Novel beta-carboline derivatives and composition for preventing or treating drug-resistant cancer comprising the same

Abstract

The present invention relates to a novel beta-carbolin derivative and a composition for the prevention or treatment of drug-resistant cancer containing the same. The beta-carbolin derivative compound according to the present invention has an anticancer effect by inhibiting STAT3 activity in drug-resistant cancer cells and suppressing cancer cell invasion and migration, and is expected to be usefully utilized as an anticancer agent for various cancers, including breast cancer, and as a therapeutic agent for drug-resistant cancer.

Description

Technology Field

[0001] The present invention relates to a novel beta-carbolin derivative and a composition for the prevention or treatment of drug-resistant cancer containing the same. Background Technology

[0003] Cancer is a life-threatening disease in which unceasing cellular proliferation invades surrounding tissues and destroys normal cells. As a leading cause of death, advancements in diagnostic technology have enabled early diagnosis, and various anticancer drugs capable of effectively suppressing the disease are currently being developed.

[0004] Methods primarily used in cancer treatment include surgical removal, chemotherapy, and radiation therapy. Among these, surgery and radiation therapy are local therapies effective only at the resection or irradiation site, whereas chemotherapy is a systemic therapy effective throughout the body. Since most cancers originate locally and metastasize throughout the body, and microscopic systemic metastasis is already present unless detected at a very early stage, recurrence is common despite effective local therapy. Therefore, most cancer treatments utilize chemotherapy in combination with local therapy, as chemotherapy is more effective against cancer that has spread throughout the body.

[0005] Chemotherapy, particularly combination chemotherapy, is the treatment of choice for delocalized tumors that cannot be treated by surgery or radiation. However, some patients experience recurrence after only a short period and do not respond to secondary chemotherapy. In other words, reduced therapeutic efficacy and cancer recurrence due to drug resistance are occurring in currently applied anticancer regimens, making it necessary to develop effective anticancer drugs that target drug-resistant cancers.

[0006] Meanwhile, signaling pathways of members of the Signal Transducer and Activator of Transcription (STAT) system are known to play an essential role in the sustained proliferation and survival of cancer cells in precancerous and advanced intractable tumors. STAT3 is a transcription factor that is overactivated in approximately 70% of all solid tumors and hematological malignancies. Activated STAT3 translocates from the cytoplasm to the nucleus to induce the expression of numerous genes, including Survivin, Bcl-XL, Mcl-1, c-Myc, Cyclin D1, p21, Cyclin E, Matrix Metalloproteinase-9, Matrix Metalloproteinase-2, and VEGF, thereby regulating a wide range of cellular processes such as cell survival, growth, migration, invasion, metastasis, and angiogenesis. Furthermore, STAT3 regulates several critical signaling pathways associated with cancer progression, including the IL-3, IL-6, and NF-κB cascades, while simultaneously activating feedback pathways that enhance its own activation.

[0007] Although STAT3 plays a crucial role in cancer progression, it was considered unsuitable as a drug target protein due to its weak binding sites. Consequently, the development of anticancer drugs targeting STAT3 has also been insufficient.

[0008] Accordingly, the inventors synthesized a beta-carbolin derivative that exhibits a STAT3 inhibitory effect in drug-resistant cancer cells and intended to utilize it as an anticancer agent against drug-resistant cancer. Prior art literature

[0010] Korean Registered Patent No. 10-2053507 The problem to be solved

[0011] The inventors conducted research to overcome the limitations of the prior art described above and to develop an effective treatment for drug-resistant cancers. As a result, they confirmed that STAT3 is overactivated in drug-resistant cancer cells and verified that STAT3 is inhibited when treated with a beta-carbolin derivative, thereby restoring anticancer effects and drug sensitivity. Based on these findings, the present invention was completed.

[0012] Accordingly, the object of the present invention is to provide a beta-carboline (β-carboline) derivative or a salt thereof.

[0013] Another object of the present invention is to provide a composition for the prevention or treatment of drug-resistant cancer comprising a beta-carboline (β-carboline) derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0014] Another objective of the present invention is to provide a composition for the prevention or treatment of cancer comprising a beta-carboline (β-carboline) derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0016] However, the technical problems that the present invention aims to solve are not limited to those mentioned above, and other unmentioned problems will be clearly understood by those skilled in the art to which the present invention belongs from the description below. means of solving the problem

[0018] To achieve the above objectives, the present invention provides a beta-carboline (β-carboline) derivative represented by the following chemical formula 1 or a salt thereof:

[0019] [Chemical Formula 1]

[0020]

[0021] (In the above chemical formula 1,

[0022] X is O, NH, or NR 1 And,

[0023] R 1 Silver hydrogen, C1-C6 alkyl group, substituted or unsubstituted phenyl group, substituted or unsubstituted benzyl group, (CH2) n R 4 , or And,

[0024] Here, R 4 is a hydroxyl group (OH), a substituted or unsubstituted amino group (NH2), a substituted or unsubstituted phenyl group, , substituted or unsubstituted indol ( ) and,

[0025] R 2 is a substituted or unsubstituted phenyl group or R 3 -C=O and,

[0026] Here, R 3 is a C1-C6 alkyl group or a substituted or unsubstituted phenyl group, and

[0027] The above 'substituted or unsubstituted' is substituted or unsubstituted with one or more substituents selected from the group consisting of a C1-C6 alkyl group, a C1-C6 alkyl group substituted with one or more halogen elements, a halogen element, a hydroxyl group (OH), a C1-C6 alkoxy group, an amino group (NH2), and a cyano group (C≡N).

[0028] The above n is 1, 2, or 3.)

[0029] As one embodiment of the present invention, the R 1 In this, the C1-C6 alkyl group is a methyl group, n -butyl group, i -Profiler, or n - It is a propyl group, and the substituted or unsubstituted phenyl group is a phenyl group substituted or unsubstituted with a methoxy group (OMe), a trifluoromethyl group (CF3), or an amino group (NH2), and the substituted or unsubstituted benzyl group t - A benzyl group substituted or unsubstituted with a butyl group, a methoxy group (OMe), a halogen element, a cyano group (C≡N), an amino group (NH2), or a hydroxyl group (OH);

[0030] The above R2 The substituted or unsubstituted phenyl group is a phenyl group substituted or unsubstituted with a methyl group, a hydroxyl group (OH), or a halogen element;

[0031] The above R 3 In this, the C1-C6 alkyl group is a methyl group or n - It is a propyl group, and the substituted or unsubstituted phenyl group is a phenyl group substituted or unsubstituted with a methyl group, a hydroxyl group (OH), or a halogen element;

[0032] The above R 4 In the example, the substituted or unsubstituted amino group (NH2) is an amino group substituted or unsubstituted with N(CH3)2, the substituted or unsubstituted phenyl group is a phenyl group substituted or unsubstituted with a methoxy group (OMe) or a hydroxyl group (OH), and the substituted or unsubstituted indole group ( ) may be an indole group substituted or unsubstituted with a methyl group, a halogen element, or a methoxy group (OMe), but is not limited thereto.

[0033] As another embodiment of the present invention, X in Formula 1 is O, NH, or NR 1 And,

[0034] R 1 Silver hydrogen, methyl group, n -butyl group, i -Profiler, n -propyl group, phenyl group, 4-methoxy(OMe)-phenyl group, 4-trifluoromethyl(CF3)-phenyl group, 4-amino(NH2)-phenyl group, benzyl group, 4- t -butyl-benzyl group, 4-methoxy(OMe)-benzyl group, 4-F-benzyl group, 4-Cl-benzyl group, 4-CN-benzyl group, 4-amino(NH2)-benzyl group, 4-OH-benzyl group, 3-OH-benzyl group, 2-OH-benzyl group, , , , , , , , , , , , , or And,

[0035] R 2 is a phenyl group, 4-methyl-phenyl group, 4-OH-phenyl group, 4-Br-phenyl group, or R 3 -C=O and,

[0036] Here, R 3 is a methyl group, n - It may be a propyl group, a phenyl group, a 4-methyl-phenyl group, a 4-OH-phenyl group, a 4-Cl-phenyl group, a 4-Br-phenyl group, a 3-Br-phenyl group, or a 2-Br-phenyl group, but is not limited thereto.

[0037] As another embodiment of the present invention, the beta-carboline derivative may be one or more compounds selected from the group consisting of the following, but is not limited thereto.

[0038]

[0040] In addition, the present invention provides a pharmaceutical composition for the prevention or treatment of drug-resistant cancer, comprising a beta-carbolin derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0041] In addition, the present invention provides a pharmaceutical composition for the prevention or treatment of cancer, comprising a beta-carbolin derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0042] In one embodiment of the present invention, the drug may be a taxane-based anticancer agent, but is not limited thereto.

[0043] In another embodiment of the present invention, the drug may be docetaxel or paclitaxel, but is not limited thereto.

[0044] In another embodiment of the present invention, the cancer may be triple-negative breast cancer, but is not limited thereto.

[0045] As another embodiment of the present invention, the composition may inhibit the activity of the Signal Transducer and Activator of Transcription 3 (STAT3), but is not limited thereto.

[0046] As another embodiment of the present invention, the composition may further include an anticancer agent, but is not limited thereto.

[0047] In addition, the present invention provides a method for preventing or treating drug-resistant cancer, comprising the step of administering a composition containing a beta-carbolin derivative or a pharmaceutically acceptable salt thereof as an active ingredient to an individual in need thereof.

[0048] In addition, the present invention provides a use for the prevention or treatment of drug-resistant cancer of a composition comprising a beta-carboline derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0049] In addition, the present invention provides a use for the manufacture of a formulation for the prevention or treatment of drug-resistant cancer, comprising a composition containing a beta-carbolin derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0050] In addition, the present invention provides a method for preventing or treating cancer, comprising the step of administering a composition containing a beta-carbolin derivative or a pharmaceutically acceptable salt thereof as an active ingredient to an individual in need thereof.

[0051] In addition, the present invention provides a use for cancer prevention or treatment of a composition comprising a beta-carbolin derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0052] In addition, the present invention provides a use for the manufacture of a cancer prevention or treatment formulation comprising a composition containing a beta-carbolin derivative or a pharmaceutically acceptable salt thereof as an active ingredient. Effects of the invention

[0054] The beta-carbolin derivative compound according to the present invention has an anticancer effect by inhibiting STAT3 activity in drug-resistant cancer cells and suppressing cancer cell invasion and migration, and is expected to be usefully utilized as an anticancer agent for various cancers, including breast cancer, and as a therapeutic agent for drug-resistant cancer. Brief explanation of the drawing

[0056] FIG. 1 is a diagram confirming the STAT3 activity inhibitory effect of a beta-carboline derivative compound according to one embodiment of the present invention. FIG. 2a is a diagram confirming the inhibitory effect on cell invasion of drug-resistant cancer cells by treatment with the beta-carbolin derivative MC0704 according to one embodiment of the present invention. FIG. 2b is a diagram confirming the inhibitory effect on cell migration of drug-resistant cancer cells by treatment with the beta-carbolin derivative MC0704 according to one embodiment of the present invention. FIG. 3 is a diagram confirming the anticancer effect of the beta-carbolin derivative MC0704 in a drug-resistant animal model according to one embodiment of the present invention. Figure 4 is a diagram confirming that the target of the beta-carboline derivative MC0704 according to one embodiment of the present invention is STAT3 through a biotin-streptavidin pull-down experiment. FIG. 5 is a diagram schematically illustrating the operation of the beta-carboline derivative MC0704 according to one embodiment of the present invention. Specific details for implementing the invention

[0057] The present invention provides a beta-carboline (β-carboline) derivative represented by the following chemical formula 1 or a salt thereof:

[0058] [Chemical Formula 1]

[0059]

[0060] (In the above chemical formula 1,

[0061] X is O, NH, or NR 1 And,

[0062] R 1 Silver hydrogen, C1-C6 alkyl group, substituted or unsubstituted phenyl group, substituted or unsubstituted benzyl group, (CH2) n R 4 , or And,

[0063] Here, R 4 is a hydroxyl group (OH), a substituted or unsubstituted amino group (NH2), a substituted or unsubstituted phenyl group, , substituted or unsubstituted indol ( ) and,

[0064] R 2 is a substituted or unsubstituted phenyl group or R 3 -C=O and,

[0065] Here, R 3 is a C1-C6 alkyl group or a substituted or unsubstituted phenyl group, and

[0066] The above 'substituted or unsubstituted' is substituted or unsubstituted with one or more substituents selected from the group consisting of a C1-C6 alkyl group, a C1-C6 alkyl group substituted with one or more halogen elements, a halogen element, a hydroxyl group (OH), a C1-C6 alkoxy group, an amino group (NH2), and a cyano group (C≡N).

[0067] The above n is 1, 2, or 3.)

[0069] In the present invention, “C1-C6 alkyl group” means a monovalent alkyl group having 1 to 6 carbon atoms. This term refers to methyl, ethyl, n -profile, i -profile, n -butyl, i -butyl, tert -butyl, nFunctional groups such as hexyl can be given as examples. The alkyl and other alkyl substituents described in the present invention include both straight-chain and branched forms. “Substituted C1-C6 alkyl group” means that one or more hydrogen atoms among the hydrogen atoms are substituted with other substituents, and the substituents are not limited but include C1-C6 alkyl groups, halogen elements, C1-C6 alkoxy groups, or benzene, etc. According to one embodiment of the present invention, the substituted C1-C6 alkyl group may be a trifluoromethyl group (CF3), but is not limited thereto.

[0070] In the present invention, the R 1 In this, the C1-C6 alkyl group may preferably be a C1-C4 alkyl group, and a methyl group, n -butyl group, i -Profiler, or n - It may be a propyl group, but is not limited thereto. In the present invention, the R 3 In this, the C1-C6 alkyl group may preferably be a C1-C3 alkyl group, and a methyl group or n - It may be a profile, but is not limited thereto.

[0071] In the present invention, "substitution" includes single substitution, double substitution, triple substitution, quadruple substitution, etc.

[0072] In the present invention, the “halogen element” may include fluorine (F), chlorine (Cl), bromine (Br), and iodine (I), and according to one embodiment of the present invention, it may be fluorine, chlorine, or bromine, but is not limited thereto.

[0073] In the present invention, the “phenyl group” is a functional group composed of carbon and hydrogen and has the chemical formula -C6H5. Here, the six carbon atoms form a circular ring structure.

[0074] In the present invention, the phenyl group may be substituted or unsubstituted, and the R 1The substituted or unsubstituted phenyl group in may be substituted or unsubstituted with a methoxy group (OMe), a trifluoromethyl group (CF3), or an amino group (NH2), but is not limited thereto. The above R 2 The substituted or unsubstituted phenyl group in may be substituted or unsubstituted with a methyl group, a hydroxyl group (OH), or a halogen element, but is not limited thereto. The above R 3 The substituted or unsubstituted phenyl group in may be substituted or unsubstituted with a methyl group, a hydroxyl group (OH), or a halogen element, but is not limited thereto. The above R 4 The substituted or unsubstituted phenyl group in the phenyl group may be substituted or unsubstituted with a methoxy group (OMe) or a hydroxyl group (OH), but is not limited thereto.

[0075] In the present invention, the “benzyl group” is a substituent or molecular fragment having a C6H5CH2- structure, and the benzyl group is characterized by a benzene ring attached to a CH2 group.

[0076] In the present invention, the benzyl group may be substituted or unsubstituted, and the R 1 The substituted or unsubstituted benzyl group in t - It may be substituted or unsubstituted with a butyl group, a methoxy group (OMe), a halogen element, a cyano group (C≡N), an amino group (NH2), or a hydroxyl group (OH), but is not limited thereto.

[0077] In the present invention, “C1-C6 alkoxy group” refers to an alkyl ether group, specifically an -OR group, where R represents “C1-C6 alkyl”. The alkoxy group is, for example, methoxy (OMe), ethoxy (OEt), n -Propoxi( O n -Pr), isopropoxy(O i -Pr), n - Butoxy( O n -Bu), iso-butoxy(O i -Bu), sec - Butoxy( O sec -Bu), tert - Butoxy( O tert -Bu), n-pentoxy(O n It may include -Pen, etc., and according to one embodiment of the present invention, it may be methoxy, but is not limited thereto.

[0078] In the present invention, the “amino group” is in the form of -NH2 in which hydrogen is bonded to a nitrogen atom, can become a positively charged cation by bonding to a proton, and can act as a nucleophile due to the non-covalent electron pair possessed by the nitrogen atom.

[0079] In the present invention, the R 4 The substituted or unsubstituted amino group (NH2) in the above may be an amino group substituted or unsubstituted with N(CH3)2, but is not limited thereto.

[0080] In the present invention, the “indole group” is a form in which indole is bonded, and indole is an aromatic heterocyclic organic compound with the molecular formula C8H7N. Indole has a two-ring structure in which a 5-membered pyrrole ring and a 6-membered benzene ring are fused. In the present invention, the indole group or The substituted or unsubstituted indole group may be an indole group substituted or unsubstituted with a methyl group, a halogen element, or a methoxy group (OMe), but is not limited thereto.

[0081] In the present invention, X in Formula 1 is O, NH, or NR 1 And,

[0082] R 1 Silver hydrogen, methyl group, n -butyl group, i -Profiler, n -propyl group, phenyl group, 4-methoxy(OMe)-phenyl group, 4-trifluoromethyl(CF3)-phenyl group, 4-amino(NH2)-phenyl, benzyl group, 4- t-butyl-benzyl group, 4-methoxy(OMe)-benzyl group, 4-F-benzyl group, 4-Cl-benzyl group, 4-CN-benzyl group, 4-amino(NH2)-benzyl group, 4-OH-benzyl group, 3-OH-benzyl group, 2-OH-benzyl group, , , , , , , , , , , , , or And,

[0083] R 2 is a phenyl group, 4-methyl-phenyl group, 4-OH-phenyl group, 4-Br-phenyl group, or R 3 -C=O and,

[0084] Here, R 3 is a methyl group, n - It may be a propyl group, a phenyl group, a 4-methyl-phenyl group, a 4-OH-phenyl group, a 4-Cl-phenyl group, a 4-Br-phenyl group, a 3-Br-phenyl group, or a 2-Br-phenyl group, but is not limited thereto.

[0085] In the present invention, the beta-carboline derivative may be one or more compounds selected from the group consisting of the following, but is not limited thereto.

[0086]

[0088] In addition, the present invention provides a pharmaceutical composition for the prevention or treatment of drug-resistant cancer, comprising a beta-carbolin derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0089] In addition, the present invention provides a pharmaceutical composition for the prevention or treatment of cancer, comprising a beta-carbolin derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0090] In the present invention, “cancer” refers collectively to a disease caused by cells having aggressive characteristics in which cells divide and grow disregarding normal growth limits, invasive characteristics in which they infiltrate surrounding tissues, and metastatic characteristics in which they spread to other parts of the body. It may include breast cancer, colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, chronic lymphoma leukemia, acute myeloid leukemia, head and neck squamous cell carcinoma, hepatocellular carcinoma, small cell lung cancer, or non-small cell lung cancer. In the present invention, the cancer may be breast cancer, and according to one experimental example of the present invention, it may be triple-negative breast cancer (TNBC), but is not limited thereto.

[0091] In the present invention, “drug resistance” refers to a decrease in the effect of a drug when the drug is used repeatedly in a fixed amount, and refers to a state in which, in order to obtain the same effect previously experienced in a patient with anticancer drug resistance, the dosage or frequency of use must be increased, or the same effect as before cannot be obtained even if the same dosage of the substance is administered as before. In the present invention, drug-resistant cancer refers to cancer that has resistance to anticancer drugs.

[0092] In the present invention, the drug may be a taxane-based anticancer agent, but is not limited thereto.

[0093] In the present invention, “Taxane” is a drug that induces apoptosis by disrupting the microtubules of the mitotic spindle and causing impaired axonal transport, and is widely used in solid tumors such as breast cancer, ovarian cancer, and lung cancer. The above-mentioned taxane-based anticancer agent may include docetaxel or paclitaxel.

[0094] In the present invention, the composition may further include an anticancer agent, and the composition may be administered in combination with the anticancer agent, but is not limited thereto.

[0095] In the present invention, anticancer agents additionally included in the composition or administered in combination with the composition include, for example, docetaxel, paclitaxel, doxorubicin, 5-fluorouracil, cisplatin, imatinib, carboplatin, oxaliplatin, tegafur, irinotecan, cyclophosphamide, cemcitabine, ifosfamide, mitomycin C, vincristine, etoposide, methotrexate, topotecan, tamoxifen, vinorelbine, Camptothecin, Danuorubicin, Chlorambucil, Bryostatin-1, Calicheamicin, Mayatansine, Levamisole, DNA recombinant interferon alfa-2a, Mitoxantrone, Nimustine, Interferon alfa-2a, Doxifluridine, Formestane, Leuprolide acetate, Megestrol acetate, Camofur, Teniposide, Bleomycin, Carmustine, Heptaplatin, Exemestane, anastrozole, estramustine,Capecitabine, goserelin acetate, polysaccharide potassium, medroxypogestone acetate, epirubicin, letrozole, pirarubicin, topotecan, altretamine, toremifene citrate, BCNU, taxotere, or actinomycin D may be included, but are not limited thereto.

[0096] In the present invention, the composition may inhibit the activity of the signal transducer and activator of transcription 3 (STAT3), but is not limited thereto.

[0097] In the present invention, "pharmaceuticalally acceptable salt" includes a salt derived from a pharmaceutically acceptable inorganic acid, organic acid, or base.

[0098] Examples of suitable acids include hydrochloric acid, bromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, formic acid, benzoic acid, malonic acid, gluconic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, etc. Acid addition salts can be prepared by conventional methods, for example, by dissolving a compound in an excess amount of an aqueous acid solution and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone, or acetonitrile. Alternatively, they can be prepared by heating an equal molar amount of the compound and an acid or alcohol in water, followed by drying the mixture by evaporation, or by suction filtration of the precipitated salt.

[0099] Salts derived from suitable bases may include alkali metals such as sodium and potassium, alkaline earth metals such as magnesium, and ammonium, but are not limited thereto. Alkali metal or alkaline earth metal salts can be obtained, for example, by dissolving a compound in an excess amount of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and then evaporating and drying the filtrate. In this case, it is particularly suitable for pharmaceutical purposes to produce sodium, potassium, or calcium salts as metal salts, and the corresponding silver salts can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

[0100] The pharmaceutical composition according to the present invention may further include a suitable carrier, excipient, and diluent commonly used in the manufacture of pharmaceutical compositions. The excipient may be one or more selected from the group consisting of, for example, diluents, binders, disintegrants, lubricants, adsorbents, humectants, film-coating materials, and controlled-release additives.

[0101] The pharmaceutical composition according to the present invention may be formulated and used in the form of external preparations such as powders, granules, sustained-release granules, enteric granules, liquids, eye drops, ellipsoids, emulsions, suspensions, ethanol tablets, troches, fragrances, limonades, tablets, sustained-release tablets, enteric tablets, sublingual tablets, hard capsules, soft capsules, sustained-release capsules, enteric capsules, pills, tinctures, soft extracts, dry extracts, fluid extracts, injections, capsules, irrigation solutions, warning agents, lotions, pastes, sprays, inhalants, patches, sterile injectable solutions, or aerosols, according to conventional methods, and the external preparations may have formulations such as creams, gels, patches, sprays, ointments, warning agents, lotions, liniments, pastes, or cataplasms.

[0102] Carriers, excipients, and diluents that may be included in the pharmaceutical composition according to the present invention include lactose, dextrose, sucrose, oligosaccharide, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil.

[0103] When formulating, it is prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants.

[0104] Excipients such as corn starch, potato starch, wheat starch, lactose, sucrose, glucose, fructose, D-mannitol, precipitated calcium carbonate, synthetic aluminum silicate, calcium monohydrogen phosphate, calcium sulfate, sodium chloride, sodium bicarbonate, refined lanolin, microcrystalline cellulose, dextrin, sodium alginate, methylcellulose, sodium carboxymethylcellulose, kaolin, urea, colloidal silica gel, hydroxypropyl starch, hydroxypropylmethylcellulose (HPMC) 1928, HPMC 2208, HPMC 2906, HPMC 2910, propylene glycol, casein, calcium lactate, primogel, etc., as additives to tablets, powders, granules, capsules, pills, and lozenges according to the present invention; Gelatin, gum arabic, ethanol, agar powder, cellulose phthalate, carboxymethylcellulose, calcium carboxymethylcellulose, glucose, purified water, sodium casein, glycerin, stearic acid, sodium carboxymethylcellulose, sodium methylcellulose, methylcellulose, microcrystalline cellulose, dextrin, hydroxycellulose, hydroxypropyl starch, hydroxymethylcellulose, refined shellac, starch paste, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, etc. may be used as binders, and hydroxypropylmethylcellulose, corn starch, agar powder, methylcellulose, bentonite, hydroxypropyl starch, sodium carboxymethylcellulose, sodium alginate, Calcium carboxymethylcellulose, calcium citrate, sodium lauryl sulfate, anhydrous silica, 1-hydroxypropylcellulose, dextran, ion exchange resin, polyvinyl acetate, formaldehyde-treated casein and gelatin, alginic acid, amylose, guar gum, sodium bicarbonate, polyvinylpyrrolidone, calcium phosphate, gelled starch, gum arabic, amylopectin, pectin, sodium polyphosphate, ethylcellulose, sucrose, magnesium aluminum silicate, D-sorbitol solution, hard anhydrous silica, etc. disintegrants;Lubricants such as calcium stearate, magnesium stearate, stearic acid, hydrogenated vegetable oil, talc, lycopodium pods, kaolin, petroleum jelly, sodium stearate, cocoa paste, sodium salicylate, magnesium salicylate, polyethylene glycol (PEG) 4000, PEG 6000, liquid paraffin, hydrogenated soybean oil (Lubri wax), aluminum stearate, zinc stearate, sodium lauryl sulfate, magnesium oxide, macrogol, synthetic aluminum silicate, anhydrous silica, higher fatty acids, higher alcohols, silicone oil, paraffin oil, polyethylene glycol fatty acid ether, starch, sodium chloride, sodium acetate, sodium oleate, dl-leucine, and hard anhydrous silica may be used.

[0105] As additives to the liquid formulation according to the present invention, water, dilute hydrochloric acid, dilute sulfuric acid, sodium citrate, monostearic acid sucroses, polyoxyethylene sorbitol fatty acid esters (tween esters), polyoxyethylene monoalkyl ethers, lanolin ethers, lanolin esters, acetic acid, hydrochloric acid, water ammonia, ammonium carbonate, potassium hydroxide, sodium hydroxide, prolamine, polyvinylpyrrolidone, ethylcellulose, sodium carboxymethylcellulose, etc. may be used.

[0106] In the syrup preparation according to the present invention, a solution of white sugar, other sugars or sweeteners, etc. may be used, and if necessary, flavorings, coloring agents, preservatives, stabilizers, suspending agents, emulsifiers, viscosity enhancers, etc. may be used.

[0107] Purified water may be used in the emulsion according to the present invention, and emulsifiers, preservatives, stabilizers, fragrances, etc. may be used as needed.

[0108] In the suspension agent according to the present invention, suspending agents such as acacia, tragacanthus, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, sodium alginate, hydroxypropylmethylcellulose (HPMC), HPMC 1828, HPMC 2906, and HPMC 2910 may be used, and surfactants, preservatives, stabilizers, coloring agents, and fragrances may be used as needed.

[0109] The injectable preparation according to the present invention comprises solvents such as distilled water for injection, 0.9% sodium chloride injection solution, Ringer's injection solution, dextrose injection solution, dextrose + sodium chloride injection solution, PEG, lactated Ringer's injection solution, ethanol, propylene glycol, non-volatile oils—sesame oil, cottonseed oil, peanut oil, soybean oil, corn oil, ethyl oleate, isopropyl myristate, and benzene benzoate; solubilizing agents such as sodium benzoate, sodium salicylate, sodium acetate, urea, urethane, monoethylacetamide, butazolidine, propylene glycol, tween, nijungtinamide, hexamine, and dimethylacetamide; and buffers such as weak acids and their salts (acetic acid and sodium acetate), weak bases and their salts (ammonia and ammonium acetate), organic compounds, proteins, albumin, peptone, and gums. It may include isotonic agents such as sodium chloride; stabilizers such as sodium bisulfite (NaHSO3), carbon dioxide gas, sodium metabisulfite (Na2S2O5), sodium sulfite (Na2SO3), nitrogen gas (N2), and ethylenediaminetetraacetic acid; sulfating agents such as sodium bisulfide 0.1%, sodium formaldehyde sulfoxylate, thiourea, disodium ethylenediaminetetraacetic acid, and sodium bisulfite acetone; non-inflammatory agents such as benzyl alcohol, chlorobutanol, procaine hydrochloride, glucose, and calcium gluconate; and suspending agents such as sodium CMC, sodium alginate, Tween 80, and aluminum monostearate.

[0110] The suppository according to the present invention comprises cocoa dough, lanolin, Witepsol, polyethylene glycol, glycerogelatin, methylcellulose, carboxymethylcellulose, a mixture of stearic acid and oleic acid, Subanal, cottonseed oil, peanut oil, palm oil, cocoa butter + cholesterol, lecithin, lanette wax, glycerol monostearate, Tween or Spandex, Imhausen, monollene (propylene glycol monostearate), glycerin, Adeps solidus, Buytyrum Tego-G, Cebes Pharma 16, hexalide base 95, Cotomar, Hydroccote SP, S-70-XXA, S-70-XX75 (S-70-XX95). Bases such as Hydrokote 25, Hydrokote 711, Idropostal, Massa estrarium (A, AS, B, C, D, E, I, T), Masa-MF, Masupol, Masupol-15, Neosupostal-N, Paramount-B, Suposiro (OSI, OSIX, A, B, C, D, H, L), suppository base type IV (AB, B, A, BC, BBG, E, BGF, C, D, 299), Supostal (N, Es), Wekovi (W, R, S, M, Fs), and Tegestor triglyceride base (TG-95, MA, 57) may be used.

[0111] Solid dosage forms for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid dosage forms are prepared by mixing at least one excipient, such as starch, calcium carbonate, sucrose or lactose, gelatin, etc., with the extract. In addition to simple excipients, lubricants such as magnesium styrate and talc are also used.

[0112] Liquid preparations for oral administration include suspensions, oral liquids, emulsions, and syrups; in addition to commonly used simple diluents such as water and liquid paraffin, they may contain various excipients, such as humectants, sweeteners, flavorings, and preservatives. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.

[0113] The pharmaceutical composition according to the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level may be determined based on factors including the type and severity of the patient's disease, drug activity, sensitivity to the drug, time of administration, route of administration and elimination rate, duration of treatment, concurrently used drugs, and other factors well known in the medical field.

[0114] The pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered as a single or multiple doses. It is important to administer an amount that obtains maximum effect with a minimum amount without side effects by considering all the above-mentioned factors, and this can be easily determined by a person skilled in the art to which the present invention belongs.

[0115] The pharmaceutical composition of the present invention may be administered to an individual by various routes. All modes of administration are expected, for example, oral administration, subcutaneous injection, intraperitoneal administration, intravenous injection, intramuscular injection, paraspinal (intradural) injection, sublingual administration, buccal mucosal administration, rectal insertion, vaginal insertion, ocular administration, ear administration, nasal administration, inhalation, spray through the mouth or nose, skin administration, transdermal administration, etc.

[0116] The pharmaceutical composition of the present invention is determined by the type of active ingredient drug, along with various relevant factors such as the disease to be treated, the route of administration, the patient's age, gender, weight, and the severity of the disease.

[0118] In addition, the present invention provides a food composition for preventing or improving drug-resistant cancer, comprising a beta-carbolin derivative or a food-grade acceptable salt thereof as an active ingredient.

[0119] In addition, the present invention provides a food composition for preventing or improving cancer, comprising a beta-carboline derivative or a food-grade acceptable salt thereof as an active ingredient.

[0120] In the present invention, the food composition may be a health functional food composition, but is not limited thereto.

[0121] In the present invention, “food-grade acceptable salt” includes a salt derived from a food-grade acceptable organic acid, inorganic acid, or base.

[0122] When the beta-carbolin derivative of the present invention or a food-grade acceptable salt thereof is used as a food additive, the beta-carbolin derivative or the food-grade acceptable salt thereof may be added as is or used together with other foods or food ingredients, and may be used appropriately according to conventional methods. The amount of the active ingredient can be appropriately determined according to the purpose of use (prevention, health, or therapeutic treatment). Generally, when manufacturing food or beverages, the beta-carbolin derivative of the present invention or the food-grade acceptable salt thereof may be added in an amount of 15% by weight or less, or 10% by weight or less, relative to the raw material. However, in the case of long-term consumption for the purpose of health and hygiene or health control, the above amount may be less than the above range, and since there are no issues regarding safety, the active ingredient may be used in an amount greater than the above range.

[0123] There are no specific restrictions on the types of the above-mentioned foods. Examples of foods to which the above-mentioned substance may be added include meat, sausage, bread, chocolate, candies, snacks, confectionery, pizza, ramen, other noodles, chewing gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages, and vitamin complexes, and include all health functional foods in the conventional sense.

[0124] The health beverage composition according to the present invention may contain various flavoring agents or natural carbohydrates as additional ingredients, as in conventional beverages. The aforementioned natural carbohydrates are monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As sweeteners, natural sweeteners such as thaumatin and stevia extract, or synthetic sweeteners such as saccharin and aspartame may be used. The proportion of the natural carbohydrates is generally about 0.01-0.20g or about 0.04-0.10g per 100 mL of the composition of the present invention.

[0125] In addition to the above, the composition of the present invention may contain various nutrients, vitamins, electrolytes, flavoring agents, coloring agents, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc. Furthermore, the composition of the present invention may contain fruit pulp for the production of natural fruit juices, fruit juice beverages, and vegetable beverages. These ingredients may be used independently or in combination. Although the proportion of these additives is not critical, it is generally selected in the range of 0.01 to 0.20 parts by weight per 100 parts by weight of the composition of the present invention.

[0126] In the present invention, the term “health functional food” is the same as “food for special health use (FoSHU)” and refers to a food with high medical or therapeutic effects that is processed to efficiently exhibit bio-regulatory functions in addition to nutritional supply. The food may be manufactured in various forms such as tablets, capsules, powders, granules, liquids, and pills to obtain useful effects for the prevention or improvement of obesity.

[0127] The health functional food of the present invention can be manufactured by methods commonly used in the industry, and can be manufactured by adding raw materials and ingredients commonly added in the industry. In addition, unlike general pharmaceuticals, it has the advantage of not having side effects that may occur from long-term use of pharmaceuticals because it is made of food, and it can be highly portable.

[0128] The above-mentioned health functional food has the advantage of providing superior effects when consumed in the form of an inner beauty food. The above-mentioned inner beauty refers to a food referred to as "edible cosmetics or beauty food," which involves absorbing various skin-beneficial ingredients into the body to change the skin's constitution to a healthy state. Just as one chooses cosmetics suited to their skin type, one can select and consume an inner beauty food tailored to their individual needs by considering their skin condition and lifestyle. For example, when a cosmetic containing the above-mentioned cosmetic composition is combined with an inner beauty food containing a rotlerin derivative or a salt thereof, the effect is significantly higher compared to using only the cosmetic or pharmaceutical product. This offers the advantage of providing not only more effective prevention or improvement of skin pigmentation but also a whitening effect.

[0129] In the present invention, the term “individual” refers to a subject requiring treatment for a disease, and more specifically, to mammals such as humans or non-human primates, mice, rats, dogs, cats, horses, and cattle.

[0130] In the present invention, “administration” means providing a predetermined composition of the present invention to an individual by any appropriate method. Accordingly, the concept of “administration” in the present invention includes not only injecting or ingesting the individual, but also applying it.

[0131] In the present invention, “prevention” refers to any act of suppressing or delaying the onset of a target disease, “treatment” refers to any act of improving or beneficially altering the target disease and associated metabolic abnormality symptoms through the administration of a pharmaceutical composition according to the present invention, and “improvement” refers to any act of reducing parameters related to the target disease, such as the severity of symptoms, through the administration of a composition according to the present invention.

[0133] In addition, the present invention provides a method for preventing or treating drug-resistant cancer, comprising the step of administering a composition containing a beta-carbolin derivative or a pharmaceutically acceptable salt thereof as an active ingredient to an individual in need thereof.

[0134] In addition, the present invention provides a use for the prevention or treatment of drug-resistant cancer of a composition comprising a beta-carboline derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0135] In addition, the present invention provides a use for the manufacture of a formulation for the prevention or treatment of drug-resistant cancer, comprising a composition containing a beta-carbolin derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0136] In addition, the present invention provides a method for preventing or treating cancer, comprising the step of administering a composition containing a beta-carbolin derivative or a pharmaceutically acceptable salt thereof as an active ingredient to an individual in need thereof.

[0137] In addition, the present invention provides a use for cancer prevention or treatment of a composition comprising a beta-carbolin derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0138] In addition, the present invention provides a use for the manufacture of a cancer prevention or treatment formulation comprising a composition containing a beta-carbolin derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0140] Hereinafter, preferred embodiments and experimental examples are presented to aid in understanding the present invention. However, the following embodiments and experimental examples are provided merely to facilitate a better understanding of the present invention, and the scope of the present invention is not limited by the following embodiments and experimental examples.

[0142] [Example] Synthesis process of β-Caboline derivatives

[0143] Example 1. Synthesis method of MC0101-MC0134

[0144] [Reaction Equation 1]

[0145]

[0147] 1-1. MC01A

[0148] L-Tryptophan methyl ester (1.68 g, 7.71 mmol), acetone (0.57 mL, 23.13 mmol), and I2 (5.87 g, 23.13 mmol) were placed in an oven-dried two-necked round-bottom flask, and DMSO (30.8 mL) was added to dissolve them. The mixture was then heated and stirred at 90 °C for 3 hours under Ar substitution. After the reaction was complete, the mixture was cooled to room temperature. EtOAc (40 mL) was added to the mixture, and the organic layer was washed twice with H2O (2 x 40 mL). The aqueous layer was extracted once more with EtOAc (40 mL), and the collected organic layer was dried and filtered with MgSO4, followed by concentration under reduced pressure. The resulting residue was purified by column chromatography (silica gel, hexane:ethyl acetate = 3:1). After purification, compound MC01A in the form of a yellow solid (1.61 g, 77.9% yield) was obtained.

[0149] Melting point (mp): 230-232 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 12.28 (s, 1H), 9.17 (s, 1H), 8.46 (d, J = 7.4 Hz, 1H), 7.85 (d, J= 8.0 Hz, 1H), 7.66-7.62 (m, 1H), 7.38-7.34 (m, 1H), 3.97 (s, 3H), 2.83 (s, 3H); 13 C-NMR (100 MHz, DMSO- d 6) δ 201.0, 165.4, 142.3, 135.5, 135.3, 135.0, 131.4, 129.4, 122.3, 121.2, 121.0, 120.2, 113.4, 52.3, 25.7; Purity: 97.8%, t R (Retention time): 14.3 minutes; HRMS (ESI) m / z C 15 H 13 N2O3[M+H] + 269.0926, found: 269.0926.

[0151] 1-2. MC01B

[0152] MC01A (0.91 g, 3.40 mmol) was dissolved in MeOH (8.50 mL), and then 2 N-NaOH (6.76 mL, 13.51 mmol) was added. The mixture was then heated and stirred at 90 °C for 3 hours. After the reaction was complete, the MeOH was removed by concentration under reduced pressure. The mixture was dissolved in H2O (50 mL) and extracted twice with EtOAc (2 x 40 mL). The aqueous layer was titrated to pH 2 using 1 N-HCl, and the solution was stirred for 30 minutes. The formed solid was washed with H2O (50 mL) and filtered. After filtration, a yellow solid MC01B (0.78 g, 91.0% yield) was obtained.

[0153] Melting point (mp): 317-319 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 12.25 (s, 1H), 9.17 (s, 1H), 8.46 (d, J = 8.3 Hz, 1H), 7.86 (d, J = 8.3 Hz, 1H), 7.64 (t,J = 8.3 Hz, 1H), 7.37 (t, J = 7.1 Hz, 1H), 2.86 (s, 3H); 13 C-NMR (100 MHz, DMSO- d 6); δ 201.1, 166.3, 142.3, 136.4, 135.1, 135.0, 131.5, 129.3, 122.2, 121.0, 120.9, 120.2, 113.4, 25.8; Purity: 99.5%, t R : 12.1 min; HRMS (ESI) m / z C 14 H 11 N2O3[M+H] + 255.0770, found: 255.0769.

[0155] 1-3. General Synthesis Conditions for β-Carboline Derivatives (MC0101-MC0134)

[0156] A carboxylic acid intermediate (1.0 equiv.) and HBTU (1.1 equiv.) were placed in an oven-dried round-bottom flask, dissolved in DMF (0.15 M), and the mixture was stirred at room temperature for 1 hour. After 1 hour, an amine (1.1 equiv.) or an alcohol (1.1 equiv.) and DIPEA (1.2 equiv.) were added to the reaction mixture and stirred for 1.5 hours. After the reaction was complete, H2O (10 mL) was added and the mixture was extracted twice with EtOAc (2 x 10 mL), and the organic layer was washed twice with H2O (2 x 10 mL). The collected organic layer was dried with MgSO4, filtered, concentrated under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, hexane:ethyl acetate = 3:1 to 1:1).

[0158] 1-3-1. MC0101

[0159] MC01B (52.6 mg, 0.21 mmol) and 4-methoxyphenethylamine (0.03 mL, 0.23 mmol) were used as starting materials according to the general synthesis conditions for β-carboline derivatives mentioned above. After purification, a yellow solid compound, MC0101 (59.8 mg, 74.0% yield), was obtained.

[0160] Melting point (mp): 194-196 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 12.15 (s, 1H), 9.07 (s, 1H), 8.65 (t, J = 6.1 Hz, 1H), 8.42 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.63-7.59 (m, 1H), 7.32 (t, J = 7.4 Hz, 1H), 7.23 (d, J = 8.6 Hz, 2H), 6.88 (dd, J = 11.7, 3.1 Hz, 2H), 3.72 (s, 3H), 3.61 (q, J = 7.0 Hz, 2H), 2.87 (t, J = 6.4 Hz, 5H); 13 C-NMR (100 MHz, DMSO- d 6) δ 200.9, 164.0, 157.7, 142.3, 138.6, 134.8, 133.8, 131.9, 131.2, 129.6, 129.3, 122.2, 120.7, 120.3, 117.8, 113.9, 113.3, 55.0, 40.7, 34.5, 26.0; Purity: 99.7%, t R : 16.2 minutes; HRMS (ESI) m / z calcd for C 23 H 22 N3O3[M+H] + 388.1661, found: 388.1660.

[0162] 1-3-2. MC0102

[0163] MC01B (30.0 mg, 0.08 mmol) and tyramine (12.5 mg, 0.09 mmol) were used as starting materials according to the general synthesis conditions for β-carboline derivatives mentioned above. After purification, a yellow solid compound, MC0102 (8.1 mg, 28.6% yield), was obtained.

[0164] Melting point (mp): 282-284 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 12.16 (s, 1H), 9.20 (s, 1H), 9.08 (s, 1H), 8.67 (t, J = 5.8 Hz, 1H), 8.44 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.6 Hz, 1H), 7.64-7.60 (m, 1H), 7.36-7.32 (m, 1H), 7.11 (dd, J = 11.0, 3.1 Hz, 2H), 6.72 (dd, J = 8.9, 2.1 Hz, 2H), 3.59 (q, J = 7.0 Hz, 2H), 2.87 (s, 3H), 2.82 (t, J = 7.4 Hz, 2H); 13 C-NMR (100 MHz, DMSO- d 6) δ 201.0, 163.9, 155.7, 142.3, 138.7, 134.8, 133.9, 132.0, 129.6, 129.4, 129.3, 122.3, 120.8, 120.3, 117.8, 115.2, 113.3, 40.8, 34.5, 26.0; Purity: 95.1%, t R : 14.0 minutes; HRMS (ESI) m / z calcd for C 22 H 20 N3O3[M+H] + 374.1505, found: 374.1494.

[0166] 1-3-3. MC0103

[0167] MC01B (58.7 mg, 0.23 mmol) and phenethylamine (0.03 mL, 0.25 mmol) were used as starting materials according to the general synthesis conditions for β-carboline derivatives mentioned above. After purification, a yellow solid compound, MC0103 (45.2 mg, 54.8% yield), was obtained.

[0168] Melting point (mp): 203-205 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 12.16 (s, 1H), 9.08 (s, 1H), 8.72 (t, J = 6.1 Hz, 1H), 8.44 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.6 Hz, 1H), 7.64-7.60 (m, 1H), 7.35-7.30 (m, 5H), 3.66 (q, J = 6.7 Hz, 2H), 2.94 (t, J = 7.4 Hz, 2H), 2.87 (s, 3H); 13 C-NMR (100 MHz, DMSO- d 6) δ 201.0, 164.0, 142.4, 139.5, 138.6, 134.8, 133.9, 131.9, 129.3, 128.7, 128.5, 126.2, 122.3, 120.8, 120.3, 117.8, 113.3, 40.5, 35.4, 26.0; Purity: 98.7%, t R : 16.5 minutes; HRMS (ESI) m / z calcd for C 22 H 20 N3O2[M+H] + 358.1556, found: 358.1555.

[0170] 1-3-4. MC0104

[0171] MC01B (58.7 mg, 0.23 mmol) and tryptamine (40.0 mg, 0.25 mmol) were used as starting materials according to the general synthesis conditions for β-carboline derivatives mentioned above. After purification, a yellow solid compound, MC0104 (42.5 mg, 47.0% yield), was obtained.

[0172] Melting point (mp): 247-249 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 12.15 (s, 1H), 10.89 (s, 1H), 9.10 (s, 1H), 8.76 (t, J = 5.8 Hz, 1H), 8.42 (d, J = 7.9 Hz, 1H), 7.84 (d, J = 8.6 Hz, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.61 (t, J = 7.9 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 7.34-7.29 (m, 2H), 7.09 (t, J = 7.3 Hz, 1H), 6.99 (t, J = 7.6 Hz, 1H), 3.74 (q, J = 6.9 Hz, 2H), 3.07 (t, J = 7.0 Hz, 2H), 2.83 (s, 3H); 13 C-NMR (100 MHz, DMSO- d 6) δ201.0, 164.0, 142.4, 138.7, 136.4, 134.8, 133.9, 132.0, 129.3, 127.3, 122.8, 122.2, 121.0, 120.8, 120.3, 118.5, 118.3, 117.8, 113.3, 111.8, 111.4, 26.0, 25.4; Purity: 97.7%, t R : 15.6 minutes; HRMS (ESI) m / z calcd for C 24 H21 N4O2[M+H] + 397.1665, found: 397.1667.

[0174] 1-3-5. MC0105

[0175] According to the above general synthesis conditions for β-carboline derivatives: MC01B (59.0 mg, 0.24 mmol) and methylamine hydrochloride (17.5 mg, 0.26 mmol) were used as starting materials. After purification, a yellow solid compound MC0105 (44.8 mg, 71.3% yield) was obtained.

[0176] Melting point (mp): 280-282 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 12.15 (s, 1H), 9.08 (s, 1H), 8.73 (q, J = 4.7 Hz, 1H), 8.45 (d, J = 7.4 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.64-7.60 (m, 1H), 7.33 (t, J = 7.1 Hz, 1H), 2.95 (d, J = 4.9 Hz, 3H), 2.92 (s, 3H); 13 C-NMR (100 MHz, DMSO- d 6) δ 201.2, 164.7, 142.3, 138.8, 134.8, 133.9, 131.9, 129.2, 122.2, 120.7, 120.3, 117.8, 113.3, 26.2, 26.0; Purity: 98.9%, t R : 12.4 minutes; HRMS (ESI) m / z calcd for C 15 H 14 N3O2[M+H] + 268.1086, found: 268.1086.

[0178] 1-3-6. MC0106

[0179] MC01B (50.0 mg, 0.20 mmol) and n-butylamine (15.8 mg, 0.22 mmol) were used as starting materials according to the general synthesis conditions for β-carboline derivatives mentioned above. After purification, a yellow solid compound, MC0106 (38.5 mg, 63.3% yield), was obtained.

[0180] Melting point (mp): 220-222 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 12.14 (s, 1H), 9.07 (s, 1H), 8.71 (t, J = 6.1 Hz, 1H), 8.43 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.64-7.59 (m, 1H), 7.33 (t, J = 7.1 Hz, 1H), 3.41 (q, J = 6.7 Hz, 2H), 2.92 (s, 3H), 1.63-1.56 (m, 2H), 1.38 (td, J = 15.0, 7.4 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H); 13 C-NMR (100 MHz, DMSO- d 6) δ 201.1, 164.1, 142.3, 138.9, 134.8, 133.9, 131.9, 129.2, 122.2, 120.7, 120.3, 117.8, 113.3, 38.7, 31.7, 26.0, 19.7, 13.8; Purity: 99.2%, t R : 16.1 minutes; HRMS (ESI) m / z calcd for C 18 H 20 N3O2[M+H] + 310.1556, found: 310.1543.

[0182] 1-3-7. MC0107

[0183] According to the above general synthesis conditions for β-carboline derivatives: MC01B (61.9 mg, 0.24 mmol) and i-propylamine (0.02 mL, 0.27 mmol) were used as starting materials. After purification, a yellow solid compound MC0107 (54.8 mg, 76.2% yield) was obtained.

[0184] Melting point (mp): 236-238 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 12.15 (s, 1H), 9.08 (s, 1H), 8.43 (d, J = 8.0 Hz, 1H), 8.29 (d, J = 8.0 Hz, 1H), 7.64-7.60 (m, 1H), 7.33 (t, J = 7.1 Hz, 1H), 4.28-4.16 (m, 1H), 2.92 (s, 3H), 2.51-2.49 (m, 1H), 1.29 (d, J = 6.7 Hz, 6H); 13 C-NMR (100 MHz, DMSO- d 6) δ 201.0, 163.2, 142.3, 138.8, 134.8, 133.9, 131.9, 129.3, 122.2, 120.7, 120.3, 117.9, 113.3, 40.8, 26.0, 22.4; Purity: 99.6%, t R : 14.8 minutes; HRMS (ESI) m / z calcd for C 17 H 18 N3O2[M+H] + 296.1399, found: 296.1401.

[0186] 1-3-8. MC0108

[0187] MC01B (52.4 mg, 0.21 mmol) and N,N-dimethylpropane-1,3-diamine (0.03 mL, 0.23 mmol) were used as starting materials according to the general synthesis conditions for β-carboline derivatives mentioned above. After purification, a yellow solid compound, MC0108 (32.4 mg, 46.5% yield), was obtained.

[0188] Melting point (mp): 189-191 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 12.15 (s, 1H), 9.08 (s, 1H), 8.92 (t, J = 5.8 Hz, 1H), 8.43 (d, J = 7.9 Hz, 1H), 7.83 (d, J = 8.6 Hz, 1H), 7.63-7.59 (m, 1H), 7.32 (t, J = 7.3 Hz, 1H), 3.49-3.43 (m, 2H), 2.91 (s, 3H), 2.34 (t, J = 6.7 Hz, 2H), 2.17 (s, 6H), 1.77-1.70 (m, 2H); 13 C-NMR (100 MHz, DMSO- d 6) δ 201.0, 164.0, 142.3, 138.8, 134.8, 133.9, 131.9, 129.3, 122.2, 120.7, 120.3, 117.9, 113.3, 57.8, 45.4, 38.2, 27.0, 25.8; Purity: 98.6%, t R : 10.0 minutes; HRMS (ESI) m / z calcd for C 19 H 23 N4O2[M+H] + 339.1821, found: 339.1819.

[0190] 1-3-9. MC0109

[0191] MC01B (50.0 mg, 0.20 mmol) and 3-amino-1-propanol (0.02 mL, 0.22 mmol) were used as starting materials according to the general synthesis conditions for β-carboline derivatives mentioned above. After purification, a yellow solid compound, MC0109 (48.0 mg, 78.3% yield), was obtained.

[0192] Melting point (mp): 185-187 ℃; 1 H₂-NMR (400 MHz, DMSO- d 6) δ 12.13 (s, 1H), 9.07 (s, 1H), 8.92 (t, J = 6.1 Hz, 1H), 8.42 (d, J = 7.4 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.62-7.58 (m, 1H), 7.34-7.30 (m, 1H), 4.73 (t, J = 4.9 Hz, 1H), 3.59 (q, J = 5.7 Hz, 2H), 3.51 (q, J = 6.5 Hz, 2H), 2.90 (s, 3H), 1.81-1.75 (m, 2H); 13 C-NMR (100 MHz, DMSO- d 6) δ 201.1, 164.1, 142.3, 138.8, 134.8, 133.9, 131.9, 129.2, 122.2, 120.7, 120.3, 117.8, 113.3, 59.4, 37.2, 32.2, 26.0; Purity: 99.4%, t R : 11.3 minutes; HRMS (ESI) m / z calcd for C 17 H 18 N3O3[M+H] + 312.1348, found: 312.1340.

[0194] 1-3-10. MC0110

[0195] MC01B (51.6 mg, 0.20 mmol) and aniline (0.02 mL, 0.23 mmol) were used as starting materials according to the general synthesis conditions for β-carboline derivatives mentioned above. After purification, a yellow solid compound, MC0110 (37.9 mg, 55.3% yield), was obtained.

[0196] Melting point (mp): 288-290 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 12.24 (s, 1H), 10.40 (s, 1H), 9.19 (s, 1H), 8.47 (d, J = 8.0 Hz, 1H), 7.91 (dd, J = 8.6, 1.2 Hz, 2H), 7.85 (d, J = 8.6 Hz, 1H), 7.63 (td, J = 7.7, 1.2 Hz, 1H), 7.44-7.40 (m, 2H), 7.35 (t, J = 8.0 Hz, 1H), 7.18-7.14 (m, 1H), 3.00 (s, 3H); 13 C-NMR (100 MHz, DMSO- d 6) δ 201.0, 162.7, 142.4, 138.4, 138.3, 135.0, 133.9, 132.2, 129.4, 128.8, 123.8, 122.3, 120.9, 120.4, 120.2, 118.4, 113.4, 26.3; Purity: 100.0 %, t R : 16.5 minutes; HRMS (ESI) m / z calcd for C 20 H 16 N3O2[M+H] + 330.1243, found: 330.1240.

[0198] 1-3-11. MC0111

[0199] MC01B (52.0 mg, 0.21 mmol) and 4-methoxyaniline (27.7 mg, 0.23 mmol) were used as starting materials according to the general synthesis conditions for β-carboline derivatives mentioned above. After purification, a yellow solid compound, MC0111 (57.0 mg, 80.5% yield), was obtained.

[0200] Melting point (mp): 234-236 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 12.23 (s, 1H), 10.31 (s, 1H), 9.19 (s, 1H), 8.47 (d, J = 7.4 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.81 (td, J = 6.1, 4.1 Hz, 2H), 7.66-7.62 (m, 1H), 7.38-7.34 (m, 1H), 6.99 (td, J = 6.1, 4.1 Hz, 2H), 3.78 (s, 3H), 3.00 (s, 3H); 13 C-NMR (100 MHz, DMSO- d 6) δ 201.1, 162.4, 155.7, 142.4, 138.6, 134.9, 133.9, 132.1, 131.5, 129.4, 122.3, 122.1, 120.9, 120.2, 118.2, 113.9, 113.3, 55.2, 26.3; Purity: 98.8%, t R : 17.0 minutes; HRMS (ESI) m / z calcd for C 21 H 18 N3O3[M+H] + 360.1348, found: 360.1345.

[0202] 1-3-12. MC0112

[0203] MC01B (54.0 mg, 0.21 mmol) and 4-trifluoromethylaniline (37.7 mg, 0.23 mmol) were used as starting materials according to the general synthesis conditions for β-carboline derivatives mentioned above. After purification, a yellow solid compound, MC0112 (34.0 mg, 40.4% yield), was obtained.

[0204] Melting point (mp): 312-314 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 12.25 (s, 1H), 10.65 (s, 1H), 9.19 (s, 1H), 8.46 (d, J = 7.3 Hz, 1H), 8.15 (d, J = 8.6 Hz, 2H), 7.84 (d, J = 8.6 Hz, 1H), 7.77 (d, J = 8.6 Hz, 2H), 7.62 (t, J = 7.6 Hz, 1H), 7.34 (t, J = 7.3 Hz, 1H), 3.01 (s, 3H); 13 C-NMR (100 MHz, DMSO- d 6) δ201.0, 163.3, 142.4, 142.0, 137.8, 135.1, 133.9, 132.2, 129.5, 128.5 (q, J CF = 269.3 Hz), 126.0 (d, J CF = 3.9 Hz), 126.0 (d, J CF = 3.9 Hz), 125.8 (q, J CF = 269.3 Hz), 124.2 (q, J CF = 31.6 Hz), 123.9 (q, J CF = 31.6 Hz), 123.6 (q, J CF = 31.6 Hz), 123.3 (q,J CF = 31.6 Hz), 123.1 (q, J CF = 269.3 Hz), 122.3, 121.0, 120.2, 120.2 (q, J CF = 269.3 Hz), 118.6, 113.4, 26.3; Purity: 99.3 %, t R : 19.5 minutes; HRMS (ESI) m / z calcd for C 21 H 15 F3N3O2[M+H] + 398.1116, found: 398.1106.

[0206] 1-3-13. MC0113

[0207] MC01B (54.5 mg, 0.214 mmol) and 4-aminoaniline (25.5 mg, 0.24 mmol) were used as starting materials according to the general synthesis conditions for β-carboline derivatives mentioned above. After purification, a yellow solid compound, MC0113 (56.3 mg, 76.3% yield), was obtained.

[0208] Melting point (mp): 241-243 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 12.15 (s, 1H), 10.07 (s, 1H), 9.11 (s, 1H), 8.40 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.62-7.58 (m, 1H), 7.54 (td, J = 6.1, 3.5 Hz, 2H), 7.31 (t, J = 8.0 Hz, 1H), 6.65 (td, J = 5.8, 3.7 Hz, 2H), 5.06 (s, 2H), 2.96 (s, 3H); 13 C-NMR (100 MHz, DMSO- d6) δ201.0, 161.9, 145.4, 142.4, 138.8, 134.8, 133.8, 132.1, 129.3, 127.5, 122.2, 122.1, 120.8, 120.2, 117.9, 113.9, 113.3, 26.2; Purity: 98.5%, t R : 11.0 minutes; HRMS (ESI) m / z calcd for C 20 H 17 N4O2[M+H] + 345.1352, found: 345.1350.

[0210] 1-3-14. MC0114

[0211] MC01B (55.7 mg, 0.22 mmol) and 5-aminoidole (31.9 mg, 0.24 mmol) were used as starting materials according to the general synthesis conditions for β-carboline derivatives mentioned above. After purification, a yellow solid compound, MC0114 (51.5 mg, 63.8% yield), was obtained.

[0212] Melting point (mp): 321-323 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 12.21 (s, 1H), 11.10 (s, 1H), 10.32 (s, 1H), 9.20 (s, 1H), 8.47 (d, J = 7.9 Hz, 1H), 8.14 (d, J = 1.2 Hz, 1H), 7.86 (d, J = 8.6 Hz, 1H), 7.63 (t, J = 7.3 Hz, 1H), 7.55 (dd, J = 8.6, 1.8 Hz, 1H), 7.44 (d, J = 9.2 Hz, 1H), 7.38-7.33 (m, 2H), 6.47 (t, J = 2.1 Hz, 1H), 3.02 (s, 3H); 13 C-NMR (100 MHz, DMSO- d6) δ 201.0, 162.2, 142.4, 138.8, 134.9, 133.8, 133.1, 132.2, 130.3, 129.4, 127.5, 126.1, 122.3, 120.8, 120.3, 118.1, 115.8, 113.3, 111.8, 111.3, 101.2, 26.3; Purity: 98.3 %, t R : 15.7 minutes; HRMS (ESI) m / z calcd for C 22 H 17 N4O2[M+H] + 369.1352, found: 369.1352.

[0214] 1-3-15. MC0115

[0215] MC01B (83.4 mg, 0.31 mmol) and (1H-indole-5-yl)methanamine (49.3 mg, 0.34 mmol) were used as starting materials according to the general synthesis conditions for β-carboline derivatives mentioned above. After purification, a yellow solid compound, MC0115 (64.4 mg, 55.0% yield), was obtained.

[0216] Melting point (mp): 259-261 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 12.15 (s, 1H), 11.01 (s, 1H), 9.19 (t, J = 6.4 Hz, 1H), 9.14 (s, 1H), 8.45 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.6 Hz, 1H), 7.64-7.60 (m, 1H), 7.57 (s, 1H), 7.36 (q, J = 4.1 Hz, 2H), 7.31 (q, J = 2.9 Hz, 1H), 7.18 (dd, J = 8.3, 1.5 Hz, 1H), 6.39 (t, J = 2.5 Hz, 1H), 4.70 (d, J= 6.7 Hz, 2H), 2.91 (s, 3H); 13 C-NMR (100 MHz, DMSO- d 6) δ201.1, 164.1, 142.3, 138.9, 135.0, 134.8, 134.0, 131.9, 130.1, 129.3, 127.6, 125.5, 122.2, 121.0, 120.8, 120.3, 118.7, 118.0, 113.3, 111.2, 100.9, 43.0, 26.0; Purity: 99.1%, t R : 15.0 minutes; HRMS (ESI) m / z calcd for C 23 H 19 N4O2[M+H] + 383.1508, found: 383.1510.

[0218] 1-3-16. MC0116

[0219] MC01B (52.5 mg, 0.21 mmol) and benzylamine (0.03 mL, 0.23 mmol) were used as starting materials according to the general synthesis conditions for β-carboline derivatives mentioned above. After purification, a yellow solid compound, MC0116 (43.8 mg, 61.7% yield), was obtained.

[0220] Melting point (mp): 248-250 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 12.18 (s, 1H), 9.32 (t, J = 6.4 Hz, 1H), 9.13 (s, 1H), 8.45 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.63 (t, J = 7.7 Hz, 1H), 7.40 (d, J = 7.4 Hz, 2H), 7.34 (t, J = 7.7 Hz, 3H), 7.25 (t, J = 7.4 Hz, 1H), 4.64 (d,J = 6.7 Hz, 2H), 2.93 (s, 3H); 13 C-NMR (100 MHz, DMSO- d 6) δ 201.2, 164.4, 142.4, 140.0, 138.7, 134.9, 134.0, 131.9, 129.3, 128.3, 127.2, 126.7, 122.3, 120.8, 120.3, 118.1, 113.3, 42.5, 26.1; Purity: 97.6%, t R : 16.0 minutes; HRMS (ESI) m / z calcd for C 21 H 18 N3O2[M+H] + 344.1399, found: 344.1388.

[0222] 1-3-17. MC0117

[0223] MC01B (130.0 mg, 0.51 mmol) and t-butylbenzylamine (0.10 mL, 0.56 mmol) were used as starting materials according to the general synthesis conditions for β-carboline derivatives mentioned above. After purification, a yellow solid compound, MC0117 (35.0 mg, 17.1% yield), was obtained.

[0224] Melting point (mp): 216-218 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 12.17 (s, 1H), 9.27 (t, J = 6.4 Hz, 1H), 9.12 (s, 1H), 8.44 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.64-7.60 (m, 1H), 7.36-7.31 (m, 5H), 4.60 (d, J = 6.1 Hz, 2H), 2.93 (s, 3H), 1.26 (s, 9H); 13 C-NMR (100 MHz, DMSO- d6) δ 201.2, 164.3, 149.1, 142.3, 138.7, 136.9, 134.9, 134.0, 131.9, 129.3, 127.0, 125.0, 122.2, 120.8, 120.3, 118.1, 113.3, 42.2, 34.1, 31.2, 26.1; Purity: 99.5%, t R : 18.9 minutes; HRMS (ESI) m / z calcd for C 25 H 26 N3O2[M+H] + 400.2025, found: 400.2023.

[0226] 1-3-18. MC0118

[0227] MC01B (60.1 mg, 0.24 mmol) and 4-methoxybenzylamine (0.03 mL, 0.26 mmol) were used as starting materials according to the general synthesis conditions for β-carboline derivatives mentioned above. After purification, a yellow solid compound, MC0118 (48.4 mg, 57.1% yield), was obtained.

[0228] Melting point (mp): 236-238 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 12.17 (s, 1H), 9.23 (t, J = 6.1 Hz, 1H), 9.12 (s, 1H), 8.43 (d, J = 7.9 Hz, 1H), 7.84 (d, J = 8.6 Hz, 1H), 7.62 (t, J = 7.6 Hz, 1H), 7.33 (dd, J = 7.6, 4.6 Hz, 3H), 6.90 (d, J = 8.6 Hz, 2H), 4.57 (d, J = 6.4 Hz, 2H), 3.72 (s, 3H), 2.92 (s, 3H); 13 C-NMR (100 MHz, DMSO- d6) δ201.2, 164.3, 158.2, 142.4, 138.7, 134.9, 134.0, 131.9, 129.3, 128.6, 122.2, 120.8, 120.3, 118.1, 113.7, 113.3, 55.1, 42.0, 26.1; Purity: 95.8%, t R : 15.7 minutes; HRMS (ESI) m / z calcd for C 22 H 20 N3O3[M+H] + 374.1505, found: 374.1510.

[0230] 1-3-19. MC0119

[0231] MC01B (63.1 mg, 0.25 mmol) and 4-fluorobenzylamine (34.2 mg, 0.27 mmol) were used as starting materials according to the general synthesis conditions for β-carboline derivatives mentioned above. After purification, a yellow solid compound, MC0119 (22.0 mg, 24.6% yield), was obtained.

[0232] Melting point (mp): 255-257 ℃; 1H-NMR (400 MHz, DMSO- d 6) δ 12.18 (s, 1H), 9.35 (t, J = 6.4 Hz, 1H), 9.12 (s, 1H), 8.44 (d, J = 7.3 Hz, 1H), 7.84 (d, J = 7.9 Hz, 1H), 7.62 (t, J = 7.9 Hz, 1H), 7.44 (dd, J = 8.3, 5.8 Hz, 2H), 7.34 (t, J = 7.3 Hz, 1H), 7.16 (t, J = 8.9 Hz, 2H), 4.61 (d, J = 6.1 Hz, 2H), 2.93 (s, 3H); 13 C-NMR (100 MHz, DMSO- d6) δ201.2, 164.5, 162.3 (d, J CF = 240.5 Hz), 159.9 (d, J CF = 240.5 Hz), 142.3, 138.6, 136.2 (d, J CF = 2.9 Hz), 136.2 (d, J CF = 2.9 Hz), 134.9, 134.1, 131.9, 129.3, 129.2 (d, J CF = 7.7 Hz), 129.2 (d, J CF = 7.7 Hz), 122.3, 120.8, 120.3, 118.1, 115.1 (d, J CF = 21.0 Hz), 114.9 (d, J CF = 21.0 Hz), 113.3, 41.9, 26.1; Purity: 99.6%, t R : 16.1 minutes; HRMS (ESI) m / z calcd for C 21 H 17 FN3O2[M+H] + 362.1305, found: 362.1289.

[0234] 1-3-20. MC0120

[0235] According to the above general synthesis conditions for β-carboline derivatives: MC01B (61.5 mg, 0.24 mmol) and 4-chlorobenzylamine (37.7 mg, 0.27 mmol) were used as starting materials. After purification, a yellow solid compound MC0120 (60.6 mg, 66.3% yield) was obtained.

[0236] Melting point (mp): 234-236 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 12.16 (s, 1H), 9.34 (t, J= 6.4 Hz, 1H), 9.11 (s, 1H), 8.42 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.63-7.59 (m, 1H), 7.40 (qd, J = 7.0, 2.5 Hz, 4H), 7.32 (t, J = 7.1 Hz, 1H), 4.62 (d, J = 6.1 Hz, 2H), 2.93 (s, 3H); 13 C-NMR (100 MHz, DMSO- d 6) δ 201.1, 164.5, 142.3, 139.0, 138.5, 134.9, 134.0, 131.9, 131.2, 129.2, 129.1, 128.2, 122.2, 120.8, 120.3, 118.1, 113.3, 41.9, 26.0; Purity: 99.2%, t R : 17.1 minutes; HRMS (ESI) m / z calcd for C 21 H 17 ClN3O2[M+H] + 378.1009, found: 378.1014.

[0238] 1-3-21. MC0121

[0239] According to the above general synthesis conditions for β-carboline derivatives: MC01B (55.0 mg, 0.22 mmol) and 4-(aminomethyl)benzonitrile (40.1 mg, 0.24 mmol) were used as starting materials. After purification, a yellow solid compound MC0121 (27.7 mg, 34.8% yield) was obtained.

[0240] Melting point (mp): 261-263 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 12.16 (s, 1H), 9.34 (t, J = 6.4 Hz, 1H), 9.11 (s, 1H), 8.42 (d, J= 8.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.63-7.59 (m, 1H), 7.40 (qd, J = 7.0, 2.5 Hz, 4H), 7.32 (t, J = 7.1 Hz, 1H), 4.62 (d, J = 6.1 Hz, 2H), 2.93 (s, 3H); 13 C-NMR (100 MHz, DMSO- d 6) δ 201.2, 164.7, 145.9, 142.4, 138.4, 134.9, 134.1, 132.3, 131.9, 129.3, 128.0, 122.3, 120.8, 120.3, 119.0, 118.2, 113.3, 109.4, 42.4, 26.1; Purity: 98.3%, t R : 15.2 minutes; HRMS (ESI) m / z calcd for C 22 H 17 N4O2[M+H] + 369.1352, found: 369.1354.

[0242] 1-3-22. MC0122

[0243] MC01B (49.9 mg, 0.20 mmol) and 4-aminobenzylamine (26.4 mg, 0.22 mmol) were used as starting materials according to the general synthesis conditions for β-carboline derivatives mentioned above. After purification, a yellow solid compound, MC0122 (33.4 mg, 47.6% yield), was obtained.

[0244] Melting point (mp): 275-277 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 12.15 (s, 1H), 9.11 (s, 1H), 9.04 (t, J = 6.1 Hz, 1H), 8.44 (d, J = 8.0 Hz, 1H), 7.83 (d, J= 8.6 Hz, 1H), 7.64-7.60 (m, 1H), 7.36-7.32 (m, 1H), 7.07 (d, J = 8.6 Hz, 2H), 6.53 (dd, J = 11.0, 2.5 Hz, 2H), 4.95 (s, 2H), 4.45 (d, J = 6.1 Hz, 2H), 2.90 (s, 3H); 13 C-NMR (100 MHz, DMSO- d 6) δ 201.1, 164.0, 147.5, 142.3, 138.9, 134.8, 134.0, 131.9, 129.3, 128.3, 126.8, 122.2, 120.8, 120.3, 118.0, 113.7, 113.3, 42.2, 26.0; Purity: 99.5%, t R : 10.7 minutes; HRMS (ESI) m / z calcd for C 21 H 19 N4O2[M+H] + 359.1508, found: 359.1493.

[0246] 1-3-23. MC0123

[0247] MC01B (53.6 mg, 0.21 mmol) and 4-hydroxybenzylamine (28.4 mg, 0.23 mmol) were used as starting materials according to the above general β-carboline derivative synthesis conditions. After purification, a yellow solid compound MC0123 (20.1 mg, 24.2% yield) was obtained.

[0248] Melting point (mp): 283-285 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 12.16 (s, 1H), 9.27 (s, 1H), 9.17 (t, J = 6.4 Hz, 1H), 9.11 (s, 1H), 8.44 (d, J = 8.0 Hz, 1H), 7.84 (d, J= 8.0 Hz, 1H), 7.64-7.60 (m, 1H), 7.35-7.32 (m, 1H), 6.73 (td, J = 5.7, 3.3 Hz, 2H), 4.52 (d, J = 6.7 Hz, 2H), 2.91 (s, 3H); 13 C-NMR (100 MHz, DMSO- d 6) δ 201.1, 164.2, 156.2, 142.3, 138.8, 134.8, 134.0, 131.9, 130.1, 129.3, 128.6, 122.2, 120.8, 120.3, 118.1, 115.0, 113.3, 42.0, 26.1; Purity: 98.0 %, t R : 13.5 minutes; HRMS (ESI) m / z calcd for C 21 H 18 N3O3[M+H] + 360.1348, found: 360.1347.

[0250] 1-3-24. MC0124

[0251] According to the above general synthesis conditions for β-carboline derivatives: MC01B (50.7 mg, 0.20 mmol) and 3-hydroxybenzylamine (27.0 mg, 0.22 mmol) were used as starting materials. After purification, a yellow solid compound MC0124 (51.8 mg, 72.4% yield) was obtained.

[0252] Melting point (mp): 240-242 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 12.16 (s, 1H), 9.33 (s, 1H), 9.24 (t, J = 6.4 Hz, 1H), 9.13 (s, 1H), 8.43 (d, J = 8.0 Hz, 1H), 7.84 (d, J= 8.6 Hz, 1H), 7.64-7.60 (m, 1H), 7.35-7.31 (m, 1H), 7.15-7.11 (m, 1H), 6.82 (d, J = 7.4 Hz, 2H), 6.65 (dd, J = 7.1, 2.1 Hz, 1H), 4.58 (d, J = 6.1 Hz, 2H), 2.94 (s, 3H); 13 C-NMR (100 MHz, DMSO- d 6) δ 201.2, 164.4, 157.4, 142.4, 141.4, 138.7, 134.9, 134.0, 131.9, 129.3, 129.2, 122.2, 120.8, 120.3, 118.1, 117.8, 114.0, 113.7, 113.3, 42.5, 26.1; Purity: 98.6%, t R : 13.7 minutes; HRMS (ESI) m / z calcd for C 21 H 18 N3O3[M+H] + 360.1348, found: 360.1338.

[0254] 1-3-25. MC0125

[0255] MC01B (50.3 mg, 0.20 mmol) and 2-hydroxybenzylamine (0.02 mL, 0.22 mmol) were used as starting materials according to the general synthesis conditions for β-carboline derivatives mentioned above. After purification, a yellow solid compound, MC0125 (34.6 mg, 48.6% yield), was obtained.

[0256] Melting point (mp): 282-284 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 12.17 (s, 1H), 9.81 (s, 1H), 9.22 (t, J = 6.1 Hz, 1H), 9.11 (s, 1H), 8.44 (d, J = 8.0 Hz, 1H), 7.83 (d,J = 8.6 Hz, 1H), 7.64-7.59 (m, 1H), 7.35-7.31 (m, 1H), 7.23 (dd, J = 7.4, 1.2 Hz, 1H), 7.10 (td, J = 7.7, 1.4 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.79-6.75 (m, 1H), 4.60 (d, J = 6.1 Hz, 2H), 2.92 (s, 3H); 13 C-NMR (100 MHz, DMSO- d 6) δ201.0, 164.4, 155.1, 142.4, 138.4, 134.9, 134.0, 132.0, 129.3, 128.5, 128.1, 125.3, 122.3, 120.8, 120.3, 118.9, 118.0, 115.2, 113.3, 38.6, 26.0; Purity: 98.3 %, t R : 15.5 minutes; HRMS (ESI) m / z calcd for C 21 H 18 N3O3[M+H] + 360.1348, found: 360.1351.

[0258] 1-3-26. MC0126

[0259] MC01B (77.8 mg, 0.31 mmol) and (1H-indol-3-yl)methanamine (49.3 mg, 0.34 mmol) were used as starting materials according to the general synthesis conditions for β-carboline derivatives mentioned above. After purification, a yellow solid compound, MC0126 (85.4 mg, 73.0% yield), was obtained.

[0260] Melting point (mp): 255-257 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 12.13 (s, 1H), 10.94 (s, 1H), 9.16 (s, 1H), 8.94 (t, J= 6.1 Hz, 1H), 8.45 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 7.4 Hz, 1H), 7.64-7.59 (m, 1H), 7.38-7.31 (m, 3H), 7.08 (td, J = 7.4, 1.2 Hz, 1H), 7.01-6.97 (m, 1H), 4.80 (d, J = 6.1 Hz, 2H), 2.86 (s, 3H); 13 C-NMR (100 MHz, DMSO- d 6) δ 200.9, 163.8, 142.3, 138.8, 136.3, 134.8, 133.9, 131.9, 129.3, 126.5, 123.9, 122.2, 121.1, 120.8, 120.3, 118.9, 118.5, 118.0, 113.3, 112.7, 111.5, 34.5, 26.0; Purity: 99.4%, t R : 15.2 minutes; HRMS (ESI) m / z calcd for C 23 H 19 N4O2[M+H] + 383.1508, found: 383.1522.

[0262] 1-3-27. MC0127

[0263] MC01B (83.4 mg, 0.33 mmol) and (1H-indol-3-yl)propanamine (62.9 mg, 0.36 mmol) were used as starting materials according to the general synthesis conditions for β-carboline derivatives mentioned above. After purification, a yellow solid compound, MC0127 (51.4 mg, 38.3% yield), was obtained.

[0264] Melting point (mp): 196-198 ℃; 1 H-NMR (400 MHz, DMSO- d6) δ12.14 (s, 1H), 10.78 (s, 1H), 9.10 (s, 1H), 8.78 (t, J = 6.1 Hz, 1H), 8.42 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.6 Hz, 1H), 7.63-7.59 (m, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.33 (dd, J = 13.2, 7.7 Hz, 2H), 7.21 (d, J = 2.5 Hz, 1H), 7.08-7.04 (m, 1H), 6.99-6.95 (m, 1H), 3.51 (q, J = 6.7 Hz, 2H), 2.93 (s, 3H), 2.81 (t, J = 7.4 Hz, 2H), 2.06-1.99 (m, 2H); 13 C-NMR (100 MHz, DMSO- d 6) δ201.1, 164.2, 142.3, 138.9, 136.4, 134.8, 133.9, 131.9, 129.2, 127.2, 122.3, 122.2, 120.8, 120.7, 120.3, 118.3, 118.1, 117.8, 114.0, 113.3, 111.3, 30.2, 26.0, 22.3; 순도: 99.6 %, t R : 16.3분; HRMS (ESI) m / z calcd for C 25 H 23 N4O2[M+H] + 411.1821, found: 411.1820.

[0266] 1-3-28. MC0128

[0267] MC01B (86.3 mg, 0.34 mmol) and β-chlorotryptamine hydrochloride (86.2 mg, 0.37 mmol) were used as starting materials according to the above general synthesis conditions for β-carboline derivatives. After purification, a yellow solid compound MC0128 (16.0 mg, 10.9% yield) was obtained.

[0268] Melting point (mp): 273-275 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 12.15 (s, 1H), 11.10 (s, 1H), 9.11 (s, 1H), 8.78 (t, J = 6.1 Hz, 1H), 8.43 (d, J = 7.9 Hz, 1H), 7.84 (d, J = 8.6 Hz, 1H), 7.70 (d, J = 1.8 Hz, 1H), 7.62 (t, J = 7.6 Hz, 1H), 7.38-7.36 (m, 2H), 7.33 (t, J = 7.6 Hz, 1H), 7.06 (dd, J = 8.6, 1.8 Hz, 1H), 3.70 (q, J = 6.9 Hz, 2H), 3.04 (t, J = 7.0 Hz, 2H), 2.83 (s, 3H); 13 C-NMR (100 MHz, DMSO- d 6) δ201.0, 164.1, 142.3, 138.7, 134.8, 133.9, 131.9, 129.3, 128.5, 124.8, 123.1, 122.2, 120.9, 120.8, 120.3, 117.9, 113.3, 112.9, 111.9, 25.9, 25.2; Purity: 97.9 %, t R : 16.5 minutes; HRMS (ESI) m / z calcd for C 24 H 20 ClN4O2[M+H]+ 431.1275, found: 431.1275.

[0270] 1-3-29. MC0129

[0271] MC01B (57.3 mg, 0.23 mmol) and -methoxytryptamine (86.2 mg, 0.37 mmol) were used as starting materials according to the general synthesis conditions for β-carboline derivatives mentioned above. After purification, a yellow solid compound, MC0129 (69.6 mg, 73.5% yield), was obtained.

[0272] Melting point (mp): 251-253 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 12.14 (s, 1H), 10.72 (d, J = 1.2 Hz, 1H), 9.11 (s, 1H), 8.73 (t, J = 5.8 Hz, 1H), 8.43 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.64-7.59 (m, 1H), 7.33 (t, J = 8.0 Hz, 1H), 7.26 (d, J = 9.2 Hz, 2H), 7.14 (d, J = 2.5 Hz, 1H), 6.74 (dd, J = 8.6, 2.5 Hz, 1H), 3.74 (q, J = 6.3 Hz, 5H), 3.04 (t, J = 7.1 Hz, 2H), 2.81 (s, 3H); 13 C-NMR (100 MHz, DMSO- d6) δ201.0, 164.0, 153.0, 142.3, 138.7, 134.8, 133.8, 131.9, 131.5, 129.2, 127.6, 123.5, 122.2, 120.7, 120.3, 117.8, 113.3, 112.0, 111.5, 111.1, 100.4, 55.3, 39.7, 25.9, 25.3; Purity: 99.5%, t R : 15.1 minutes; HRMS (ESI) m / z calcd for C 25 H 23 N4O3[M+H] + 427.1770, found: 427.1771.

[0274] 1-3-30. MC0130

[0275] MC01B (75.5 mg, 0.30 mmol) and 2-methyltryptamine (56.9 mg, 0.33 mmol) were used as starting materials according to the general synthesis conditions for β-carboline derivatives mentioned above. After purification, a yellow solid compound, MC0130 (82.3 mg, 67.7% yield), was obtained.

[0276] Melting point (mp): 242-244 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 12.12 (s, 1H), 10.75 (s, 1H), 9.10 (s, 1H), 8.67 (t, J = 6.1 Hz, 1H), 8.40 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.62-7.56 (m, 2H), 7.33-7.25 (m, 2H), 7.00-6.97 (m, 1H), 6.95-6.91 (m, 1H), 3.63 (q, J = 7.0 Hz, 2H), 3.00 (t, J = 7.4 Hz, 2H), 2.79 (s, 3H), 2.38 (s, 3H); 13C-NMR (100 MHz, DMSO- d 6) δ200.9, 164.0, 142.3, 138.8, 135.3, 134.8, 133.8, 132.2, 131.9, 129.2, 128.4, 122.1, 120.7, 120.2, 120.0, 118.1, 117.8, 117.5, 113.3, 110.4, 107.4, 40.0, 25.8, 24.2, 11.3 Purity: 99.2 %, t R : 16.2 minutes; HRMS (ESI) m / z calcd for C 25 H 23 N4O2[M+H] + 411.1821, found: 411.1811.

[0278] 1-3-31. MC0131

[0279] MC01B (54.9 mg, 0.22 mmol) and dimethylamine (18.2 mg, 0.24 mmol) were used as starting materials according to the general synthesis conditions for β-carboline derivatives mentioned above. After purification, a yellow solid compound, MC0131 (52.6 mg, 86.5% yield), was obtained.

[0280] Melting point (mp): 213-215 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 12.08 (s, 1H), 8.76 (s, 1H), 8.38 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.6 Hz, 1H), 7.63-7.59 (m, 1H), 7.34-7.30 (m, 1H), 3.21 (s, 3H), 3.11 (s, 3H), 2.79 (s, 3H); 13 C-NMR (100 MHz, DMSO- d6) δ 200.8, 168.0, 142.2, 141.9, 133.8, 133.3, 131.7, 129.2, 122.1, 120.6, 120.1, 119.9, 113.2, 35.7, 25.9; Purity: 97.0 %, t R : 12.2 minutes; HRMS (ESI) m / z calcd for C 16 H 16 N3O2[M+H] + 282.1243, found: 282.1241.

[0282] 1-3-32. MC0132

[0283] MC01B (51.6 mg, 0.20 mmol) and dipropylamine (0.03 mL, 0.22 mmol) were used as starting materials according to the general synthesis conditions for β-carboline derivatives mentioned above. After purification, a yellow solid compound, MC0132 (58.9 mg, 86.0% yield), was obtained.

[0284] Melting point (mp): 193-195 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 12.07 (s, 1H), 8.71 (s, 1H), 8.39 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.6 Hz, 1H), 7.63-7.59 (m, 1H), 7.33-7.29 (m, 1H), 3.43 (td, J = 15.2, 7.6 Hz, 4H), 2.77 (s, 3H), 1.73-1.63 (m, 4H), 0.96 (t, J = 7.4 Hz, 3H), 0.71 (t, J = 7.4 Hz, 3H); 13 C-NMR (100 MHz, DMSO- d6) δ 200.7, 168.2, 142.9, 142.3, 133.8, 133.3, 131.8, 129.2, 122.2, 120.5, 120.0, 119.7, 113.2, 50.2, 47.1, 25.7, 21.8, 20.4, 11.4, 10.9; Purity: 97.9%, t R : 16.7 minutes; HRMS (ESI) m / z calcd for C 20 H 24 N3O2[M+H] + 338.1869, found: 338.1860.

[0286] 1-3-33. MC0133

[0287] MC01B (60.8 mg, 0.24 mmol) and dibenzylamine (51.9 mg, 0.26 mmol) were used as starting materials according to the above general β-carboline derivative synthesis conditions. After purification, a yellow solid compound MC0133 (86.9 mg, 83.9% yield) was obtained.

[0288] Melting point (mp): 200-202 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 12.07 (s, 1H), 8.93 (s, 1H), 8.42 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.6 Hz, 1H), 7.63-7.59 (m, 1H), 7.40-7.24 (m, 11H), 4.83 (s, 2H), 4.70 (s, 2H), 2.43 (s, 3H); 13 C-NMR (100 MHz, DMSO- d6) δ 200.7, 168.7, 142.3, 141.6, 137.5, 137.2, 134.0, 133.3, 131.8, 129.3, 128.5, 128.4, 127.8, 127.2, 127.1, 122.2, 120.7, 120.5, 120.1, 113.2, 51.4, 48.0, 25.6; Purity: 99.9%, t R : 19.0 minutes; HRMS (ESI) m / z calcd for C 28 H 24 N3O2[M+H] + 434.1869, found: 434.1858.

[0290] 1-3-34. MC0134

[0291] MC01B (93.0 mg, 0.37 mmol) and tryptophol (64.8 mg, 0.40 mmol) were used as starting materials according to the general synthesis conditions for β-carboline derivatives mentioned above. After purification, a yellow solid compound, MC0134 (70.1 mg, 48.2% yield), was obtained.

[0292] Melting point (mp): 214-216 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 12.26 (s, 1H), 10.90 (s, 1H), 9.10 (s, 1H), 8.42 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 8.6 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.39-7.35 (m, 3H), 7.10-7.06 (m, 1H), 7.00 (dd, J = 8.6, 7.4 Hz, 1H), 4.62 (t, J = 6.7 Hz, 2H), 3.25 (t, J = 6.7 Hz, 2H), 2.85 (s, 3H); 13 C-NMR (100 MHz, DMSO- d6) δ 201.0, 164.9, 142.2, 137.2, 136.1, 135.7, 135.3, 135.0, 131.3, 129.3, 127.3, 123.4, 122.1, 121.1, 121.0, 120.9, 120.2, 118.4, 118.3, 113.4, 111.4, 110.3, 65.4, 25.6, 24.4; Purity: 98.6 %, t R : 17.1 minutes; HRMS (ESI) m / z calcd for C 24 H 20 N3O3[M+H] + 398.1505, found: 398.1504.

[0294] Example 2. Synthesis method of MC0204-MC1304

[0295] [Reaction Equation 2]

[0296]

[0298] 2-1. General Synthesis Conditions for 1-Ketone-β-Carboline Backbone (MC02A-MC09A)

[0299] L-Tryptophan methyl ester (1.0 equiv.), ketone (1.2 equiv.), and I2 (1.2 equiv.) were placed in an oven-dried two-necked round-bottom flask and dissolved in DMSO (0.25 M). Then, the mixture was heated and stirred at 90 °C for 3 hours under Ar substitution. After the reaction was complete, the mixture was cooled to room temperature. EtOAc (40 mL) was added to the mixture, and the organic layer was washed twice with H2O (2 x 40 mL). The aqueous layer was extracted once more with EtOAc (40 mL), and the collected organic layer was dried and filtered with MgSO4, followed by concentration under reduced pressure. The resulting residue was purified by column chromatography (silica gel, hexane:ethyl acetate = 3:1).

[0301] 2-1-1. MC03A

[0302] According to the general 1-Ketone-β-carboline backbone synthesis conditions above, L-tryptophan methyl ester (0.22 g, 1.01 mmol) and acetophenone (0.30 g, 1.21 mmol) were used as starting materials. After purification, a yellow solid compound MC03A (0.18 g, 53.1% yield) was obtained.

[0303] Melting point (mp): 252-254 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 12.43 (s, 1H), 9.16 (s, 1H), 8.48 (d, J = 7.9 Hz, 1H), 8.39 (d, J = 7.3 Hz, 2H), 7.85 (d, J = 7.9 Hz, 1H), 7.71 (t, J = 7.3 Hz, 1H), 7.65 (t, J = 7.9 Hz, 1H), 7.60 (t, J = 7.6 Hz, 2H), 7.37 (t, J = 7.6 Hz, 1H), 3.93 (s, 3H); 13 C-NMR (100 MHz, DMSO- d 6) δ 192.5, 165.4, 142.1, 136.8, 136.7, 135.8, 135.1, 132.9, 131.4, 131.3, 129.5, 128.2, 122.3, 121.1, 120.6, 120.5, 113.3, 52.3; Purity: 99.0%, t R : 17.2 min; HRMS (ESI) m / z C 20 H 15 N2O3[M+H] + 331.1083, found: 331.1080.

[0305] 2-1-2. MC07A

[0306] L-tryptophan methyl ester (0.97 g, 3.80 mmol) and 4'-bromoacetophenone (0.91 g, 4.56 mmol) were used as starting materials according to the general 1-Ketone-β-carboline backbone synthesis conditions above. After purification, a yellow solid compound MC07A (1.20 g, 77.2% yield) was obtained.

[0307] Melting point (mp): 225-227 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 12.45 (s, 1H), 9.16 (s, 1H), 8.48 (d, J = 7.9 Hz, 1H), 8.35 (dt, J = 9.0, 2.1 Hz, 2H), 7.85 (d, J = 8.6 Hz, 1H), 7.82-7.80 (m, 2H), 7.65 (t, J = 7.3 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 3.94 (s, 3H); 13 C-NMR (100 MHz, DMSO- d 6) δ 191.3, 165.3, 142.1, 136.7, 135.8, 135.4, 135.1, 133.3, 131.6, 131.2, 129.5, 127.1, 122.3, 121.1, 120.8, 120.4, 113.4, 52.4; Purity: 97.0%, t R : 18.9 min; HRMS (ESI) m / z C 20 H 14 BrN2O3[M+H] + 411.0167, found: 411.0159.

[0309] MC02A, MC04A-MC06A and MC08A-MC09A were obtained by following the above general 1-Ketone-β-carboline backbone synthesis procedure using the corresponding ketone.

[0311] 2-2. General Synthesis Conditions for 1-Phenyl-β-Carboline Backbone (MC10A-MC13A)

[0312] L-Tryptophan methyl ester (1.0 equiv.) and Ar-CHO (2.0 equiv.) were placed in an oven-dried two-necked round-bottom flask and dissolved in NMP (0.2 M). Then, the mixture was heated and stirred at 140 °C for 24 hours under O2 substitution. After the reaction was complete, the mixture was cooled to room temperature. EtOAc (40 mL) was added to the mixture, and the organic layer was washed twice with H2O (2 x 40 mL). The aqueous layer was extracted once more with EtOAc (20 mL), and the collected organic layer was dried and filtered with MgSO4, followed by concentration under reduced pressure. The resulting residue was purified by column chromatography (silica gel, hexane:ethyl acetate = 7:3).

[0314] 2-2-1. MC13A

[0315] L-tryptophan methyl ester (0.22 g, 1.00 mmol) and 4-bromobenzaldehyde (0.20 mL, 2.00 mmol) were used as starting materials according to the general 1-phenyl-β-carboline backbone synthesis conditions above. After purification, a yellow solid compound MC13A (0.34 g, 88.5% yield) was obtained.

[0316] Melting point (mp): 288-290 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 11.95 (s, 1H), 8.92 (s, 1H), 8.42 (d, J = 8.0 Hz, 1H), 7.97 (d, J = 8.6 Hz, 2H), 7.82 (d, J = 8.6 Hz, 2H), 7.68 (d, J = 8.6 Hz, 1H), 7.61 (t, J = 7.7 Hz, 1H), 7.33 (t,J = 7.4 Hz, 1H), 3.93 (s, 3H); 13 C-NMR (100 MHz, DMSO- d 6) δ 165.9, 141.5, 140.8, 136.7, 136.6, 134.5, 130.7, 129.4, 128.8, 122.4, 122.1, 121.1, 120.5, 116.9, 112.7, 52.1; Purity: 99.1%, t R : 15.2 min; HRMS (ESI) m / z C 19 H 14 BrN2O2[M+H] + 383.0218, found: 383.0223.

[0318] MC10A-MC12A were obtained by following the above general procedure for 1-phenyl-β-carboline backbone synthesis using the corresponding benzaldehyde.

[0320] 2-3. General Hydrolysis Conditions of Methyl Ester Intermediates

[0321] A methyl ester intermediate (1 equiv.) was dissolved in MeOH (0.4 M), 2 N-NaOH (4.0 equiv.) was added, and the mixture was heated and stirred at 90 °C for 3 hours. After the reaction was complete, the MeOH was removed by concentration under reduced pressure. The mixture was dissolved in H2O (50 mL) and extracted twice with EtOAc (2 x 40 mL). The aqueous layer was titrated to pH 2 using 1 N-HCl, and the solution was stirred for 30 minutes. The formed solid was washed with H2O (50 mL) and filtered.

[0323] 2-3-1. MC03B

[0324] MC03A (0.08 g, 0.24 mmol) and 2 N-NaOH (0.47 mL, 0.94 mmol) were used as starting materials according to the hydrolysis conditions of the above general methyl ester intermediate. After filtration, a yellow solid compound MC03B (0.07 g, 90.0% yield) was obtained.

[0325] Melting point (mp): 300-302 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 12.40 (s, 1H), 9.17 (s, 1H), 8.48 (d, J = 7.9 Hz, 1H), 8.41 (d, J = 7.3 Hz, 2H), 7.85 (d, J = 7.9 Hz, 1H), 7.70 (t, J = 7.3 Hz, 1H), 7.65 (t, J = 7.9 Hz, 1H), 7.60 (t, J = 7.3 Hz, 2H), 7.37 (t, J = 7.6 Hz, 1H); 13 C-NMR (100 MHz, DMSO- d 6) δ 192.6, 166.5, 142.1, 136.9, 136.7, 136.4, 135.7, 132.8, 131.5, 131.3, 129.4, 128.2, 122.3, 121.0, 120.5, 113.3; Purity: 98.1%, t R : 14.7 min; HRMS (ESI) m / z C 19 H 13 N2O3[M+H] + 317.0926, found: 317.0924.

[0327] 2-3-2. MC07B

[0328] MC07A (0.53 g, 1.30 mmol) and 2 N-NaOH (2.6 mL, 5.20 mmol) were used as starting materials according to the hydrolysis conditions of the above general methyl ester intermediate. After filtration, a yellow solid compound MC07B (0.31 g, 60.3% yield) was obtained.

[0329] Melting point (mp): 305-307 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 12.43 (s, 1H), 9.19 (s, 1H), 8.49 (d, J = 8.0 Hz, 1H), 8.36 (dt, J = 9.0, 2.1 Hz, 2H), 7.86 (d, J = 8.6 Hz, 1H), 7.84-7.81 (m, 2H), 7.68-7.64 (m, 1H), 7.38 (t, J = 7.1 Hz, 1H); 13 C-NMR (100 MHz, DMSO- d 6) δ 191.6, 166.5, 142.2, 136.7, 136.4, 135.9, 135.3, 133.3, 131.6, 131.2, 129.5, 127.1, 122.3, 121.1, 120.8, 120.5, 113.4; Purity: 100.0 %, t R : 16.0 min; HRMS (ESI) m / z C 19 H 12 BrN2O3[M+H] + 395.0031, found: 395.0012.

[0331] 2-3-3. MC13B

[0332] MC13A (0.04 g, 0.11 mmol) and 2 N-NaOH (0.21 mL, 0.42 mmol) were used as starting materials according to the hydrolysis conditions of the above general methyl ester intermediate. After filtration, a yellow solid compound MC13B (0.03 g, 68.8% yield) was obtained.

[0333] Melting point (mp): 308-310 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 11.96 (s, 1H), 8.92 (s, 1H), 8.42 (d, J = 7.9 Hz, 1H), 8.03 (d, J = 7.3 Hz, 2H), 7.82 (d, J = 6.7 Hz, 2H), 7.68 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 15.3 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H); 13 C-NMR (100 MHz, DMSO- d 6) δ 166.9, 141.6, 140.3, 136.7, 134.4, 131.6, 130.8, 129.7, 128.8, 122.4, 122.1, 121.1, 120.4, 116.5, 112.7; Purity: 96.0 %, t R : 12.9 min; HRMS (ESI) m / z C 18 H 12 BrN2O2[M+H] + 367.0082, found: 367.0087.

[0335] MC02B, MC04B-MC06B, and MC08B-MC12B were obtained by following the hydrolysis conditions procedure of the above general methyl ester intermediate using the corresponding methyl ester.

[0337] 2-4. General Synthesis Conditions for β-Carboline Derivatives (MC0204-MC1304)

[0338] Carboxylic acid intermediate (1.0 equiv.) and HBTU (1.1 equiv.) were placed in an oven-dried round-bottom flask and dissolved by adding DMF (0.15 M). The mixture was stirred at room temperature for 1 hour, and after 1 hour, amine (1.1 equiv.) and DIPEA (1.2 equiv.) were added to the reaction mixture and stirred for 1.5 hours. After the reaction was complete, H2O (10 mL) was added and extracted twice with EtOAc (2 x 10 mL). The organic layer was washed twice with H2O (2 x 10 mL), and the collected organic layer was dried with MgSO4, filtered, concentrated under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, hexane:ethyl acetate = 3:1 to 1:1).

[0340] 2-4-1. MC0204

[0341] MC02B (65.6 mg, 0.23 mmol) and tryptamine (41.0 mg, 0.26 mmol) were used as starting materials according to the general synthesis conditions for β-carboline derivatives mentioned above. After purification, a yellow solid compound, MC0204 (34.5 mg, 35.0% yield), was obtained.

[0342] Melting point (mp): 241-243 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 12.21 (s, 1H), 10.88 (s, 1H), 9.10 (s, 1H), 8.71 (t, J = 5.8 Hz, 1H), 8.44 (d, J = 7.9 Hz, 1H), 7.82 (d, J = 7.9 Hz, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.62 (t, J = 7.3 Hz, 1H), 7.34 (dd, J = 13.1, 8.3 Hz, 2H), 7.27 (d,J = 1.8 Hz, 1H), 7.10-7.06 (m, 1H), 6.98 (t, J = 7.0 Hz, 1H), 3.74 (q, J = 6.9 Hz, 2H), 3.06 (t, J = 7.3 Hz, 2H), 1.76 (td, J = 14.7, 7.3 Hz, 2H), 1.00 (t, J = 7.3 Hz, 3H); 13 C-NMR (100 MHz, DMSO- d 6) δ202.8, 164.0, 144.1, 143.6, 142.3, 138.7, 136.4, 134.8, 133.7, 131.9, 129.3, 127.3, 126.6, 122.8, 122.2, 121.0, 120.8, 120.3, 118.5, 118.2, 117.8, 113.3, 111.7, 111.4, 38.6, 25.4, 17.1, 13.8; Purity: 97.3 %, t R : 17.4 minutes; HRMS (ESI) m / z calcd for C 26 H 25 N4O2[M+H] + 425.1978, found: 425.1977.

[0344] 2-4-2. MC0304

[0345] MC03B (66.1 mg, 0.21 mmol) and tryptamine (36.8 mg, 0.23 mmol) were used as starting materials according to the above general β-carboline derivative synthesis conditions. After purification, a yellow solid compound MC0304 (72.5 mg, 75.7% yield) was obtained.

[0346] Melting point (mp): 245-247 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 12.35 (s, 1H), 10.82 (s, 1H), 9.14 (s, 1H), 8.49 (d,J = 8.0 Hz, 1H), 8.08-8.05 (m, 3H), 7.84 (d, J = 8.0 Hz, 1H), 7.67-7.62 (m, 2H), 7.55 (d, J = 8.0 Hz, 1H), 7.46 (t, J = 7.7 Hz, 2H), 7.36 (t, J = 7.4 Hz, 2H), 7.11 (d, J = 2.5 Hz, 1H), 7.06 (t, J = 7.1 Hz, 1H), 6.93 (t, J = 7.1 Hz, 1H), 3.69 (q, J = 6.7 Hz, 2H), 2.98 (t, J = 6.7 Hz, 2H); 13 C-NMR (100 MHz, DMSO- d 6) δ193.2, 164.1, 142.2, 138.4, 136.9, 136.5, 136.4, 134.0, 132.6, 132.1, 130.6, 129.4, 128.1, 127.2, 122.7, 122.4, 121.0, 120.9, 120.5, 118.3, 118.2, 117.3, 113.2, 111.6, 111.4, 25.2; Purity: 98.4 %, t R : 17.5 minutes; HRMS (ESI) m / z calcd for C 29 H 23 N4O2[M+H] + 459.1821, found: 459.1821.

[0348] 2-4-3. MC0404

[0349] According to the above general synthesis conditions for β-carboline derivatives: MC04B (60.5 mg, 0.18 mmol) and tryptamine (32.2 mg, 0.20 mmol) were used as starting materials. After purification, a yellow solid compound MC0404 (44.2 mg, 51.1% yield) was obtained.

[0350] 녹는점(m.p): 250-252 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 12.31 (s, 1H), 10.87 (s, 1H), 9.13 (s, 1H), 8.47 (d, J = 8.0 Hz, 1H), 8.10 (t, J = 6.1 Hz, 1H), 7.99 (d, J = 8.0 Hz, 2H), 7.83 (d, J = 8.6 Hz, 1H), 7.64 (t, J = 7.4 Hz, 1H), 7.58 (d, J = 7.4 Hz, 1H), 7.38-7.33 (m, 2H), 7.21 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 1.8 Hz, 1H), 7.09-7.06 (m, 1H), 6.96-6.92 (m, 1H), 3.70 (q, J = 6.5 Hz, 2H), 3.00 (t, J = 7.1 Hz, 2H), 2.37 (s, 3H); 13 C-NMR (100 MHz, DMSO- d 6) δ192.5, 164.2, 143.1, 142.2, 138.3, 136.5, 136.4, 134.4, 134.1, 132.0, 130.8, 129.4, 128.8, 127.3, 122.7, 122.3, 121.0, 120.8, 120.5, 118.4, 118.3, 117.2, 113.2, 111.6, 111.5, 25.3, 21.2; 순도: 98.5 %, t R : 18.3분; HRMS (ESI) m / z calcd for C 30 H 25 N4O2[M+H] + 473.1978, found: 473.1980.

[0352] 2-4-4. MC0504

[0353] MC05B (63.3 mg, 0.19 mmol) and tryptamine (41.0 mg, 0.26 mmol) were used as starting materials according to the general synthesis conditions for β-carboline derivatives mentioned above. After purification, a yellow solid compound, MC0504 (33.5 mg, 0.21% yield), was obtained.

[0354] Melting point (mp): 244-246 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 12.22 (s, 1H), 10.80 (s, 1H), 10.50 (s, 1H), 9.11 (s, 1H), 8.47 (d, J = 8.0 Hz, 1H), 8.27 (t, J = 5.8 Hz, 1H), 8.12 (d, J = 8.6 Hz, 2H), 7.80 (d, J = 8.6 Hz, 1H), 7.65-7.59 (m, 2H), 7.35 (t, J = 7.1 Hz, 2H), 7.16 (d, J = 2.1 Hz, 1H), 7.05 (t, J = 7.1 Hz, 1H), 6.95-6.92 (m, 3H), 3.68 (q, J = 6.7 Hz, 2H), 3.01 (t, J = 7.1 Hz, 2H); 13 C-NMR (100 MHz, DMSO- d 6) δ191.0, 164.3, 162.3, 142.1, 138.3, 136.3, 136.3, 135.4, 133.6, 131.6, 129.3, 127.8, 127.2, 122.6, 122.3, 121.0, 120.7, 120.6, 118.4, 118.3, 116.7, 115.2, 113.1, 111.8, 111.4, 48.6, 40.0, 25.3; Purity: 97.8%, t R: 15.3 minutes; HRMS (ESI) m / z calcd for C 29 H 23 N4O3[M+H] + 475.1770, found: 475.1767.

[0356] 2-4-5. MC0523

[0357] MC05B (100.0 mg, 0.30 mmol) and 4-(aminomethyl)phenol (40.8 mg, 0.33 mmol) were used as starting materials according to the general synthesis conditions for β-carboline derivatives mentioned above. After purification, a yellow solid compound, MC0523 (34.5 mg, 35.0% yield), was obtained.

[0358] Melting point (mp): 286-288 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 12.24 (s, 1H), 10.52 (s, 1H), 9.35 (s, 1H), 9.10 (s, 1H), 8.48 (t, J = 6.1 Hz, 2H), 8.19 (d, J = 8.6 Hz, 2H), 7.80 (d, J = 8.0 Hz, 1H), 7.63 (t, J = 7.4 Hz, 1H), 7.34 (t, J = 7.4 Hz, 1H), 7.20 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 8.6 Hz, 2H), 6.77 (d, J = 8.6 Hz, 2H), 4.49 (d, J = 6.1 Hz, 2H); 13 C-NMR (100 MHz, DMSO- d6) δ164.2, 162.2, 156.4, 142.1, 138.2, 136.4, 135.4, 133.7, 131.7, 129.5, 129.3, 128.5, 127.8, 122.3, 120.7, 120.6, 116.9, 115.2, 115.1, 113.1, 42.1; Purity: 96.1 %, t R : 13.8 minutes; HRMS (ESI) m / z calcd for C 26 H 20 N3O4[M+H] + 438.1454, found: 438.1444.

[0360] 2-4-6. MC0604

[0361] MC06B (62.8 mg, 0.18 mmol) and tryptamine (31.6 mg, 0.20 mmol) were used as starting materials according to the general synthesis conditions for β-carboline derivatives mentioned above. After purification, a yellow solid compound, MC0604 (74.3 mg, 84.2% yield), was obtained.

[0362] Melting point (mp): 238-240 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 12.35 (s, 1H), 10.88 (s, 1H), 9.14 (s, 1H), 8.45 (d, J = 7.9 Hz, 1H), 8.10-8.07 (m, 3H), 7.84 (d, J = 8.6 Hz, 1H), 7.63 (t, J = 7.9 Hz, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.47 (d, J = 7.9 Hz, 2H), 7.37 (d, J = 8.3 Hz, 1H), 7.34 (t, J = 7.3 Hz, 1H), 7.15 (s, 1H), 7.07 (t, J = 7.6 Hz, 1H), 6.94 (t,J = 7.3 Hz, 1H), 3.70 (q, J = 6.5 Hz, 2H), 3.01 (t, J = 7.0 Hz, 2H); 13 C-NMR (100 MHz, DMSO- d 6) δ191.9, 164.1, 142.3, 138.5, 137.6, 136.6, 136.4, 135.5, 133.6, 132.5, 132.2, 129.5, 128.3, 127.2, 122.7, 122.3, 121.0, 120.9, 120.5, 118.4, 118.3, 117.6, 113.2, 111.7, 111.5, 39.9, 25.2; Purity: 97.4 %, t R : 18.6 minutes; HRMS (ESI) m / z calcd for C 29 H 22 ClN4O2[M+H] + 493.1431, found: 493.1419.

[0364] 2-4-7. MC0704

[0365] MC07B (60.3 mg, 0.15 mmol) and tryptamine (26.9 mg, 0.17 mmol) were used as starting materials according to the general synthesis conditions for β-carboline derivatives mentioned above. After purification, a yellow solid compound, MC0704 (30.8 mg, 37.5% yield), was obtained.

[0366] Melting point (mp): 269-271 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 12.36 (s, 1H), 10.84 (s, 1H), 9.16 (s, 1H), 8.49 (d, J = 8.0 Hz, 1H), 8.10 (t, J = 5.8 Hz, 1H), 8.01 (d, J = 8.6 Hz, 2H), 7.84 (d, J= 8.0 Hz, 1H), 7.67-7.63 (m, 3H), 7.57 (d, J = 8.0 Hz, 1H), 7.37 (dd, J = 7.7, 5.8 Hz, 2H), 7.13 (d, J = 1.8 Hz, 1H), 7.08-7.05 (m, 1H), 6.94 (t, J = 7.7 Hz, 1H), 3.68 (q, J = 6.5 Hz, 2H), 3.00 (t, J = 7.1 Hz, 2H); 13 C-NMR (100 MHz, DMSO- d 6) δ192.1, 164.1, 142.3, 138.5, 136.3, 135.8, 133.7, 132.6, 132.2, 131.2, 129.5, 127.2, 126.8, 122.7, 122.4, 121.0, 120.9, 120.5, 118.3, 118.3, 117.6, 113.2, 111.7, 111.5, 39.9, 25.2; Purity: 99.1%, t R : 18.8 minutes; HRMS (ESI) m / z calcd for C 29 H 22 BrN4O2[M+H] + 539.0906, found: 539.0913.

[0368] 2-4-8. MC0723

[0369] MC07B (59.7 mg, 0.15 mmol) and 4-(aminomethyl)phenol (20.6 mg, 0.17 mmol) were used as starting materials according to the general synthesis conditions for β-carboline derivatives mentioned above. After purification, a yellow solid compound, MC0723 (45.2 mg, 59.8% yield), was obtained.

[0370] Melting point (mp): 264-266 ℃; 1 H-NMR (400 MHz, DMSO- d6) δ 12.38 (s, 1H), 9.43 (s, 1H), 9.14 (s, 1H), 8.50 (d, J = 7.9 Hz, 1H), 8.29 (t, J = 6.1 Hz, 1H), 8.10 (d, J = 7.9 Hz, 2H), 7.84 (d, J = 7.9 Hz, 1H), 7.71 (d, J = 8.6 Hz, 2H), 7.65 (t, J = 7.6 Hz, 1H), 7.37 (t, J = 7.3 Hz, 1H), 7.18 (d, J = 8.6 Hz, 2H), 6.76 (dd, J = 11.0, 3.1 Hz, 2H), 4.45 (d, J = 6.1 Hz, 2H); 13 C-NMR (100 MHz, DMSO- d 6) δ192.2, 163.9, 156.5, 142.3, 138.4, 136.6, 135.9, 133.7, 132.7, 132.2, 131.2, 129.5, 129.1, 128.7, 126.7, 122.4, 120.9, 120.5, 117.6, 115.2, 113.3, 42.2; Purity: 96.7 %, t R : 16.3 minutes; HRMS (ESI) m / z calcd for C 26 H 19 BrN3O3[M+H] + 502.0589, found: 502.0576.

[0372] 2-4-9. MC0804

[0373] MC08B (200.0 mg, 0.51 mmol) and tryptamine (89.2 mg, 0.56 mmol) were used as starting materials according to the above general synthesis conditions for β-carboline derivatives. After purification, a yellow solid compound MC0804 (190.5 mg, 63.4% yield) was obtained.

[0374] 녹는점(m.p): 241-243 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 12.40 (s, 1H), 10.83-10.79 (1H), 9.15 (s, 1H), 8.51 (d, J = 8.3 Hz, 1H), 8.35 (s, 1H), 8.12 (t, J = 6.0 Hz, 1H), 8.05 (d, J = 7.8 Hz, 1H), 7.86 (t, J = 8.0 Hz, 2H), 7.65 (t, J = 7.8 Hz, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.32-7.45 (m, 3H), 7.12 (d, J = 2.3 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 6.93 (t, J = 7.6 Hz, 1H), 3.67 (q, J = 6.7 Hz, 2H), 3.00 (t, J = 7.3 Hz, 2H); 13 C-NMR (100 MHz, DMSO- d 6) δ191.7, 164.0, 142.3, 138.9, 138.4, 136.6, 136.3, 135.1, 133.3, 133.2, 132.3, 130.3, 129.6, 129.5, 127.2, 122.6, 122.4, 121.3, 121.0, 120.5, 118.3, 118.2, 117.6, 113.3, 111.5, 111.4, 25.4; 순도: 99.8 %, t R : 18.9분; HRMS (ESI) m / z calcd for C 29 H 22 BrN4O2[M+H] + 539.0906, found: 539.0915.

[0376] 2-4-10. MC0904

[0377] MC09B (200.0 mg, 0.51 mmol) and tryptamine (89.2 mg, 0.56 mmol) were used as starting materials according to the general synthesis conditions for β-carboline derivatives mentioned above. After purification, a yellow solid compound, MC0904 (193.3 mg, 71.1% yield), was obtained.

[0378] Melting point (mp): 238-240 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 12.54 (s, 1H), 10.82 (d, J = 1.2 Hz, 1H), 9.13 (s, 1H), 8.50 (d, J = 7.4 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.69-7.64 (m, 2H), 7.60-7.56 (m, 2H), 7.50 (d, J = 8.0 Hz, 1H), 7.47-7.43 (m, 1H), 7.42-7.36 (m, 3H), 7.11-7.07 (m, 1H), 6.99-6.95 (m, 2H), 3.61 (q, J = 6.5 Hz, 2H), 2.85 (t, J = 6.7 Hz, 2H); 13 C-NMR (100 MHz, DMSO- d 6) δ195.7, 163.6, 142.5, 140.1, 138.5, 136.4, 136.0, 132.6, 132.4, 131.5, 129.9, 129.7, 127.1, 127.0, 122.6, 122.5, 121.2, 121.0, 120.4, 119.2, 118.3, 118.0, 113.4, 111.4, 111.2, 25.1; Purity: 99.0%, t R : 17.6 minutes; HRMS (ESI) m / z calcd for C 29 H 22 BrN4O2[M+H] +539.0906, found: 539.0888.

[0380] 2-4-11. MC1004

[0381] MC10B (47.5 mg, 0.17 mmol) and tryptamine (29.0 mg, 0.18 mmol) were used as starting materials according to the general synthesis conditions for β-carboline derivatives mentioned above. After purification, a yellow solid compound, MC1004 (61.1 mg, 86.0% yield), was obtained.

[0382] Melting point (mp): 181-183 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 11.87 (s, 1H), 10.90 (s, 1H), 8.88 (s, 1H), 8.79 (t, J = 6.1 Hz, 1H), 8.42 (d, J = 7.9 Hz, 1H), 8.10 (d, J = 7.3 Hz, 2H), 7.63-7.76 (4H), 7.54-7.63 (2H), 7.39 (d, J = 7.9 Hz, 1H), 7.34-7.28 (m, 2H), 7.09 (t, J = 7.6 Hz, 1H), 6.99 (t, J = 7.3 Hz, 1H), 3.74 (q, J = 6.7 Hz, 2H), 3.06 (t, J = 7.3 Hz, 2H); 13 C-NMR (100 MHz, DMSO- d 6) δ164.6, 141.6, 140.5, 139.9, 137.5, 136.4, 134.2, 130.0, 128.9, 128.9, 128.7, 128.6, 127.3, 122.8, 122.0, 121.3, 121.0, 120.2, 118.5, 118.3, 112.9, 112.7, 111.9, 111.4, 25.5; Purity: 97.8%, t R: 16.1 minutes; HRMS (ESI) m / z calcd for C 28 H 23 N4O [M+H] + 431.1872, found: 431.1862.

[0384] 2-4-12. MC1104

[0385] MC11B (50.0 mg, 0.17 mmol) and tryptamine (29.0 mg, 0.18 mmol) were used as starting materials according to the general synthesis conditions for β-carboline derivatives mentioned above. After purification, a yellow solid compound, MC1104 (62.4 mg, 85.3% yield), was obtained.

[0386] Melting point (mp): 151-153 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 11.81 (s, 1H), 10.89 (d, J = 1.8 Hz, 1H), 8.84 (s, 1H), 8.76 (t, J = 6.1 Hz, 1H), 8.40 (d, J = 8.0 Hz, 1H), 8.00 (d, J = 8.0 Hz, 2H), 7.69 (t, J = 8.6 Hz, 2H), 7.61-7.57 (m, 1H), 7.46 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.6 Hz, 1H), 7.32-7.27 (m, 2H), 7.09 (td, J = 7.4, 1.2 Hz, 1H), 7.00-6.96 (m, 1H), 3.73 (q, J = 7.0 Hz, 2H), 3.05 (t, J = 7.4 Hz, 2H), 2.46 (s, 3H); 13 C-NMR (100 MHz, DMSO- d6) δ164.7, 141.6, 140.6, 139.8, 138.5, 136.4, 134.7, 134.1, 129.9, 129.4, 128.6, 127.3, 122.8, 122.0, 121.3, 121.0, 120.2, 118.5, 118.3, 112.7, 112.6, 111.8, 111.4, 39.7, 25.5, 21.0; Purity: 97.5 %, t R : 16.8 minutes; HRMS (ESI) m / z calcd for C 29 H 25 N4O [M+H] + 445.2028, found: 445.2025.

[0388] 2-4-13. MC1204

[0389] MC12B (50.0 mg, 0.16 mmol) and tryptamine (29.0 mg, 0.18 mmol) were used as starting materials according to the general synthesis conditions for β-carboline derivatives mentioned above. After purification, a yellow solid compound, MC1204 (54.8 mg, 75.1% yield), was obtained.

[0390] Melting point (mp): 183-185 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 11.75 (s, 1H), 10.90 (d, J = 1.8 Hz, 1H), 9.90 (s, 1H), 8.77 (q, J = 5.5 Hz, 2H), 8.38 (d, J = 8.0 Hz, 1H), 7.96 (dt, J = 9.2, 2.3 Hz, 2H), 7.69 (t, J = 8.9 Hz, 2H), 7.60-7.56 (m, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.32-7.27 (m, 2H), 7.12-7.04 (m, 3H), 6.99 (t, J= 7.1 Hz, 1H), 3.73 (q, J = 6.7 Hz, 2H), 3.06 (t, J = 7.1 Hz, 2H), 2.67 (s, 1H); 13 C-NMR (100 MHz, DMSO- d 6) δ164.8, 158.4, 141.5, 140.9, 139.7, 136.4, 133.9, 130.1, 129.7, 128.4, 128.4, 127.3, 125.5, 122.8, 121.9, 121.4, 121.1, 120.1, 118.5, 118.3, 115.7, 112.7, 112.1, 111.9, 111.5, 38.3, 25.5; Purity: 98.9%, t R : 14.0 minutes; HRMS (ESI) m / z calcd for C 28 H 23 N4O2[M+H] + 447.1821, found: 447.1817.

[0392] 2-4-14. MC1304

[0393] MC13B (50.0 mg, 0.14 mmol) and tryptamine (23.9 mg, 0.15 mmol) were used as starting materials according to the general synthesis conditions for β-carboline derivatives mentioned above. After purification, a yellow solid compound, MC1304 (45.3 mg, 65.4% yield), was obtained.

[0394] Melting point (mp): 217-219 ℃; 1 H-NMR (400 MHz, DMSO- d 6) δ 11.88 (s, 1H), 10.89 (d, J = 1.8 Hz, 1H), 8.87 (s, 1H), 8.75 (t, J = 5.8 Hz, 1H), 8.42 (d, J = 8.0 Hz, 1H), 8.04 (dt, J = 9.0, 2.1 Hz, 2H), 7.84 (dt,J = 9.0, 2.1 Hz, 2H), 7.67 (t, J = 8.0 Hz, 2H), 7.60 (td, J = 7.7, 1.2 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.34-7.30 (m, 1H), 7.28 (d, J = 2.5 Hz, 1H), 7.08 (td, J = 7.4, 1.2 Hz, 1H), 6.99-6.95 (m, 1H), 3.71 (q, J = 7.0 Hz, 2H), 3.04 (t, J = 7.4 Hz, 2H); 13 C-NMR (100 MHz, DMSO- d 6) δ164.5, 141.6, 139.9, 139.2, 136.6, 136.4, 134.1, 131.7, 130.7, 130.2, 128.8, 127.3, 122.8, 122.4, 122.1, 121.2, 121.0, 120.3, 118.5, 118.3, 113.2, 112.6, 111.8, 111.4, 39.6, 25.4; Purity: 99.3%, t R : 17.8 minutes; HRMS (ESI) m / z calcd for C 28 H 21 BrN4O [M+H] + 511.0957, found: 511.0963.

[0396] [Experimental Example]

[0397] Experimental Example 1. Confirmation of anticancer and STAT3 inhibitory effects of beta-carbolin derivatives on drug-resistant cancer cell lines

[0398] Among the beta-carboline derivative compounds synthesized in the above examples, seven highly active anticancer substances—MC0104, MC0122, MC0123, MC0134, MC0504, MC0704, and MC1304—were selected and IC50 in docetaxel-resistant cell lines 50Human breast cancer (MDA-MB-231), human embryonic kidney (HEK-293), and normal lung epithelial (MRC-5) cells were obtained from the American Type Culture Collection (ATCC, Manassas, VA), and cells were cultured in DMEM supplemented with 10% heat-inactivated FBS (Gibco, Grand Island, NY), 100 units / mL penicillin, 100 μg / mL streptomycin, and 0.25 μg / mL amphotericin B.

[0399] The docetaxel-resistant cell line MDA-MB-231-DTR was constructed by culturing MDA-MB-231 cells with increasing docetaxel doses (0.02–2 μM). Cells were cultured at 37 °C with 5% CO2 in a humidified atmosphere. The prepared cells were placed in 3.5 × 10⁻⁶ 96-well culture plates. 4 to 7 x 10 4 Cells were inoculated at a density of cell / mL and co-cultured with the above compound for 72 hours. At the end of the experiment, cells were fixed with 10% TCA solution, and cell proliferation was confirmed by sulforhodamine B (SRB) assay. IC 50 The values ​​were calculated through nonlinear regression analysis using TableCurve 2D v5.01. As shown in Table 1 below, the SRB analysis confirmed that cytotoxicity was maintained in drug-resistant cell lines for all seven beta-carbolin derivative compounds.

[0400] compound IC 50 (μM) MC0104 8.21 ± 0.42 MC0122 15.48 ± 0.60 MC0123 3.66 ± 0.18 MC0134 8.48 ± 0.74 MC0504 6.62 ± 0.33 MC0704 2.96 ± 0.28 MC1304 6.81 ± 0.27

[0402] In addition, the inhibitory effects of selected beta-carbolin derivative compounds on STAT3 were measured. To this end, HEK-293 cells were injected with a phospho-STAT3-Luc reporter vector and Firefly and Renilla luciferase vectors. Subsequently, HEK-293 cells were subjected to a dual luciferase activity assay. Luciferase signals were corrected for Renilla luciferase signals, and the data were presented as relative values ​​compared to DMSO-treated controls. As a result, as shown in Figure 1, three compounds—MC0504, MC0704, and MC1304—exhibited strong STAT3 inhibitory effects, with MC0704 showing the strongest inhibitory effect.

[0404] Experimental Example 2. Confirmation of growth and metastasis inhibitory effects of beta-carboline derivative compounds on drug-resistant cancer cell lines

[0405] The growth and metastatic inhibitory effects of docetaxel-resistant cell lines were confirmed using the MC0704 compound, which showed the strongest anticancer activity and STAT3 inhibitory effect in Experiment Example 1 above.

[0406] The effect of MC0704 on cell invasiveness was first investigated. For this purpose, 24-well Transwell membrane inserts (diameter 6.5 mm, pore size 8 μm, Corning, Tewksbury, MA) were coated with 10 μL of type I collagen (0.5 mg / mL, BD Biosciences, San Diego, CA) and 20 μL of a 1:20 mixture of Matrigel (BD Biosciences) in PBS. Then, after treatment with MC0704 for 24 hours, MDA-MB-231 human triple-negative breast cancer (TNBC) cells (blastocysts or docetaxel-resistant cells) were collected, resuspended in serum-free medium, and reseeded into the upper chambers of the Matrigel-coated Transwell inserts (3 x 10⁶). 5(Canine cell / chamber). Medium containing 30% FBS was used as a chemotactic attractant for the lower chamber. After 24 hours of incubation, cells that had invaded the outer surface of the lower chamber were fixed, stained using the Diff-Quik Staining Kit (Sysmex, Kobe, Japan), and imaged using the Vectra 3.0 Automated Quantitative Pathology Imaging System (PerkinElmer, Waltham, MA). Representative images from three individual experiments were evaluated, and the number of infiltrated cells was semi-quantified using ImageJ 1.52a software (National Institutes of Health, Bethesda, MD). As a result, it was confirmed that MC0704 effectively inhibited the invasiveness of resistant cancer cells, as shown in Figure 2a.

[0407] In addition, the effect of MC0704 on cell motility was investigated. To this end, MDA-MB-231 human triple-negative breast cancer (TNBC) cells (blast cells or docetaxel-resistant cells) were grown in 6-well plates to 90% confluence. Subsequently, the cell monolayer was artificially scraped using an SPL Scar Scratcher (SPL Life Sciences, Pocheon, Korea), washed with PBS, and the exfoliated cells were removed. Cells with specific intercellular spaces were cultured for 24 hours in media containing 1% FBS and various concentrations of MC0704. The filling phenomenon of the intercellular spaces due to cell migration was captured at 0 and 24 hours using an inverted microscope (Olympus, Tokyo, Japan). The intercellular space was quantified using ImageJ 1.52a software and expressed as the percentage of cell migration to the intercellular space at 0 hours. As a result, it was confirmed that MC0704 effectively inhibits the motility of resistant cancer cells, as shown in Figure 2b.

[0409] Experimental Example 3. Confirmation of anticancer effect of beta-carbolite derivative compounds using a drug-resistant animal model

[0410] A docetaxel-resistant animal model was established to verify the anticancer efficacy of MC0704 at the animal level. Specifically, MDA-MB-231-DTR cells (4 × 10⁶ 6 An animal model of drug-resistant tumors was established by subcutaneously injecting cells / mouse) into the flank of 5-6 week old, 18g BALB / c nude mice. The prepared animals were administered intraperitoneally daily for 12 days a control group (DMSO:cremophor:saline = 10:10:80), docetaxel (5 mg / kg), paclitaxel (5 mg / kg), MC0704 (10 mg / kg), and a combination drug group (docetaxel: 5 mg / kg, MC0704: 10 mg / kg). Primary tumor volume was measured every 2-3 days. After 12 days, tumor tissue was excised from the mice and the tumor weight was measured. Additionally, general toxicity was indirectly assessed by measuring the mouse body weight during the 12 days of drug administration. As a result, as shown in Figure 3, MC0704 showed anticancer efficacy without significant toxicity even in drug-resistant animal models, and it was confirmed that the anticancer efficacy increased when combined with docetaxel.

[0412] Experimental Example 4. Confirmation of STAT3 as the target protein of a beta-carboline derivative compound

[0413] A biotin-streptavidin pull-down experiment was performed to confirm that the target protein of MC0704 is STAT3.

[0414] A pull-down experiment was performed using a derivative of MC0704 to which biotin was attached. 20 μM of the biotin-attached MC0704 compound was added to MDA-MB-231-DTR cell lysates and incubated with stirring at 4°C for 1 hour, after which a streptavidin pull-down experiment was performed. Western blot analysis of the level of STAT3 bound to the compound confirmed that MC0704 strongly bound to STAT3 compared to the control group, as shown in Figure 4. This further verified that the target protein of MC0704 is STAT3.

[0416] The foregoing description of the present invention is for illustrative purposes only, and those skilled in the art will understand that other specific forms can be easily modified without altering the technical spirit or essential features of the present invention. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive.

Claims

Claim 1 Pharmaceutical composition for the prevention or treatment of docetaxel-resistant breast cancer comprising, as an active ingredient, a beta-carboline derivative represented by the following chemical formula 1 or a salt thereof: [Chemical Formula 1] (In the above Chemical Formula 1, X is O, NH, or NR 1 and, R 1 Silver hydrogen, C1-C6 alkyl group, substituted or unsubstituted phenyl group, substituted or unsubstituted benzyl group, (CH2) n R 4 , or and, here R 4 is a hydroxyl group (OH), a substituted or unsubstituted amino group (NH2), a substituted or unsubstituted phenyl group, , substituted or unsubstituted indol ( ) and,R 2 is a substituted or unsubstituted phenyl group or R 3 -C=O and here R 3 is a C1-C6 alkyl group or a substituted or unsubstituted phenyl group, and the 'substituted or unsubstituted' is substituted or unsubstituted with one or more substituents selected from the group consisting of a C1-C6 alkyl group, a C1-C6 alkyl group substituted with one or more halogen elements, a halogen element, a hydroxyl group (OH), a C1-C6 alkoxy group, an amino group (NH2), and a cyano group (C≡N), and the n is 1, 2, or 3. Claim 2 In paragraph 1, the above R 1 In this, the C1-C6 alkyl group is a methyl group, n -butyl group, i -Profiler, or n - It is a propyl group, and the substituted or unsubstituted phenyl group is a phenyl group substituted or unsubstituted with a methoxy group (OMe), a trifluoromethyl group (CF3), or an amino group (NH2), and the substituted or unsubstituted benzyl group t - A benzyl group substituted or unsubstituted with a butyl group, a methoxy group (OMe), a halogen element, a cyano group (C≡N), an amino group (NH2), or a hydroxyl group (OH); and the above R 2 The substituted or unsubstituted phenyl group in is a phenyl group substituted or unsubstituted with a methyl group, a hydroxyl group (OH), or a halogen element; and the above R 3 In this, the C1-C6 alkyl group is a methyl group or n - It is a propyl group, and the substituted or unsubstituted phenyl group is a phenyl group substituted or unsubstituted with a methyl group, a hydroxyl group (OH), or a halogen element; and the above R 4 In the example, the substituted or unsubstituted amino group (NH2) is an amino group substituted or unsubstituted with N(CH3)2, the substituted or unsubstituted phenyl group is a phenyl group substituted or unsubstituted with a methoxy group (OMe) or a hydroxyl group (OH), and the substituted or unsubstituted indole group ( A pharmaceutical composition for the prevention or treatment of docetaxel-resistant breast cancer, characterized in that ) is an indole group substituted or unsubstituted with a methyl group, a halogen element, or a methoxy group (OMe). Claim 3 In claim 1, X in Chemical Formula 1 is O, NH, or NR 1 and, R 1 Silver hydrogen, methyl group, n -butyl group, i -Profiler, n -propyl group, phenyl group, 4-methoxy(OMe)-phenyl group, 4-trifluoromethyl(CF3)-phenyl group, 4-amino(NH2)-phenyl group, benzyl group, 4- t -butyl-benzyl group, 4-methoxy(OMe)-benzyl group, 4-F-benzyl group, 4-Cl-benzyl group, 4-CN-benzyl group, 4-amino(NH2)-benzyl group, 4-OH-benzyl group, 3-OH-benzyl group, 2-OH-benzyl group, , , , , , , , , , , , , or and, R 2 is a phenyl group, 4-methyl-phenyl group, 4-OH-phenyl group, 4-Br-phenyl group, or R 3 -C=O and here R 3 is a methyl group, n A pharmaceutical composition for the prevention or treatment of docetaxel-resistant breast cancer, characterized by being a propyl group, a phenyl group, a 4-methyl-phenyl group, a 4-OH-phenyl group, a 4-Cl-phenyl group, a 4-Br-phenyl group, a 3-Br-phenyl group, or a 2-Br-phenyl group. Claim 4 A pharmaceutical composition for the prevention or treatment of docetaxel-resistant breast cancer according to claim 1, characterized in that the beta-carbolin derivative is one or more compounds selected from the group consisting of the following. Claim 5 delete Claim 6 delete Claim 7 delete Claim 8 A pharmaceutical composition for the prevention or treatment of docetaxel-resistant breast cancer, characterized in that, in claim 1, the breast cancer is triple-negative breast cancer. Claim 9 A pharmaceutical composition for the prevention or treatment of docetaxel-resistant breast cancer, characterized in that, in claim 1, the composition inhibits the activity of a signal transducer and activator of transcription 3 (STAT3). Claim 10 A pharmaceutical composition for the prevention or treatment of docetaxel-resistant breast cancer, characterized in that, in claim 1, the composition further comprises an anticancer agent. Claim 11 delete Claim 12 delete Claim 13 delete

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