Novel β-carboline derivative and pharmaceutical composition for preventing or treating drug-resistant cancer, comprising same

Abstract

The present invention relates to a novel beta-carboline derivative and a composition for preventing or treating drug-resistant cancer comprising same. The β-carboline derivative compounds of the present invention inhibit STAT3 activity in drug-resistant cancer cells and suppress cancer cell invasion and migration, thereby exhibiting anticancer effects. Accordingly, the compounds are expected to be advantageously applicable as an anticancer agent for various cancers including breast cancer and a therapeutic agent for drug-resistant cancer.

Description

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

[0001] The present invention relates to a novel beta-carboline derivative and a composition comprising the same for preventing or treating drug-resistant cancer.

[0002] This invention claims priority to Republic of Korea Patent Application No. 10-2023-0184795, filed December 18, 2023, the entire disclosure of which is incorporated herein by reference.

[0003]

[0004] Cancer is a life-threatening disease caused by the unstoppable proliferation of cells, which invade surrounding tissues and destroy normal cells. As a leading cause of death, advances in diagnostic technology have led to earlier diagnosis and the development of various anticancer drugs that can effectively suppress cancer.

[0005] Common cancer treatments include surgery, chemotherapy, and radiation therapy. Surgery and radiation therapy are local therapies, effective only at the site of resection or irradiation, while chemotherapy is a systemic therapy, affecting the entire body. Most cancers originate locally and spread throughout the body. Except in cases detected very early, microscopic systemic metastases often already exist. Therefore, despite effective local therapies, recurrences are common. Therefore, most cancer treatments utilize both local and systemic therapies, often combined with chemotherapy, which is more effective against cancer that has spread throughout the body.

[0006] Chemotherapy, particularly combination chemotherapy, is the treatment of choice for delocalized tumors that cannot be treated with surgery or radiation. However, some patients relapse after only a short period of time and do not respond to second-line chemotherapy. Therefore, drug resistance in currently used chemotherapy regimens is leading to reduced therapeutic efficacy and cancer recurrence, necessitating the development of effective anticancer agents targeting drug-resistant cancers.

[0007] Meanwhile, signal transduction pathways of members of the Signal Transducer and Activator of Transcription (STAT) family are known to play an essential role in the sustained proliferation and survival of cancer cells in precancerous and advanced refractory 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, where it induces 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 important signaling pathways associated with cancer progression, including the IL-3, IL-6, and NF-κ cascades, while also activating feedback pathways that reinforce its own activation.

[0008] Despite being a crucial factor in cancer progression, STAT3 has been considered unsuitable as a drug target protein due to its weak drug-binding site. Consequently, the development of anticancer drugs targeting STAT3 remains inadequate.

[0009] Accordingly, the inventors of the present invention synthesized a beta-carboline derivative that exhibits a STAT3 inhibitory effect in drug-resistant cancer cells and attempted to utilize it as an anticancer agent for drug-resistant cancer.

[0010]

[0011] The present inventors have conducted research to overcome the limitations of the prior art and develop an effective treatment for drug-resistant cancer cells, and as a result, confirmed that STAT3 is over-activated in drug-resistant cancer cells, and confirmed that when treated with a beta-carbolin derivative, STAT3 is suppressed, resulting in an anticancer effect and recovery of drug sensitivity. Based on this, the present invention has been completed.

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

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

[0014] Another object of the present invention is to provide a composition for preventing or treating cancer, comprising a β-carboline derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0015]

[0016] However, the technical problems to be solved by the present invention are not limited to the problems mentioned above, and other problems not mentioned can be clearly understood by a person having ordinary skill in the technical field to which the present invention belongs from the description below.

[0017]

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

[0019] [Chemical Formula 1]

[0020]

[0021] (In the above chemical formula 1,

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

[0023] R 1 is 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 indole group ( ) and

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

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

[0027] The above 'substituted or unsubstituted' means 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] (where n is 1, 2, or 3)

[0029] As one embodiment of the present invention, the R 1In the C1-C6 alkyl group, a methyl group, n-butyl group, i-propyl group, or n-propyl group is a 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 a substituted or unsubstituted benzyl group is a benzyl group substituted or unsubstituted with a t-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 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;

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

[0032] The above R 4 In 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, in the chemical formula 1, X is O, NH, or NR 1 And,

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

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

[0036] Here R 3 may be, but is not limited to, a methyl group, an n-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.

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

[0038]

[0039] In addition, the present invention provides a pharmaceutical composition for preventing or treating drug-resistant cancer, comprising a beta-carboline derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0040] In addition, the present invention provides a pharmaceutical composition for preventing or treating cancer, comprising a beta-carboline derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0041] As one embodiment of the present invention, the drug may be a taxane-based anticancer drug, but is not limited thereto.

[0042] In another embodiment of the present invention, the drug may be, but is not limited to, docetaxel or paclitaxel.

[0043] As another embodiment of the present invention, the cancer may be, but is not limited to, triple-negative breast cancer.

[0044] As another embodiment of the present invention, the composition can inhibit the activity of Signal Transducer and Activator of Transcription 3 (STAT3), but is not limited thereto.

[0045] As another embodiment of the present invention, the composition may further include, but is not limited to, an anticancer agent.

[0046] In addition, the present invention provides a method for preventing or treating drug-resistant cancer, comprising a step of administering to a subject in need thereof a composition comprising a beta-carboline derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0047] In addition, the present invention provides a composition comprising a beta-carboline derivative or a pharmaceutically acceptable salt thereof as an active ingredient for use in preventing or treating drug-resistant cancer.

[0048] In addition, the present invention provides a use for the preparation of a drug-resistant cancer prevention or treatment agent comprising 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 method for preventing or treating cancer, comprising a step of administering to a subject in need thereof a composition comprising a beta-carboline derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0050] In addition, the present invention provides a composition comprising a beta-carboline derivative or a pharmaceutically acceptable salt thereof as an active ingredient for the prevention or treatment of cancer.

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

[0052]

[0053] The beta-carboline derivative compound according to the present invention has an anticancer effect by inhibiting STAT3 activity in drug-resistant cancer cells and inhibiting cancer cell invasion and migration, etc., and is expected to be useful as an anticancer agent for various cancers including breast cancer and as a treatment for drug-resistant cancer.

[0054]

[0055] Figure 1 is a drawing confirming the STAT3 activity inhibitory effect of a beta-carboline derivative compound according to one embodiment of the present invention.

[0056] FIG. 2a is a drawing confirming the effect of inhibiting cell invasion of drug-resistant cancer cells by treatment with beta-carboline derivative MC0704 according to one embodiment of the present invention.

[0057] FIG. 2b is a drawing confirming the cell mobility inhibition effect of drug-resistant cancer cells by treatment with beta-carbolin derivative MC0704 according to one embodiment of the present invention.

[0058] FIG. 3 is a drawing confirming the anticancer effect of the beta-carboline derivative MC0704 in a drug-resistant animal model according to one embodiment of the present invention.

[0059] FIG. 4 is a drawing confirming through a biotin-streptavidin pull-down experiment that the target of the beta-carboline derivative MC0704 according to one embodiment of the present invention is STAT3.

[0060] Figure 5 is a diagram schematically showing the action of a beta-carboline derivative MC0704 according to one embodiment of the present invention.

[0061]

[0062] The present invention provides a beta-carboline derivative or a salt thereof represented by the following chemical formula 1:

[0063] [Chemical Formula 1]

[0064]

[0065] (In the above chemical formula 1,

[0066] X is O, NH, or NR 1 And,

[0067] R 1 is hydrogen, C1-C6 alkyl group, substituted or unsubstituted phenyl group, substituted or unsubstituted benzyl group, (CH2) n R 4 , or And,

[0068] Here R 4 is a hydroxyl group (OH), a substituted or unsubstituted amino group (NH2), a substituted or unsubstituted phenyl group, , substituted or unsubstituted indole group ( ) and

[0069] R 2 is a substituted or unsubstituted phenyl group or R 3 -C=O,

[0070] Here R 3 is a C1-C6 alkyl group or a substituted or unsubstituted phenyl group,

[0071] The above 'substituted or unsubstituted' means 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).

[0072] (where n is 1, 2, or 3)

[0073]

[0074] In the present invention, “C1-C6 alkyl group” means a monovalent alkyl group having 1 to 6 carbon atoms. This term includes functional groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, n-hexyl, etc. The alkyl and other substituents comprising alkyl moieties described in the present invention include both straight-chain and branched forms. “Substituted C1-C6 alkyl group” means that at least one hydrogen atom is substituted with another substituent, and the substituent includes, but is not limited to, a C1-C6 alkyl group, a halogen element, a C1-C6 alkoxy group, or benzene. According to one embodiment of the present invention, the substituted C1-C6 alkyl group may be, but is not limited to, a trifluoromethyl group (CF3).

[0075] In the present invention, the R 1 In the present invention, the C1-C6 alkyl group may be preferably a C1-C4 alkyl group, and may be a methyl group, n-butyl group, i-propyl group, or n-propyl group, but is not limited thereto. In the present invention, the R 3 In the C1-C6 alkyl group, it may preferably be a C1-C3 alkyl group, and may be a methyl group or an n-propyl group, but is not limited thereto.

[0076] In the present invention, “substitution” includes single substitution, double substitution, triple substitution, quadruple substitution, etc.

[0077] 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, may be fluorine, chlorine, or bromine, but is not limited thereto.

[0078] In the present invention, the “phenyl group” is a functional group composed of carbon and hydrogen and has the chemical formula -C6H5. Here, six carbon atoms form a cyclic ring structure.

[0079] In the present invention, the phenyl group may be substituted or unsubstituted, and the R 1 The substituted or unsubstituted phenyl group in R may be substituted or unsubstituted with a methoxy group (OMe), a trifluoromethyl group (CF3), or an amino group (NH2), but is not limited thereto. 2 The substituted or unsubstituted phenyl group in R may be substituted or unsubstituted with a methyl group, a hydroxyl group (OH), or a halogen element, but is not limited thereto. 3 The substituted or unsubstituted phenyl group in R may be substituted or unsubstituted with a methyl group, a hydroxyl group (OH), or a halogen element, but is not limited thereto. 4 The substituted or unsubstituted phenyl group in may be substituted or unsubstituted with a methoxy group (OMe) or a hydroxyl group (OH), but is not limited thereto.

[0080] In the present invention, a “benzyl group” is a substituent or molecular fragment having a C6H5CH2- structure, wherein the benzyl group is characterized by a benzene ring attached to a CH2 group.

[0081] In the present invention, the benzyl group may be substituted or unsubstituted, and the R 1 The substituted or unsubstituted benzyl group in may be substituted or unsubstituted with a t-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.

[0082] In the present invention, “C1-C6 alkoxy group” means an alkyl ether group -OR group, where R means “C1-C6 alkyl”. The alkoxy group may include, for example, methoxy (OMe), ethoxy (OEt), n-propoxy (On-Pr), isopropoxy (Oi-Pr), n-butoxy (On-Bu), iso-butoxy (Oi-Bu), sec-butoxy (Osec-Bu), tert-butoxy (Otert-Bu), n-pentoxy (On-Pen), etc., and according to one embodiment of the present invention, it may be methoxy, but is not limited thereto.

[0083] In the present invention, the “amino group” is in the form of -NH2 in which hydrogen is bonded to a nitrogen atom, can combine with a proton to become a cation with a positive charge, and can act as a nucleophile due to the unshared electron pair possessed by the nitrogen atom.

[0084] In the present invention, the R 4 The substituted or unsubstituted amino group (NH2) in may be an amino group substituted or unsubstituted with N(CH3)2, but is not limited thereto.

[0085] In the present invention, the “indole group” is a form in which indole is bonded, and indole is an aromatic heterocyclic organic compound with a molecular formula of C8H7N. Indole has a two-ring structure in which a five-membered pyrrole ring and a six-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.

[0086] In the present invention, in the chemical formula 1, X is O, NH, or NR 1 And,

[0087] R 1is hydrogen, methyl, n-butyl, i-propyl, n-propyl, phenyl, 4-methoxy(OMe)-phenyl, 4-trifluoromethyl(CF3)-phenyl, 4-amino(NH2)-phenyl, benzyl, 4-t-butyl-benzyl, 4-methoxy(OMe)-benzyl, 4-F-benzyl, 4-Cl-benzyl, 4-CN-benzyl, 4-amino(NH2)-benzyl, 4-OH-benzyl, 3-OH-benzyl, 2-OH-benzyl, , , , , , , , , , , , , or And,

[0088] R 2 is a phenyl group, a 4-methyl-phenyl group, a 4-OH-phenyl group, a 4-Br-phenyl group, or R 3 -C=O,

[0089] Here R 3 may be, but is not limited to, a methyl group, an n-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.

[0090] In the present invention, the beta-carboline derivative may be one or more compounds selected from the group consisting of, but is not limited thereto.

[0091]

[0092] In addition, the present invention provides a pharmaceutical composition for preventing or treating drug-resistant cancer, comprising a beta-carboline derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0093] In addition, the present invention provides a pharmaceutical composition for preventing or treating cancer, comprising a beta-carboline derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0094] In the present invention, “cancer” is a general term for a disease caused by cells that have an aggressive characteristic in which cells divide and grow while ignoring normal growth limits, an invasive characteristic in which cells infiltrate surrounding tissues, and a metastatic characteristic in which cells spread to other parts of the body, and may include breast cancer, colon cancer, glioblastoma, gastric cancer, ovarian cancer, chronic lymphocytic 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.

[0095] In the present invention, "drug resistance" refers to a decrease in the effectiveness of a drug when administered repeatedly in a quantitative manner. In patients with anticancer drug resistance, this refers to a condition in which the dosage or frequency of administration must be increased to achieve the same effect as previously experienced, or even when administered at the same dose as before, the same effect cannot be achieved. In the present invention, "drug-resistant cancer" refers to cancer that is resistant to anticancer drugs.

[0096] In the present invention, the drug may be a taxane-based anticancer drug, but is not limited thereto.

[0097] In the present invention, “Taxane” is a drug that induces apoptosis by disrupting the microtubules of the mitotic spindle and thereby causing axonal transport disorders, and is widely used in solid tumors such as breast cancer, ovarian cancer, and lung cancer. The taxane-based anticancer agent may include docetaxel or paclitaxel.

[0098] In the present invention, the composition may further include an anticancer agent, and the composition may be administered in combination with an anticancer agent, but is not limited thereto.

[0099] In the present invention, anticancer agents additionally included in the composition or co-administered 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, carmofur, teniposide, bleomycin, carmustine, heptaplatin, exemestane, anastrozole, estramustine,May include, but are not limited to, capecitabine, goserelin acetate, polysaccharide potassium, medroxypogesterone acetate, epirubicin, letrozole, pirarubicin, topotecan, altretamine, toremifene citrate, BCNU, taxotere, or actinomycin D.

[0100] In the present invention, the composition can inhibit the activity of Signal Transducer and Activator of Transcription 3 (STAT3), but is not limited thereto.

[0101] In the present invention, “pharmaceutically acceptable salt” includes a salt derived from a pharmaceutically acceptable inorganic acid, organic acid, or base.

[0102] Examples of suitable acids include hydrochloric acid, hydrobromic 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, and the like. Acid addition salts can be prepared by conventional methods, for example, by dissolving the compound in an excess 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 equimolar amounts of the compound and the acid or alcohol in water, followed by evaporation of the mixture to dryness, or by suction filtration of the precipitated salt.

[0103] Salts derived from suitable bases may include, but are not limited to, alkali metals such as sodium and potassium, alkaline earth metals such as magnesium, and ammonium. Alkali metal or alkaline earth metal salts can be obtained, for example, by dissolving a compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering out the undissolved compound salt, and then evaporating and drying the filtrate. In this case, it is pharmaceutically suitable to prepare sodium, potassium, or calcium salts as the metal salt, 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).

[0104] The pharmaceutical composition according to the present invention may further comprise suitable carriers, excipients, and diluents commonly used in the manufacture of pharmaceutical compositions. The excipients may be, for example, one or more selected from the group consisting of diluents, binders, disintegrants, lubricants, adsorbents, moisturizers, film-coating materials, and controlled-release additives.

[0105] 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-coated granules, liquids, eye drops, ellipsoids, emulsions, suspensions, alcohols, troches, aromatic waters, limonades, tablets, sustained-release tablets, enteric-coated tablets, sublingual tablets, hard capsules, soft capsules, sustained-release capsules, enteric capsules, pills, tinctures, soft extracts, dry extracts, fluid extracts, injections, capsules, irrigation solutions, ointments, lotions, pastes, sprays, inhalants, patches, sterile injection solutions, or aerosols, according to a conventional method, and the external preparations may have formulations such as creams, gels, patches, sprays, ointments, ointments, lotions, liniments, pastes, or cataplasmas.

[0106] Carriers, excipients and diluents that may be included in the pharmaceutical composition according to the present invention include lactose, dextrose, sucrose, oligosaccharides, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

[0107] When formulating, it is usually prepared using diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrants, and surfactants.

[0108] The additives of the tablets, powders, granules, capsules, pills, and troches according to the present invention include excipients such as corn starch, potato starch, wheat starch, lactose, sucrose, glucose, fructose, D-mannitol, precipitated calcium carbonate, synthetic aluminum silicate, calcium hydrogen phosphate, calcium sulfate, sodium chloride, sodium bicarbonate, purified lanolin, microcrystalline cellulose, dextrin, sodium alginate, methylcellulose, sodium carboxymethylcellulose, kaolin, urea, colloidal silica gel, hydroxypropyl starch, hydroxypropyl methylcellulose (HPMC) 1928, HPMC 2208, HPMC 2906, HPMC 2910, propylene glycol, casein, calcium lactate, and Primogel; Gelatin, gum arabic, ethanol, agar powder, cellulose acetate phthalate, carboxymethylcellulose, calcium carboxymethylcellulose, glucose, purified water, sodium caseinate, glycerin, stearic acid, sodium carboxymethylcellulose, sodium methylcellulose, methylcellulose, microcrystalline cellulose, dextrin, hydroxycellulose, hydroxypropyl starch, hydroxymethylcellulose, refined shellac, starch starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, polyvinyl pyrrolidone, and binders such as hydroxypropyl methylcellulose, corn starch, agar powder, methylcellulose, bentonite, hydroxypropyl starch, sodium carboxymethylcellulose, sodium alginate, Disintegrants such as carboxymethylcellulose calcium, calcium citrate, sodium lauryl sulfate, anhydrous silicic acid, 1-hydroxypropyl cellulose, dextran, ion exchange resin, polyvinyl acetate, formaldehyde-treated casein and gelatin, alginic acid, amylose, guar gum, baking soda, polyvinylpyrrolidone, calcium phosphate, gelled starch, gum arabic, amylopectin, pectin, sodium polyphosphate, ethylcellulose, sucrose, magnesium aluminum silicate, di-sorbitol solution, and light anhydrous silicic acid;Lubricants such as calcium stearate, magnesium stearate, stearic acid, hydrogenated vegetable oil, talc, lycopodium dentata, kaolin, petrolatum, sodium stearate, cacao butter, 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 silicic acid, higher fatty acids, higher alcohols, silicone oil, paraffin oil, polyethylene glycol fatty acid ether, starch, sodium chloride, sodium acetate, sodium oleate, dl-leucine, and light anhydrous silicic acid can be used.

[0109] As additives of the liquid formulation according to the present invention, water, dilute hydrochloric acid, dilute sulfuric acid, sodium citrate, monostearate sucrose, polyoxyethylene sorbitol fatty acid esters (twin esters), polyoxyethylene monoalkyl ethers, lanolin ethers, lanolin esters, acetic acid, hydrochloric acid, ammonia water, ammonium carbonate, potassium hydroxide, sodium hydroxide, prolamine, polyvinylpyrrolidone, ethylcellulose, sodium carboxymethylcellulose, etc. can be used.

[0110] The syrup according to the present invention may include a solution of white sugar, other sugars, or sweeteners, and may also include a fragrance, a coloring agent, a preservative, a stabilizer, a suspending agent, an emulsifier, a viscosity modifier, and the like, as needed.

[0111] Purified water may be used in the emulsion according to the present invention, and emulsifiers, preservatives, stabilizers, fragrances, etc. may be used as needed.

[0112] The suspension according to the present invention may include suspending agents such as acacia, tragacanth, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, sodium alginate, hydroxypropylmethylcellulose (HPMC), HPMC 1828, HPMC 2906, and HPMC 2910, and surfactants, preservatives, stabilizers, colorants, and fragrances may be used as needed.

[0113] The injection according to the present invention includes a solvent such as distilled water for injection, 0.9% sodium chloride injection, Ringer's injection, dextrose injection, dextrose + sodium chloride injection, PEG, lactated Ringer's injection, ethanol, propylene glycol, non-volatile oils - sesame oil, cottonseed oil, peanut oil, soybean oil, corn oil, ethyl oleate, isopropyl myristate, and benzene benzoate; a solubilizing agent such as sodium benzoate, sodium salicylate, sodium acetate, urea, urethane, monoethylacetamide, butazolidine, propylene glycol, tween, nitrile acid amide, hexamine, and dimethylacetamide; a buffer 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; oxidizing agents such as sodium bisulfite 0.1%, sodium formaldehyde sulfoxylate, thiourea, disodium ethylenediaminetetraacetic acid, and acetone sodium bisulfite; analgesics such as benzyl alcohol, chlorobutanol, procaine hydrochloride, glucose, and calcium gluconate; and suspending agents such as sodium cis-methylenediamine, sodium alginate, Tween 80, and aluminum monostearate.

[0114] The suppository according to the present invention comprises cocoa butter, lanolin, withepsol, polyethylene glycol, glycerogelatin, methylcellulose, carboxymethylcellulose, a mixture of stearic acid and oleic acid, Subanal, cottonseed oil, peanut oil, palm oil, cocoa butter + cholesterol, lecithin, ranet wax, glycerol monostearate, Tween or Span, Imhausen, monolene (propylene glycol monostearate), glycerin, Adeps solidus, Buytyrum Tego-G, Cebes Pharma 16, hexalide base 95, Cotomar, Hydroxocote SP, S-70-XXA, S-70-XX75 (S-70-XX95), Mechanisms such as Hydrokote 25, Hydrokote 711, Idropostal, Massa estrarium (A, AS, B, C, D, E, I, T), Massa-MF, Masupol, Masupol-15, Neosupostal-N, Paramound-B, Suposiro (OSI, OSIX, A, B, C, D, H, L), Suppository type IV (AB, B, A, BC, BBG, E, BGF, C, D, 299), Supostal (N, Es), Wecovi (W, R, S, M, Fs), Tezester triglyceride basis (TG-95, MA, 57) can be used.

[0115] Solid dosage forms for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid dosage forms are prepared by mixing the extract with at least one excipient, such as starch, calcium carbonate, sucrose or lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used.

[0116] Liquid preparations for oral administration include suspensions, solutions, emulsions, and syrups. In addition to commonly used simple diluents such as water and liquid paraffin, they may contain various excipients such as wetting agents, sweeteners, flavoring agents, and preservatives. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solvents and suspensions can include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.

[0117] 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. The effective dosage level can be determined based on factors including the type and severity of the patient's disease, drug activity, drug sensitivity, administration time, administration route and excretion rate, treatment period, concurrently used drugs, and other factors well known in the medical field.

[0118] The pharmaceutical composition according to the present invention can be administered as an individual therapeutic agent or in combination with other therapeutic agents. It can be administered sequentially or simultaneously with conventional therapeutic agents, or in single or multiple doses. Taking all of the above factors into account, it is important to administer an amount that achieves maximum efficacy with minimal side effects. This amount can be readily determined by those skilled in the art to which the present invention pertains.

[0119] The pharmaceutical composition of the present invention can be administered to a subject via various routes. All modes of administration are conceivable, including oral ingestion, subcutaneous injection, intraperitoneal administration, intravenous injection, intramuscular injection, intrathecal injection, sublingual administration, buccal mucosal administration, rectal insertion, vaginal insertion, ocular administration, otic administration, nasal administration, inhalation, oral or nasal spraying, dermal administration, and transdermal administration.

[0120] The pharmaceutical composition of the present invention is determined according to the type of drug as an active ingredient along with various related factors such as the disease to be treated, route of administration, age, sex, weight of the patient, and severity of the disease.

[0121]

[0122] In addition, the present invention provides a food composition for preventing or improving drug-resistant cancer, comprising a beta-carboline derivative or a food-related acceptable salt thereof as an active ingredient.

[0123] In addition, the present invention provides a food composition for preventing or improving cancer, comprising a beta-carboline derivative or a food-related acceptable salt thereof as an active ingredient.

[0124] In the present invention, the food composition may be a health functional food composition, but is not limited thereto.

[0125] In the present invention, “food-wise acceptable salt” includes a salt derived from a food-wise acceptable organic acid, inorganic acid, or base.

[0126] When the beta-carboline derivative of the present invention or its food-scientifically acceptable salt is used as a food additive, the beta-carboline derivative or its food-scientifically acceptable salt can be added as is or used together with other foods or food ingredients, and can be used appropriately according to a conventional method. The mixing amount of the active ingredient can be appropriately determined depending on the purpose of use (prevention, health, or therapeutic treatment). Generally, when manufacturing a food or beverage, the beta-carboline derivative of the present invention or its food-scientifically acceptable salt can be added in an amount of 15 wt% or less, or 10 wt% or less, based on the raw material. However, in the case of long-term intake for the purpose of health and hygiene or health control, the amount can be below the above range, and since there is no problem in terms of safety, the active ingredient can also be used in an amount above the above range.

[0127] There are no specific restrictions on the types of the above foods. Examples of foods to which the above substances can be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages, and vitamin complexes, and all health functional foods in the conventional sense are included.

[0128] The health beverage composition according to the present invention may contain various flavoring agents or natural carbohydrates as additional ingredients, like conventional beverages. The natural carbohydrates mentioned above 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 a sweetener, natural sweeteners such as thaumatin and stevia extract, or synthetic sweeteners such as saccharin and aspartame can be used. The proportion of the natural carbohydrate is generally about 0.01-0.20 g, or about 0.04-0.10 g, per 100 mL of the composition of the present invention.

[0129] 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 colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc. In addition, the composition of the present invention may contain fruit pulp for the production of natural fruit juice, fruit juice drinks, and vegetable drinks. These ingredients may be used independently or in combination. The proportion of these additives is not particularly critical, but is typically selected within the range of 0.01 to 0.20 parts by weight per 100 parts by weight of the composition of the present invention.

[0130] In the present invention, “health functional food” is the same term as food for special health use (FoSHU), and means a food with high medical or therapeutic effects that is processed to efficiently exhibit a bioregulatory function in addition to providing nutrition. The food can be manufactured in various forms such as tablets, capsules, powders, granules, liquids, and pills to obtain a useful effect in preventing or improving obesity.

[0131] The health functional food of the present invention can be manufactured using methods commonly used in the art, and can be manufactured by adding raw materials and ingredients commonly used in the art. Furthermore, unlike conventional drugs, it has the advantage of being food-based, eliminating the side effects that can occur with long-term use of drugs, and can be highly portable.

[0132] The above health functional food has the advantage of having even better effects when consumed in the form of inner beauty food. The inner beauty is referred to as an "edible cosmetic or beauty food" and refers to a food that changes the skin constitution to a healthy one by allowing various skin-friendly ingredients to be absorbed into the body. Just as one selects cosmetics that suit one's skin type, one can select and consume inner beauty food that suits one's skin condition and lifestyle. For example, when a cosmetic containing the above cosmetic composition is combined with an inner beauty food containing a rottlerin derivative or its salt, the effect is significantly enhanced compared to using cosmetics or medication alone, and can have the advantage of having a more effective skin pigmentation prevention or improvement effect as well as a whitening effect.

[0133] In the present invention, “subject” means a subject requiring treatment for a disease, and more specifically, means a mammal such as a human or non-human primate, mouse, rat, dog, cat, horse, and cow.

[0134] In the present invention, "administration" means providing a given composition of the present invention to a subject by any suitable method. Therefore, in the present invention, "administration" includes not only injection or ingestion into a subject, but also application.

[0135] In the present invention, “prevention” means any action that suppresses or delays the onset of a target disease, “treatment” means any action that improves or beneficially changes a target disease and its metabolic abnormality symptoms by administering a pharmaceutical composition according to the present invention, and “improvement” means any action that reduces a parameter related to a target disease, for example, the severity of a symptom, by administering a composition according to the present invention.

[0136]

[0137] In addition, the present invention provides a method for preventing or treating drug-resistant cancer, comprising a step of administering to a subject in need thereof a composition comprising a beta-carboline derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0138] In addition, the present invention provides a composition comprising a beta-carboline derivative or a pharmaceutically acceptable salt thereof as an active ingredient for use in preventing or treating drug-resistant cancer.

[0139] In addition, the present invention provides a use for the preparation of a drug-resistant cancer prevention or treatment agent comprising a composition comprising a beta-carboline derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0140] In addition, the present invention provides a method for preventing or treating cancer, comprising a step of administering to a subject in need thereof a composition comprising a beta-carboline derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0141] In addition, the present invention provides a composition comprising a beta-carboline derivative or a pharmaceutically acceptable salt thereof as an active ingredient for the prevention or treatment of cancer.

[0142] In addition, the present invention provides a use for the preparation of a preparation for preventing or treating cancer, comprising a composition comprising a beta-carboline derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0143]

[0144] Hereinafter, preferred examples and experimental examples are presented to aid in understanding the present invention. However, the following examples and experimental examples are provided solely to facilitate a better understanding of the present invention, and the scope of the present invention is not limited by the following examples and experimental examples.

[0145]

[0146] [Example] Synthesis process of β-carboline derivatives

[0147] Example 1. Synthesis of MC0101-MC0134

[0148] [Reaction Formula 1]

[0149]

[0150]

[0151] 1-1. MC01A

[0152] 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, dissolved in DMSO (30.8 mL), and stirred and heated at 90 °C for 3 h under Ar substitution. After completion of the reaction, 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 again with EtOAc (40 mL), and the combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, hexane:ethyl acetate = 3:1). After purification, compound MC01A (1.61 g, 77.9% yield) was obtained as a yellow solid.

[0153] Melting point (mp): 230-232 ℃; 1H-NMR (400 MHz, DMSO-d6) δ12.28 (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-d6) δ201.0, 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.

[0154]

[0155] 1-2. MC01B

[0156] MC01A (0.91 g, 3.40 mmol) was dissolved in MeOH (8.50 mL), and 2 N-NaOH (6.76 mL, 13.51 mmol) was added. The mixture was then heated and stirred at 90 °C for 3 h. After completion of the reaction, MeOH was removed by concentration under reduced pressure. The mixture was dissolved in H2O (50 mL), and then extracted twice with EtOAc (2 x 40 mL). The aqueous layer was adjusted to pH 2 with 1 N-HCl, and the solution was stirred for 30 min. 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.

[0157] Melting point (mp): 317-319 ℃; 1H-NMR (400 MHz, DMSO-d6) δ12.25 (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-d6); δ201.1, 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.

[0158]

[0159] 1-3. General conditions for the synthesis of β-carboline derivatives (MC0101-MC0134)

[0160] 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 h. After 1 h, amine (1.1 equiv.) or alcohol (1.1 equiv.) and DIPEA (1.2 equiv.) were added to the reaction mixture and stirred for 1.5 h. After completion of the reaction, H2O (10 mL) was added, extracted twice with EtOAc (2 x 10 mL), and the organic layer was washed twice with H2O (2 x 10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure, and the obtained residue was purified by column chromatography (silica gel, hexane:ethyl acetate = 3:1 ~ 1:1).

[0161]

[0162] 1-3-1. MC0101

[0163] According to the general synthetic conditions for β-carboline derivatives, MC01B (52.6 mg, 0.21 mmol) and 4-methoxyphenethylamine (0.03 mL, 0.23 mmol) were used as starting materials. After purification, compound MC0101 (59.8 mg, 74.0% yield) was obtained as a yellow solid.

[0164] Melting point (mp): 194-196 ℃; 1 H-NMR (400 MHz, DMSO-d6) δ12.15 (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-d6) δ200.9, 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.

[0165]

[0166] 1-3-2. MC0102

[0167] MC01B (30.0 mg, 0.08 mmol) and tyramine (12.5 mg, 0.09 mmol) were used as starting materials according to the general synthetic conditions for β-carboline derivatives. After purification, compound MC0102 (8.1 mg, 28.6% yield) was obtained as a yellow solid.

[0168] Melting point (mp): 282-284 ℃; 1 H-NMR (400 MHz, DMSO-d6) δ12.16 (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-d6) δ201.0, 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.

[0169]

[0170] 1-3-3. MC0103

[0171] According to the general synthetic conditions for β-carboline derivatives, MC01B (58.7 mg, 0.23 mmol) and phenethylamine (0.03 mL, 0.25 mmol) were used as starting materials. After purification, compound MC0103 (45.2 mg, 54.8% yield) was obtained as a yellow solid.

[0172] Melting point (mp): 203-205 ℃; 1 H-NMR (400 MHz, DMSO-d6) δ12.16 (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-d6) δ201.0, 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.

[0173]

[0174] 1-3-4. MC0104

[0175] According to the general synthetic conditions for β-carboline derivatives, MC01B (58.7 mg, 0.23 mmol) and tryptamine (40.0 mg, 0.25 mmol) were used as starting materials. After purification, compound MC0104 (42.5 mg, 47.0% yield) was obtained as a yellow solid.

[0176] Melting point (mp): 247-249 ℃; 1 H-NMR (400 MHz, DMSO-d6) δ12.15 (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-d6) δ164.0, 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 H 21 N4O2[M+H] + 397.1665, found: 397.1667.

[0177]

[0178] 1-3-5. MC0105

[0179] According to the general synthetic 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, compound MC0105 (44.8 mg, 71.3% yield) was obtained as a yellow solid.

[0180] Melting point (mp): 280-282 ℃; 1 H-NMR (400 MHz, DMSO-d6) δ12.15 (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-d6) δ201.2, 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.

[0181]

[0182] 1-3-6. MC0106

[0183] According to the general synthetic conditions for β-carboline derivatives, MC01B (50.0 mg, 0.20 mmol) and n-butylamine (15.8 mg, 0.22 mmol) were used as starting materials. After purification, compound MC0106 (38.5 mg, 63.3% yield) was obtained as a yellow solid.

[0184] Melting point (mp): 220-222 ℃; 1 H-NMR (400 MHz, DMSO-d6) δ12.14 (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-d6) δ201.1, 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.

[0185]

[0186] 1-3-7. MC0107

[0187] According to the general synthetic 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, compound MC0107 (54.8 mg, 76.2% yield) was obtained as a yellow solid.

[0188] Melting point (mp): 236-238 ℃; 1H-NMR (400 MHz, DMSO-d6) δ12.15 (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-d6) δ201.0, 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.

[0189]

[0190] 1-3-8. MC0108

[0191] According to the general synthetic conditions for β-carboline derivatives, 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. After purification, compound MC0108 (32.4 mg, 46.5% yield) was obtained as a yellow solid.

[0192] Melting point (mp): 189-191 ℃; 1H-NMR (400 MHz, DMSO-d6) δ12.15 (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-d6) δ201.0, 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.

[0193]

[0194] 1-3-9. MC0109

[0195] According to the general synthetic conditions for β-carboline derivatives, MC01B (50.0 mg, 0.20 mmol) and 3-amino-1-propanol (0.02 mL, 0.22 mmol) were used as starting materials. After purification, compound MC0109 (48.0 mg, 78.3% yield) was obtained as a yellow solid.

[0196] Melting point (mp): 185-187 ℃; 1H -NMR (400 MHz, DMSO-d6) δ12.13 (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-d6) δ201.1, 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.

[0197]

[0198] 1-3-10. MC0110

[0199] According to the general synthetic conditions for β-carboline derivatives, MC01B (51.6 mg, 0.20 mmol) and aniline (0.02 mL, 0.23 mmol) were used as starting materials. After purification, compound MC0110 (37.9 mg, 55.3% yield) was obtained as a yellow solid.

[0200] Melting point (mp): 288-290 ℃; 1H-NMR (400 MHz, DMSO-d6) δ12.24 (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-d6) δ201.0, 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.

[0201]

[0202] 1-3-11. MC0111

[0203] According to the general synthetic conditions for β-carboline derivatives, MC01B (52.0 mg, 0.21 mmol) and 4-methoxyaniline (27.7 mg, 0.23 mmol) were used as starting materials. After purification, compound MC0111 (57.0 mg, 80.5% yield) was obtained as a yellow solid.

[0204] Melting point (mp): 234-236 ℃; 1H-NMR (400 MHz, DMSO-d6) δ12.23 (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-d6) δ201.1, 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.

[0205]

[0206] 1-3-12. MC0112

[0207] According to the general synthetic conditions for β-carboline derivatives, MC01B (54.0 mg, 0.21 mmol) and 4-trifluoromethylaniline (37.7 mg, 0.23 mmol) were used as starting materials. After purification, compound MC0112 (34.0 mg, 40.4% yield) was obtained as a yellow solid.

[0208] Melting point (mp): 312-314 ℃; 1H-NMR (400 MHz, DMSO-d6) δ12.25 (s, 1H), 10.65 (s, 1H), 9.19 (s, 1H), 8.46 (d,J= 7.3 Hz, 1H), 8.15 (d,J= 84.6 Hz), J. 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-d6) δ163.3, 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; 순도: 99.3 %,t R : 19.5pm; HRMS (ESI) m / z calcd for C 21 H 15 F3N3O2[M+H] + 398.1116, found: 398.1106.

[0209]

[0210] 1-3-13. MC0113

[0211] According to the general synthetic conditions for β-carboline derivatives, MC01B (54.5 mg, 0.214 mmol) and 4-aminoaniline (25.5 mg, 0.24 mmol) were used as starting materials. After purification, compound MC0113 (56.3 mg, 76.3% yield) was obtained as a yellow solid.

[0212] Melting point (mp): 241-243 ℃; 1 H-NMR (400 MHz, DMSO-d6) δ12.15 (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) δ161.9, 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.

[0213]

[0214] 1-3-14. MC0114

[0215] According to the general synthetic conditions for β-carboline derivatives, MC01B (55.7 mg, 0.22 mmol) and 5-aminoidole (31.9 mg, 0.24 mmol) were used as starting materials. After purification, compound MC0114 (51.5 mg, 63.8% yield) was obtained as a yellow solid.

[0216] Melting point (mp): 321-323 ℃; 1 H-NMR (400 MHz, DMSO-d6) δ12.21 (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) δ201.0, 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.

[0217]

[0218] 1-3-15. MC0115

[0219] According to the general synthetic conditions for β-carboline derivatives, MC01B (83.4 mg, 0.31 mmol) and (1H-indole-5-yl)methanamine (49.3 mg, 0.34 mmol) were used as starting materials. After purification, compound MC0115 (64.4 mg, 55.0% yield) was obtained as a yellow solid.

[0220] Melting point (mp): 259-261 ℃; 1 H-NMR (400 MHz, DMSO-d6) δ12.15 (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-d6) δ164.1, 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.

[0221]

[0222] 1-3-16. MC0116

[0223] According to the general synthetic conditions for β-carboline derivatives, MC01B (52.5 mg, 0.21 mmol) and benzylamine (0.03 mL, 0.23 mmol) were used as starting materials. After purification, compound MC0116 (43.8 mg, 61.7% yield) was obtained as a yellow solid.

[0224] Melting point (mp): 248-250 ℃; 1 H-NMR (400 MHz, DMSO-d6) δ12.18 (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-d6) δ201.2, 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.

[0225]

[0226] 1-3-17. MC0117

[0227] According to the general synthetic conditions for β-carboline derivatives, MC01B (130.0 mg, 0.51 mmol) and t-butylbenzylamine (0.10 mL, 0.56 mmol) were used as starting materials. After purification, compound MC0117 (35.0 mg, 17.1% yield) was obtained as a yellow solid.

[0228] Melting point (mp): 216-218 ℃; 1 H-NMR (400 MHz, DMSO-d6) δ12.17 (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) δ201.2, 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.

[0229]

[0230] 1-3-18. MC0118

[0231] According to the general synthetic conditions for β-carboline derivatives, MC01B (60.1 mg, 0.24 mmol) and 4-methoxybenzylamine (0.03 mL, 0.26 mmol) were used as starting materials. After purification, compound MC0118 (48.4 mg, 57.1% yield) was obtained as a yellow solid.

[0232] Melting point (mp): 236-238 ℃; 1 H-NMR (400 MHz, DMSO-d6) δ12.17 (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) δ164.3, 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.

[0233]

[0234] 1-3-19. MC0119

[0235] According to the general synthetic conditions for β-carboline derivatives, MC01B (63.1 mg, 0.25 mmol) and 4-fluorobenzylamine (34.2 mg, 0.27 mmol) were used as starting materials. After purification, compound MC0119 (22.0 mg, 24.6% yield) was obtained as a yellow solid.

[0236] Melting point (mp): 255-257 ℃; 1 H-NMR (400 MHz, DMSO-d6) δ12.18 (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) δ164.5, 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 17FN3O2[M+H] + 362.1305, found: 362.1289.

[0237]

[0238] 1-3-20. MC0120

[0239] According to the general synthetic conditions for β-carboline derivatives mentioned above: MC01B (61.5 mg, 0.24 mmol) and 4-chlorobenzylamine (37.7 mg, 0.27 mmol) were used as starting materials. After purification, compound MC0120 (60.6 mg, 66.3% yield) was obtained as a yellow solid.

[0240] Melting point (mp): 234-236 ℃; 1 H-NMR (400 MHz, DMSO-d6) δ12.16 (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-d6) δ201.1, 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.

[0241]

[0242] 1-3-21. MC0121

[0243] According to the general synthetic conditions for β-carboline derivatives mentioned above: MC01B (55.0 mg, 0.22 mmol) and 4-(aminomethyl)benzonitrile (40.1 mg, 0.24 mmol) were used as starting materials. After purification, compound MC0121 (27.7 mg, 34.8% yield) was obtained as a yellow solid.

[0244] Melting point (mp): 261-263 ℃; 1 H-NMR (400 MHz, DMSO-d6) δ12.16 (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-d6) δ201.2, 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.

[0245]

[0246] 1-3-22. MC0122

[0247] According to the general synthetic conditions for β-carboline derivatives, MC01B (49.9 mg, 0.20 mmol) and 4-aminobenzylamine (26.4 mg, 0.22 mmol) were used as starting materials. After purification, compound MC0122 (33.4 mg, 47.6% yield) was obtained as a yellow solid.

[0248] Melting point (mp): 275-277 ℃; 1 H-NMR (400 MHz, DMSO-d6) δ12.15 (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-d6) δ201.1, 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.

[0249]

[0250] 1-3-23. MC0123

[0251] According to the general synthetic conditions for β-carboline derivatives, MC01B (53.6 mg, 0.21 mmol) and 4-hydroxybenzylamine (28.4 mg, 0.23 mmol) were used as starting materials. After purification, compound MC0123 (20.1 mg, 24.2% yield) was obtained as a yellow solid.

[0252] Melting point (mp): 283-285 ℃; 1 H-NMR (400 MHz, DMSO-d6) δ12.16 (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-d6) δ201.1, 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.

[0253]

[0254] 1-3-24. MC0124

[0255] According to the general synthetic conditions for β-carboline derivatives mentioned above: MC01B (50.7 mg, 0.20 mmol) and 3-hydroxybenzylamine (27.0 mg, 0.22 mmol) were used as starting materials. After purification, compound MC0124 (51.8 mg, 72.4% yield) was obtained as a yellow solid.

[0256] Melting point (mp): 240-242 ℃; 1 H-NMR (400 MHz, DMSO-d6) δ12.16 (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-d6) δ201.2, 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.

[0257]

[0258] 1-3-25. MC0125

[0259] According to the general synthetic conditions for β-carboline derivatives, MC01B (50.3 mg, 0.20 mmol) and 2-hydroxybenzylamine (0.02 mL, 0.22 mmol) were used as starting materials. After purification, compound MC0125 (34.6 mg, 48.6% yield) was obtained as a yellow solid.

[0260] Melting point (mp): 282-284 ℃; 1 H-NMR (400 MHz, DMSO-d6) δ12.17 (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-d6) δ164.4, 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.

[0261]

[0262] 1-3-26. MC0126

[0263] According to the general synthetic conditions for β-carboline derivatives, MC01B (77.8 mg, 0.31 mmol) and (1H-indol-3-yl)methanamine (49.3 mg, 0.34 mmol) were used as starting materials. After purification, compound MC0126 (85.4 mg, 73.0% yield) was obtained as a yellow solid.

[0264] Melting point (mp): 255-257 ℃; 1 H-NMR (400 MHz, DMSO-d6) δ12.13 (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-d6) δ200.9, 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.

[0265]

[0266] 1-3-27. MC0127

[0267] According to the general synthetic conditions for β-carboline derivatives, MC01B (83.4 mg, 0.33 mmol) and (1H-indol-3-yl)propanamine (62.9 mg, 0.36 mmol) were used as starting materials. After purification, compound MC0127 (51.4 mg, 38.3% yield) was obtained as a yellow solid.

[0268] Melting point (mp): 196-198 ℃; 1 H-NMR (400 MHz, DMSO-d6) δ(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-d6) δ164.2, 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; Purity: 99.6%,t R : 16.3 minutes; HRMS (ESI) m / z calcd for C 25 H 23 N4O2[M+H] + 411.1821, found: 411.1820.

[0269]

[0270] 1-3-28. MC0128

[0271] According to the general synthetic conditions for β-carboline derivatives, MC01B (86.3 mg, 0.34 mmol) and -chlorotryptamine hydrochloride (86.2 mg, 0.37 mmol) were used as starting materials. After purification, compound MC0128 (16.0 mg, 10.9% yield) was obtained as a yellow solid.

[0272] Melting point (mp): 273-275 ℃; 1 H-NMR (400 MHz, DMSO-d6) δ12.15 (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-d6) δ164.1, 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.

[0273]

[0274] 1-3-29. MC0129

[0275] According to the general synthetic conditions for β-carboline derivatives, MC01B (57.3 mg, 0.23 mmol) and -methoxytryptamine (86.2 mg, 0.37 mmol) were used as starting materials. After purification, compound MC0129 (69.6 mg, 73.5% yield) was obtained as a yellow solid.

[0276] Melting point (mp): 251-253 ℃; 1 H-NMR (400 MHz, DMSO-d6) δ12.14 (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) δ164.0, 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.

[0277]

[0278] 1-3-30. MC0130

[0279] According to the general synthetic conditions for β-carbolien derivatives, MC01B (75.5 mg, 0.30 mmol) and 2-methyltryptamine (56.9 mg, 0.33 mmol) were used as starting materials. After purification, compound MC0130 (82.3 mg, 67.7% yield) was obtained as a yellow solid.

[0280] Melting point (mp): 242-244 ℃; 1 H-NMR (400 MHz, DMSO-d6) δ12.12 (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); 13 C-NMR (100 MHz, DMSO-d6) δ164.0, 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.

[0281]

[0282] 1-3-31. MC0131

[0283] According to the general synthetic conditions for β-carboline derivatives, MC01B (54.9 mg, 0.22 mmol) and dimethylamine (18.2 mg, 0.24 mmol) were used as starting materials. After purification, compound MC0131 (52.6 mg, 86.5% yield) was obtained as a yellow solid.

[0284] Melting point (mp): 213-215 ℃; 1 H-NMR (400 MHz, DMSO-d6) δ12.08 (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) δ200.8, 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.

[0285]

[0286] 1-3-32. MC0132

[0287] According to the general synthetic conditions for β-carboline derivatives, MC01B (51.6 mg, 0.20 mmol) and dipropylamine (0.03 mL, 0.22 mmol) were used as starting materials. After purification, compound MC0132 (58.9 mg, 86.0% yield) was obtained as a yellow solid.

[0288] Melting point (mp): 193-195 ℃; 1H-NMR (400 MHz, DMSO-d6) δ12.07 (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) δ200.7, 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.

[0289]

[0290] 1-3-33. MC0133

[0291] According to the general synthetic conditions for β-carboline derivatives, MC01B (60.8 mg, 0.24 mmol) and dibenzylamine (51.9 mg, 0.26 mmol) were used as starting materials. After purification, compound MC0133 (86.9 mg, 83.9% yield) was obtained as a yellow solid.

[0292] Melting point (mp): 200-202 ℃; 1H-NMR (400 MHz, DMSO-d6) δ12.07 (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) δ200.7, 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.

[0293]

[0294] 1-3-34. MC0134

[0295] According to the general synthetic conditions for β-carboline derivatives, MC01B (93.0 mg, 0.37 mmol) and tryptophol (64.8 mg, 0.40 mmol) were used as starting materials. After purification, compound MC0134 (70.1 mg, 48.2% yield) was obtained as a yellow solid.

[0296] Melting point (mp): 214-216 ℃; 1H-NMR (400 MHz, DMSO-d6) δ12.26 (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) δ201.0, 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.

[0297]

[0298] Example 2. Synthesis of MC0204-MC1304

[0299] [Reaction Formula 2]

[0300]

[0301]

[0302] 2-1. General 1-Ketone-β-carboline skeleton synthesis conditions (MC02A-MC09A)

[0303] 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 DMSO (0.25 M) was added to dissolve. Then, the mixture was heated and stirred at 90 °C for 3 h under Ar substitution. After completion of the reaction, 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 again with EtOAc (40 mL), and the combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, hexane:ethyl acetate = 3:1).

[0304]

[0305] 2-1-1. MC03A

[0306] According to the general 1-Ketone-β-carboline skeleton synthesis conditions mentioned 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, compound MC03A (0.18 g, 53.1% yield) was obtained as a yellow solid.

[0307] Melting point (mp): 252-254 ℃; 1 H-NMR (400 MHz, DMSO-d6) δ12.43 (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); 13C-NMR (100 MHz, DMSO-d6) δ192.5, 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.

[0308]

[0309] 2-1-2. MC07A

[0310] According to the general 1-Ketone-β-carboline skeleton synthesis conditions mentioned above, L-tryptophan methyl ester (0.97 g, 3.80 mmol) and 4'-bromoacetophenone (0.91 g, 4.56 mmol) were used as starting materials. After purification, compound MC07A (1.20 g, 77.2% yield) was obtained as a yellow solid.

[0311] Melting point (mp): 225-227 ℃; 1 H-NMR (400 MHz, DMSO-d6) δ12.45 (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); 13C-NMR (100 MHz, DMSO-d6) δ191.3, 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.

[0312]

[0313] MC02A, MC04A-MC06A and MC08A-MC09A were obtained by following the general 1-Ketone-β-carboline skeleton synthesis procedure using the corresponding ketone.

[0314]

[0315] 2-2. General 1-Phenyl-β skeleton synthesis conditions (MC10A-MC13A)

[0316] 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 NMP (0.2 M) was added to dissolve. The mixture was heated and stirred at 140 °C for 24 h under O2 substitution. After completion of the reaction, 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 again with EtOAc (20 mL), and the combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, hexane:ethyl acetate = 7:3).

[0317]

[0318] 2-2-1. MC13A

[0319] According to the general 1-Phenyl-β-carboline skeleton synthesis conditions mentioned above, L-tryptophan methyl ester (0.22 g, 1.00 mmol) and 4-bromobenzaldehyde (0.20 mL, 2.00 mmol) were used as starting materials. After purification, compound MC13A (0.34 g, 88.5% yield) was obtained as a yellow solid.

[0320] Melting point (mp): 288-290 ℃; 1 H-NMR (400 MHz, DMSO-d6) δ11.95 (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-d6) δ165.9, 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.

[0321]

[0322] MC10A-MC12A were obtained by following the general 1-Phenyl-β-carboline skeleton synthesis procedure using the corresponding benzaldehyde.

[0323]

[0324] 2-3. Hydrolysis conditions of general methyl ester intermediates

[0325] The 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 h. After the reaction was completed, 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 with 1 N-HCl, and the solution was stirred for 30 min. The formed solid was washed with H2O (50 mL) and filtered.

[0326]

[0327] 2-3-1. MC03B

[0328] According to the hydrolysis conditions of the above general methyl ester intermediate, MC03A (0.08 g, 0.24 mmol) and 2 N-NaOH (0.47 mL, 0.94 mmol) were used as starting materials. After filtration, compound MC03B (0.07 g, 90.0% yield) was obtained as a yellow solid.

[0329] Melting point (mp): 300-302 ℃; 1 H-NMR (400 MHz, DMSO-d6) δ12.40 (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-d6) δ192.6, 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.

[0330]

[0331] 2-3-2. MC07B

[0332] 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, compound MC07B (0.31 g, 60.3% yield) was obtained as a yellow solid.

[0333] Melting point (mp): 305-307 ℃; 1 H-NMR (400 MHz, DMSO-d6) δ12.43 (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-d6) δ191.6, 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.

[0334]

[0335] 2-3-3. MC13B

[0336] 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, compound MC13B (0.03 g, 68.8% yield) was obtained as a yellow solid.

[0337] Melting point (mp): 308-310 ℃; 1 H-NMR (400 MHz, DMSO-d6) δ11.96 (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-d6) δ166.9, 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.

[0338]

[0339] MC02B, MC04B-MC06B and MC08B-MC12B were obtained by following the general procedure for hydrolysis of the above methyl ester intermediate using the corresponding methyl ester.

[0340]

[0341] 2-4. General conditions for the synthesis of β-carboline derivatives (MC0204-MC1304)

[0342] Carboxylic acid intermediate (1.0 equiv.) and HBTU (1.1 equiv.) were placed in an oven-dried round-bottom flask and dissolved in DMF (0.15 M). The mixture was stirred at room temperature for 1 h, and after 1 h, amine (1.1 equiv.) and DIPEA (1.2 equiv.) were added to the reaction mixture and stirred for 1.5 h. After completion of the reaction, 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 combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, hexane:ethyl acetate = 3:1 ~ 1:1).

[0343]

[0344] 2-4-1. MC0204

[0345] According to the general synthetic conditions for β-carboline derivatives, MC02B (65.6 mg, 0.23 mmol) and tryptamine (41.0 mg, 0.26 mmol) were used as starting materials. After purification, compound MC0204 (34.5 mg, 35.0% yield) was obtained as a yellow solid.

[0346] Melting point (mp): 241-243 ℃; 1H-NMR (400 MHz, DMSO-d6) δ12.21 (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-d6) δ164.0, 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.

[0347]

[0348] 2-4-2. MC0304

[0349] According to the general synthetic conditions for β-carboline derivatives, MC03B (66.1 mg, 0.21 mmol) and tryptamine (36.8 mg, 0.23 mmol) were used as starting materials. After purification, compound MC0304 (72.5 mg, 75.7% yield) was obtained as a yellow solid.

[0350] 녹는점(m.p): 245-247 ℃; 1 H-NMR (400 MHz, DMSO-d6) δ12.35 (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-d6) δ164.1, 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; 순도: 98.4 %,t R : 17.5분; HRMS (ESI) m / z calcd for C 29 H 23 N4O2[M+H] + 459.1821, found: 459.1821.

[0351]

[0352] 2-4-3. MC0404

[0353] According to the general synthetic conditions for β-carboline derivatives mentioned above: MC04B (60.5 mg, 0.18 mmol) and tryptamine (32.2 mg, 0.20 mmol) were used as starting materials. After purification, compound MC0404 (44.2 mg, 51.1% yield) was obtained as a yellow solid.

[0354] Melting point (mp): 250-252 ℃; 1 H-NMR (400 MHz, DMSO-d6) δ12.31 (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-d6) δ164.2, 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; Purity: 98.5%,t R : 18.3 minutes; HRMS (ESI) m / z calcd for C 30 H 25 N4O2[M+H] + 473.1978, found: 473.1980.

[0355]

[0356] 2-4-4. MC0504

[0357] According to the general synthetic conditions for β-carboline derivatives, MC05B (63.3 mg, 0.19 mmol) and tryptamine (41.0 mg, 0.26 mmol) were used as starting materials. After purification, compound MC0504 (33.5 mg, 0.21% yield) was obtained as a yellow solid.

[0358] Melting point (mp): 244-246 ℃; 1 H-NMR (400 MHz, DMSO-d6) δ12.22 (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-d6) δ164.3, 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.

[0359]

[0360] 2-4-5. MC0523

[0361] According to the general synthetic conditions for β-carboline derivatives, MC05B (100.0 mg, 0.30 mmol) and 4-(aminomethyl)phenol (40.8 mg, 0.33 mmol) were used as starting materials. After purification, compound MC0523 (34.5 mg, 35.0% yield) was obtained as a yellow solid.

[0362] Melting point (mp): 286-288 ℃; 1 H-NMR (400 MHz, DMSO-d6) δ12.24 (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) δ162.2, 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.

[0363]

[0364] 2-4-6. MC0604

[0365] According to the general synthetic conditions for β-carboline derivatives, MC06B (62.8 mg, 0.18 mmol) and tryptamine (31.6 mg, 0.20 mmol) were used as starting materials. After purification, compound MC0604 (74.3 mg, 84.2% yield) was obtained as a yellow solid.

[0366] Melting point (mp): 238-240 ℃; 1 H-NMR (400 MHz, DMSO-d6) δ12.35 (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-d6) δ164.1, 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.

[0367]

[0368] 2-4-7. MC0704

[0369] According to the general synthetic conditions for β-carboline derivatives, MC07B (60.3 mg, 0.15 mmol) and tryptamine (26.9 mg, 0.17 mmol) were used as starting materials. After purification, compound MC0704 (30.8 mg, 37.5% yield) was obtained as a yellow solid.

[0370] Melting point (mp): 269-271 ℃; 1 H-NMR (400 MHz, DMSO-d6) δ12.36 (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-d6) δ164.1, 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.

[0371]

[0372] 2-4-8. MC0723

[0373] According to the general synthetic conditions for β-carboline derivatives, MC07B (59.7 mg, 0.15 mmol) and 4-(aminomethyl)phenol (20.6 mg, 0.17 mmol) were used as starting materials. After purification, compound MC0723 (45.2 mg, 59.8% yield) was obtained as a yellow solid.

[0374] Melting point (mp): 264-266 ℃; 1 H-NMR (400 MHz, DMSO-d6) δ12.38 (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-d6) δ163.9, 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.

[0375]

[0376] 2-4-9. MC0804

[0377] According to the general synthetic conditions of β-carboline derivatives, MC08B (200.0 mg, 0.51 mmol) and tryptamine (89.2 mg, 0.56 mmol) were used as starting materials. After purification, compound MC0804 (190.5 mg, 63.4% yield) was obtained as a yellow solid.

[0378] Melting point (mp): 241-243 ℃; 1 H-NMR (400 MHz, DMSO-d6) δ12.40 (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-d6) δ164.0, 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; Purity: 99.8%,t R : 18.9 minutes; HRMS (ESI) m / z calcd for C 29 H 22 BrN4O2[M+H] + 539.0906, found: 539.0915.

[0379]

[0380] 2-4-10. MC0904

[0381] According to the general synthetic conditions for β-carboline derivatives, MC09B (200.0 mg, 0.51 mmol) and tryptamine (89.2 mg, 0.56 mmol) were used as starting materials. After purification, compound MC0904 (193.3 mg, 71.1% yield) was obtained as a yellow solid.

[0382] Melting point (mp): 238-240 ℃; 1 H-NMR (400 MHz, DMSO-d6) δ12.54 (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-d6) δ163.6, 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.

[0383]

[0384] 2-4-11. MC1004

[0385] According to the general synthetic conditions for β-carboline derivatives, MC10B (47.5 mg, 0.17 mmol) and tryptamine (29.0 mg, 0.18 mmol) were used as starting materials. After purification, compound MC1004 (61.1 mg, 86.0% yield) was obtained as a yellow solid.

[0386] Melting point (mp): 181-183 ℃; 1 H-NMR (400 MHz, DMSO-d6) δ11.87 (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-d6) δ141.6, 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.

[0387]

[0388] 2-4-12. MC1104

[0389] According to the general synthetic conditions for β-carboline derivatives, MC11B (50.0 mg, 0.17 mmol) and tryptamine (29.0 mg, 0.18 mmol) were used as starting materials. After purification, compound MC1104 (62.4 mg, 85.3% yield) was obtained as a yellow solid.

[0390] Melting point (mp): 151-153 ℃; 1 H-NMR (400 MHz, DMSO-d6) δ11.81 (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) δ141.6, 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.

[0391]

[0392] 2-4-13. MC1204

[0393] According to the general synthetic conditions for β-carboline derivatives, MC12B (50.0 mg, 0.16 mmol) and tryptamine (29.0 mg, 0.18 mmol) were used as starting materials. After purification, compound MC1204 (54.8 mg, 75.1% yield) was obtained as a yellow solid.

[0394] Melting point (mp): 183-185 ℃; 1 H-NMR (400 MHz, DMSO-d6) δ11.75 (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-d6) δ158.4, 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.

[0395]

[0396] 2-4-14. MC1304

[0397] According to the general synthetic conditions for β-carboline derivatives, MC13B (50.0 mg, 0.14 mmol) and tryptamine (23.9 mg, 0.15 mmol) were used as starting materials. After purification, compound MC1304 (45.3 mg, 65.4% yield) was obtained as a yellow solid.

[0398] Melting point (mp): 217-219 ℃; 1 H-NMR (400 MHz, DMSO-d6) δ11.88 (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-d6) δ141.6, 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.

[0399]

[0400] [Experimental Example]

[0401] Experimental Example 1. Confirmation of the anticancer and STAT3 inhibitory effects of beta-carboline derivatives on drug-resistant cancer cell lines.

[0402] 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 IC in docetaxel-resistant cell lines. 50 were confirmed. Human 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 the 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.

[0403] The docetaxel-resistant cell line, MDA-MB-231-DTR, was established by culturing MDA-MB-231 cells with increasing doses of docetaxel (0.02–2 μM). The cells were cultured at 37°C in a humidified atmosphere with 5% CO2. The prepared cells were seeded in 96-well culture plates at a density of 3.5 × 10 4 7x10 4 The cells were seeded at a density of 10 cells / mL and then cultured with the compound for 72 hours. At the end of the experiment, the cells were fixed with 10% TCA solution and sulforhodamine B (SRB) assay was performed to confirm cell proliferation. IC 50The values ​​were calculated through nonlinear regression analysis using TableCurve 2D v5.01. As shown in Table 1 below, the SRB assay results confirmed that all seven beta-carboline derivative compounds maintained cytotoxicity even in drug-resistant cell lines.

[0404] Compound IC 50 (μM)MC01048.21 ± 0.42MC012215.48 ± 0.60MC01233.66 ± 0.18MC01348.48 ± 0.74MC05046.62 ± 0.33MC07042.96 ± 0.28MC13046.81 ± 0.27

[0405]

[0406] Additionally, the inhibitory effects of selected beta-carboline derivative compounds on STAT3 were measured. To this end, HEK-293 cells were transfected with the phospho-STAT3-Luc reporter vector and the Firefly and Renilla luciferase vectors. The HEK-293 cells were then subjected to a dual luciferase activity assay. Luciferase signals were corrected for Renilla luciferase signals, and data were presented as relative values ​​to the DMSO-treated control. As a result, as shown in Figure 1, three compounds (MC0504, MC0704, and MC1304) exhibited strong STAT3 inhibitory effects, with MC0704 exhibiting the strongest inhibitory effect.

[0407]

[0408] Experimental Example 2. Confirmation of the growth and metastatic inhibition effects of beta-carboline derivative compounds on drug-resistant cancer cell lines.

[0409] In the above experimental example 1, the MC0704 compound, which showed the strongest anticancer activity and STAT3 inhibition effect, was used to confirm the growth and metastatic inhibition effect of docetaxel-resistant cell lines.

[0410] The effect of MC0704 on cell invasiveness was first investigated. For this purpose, 24-well Transwell membrane inserts (6.5 mm diameter, 8 μm pore size, Corning, Tewksbury, MA) were coated with 20 μL of a 1:20 mixture of 10 μL of type I collagen (0.5 mg / mL, BD Biosciences, San Diego, CA) and Matrigel (BD Biosciences) in PBS. Then, after treatment with MC0704 for 24 h, MDA-MB-231 human triple-negative breast cancer (TNBC) cells (parental or docetaxel-resistant cells) were collected, resuspended in serum-free medium, and reseeded (3 × 10 5 (Cells / chamber). Medium containing 30% FBS was used as a chemoattractant in the lower chamber. After 24 h of incubation, cells invading 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, as shown in Figure 2a, it was confirmed that MC0704 effectively inhibited the invasiveness of resistant cancer cells.

[0411] Furthermore, the effect of MC0704 on cell motility was investigated. To this end, MDA-MB-231 human triple-negative breast cancer (TNBC) cells (parental or docetaxel-resistant) were grown to 90% confluence in 6-well plates. The cell monolayer was artificially scraped using a SPL Scar Scratcher (SPL Life Sciences, Pocheon, Korea), washed with PBS, and detached cells were removed. Cells with defined gaps were cultured with medium containing 1% FBS and various concentrations of MC0704 for 24 h. The filling of the gaps by cell migration was captured using an inverted microscope (Olympus, Tokyo, Japan) at 0 and 24 h. The gap area was quantified using ImageJ 1.52a software and expressed as the percentage of cell migration relative to the gap area at 0 h. As a result, as shown in Fig. 2b, it was confirmed that MC0704 effectively inhibited the mobility of resistant cancer cells.

[0412]

[0413] Experimental Example 3. Confirmation of the anticancer effect of beta-carboline derivative compounds using a drug-resistant animal model.

[0414] The anticancer efficacy of MC0704 was verified at the animal level by establishing a docetaxel-resistant animal model. Specifically, MDA-MB-231-DTR cells (4 × 10 6A resistant tumor-bearing animal model was established by subcutaneously injecting MC0704 (10 mg / kg) (cells / mouse) into the flank of 5-6 week-old 18 g BALB / c nude mice. The prepared animals were administered intraperitoneally daily with a control group (DMSO:cremophor:saline = 10:10:80), docetaxel (5 mg / kg), paclitaxel (5 mg / kg), MC0704 (10 mg / kg), and the combined drug group (docetaxel: 5 mg / kg, MC0704: 10 mg / kg) for 12 days. The primary tumor volume was measured every 2-3 days. After 12 days, tumor tissues were excised from the mice and the tumor weights were measured. In addition, the general toxicity was indirectly confirmed by measuring the mouse body weights for 12 days of drug administration. As a result, as shown in Fig. 3, it was confirmed that MC0704 exhibited anticancer efficacy without significant toxicity even in a drug-resistant animal model, and that the anticancer efficacy increased when combined with docetaxel.

[0415]

[0416] Experimental Example 4. Confirmation of STAT3 as a target protein for beta-carboline derivative compounds.

[0417] To confirm that the target protein of MC0704 is STAT3, a biotin-streptavidin pull-down experiment was performed.

[0418] A pull-down experiment was performed using a biotin-tagged derivative of MC0704. MDA-MB-231-DTR cell lysates were incubated with 20 μM biotin-tagged MC0704 for 1 hour at 4°C with stirring, followed by streptavidin pull-down experiments. 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 validated the target protein of MC0704 as STAT3.

[0419]

[0420] The foregoing description of the present invention is provided for illustrative purposes only. Those skilled in the art will readily appreciate that the present invention can be readily modified into other specific forms without altering the technical spirit or essential characteristics of the present invention. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive.

[0421]

[0422] The beta-carboline derivative compound according to the present invention has an anticancer effect by inhibiting STAT3 activity in drug-resistant cancer cells and inhibiting cancer cell invasion and migration, etc., and thus can be usefully used as an anticancer agent for various cancers including breast cancer and as a treatment for drug-resistant cancer, and thus has industrial applicability.

Claims

1. A beta-carboline derivative or a salt thereof represented by the following chemical formula 1: [Chemical Formula 1] (In the above chemical formula 1, X is O, NH, or NR 1 And, R 1 is 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 indole group ( ) and R 2 is a substituted or unsubstituted phenyl group or R 3 -C=O, Here R 3 is a C1-C6 alkyl group or a substituted or unsubstituted phenyl group, The above 'substituted or unsubstituted' means 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). (where n is 1, 2, or 3) 2. In paragraph 1, Above R 1 In , the C1-C6 alkyl group is a methyl group, n-butyl group, i-propyl group, or n-propyl group, 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 is a benzyl group substituted or unsubstituted with a t-butyl group, a methoxy group (OMe), a halogen element, a cyano group (C≡N), an amino group (NH2), or a hydroxyl group (OH); Above R 2 In 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; Above R 3 In the C1-C6 alkyl group, the group is a methyl group or an n-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; Above R 4 In 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 ( ) is a beta-carboline derivative or a salt thereof, characterized in that it is an indole group substituted or unsubstituted with a methyl group, a halogen element, or a methoxy group (OMe).

3. In paragraph 1, In the above chemical formula 1, X is O, NH, or NR 1 And, R 1 is hydrogen, methyl group, n-butyl group, i-propyl group, 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, a 4-methyl-phenyl group, a 4-OH-phenyl group, a 4-Br-phenyl group, or R 3 -C=O, Here R 3 A beta-carboline derivative or a salt thereof, characterized in that the group is a methyl group, an n-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.

4. In paragraph 1, A beta-carboline derivative or a salt thereof, characterized in that the beta-carboline derivative is at least one compound selected from the group consisting of:

5. A pharmaceutical composition for preventing or treating drug-resistant cancer, comprising a beta-carboline derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 as an active ingredient.

6. In paragraph 5, A pharmaceutical composition for preventing or treating drug-resistant cancer, characterized in that the drug is a taxane series anticancer agent.

7. In paragraph 6, A pharmaceutical composition for preventing or treating drug-resistant cancer, characterized in that the drug is docetaxel or paclitaxel.

8. In paragraph 5, A pharmaceutical composition for preventing or treating drug-resistant cancer, characterized in that the cancer is triple-negative breast cancer.

9. In paragraph 5, A pharmaceutical composition for preventing or treating drug-resistant cancer, characterized in that the composition inhibits the activity of Signal Transducer and Activator of Transcription 3 (STAT3).

10. In paragraph 5, A pharmaceutical composition for preventing or treating drug-resistant cancer, characterized in that the composition further comprises an anticancer agent.

11. A pharmaceutical composition for preventing or treating cancer, comprising a beta-carboline derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 as an active ingredient.

12. In paragraph 11, A pharmaceutical composition for preventing or treating cancer, characterized in that the cancer is triple-negative breast cancer.

13. In paragraph 11, A pharmaceutical composition for preventing or treating cancer, characterized in that the composition further comprises an anticancer agent.

14. A method for preventing or treating drug-resistant cancer, comprising a step of administering to a subject in need thereof a composition comprising a beta-carboline derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 as an active ingredient.

15. Use of a composition comprising a beta-carboline derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 as an active ingredient for preventing or treating drug-resistant cancer.

16. Use of a composition comprising a beta-carboline derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 as an active ingredient for the manufacture of a preparation for preventing or treating drug-resistant cancer.

17. A method for preventing or treating cancer, comprising a step of administering to a subject in need thereof a composition comprising a beta-carboline derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 as an active ingredient.

18. Use of a composition comprising a beta-carboline derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 as an active ingredient for preventing or treating cancer.

19. Use of a composition comprising a beta-carboline derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 as an active ingredient for the manufacture of a preparation for preventing or treating cancer.

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