dependent manner compared to the untreated group (vehicle) (Figures 77 and 78). Tight junctions are known to be mediated by a signal transduction mechanism involving phosphorylation of AMPK protein. Therefore, to confirm whether AMPK is involved in the increase in tight junctions by HKFY-34, we confirmed the expression of p-AMPK in HT-29 cells (Figures 79 and 80).

[0154] As a result, the expression of p-AMPK protein was increased by HKFY-34 in a dose-dependent manner compared to the untreated group (vehicle) (Figure 79). In addition, it was confirmed that the expression level of p-AMPK increased by HKFY-34 treatment was reduced when the cells were pretreated with an AMPK inhibitor (STO-609) and then treated with HKFY-34 (Figure 80). These results indicate that HKFY-34 acts as a GPR39 agonist, thereby enhancing tight junctions.

[0155] Experimental Example 6. Evaluation of the anti-inflammatory activity of HKFY-34 in a cell model of inflammatory bowel disease To confirm the effect of HKFY-34 on the anti-inflammatory action, which is one of the gastrointestinal protective functions (barrier function) of GPR39, we evaluated the anti-inflammatory activity of HKFY-34 in a cell model of inflammatory bowel disease (IBD). Specifically, HT-29 cells were treated with 1 μg / mL LPS to induce inflammation to prepare an inflammatory bowel disease model, and then treated with different concentrations of HKFY-34.Then, the expression levels of ulcerative colitis inflammatory factors mRNA (Figure 81) and protein (Figure 82) were measured by qPCR and ELISA.

[0156] As a result, the mRNA expression levels of the pro-inflammatory cytokines IL-8, IL-6, IL-1β, and TNF-α, which were increased by LPS treatment, were significantly decreased by HKFY-34 treatment in a dose-dependent manner (Figure 81). Furthermore, the secretion levels of IL-8, IL-6, IL-1β, and TNF-α in HT-29 cells treated with LPS were also significantly decreased by HKFY-34 treatment in a dose-dependent manner (Figure 82). These results indicate that HKFY-34, which acts as a GPR39 agonist, may have the effect of alleviating and treating inflammation in inflammatory bowel disease.

[0157] Experimental Example 7. Evaluation of the anti-inflammatory activity of HKFY-34 in an animal model of inflammatory bowel disease The anti-inflammatory activity of HKFY-34 was evaluated in an animal model of inflammatory bowel disease. Specifically, an animal model of ulcerative colitis, one of inflammatory bowel diseases, was created by administering water containing 3% DSS (dextran sodium sulfate) to C57BL6 / J mice (Central Lab. Animal Inc.). Untreated (vehicle) mice served as the control group, mice fed only DSS (vehicle + 3% DSS) served as the negative control group, and mice treated with DSS followed by intraperitoneal administration of 50 mg / kg SASP (sulfasalazine) (SASP 50 mg / kg + 3% DSS) served as the positive control group. For the test groups, mice were intraperitoneally administered 0.1 mg / kg, 1 mg / kg, and 10 mg / kg HKFY-34, respectively. HKFY-34 was administered once daily for 5 days, and fecal status and weight loss were measured in subjects during the administration period. Fecal status was observed for the degree of fecal softness (fecal hardness, diarrhea) and bloody stool (fecal bleeding), and a score was assigned from 0 (lowest) to 3 (highest) in proportion to the severity compared to the control group.

[0158] As a result, weight loss, a symptom of ulcerative colitis, was significantly inhibited by HKFY-34 in a dose-dependent manner in the test group administered HKFY-34, compared to the positive control group SASP (Figure 83). Furthermore, the colon length of all subjects who completed the treatment was measured, and HKFY-34 dose-dependently reduced colon length contraction due to inflammatory damage in the HKFY-34 test group, compared to the negative control group (Figure 84). Furthermore, observation of the stool of each subject confirmed that ulcerative colitis was alleviated in a dose-dependent manner in the test group administered HKFY-34 (FIGS. 85 and 86). To confirm the anti-inflammatory effect of HKFY-34 administration on colonic tissue, the mRNA expression levels of pro-inflammatory cytokines in colonic tissue of each group were confirmed by qPCR. As a result, the mRNA expression levels of IL-8, IL-6, IL-1β, and TNF-α in intestinal tissue were significantly decreased in the HKFY-34 administration group compared to the negative control group (Figure 87). In addition, the concentrations of IL-1β and TNF-α in the blood were significantly decreased in the HKFY-34 test group compared to the negative control group (Figure 88). For histological analysis of the colonic tissues of each group, H&E (hematoxylin and eosin) staining was performed on the colonic tissues of the negative control group, positive control group, and test group. The infiltration rate of immune cells (macrophages) in the colonic mucosa, the loss rate of mucus-secreting cells, the structural collapse rate of colonic villi, and the loss rate of secretory glands were confirmed for the stained tissues, and the degree of damage was analyzed and scored compared to the control group. As a result, it was confirmed that the degree of damage caused by inflammation of the colonic tissue was alleviated in the test group administered HKFY-34 compared to the negative control group (Figure 89). In addition, we confirmed the expression levels of factors important for tight junctions in colonic tissue in each subject, and found that in subjects treated with HKFY-34, the mRNA expression levels of ZO-1 and occludin were significantly increased by HKFY-34 in a dose-dependent manner (Figure 90).

[0159] Experimental Example 8. Evaluation of anti-inflammatory activity of HKFY-34 in an inflammatory bowel disease-induced GPR39-deficient mouse model To confirm the effect of HKFY-34 in an inflammatory bowel disease model using GPR39 as a target substance, we used GPR39-deficient mice (GPR39 knockout (KO), Gpr39 - / - ) to create a disease model of ulcerative colitis, with wild-type mice born from the same litter serving as controls for each treatment group of GPR39-deficient mice. Specifically, an animal model of ulcerative colitis was created by giving water containing 3% DSS to GPR39-deficient mice (Lexicon Pharmaceuticals) and wild-type mice in the same manner as in Experimental Example 7. GPR39 KO mice given only DSS (vehicle + 3% DSS) served as the negative control group, and GPR39 KO mice given HKFY-34 (10 mg / kg) (HKFY-34 10 mg / kg + 3% DSS) served as the test group. Intraperitoneal administration was performed once a day for 5 days.

[0160] As a result, weight loss was inhibited by administration of HKFY-34 in ulcerative colitis-induced wild-type mice, whereas no inhibitory effect of HKFY-34 on weight loss was observed in ulcerative colitis-induced GPR39-deficient mice (Figure 91). Furthermore, the decrease in colon length was inhibited by administration of HKFY-34 in ulcerative colitis-induced wild-type mice, whereas the inhibitory effect of HKFY-34 on the shortening of colon length was not observed in ulcerative colitis-induced GPR39-deficient mice (Figure 92). When the stool condition of GPR39-deficient mice with ulcerative colitis was observed, the HKFY-34 administration test group showed no effect of reducing stool hardness or bloody stool compared to the negative control group (Figures 93 and 94). Histological analysis by H&E (hematoxylin-eosin) staining showed that inflammatory damage in colon tissue was reduced in the HKFY-34-administered test group in ulcerative colitis-induced wild-type mice, whereas HKFY-34 did not show any effect of reducing inflammatory damage in ulcerative colitis-induced GPR39-deficient mice (Figure 95). These results show that HKFY-34 did not alleviate ulcerative colitis in GPR39-deficient mice, indicating that HKFY-34 is an agonist that targets GPR39.

Claims

1. A composition for preventing or treating inflammatory bowel disease, comprising a compound represented by the following formula 1 or a pharma- ceutically acceptable salt thereof: [Formula 1] 【Chemistry 1】 (In formula 1, A is -C(-R ０ )-, -N= or -N(-R １ ) -, and Cy is C ６～１４ aryl or 6-membered heteroaryl; R1 is hydrogen or a C 6-14 aryl or C 3-10 cycloalkyl substituted with １～６ is alkyl, R 3 is (i) hydrogen, C 3-10 cycloalkyl, C 6-14 aryl optionally substituted with C 1-6 alkyl, or an amine protecting group; (ii) methyl substituted with one phenyl, said phenyl with or without one or more substituents selected from the group consisting of halogen, —OH, C 6-14 aryl substituted with 5- to 6-membered heteroaryl, C 1-6 alkyl, and C 1-6 alkoxy; or (iii) C 1-6 alkyl substituted by two or three phenyl, said phenyl having or having one or more substituents selected from the group consisting of halogen, —OH, C 1-6 alkyl, and C 1-6 alkoxy; R ２ is hydrogen, C 6-14 aryl optionally substituted with C 1-6 alkyl, or 5- to 6-membered heteroaryl; R ０ is hydrogen or R ０ and R ２ are linked together to form a benzene ring together with the two carbon atoms to which they are attached, n is 3 or 4; R ４ is a C5-C17 alkylcarbonyl; R ５ is hydrogen, halogen, CF ３ Or C １～６ is alkyl, when R 3 is methyl substituted with two phenyl, wherein at least one of said phenyl has one or more substituents selected from the group consisting of halogen, —OH, C 1-6 alkyl and C 1-6 alkoxy, R 5 is not hydrogen; R ６ is hydrogen, C １～１０ Alkyl or -S(=O) ２ OH, R ７ and R ８ are each independently hydrogen, halogen, nitro, amine or C １～６ is alkyl, R ９ is -OH or -NH ２ and R １０ is hydrogen, an amine protecting group, or biotin; Each of the heteroaryls independently contains at least one heteroatom selected from the group consisting of N, S, and O.

2. A is -N(R 1 )-, R １ But hydrogen, 【Chemistry 2】 or 【Chemistry 3】 2. The composition of claim 1 ,

3. A is -C(R 0 )-, R ２ is hydrogen, 【Chemistry 4】 or 【Chemistry 5】 and R ０ is hydrogen or R ０ and R ２ The composition of claim 1 , wherein:

4. R ３ but, 【Chemistry 6】 and 【Chemistry 7】 The composition of claim 1 , which is selected from the group consisting of:

5. A is -C(-R ０ 2. The composition of claim 1, wherein N=- or -N=.

6. R ３ but, 【Chemistry 8】 2. The composition of claim 1 ,

7. R ４ The composition of claim 1 , wherein is heptylcarbonyl.

8. R ５ is methyl or CF ３ 2. The composition of claim 1 ,

9. R ６ is hydrogen or S(=O) ２ 2. The composition of claim 1, wherein said alkyl group is OH.

10. R ７ and R ８ The composition of claim 1 , wherein each is independently hydrogen or an amine.

11. R ９ The composition of claim 1 , wherein is —OH.

12. R １０ The composition of claim 1, wherein is hydrogen, p-toluenesulfonyl (Ts), t-butoxycarbonyl (Boc), or biotin.

13. The composition of claim 1 , wherein Cy is pyridyl, naphthyl, or phenyl.

14. The compound is selected from the group consisting of: 1) N6-octanoyl-N2-(Nt-trityl-L-histidyl)-L-lysyl-L-phenylalanyl-L-tyrosine, 2) N6-octanoyl-N2-(Na-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoyl)-Nt-trityl-L-histidyl)-L-lysyl-L-phenylalanyl-L-tyrosine; 3) N2-(Nt-benzyl-L-histidyl)-N6-octanoyl-L-lysyl-L-phenylalanyl-L-tyrosine, 4) N6-octanoyl-N2-(Nt-trityl-D-histidyl)-L-lysyl-L-phenylalanyl-L-tyrosine, 5) N2-(Nt-(diphenyl(p-tolyl)methyl)-L-histidyl)-N6-octanoyl-L-lysyl-L-phenylalanyl-L-tyrosine, 7) N2-((S)-2-amino-3-(3-(2-cyclohexylethyl)-2,3-dihydro-1H-imidazol-4-yl)propanoyl)-N6-octanoyl-L-lysyl-L-phenylalanyl-L-tyrosine, 12) N6-(non-1-en-2-yl)-N2-(Nt-trityl-L-histidyl)-L-lysyl-D-phenylalanyl-L-tyrosine, 13) ((R)-2-((S)-2-((S)-2-amino-3-(1-trityl-1H-imidazol-4-yl)propanamido)-6-(non-1-en-2-ylamino)hexanamido)-3-(4-chlorophenyl)propanoyl)-L-tyrosine, 14) ((R)-2-((S)-2-((R)-2-amino-3-(1-trityl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(4-chlorophenyl)propanoyl)-D-tyrosine, 15) ((R)-2-((S)-2-((S)-2-amino-3-(1-trityl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(4-chlorophenyl)propanoyl)-D-tyrosine, 16) ((R)-2-((R)-2-((S)-2-amino-3-(1-trityl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(4-chlorophenyl)propanoyl)-L-tyrosine, 17) N2-(Nt-(2,2-diphenylethyl)-L-histidyl)-N6-octanoyl-L-lysyl-L-phenylalanyl-L-tyrosine, 18) N2-(Nt-(9H-fluoren-9-yl)-L-histidyl)-N6-octanoyl-L-lysyl-L-phenylalanyl-L-tyrosine, 23) N2-(Nt-(adamantan-1-yl)-L-histidyl)-N6-octanoyl-L-lysyl-L-phenylalanyl-L-tyrosine, 24) N6-decanoyl-N2-(Nt-trityl-L-histidyl)-L-lysyl-L-phenylalanyl-L-tyrosine, 25) N6-dodecanoyl-N2-(Nt-trityl-L-histidyl)-L-lysyl-L-phenylalanyl-L-tyrosine, 26) N6-tetradecanoyl-N2-(Nt-trityl-L-histidyl)-L-lysyl-L-phenylalanyl-L-tyrosine, 27) N6-palmitoyl-N2-(Nt-trityl-L-histidyl)-L-lysyl-L-phenylalanyl-L-tyrosine, 28) ((R)-2-((S)-2-((S)-2-amino-3-(1-trityl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(4-fluorophenyl)propanoyl)-L-tyrosine, 29) ((R)-2-((S)-2-((S)-2-amino-3-(1-trityl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(4-bromophenyl)propanoyl)-L-tyrosine, 30) ((R)-2-((S)-2-((S)-2-amino-3-(1-trityl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanoyl)-L-tyrosine, 31) ((R)-2-((S)-2-((R)-2-amino-3-(1-trityl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanoyl)-L-tyrosine, 32) ((2R)-2-((2S)-2-((2S)-2-amino-3-(1-((2,4-difluorophenyl)(phenyl)methyl)-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanoyl)-L-tyrosine, 33) N2-(Nt-benzhydryl-L-histidyl)-N6-octanoyl-L-lysyl-L-phenylalanyl-L-tyrosine, 34) ((R)-2-((S)-2-((S)-2-amino-3-(1-benzhydryl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanoyl)-L-tyrosine, 35) (S)-2-((R)-2-((S)-2-((S)-2-amino-3-(1-benzhydryl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanamido)-3-(4-(sulfooxy)phenyl)propanoic acid, 36) (S)-2-((R)-2-((S)-2-((S)-2-amino-3-(1-benzhydryl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanamido)-3-(4-hydroxy-2,6-dimethylphenyl)propanoic acid, 45) ((S)-3-([1,1'-biphenyl]-4-yl)-2-((S)-6-octanamido-2-((S)-2-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)-3-(1-trityl-1H-imidazol-4-yl)propanamido)hexanamido)propanoyl)-L-tyrosine, 57) ((R)-2-((S)-2-((S)-2-amino-3-(2-phenyl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanoyl)-L-tyrosine, 58) ((R)-2-((S)-2-((S)-2-amino-3-(1-phenyl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanoyl)-L-tyrosine, 59) ((R)-2-((S)-2-((S)-2-amino-3-(1,2-diphenyl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanoyl)-L-tyrosine, 60) ((R)-2-((S)-2-((S)-2-amino-3-(2-(4-(tert-butyl)phenyl)-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanoyl)-L-tyrosine, 61) ((R)-2-((S)-2-((S)-2-amino-3-(1-(4-(tert-butyl)phenyl)-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanoyl)-L-tyrosine, 62) ((R)-2-((S)-2-((R)-2-amino-3-(1-benzhydryl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanoyl)-L-tyrosine, 63) ((R)-2-((S)-2-((S)-2-amino-3-(2-(thiophen-2-yl)-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanoyl)-L-tyrosine, 64) ((2R)-2-((2S)-2-((2S)-2-amino-3-(1-((4-methoxyphenyl)(phenyl)methyl)-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanoyl)-L-tyrosine, 65) ((2R)-2-((2S)-2-((2S)-2-amino-3-(1-((4-hydroxyphenyl)(phenyl)methyl)-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanoyl)-L-tyrosine, 66) N-((S)-5-((S)-2-amino-3-(1-benzhydryl-1H-imidazol-4-yl)propanamide)-6-(((R)-1-(((S)-1-amino-3-(4-hydroxyphenyl)-1-oxopropan-2-yl)amino)-1-oxo-3-(p-tolyl)propan-2-yl)amino)-6-oxohexyl)octanamide, 67) (S)-2-((R)-2-((S)-2-((S)-2-amino-3-(1-benzhydryl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanamido)-3-(3-chloro-4-hydroxyphenyl)propanoic acid, 68) (S)-2-((R)-2-((S)-2-((S)-2-amino-3-(1-benzhydryl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanamido)-3-(4-hydroxy-3-nitrophenyl)propanoic acid, 69) (S)-2-((R)-2-((S)-2-((S)-2-amino-3-(1-benzhydryl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanamido)-3-(4-hydroxy-3,5-dinitrophenyl)propanoic acid, 70) (S)-2-((R)-2-((S)-2-((S)-2-amino-3-(1-benzhydryl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanamido)-3-(3-amino-4-hydroxyphenyl)propanoic acid, 71) ((R)-2-((S)-2-((S)-2-amino-3-(1-benzhydryl-1H-imidazol-4-yl)propanamido)-5-octanamidopentanamido)-3-(p-tolyl)propanoyl)-L-tyrosine, 72) ((S)-2-((S)-2-((S)-3-(1-benzhydryl-1H-imidazol-4-yl)-2-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanoyl)-L-tyrosine, 73) ((R)-2-((S)-2-((S)-2-amino-3-(1-trityl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(pyridin-3-yl)propanoyl)-L-tyrosine, 74) ((R)-2-((S)-2-((S)-2-amino-3-(1-trityl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(naphthalen-2-yl)propanoyl)-L-tyrosine, 75) ((R)-2-((S)-2-((S)-2-amino-3-(1-tosyl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanoyl)-L-tyrosine, 76) ((R)-2-((S)-2-((S)-2-amino-3-(1-trityl-1H-imidazol-4-yl)propanamido)-6-octanamidohexanamido)-3-(4-(trifluoromethyl)phenyl)propanoyl)-L-tyrosine, 77) ((R)-2-((S)-2-((S)-3-(1-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-1H-imidazol-4-yl)-2-aminopropanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanoyl)-L-tyrosine, and 78) ((R)-2-((S)-2-((S)-2-((tert-butoxycarbonyl)amino)-3-(1H-indol-3-yl)propanamido)-6-octanamidohexanamido)-3-(p-tolyl)propanoyl)-L-tyrosine The composition of claim 1, which is any one selected from the group consisting of:

15. The composition of claim 1 , wherein the compound of formula 1 further comprises two amino acids attached to the N-terminus thereof.

16. The compound is １ ) - (X ２ )-[His(trt)-Lys(caprylic acid)-Phe-Tyr (In the formula, X １ and X ２ are each independently any one amino acid selected from the 20 amino acids, His(trt) is N-trityl-L-histidine, Lys (caprylic acid) is N-octanoyl-L-lysine, Phe is phenylalanine, and Tyr is tyrosine.

17. The compound is 37) The composition according to claim 16, which is N2-(Na-glycyl-L-seryl-Nt-trityl-L-histidyl)-N6-octanyl-L-lysyl-L-phenylalanyl-L-tyrosine.

18. The composition of claim 1, wherein the compound represented by formula 1 further comprises 1 to 10 amino acids bound to the C-terminus thereof.

19. The compound is [His(trt)-Lys(caprylic acid)-Phe-Tyr]-(X ３ ) ａ - (X ４ ) ｂ - (X ５ ) ｃ - (X ６ ) ｄ - (X ７ ) ｅ - (X ８ ) ｆ - (X ９ ) ｇ (In the formula, X ３ ~X ９ are each independently any one amino acid selected from 20 amino acids, His (trt) is N-trityl-L-histidine, Lys (caprylic acid) is N-octanoyl-L-lysine, Phe is phenylalanine, Tyr is tyrosine, and a to g are 0 or 1, with at least one of them being 1.

20. The compound is selected from the group consisting of: 38) (3S,6S,9S,12S,15S)-15-((S)-2-amino-3-(1-trityl-1H-imidazol-4-yl)propanamide)-12-benzyl-3-(((6S,9S,12S,15S)-1,18-diamino-6-(((S)-1-amino-1-oxo-3-phenylpropan-2-yl)carbamoyl)-12-(3- amino-3-oxopropyl)-1-imino-9-methyl-8,11,14,18-tetraoxo-2,7,10,13-tetraazaoctadecan-15-yl)carbamoyl)-9-(4-hydroxybenzyl)-6-(hydroxymethyl)-5,8,11,14,21-pentaoxo-4,7,10,13,20-pentaazaoctacosanoic acid, 39) (3S,6S,9S,12S,15S,18S)-3-((2-(((S)-1-(((S)-1-(((S)-1-amino-1-oxo-3-phenylpropan-2-yl)amino)-5-guanidino-1-oxopentan-2-yl)amino)-1-oxopropan-2-yl)amino)-2-oxoethyl)carbamoyl)-18-((S )-2-amino-3-(1-trityl-1H-imidazol-4-yl)propanamido)-6-(3-amino-3-oxopropyl)-15-benzyl-12-(4-hydroxybenzyl)-9-(hydroxymethyl)-5,8,11,14,17,24-hexaoxo-4,7,10,13,16,23-hexaazahentriacontanoic acid, 40) (S)-2-((2S,5S,8S,11S,14S)-2-((1H-imidazol-4-yl)methyl)-14-((S)-2-amino-3-(1-trityl-1H-imidazol-4-yl)propanamide)-11-benzyl-8-(4-hydroxybenzyl)-5-(hydroxymethyl)-4,7,10,13,20-pentaoxo-3,6,9,12, 19-pentaazaheptacosane amide)-N1-((S)-5-amino-1-(((S)-1-(((S)-1-(((S)-1-amino-1-oxo-3-phenylpropan-2-yl)amino)-5-guanidino-1-oxopentan-2-yl)amino)-1-oxopropan-2-yl)amino)-1,5-dioxopentan-2-yl)pentanediamide, 41) (3S,6S,9S,12S,15S,18S)-3-((2-(((S)-1-(((S)-1-(((S)-1-amino-1-oxo-3-phenylpropan-2-yl)amino)-5-guanidino-1-oxopentan-2-yl)amino)-1-oxopropan-2-yl)amino)-2-oxoethyl)carbamoyl)-18-((S )-2-amino-3-(1-trityl-1H-imidazol-4-yl)propanamido)-6-(3-amino-3-oxopropyl)-15-benzyl-12-(4-hydroxybenzyl)-9-(hydroxymethyl)-5,8,11,14,17,24-hexaoxo-4,7,10,13,16,23-hexaazahentriacontanoic acid, 42) (S)-2-((2S,5S,8S,11S)-2-((1H-imidazol-4-yl)methyl)-11-((S)-2-amino-3-(1-trityl-1H-imidazol-4-yl)propanamide)-8-benzyl-5-(4-hydroxybenzyl)-4,7,10,17-tetraoxo-3,6,9,16-tetraazatetracosanamide)-N1-((S)-5-amino-1-(((S)-1-(((S)-1-(((S)-1-amino-1-oxo-3-phenylpropan-2-yl)amino)-5-guanidino-1-oxopentan-2-yl)amino)-1-oxopropan-2-yl)amino)-1,5-dioxopentan-2-yl)pentanediamide, 43) (S)-N1-((S)-1-(((S)-1-(((S)-1-amino-1-oxo-3-phenylpropan-2-yl)amino)-5-guanidino-1-oxopentan-2-yl)amino)-1-oxopropan-2-yl)-2-((2S,5S,8S,11S,14S)-2-(2-amino-2-oxoethyl)-14-((S)-2-amino-3-(1-trityl-1H-imidazol-4-yl)propanamide)-5-(3-amino-3-oxopropyl)-11-benzyl-8-(4-hydroxybenzyl)-4,7,10,13,20-pentaoxo-3,6,9,12,19-pentaazaheptacosanamide)pentanediamide, 44) N6-octanoyl-N2-(Nt-trityl-L-histidyl)-L-lysyl-L-phenylalanyl-L-tyrosyl-L-tryptophan, and 56) (6S,9S,12S,15S,18S)-1-amino-6-(((S)-1-amino-1-oxo-3-phenylpropan-2-yl)carbamoyl)-18-((S)-2-((S)-2-((S)-2-amino-3-(1-trityl-1H-imidazol-4-yl)propanamide)-6-(non-1-en-2-ylamino)hexanamide)-3-phenylpropanamide)-3-(4-hydroxyphenyl)propanamide)-12,15-bis(3-amino-3-oxopropyl)-1-imino-9-methyl-8,11,14,17-tetraoxo-2,7,10,13,16-pentaaza-20-icosanoic acid 20. The composition of claim 19, which is any one selected from the group consisting of:

21. A composition for preventing or treating inflammatory bowel disease according to any one of claims 1 to 20, said composition being a pharmaceutical composition comprising a compound or a pharma- ceutically acceptable salt thereof as an active ingredient.

22. A composition for preventing or alleviating inflammatory bowel disease as described in any one of claims 1 to 20, said composition being a health functional food composition comprising a compound or a biologically acceptable salt thereof as an active ingredient.

23. Use of the compound or a pharma- ceutically acceptable salt thereof for the manufacture of a composition for preventing or treating an inflammatory bowel disease according to any one of claims 1 to 20.

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