Amino acid derivative, its preparation method and pharmaceutical composition for treating hepatitis containing the same

Abstract

The present invention relates to a novel amino acid derivative, a method for producing the same, and a pharmaceutical composition for treating hepatitis B or hepatitis D containing the same. The compound represented by Chemical Formula 1 according to the present invention has excellent effect of binding to NTCP and inhibiting the binding of HBV PreS1 peptide, thereby inhibiting the intracellular entry and cell attachment of HBV virus, and is therefore useful as a composition for preventing, treating, or ameliorating diseases caused by HBV and HDV infection.

Description

[Technical Field]

[0001] The present invention relates to a novel amino acid derivative, a method for producing the same, and a pharmaceutical composition containing the same for treating hepatitis. [Background technology]

[0002] Since its discovery in 1967 by Blumberg (who was awarded the Nobel Prize in Medicine in 1976), the Hepatitis B virus (HBV) has become known as one of the viruses with the highest infection rate in the world, causing great harm to humanity. HBV infection can progress through a variety of clinical stages, from asymptomatic infection to chronic infection, liver cirrhosis, and hepatocellular carcinoma, increasing the incidence and mortality rate of chronic diseases. Chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma caused by HBV infection are the leading causes of death among men in their 50s in South Korea. In particular, the mortality rate from hepatocellular carcinoma, which is primarily caused by HBV infection, ranks 17th in the world and far and away the highest among OECD countries.

[0003] Hepatitis D virus (HDV) is a disease caused by the hepatitis D virus. In 1977, Italian Rizzetto and others first identified the virus in the nuclei of hepatocytes of patients with chronic hepatitis B. HDV is a defective RNA virus, unique in that it possesses a circular RNA genome, a structure found only in plant viruses. The nucleocapsid, consisting of the RNA genome and HDV antigens, is surrounded by an envelope composed of the hepatitis B virus surface antigen (HBsAg), and the virus replicates via a double rolling circle mechanism. Acute hepatitis D occurs when HDV and HBV are co-infected, or when HDV is superinfected in patients with existing chronic hepatitis B. Therefore, HDV infection can occur in patients with concomitant HBV infection. Superinfection with HDV is known to cause more severe liver damage and progress more rapidly to cirrhosis than HBV infection alone. Thus, the unmet medical need evident in HBV infection is even more pressing in HBV and HDV co-infected subjects.

[0004] For these reasons, hepatitis B and D urgently require effective treatment strategies.

[0005] While the development of vaccines has made it possible to partially prevent hepatitis B, existing hepatitis B treatments consist of nucleos(t)ide inhibitors (NRTIs) that inhibit the activity of the viral reverse transcriptase (RT) and interferon α. ​​Unlike hepatitis C treatments, which can be cured, NRTIs target a late stage of the virus's life cycle and do not eliminate the viral cccDNA, making them ineffective as a cure. Interferons also have a high risk of side effects and resistance due to long-term administration, making them ineffective as a cure. Therefore, new treatment strategies are needed. Clinical trials have been ongoing to achieve greater efficacy by combining existing NRTIs with interferons, but none of the existing combination therapies have achieved greater efficacy than monotherapy.

[0006] On the other hand, recently, Na+ has been shown to act as a host receptor during HBV infection. + Taurocholate cotransporting peptide (NTCP) has been identified as a target for suppressing viral infection. Genetic deletion of NTCP prevented viral infection, and endogenous ligands inhibited viral attachment. NTCP inhibitors, such as viral PreS1 peptides and TLR7 agonists to enhance host immune function, are currently under development. However, no therapeutic agents are currently in clinical use. In particular, no novel synthetic small molecule compounds targeting the binding of NTCP to PreS1 have been reported.

[0007] Therefore, in order to develop a fundamental treatment method using a therapeutic agent with a new mechanism that targets and inhibits the early stage of the viral life cycle, different from existing therapeutic agents, the inventors have researched a substance that can exhibit an antiviral effect with a new mechanism that inhibits the cell entry process, which is the earliest stage of viral infection. As a result, they discovered a novel substance that can inhibit viral entry into cells by blocking the NTCP binding of PreS1, a viral receptor binding peptide, and confirmed that this substance exhibits an inhibitory ability that is several tens of times higher than endogenous bile acids that have previously been reported to inhibit PreS1 binding, thereby completing the present invention. Summary of the Invention [Problem to be solved by the invention]

[0008] An object of the present invention is to provide novel compounds that are effective in treating hepatitis.

[0009] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating hepatitis.

[0010] A further object of the present invention is to provide a functional health food composition for preventing or ameliorating hepatitis. [Means for solving the problem]

[0011] To achieve the above purpose,

[0012] The present invention provides a compound in which an amino acid is bound to a bile acid, an enantiomer thereof, a diastereomer thereof, or a pharmaceutically acceptable salt thereof.

[0013] Furthermore, the present invention provides a pharmaceutical composition for preventing or treating hepatitis, which comprises a compound in which an amino acid is bound to a bile acid, an optical isomer thereof, a partial stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0014] Furthermore, the present invention provides a functional health food composition for preventing or ameliorating hepatitis, which comprises a compound in which an amino acid is bound to a bile acid, an optical isomer thereof, a partial stereoisomer thereof, or a nutmologically acceptable carrier thereof.

[0015] The present invention also provides a method for treating hepatitis, comprising administering a therapeutically effective amount of a compound in which an amino acid is bound to a bile acid, an optical isomer thereof, a partial stereoisomer thereof, or a pharmaceutically acceptable salt thereof to a patient in need of treatment for hepatitis. [Effects of the Invention]

[0016] The compound represented by Chemical Formula 1 according to the present invention has an excellent effect of inhibiting the binding of HBV or HDV PreS1 peptide by binding to NTCP, thereby inhibiting the intracellular entry and cell attachment of HBV or HDV, and is therefore useful as a composition for preventing, treating, or ameliorating diseases caused by HBV and HDV infection. [Brief explanation of the drawings]

[0017] [Figure 1] 1 is a graph showing the results of confirming the inhibitory ability of the compounds of Example 1, Examples 38 to 56 and Comparative Example 1 according to the present invention to inhibit the binding of PreS1 to an NTCP-expressing cell line. [Figure 2] 1 is a graph showing the results of confirming the ability of the compounds of Example 1 (LCA-Ile), Example 50 (LCA-Trp), Example 52 (LCA-Tyr), and Example 44 (LCA-Val) according to the present invention to inhibit the binding of PreS1 to an NTCP-expressing cell line. [Figure 3] 1 is a graph showing the results of confirming the ability of the compounds of Examples 1 to 3, 6 to 11, 14 to 15, and 44 according to the present invention, and Comparative Examples 1 to 6 to inhibit the binding of PreS1 to an NTCP-expressing cell line. [Figure 4]1 is a graph showing the ability of the compounds of Example 1 (LCA-Ile), Example 44 (LCA-Val), Example 2 (UDCA-Ile), and Example 3 (UDCA-Val) according to the present invention to inhibit the binding of fluorescently labeled preS1 peptide through fluorescence imaging. [Figure 5] 1 is a graph showing the results of confirming the toxicity at the cellular level for the compounds of Example 1 (LCA-Ile), Example 44 (LCA-Val), Example 2 (UDCA-Ile), and Example 3 (UDCA-Val) according to the present invention. [Figure 6] This is a virus infection experiment protocol to evaluate the ability to inhibit intracellular HBV virus entry by performing enzyme-linked immunosorbent assay (ELISA) and Southern blot analysis for HBeAg. [Figure 7] 1 is a graph showing the results of HBeAg absorbance (OD) levels determined through HBeAg ELISA analysis for the compounds of Example 1 (LCA-Ile), Example 44 (LCA-Val), Example 52 (LCA-Tyr), Example 51 (LCA-Ser), Example 55 (LCA-Glu), Example 2 (UDCA-Ile), Example 3 (UDCA-Val), Example 25 (LCA-Val-Trp), Example 10 (DCA-Ile), Comparative Example 1 (LCA), and Comparative Example 2 (UDCA) according to the present invention. [Figure 8] 1 is a graph showing the results of Southern blot analysis of HBeAg DNA and its quantified relative replication rate (%) for the compounds of Example 1 (LCA-Ile), Example 44 (LCA-Val), Example 52 (LCA-Tyr), Example 51 (LCA-Ser), Example 55 (LCA-Glu), Example 2 (UDCA-Ile), Example 3 (UDCA-Val), Example 25 (LCA-Val-Trp), Example 10 (DCA-Ile), Comparative Example 1 (LCA), and Comparative Example 2 (UDCA) according to the present invention. [Figure 9]1 is a graph showing the results of confirming the inhibitory ability of the compounds of Examples 4 to 5, 12 to 13, 16 to 17 according to the present invention, and Comparative Example 2 (UDCA), Comparative Example 5 (DCA), and Comparative Example 6 (CDCA) to inhibit the binding of PreS1 to an NTCP-expressing cell line. [Figure 10] 1 is a graph showing the results of examining the inhibitory ability of the compound of Example 4 (UDCA-Trp) according to the present invention to the binding of PreS1 to an NTCP-expressing cell line at different concentrations. DETAILED DESCRIPTION OF THE INVENTION

[0018] The present invention will be described in detail below.

[0019] Compound, its optical isomer, its partial stereoisomer or pharmaceutically acceptable salt thereof

[0020] The present invention provides a compound represented by the following chemical formula 1 in which an amino acid is bound to a bile acid, an optical isomer thereof, a partial stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0021] [C1]

[0022] [ka]

[0023] In the above Chemical Formula 1,

[0024] R 1 , R 2 and R 3 are independently hydrogen or hydroxy;

[0025] JPEG0007754523000002.jpg37170

[0026] JPEG0007754523000003.jpg115170

[0027] Preferably,

[0028] R 1 , R 2 and R 3 are independently hydrogen or hydroxy;

[0029] JPEG0007754523000004.jpg33169

[0030] More preferably, at least one of R1, R2 and R3 is hydrogen.

[0031] In one embodiment according to the present invention,

[0032] R 1 , R 2 and R 3 are independently hydrogen;

[0033] JPEG0007754523000005.jpg31149

[0034] In one embodiment of the present invention, the bile acid is lithocholic acid (LCA), ursodeoxycholic acid (UDCA), cholic acid (CA), hyodeoxycholic acid (HDCA), deoxycholic acid (DCA), or chenodeoxycholic acid (CDCA).

[0035] In one embodiment of the present invention, preferred examples of the compound represented by Chemical Formula 1 include the following compounds, the chemical structures of which are shown in Tables 1 and 2 below.

[0036] 1) (2S,3R)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylpentanoic acid (LCA-Ile);

[0037] 2) (2S,3R)-2-((R)-4-((3R,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylpentanoic acid (UDCA-Ile);

[0038] 3) (S)-2-((R)-4-((3R,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanoic acid (UDCA-Val);

[0039] 4) (S)-2-((R)-4-((3R,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-(1H-indol-3-yl)propanoic acid (UDCA-Trp);

[0040] 5) (S)-2-((R)-4-((3R,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-(4-hydroxyphenyl)propanoic acid (UDCA-Tyr);

[0041] 6) (2S,3R)-3-methyl-2-((R)-4-((3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3,7,12-trihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamide)pentanoic acid (CA-Ile);

[0042] 7) (S)-3-methyl-2-((R)-4-((3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3,7,12-trihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)butanoic acid (CA-Val);

[0043] 8) (2S,3R)-2-((R)-4-((3R,5R,6S,8S,9S,10R,13R,14S,17R)-3,6-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylpentanoic acid (HDCA-Ile);

[0044] 9) (S)-2-((R)-4-((3R,5R,6S,8S,9S,10R,13R,14S,17R)-3,6-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanoic acid (HDCA-Val);

[0045] 10) (2S,3R)-2-((R)-4-((3R,5R,8R,9S,10S,12S,13R,14S,17R)-3,12-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylpentanoic acid (DCA-Ile);

[0046] 11) (S)-2-((R)-4-((3R,5R,8R,9S,10S,12S,13R,14S,17R)-3,12-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanoic acid (DCA-Val);

[0047] 12) (S)-2-((R)-4-((3R,5R,8R,9S,10S,12S,13R,14S,17R)-3,12-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-(1H-indol-3-yl)propanoic acid (DCA-Trp);

[0048] 13) (S)-2-((R)-4-((3R,5R,8R,9S,10S,12S,13R,14S,17R)-3,12-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-(4-hydroxyphenyl)propanoic acid (DCA-Tyr);

[0049] 14) (2S,3R)-2-((R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylpentanoic acid (CDCA-Ile);

[0050] 15) (S)-2-((R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanoic acid (CDCA-Val);

[0051] 16) (S)-2-((R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-(1H-indol-3-yl)propanoic acid (CDCA-Trp);

[0052] 17) (S)-2-((R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-(4-hydroxyphenyl)propanoic acid (CDCA-Tyr);

[0053] 18) 2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)acetic acid (LCA-Val-Gly);

[0054] 19) (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)propanoic acid (LCA-Val-Ala);

[0055] 20) (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-3-methylbutanoic acid (LCA-Val-Val);

[0056] 21) (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamide)-3-methylbutanamide)- 3-Methylbutanamide)- 4-methylpentanoic acid (LCA-Val-Leu);

[0057] 22) (2S,3R)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-3-methylpentanoic acid (LCA-Val-Ile);

[0058] 23) (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-4-(methylthio)butanoic acid (LCA-Val-Met);

[0059] 24) (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-3-phenylpropanoic acid (LCA-Val-Phe);

[0060] 25) (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-3-(1H-indol-3-yl)propanoic acid (LCA-Val-Trp);

[0061] 26) 1-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanoyl)pyrrolidine-2-carboxylic acid (LCA-Val-Pro);

[0062] 27) (S)-3-hydroxy-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)propanoic acid (LCA-Val-Ser);

[0063] 28) (2S,3S)-3-hydroxy-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)butanoic acid (LCA-Val-Thr);

[0064] 29) (R)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-3-mercaptopropanoic acid (LCA-Val-Cys);

[0065] 30) (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-3-(4-hydroxyphenyl)propanoic acid (LCA-Val-Tyr);

[0066] 31) (S)-4-amino-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-4-oxobutanoic acid (LCA-Val-Asn);

[0067] 32) (S)-5-amino-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-5-oxopentanoic acid (LCA-Val-Gln);

[0068] 33) (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)succinic acid (LCA-Val-Asp);

[0069] 34) (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)pentanedioic acid (LCA-Val-Glu);

[0070] 35) (S)-6-amino-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)hexanoic acid (LCA-Val-Lys);

[0071] 36) (S)-5-guanidino-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)pentanoic acid (LCA-Val-Arg); and

[0072] 37) (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-3-(1H-imidazol-4-yl)propanoic acid (LCA-Val-His).

[0073] The compound of the present invention represented by Chemical Formula 1 can be used in the form of a pharmaceutically acceptable salt, and useful salts include acid addition salts formed with a pharmaceutically acceptable free acid. The term "pharmaceutically acceptable salt" refers to any organic or inorganic addition salt of the base compound of Chemical Formula 1 that is relatively non-toxic and harmless to patients at concentrations that have an effective effect, and the side effects attributable to the salt do not diminish the beneficial effects of the base compound of Chemical Formula 1. These salts can be made with inorganic or organic acids as free acids, with inorganic acids such as hydrochloric acid, bromic acid, nitric acid, sulfuric acid, perchloric acid, and phosphoric acid, and organic acids such as citric acid, acetic acid, lactic acid, maleic acid, fumaric acid, gluconic acid, methanesulfonic acid, glycolic acid, succinic acid, tartaric acid, galacturonic acid, embonic acid, glutamic acid, aspartic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, 4-toluenesulfonic acid, salicylic acid, citric acid, benzoic acid, and malonic acid. These salts also include alkali metal salts (such as sodium salts and potassium salts) and alkaline earth metal salts (such as calcium salts and magnesium salts). For example, acid addition salts include acetate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / hydrochloride, Included are bromate / bromine oxide, hydroiodide / hydrogen iodide oxide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate, trifluoroacetate, aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, zinc salts, and the like, of which hydrochloride or trifluoroacetate salts are preferred.

[0074] Furthermore, the compound of the present invention represented by Chemical Formula 1 includes not only pharmaceutically acceptable salts but also all salts, isomers, hydrates and solvates that can be prepared by conventional methods.

[0075] The addition salts according to the present invention can be prepared by a conventional method, for example, by dissolving the compound of Formula 1 in a water-miscible organic solvent such as acetone, methanol, ethanol, or acetonitrile, adding an excess amount of an organic acid or an aqueous solution of an inorganic acid, followed by precipitation or crystallization. Subsequently, the solvent or excess acid is evaporated from the mixture, and the mixture is dried to obtain the addition salt, or the precipitated salt can be filtered off with suction.

[0076] The present invention relates to any and all tautomers of the compounds of Formula 1 that have anti-HBV activity, and it is understood that certain compounds of Formula 1 can exist in solvated and non-solvated forms, e.g., hydrated forms, and it is understood that the present invention encompasses all such solvated forms that have anti-HBV activity.

[0077] Compound manufacturing method

[0078] The present invention relates to a method for producing a compound of formula (I) comprising the steps of:

[0079] Step 1: dissolving compound 2 and compound 3 in an organic solvent and reacting them to obtain compound 4; and

[0080] reacting compound 4 with sodium hydroxide or trifluoroacetic acid to obtain compound 1 (step 2);

[0081] The present invention provides a method for preparing a compound represented by formula 1, comprising:

[0082] [Anti 1]

[0083] [ka]

[0084] In the reaction formula 1,

[0085] R 1 , R 2 and R 3 is as defined above;

[0086] R 4 is R 5 and;

[0087] R 5 is as defined above;

[0088] JPEG0007754523000007.jpg119168

[0089] In the production method according to the present invention, it is preferable that the R 1 , R 2 and R 3 At least one of these is hydrogen.

[0090] In the preparation method according to the present invention, the organic solvent in step 1 may be at least one selected from the group consisting of dichloromethane (DCM), dimethylformamide (DMF), ethanol, tetrahydrofuran (THF), benzene, KOH / MeOH, MeOH, toluene, hexane, dimethylacetamide (DMA), diisopropyl ether, diethyl ether, dioxane, dimethyl sulfoxide (DMSO), acetone, and chlorobenzene, preferably at least one selected from the group consisting of dichloromethane (DCM) and dimethylformamide (DMF).

[0091] In the method of the present invention, in step 1, one or more substances selected from the group consisting of N-methylmorpholine (NMM), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), and 4-dimethylaminopyridine (DMAP) may be further added during the reaction.

[0092] In the method of the present invention, the reaction in step 2 may be carried out using one or more solvents selected from the group consisting of dichloromethane (DCM), dimethylformamide (DMF), ethanol, tetrahydrofuran (THF), benzene, KOH / MeOH, MeOH, toluene, hexane, dimethylacetamide (DMA), diisopropyl ether, diethyl ether, dioxane, dimethyl sulfoxide (DMSO), acetone, and chlorobenzene, and preferably using one or more solvents selected from the group consisting of dichloromethane (DCM) and ethanol.

[0093] Further, the present invention provides a method for producing a compound according to the present invention, as shown in the following reaction formula 2:

[0094] Step 1: dissolving compound 5 and compound 3 in an organic solvent and reacting them to obtain compound 6; and

[0095] Step 2: reacting compound 6 with sodium hydroxide, trifluoroacetic acid or Pd / C (Palladium on carbon) and hydrogen gas (H2 gas) to obtain compound 1;

[0096] The present invention provides a method for preparing a compound represented by formula 1, comprising:

[0097] [Anti 2]

[0098] [ka]

[0099] In the reaction scheme 2,

[0100] R 1 , R 2 and R 3 is as defined above;

[0101] JPEG0007754523000009.jpg2787

[0102] R5 is as defined above;

[0103] JPEG0007754523000010.jpg123165

[0104] JPEG0007754523000011.jpg2387

[0105] JPEG0007754523000012.jpg2487

[0106] In the production method according to the present invention, it is preferable that the R 1 , R 2 and R 3 At least one of these is hydrogen.

[0107] More preferably, the R 1 , R 2 and R 3 are also independently hydrogen.

[0108] In the preparation method according to the present invention, the organic solvent in Step 1 of Reaction Scheme 2 may be at least one selected from the group consisting of dichloromethane (DCM), dimethylformamide (DMF), ethanol, tetrahydrofuran (THF), benzene, KOH / MeOH, MeOH, toluene, hexane, dimethylacetamide (DMA), diisopropyl ether, diethyl ether, dioxane, dimethyl sulfoxide (DMSO), acetone, and chlorobenzene, and preferably at least one selected from the group consisting of dichloromethane (DCM) and dimethylformamide (DMF).

[0109] In the preparation method according to the present invention, in step 1 of Reaction Scheme 2, one or more substances selected from the group consisting of 1-hydroxybenzotriazole (HOBt), hexafluorophosphate azabenztriazole tetramethyluronium (HATU), and N,N-diisopropylethylamine (DIPEA) may be further added during the reaction.

[0110] In the preparation method according to the present invention, the reaction in Step 2 of Reaction Scheme 2 may be carried out in one or more solvents selected from the group consisting of dichloromethane (DCM), dimethylformamide (DMF), ethanol, tetrahydrofuran (THF), benzene, KOH / MeOH, MeOH, toluene, hexane, dimethylacetamide (DMA), diisopropyl ether, diethyl ether, dioxane, dimethyl sulfoxide (DMSO), acetone, and chlorobenzene, and preferably in one or more solvents selected from the group consisting of dichloromethane (DCM) and ethanol.

[0111] Pharmaceutical composition for preventing or treating hepatitis

[0112] The present invention provides a pharmaceutical composition for preventing or treating hepatitis, comprising a compound represented by the following chemical formula 1 in which an amino acid is bound to a bile acid, an optical isomer thereof, a partial stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0113] [C1]

[0114] [ka]

[0115] In the above Chemical Formula 1,

[0116] R 1 , R 2 and R 3 are independently hydrogen or hydroxy;

[0117] JPEG0007754523000014.jpg2390

[0118] JPEG0007754523000015.jpg114167

[0119] In the pharmaceutical composition according to the present invention, preferably, 1 , R 2 and R 3At least one of these is hydrogen.

[0120] Preferred examples of the compound represented by Chemical Formula 1 include the following compounds, the chemical structures of which are shown in Tables 1 to 3 below.

[0121] 1) (2S,3R)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylpentanoic acid (LCA-Ile);

[0122] 2) (2S,3R)-2-((R)-4-((3R,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylpentanoic acid (UDCA-Ile);

[0123] 3) (S)-2-((R)-4-((3R,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanoic acid (UDCA-Val);

[0124] 4) (S)-2-((R)-4-((3R,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-(1H-indol-3-yl)propanoic acid (UDCA-Trp);

[0125] 5) (S)-2-((R)-4-((3R,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-(4-hydroxyphenyl)propanoic acid (UDCA-Tyr);

[0126] 6) (2S,3R)-3-methyl-2-((R)-4-((3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3,7,12-trihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamide)pentanoic acid (CA-Ile);

[0127] 7) (S)-3-methyl-2-((R)-4-((3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3,7,12-trihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)butanoic acid (CA-Val);

[0128] 8) (2S,3R)-2-((R)-4-((3R,5R,6S,8S,9S,10R,13R,14S,17R)-3,6-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylpentanoic acid (HDCA-Ile);

[0129] 9) (S)-2-((R)-4-((3R,5R,6S,8S,9S,10R,13R,14S,17R)-3,6-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanoic acid (HDCA-Val);

[0130] 10) (2S,3R)-2-((R)-4-((3R,5R,8R,9S,10S,12S,13R,14S,17R)-3,12-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylpentanoic acid (DCA-Ile);

[0131] 11) (S)-2-((R)-4-((3R,5R,8R,9S,10S,12S,13R,14S,17R)-3,12-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanoic acid (DCA-Val);

[0132] 12) (S)-2-((R)-4-((3R,5R,8R,9S,10S,12S,13R,14S,17R)-3,12-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-(1H-indol-3-yl)propanoic acid (DCA-Trp);

[0133] 13) (S)-2-((R)-4-((3R,5R,8R,9S,10S,12S,13R,14S,17R)-3,12-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-(4-hydroxyphenyl)propanoic acid (DCA-Tyr);

[0134] 14) (2S,3R)-2-((R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylpentanoic acid (CDCA-Ile);

[0135] 15) (S)-2-((R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanoic acid (CDCA-Val);

[0136] 16) (S)-2-((R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-(1H-indol-3-yl)propanoic acid (CDCA-Trp);

[0137] 17) (S)-2-((R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-(4-hydroxyphenyl)propanoic acid (CDCA-Tyr);

[0138] 18) 2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)acetic acid (LCA-Val-Gly);

[0139] 19) (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)propanoic acid (LCA-Val-Ala);

[0140] 20) (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-3-methylbutanoic acid (LCA-Val-Val);

[0141] 21) (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamide)-3-methylbutanamide)- 3-Methylbutanamide)- 4-methylpentanoic acid (LCA-Val-Leu);

[0142] 22) (2S,3R)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-3-methylpentanoic acid (LCA-Val-Ile);

[0143] 23) (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-4-(methylthio)butanoic acid (LCA-Val-Met);

[0144] 24) (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-3-phenylpropanoic acid (LCA-Val-Phe);

[0145] 25) (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-3-(1H-indol-3-yl)propanoic acid (LCA-Val-Trp);

[0146] 26) 1-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanoyl)pyrrolidine-2-carboxylic acid (LCA-Val-Pro);

[0147] 27) (S)-3-hydroxy-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)propanoic acid (LCA-Val-Ser);

[0148] 28) (2S,3S)-3-hydroxy-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)butanoic acid (LCA-Val-Thr);

[0149] 29) (R)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-3-mercaptopropanoic acid (LCA-Val-Cys);

[0150] 30) (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-3-(4-hydroxyphenyl)propanoic acid (LCA-Val-Tyr);

[0151] 31) (S)-4-amino-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-4-oxobutanoic acid (LCA-Val-Asn);

[0152] 32) (S)-5-amino-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-5-oxopentanoic acid (LCA-Val-Gln);

[0153] 33) (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)succinic acid (LCA-Val-Asp);

[0154] 34) (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)pentanedioic acid (LCA-Val-Glu);

[0155] 35) (S)-6-amino-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)hexanoic acid (LCA-Val-Lys);

[0156] 36) (S)-5-guanidino-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)pentanoic acid (LCA-Val-Arg);

[0157] 37) (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-3-(1H-imidazol-4-yl)propanoic acid (LCA-Val-His);

[0158] 38) 1-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoyl)pyrrolidine-2-carboxylic acid (LCA-Pro);

[0159] 39) (2S,3S)-3-hydroxy-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)butanoic acid (LCA-Thr);

[0160] 40) (R)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-mercaptopropanoic acid (LCA-Cys);

[0161] 41) (S)-5-amino-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamine Do- 5-oxopentanoic acid (LCA-Gln);

[0162] 42) (S)-5-guanidino-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamide)pentanoic acid (LCA-Arg);

[0163] 43) (S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-(1H-imidazol-5-yl)propanoic acid (LCA-His);

[0164] 44) (S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanoic acid (LCA-Val);

[0165] 45) 2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamide)-3-acetic acid (LCA-Gly);

[0166] 46) (S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-propanoic acid (LCA-Ala);

[0167] 47) (S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylpentanoic acid (LCA-Leu);

[0168] 48) (S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-4-(methylthio)butanoic acid (LCA-Met);

[0169] 49) (S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-phenylpropanoic acid (LCA-Phe);

[0170] 50) (S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-(1H-indol-3-yl)propanoic acid (LCA-Trp);

[0171] 51) (S)-3-hydroxy-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)propanoic acid (LCA-Ser);

[0172] 52) (S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-(4-hydroxyphenyl)propanoic acid (LCA-Tyr);

[0173] 53) (S)-4-amino-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-4-oxobutanoic acid (LCA-Asn);

[0174] 54) (S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamide)succinic acid (LCA-Asp);

[0175] 55) (S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)pentanedioic acid (LCA-Glu); and

[0176] 56) (S)-6-Amino-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)hexanoic acid (LCA-Lys).

[0177] In the pharmaceutical composition according to the present invention, the hepatitis may be hepatitis B or hepatitis D.

[0178] The compound represented by Formula 1 according to the present invention is a compound having a structure similar to that of HBV PreS1 (Myr-GTNLSVPNPLGFFPDHQLDPAFGANSNNPDWDFNPNKDHWPEANQV-Lys(FITC)) and NTCP (Na + It has excellent inhibitory effects on binding to NTCP-expressing cell lines and / or on HBV virus invasion and infection in HepG2-NTCP cells, a human NTCP-expressing cell line (see Experimental Examples 1 to 4).

[0179] In the pharmaceutical composition according to the present invention,

[0180] R 1 , R 2 and R 3 are independently hydrogen or hydroxy;

[0181] JPEG0007754523000016.jpg119167

[0182] JPEG0007754523000017.jpg3567

[0183] The present inventors have confirmed that the compound is a combination of HBV PreS1 (Myr-GTNLSVPNPLgFFPDHQLDPAFGANSNNPDWDFNPNKDHWPEANQV-Lys(FITC)) peptide and Na + The effect of inhibiting binding with Taurocholate Cotransporting Peptide (NTCP) and / or the effect of inhibiting HBV virus entry into cells and infection was confirmed (see Experimental Examples 1 to 4).

[0184] In the pharmaceutical composition according to the present invention,

[0185] Preferably, the R 1 , R 2 and R 3 are independently hydrogen or hydroxy;

[0186] R 1 , R 2 and R 3 wherein two or more of the groups are hydrogen;

[0187] JPEG0007754523000018.jpg81168

[0188] In this regard, the compound represented by Chemical Formula 1 has been shown to have a superior effect in inhibiting HBV virus entry into cells and infection (see Experimental Example 4), as well as in inhibiting the binding of HBV PreS1 peptide to NTCP, compared to conventional lithocholic acid and its derivatives (see Experimental Examples 1 to 3).

[0189] In the pharmaceutical composition according to the present invention,

[0190] More preferably, the R 1 , R 2 and R 3 are independently hydrogen or hydroxy;

[0191] R 1 , R 2 and R 3 wherein two or more of the groups are hydrogen;

[0192] JPEG0007754523000019.jpg58167

[0193] In this case, the compound represented by Chemical Formula 1 has the effect of inhibiting HBV virus entry into cells and infection (see Experimental Example 4), and also has an improved ability to inhibit the binding of HBV PreS1 peptide and NTCP, suppressing the binding to less than 40% compared to the group treated with PreS1 alone (see Experimental Examples 1 to 3).

[0194] In the pharmaceutical composition according to the present invention,

[0195] More preferably, the R 1 , R 2 and R 3 are independently hydrogen or hydroxy;

[0196] R 1 , R 2 and R 3 wherein two or more of the groups are hydrogen;

[0197] JPEG0007754523000020.jpg58167

[0198] In this case, the compound represented by Chemical Formula 1 has the effect of inhibiting HBV virus entry into cells and infection (see Experimental Example 4), and also has an improved ability to inhibit the binding of HBV PreS1 peptide and NTCP, suppressing the binding to less than 20% compared to the group treated with PreS1 alone (see Experimental Examples 1 to 3).

[0199] In the pharmaceutical composition according to the present invention,

[0200] More preferably, the R 1 , R 2 and R 3 are independently hydrogen or hydroxy;

[0201] R 1 , R 2 and R 3 wherein two or more of the groups are hydrogen;

[0202] JPEG0007754523000021.jpg32160

[0203] In this case, the compound represented by Chemical Formula 1 has the effect of inhibiting HBV virus entry into cells and infection (see Experimental Example 4), and also has an improved ability to inhibit the binding of HBV PreS1 peptide and NTCP, suppressing the binding to less than 5% compared to the group treated with PreS1 alone (see Experimental Examples 1 to 3).

[0204] In the pharmaceutical composition according to the present invention,

[0205] Most preferably, the R 1 is hydrogen;

[0206] R 2 and R 3 are independently hydrogen or hydroxy;

[0207] R 2 and R 3 wherein at least one of the groups is hydrogen;

[0208] JPEG0007754523000022.jpg2394

[0209] In this regard, the compound represented by Chemical Formula 1 has significantly improved inhibitory effects on the binding of HBV PreS1 peptide to NTCP and on the cellular invasion and infection of HBV virus compared to HBV inducers and other derivatives with similar structures (see Experimental Examples 1 to 4).

[0210] According to one embodiment of the present invention, the compound represented by Chemical Formula 1 is preferably one or more of the following compounds:

[0211] 1) (2S,3R)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylpentanoic acid (LCA-Ile);

[0212] 2) (2S,3R)-2-((R)-4-((3R,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylpentanoic acid (UDCA-Ile);

[0213] 3) (S)-2-((R)-4-((3R,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanoic acid (UDCA-Val);

[0214] 4) (S)-2-((R)-4-((3R,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-(1H-indol-3-yl)propanoic acid (UDCA-Trp);

[0215] 10) (2S,3R)-2-((R)-4-((3R,5R,8R,9S,10S,12S,13R,14S,17R)-3,12-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylpentanoic acid (DCA-Ile);

[0216] 12) (S)-2-((R)-4-((3R,5R,8R,9S,10S,12S,13R,14S,17R)-3,12-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-(1H-indol-3-yl)propanoic acid (DCA-Trp); and

[0217] 16) (S)-2-((R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-(1H-indol-3-yl)propanoic acid (CDCA-Trp).

[0218] Therefore, the compound represented by Chemical Formula 1 according to the present invention has an excellent effect of inhibiting the binding of HBV PreS1 peptide by binding to NTCP, and through this effect, has the effect of inhibiting the intracellular entry and cell attachment of HBV virus, and is therefore useful as a pharmaceutical composition for preventing or treating diseases caused by HBV infection.

[0219] The compound represented by Chemical Formula 1 according to the present invention can be used to treat and inhibit the progression of patients with chronic hepatitis B or D, and in particular, can be used to inhibit new infections in patients who have undergone liver transplantation due to cirrhosis or hepatocellular carcinoma. It can also be used to prevent or treat liver damage, hepatitis, cirrhosis, and liver cancer associated with chronic hepatitis B or D caused by HBV or HDV hepatitis by targeting NTCP and inhibiting HBV entry into cells, thereby targeting the early stage of viral infection.

[0220] In addition, the compound of the present invention represented by Chemical Formula 1 can be used alone or in combination with existing therapeutic agents to treat and inhibit the progression of chronic hepatitis B or D in patients with the disease.

[0221] When the composition of the present invention is used as a pharmaceutical, the pharmaceutical composition containing the compound represented by Chemical Formula 1, its optical isomer, its partial stereoisomer, or a pharmaceutically acceptable salt thereof as an active ingredient may be formulated and administered in various oral or parenteral dosage forms as described below, but is not limited thereto, during clinical administration.

[0222] Dosage forms for oral administration include, for example, tablets, pills, hard / soft capsules, liquids, suspensions, emulsions, syrups, granules, elixirs, etc., which contain, in addition to the active ingredient, diluents (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine), lubricants (e.g., silica, talc, stearic acid and its magnesium or calcium salts, and / or polyethylene glycol). Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidine, and may optionally contain disintegrants or boiling mixtures such as starch, agar, alginic acid or its sodium salt, and / or absorbents, colorants, flavors, and sweeteners.

[0223] Furthermore, the dosage of the compound represented by Chemical Formula 1 according to the present invention to a human body varies depending on the age, weight, sex, dosage form, health condition, and severity of disease of the patient. For an adult patient weighing 70 kg, the dosage is generally 0.1 to 1,000 mg / day, preferably 1 to 500 mg / day. The dosage may be administered once or several times a day at regular intervals as determined by a doctor or pharmacist.

[0224] Health functional food composition for preventing or improving hepatitis

[0225] The present invention provides a health functional food composition for preventing or ameliorating hepatitis, which comprises a compound represented by the following chemical formula 1 in which an amino acid is bound to a bile acid, an optical isomer thereof, a partial stereoisomer thereof, or a nutrient-based acceptable carrier thereof:

[0226] [C1]

[0227] [ka]

[0228] In the above Chemical Formula 1,

[0229] R 1 , R 2 and R 3 are independently hydrogen or hydroxy;

[0230] JPEG0007754523000024.jpg2196

[0231] JPEG0007754523000025.jpg115166

[0232] In the functional health food composition according to the present invention, it is preferable that the R 1 , R 2 and R 3 At least one of these is hydrogen.

[0233] In the health functional food composition according to the present invention, the hepatitis may be hepatitis B or hepatitis D.

[0234] When the composition of the present invention is used as a functional health food, the type of food is not particularly limited. Examples of foods to which the composition of the present invention can be added include drinks, meat, sausages, bread, biscuits, rice cakes, chocolate, candies, snacks, sweets, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, drinking water, alcoholic beverages, vitamin complexes, dairy products and processed dairy products, etc., which all include functional health foods in the usual sense.

[0235] The functional health food composition of the present invention containing the compound represented by Chemical Formula 1 can be added directly to food or used with other foods or food ingredients in a conventional manner. The amount of the active ingredient to be added is determined appropriately depending on the intended use (prevention or improvement). Generally, the amount of the composition in a functional health food can be added in an amount of 0.1 to 90 parts by weight based on the total weight of the food. However, in the case of long-term intake for the purpose of maintaining or regulating health, the amount is within the above range, and since there is no safety issue, the active ingredient can be used in an amount greater than the above range.

[0236] The health functional food composition of the present invention containing the compound represented by Chemical Formula 1 is not particularly limited in terms of other ingredients, except for the composition of the present invention as an essential ingredient in the indicated ratio. Similar to ordinary beverages, it may contain various flavorings or natural carbohydrates as additional ingredients. Examples of the natural carbohydrates include monosaccharides such as glucose and fructose; disaccharides such as maltose and sucrose; and polysaccharides such as common sugars like dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. Other flavorings that can be advantageously used include natural flavorings (thaumatin, stevia extracts (e.g., rebaudioside A, glycyrrhizin), and synthetic flavorings (saccharin, aspartame, etc.). The amount of the natural carbohydrates is generally about 1 to 20 g, preferably about 5 to 12 g, per 100 g of the health functional food composition of the present invention.

[0237] In addition, the health functional food composition of the present invention containing the compound represented by Chemical Formula 1 may contain various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, colorants and enhancers (cheese, chocolate, etc.), pectinic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonation agents used in carbonated drinks, etc. In addition, the health functional food composition of the present invention may contain natural fruit juice and fruit pulp for producing fruit juice drinks and vegetable drinks.

[0238] These ingredients can be used independently or in combination. The ratio of these additives is not particularly important, but is generally selected in the range of 0.1 to about 20 parts by weight per 100 parts by weight of the health functional food composition containing the active substance of the present invention.

[0239] The present invention will be described in more detail below with reference to the following examples, but the following examples are merely illustrative of the present invention and are not intended to limit the scope of the present invention.

[0240] The present invention will now be described in more detail with reference to the following examples.

[0241] The examples are provided to illustrate the present invention, and the content of the present invention is not limited to the following examples.

[0242] <Preparation example> Equipment and reagents

[0243] All starting materials and reagents used in the examples were purchased from Aldrich, Alfa Aesar, TCI, etc. All glass used in the reactions was dried in an oven at 80°C before use. Reactions involving air- and moisture-sensitive compounds were carried out by injecting Ar gas. Reaction progress was monitored using thin-layer chromatography, UV light, p-Anisaldehyde, and ninhydrin. Column chromatography was performed using silica gel 60 (230-400 mesh) in combination with solvents such as hexane, ethyl acetate, dichloromethane, and methane.

[0244] 1 H-NMR spectra were obtained using a Bruker Avance 400 (400 MHz for 1 H) spectrometers. 1H NMR chemical shift values ​​were expressed in parts per million (ppm) using TM (tetramethylsilane) as an internal standard. NMR signals were expressed as s (singlet), m (multiplet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), etc., and coupling constants were expressed in hertz (Hz).

[0245] Example 1: Preparation of (2S,3R)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylpentanoic acid (LCA-Ile)

[0246] [ka]

[0247] The starting materials, lithocholic acid (100 mg, 0.264 mmol), L-isoleucine methyl ester hydrochloride (53 mg, 0.290 mmol), and N-methylmorpholine (NMM) (0.476 mmol), were dissolved in 6 mL of dry DCM. Then, 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (0.264 mmol) was added, and the mixture was filled with Ar gas and allowed to react overnight at room temperature. Once the starting material was confirmed by TLC, the reaction was stopped with 2N HCl and diluted with DCM. The organic layer was extracted by washing with DCM and H2O. The extracted organic layer was dried over MgSO4, and the solvent was removed using an evaporator. The reaction mixture was purified using column chromatography to obtain the intermediate (100 mg, 49%). To remove the protected moiety, the intermediate (91.5 mg, 0.182 mmol) was dissolved in 9 mL of ethanol, and 6 mL of 15% w / v sodium hydroxide was added and the reaction was allowed to proceed for 30 minutes. When TLC confirmed that the starting material had disappeared, the ethanol was removed using an evaporator, and the mixture was acidified with concentrated hydrochloric acid at 0°C. The resulting precipitate was filtered and washed with water to obtain the final compound (Example 1; LCA-Ile) (86 mg, 97%).

[0248] (2S,3R)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylpentanoic acid; 1H-NMR (400MHz, DMSO-d6)δ=0.60(s, 3H, CH3), 0.80-0.90(m, 13H), 0.99-1. 22(m, 11H), 1.29-1.39(m, 7H), 1.46-1.55(m, 2H), 1.58-1.82(m, 6H), 1.82- 1.88(m, 1H), 1.99-2.08(m, 1H), 2.15-2.23(m, 1H), 3.32-3.35(m, 1H), 4.1 5(t, J=7.0Hz, 1H, CHCHCH3CH2), 4.45(s, 1H, OH), 7.94(d, J=8.4Hz, 1H, NH). 12.50(bs, 1H, COOH).

[0249] Example 2: Preparation of (2S,3R)-2-((R)-4-((3R,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylpentanoic acid (UDCA-Ile)

[0250] [ka]

[0251] The starting materials, ursodeoxycholic acid (100 mg, 0.255 mmol), L-isoleucine methyl ester hydrochloride (51 mg, 0.281 mmol), and N-methylmorpholine (NMM) (0.459 mmol), were dissolved in 5 mL of dry DCM. Then, 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (0.281 mmol) was added, and the intermediate (121 mg, 91%) was obtained in the same manner as in Example 1. To remove the protected moiety, the intermediate (30 mg, 0.058 mmol) was dissolved in 2 mL of ethanol, and 2 mL of 15% w / v sodium hydroxide was added and the reaction was allowed to proceed for 30 minutes. Then, deprotection was carried out in the same manner as in Example 1, yielding the final compound (Example 2; UDCA-Ile) (19 mg, 66%).

[0252] (2S,3R)-2-((R)-4-((3R,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylpentanoic acid; 1 H-NMR (400MHz, DMSO-d6)δ=0.61(s, 3H, CH3), 0.79-0.94(m, 13H), 1.08-1.2 5(m, 9H), 1.28-1.41(m, 7H), 1.42-1.51(m, 3H), 1.60-1.86(m, 6H), 1.88-1.9 8(m, 1H), 1.98-2.11(m, 1H), 2.14-2.26(m, 1H), 3.87(d, J=6.6Hz, 1H, OH), 4. 15(t, J=7.3Hz, 1H, CHCHCH3CH2), 4.44(s, 1H, OH), 7.91(d, J=8.4Hz, 1H, NH). 12.45(bs, 1H, COOH).

[0253] Example 3: Preparation of (S)-2-((R)-4-((3R,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanoic acid (UDCA-Val)

[0254] [ka]

[0255] The starting materials, ursodeoxycholic acid (100 mg, 0.255 mmol), L-Valine Methyl ester hydrochloride (50 mg, 0.281 mmol), and N-Methylmorpholine (NMM) (0.459 mmol), were dissolved in 5 mL of dry DCM. Then, 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (0.281 mmol) was added, and the intermediate (110 mg, 86%) was obtained in the same manner as in Example 1. To remove the protected moiety, the intermediate (30 mg, 0.058 mmol) was dissolved in 2 mL of ethanol, and 2 mL of 15% w / v sodium hydroxide was added and the reaction was allowed to proceed for 30 minutes. The deprotection process was then carried out in the same manner as in Example 1, yielding the final compound (Example 3; UDCA-Val) (28 mg, 98%).

[0256] (S)-2-((R)-4-((3R,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylbutanoic acid; 1H-NMR (400MHz, DMSO-d6) δ=0.61(s, 3H, CH3), 0.82-0.93(m, 13H), 1.05-1.25(m, 8H), 1.26-1.41(m, 7H), 1.42-1.52(m, 3H), 1.60-1.70(m, 3H), 1.70-1.89(m, 2H), 1.89-1.98(m, 1H), 1.98-2.11(m, 3H), 2.15-2.27(m, 1H), 3.87(d, J=7.0Hz, 1H, OH ), 4.11(t, J=7.0Hz, 1H, CHCHCH3CH2), 4.45(s, 1H, OH), 7.89(d, J=9.9Hz, 1H, NH). 12.40(bs, 1H, COOH).

[0257] Example 4: Preparation of (S)-2-((R)-4-((3R,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-(1H-indol-3-yl)propanoic acid (UDCA-Trp)

[0258] [ka]

[0259] The starting materials, ursodeoxycholic acid (50 mg, 0.127 mmol), L-tryptophan methyl ester hydrochloride (39 mg, 0.152 mmol), and 4-dimethylaminopyridine (1.5 mg, 0.013 mmol), were dissolved in 3 mL of dry DCM. Then, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (0.153 mmol) was added, and the intermediate (59 mg, 83%) was obtained in the same manner as in Example 1. To remove the protected moiety, the intermediate (50 mg, 0.084 mmol) was dissolved in 9 mL of ethanol, and 6 mL of 15% w / v sodium hydroxide was added. The reaction was allowed to proceed for 30 minutes. The deprotection process was then carried out in the same manner as in Example 1, yielding the final compound (Example 4; UDCA-Trp) (24 mg, 40%).

[0260] 1 H-NMR (500MHz, DMSO-d6) δ=0.59(s, 3H), 0.83-0.87(m, 7H), 0.87-0.99(m, 2H), 1.00-1.50(m, 15H), 1.53-1.74( m, 4H), 1.77-1.86(m, 1H), 1.88-2.01(m, 2H), 2.03-2.11(m, 1H), 2.94-3.00(m, 1H), 3.11-3.17(m, 1H), 3.23-3.3 5(m, 2H), 3.88(d, J=5.6Hz, 1H), 4.39-4.44(m, 1H), 4.45(d, J=3.6Hz, 1H), 6.94-6.98(m, 1H), 7.03-7.07(m, 1H), 7.09-7.11(m, 1H), 7.32(dJ=6.4Hz, 1H), 7.51(d, J=6.4Hz, 1H), 7.98-8.02(m, 1H), 10.83(s, 1H), 12.58(bs, 1H).

[0261] Example 5: Preparation of (S)-2-((R)-4-((3R,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-(4-hydroxyphenyl)propanoic acid (UDCA-Tyr)

[0262] [ka]

[0263] The starting materials, ursodeoxycholic acid (100 mg, 0.255 mmol) and L-tyrosine methyl ester hydrochloride (71 mg, 0.306 mmol), were dissolved in 3 mL of dry DCM. Then, 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (0.153 mmol) was added, and the intermediate (118 mg, 81%) was obtained in the same manner as in Example 1. To remove the protected moiety, the intermediate (50 mg, 0.084 mmol) was dissolved in 9 mL of ethanol, and 6 mL of 15% w / v sodium hydroxide was added and the reaction was allowed to proceed for 30 minutes. Then, deprotection was carried out in the same manner as in Example 1, yielding the final compound (Example 5; UDCA-Tyr) (27 mg, 57%).

[0264] 1H-NMR (500MHz, DMSO-d6) δ=0.60(s, 3H), 0.82-0.88(m, 6H), 0.89-1.01(m, 2H), 1.02-1.24(m, 6H), 1.25-1. 50(m, 10H), 1.53-1.60(m, 1H), 1.61-1.76(m, 3H), 1.79-1.87(m, 1H), 1.89-1.98(m, 2H), 2.02-2.09(m, 1H), 2.67-2.74(m, 1H), 2.86-2.92(m, 1H), 3.24(bs, 2H), 3.88(d, J=5.6Hz, 1H), 4.25-4.31(m, 1H), 4.45(d, J=3 .6Hz, 1H), 6.63(d, J=6.8Hz, 2H), 6.99(d, J=6.8Hz, 2H), 8.02(d, J=6.4Hz, 1H), 9.20(s, 1H), 12.55(bs, 1H).

[0265] Example 6: Preparation of (2S,3R)-3-methyl-2-((R)-4-((3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3,7,12-trihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)pentanoic acid (CA-Ile)

[0266] [ka]

[0267] The starting materials, cholic acid (300 mg, 0.742 mmol), L-Isoleucine Methyl ester hydrochloride (162 mg, 0.890 mmol), and N-Methylmorpholine (NMM) (1.113 mmol), were dissolved in 4 mL of dry DCM. Then, 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (0.965 mmol) was added, and the intermediate (349 mg, 90%) was obtained in the same manner as in Example 1. To remove the protected moiety, the intermediate (30 mg, 0.056 mmol) was dissolved in 2.7 mL of ethanol, and 1.8 mL of 15% w / v sodium hydroxide was added. The reaction was allowed to proceed for 30 minutes. The deprotection process was then carried out in the same manner as in Example 1, yielding the final compound (Example 6; CA-Ile) (24 mg, 79%).

[0268] (2S,3R)-3-methyl-2-((R)-4-((3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3,7,12-trihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)pentanoic acid; 1 H-NMR (400MHz, DMSO-d6)δ=0.58(s, 3H, CH3), 0.76-0.88(m, 10H), 0.89-0. 96(m, 3H), 1.08-1.48(m, 14H), 1.56-1.68(m, 3H), 1.68-1.82(m, 4H), 1.92- 2.07(m, 2H), 2.08-2.27(m, 3H), 3.12-3.24(m, 1H, CH), 3.60(s, 1H, CH), 3.7 8(s, 1H, CH), 4.15(t, J=6.6Hz, 1H, CHCHCH3CH2), 7.91(d, J=8.2Hz, 1H, NH). 12.34(bs, 1H, COOH).

[0269] Example 7: Preparation of (S)-3-methyl-2-((R)-4-((3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3,7,12-trihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)butanoic acid (CA-Val)

[0270] [ka]

[0271] The starting materials, cholic acid (300 mg, 0.742 mmol), L-Valine Methyl ester hydrochloride (149 mg, 0.890 mmol), and N-Methylmorpholine (NMM) (1.113 mmol) were dissolved in 4 mL of dry DCM. Then, 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (0.965 mmol) was added, and the intermediate (333 mg, 88%) was obtained in the same manner as in Example 1. To remove the protected moiety, the intermediate (50 mg, 0.096 mmol) was dissolved in 4.5 mL of ethanol, and 3 mL of 15% w / v sodium hydroxide was added. The reaction was allowed to proceed for 30 minutes. The deprotection process was then carried out in the same manner as in Example 1, yielding the final compound (Example 7; CA-Val) (31 mg, 64%).

[0272] (S)-3-methyl-2-((R)-4-((3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3,7,12-trihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)butanoic acid; 1H-NMR (400MHz, DMSO-d6)δ=0.58(s, 3H, CH3), 0.73-0.90(m, 10H), 0.90-1. 01(m, 3H), 1.06-1.51(m, 11H), 1.53-1.69(m, 3H), 1.69-1.84(m, 3H), 1.90- 2.08(m, 3H), 2.08-2.30(m, 3H), 3.10-3.17(m, 1H, CH), 3.60(s, 1H, CH), 3.7 8(s, 1H, CH), 4.11(t, J=5.6Hz, 1H, CHCHCH3CH2), 7.90(d, J=7.5Hz, 1H, NH). 12.46(bs, 1H, COOH).

[0273] Example 8: Preparation of (2S,3R)-2-((R)-4-((3R,5R,6S,8S,9S,10R,13R,14S,17R)-3,6-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylpentanoic acid (HDCA-Ile)

[0274] [ka]

[0275] The starting materials, hydroxycholic acid (300 mg, 0.764 mmol), L-isoleucine methyl ester hydrochloride (167 mg, 0.917 mmol), and N-methylmorpholine (NMM) (1.146 mmol) were dissolved in 4 mL of dry DCM. Then, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (0.993 mmol) was added, and the intermediate (300 mg, 76%) was obtained in the same manner as in Example 1. To remove the protected moiety, the intermediate (30 mg, 0.058 mmol) was dissolved in 2.7 mL of ethanol, and 1.8 mL of 15% w / v sodium hydroxide was added. The reaction was allowed to proceed for 30 minutes. The deprotection process was then carried out in the same manner as in Example 1, yielding the final compound (Example 8; HDCA-Ile) (15 mg, 52%).

[0276] (2S,3R)-2-((R)-4-((3R,5R,6S,8S,9S,10R,13R,14S,17R)-3,6-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylpentanoic acid; 1 H-NMR (400MHz, DMSO-d6)δ=0.59(s, 3H, CH3), 0.78-0.91(m, 12H), 0.92-1.25(m , 13H), 1.29-1.54(m, 9H), 1.59-1.69(m, 2H), 1.69-1.81(m, 2H), 1.87-1.95(m, 1 H), 1.97-2.07(m, 1H), 2.15-2.24(m, 1H), 3.77-3.85(m, 1H, CH), 4.15(t, J=8.0H z, 1H, CHCHCH3CH2), 4.25 (s, 1H, OH), 4.44 (s, 1H, OH), 7.92 (d, J=8.6Hz, 1H, NH). 12.32(bs, 1H, COOH).

[0277] Example 9: Preparation of (S)-2-((R)-4-((3R,5R,6S,8S,9S,10R,13R,14S,17R)-3,6-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanoic acid (HDCA-Val)

[0278] [ka]

[0279] The starting materials, hydroxycholic acid (300 mg, 0.764 mmol), L-valine methyl ester hydrochloride (154 mg, 0.917 mmol), and N-methylmorpholine (NMM) (1.146 mmol) were dissolved in 4 mL of dry DCM. Then, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (0.993 mmol) was added, and the intermediate (355 mg, 92%) was obtained in the same manner as in Example 1. To remove the protected moiety, the intermediate (40 mg, 0.079 mmol) was dissolved in 3.7 mL of ethanol, and 2.5 mL of 15% w / v sodium hydroxide was added. The reaction was allowed to proceed for 30 minutes. The deprotection process was then carried out in the same manner as in Example 1, yielding the final compound (Example 9; HDCA-Val) (30 mg, 77%).

[0280] (S)-2-((R)-4-((3R,5R,6S,8S,9S,10R,13R,14S,17R)-3,6-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylbutanoic acid; 1H-NMR (400MHz, DMSO-d6)δ=0.59(s, 3H, CH3), 0.80-0.92(m, 12H), 0.91-1.25(m , 11H), 1.26-1.56(m, 8H), 1.60-1.70(m, 2H), 1.71-1.86(m, 2H), 1.88-1.95(m, 1 H), 1.97-2.08(m, 2H), 2.16-2.26(m, 1H), 3.77-3.86(m, 1H, CH), 4.11(t, J=7.1H z, 1H, CHCHCH3CH2), 4.24 (s, 1H, OH), 4.42 (s, 1H, OH), 7.91 (d, J=7.2Hz, 1H, NH). 12.48(bs, 1H, COOH).

[0281] Example 10: Preparation of (2S,3R)-2-((R)-4-((3R,5R,8R,9S,10S,12S,13R,14S,17R)-3,12-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylpentanoic acid (DCA-Ile)

[0282] [ka]

[0283] The starting materials, deoxycholic acid (200 mg, 0.509 mmol), L-isoleucine methyl ester hydrochloride (110 mg, 0.611 mmol), and N-methylmorpholine (NMM) (0.764 mmol), were dissolved in 4 mL of dry DCM. Then, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (0.764 mmol) was added, and the intermediate (208 mg, 79%) was obtained in the same manner as in Example 1. To remove the protected moiety, the intermediate (50 mg, 0.096 mmol) was dissolved in 2.7 mL of ethanol, and 1.8 mL of 15% w / v sodium hydroxide was added. The reaction was allowed to proceed for 30 minutes. The deprotection process was then carried out in the same manner as in Example 1, yielding the final compound (Example 10; DCA-Ile) (44 mg, 90%).

[0284] (2S,3R)-2-((R)-4-((3R,5R,8R,9S,10S,12S,13R,14S,17R)-3,12-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylpentanoic acid; 1 H-NMR (400MHz, DMSO-d6)δ=0.59(s, 3H, CH3), 0.78-0.88(m, 10H), 0.88-0.95(m, 3H) , 0.96-1.22(m, 6H), 1.21-1.41(m, 9H), 1.41-1.56(m, 3H), 1.56-1.68(m, 3H), 1.69-1 .86(m, 5H), 1.96-2.09(m, 1H), 2.13-2.25(m, 1H), 3.75-3.81(m, 1H, CH), 4.13(s, 1H) , OH), 4.18(t, J=4.2Hz, 1H, CHCHCH3CH2), 4.46(s, 1H, OH), 7.91(d, J=8.0Hz, 1H, NH). 12.46(bs, 1H, COOH).

[0285] Example 11: Preparation of (S)-2-((R)-4-((3R,5R,8R,9S,10S,12S,13R,14S,17R)-3,12-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanoic acid (DCA-Val)

[0286] [ka]

[0287] The starting materials, deoxycholic acid (200 mg, 0.509 mmol), L-Valine Methyl ester hydrochloride (102 mg, 0.611 mmol), and N-Methylmorpholine (NMM) (0.764 mmol), were dissolved in 4 mL of dry DCM. Then, 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (0.764 mmol) was added, and the intermediate (204 mg, 79%) was obtained in the same manner as in Example 1. To remove the protected moiety, the intermediate (50 mg, 0.099 mmol) was dissolved in 4.6 mL of ethanol, and 3.1 mL of 15% w / v sodium hydroxide was added. The reaction was allowed to proceed for 30 minutes. The deprotection process was then carried out in the same manner as in Example 1, yielding the final compound (Example 11; DCA-Val) (40 mg, 82%).

[0288] (S)-2-((R)-4-((3R,5R,8R,9S,10S,12S,13R,14S,17R)-3,12-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylbutanoic acid; 1H-NMR (400MHz, DMSO-d6)δ=0.59(s, 3H, CH3), 0.80-0.89(m, 10H), 0.89-0.96(m, 3H) , 0.97-1.21(m, 5H), 1.23-1.40(m, 8H), 1.40-1.56(m, 3H), 1.56-1.67(m, 3H), 1.69-1 .85(m, 4H), 1.96-2.06(m, 2H), 2.15-2.27(m, 1H), 3.74-3.82(m, 1H, CH), 4.11(t, J= 7.3Hz, 1H, CHCHCH3CH2), 4.18(s, 1H, OH), 4.47(s, 1H, OH), 7.90(d, J=8.4Hz, 1H, NH). 12.49(bs, 1H, COOH).

[0289] Example 12: Preparation of (S)-2-((R)-4-((3R,5R,8R,9S,10S,12S,13R,14S,17R)-3,12-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-(1H-indol-3-yl)propanoic acid (DCA-Trp)

[0290] [ka]

[0291] The starting materials, deoxycholic acid (50 mg, 0.127 mmol) and L-tryptophan methyl ester hydrochloride (39 mg, 0.152 mmol), were dissolved in 3 mL of dry DCM. Then, 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (0.153 mmol) was added, and the intermediate (62 mg, 83%) was obtained in the same manner as in Example 1. To remove the protected moiety, the intermediate (50 mg, 0.084 mmol) was dissolved in 9 mL of ethanol, and 6 mL of 15% w / v sodium hydroxide was added and the reaction was allowed to proceed for 30 minutes. The deprotection process was then carried out in the same manner as in Example 1, yielding the final compound (Example 12; DCA-Trp) (24 mg, 39%).

[0292] 1 H-NMR (500MHz, DMSO-d6) δ=0.57(s, 3H), 0.79-0.90(m, 7H), 0.90-1.49(m, 16H), 1.53-1.83(m, 6H), 1.86-1. 92(m, 1H), 1.93-2.02(m, 1H), 2.04-2.12(m, 1H), 2.94-3.00(m, 1H), 3.11-3.21(m, 2H), 3.59-3.64(m, 1H), 4 .14(d, J=2.8Hz, 1H), 4.33(d, J=3.6Hz, 1H), 4.45-4.39(m, 1H), 6.94-6.98(m, 1H), 7.03-7.07(m, 1H), 7.10- 7.12 (m, 1H), 7.32 (d, J=6.4Hz, 1H), 7.51 (d, J=6.4Hz, 1H), 8.05 (d, J=6Hz, 1H), 10.84 (s, 1H), 12.59 (bs, 1H).

[0293] Example 13: Preparation of (S)-2-((R)-4-((3R,5R,8R,9S,10S,12S,13R,14S,17R)-3,12-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-(4-hydroxyphenyl)propanoic acid (DCA-Tyr)

[0294] [ka]

[0295] The starting materials, deoxycholic acid (100 mg, 0.255 mmol) and L-tyrosine methyl ester hydrochloride (71 mg, 0.306 mmol), were dissolved in 3 mL of dry DCM. Then, 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (0.153 mmol) was added, and the intermediate (110 mg, 76%) was obtained in the same manner as in Example 1. To remove the protected moiety, the intermediate (50 mg, 0.088 mmol) was dissolved in 9 mL of ethanol, and 6 mL of 15% w / v sodium hydroxide was added and the reaction was allowed to proceed for 30 minutes. Then, deprotection was carried out in the same manner as in Example 1, yielding the final compound (Example 13; DCA-Tyr) (24 mg, 49%).

[0296] 1 H-NMR (500MHz, DMSO-d6) δ=0.57(s, 3H), 0.84(s, 3H), 0.85-0.90(m, 4H), 0.91-1.13(m, 4H), 1.13-1. 38(m, 9H), 1.41-1.65(m, 6H), 1.65-1.83(m, 4H), 1.90-1.98(m, 1H), 2.02-2.10(m, 1H), 2.67-2.73(m , 1H), 2.86-2.92(m, 1H), 3.77(bs, 1H), 4.19(d, J=3.2Hz, 1H), 4.24-4.30(m, 1H), 4.47(d, J=3.6Hz, 1 H), 6.63(d, J=6.8Hz, 2H), 6.99(d, J=6.8Hz, 2H), 8.02(d, J=6.4Hz, 1H), 9.19(s, 1H), 12.56(bs, 1H).

[0297] Example 14: Preparation of (2S,3R)-2-((R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylpentanoic acid (CDCA-Ile)

[0298] [ka]

[0299] The starting materials, chenodeoxycholic acid (200 mg, 0.509 mmol), L-isoleucine methyl ester hydrochloride (110 mg, 0.611 mmol), and N-methylmorpholine (NMM) (0.916 mmol), were dissolved in 5 mL of dry DCM. Then, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (0.764 mmol) was added, and the intermediate (206 mg, 78%) was obtained in the same manner as in Example 1. To remove the protected moiety, the intermediate (50 mg, 0.096 mmol) was dissolved in 4.5 mL of ethanol, and 3 mL of 15% w / v sodium hydroxide was added. The reaction was allowed to proceed for 30 minutes. The deprotection process was then carried out in the same manner as in Example 1, yielding the final compound (Example 14; CDCA-Ile) (44 mg, 90%).

[0300] (2S,3R)-2-((R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylpentanoic acid; 1H-NMR (400MHz, DMSO-d6) δ=0.55(s, 3H, CH3), 0.64-0.92(m, 13H), 1.04-1.28(m, 8H), 1.29-1.50(m, 7H), 1.59-1.85(m, 6H), 1.87-1.94(m, 1H), 1.96-2.10(m, 2H) , 2.14-2.26(m, 2H), 3.13-3.23(m, 1H, CH), 3.59-3.65(m, 1H, CH), 4.10(t, J=4.2 Hz, 1H, CHCHCH3CH2), 4.12 (s, 1H, OH), 4.31 (s, 1H, OH), 7.90 (d, J=9.1Hz, 1H, NH). 12.47(bs, 1H, COOH).

[0301] Example 15: Preparation of (S)-2-((R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanoic acid (CDCA-Val)

[0302] [ka]

[0303] The starting materials, chenodeoxycholic acid (200 mg, 0.509 mmol), L-valine methyl ester hydrochloride (102 mg, 0.611 mmol), and N-methylmorpholine (NMM) (0.916 mmol), were dissolved in 4 mL of dry DCM. Then, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (0.764 mmol) was added, and the intermediate (199 mg, 77%) was obtained in the same manner as in Example 1. To remove the protected moiety, the intermediate (50 mg, 0.099 mmol) was dissolved in 4.6 mL of ethanol, and 3.1 mL of 15% w / v sodium hydroxide was added. The reaction was allowed to proceed for 30 minutes. The deprotection process was then carried out in the same manner as in Example 1, yielding the final compound (Example 15; CDCA-Val) (45 mg, 87%).

[0304] (S)-2-((R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylbutanoic acid; 1 H-NMR (400MHz, DMSO-d6) δ=0.59(s, 3H, CH3), 0.77-0.92(m, 13H), 1.03-1.27(m, 9H), 1.28-1.51(m, 8H), 1.59-1.84(m, 7H), 1.86-1.95(m, 1H), 1.99-1.21(m, 1H) , 2.12-2.26(m, 2H), 3.11-3.23(m, 1H, CH), 3.58-3.65(m, 1H, CH), 4.11(s, 1H, OH ), 4.14(t, J=7.2Hz, 1H, CHCHCH3CH2), 4.31(s, 1H, OH), 7.91(d, J=8.8Hz, 1H, NH). 12.46(bs, 1H, COOH).

[0305] Example 16: Preparation of (S)-2-((R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-(1H-indol-3-yl)propanoic acid (CDCA-Trp)

[0306] [ka]

[0307] The starting materials, chenodeoxycholic acid (50 mg, 0.127 mmol) and L-tryptophan methyl ester hydrochloride (39 mg, 0.152 mmol), were dissolved in 3 mL of dry DCM. Then, 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (0.153 mmol) was added, and the intermediate (50 mg, 66%) was obtained in the same manner as in Example 1. To remove the protected moiety, the intermediate (50 mg, 0.084 mmol) was dissolved in 9 mL of ethanol, and 6 mL of 15% w / v sodium hydroxide was added and the reaction was allowed to proceed for 30 minutes. Then, deprotection was carried out in the same manner as in Example 1, yielding the final compound (Example 16; CDCA-Trp) (26 mg, 53%).

[0308] 1H-NMR (500MHz, DMSO-d6)δ=0.56(s, 3H), 0.81-0.90(m, 8H), 0.91-1.36(m, 14H), 1.41-1.64(m, 4H), 1.65-1.8 2(m, 2H), 1.92-2.00(m, 1H), 2.04-2.11(m, 1H), 2.94-3.00(m, 1H), 3.11-3.16(m, 1H), 3.34-3.39(m, 1H), 3.7 7(bs, 1H), 4.19(bs, 1H), 4.37-4.44(m, 1H), 4.47(d, J=3.6Hz, 1H), 6.94-6.98(m, 1H), 7.03-7.07(m, 1H), 7.1 0-7.12(m, 1H), 7.31(d, J=6.4Hz, 2H), 7.51(d, J=6.4Hz, 2H), 8.01-8.06(m, 1H), 10.83(s, 1H), 12.59(bs, 1H).

[0309] Example 17: Preparation of (S)-2-((R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-(4-hydroxyphenyl)propanoic acid (CDCA-Tyr)

[0310] [ka]

[0311] The starting materials, chenodeoxycholic acid (100 mg, 0.255 mmol) and L-tyrosine methyl ester hydrochloride (71 mg, 0.306 mmol), were dissolved in 3 mL of dry DCM. Then, 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (0.153 mmol) was added, and the intermediate (123 mg, 85%) was obtained in the same manner as in Example 1. To remove the protected moiety, the intermediate (50 mg, 0.088 mmol) was dissolved in 9 mL of ethanol, and 6 mL of 15% w / v sodium hydroxide was added and the reaction was allowed to proceed for 30 minutes. The deprotection process was then carried out in the same manner as in Example 1, yielding the final compound (Example 17; CDCA-Tyr) (27 mg, 57%).

[0312] 1 H-NMR (500MHz, DMSO-d6) δ=0.58(s, 3H), 0.80-0.91(m, 6H), 0.91-1.49(m, 16H), 1.52-1.83(m, 6 H), 1.85-2.00(m, 2H), 2.02-2.10(m, 1H), 2.14-2.23(m, 1H), 2.67-2.73(m, 1H), 2.86-2.92(m, 1H) ), 3.13-3.22(m, 1H), 3.62(s, 1H), 4.12(d, J=2.4Hz, 1H), 4.24-4.30(m, 1H), 4.32(d, J=4Hz, 1H), 6.62(d, J=6.8Hz, 2H), 6.99(d, J=6.8Hz, 2H), 8.01(d, J=6.4Hz, 1H), 9.19(s, 1H), 12.58(bs, 1H).

[0313] Table 1 below shows the chemical structures of Examples 1 to 17.

[0314] [Table 1]

[0315] Example 18: Preparation of 2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)acetic acid (LCA-Val-Gly)

[0316] [ka]

[0317] The starting materials, Lithocholic acid-Val (100 mg, 0.210 mmol), L-glycine methyl ester hydrochloride (0.252 mmol), and 1-hydroxybenzotriazole hydrate (0.252 mmol), were dissolved in 3 mL of dry DCM. Then, 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (0.252 mmol) was added, and the intermediate (110 mg, 95%) was obtained in the same manner as in Example 1. To remove the protected moiety, the intermediate (50 mg, 0.091 mmol) was dissolved in 5 mL of ethanol, and 3 mL of 15% w / v sodium hydroxide was added and the reaction was allowed to proceed for 30 minutes. The deprotection process was then carried out in the same manner as in Example 1, yielding the final compound (Example 18; LCA-Val-Gly) (38 mg, 79%).

[0318] 2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylbutanamido)acetic acid; 1H-NMR (400MHz, DMSO-d6)δ=0.60(s, 3H, CH3), 0.79-0.90(m, 13H), 0.97-1.08(m, 4H) , 1.12-1.24(m, 6H), 1.27-1.39(m, 7H), 1.46-1.55(m, 2H), 1.57-1.70(m, 3H), 1.73-1 .84(m, 2H), 1.90-2.06(m, 3H), 2.16-2.24(m, 1H), 3.67(d, J=16.24Hz, 1H, CH), 4.16 (t, J=7.62Hz, 2H, CH2), 4.45(s, 1H, OH), 7.82(d, J=8.44Hz, 1H, NH), 8.12(s, 1H, NH).

[0319] Example 19: Preparation of (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)propanoic acid (LCA-Val-Ala)

[0320] [ka]

[0321] The starting materials, Lithocholic acid-Val (50 mg, 0.105 mmol), L-Alanine Methyl ester hydrochloride (0.126 mmol), and 1-hydroxybenzotriazole hydrate (0.126 mmol), were dissolved in 3 mL of dry DCM. Then, 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (0.126 mmol) was added, and the intermediate (43 mg, 81%) was obtained in the same manner as in Example 1. To remove the protected moiety, the intermediate (33 mg, 0.058 mmol) was dissolved in 3 mL of ethanol, and 2 mL of 15% w / v sodium hydroxide was added. The reaction was allowed to proceed for 30 minutes. The deprotection process was then carried out in the same manner as in Example 1, yielding the final compound (Example 19; LCA-Val-Ala) (26.5 mg, 83%).

[0322] (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylbutanamido)propanoic acid; 1 H-NMR (400MHz, DMSO-d6) δ=0.59(s, 3H, CH3), 0.79-0.91(m, 13H), 0.97-1.21(m, 1 0H), 1.24-1.38(m, 10H), 1.45-1.56(m, 2H), 1.58-1.70(m, 3H), 1.73-1.84(m, 2H), 1.86-1.96(m, 2H), 1.97-2.06(m, 1H), 2.14-2.24(m, 1H), 4.10-4.23(m, 2H, CHCH3 , CH), 7.80 (d, J=8.88Hz, 1H, NH), 8.23 ​​(d, J=6.04Hz, 1H, NH), 12.47 (bs, 1H, COOH).

[0323] Example 20: Preparation of (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-3-methylbutanoic acid (LCA-Val-Val)

[0324] [ka]

[0325] The starting materials, Lithocholic acid-Val (50 mg, 0.105 mmol), L-Valine methyl ester hydrochloride (0.126 mmol), and 1-hydroxybenzotriazole hydrate (0.126 mmol) were dissolved in 3 mL of dry DCM. Then, 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (0.126 mmol) was added, and the intermediate (59 mg, 95%) was obtained in the same manner as in Example 1. To remove the protected moiety, the intermediate (50 mg, 0.085 mmol) was dissolved in 2 mL of ethanol, and 2 mL of 15% w / v sodium hydroxide was added. The reaction was allowed to proceed for 30 minutes. The deprotection process was then carried out in the same manner as in Example 1, yielding the final compound (Example 2; LCA-Val-Val) (40 mg, 82%).

[0326] (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylbutanamido)-3-methylbutanoic acid; 1H-NMR (400MHz, DMSO-d6)δ=0.59(s, 3H, CH3), 0.79-0.90(m, 19H), 0.97-1.23(m, 10H), 1.27-1 .38(m, 7H), 1.45-1.54(m, 2H), 1.58-1.70(m, 3H), 1.73-1.83(m, 2H), 1.88-1.96(m, 2H), 1.99- 2.08(m, 2H), 2.14-2.23(m, 1H), 4.08(dd, J=7.72, 5.80Hz, 1H, CH), 4.24(t, J=8.20Hz, 1H, CH) , 4.45(s, 1H, OH), 7.81(d, J=8.80Hz, 1H, NH), 7.90(d, J=8.00Hz, 1H, NH), 12.56(bs, 1H, COOH).

[0327] Example 21: (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamide)-3-methylbutanamide)- 3-Methylbutanamide)- 4-Methylpentane acid( LCA-Val-Leu)

[0328] [ka]

[0329] The starting materials, Lithocholic acid-Val (100 mg, 0.210 mmol), L-Leucine Methyl Ester Hydrochloride (0.252 mmol), and 1-hydroxybenzotriazole hydrate (0.252 mmol) were dissolved in 3 mL of dry DCM. Then, 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (0.252 mmol) was added, and the intermediate (109 mg, 82%) was obtained in the same manner as in Example 1. To remove the protected moiety, the intermediate (50 mg, 0.081 mmol) was dissolved in 3 mL of ethanol, and 2 mL of 15% w / v sodium hydroxide was added. The reaction was allowed to proceed for 30 minutes. The deprotection process was then carried out in the same manner as in Example 1, yielding the final compound (Example 21; LCA-Val-Leu) (40 mg, 85%).

[0330] (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylbutanamido)-4-methylpentanoic acid; 1 H-NMR (400MHz, DMSO-d6)δ=0.60(s, 3H, CH3), 0.79-0.91(m, 19H), 0.96-1.23(m, 10H), 1 .27-1.39(m, 7H), 1.45-1.54(m, 4H), 1.58-1.70(m, 4H), 1.73-1.83(m, 2H), 1.87-1.96( m, 2H), 1.99-2.09(m, 1H), 2.12-2.22(m, 1H), 4.16(q, J=7.33Hz, 2H, CH, CHCH2), 4.45(b s, 1H, OH), 7.79 (d, J=8.84Hz, 1H, NH), 8.07 (d, J=7.04Hz, 1H, NH), 12.52 (bs, 1H, COOH).

[0331] Example 22: Preparation of (2S,3R)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylbutanamido)-3-methylpentanoic acid (LCA-Val-Ile)

[0332] [ka]

[0333] The starting materials, Lithocholic acid-Val (100 mg, 0.210 mmol), L-Isoleucine methyl ester hydrochloride (0.252 mmol), and 1-hydroxybenzotriazole hydrate (0.252 mmol), were dissolved in 3 mL of dry DCM. Then, 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (0.252 mmol) was added, and the intermediate (121 mg, 82%) was obtained in the same manner as in Example 1. To remove the protected moiety, the intermediate (50 mg, 0.083 mmol) was dissolved in 3 mL of ethanol, and 2 mL of 15% w / v sodium hydroxide was added. The reaction was allowed to proceed for 30 minutes. The deprotection process was then carried out in the same manner as in Example 1, yielding the final compound (Example 22; LCA-Val-Ile) (37 mg, 75%).

[0334] (2S,3R)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylbutanamido)-3-methylpentanoic acid; 1H-NMR (400MHz, DMSO-d6)δ=0.60(s, 3H, CH3), 0.80-0.89(m, 19H), 0.97-1.23(m, 13H), 1.28-1. 38(m, 7H), 1.45-1.55(m, 2H), 1.57-1.70(m, 3H), 1.71-1.83(m, 3H), 1.87-1.96(m, 2H), 1.99-2 .08(m, 1H), 2.13-2.22(m, 1H), 4.11(t, J=7.12Hz, 1H, CH), 4.23(t, J=7.76Hz, 1H, CH), 4.46(d, J=4.52Hz, 1H, OH), 7.80(d, J=8.72Hz, 1H, NH), 7.92(d, J=8.40Hz, 1H, NH), 12.54(bs, 1H, COOH).

[0335] Example 23: Preparation of (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-4-(methylthio)butanoic acid (LCA-Val-Met)

[0336] [ka]

[0337] The starting materials, Lithocholic acid-Val (100 mg, 0.210 mmol), L-Methionine methyl ester hydrochloride (0.252 mmol), and 1-hydroxybenzotriazole hydrate (0.252 mmol) were dissolved in 3 mL of dry DCM. Then, 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (0.252 mmol) was added, and the intermediate (100 mg, 79%) was obtained in the same manner as in Example 1. To remove the protected moiety, the intermediate (40 mg, 0.066 mmol) was dissolved in 2 mL of ethanol, and 1 mL of 15% w / v sodium hydroxide was added and the reaction was allowed to proceed for 30 minutes. The final compound (Example 23; LCA-Val-Met) was obtained (31 mg, 79%) by deprotection in the same manner as in Example 1.

[0338] (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylbutanamido)-4-(methylthio)butanoic acid; 1 H-NMR (400MHz, DMSO-d6)δ=0.60(s, 3H, CH3), 0.80-0.90(m, 13H), 0.96-1.23(m, 11H), 1.28 -1.38(m, 7H), 1.28-1.38(m, 7H), 1.46-1.71(m, 5H), 1.74-1.96(m, 6H), 2.00-2.10(m, 5H), 2 .12-2.21(m, 1H), 4.14(t, J=7.86Hz, 1H, CH), 4.21-4.29(m, 1H, CHCH2), 4.46(d, J=3.68Hz, 1 H, OH), 7.82 (t, J=8.26Hz, 1H, NH), 8.19 (dd, J=27.68, 7.72Hz, 1H, NH), 12.64 (bs, 1H, COOH).

[0339] Example 24: Preparation of (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-3-phenylpropanoic acid (LCA-Val-Phe)

[0340] [ka]

[0341] The starting materials, Lithocholic acid-Val (100 mg, 0.210 mmol), L-Phenylalanine Methyl ester hydrochloride (0.252 mmol), and 1-hydroxybenzotriazole hydrate (0.252 mmol), were dissolved in 3 mL of dry DCM. Then, 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (0.252 mmol) was added, and the intermediate (119 mg, 89%) was obtained in the same manner as in Example 1. To remove the protected moiety, the intermediate (50 mg, 0.076 mmol) was dissolved in 5 mL of ethanol, and 3 mL of 15% w / v sodium hydroxide was added. The reaction was allowed to proceed for 30 minutes. The deprotection reaction was then carried out in the same manner as in Example 1, yielding the final compound (Example 24; LCA-Val-Phe) (33.2 mg, 69%).

[0342] (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylbutanamido)-3-phenylpropanoic acid; 1H-NMR (400MHz, DMSO-d6)δ=0.59(s, 3H, CH3), 0.75-0.90(m, 13H), 0.97-1.09(m, 4H), 1.10-1.25(m, 6H), 1.27- 1.38(m, 7H), 1.46-1.54(m, 2H), 1.56-1.70(m, 3H), 1.73-1.83(m, 2H), 1.87-2.03(m, 3H), 2.88(q, J=7.65Hz, 1H , CH3), 3.02(q, J=6.37Hz, 1H, CH3), 4.16(t, J=8.20Hz, 1H, CH), 4.38(q, J=7.19Hz, 1H, CHCH2), 4.46(d, J=4.40 Hz, 1H, OH), 7.16-7.27(m, 5H, Ar), 7.73(d, J=9.28Hz, 1H, NH), 8.18(d, J=8.60Hz, 1H, NH), 12.68(bs, 1H, COOH).

[0343] Example 25: Preparation of (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-3-(1H-indol-3-yl)propanoic acid (LCA-Val-Trp)

[0344] [ka]

[0345] The starting materials, Lithocholic acid-Val (100 mg, 0.210 mmol), L-Tryptophan Methyl Ester Hydrochloride (0.252 mmol), and 1-hydroxybenzotriazole hydrate (0.252 mmol), were dissolved in 3 mL of dry DCM. Then, 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (0.252 mmol) was added, and the intermediate (134 mg, 94%) was obtained in the same manner as in Example 1. To remove the protected moiety, the intermediate (50 mg, 0.073 mmol) was dissolved in 2 mL of ethanol, and 1 mL of 15% w / v sodium hydroxide was added and the reaction was allowed to proceed for 30 minutes. The deprotection process was then carried out in the same manner as in Example 1, yielding the final compound (Example 25; LCA-Val-Trp) (38.6 mg, 80%).

[0346] (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1 H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylbutanamido)-3-(1H-indol-3-yl)propanoic acid; 1H-NMR (400MHz, DMSO-d6) δ=0.58(s, 3H, CH3), 0.78-0.90(m, 13H), 0.97-1.22(m, 10H), 1.26-1.39(m, 7H), 1.44-1.54(m, 2H), 1.56-1.70(m, 4H), 1.72-1.83(m, 2H), 1.88-2.02(m, 2H), 2.13-2.23(m, 1H), 3.02(q, J=7.28Hz, 1H, CH2), 3.14(q, J=7.13Hz, 1 H, CH2), 4.20(t, J=7.36Hz, 1H, CH), 4.45(m, 2H, OH, CH), 6.96(t, J=7.28Hz, 1H, Ar), 7.05(t, J=7.08Hz, 1H, Ar), 7.16(s, 1H, A r), 7.31 (d, J=8.24Hz, 1H, Ar), 7.51 (d, J=8.24Hz, 1H, Ar), 7.75 (d, J=8.24Hz, 1H, NH), 10.85 (s, 1H, NH), 12.55 (bs, 1H, COOH).

[0347] Example 26: Preparation of 1-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanoyl)pyrrolidine-2-carboxylic acid (LCA-Val-Pro)

[0348] [ka]

[0349] The starting materials, Lithocholic acid-Val (70 mg, 0.147 mmol), L-Proline Methyl Ester Hydrochloride (0.176 mmol), and 1-hydroxybenzotriazole hydrate (0.176 mmol), were dissolved in 2 mL of dry DCM. Then, 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (0.176 mmol) was added, and the intermediate (66 mg, 76%) was obtained in the same manner as in Example 1. To remove the protected moiety, the intermediate (50 mg, 0.085 mmol) was dissolved in 2 mL of ethanol, and 2 mL of 15% w / v sodium hydroxide was added. The reaction was allowed to proceed for 30 minutes. The deprotection process was then carried out in the same manner as in Example 1, yielding the final compound (Example 26; LCA-Val-Pro) (25 mg, 52%).

[0350] 1-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylbutanoyl)pyrrolidine-2-carboxylic acid; 1 H-NMR (400MHz, DMSO-d6) δ=0.59(s, 3H, CH3), 0.80-0.93(m, 13H), 0.97-1.22(m, 10H), 1.27-1.38(m, 7H), 1.46-1.71(m, 5H), 1.73-2.02(m, 7H), 2.07-2.20(m, 2H), 3,31-3.40 (m, 1H), 1.46-1.71(m, 5H), 3.56(q, J=7.29Hz, 1H, CH2), 3.81(q, J=7.64Hz, 1H, CH2), 4. 20(s, 1H, CH), 4.27(t, J=8.74Hz, 1H, CH), 4.66(bs, 1H, OH), 8.04(d, J=8.28Hz, 1H, NH).

[0351] Example 27: Preparation of (S)-3-hydroxy-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)propanoic acid (LCA-Val-Ser)

[0352] [ka]

[0353] The starting materials, Lithocholic acid-Val (100 mg, 0.210 mmol), L-Serine Methyl Ester Hydrochloride (0.252 mmol), and 1-hydroxybenzotriazole hydrate (0.252 mmol), were dissolved in 3 mL of dry DCM. Then, 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (0.252 mmol) was added, and the intermediate (113 mg, 91%) was obtained in the same manner as in Example 1. To remove the protected moiety, the intermediate (40 mg, 0.069 mmol) was dissolved in 2 mL of ethanol, and 2 mL of 15% w / v sodium hydroxide was added. The reaction was allowed to proceed for 30 minutes. The deprotection process was then carried out in the same manner as in Example 1, yielding the final compound (Example 27; LCA-Val-Ser) (35.2 mg, 91%).

[0354] (S)-3-hydroxy-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylbutanamido)propanoic acid; 1H-NMR (400MHz, DMSO-d6)δ=0.60(s, 3H, CH3), 0.79-0.91(m, 13H), 0.97-1.2 4(m, 11H), 1.27-1.39(m, 7H), 1.45-1.70(m, 6H), 1.73-1.85(m, 2H), 1.88-2 .07(m, 2H), 2,17-2.26(m, 1H), 3.58-3.70(m, 2H), 4.18-4.27(m, 2H), 4.45( d, J=4.72Hz, 1H, OH), 7.82(d, J=9.08Hz, 1H, NH), 8.04(d, J=7.92Hz, 1H, NH).

[0355] Example 28: Preparation of (2S,3S)-3-hydroxy-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)butanoic acid (LCA-Val-Thr)

[0356] [ka]

[0357] The starting materials, Lithocholic acid-Val (100 mg, 0.210 mmol), L-Threonine Methyl ester hydrochloride (0.252 mmol), and 1-hydroxybenzotriazole hydrate (0.252 mmol), were dissolved in 3 mL of dry DCM. Then, 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (0.252 mmol) was added, and the intermediate (115 mg, 93%) was obtained in the same manner as in Example 1. To remove the protected moiety, the intermediate (51.2 mg, 0.087 mmol) was dissolved in 3 mL of ethanol, and 2 mL of 15% w / v sodium hydroxide was added. The reaction was allowed to proceed for 30 minutes. The deprotection process was then carried out in the same manner as in Example 1, yielding the final compound (Example 28; LCA-Val-Thr) (50 mg, 99%).

[0358] (2S,3S)-3-hydroxy-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylbutanamido)butanoic acid; 1 H-NMR (400MHz, DMSO-d6) δ=0.59(s, 3H, CH3), 0.80-0.91(m, 13H), 0.97-1.23(m, 13H ), 1.27-1.39(m, 7H), 1.45-1.71(m, 5H), 1.73-1.85(m, 2H), 1.89-2.09(m, 3H), 2.14 -2.24(m, 1H), 4.08-4.21(m, 2H), 4.25(q, J=6.61Hz, 1H, CH), 4.45(s, 1H, OH), 4.87( s, 1H), 7.73 (t, J=6.04Hz, 1H, NH), 7.86 (t, J=6.18Hz, 1H, NH), 12.50 (bs, 1H, COOH).

[0359] Example 29: Preparation of (R)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-3-mercaptopropanoic acid (LCA-Val-Cys)

[0360] [ka]

[0361] The starting materials, Lithocholic acid-Val (50 mg, 0.105 mmol), L-Cysteine ​​Methyl Ester Hydrochloride (0.126 mmol), HATU (0.126 mmol), and N,N-Diisopropylethylamine (DIPEA) (0.126 mmol) were dissolved in 3 mL of dry DCM. The same procedure as for Example 1 was then used to obtain the intermediate (10 mg, 17%). To remove the protected moiety, the intermediate (10 mg, 0.017 mmol) was dissolved in 1 mL of ethanol, and 1 mL of 15% w / v sodium hydroxide was added and the reaction was allowed to proceed for 30 minutes. The deprotection process was then carried out in the same manner as for Example 1 to obtain the final compound (Example 29; LCA-Val-Cys) (1.7 mg, 17%).

[0362] (R)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylbutanamido)-3-mercaptopropanoic acid; 1H-NMR (400MHz, DMSO-d6)δ=0.60(s, 3H, CH3), 0.81-0.91(m, 13H), 0.98-1.24(m, 10H), 1.27-1 .39(m, 7H), 1.45-1.55(m, 2H), 1.58-1.71(m, 3H), 1.72-1.85(m, 2H), 1.88-2.08(m, 3H), 2.16 -2.26(m, 1H), 2.70-2.89(m, 2H), 4.17(t, J=7.44Hz, 1H, CH), 4.32-4.38(m, 1H, CH), 4.45(d, J =4.28Hz, 1H, OH), 7.87(d, J=9.12Hz, 1H, NH), 8.16(d, J=7.56Hz, 1H, NH), 12.85(bs, 1H, COOH).

[0363] Example 30: Preparation of (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-3-(4-hydroxyphenyl)propanoic acid (LCA-Val-Tyr)

[0364] [ka]

[0365] The starting materials, Lithocholic acid-Val (100 mg, 0.210 mmol), L-Tyrosine methyl ester hydrochloride (0.252 mmol), and 1-hydroxybenzotriazole hydrate (0.252 mmol) were dissolved in 3 mL of dry DCM. Then, 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (0.252 mmol) was added, and the intermediate (100 mg, 73%) was obtained in the same manner as in Example 1. To remove the protected moiety, the intermediate (45 mg, 0.069 mmol) was dissolved in 3 mL of ethanol, and 2 mL of 15% w / v sodium hydroxide was added. The reaction was allowed to proceed for 30 minutes. The deprotection process was then carried out in the same manner as in Example 1, yielding the final compound (Example 30; LCA-Val-Tyr) (33 mg, 75%).

[0366] (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H -cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylbutanamido)-3-(4-hydroxyphenyl)propanoic acid; 1H-NMR (400MHz, DMSO-d6)δ=0.60(s, 3H, CH3), 0.76-0.91(m, 12H), 0.96-1.23(m, 10H), 1.27-1.39(m, 7H), 1.45-1.55(m, 2H), 1.57-1.71(m, 3H), 1.74-1.94(m, 3H), 1.95-2.04(m, 1H), 2.14-2.23(m, 1H), 2.71-2.9 2(m, 2H), 4.13-4.21(m, 1H), 4.26-4.34(m, 1H), 4.46(s, 1H, OH), 6.62(d, J=6.64Hz, 2H, Ar), 6.99(d, J=6. 64Hz, 2H, Ar), 7.72 (d, J=9.00Hz, 1H, NH), 8.07-8.12 (m, 1H, NH), 9.20 (s, 1H, Ar-OH), 12.57 (bs, 1H, COOH).

[0367] Example 31: Preparation of (S)-4-amino-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-4-oxobutanoic acid (LCA-Val-Asn)

[0368] [ka]

[0369] The starting materials, Lithocholic acid-Val (100 mg, 0.210 mmol), L-Asparagine tert-butyl ester hydrochloride (0.252 mmol), and 1-hydroxybenzotriazole hydrate (0.252 mmol), were dissolved in 1 mL of dry DCM. Then, 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (0.252 mmol) was added, and the intermediate (117 mg, 86%) was obtained in the same manner as in Example 1. To remove the protected moiety, the intermediate (50 mg, 0.077 mmol) was dissolved in 2 mL of DCM and 1 mL of TFA was added, and the reaction was carried out. When TLC confirmed that the starting material had disappeared, the solvent was removed using an evaporator, and the process of dissolving in methanol and removing the solvent was repeated three times. The reaction mixture was purified through column chromatography to obtain the final compound (Example 31; LCA-Val-Asn) (26 mg, 57%).

[0370] (S)-4-amino-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylbutanamido)-4-oxobutanoic acid; 1H-NMR (400MHz, DMSO-d6) δ=0.61(s, 3H, CH3), 0.78-0.92(m, 13H), 0.97-1.27(m, 11H), 1.30-1.41(m, 5H), 1.45-1.55(m, 3H), 1.57-1.67(m, 2H), 1.71-1.85(m, 3H), 1.87-2.04(m, 3H), 2.18-2.27(m, 1H), 2 .38-2.57(m, 2H) 4.16(dd, J=8.66, 6.74Hz, 1H, CH), 4.40(d, J=6.49Hz, 1H, OH), 4.88-4.98(m, 1H, CH), 6.91(s, 1H, NHH), 7.45(s, 1H, NHH), 7.83(d, J=8.96Hz, 1H, NH), 7.99(s, 1H, NH), 12.53(bs, 1H, COOH).

[0371] Example 32: Preparation of (S)-5-amino-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-5-oxopentanoic acid (LCA-Val-Gln)

[0372] [ka]

[0373] The starting materials, Lithocholic acid-Val (100 mg, 0.210 mmol), L-Glutamine tert-butyl ester hydrochloride (0.252 mmol), and 1-hydroxybenzotriazole hydrate (0.252 mmol), were dissolved in 3 mL of dry DCM and 1 mL of DMF. Then, 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (0.252 mmol) was added, and the intermediate (126 mg, 91%) was obtained in the same manner as in Example 1. To remove the protected moiety, the intermediate (60 mg, 0.083 mmol) was dissolved in 2 mL of DCM and 1 mL of TFA was added, and the reaction was carried out. When TLC confirmed that the starting material had disappeared, the solvent was removed using an evaporator, and the process of dissolving in methanol and removing the solvent was repeated three times. The reaction mixture was purified through column chromatography to obtain the final compound (Example 32; LCA-Val-Gln) (26 mg, 57%).

[0374] (S)-5-amino-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylbutanamido)-5-oxopentanoic acid; 1 H-NMR (400MHz, DMSO-d6)δ=0.60(s, 3H, CH3), 0.78-0.90(m, 13H), 0.97-1.24(m, 1 0H), 1.27-1.39(m, 7H), 1.44-1.70(m, 5H), 1.71-1.83(m, 3H), 1.87-1.99(m, 3H), 2.05-2.16(m, 2H), 2.18-2.29(m, 2H), 3.32-3.41(m, 1H), 4.05-4.28(m, 3H), 6.78 (s, 1H), 7.26(s, 1H), 7.74-7.84(m, 1H), 8.14-8.25(m, 1H), 12.46(bs, 1H, COOH).

[0375] Example 33: Preparation of (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)succinic acid (LCA-Val-Asp)

[0376] [ka]

[0377] The starting materials, Lithocholic acid-Val (100 mg, 0.210 mmol), L-Aspartic acid dimethyl ester hydrochloride (0.252 mmol), and 1-hydroxybenzotriazole hydrate (0.252 mmol), were dissolved in 3 mL of dry DCM. Then, 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (0.252 mmol) was added, and the intermediate (93.6 mg, 72%) was obtained in the same manner as in Example 1. To remove the protected moiety, the intermediate (40 mg, 0.065 mmol) was dissolved in 3 mL of ethanol, and 2 mL of 15% w / v sodium hydroxide was added. The reaction was allowed to proceed for 30 minutes. The deprotection process was then carried out in the same manner as in Example 1, yielding the final compound (Example 33; LCA-Val-Asp) (36.4 mg, 95%).

[0378] succinic acid; 1H-NMR (400MHz, DMSO-d6) δ=0.59(d, J=5.04Hz, 3H, CH3), 0.77-0.91(m, 12H), 0.95-1.23(m, 11 H), 1.27-1.40(m, 7H), 1.44-1.55(m, 2H), 1.56-1.71(m, 3H), 1.72-1.84(m, 2H), 1.87-2.06(m , 3H), 2.09-2.27(m, 2H), 2.51-2.72(m, 2H), 4.16-4.23(m, 1H), 4.47-4.55(m, 1H, OH), 7.76-7 .85(m, 1H, NH), 8.26(dd, J=22.24, 8.00Hz, 1H, NH), 12.67(bs, 1H, COOH), 12.80(bs, 1H, COOH).

[0379] Example 34: Preparation of (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)pentanedioic acid (LCA-Val-Glu)

[0380] [ka]

[0381] The starting materials, Lithocholic acid-Val (100 mg, 0.210 mmol), Dimethyl L-Glutamate Hydrochloride (0.252 mmol), and 1-hydroxybenzotriazole hydrate (0.252 mmol), were dissolved in 2 mL of dry DCM. Then, 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (0.252 mmol) was added, and the intermediate was obtained in the same manner as in Example 1 (62.8 mg, 94%). To remove the protected moiety, the intermediate (10 mg, 0.016 mmol) was dissolved in 2 mL of ethanol, and 1 mL of 15% w / v sodium hydroxide was added and the reaction was allowed to proceed for 30 minutes. The deprotection process was then carried out in the same manner as in Example 1, yielding the final compound (Example 34; LCA-Val-Glu) (9 mg, 92%).

[0382] (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylbutanamido)pentanedioic acid; 1 H-NMR (400MHz, DMSO-d6) δ=0.59(d, J=3.2Hz, 3H, CH3), 0.79-0.91(m, 13H), 0.96-1 .24(m, 11H), 1.26-1.39(m, 7H), 1.45-1.71(m, 5H), 1.72-1.84(m, 3H), 1.87-2.06( m, 3H), 2.10-2.30(m, 3H), 4.13-4.26(m, 3H), 4.45(bs, 1H, OH), 7.77-7.83(m, 1H, N H), 8.20 (dd, J=26.12, 7.48Hz, 1H, NH), 12.15 (bs, 1H, COOH), 12.56 (bs, 1H, COOH).

[0383] Example 35: Preparation of (S)-6-amino-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)hexanoic acid (LCA-Val-Lys)

[0384] [ka]

[0385] The starting materials, Lithocholic acid-Val (100 mg, 0.210 mmol), Nepsilon-Benzyloxycarbonyl-L-Lysine benzyl ester hydrochloride (0.252 mmol), and 1-hydroxybenzotriazole hydrate (0.252 mmol), were dissolved in 1 mL of dry DCM. Then, 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (0.252 mmol) was added, and the intermediate (171 mg, 98%) was obtained in the same manner as in Example 1. To remove the protected moiety, the intermediate (50 mg, 0.061 mmol) was dissolved in 5 mL of ethanol and 10% Pd / C was added to proceed with the reaction. When TLC confirmed that the starting material was gone, the Pd / C was removed through a Celite filter, the ethanol was removed using an evaporator, and the reaction mixture was purified through column chromatography to obtain the final compound (Example 35; LCA-Val-Lys) (37 mg, 87%).

[0386] Hexanoic acid; 1 H-NMR (400MHz, DMSO-d6)δ=0.61(s, 3H, CH3), 0.77-0.91(m, 13H), 0.97-1.4 2(m, 23H), 1.45-1.70(m, 8H), 1.73-1.85(m, 3H), 1.89-2.08(m, 2H), 2.18-2 .30(m, 2H), 3.64-3.72(m, 1H), 2.18-2.30(m, 2H), 4.02(t, J=6.76Hz, 1H, CH ), 4.45(bs, 1H, OH), 7.37(d, J=5.60Hz, 1H, NH), 7.95(d, J=8.08Hz, 1H, NH).

[0387] Example 36: Preparation of (S)-5-guanidino-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)pentanoic acid (LCA-Val-Arg)

[0388] [ka]

[0389] The starting materials, Lithocholic acid-Val (100 mg, 0.210 mmol), L-Arginine methyl ester dihydrochloride (0.252 mmol), N-Methylmorpholine (NMM) (0.273 mmol), and 1-hydroxybenzotriazole hydrate (0.273 mmol) were dissolved in 2 mL of dry DMF. Then, 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (0.273 mmol) was added, and the intermediate (102 mg, 70%) was obtained in the same manner as in Example 1. To remove the protected moiety, the intermediate (22 mg, 0.034 mmol) was dissolved in 1 mL of ethanol and 1 mL of 15% w / v sodium hydroxide was added. The reaction was allowed to proceed for 30 minutes. Thereafter, deprotection was carried out in the same manner as in Example 1 to obtain the final compound (Example 36; LCA-Val-Arg) (19 mg, 88%).

[0390] (S)-5-guanidino-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylbutanamido)pentanoic acid; 1H-NMR (400MHz, DMSO-d6) δ=0.60(s, 3H, CH3), 0.80-0.90(m, 13H), 0.96-1.25(m, 12H), 1.27-1. 39(m, 7H), 1.44-1.54(m, 4H), 1.57-1.84(m, 6H), 1.88-2.05(m, 3H), 2.18-2.26(m, 1H), 3.09(q , J=6.36Hz, 1H), 3.33-3.40(m, 1H, H-OH), 4.13-4.19(m, 2H), 6.87(bs, 1H), 7.32(bs, 1H), 7.57 (t, J=5.24Hz, 1H), 7.84 (d, J=9.44Hz, 1H, NH), 8.21 (d, J=7.48Hz, 1H, NH), 12.64 (bs, 1H, COOH).

[0391] Example 37: Preparation of (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-3-(1H-imidazol-4-yl)propanoic acid (LCA-Val-His)

[0392] [ka]

[0393] The starting materials, Lithocholic acid-Val (100 mg, 0.210 mmol), L-histidine methyl ester dihydrochloride (0.252 mmol), N-methylmorpholine (NMM) (0.273 mmol), and 1-hydroxybenzotriazole hydrate (0.273 mmol) were dissolved in 2 mL of dry DMF. Then, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (0.273 mmol) was added, and the intermediate (104 mg, 79%) was obtained in the same manner as in Example 1. To remove the protected moiety, the intermediate (50 mg, 0.079 mmol) was dissolved in 2 mL of ethanol and 2 mL of 15% w / v sodium hydroxide was added. The reaction was allowed to proceed for 30 minutes. Thereafter, deprotection was carried out in the same manner as in Example 1 to obtain the final compound (Example 37; LCA-Val-His) (20 mg, 41%).

[0394] (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H- cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylbutanamido)-3-(1H-imidazol-4-yl)propanoic acid; 1H-NMR (400MHz, DMSO-d6) δ=0.59(s, 3H, CH3), 0.80-0.91(m, 13H), 0.96-1.24(m, 11H), 1.27-1.38(m , 7H), 1.45-1.71(m, 5H), 1.72-1.83(m, 2H), 1.87-2.05(m, 3H), 2.16-2.26(m, 1H), 2.97-3.04(m, 1H) , 3.10-3.17(m, 1H), 4.06(t, J=8.206Hz, 1H, CH), 4.50-4.58(m, 1H, OH), 7.42(s, 1H, CH), 7.91(d, J=8 .56Hz, 1H, NH), 8.42 (d, J=7.60Hz, 1H, NH), 9.00 (s, 1H, CH), 12.92 (bs, 1H, COOH), 14.18 (bs, 1H, NH).

[0395] The chemical structures of Examples 18 to 37 are shown in Table 2 below.

[0396] [Table 2]

[0397] Example 38: Preparation of 1-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoyl)pyrrolidine-2-carboxylic acid (LCA-Pro)

[0398] The final compound (Example 38; LCA-Pro) was obtained using lithocholic acid (100 mg, 0.264 mmol) and L-proline methyl ester hydrochloride as starting materials in the same manner as in Compound 1.

[0399] 1 H-NMR (400MHz, DMSO-d6) δ=0.61(s, 3H, CH3), 0.82-0.91(m, 7H), 0.98-1.22(m, 10H), 1.23-1.39(m, 7H), 1.45-1.71(m, 6H), 1.72-1.95(m, 6H), 1.99-2.31(m, 4H), 3.34-3.36(m, 1H), 3.47-3.52(m, 1H), 4.18(q, J=4.17, 1H, CH), 12.33(bs, 1H, COOH).

[0400] Example 39: Preparation of (2S,3S)-3-hydroxy-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)butanoic acid (LCA-Thr)

[0401] The final compound (Example 39; LCA-Thr) was obtained using lithocholic acid and L-threonine methyl ester hydrochloride as starting materials and the same method as for Compound 1.

[0402] 1 H-NMR (400MHz, DMSO-d6)δ=0.60(s, 3H, CH3), 0.80-0.90(m, 13H), 0.99-1. 22(m, 11H), 1.29-1.39(m, 7H), 1.46-1.55(m, 2H), 1.58-1.82(m, 6H), 1.82- 1.88(m, 1H), 1.99-2.08(m, 1H), 2.15-2.23(m, 1H), 3.32-3.35(m, 1H), 4.1 5(t, J=7.0Hz, 1H, CHCHCH3CH2), 4.45(s, 1H, OH), 7.94(d, J=8.4Hz, 1H, NH). 12.50(bs, 1H, COOH).

[0403] Example 40: Preparation of (R)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-mercaptopropanoic acid (LCA-Cys)

[0404] The final compound (Example 40; LCA-Cys) was obtained using lithocholic acid and L-cysteine ​​methyl ester hydrochloride as starting materials and the same method as for Compound 1.

[0405] 1H-NMR (400MHz, DMSO-d6)δ=0.61(s, 3H, CH3), 0.82-0.93(m, 7H), 0.98-1.24(m, 10H), 1.26-1.40(m, 7H), 1.44-1.71(m, 6H), 1.72-1.85(m, 2H), 1. 89-1.96(m, 1H), 2.00-2.09(m, 1H), 2.13-2.22(m, 1H), 2.66-2.77(m, 1H) ), 2.78-2.89(m, 1H), 4.30-4.39(m, 1H), 4.45(bs, 1H, OH), 8.13(d, J=7.2 0、 1H, NH), 12.80(bs, 1H, COOH).

[0406] Example 41: (S)-5-amino-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamine Do- Production of 5-oxopentanoic acid (LCA-Gln)

[0407] The final compound (Example 41; LCA-Gln) was obtained using lithocholic acid and L-Glutamine tertbutyl ester hydrochloride as starting materials in the same manner as in Compound 1.

[0408] 1 H-NMR (400MHz, DMSO-d6)δ=0.61(s, 3H, CH3), 0.84-0.92(m, 7H), 1.01-1.12(m, 5H), 1.16-1.27(m, 9H), 1.31-1.40(m, 5H), 1.45-1.56(m, 4H), 1. 70-1.83(m, 4H), 1.88-1.95(m, 2H), 2.06-2.13(m, 2H), 4.07-4.14(m, 1H ), 4.88-4.98(m, 1H), 6.79(s, 1H, NHH), 7.30(s, 1H, NHH), 8.08(d, J=7.8 4、 1H, NH), 12.51(bs, 1H, COOH).

[0409] Example 42: Preparation of (S)-5-guanidino-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)pentanoic acid (LCA-Arg)

[0410] The final compound (Example 42; LCA-Arg) was obtained using lithocholic acid and L-arginine methyl ester dihydrochloride as starting materials and the same method as for Compound 1.

[0411] 1 H-NMR (400MHz, DMSO-d6)δ=0.60(s, 3H, CH3), 0.83-0.90(s, 7H), 0.99-1.22(m, 12H), 1.29-1.39(m, 8H), 1. 45-1.56(m, 4H), 1.58-1.70(m, 4H), 1.74-1.83(m, 2H), 1.94-2.02(m, 1H), 2.10-2.19(m, 1H), 3.03(d, J=5.0 8、 1H), 3.92(q, J=6.6 4、 1H), 4.44(s, 1H, OH), 5.76(s, 1H), 7.17-7.84(m, 4H), 9.30(s, 1H).

[0412] Example 43: Preparation of (S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-(1H-imidazol-5-yl)propanoic acid (LCA-His)

[0413] The final compound (Example 43; LCA-His) was obtained using lithocholic acid and L-histidine methyl ester dihydrochloride as starting materials and the same method as for Compound 1.

[0414] 1H-NMR (400MHz, DMSO-d6)δ=0.58(s, 3H, CH3), 0.80-0.89(s, 7H), 0.96-1.22(m, 10H ), 1.26-1.39(m, 8H), 1.45-1.70(m, 4H), 1.63-1.70(m, 1H), 1.72-1.81(m, 2H), 1.8 7-1.94(m, 1H), 1.95-2.02(m, 1H), 2.04-2.12(m, 1H), 2.95(dd, J=15.24, 9.84Hz, 1 H), 3.11(dd, J=15.10, 5.22Hz, 1H), 4.44-4.56(m, 2H), 7.35(s, 1H), 8.23(d, J=8.4 4、 1H, NH), 8.94(s, 1H), 13.98(bs, 1H).

[0415] Example 44 Preparation of (S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanoic acid (LCA-Val)

[0416] The final compound (Example 44; LCA-Val) was obtained using lithocholic acid and L-valine methyl ester hydrochloride as starting materials and the same method as for Compound 1.

[0417] 1 H-NMR (400MHz, DMSO-d6)δ=0.60(s, 3H), 0.80-0.95(m, 13H), 0.95-2.27(m, 28H) ), 3.30-3.33(m, 1H), 4.05-4.15(m, 1H), 4.38-4.48(m, 1H), 7.83-7.92(m, 1H). 12.46(bs, 1H).

[0418] Example 45 Preparation of 2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamide)-3-acetic acid (LCA-Gly)

[0419] The final compound (Example 45; LCA-Gly) was obtained using lithocholic acid and L-glycine methyl ester hydrochloride as starting materials and the same method as in Compound 1.

[0420] 1 H-NMR (400MHz, DMSO-d6)δ=0.60(s, 3H), 0.83-0.90(m, 6H), 0.92-2.18(m, 28H), 3.19- 3.33 (m, 1H), 3.62 (d, J=6Hz, 2H), 4.40-4.46 (m, 1H), 7.88-7.96 (m, 1H), 12.45 (bs, 1H).

[0421] Example 46 Preparation of (S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-propanoic acid (LCA-Ala)

[0422] The final compound (Example 46; LCA-Ala) was obtained using lithocholic acid and L-alanine methyl ester hydrochloride as starting materials and the same method as for Compound 1.

[0423] 1 H-NMR (400MHz, DMSO-d6)δ=0.60(s, 3H), 0.83-0.93(m, 9H), 0.98-2.16(m, 28H), 3.19- 3.33(m, 1H), 3.56-3.68(m, 1H), 4.40-4.46(m, 1H), 7.88-7.96(m, 1H), 12.45(bs, 1H).

[0424] Example 47 Preparation of (S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylpentanoic acid (LCA-Leu)

[0425] The final compound (Example 47; LCA-Leu) was obtained using lithocholic acid and L-leucine methyl ester hydrochloride as starting materials and the same method as for Compound 1.

[0426] 1 H-NMR (400MHz, DMSO-d6)δ=0.60(s, 3H), 0.83-0.90(m, 13H), 0.92-2.18(m, 30H), 3.29 -3.36(m, 1H), 4.13-4.23(m, 1H), 4.40-4.47(m, 1H), 8.00-8.20(m, 1H), 12.43(bs, 1H).

[0427] Example 48 Preparation of (S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-4-(methylthio)butanoic acid (LCA-Met)

[0428] The final compound (Example 48; LCA-Met) was obtained using lithocholic acid and L-methionine methyl ester hydrochloride as starting materials and the same method as in Compound 1.

[0429] 1 H-NMR (400MHz, DMSO-d6)δ=0.60(s, 3H), 0.83-0.90(m, 7H), 0.92-2.18(m, 34H), 3.19- 3.33(m, 1H), 4.20-4.29(m, 1H), 4.41-4.48(m, 1H), 8.00-8.09(m, 1H), 12.57(bs, 1H).

[0430] Example 49 Preparation of (S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-phenylpropanoic acid (LCA-Phe)

[0431] The final compound (Example 49; LCA-Phe) was obtained using lithocholic acid and L-phenylalanine methyl ester hydrochloride as starting materials and the same method as for Compound 1.

[0432] 1 H-NMR (400MHz, DMSO-d6) δ=0.58(s, 3H), 0.78-0.88(m, 6H), 0.91-2.09(m, 28H), 2.77-2.88(m, 1H), 2.97-3.07(m, 1H), 3.27-3.39(m, 1H), 4.24-4.33(m, 1H), 4.38-4.50(m, 1H), 7.07-7.28(m, 5H), 7.85-7.97(m, 1H), 12.45(bs, 1H)

[0433] Example 50 Preparation of (S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-(1H-indol-3-yl)propanoic acid (LCA-Trp)

[0434] The final compound (Example 50; LCA-Trp) was obtained using lithocholic acid and L-tryptophan methyl ester hydrochloride as starting materials and the same method as for Compound 1.

[0435] 1H-NMR (400MHz, DMSO-d6)δ=0.61(s, 3H), 0.79-0.91(m, 7H), 0.91-2.12(m, 28H) ), 2.93-3.01(m, 1H), 3.10-3.17(m, 1H), 3.32-3.42(m, 1H), 4.38-4.46(m, 1H), 6.96(t, J=7.6Hz, 1H), 7.05(t, J=7.6Hz, 1H), 7.09-7.13(m, 1H), 7.32(d, J=7.6 Hz, 1H), 7.51(d, J=8Hz, 1H), 8.06(d, J=8Hz, 1H), 10.83(s, 1H), 12.56(bs, 1H).

[0436] Example 51 Preparation of (S)-3-hydroxy-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)propanoic acid (LCA-Ser)

[0437] The final compound (Example 51; LCA-Ser) was obtained using lithocholic acid and L-serine methyl ester hydrochloride as starting materials and the same method as for Compound 1.

[0438] 1 H-NMR (400MHz, DMSO-d6)δ=0.60(s, 3H), 0.83-0.91(m, 7H), 0.91-1.40(m, 18H), 1.42-1.96(m, 7H), 1.99-2.21(m, 2H), 3.3 0-3.38(m, 1H), 3.53-3.68(m, 2H), 4.18-4.27(m, 1H), 4.41-4.47(m, 1H), 4.93(bs, 1H), 7.93(d, J=8Hz, 1H), 12.51(bs, 1H).

[0439] Example 52 Preparation of (S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-(4-hydroxyphenyl)propanoic acid (LCA-Tyr)

[0440] The final compound (Example 52; LCA-Tyr) was obtained using lithocholic acid and L-tyrosine methyl ester hydrochloride as starting materials and the same method as for Compound 1.

[0441] 1 H-NMR (400MHz, DMSO-d6) δ=0.58(s, 3H), 0.80-0.91(m, 7H), 0.91-1.39(m, 1 7H), 1.42-1.83(m, 7H), 1.85-2.11(m, 3H), 2.65-2.74(m, 1H), 2.85-2.92(m , 1H), 3.29-3.37(m, 1H), 4.23-4.31(m, 1H), 4.42-4.48(m, 1H), 6.62(d, J=8 Hz, 2H), 6.99(d, J=8Hz, 2H), 7.99-8.04(m, 1H), 9.19(s, 1H), 12.57(bs, 1H).

[0442] Example 53 Preparation of (S)-4-amino-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-4-oxobutanoic acid (LCA-Asn)

[0443] The final compound (Example 53; LCA-Asn) was obtained using lithocholic acid and L-asparagine tert-butyl ester hydrochloride as starting materials in the same manner as in Compound 1.

[0444] 1H-NMR (400MHz, DMSO-d6)δ=0.61(s, 3H), 0.83-0.93(m, 7H), 0.95-2.16(m, 27H), 2.36-2.56(m, 2H), 3.23-3.3 5(m, 1H), 4.40-4.50(m, 1H), 4.87-4.98(m, 1H), 6.87(s, 1H), 7.34(s, 1H), 7.92-7.99(m, 1H), 12.45(bs, 1H).

[0445] Example 54 Preparation of (S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamide)succinic acid (LCA-Asp)

[0446] The final compound (Example 54; LCA-Asp) was obtained using lithocholic acid and L-aspartic acid dimethyl ester hydrochloride as starting materials and the same method as for Compound 1.

[0447] 1 H-NMR (400MHz, DMSO-d6)δ=0.60(s, 3H), 0.81-0.90(m, 7H), 0.91-2.16(m, 28H), 2.47-2.56(m, 1H), 2.6 1-2.69(m, 1H), 3.28-3.37(m, 1H), 4.42-4.51(m, 1H), 8.08-8.16(m, 1H), 12.37(bs, 1H), 12.62(bs, 1H).

[0448] Example 55 Preparation of (S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamide)pentanedioic acid (LCA-Glu)

[0449] The final compound (Example 55; LCA-Glu) was obtained using lithocholic acid and dimethyl L-glutamate hydrochloride as starting materials in the same manner as in Compound 1.

[0450] 1 H-NMR (400MHz, DMSO-d6) δ=0.60(s, 3H), 0.83-0.91(m, 7H), 0.91-2.20(m, 27H), 2.20-2.55(m, 4 H), 3.32-3.37(m, 1H), 4.11-4.19(m, 1H), 4.44-4.50(m, 1H), 8.01-8.10(m, 1H), 12.50(bs, 2H).

[0451] Example 56 Preparation of (S)-6-amino-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)hexanoic acid (LCA-Lys)

[0452] The final compound (Example 56; LCA-Lys) was obtained using lithocholic acid and nepsilon-benzyloxycarbonyl-L-lysine benzyl ester hydrochloride as starting materials and the same method as for Compound 35.

[0453] 1 H-NMR (400MHz, DMSO-d6) δ=0.59(s, 3H), 0.75-2.17(m, 42H), 3.13-3.18(m, 2H) ), 3.26-3.37(m, 1H), 4.08-4.16(m, 1H), 4.42-4.50(m, 1H), 7.06-7.13(m, 1H).

[0454] The chemical structures of Examples 38 to 56 are shown in Table 3 below.

[0455] [Table 3]

[0456] Comparative Examples 1 to 6 Preparation of Lithocholic Acid and Its Derivatives

[0457] As comparative examples, known compounds lithocholic acid (LCA), ursodeoxycholic acid (UDCA), cholic acid (CA), hyodeoxycholic acid (HDCA), deoxycholic acid (DCA), and chenodeoxycholic acid (CDCA) were prepared.

[0458] The chemical structures of Comparative Examples 1 to 6 are shown in Table 4 below.

[0459] [Table 4]

[0460] <Experimental Example 1> Evaluation of the ability to inhibit the binding of preS1 to NTCP-expressing cell lines

[0461] 1-1. Comparison of Example 1, Examples 38 to 56 and Comparative Example 1

[0462] HepG2-hNTCP-C4 cell line, which expresses NTCP, was cultured in a 6-well plate at 2 × 10 5The cells were seeded at a density of 1 / well and incubated overnight for 2 days. When the confluency reached 80%, the cells were incubated at 4°C for 30 minutes. Then, PreS1 (Myr-GTNLSVPNPLGFFPDHQLDPAFGANSNNPDWDFNPNKDHWPEANQV-Lys(FITC)) 20 nM, the compounds of Examples 1, 38, and 56, or the compound of Comparative Example 1 were diluted in culture media at 4°C to a concentration of 50 μM. After 2 hours, the media was removed and the cells were washed three times with 4°C PBS. To remove the cells from the plate, 500 μL of 0.5 mM EDTA PBS solution was added and the cells were incubated at 37°C for 15 minutes. Cell removal was confirmed under an optical microscope. The cells were removed by pipetting, collected in a 1.5 ml tube, and centrifuged (4000 rpm, 4°C, 3 minutes). After suction of Supernatant, the pellets were washed three times with 4°C PBS and then green fluorescence was measured by flow cytometry. Taurocholic acid (TCA), a compound known to act as a substrate for NTCP and to reduce the entry of HBV or HDV, was used as a positive control.

[0463] FIG. 1 is a graph showing the results of confirming the inhibitory ability of the compounds of Example 1, Examples 38 to 56 and Comparative Example 1 according to the present invention to inhibit the binding of PreS1 to an NTCP-expressing cell line.

[0464] In the upper graph of Figure 1, black (1) and red (2) represent the untreated negative control group and the HBV-induced group (HBV preS1) treated with PreS1 alone, respectively. Blue (HBV preS1 + HBV entry inhibitor) (3) represents the fluorescence value for each example or comparative example. The closer the value to the negative control, the greater the inhibition of PreS1 binding to the NTCP cell line. The lower graph of Figure 1 shows the relative fluorescence value (%) compared to the HBV-induced group (HBV PreS1) treated with PreS1 alone. The lower the value, the greater the inhibition of PreS1 binding to NTCP.

[0465] As a result of the analysis, compared to Comparative Example 1 (LCA), Example 46 (LCA-Ala), Example 44 (LCA-Val), Example 47 (LCA-Leu), Example 1 (LCA-Ile), Example 48 (LCA-Met), Example 49 (LCA-Phe), Example 50 (LCA-Trp), Example 38 (LCA-Pro), Example 51 (LCA-Ser), Example 39 (LCA-Thr), Example 40 (LCA-Cys), and Example 52 (LCA-Tyr) were found to be more effective than those of Comparative Example 1 (LCA). The relative fluorescence intensities of Example 56 (LCA-Lys) and Example 43 (LCA-His) were low, and the relative fluorescence intensities of Example 44 (LCA-Val), Example 47 (LCA-Leu), Example 1 (LCA-Ile), Example 48 (LCA-Met), Example 50 (LCA-Trp), Example 38 (LCA-Pro), Example 39 (LCA-Thr), Example 40 (LCA-Cys) and Example 52 (LCA-Tyr) were even lower.

[0466] Among these, Example 44 (LCA-Val), Example 47 (LCA-Leu), Example 1 (LCA-Ile), Example 48 (LCA-Met), Example 50 (LCA-Trp), Example 38 (LCA-Pro), Example 40 (LCA-Cys) and Example 52 (LCA-Tyr) were confirmed to have significantly superior binding inhibitory power, with relative fluorescence intensities of 20% or less. In particular, the relative fluorescence intensities were confirmed to be less than 5% compared to the HBV-induced group treated with PreS1 only (HBV PreS1), confirming that the inhibitory power of the compounds of Example 44 (LCA-Val), Example 1 (LCA-Ile), Example 50 (LCA-Trp) and Example 52 (LCA-Tyr) was the most excellent.

[0467] 1-2. Comparison of treatment concentrations of Examples 1, 44, 50, and 52

[0468] The four compounds that showed good inhibitory activity in Experimental Example 1-1, Example 1 (LCA-Ile), Example 50 (LCA-Trp), Example 52 (LCA-Tyr), and Example 44 (LCA-Val), were examined for concentration dependency. The experimental method was the same as in Experimental Example 1-1, and PreS1 (20 nM) and each compound were treated at four concentrations (0.2 μM, 2 μM, 10 μM, and 50 μM).

[0469] FIG. 2 is a graph showing the results of confirming the ability of the compounds of Example 1 (LCA-Ile), Example 50 (LCA-Trp), Example 52 (LCA-Tyr), and Example 44 (LCA-Val) according to the present invention to inhibit the binding of PreS1 to an NTCP-expressing cell line.

[0470] The graphs show the untreated negative control group and the HBV-induced group treated with PreS1 only (HBV PreS1), and the groups treated with the example compounds (HBV PreS1 + HBV entry inhibitor) are shown by concentration.

[0471] As shown in Figure 2, it was confirmed that Example 1 (LCA-Ile), Example 50 (LCA-Trp), Example 52 (LCA-Tyr), and Example 44 (LCA-Val) all have the effect of inhibiting the binding of PreS1 to NTCP-expressing cell lines in a concentration-dependent manner.

[0472] 1-3. Comparison of Examples 1 to 3, Examples 6 to 11, Examples 14 to 15, Example 44 and Comparative Examples 1 to 6

[0473] Anticipating a structural similarity between compounds composed of bile acids and amino acids, an experiment was conducted to evaluate the inhibitory ability of each of the bile acids of Comparative Example 1 (Lithocholic acid, LCA), Comparative Example 2 (Ursodeoxycholic acid, UDCA), Comparative Example 3 (Cholic acid, CA), Comparative Example 4 (Hyodeoxycholic acid, HDCA), Comparative Example 5 (Deoxycholic acid, DCA), and Comparative Example 6 (Chenodeoxycholic acid, CDCA) on the binding of PreS1 to NTCP-expressing cell lines. In addition, Example 1 (LCA-Ile) and Example 44 (LCA-Val) and their bile acid moieties (Lithocholic An experiment was conducted to evaluate the ability of compounds in which the UDCA Ile (UDCA Ile) was substituted with other bile acids of Comparative Examples 2 to 6, namely, Example 2 (UDCA-Ile), Example 3 (UDCA-Val), Example 6 (CA-Ile), Example 7 (CA-Val), Example 8 (HDCA-Ile), Example 9 (HDCA-Val), Example 10 (DCA-Ile), Example 11 (DCA-Val), Example 14 (CDCA-Ile), and Example 15 (CDCA-Val), to inhibit the binding of PreS1 and NTCP-expressing cell lines. The experimental method was the same as in Experimental Example 1-1, and 18 compounds of Comparative Examples 1 to 6, Examples 1 to 3, Examples 6 to 11, Examples 14 to 15, and Example 44 were treated at a concentration of 50 μM together with 20 nM PreS1.

[0474] FIG. 3 is a graph showing the results of confirming the ability of the compounds of Examples 1 to 3, 6 to 11, 14 to 15, and 44 according to the present invention, and Comparative Examples 1 to 6, to inhibit the binding of PreS1 to an NTCP-expressing cell line.

[0475] As a result of the analysis, it was confirmed that the compounds of Example 1 (LCA-Ile), Example 44 (LCA-Val), Example 2 (UDCA-Ile), Example 3 (UDCA-Val), Example 8 (HDCA-Ile), Example 9 (HDCA-Val), Example 10 (DCA-Ile) and Example 14 (CDCA-Ile) have relatively superior inhibitory ability on the binding of PreS1 to NTCP-expressing cell lines.

[0476] 1-4. Comparison of Examples 4 to 5, Examples 12 to 13, Examples 16 to 17 and Comparative Examples 2, 5 and 6

[0477] 9 shows an evaluation experiment conducted to confirm the extent to which the compounds of Examples 4 to 5, 12 to 13, 16 to 17 according to the present invention, and Comparative Example 2 (ursodeoxycholic acid, UDCA), Comparative Example 5 (deoxycholic acid, DCA), and Comparative Example 6 (chenodeoxycholic acid, CDCA) can inhibit the binding of PreS1 to an NTCP-expressing cell line. The experimental method was the same as in Experimental Example 1-1.

[0478] In the upper graph of Figure 9, gray (3) and red (2) represent the untreated negative control group (Not-treated) and the HBV-induced group treated with PreS1 only (PreS1-FITC), respectively. Blue (1) represents the fluorescence value for each example or comparative example.

[0479] As a result of the analysis, when Comparative Example 2 (UDCA) was compared with Example 4 (UDCA-Trp) or Example 5 (UDCA-Tyr), the relative fluorescence intensity of Example 4 or Example 5 was lower. Compared to the HBV-induced group treated with PreS1 only (PreS1-FITC), the degree of competitive inhibition was approximately two-fold, confirming its superior binding inhibitory power.

[0480] When Comparative Example 5 (DCA) was compared with Example 12 (DCA-Trp) or Example 13 (DCA-Tyr), the relative fluorescence intensity of Example 12 or Example 13 was the same or lower. Compared to the HBV-induced group treated with PreS1 only (PreS1-FITC), the degree of competitive inhibition between Comparative Example 5 and Example 12 was 11.6% different, confirming their superior binding inhibitory power.

[0481] When Comparative Example 6 (CDCA) was compared with Example 16 (CDCA-Trp) or Example 17 (CDCA-Tyr), the relative fluorescence intensity of Example 16 or Example 17 was lower. Compared to the HBV-induced group treated with PreS1 only (PreS1-FITC), the degree of competitive inhibition between Comparative Example 6 and Example 16 was 17.8% different, confirming their superior binding inhibitory power.

[0482] 1-5. Comparison of treatment concentrations in Example 4

[0483] We further examined whether concentration dependency was observed for Example 4 (UDCA-Trp), which showed good inhibitory activity in Experimental Examples 1-4. The experimental method was the same as in Experimental Example 1-1, and involved treatment with 20 nM PreS1 and each compound at four concentrations (2 μM, 10 μM, 20 μM, and 50 μM).

[0484] FIG. 10 is a graph showing the results of confirming the ability of the compound of Example 4 (UDCA-Trp) according to the present invention to inhibit the binding between PreS1 and an NTCP-expressing cell line.

[0485] In the graph, gray (3) and red (2) represent the untreated negative control group (Not-treated) and the HBV-induced group treated with PreS1 only (PreS1-FITC), respectively, and blue (1) represents the fluorescence values ​​of the compound of Example 4 (UDCA-Trp) treated at four different concentrations.

[0486] As shown in FIG. 10, it was confirmed that Example 4 (UDCA-Trp) had the effect of inhibiting the binding of PreS1 to the NTCP-expressing cell line in a concentration-dependent manner.

[0487] <Experimental Example 2> Evaluation of the ability to inhibit binding of fluorescently labeled PreS1 peptide

[0488] Based on the results of Experimental Examples 1-1 to 1-3, experiments were conducted to evaluate the inhibitory ability of Example 1 (LCA-Ile), Example 44 (LCA-Val), and Examples 2 (UDCA-Ile) and 3 (UDCA-Val), which are forms of UDCA that are known to have low toxicity when decomposed in the human body and have an amino acid attached thereto, to inhibit the binding of PreS1 to NTCP.

[0489] Specifically, a fibronectin-coated cover slip was placed on a 24-well plate, and 1 × 10 HepG2-hNTCP-C4 cells, an NTCP-expressing cell line, were added. 5 The cells were seeded at a density of 100 μM and incubated overnight. Then, 20 nM PreS1 and 50 μM each of the compounds from Examples 1, 8, 9, and 44 were diluted in 4°C culture media and treated. After 2 hours, the media was removed by suction, followed by washing twice with 4°C PBS. The cells were then fixated with 4% paraformaldehyde for 20 minutes and washed twice with 4°C PBS. The cells were then treated with 300 nM 4',6-diamidino-2-phenylindole (DAPI) to stain the nuclei for 20 minutes, followed by washing once with distilled water (DW) and twice with 4°C PBS. Then, 10 μL of Mounting Media was loaded onto a glass slide, a cover slip was placed on top, and the cells were observed under a fluorescence microscope.

[0490] Figure 4 is a graph showing the ability of the compounds of Example 1 (LCA-Ile), Example 44 (LCA-Val), Example 2 (UDCA-Ile), and Example 3 (UDCA-Val) according to the present invention to inhibit fluorescently labeled preS1 peptide binding through fluorescence imaging.

[0491] Green fluorescence was observed when PreS1 bound to NTCP-expressing cell lines via FITC conjugation to PreS1. Experimental results confirmed that treatment with each of the compounds of Example 1 (LCA-Ile), Example 44 (LCA-Val), Example 2 (UDCA-Ile), and Example 3 (UDCA-Val) at two concentrations (10 μM and 50 μM) inhibited the binding of PreS1 to NTCP in a concentration-dependent manner, compared to an HBV-induced group treated with PreS1 alone.

[0492] <Experimental Example 3> Evaluation of cytotoxicity

[0493] Cytotoxicity of Example 1 (LCA-Ile), Example 44 (LCA-Val), Example 2 (UDCA-Ile), and Example 3 (UDCA-Val) was evaluated using Jurkat cell line, a human T lymphocyte-derived cell line. Jurkat cell line was cultured in a 96-well plate at 5 × 10 4 After seeding at a density of 10 μM and incubating overnight, the cells were treated with each compound at 0.2–50 μM for 24 or 48 hours. WST-1, a reagent used to measure cell viability, was loaded at 10 μl per well, and absorbance was measured at 440 nm using a microplate reader two hours later. The mean value of the negative control group (NC), treated with DMSO only, was set at 1 to evaluate the cytotoxicity of the remaining experimental groups.

[0494] FIG. 5 is a graph showing the results of confirming the toxicity at the cellular level for the compounds of Example 1 (LCA-Ile), Example 44 (LCA-Val), Example 2 (UDCA-Ile), and Example 3 (UDCA-Val) according to the present invention.

[0495] When the compounds were treated for 24 and 48 hours, almost no cytotoxicity was observed. It was confirmed that the UDCA-based compounds, Examples 2 and 3, showed less toxicity than the LCA (Lithocholic acid)-based compounds, Examples 1 and 44.

[0496] <Experimental Example 4> Evaluation of the ability to inhibit intracellular HBV virus entry

[0497] 4-1. Viral infection experiment protocol

[0498] To evaluate the ability to inhibit intracellular HBV virus entry, we performed an enzyme-linked immunosorbent assay (ELISA) to measure HBeAg, an antigen in the HBV core region that is associated with high infectivity, and a Southern blot analysis to measure HBV DNA. The virus infection experiment protocols for these two analyses are shown in Figure 6.

[0499] Specifically, HepG2-NTCP cells were cultured in 6-well plates and incubated overnight. Then, they were treated with 20 μM HBV inhibitors or 200 nM Myrcludex-B (MyrB), a positive control, and cultured for 24 hours. The cells were infected with HBV at 3,000 genome equivalents per ml / cell (Geq / cell). One day after infection, the cell culture medium was changed (medium changing) to remove any virus that had not adhered to the cell membrane. Four days after infection, another medium change (MC) was performed to measure the amount of virus that had entered the cells. Two days after the change, the supernatant was subjected to HBeAg ELISA analysis, and the cell pellet was used for Southern blot analysis.

[0500] 4-2.HBeAg ELISA analysis

[0501] The supernatant obtained in Experimental Example 4-1 was subjected to HBeAg ELISA analysis using an HBeAg ELISA kit (Sanbio, Wantai HBeAg ELISA, cat#WB-2496).

[0502] First, 50 μL each of a negative control (Mock), a positive control (MyrB), and a sample according to the present invention was loaded in triplicate onto a Capture Ab-coated 96-well plate. The samples used were Example 1 (LCA-Ile), Example 44 (LCA-Val), Example 52 (LCA-Tyr), Example 51 (LCA-Ser), Example 55 (LCA-Glu), Example 2 (UDCA-Ile), Example 3 (UDCA-Val), Example 25 (LCA-Val-Trp), Example 10 (DCA-Ile), Comparative Example 1 (LCA), and Comparative Example 2 (UDCA).

[0503] 50 μl of HRP-conjugated detection antibody was added to each well and incubated at 37°C for 30 minutes. 200 μl of washing buffer (1X PBS, 0.5% Tween 20) was added to each well and washed five times. 50 μl of chromogen solution A and 50 μl of chromogen solution B were added to each well and incubated in the dark at 37°C for 15 minutes. 50 μl of stop solution was added to each well to terminate the reaction, and the optical density (OD) was measured at 450 nm to determine the amount of HBeAg.

[0504] FIG. 7 is a graph showing the results of HBeAg absorbance (OD) levels determined through HBeAg ELISA assay for the compounds of Example 1 (LCA-Ile), Example 44 (LCA-Val), Example 52 (LCA-Tyr), Example 51 (LCA-Ser), Example 55 (LCA-Glu), Example 2 (UDCA-Ile), Example 3 (UDCA-Val), Example 25 (LCA-Val-Trp), Example 10 (DCA-Ile), Comparative Example 1 (LCA), and Comparative Example 2 (UDCA) according to the present invention.

[0505] As a result of the analysis, Example 1 (LCA-Ile), Example 44 (LCA-Val), Example 51 (LCA-Ser), Example 2 (UDCA-Ile), Example 3 (UDCA-Val) and Example 10 (DCA-Ile) showed relatively lower HBeAg absorbance levels compared to the negative control group (Mock), and Example 1 (LCA-Ile), Example 44 (LCA-Val), Example 2 (UDCA-Ile), Example 3 (UDCA-Val) and Example 10 (DCA-Ile) showed lower levels than Comparative Example 1 (LCA) and Comparative Example 2 (UDCA), confirming their excellent efficacy in inhibiting HBV viral infection.

[0506] 4-3. Southern blot analysis

[0507] Southern blot analysis for HBeAg DNA measurement was performed on the cell pellets obtained by the method of Experimental Example 4-1 using Example 1 (LCA-Ile), Example 44 (LCA-Val), Example 52 (LCA-Tyr), Example 51 (LCA-Ser), Example 55 (LCA-Glu), Example 2 (UDCA-Ile), Example 3 (UDCA-Val), Example 25 (LCA-Val-Trp), Example 10 (DCA-Ile), Comparative Example 1 (LCA), and Comparative Example 2 (UDCA).

[0508] First, the cell pellet was pipetted with 100 μl of HEPES lysis buffer (10 mM HEPES, 100 mM NaCl, 1 mM EDTA, 1% NP-40), placed on ice for 20 minutes, and then centrifuged at 4°C and 13,000 rpm in a centrifuge. The supernatant was transferred to a new microtube, and 4.5 μl of nuclease buffer I (10 mM CaCl2, 12 mM MgCl2, 10 units of DNase) was added and incubated at 37°C for 2 hours. 40 μl of 26% PEG solution was added and incubated on ice for 1 hour. After centrifugation at 13,000 rpm for 30 minutes at 4°C, the supernatant was removed. The pellet was dissolved in 100 μl of nuclease buffer II (10 mM Tris, 8 mM CaCl2, 6 mM MgCl2), and then 287.5 μl of 0.5% SDS buffer (25 mM Tris, 10 mM EDTA, 0.5% SDS, 100 mM NaCl) and 12.5 μl of 20 mg / ml proteinase K were added. The mixture was then incubated at 37°C for 2 hours. 400 μl of phenol-chloroform-isoamyl alcohol was added, followed by vortexing and centrifugation at 13,000 rpm at room temperature. The supernatant was transferred to a new tube, and 40 μl of 3 M NaOAc was added. 800 μl of 100% ethanol was added, inverted, and incubated overnight at -20°C. After centrifugation at 13,000 rpm at 4°C for 30 minutes, the supernatant was removed and the resulting pellet was mixed with 800 μl of 70% ethanol. After mixing, the pellet was centrifuged at 13,000 rpm at 4°C for 10 minutes and the supernatant was discarded. The ethanol was allowed to dry for 5 minutes to leave the HBV DNA pellet, which was then redissolved in 15 μl of TE buffer (10 mM Tris, 1 mM EDTA). The HBV DNA sample was loaded onto a 1% agarose gel and electrophoresed. HBV dsDNA was denatured to ssDNA by immersion in denaturation buffer (0.25 N NaOH, 1 M NaCl) for 30 minutes.The DNA was transferred from the gel to a nylon membrane using transfer buffer (0.4M NaOH). The membrane was then neutralized by wetting with 2X SSC buffer (Sigma, cat# 85639) and air-dried. The membrane was then immersed in Church buffer (10% BSA, 0.5M EDTA, 1M NaPi, 20% SDS) and hybridized with radioisotopes using a Mega Prime kit (GE Healthcare, RPN1607). After washing three times with washing buffer (2X SSC, 0.1% SDS), the DNA was measured using a radioisotope measurement device. The relative replication rate (%) was calculated and expressed compared to the negative control (mock).

[0509] FIG. 8 is a graph showing the results of Southern blot analysis of HBeAg DNA and its quantified relative replication rate (%) for the compounds of Example 1 (LCA-Ile), Example 44 (LCA-Val), Example 52 (LCA-Tyr), Example 51 (LCA-Ser), Example 55 (LCA-Glu), Example 2 (UDCA-Ile), Example 3 (UDCA-Val), Example 25 (LCA-Val-Trp), Example 10 (DCA-Ile), Comparative Example 1 (LCA), and Comparative Example 2 (UDCA) according to the present invention.

[0510] As a result, in the cases of Example 1 (LCA-Ile), Example 44 (LCA-Val), Example 52 (LCA-Tyr), Example 55 (LCA-Glu), Example 2 (UDCA-Ile), Example 3 (UDCA-Val), Example 25 (LCA-Val-Trp), and Example 10 (DCA-Ile), relatively low amounts of HBeAg DNA were detected compared to the negative control group (Mock), and less than 80% was detected in Example 1 (LCA-Ile), Example 44 (LCA-Val), Example 52 (LCA-Tyr), Example 2 (UDCA-Ile), Example 3 (UDCA-Val), and Example 10 (DCA-Ile). In particular, in the cases of Example 1 (LCA-Ile), Example 44 (LCA-Val), Example 2 (UDCA-Ile), Example 3 (UDCA-Val) and Example 10 (DCA-Ile), the detection rate was less than 70%, demonstrating excellent efficacy in inhibiting intracellular HBV virus entry.

[0511] Meanwhile, the compound represented by Formula 1 according to the present invention can be formulated in various forms depending on the purpose. The following are examples of some formulation methods containing the compound represented by Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.

[0512] <Formulation Example 1> Manufacturing of powder

[0513] 2g of compound of formula 1

[0514] 1g lactose

[0515] The above ingredients were mixed and filled into an airtight cloth to prepare a powder.

[0516] <Formulation Example 2> Tablet manufacturing

[0517] 100mg of compound of formula 1

[0518] 100mg corn starch

[0519] Lactose 100mg

[0520] Magnesium stearate 2mg

[0521] The above ingredients were mixed and then compressed into tablets by a conventional tablet manufacturing method.

[0522] <Formulation Example 3> Production of capsules

[0523] 100mg of compound of formula 1

[0524] 100mg corn starch

[0525] Lactose 100mg

[0526] Magnesium stearate 2mg

[0527] The above ingredients were mixed and then filled into gelatin capsules by a conventional capsule manufacturing method to produce capsules.

[0528] <Formulation Example 4> Manufacture of injections

[0529] 100mg of compound of formula 1

[0530] Mannitol 180mg

[0531] Na2HPO4·2H2O 26mg

[0532] Distilled water 2974mg

[0533] Injections were prepared by a conventional method for preparing injections, containing the above ingredients in the indicated amounts.

[0534] Examples of functional health foods

[0535] The compound represented by Formula 1 according to the present invention can be prepared as a health functional food in various forms depending on the purpose. The following are examples of methods for preparing health functional foods containing the active substance according to the present invention as an active ingredient, but the present invention is not limited thereto.

[0536] <Production example of functional health foods 1> Production of functional health foods

[0537] 100mg of compound of formula 1

[0538] Vitamin mixture (appropriate amount)

[0539] Vitamin A acetate 70 μg

[0540] Vitamin E 1.0mg

[0541] Vitamin B1 0.13mg

[0542] Vitamin B2 0.15mg

[0543] Vitamin B6 0.5mg

[0544] Vitamin B12 0.2 μg

[0545] Vitamin C 10mg

[0546] Biotin 10 μg

[0547] Nicotinamide 1.7mg

[0548] Folic acid 50μg

[0549] Calcium pantothenate 0.5mg

[0550] Appropriate amount of inorganic mixture

[0551] Ferrous sulfate 1.75mg

[0552] Zinc oxide 0.82mg

[0553] Magnesium carbonate 25.3mg

[0554] Monobasic potassium phosphate 15mg

[0555] Dicalcium phosphate 55mg

[0556] Potassium citrate 90mg

[0557] Calcium carbonate 100mg

[0558] Magnesium chloride 24.8mg

[0559] The composition ratio of the above vitamin and mineral mixture is a preferred example of a mixture of ingredients that are relatively suitable for health functional foods, but the mixing ratio may be modified as desired. After mixing the above ingredients using a conventional method for producing health functional foods, granules can be produced and used to produce a health functional food composition using a conventional method.

[0560] <Health functional food manufacturing example 2> Manufacturing of health functional drinks

[0561] 100mg of compound of formula 1

[0562] Citric acid 100mg

[0563] Oligosaccharides 100mg

[0564] Plum concentrate 2mg

[0565] Taurine 100mg

[0566] Add purified water to make a total of 500mL

[0567] The above ingredients are mixed according to a typical method for producing a health drink, then stirred and heated at 85°C for about 1 hour, and the resulting solution is filtered into a sterilized container, sealed, sterilized, and stored refrigerated before being used to produce the health drink composition of the present invention. The above composition ratio is a preferred example of a mixture of ingredients that are relatively suitable for luxury drinks, but the composition ratio may be freely modified depending on regional and ethnic preferences, such as consumer class, consumer country, and intended use.

[0568] The present invention has been described above with reference to preferred embodiments. Those skilled in the art will recognize that the present invention can be embodied in various modified forms without departing from the essential characteristics of the present invention. Therefore, the disclosed embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the present invention is specifically indicated in the claims, not the foregoing description, and all variations within the range of equivalents thereto should be construed as being within the scope of the present invention.

Claims

1. A compound represented by the following chemical formula 1 in which an amino acid is bound to a bile acid, an optical isomer thereof, a partial stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical formula 1] 【Chemical 1】 In the above Chemical Formula 1, R １ , R ２ and R ３ are independently hydrogen or hydroxy; 【change】 (S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-(4-hydroxyphenyl)propanoic acid (LCA-Tyr); (R)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-(4-hydroxyphenyl)propanoic acid (LCA-D-Tyr); (S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-(1H-indol-3-yl)propanoic acid (LCA-Trp); (R)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-(1H-indol-3-yl)propanoic acid (LCA-D-Trp); (S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanoic acid (LCA-Val); (R)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanoic acid (LCA-D-Val); (S)-2-((R)-4-((3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3,7,12-trihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamide)-3-(4-hydroxyphenyl)propanoic acid (CA-Tyr); (2S,3R)-3-methyl-2-((R)-4-((3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3,7,12-trihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)pentanoic acid (CA-Ile); (2R,3S)-3-methyl-2-((R)-4-((3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3,7,12-trihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamide)pentanoic acid (CA-D-Ile); (S)-3-methyl-2-((R)-4-((3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3,7,12-trihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)butanoic acid (CA-Val); (R)-3-methyl-2-((R)-4-((3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3,7,12-trihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)butanoic acid (CA-D-Val); (S)-2-((R)-4-((3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3,7,12-trihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamide)-3-(1H-indol-3-yl)propanoic acid (CA-Trp); (S)-2-((R)-4-((3R,5R,8R,9S,10S,12S,13R,14S,17R)-3,12-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-(4-hydroxyphenyl)propanoic acid (DCA-Tyr); and (S)-2-((R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-(4-hydroxyphenyl)propanoic acid (CDCA-Tyr) (Excluding).

2. The compound represented by Formula 1 is R ４ but The compound according to claim 1, its optical isomer, its partial stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that it is selected from:

3. The compound according to claim 1, its optical isomer, its partial stereoisomer, or a pharmaceutically acceptable salt thereof, characterized in that the bile acid is selected from the group consisting of lithocholic acid (LCA), ursodeoxycholic acid (UDCA), cholic acid (CA), hyodeoxycholic acid (HDCA), deoxycholic acid (DCA), and chenodeoxycholic acid (CDCA).

4. The compound of claim 1, wherein the compound represented by Chemical Formula 1 is any one selected from the following group of compounds, an optical isomer thereof, a partial stereoisomer thereof, or a pharmaceutically acceptable salt thereof: 1) (2S,3R)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylpentanoic acid (LCA-Ile); 2) (2S,3R)-2-((R)-4-((3R,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylpentanoic acid (UDCA-Ile); 3) (S)-2-((R)-4-((3R,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanoic acid (UDCA-Val); 4) (S)-2-((R)-4-((3R,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-(1H-indol-3-yl)propanoic acid (UDCA-Trp); 5) (S)-2-((R)-4-((3R,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-(4-hydroxyphenyl)propanoic acid (UDCA-Tyr); 8) (2S,3R)-2-((R)-4-((3R,5R,6S,8S,9S,10R,13R,14S,17R)-3,6-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylpentanoic acid (HDCA-Ile); 9) (S)-2-((R)-4-((3R,5R,6S,8S,9S,10R,13R,14S,17R)-3,6-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanoic acid (HDCA-Val); 10) (2S,3R)-2-((R)-4-((3R,5R,8R,9S,10S,12S,13R,14S,17R)-3,12-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylpentanoic acid (DCA-Ile); 11) (S)-2-((R)-4-((3R,5R,8R,9S,10S,12S,13R,14S,17R)-3,12-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylbutanoic acid (DCA-Val); 12) (S)-2-((R)-4-((3R,5R,8R,9S,10S,12S,13R,14S,17R)-3,12-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-(1H-indol-3-yl)propanoic acid (DCA-Trp); 14) (2S,3R)-2-((R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylpentanoic acid (CDCA-Ile); 15) (S)-2-((R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylbutanoic acid (CDCA-Val); 16) (S)-2-((R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-(1H-indol-3-yl)propanoic acid (CDCA-Trp); 18) 2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)acetic acid (LCA-Val-Gly); 19) (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)propanoic acid (LCA-Val-Ala); 20) (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-3-methylbutanoic acid (LCA-Val-Val); 21) (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-3-methylbutanamido)-4-methylpentanoic acid (LCA-Val-Leu); 22) (2S,3R)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylbutanamido)-3-methylpentanoic acid (LCA-Val-Ile); 23) (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-4-(methylthio)butanoic acid (LCA-Val-Met); 24) (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-3-phenylpropanoic acid (LCA-Val-Phe); 25) (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-3-(1H-indol-3-yl)propanoic acid (LCA-Val-Trp); 26) 1-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanoyl)pyrrolidine-2-carboxylic acid (LCA-Val-Pro); 27) (S)-3-hydroxy-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)propanoic acid (LCA-Val-Ser); 28) (2S,3S)-3-hydroxy-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylbutanamido)butanoic acid (LCA-Val-Thr); 29) (R)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-3-mercaptopropanoic acid (LCA-Val-Cys); 30) (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-3-(4-hydroxyphenyl)propanoic acid (LCA-Val-Tyr); 31) (S)-4-amino-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-4-oxobutanoic acid (LCA-Val-Asn); 32) (S)-5-amino-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-5-oxopentanoic acid (LCA-Val-Gln); 33) (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)succinic acid (LCA-Val-Asp); 34) (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylbutanamido)pentanedioic acid (LCA-Val-Glu); 35) (S)-6-amino-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylbutanamido)hexanoic acid (LCA-Val-Lys); 36) (S)-5-guanidino-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylbutanamido)pentanoic acid (LCA-Val-Arg); and 37) (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-3-(1H-imidazol-4-yl)propanoic acid (LCA-Val-His).

5. A pharmaceutical composition for preventing or treating hepatitis, comprising a compound represented by the following chemical formula 1 in which an amino acid is bound to a bile acid, an optical isomer thereof, a partial stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical formula 1] 【Chemistry 2】 In the above Chemical Formula 1, R １ , R ２ and R ３ are independently hydrogen or hydroxy; 【change】

6. 6. The pharmaceutical composition for preventing or treating hepatitis according to claim 5, wherein the bile acid is selected from the group consisting of lithocholic acid (LCA), ursodeoxycholic acid (UDCA), cholic acid (CA), hyodeoxycholic acid (HDCA), deoxycholic acid (DCA), and chenodeoxycholic acid (CDCA).

7. The pharmaceutical composition according to claim 5, wherein the hepatitis is hepatitis B or hepatitis D.

8. The pharmaceutical composition according to claim 5, wherein the compound represented by Chemical Formula 1 is any one selected from the following compound group: 1) (2S,3R)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylpentanoic acid (LCA-Ile); 2) (2S,3R)-2-((R)-4-((3R,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylpentanoic acid (UDCA-Ile); 3) (S)-2-((R)-4-((3R,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanoic acid (UDCA-Val); 4) (S)-2-((R)-4-((3R,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-(1H-indol-3-yl)propanoic acid (UDCA-Trp); 5) (S)-2-((R)-4-((3R,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-(4-hydroxyphenyl)propanoic acid (UDCA-Tyr); 6) (2S,3R)-3-methyl-2-((R)-4-((3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3,7,12-trihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)pentanoic acid (CA-Ile); 7) (S)-3-methyl-2-((R)-4-((3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3,7,12-trihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)butanoic acid (CA-Val); 8) (2S,3R)-2-((R)-4-((3R,5R,6S,8S,9S,10R,13R,14S,17R)-3,6-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylpentanoic acid (HDCA-Ile); 9) (S)-2-((R)-4-((3R,5R,6S,8S,9S,10R,13R,14S,17R)-3,6-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanoic acid (HDCA-Val); 10) (2S,3R)-2-((R)-4-((3R,5R,8R,9S,10S,12S,13R,14S,17R)-3,12-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylpentanoic acid (DCA-Ile); 11) (S)-2-((R)-4-((3R,5R,8R,9S,10S,12S,13R,14S,17R)-3,12-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylbutanoic acid (DCA-Val); 12) (S)-2-((R)-4-((3R,5R,8R,9S,10S,12S,13R,14S,17R)-3,12-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-(1H-indol-3-yl)propanoic acid (DCA-Trp); 13) (S)-2-((R)-4-((3R,5R,8R,9S,10S,12S,13R,14S,17R)-3,12-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-(4-hydroxyphenyl)propanoic acid (DCA-Tyr); 14) (2S,3R)-2-((R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylpentanoic acid (CDCA-Ile); 15) (S)-2-((R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylbutanoic acid (CDCA-Val); 16) (S)-2-((R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-(1H-indol-3-yl)propanoic acid (CDCA-Trp); 17) (S)-2-((R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-(4-hydroxyphenyl)propanoic acid (CDCA-Tyr); 18) 2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)acetic acid (LCA-Val-Gly); 19) (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)propanoic acid (LCA-Val-Ala); 20) (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-3-methylbutanoic acid (LCA-Val-Val); 21) (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-3-methylbutanamido)-4-methylpentanoic acid (LCA-Val-Leu); 22) (2S,3R)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylbutanamido)-3-methylpentanoic acid (LCA-Val-Ile); 23) (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-4-(methylthio)butanoic acid (LCA-Val-Met); 24) (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-3-phenylpropanoic acid (LCA-Val-Phe); 25) (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-3-(1H-indol-3-yl)propanoic acid (LCA-Val-Trp); 26) 1-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanoyl)pyrrolidine-2-carboxylic acid (LCA-Val-Pro); 27) (S)-3-hydroxy-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)propanoic acid (LCA-Val-Ser); 28) (2S,3S)-3-hydroxy-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylbutanamido)butanoic acid (LCA-Val-Thr); 29) (R)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-3-mercaptopropanoic acid (LCA-Val-Cys); 30) (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-3-(4-hydroxyphenyl)propanoic acid (LCA-Val-Tyr); 31) (S)-4-amino-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-4-oxobutanoic acid (LCA-Val-Asn); 32) (S)-5-amino-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-5-oxopentanoic acid (LCA-Val-Gln); 33) (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)succinic acid (LCA-Val-Asp); 34) (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylbutanamido)pentanedioic acid (LCA-Val-Glu); 35) (S)-6-amino-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylbutanamido)hexanoic acid (LCA-Val-Lys); 36) (S)-5-guanidino-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)pentanoic acid (LCA-Val-Arg); 37) (S)-2-((S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanamido)-3-(1H-imidazol-4-yl)propanoic acid (LCA-Val-His); 38) 1-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoyl)pyrrolidine-2-carboxylic acid (LCA-Pro); 39) (2S,3S)-3-hydroxy-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)butanoic acid (LCA-Thr); 40) (R)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-mercaptopropanoic acid (LCA-Cys); 41) (S)-5-amino-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamide-5-oxopentanoic acid (LCA-Gln); 42) (S)-5-guanidino-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)pentanoic acid (LCA-Arg); 43) (S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-(1H-imidazol-5-yl)propanoic acid (LCA-His); 44) (S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-methylbutanoic acid (LCA-Val); 45) 2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-acetic acid (LCA-Gly); 46) (S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-propanoic acid (LCA-Ala); 47) (S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-methylpentanoic acid (LCA-Leu); 48) (S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-4-(methylthio)butanoic acid (LCA-Met); 49) (S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)-3-phenylpropanoic acid (LCA-Phe); 50) (S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-(1H-indol-3-yl)propanoic acid (LCA-Trp); 51) (S)-3-hydroxy-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)propanoic acid (LCA-Ser); 52) (S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)-3-(4-hydroxyphenyl)propanoic acid (LCA-Tyr); 53) (S)-4-amino-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamide)-4-oxobutanoic acid (LCA-Asn); 54) (S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamide)succinic acid (LCA-Asp); 55) (S)-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanamido)pentanedioic acid (LCA-Glu); and 56) (S)-6-amino-2-((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanamido)hexanoic acid (LCA-Lys).

9. A functional health food composition for preventing or ameliorating hepatitis, comprising a compound represented by the following chemical formula 1 in which an amino acid is bound to a bile acid, an optical isomer thereof, a partial stereoisomer thereof, or a nutritive carrier thereof: [Chemical formula 1] 【Chemistry 3】 In the above Chemical Formula 1, R １ , R ２ and R ３ are independently hydrogen or hydroxy; 【change】

10. 10. The health functional food composition for preventing or ameliorating hepatitis according to claim 9, wherein the bile acid is selected from the group consisting of lithocholic acid (LCA), ursodeoxycholic acid (UDCA), cholic acid (CA), hyodeoxycholic acid (HDCA), deoxycholic acid (DCA), and chenodeoxycholic acid (CDCA).

11. The functional health food composition according to claim 9, wherein the hepatitis is hepatitis B or hepatitis D.

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