Benzoselenophene compounds, pharmaceutical compositions containing the same, and antibody-drug conjugates

Abstract

To provide a water-soluble benzoselenophene derivative that is applicable as antibody-drug conjugate.SOLUTION: A benzoselenophene-based compound represented by the following chemical formula 1 is provided. In the formula, R1 is a substituted or unsubstituted amino group, or a C1-6 alkylamino group, R2 and R3 are each independently hydrogen, fluorine, chlorine, bromine, iodine, or a substituted or unsubstituted C1-5 alkyl group, R4 and R5 are each independently hydrogen, or a substituted or unsubstituted C1-5 alkyl group, and X is a halogen element.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present application relates to benzoselenophene compounds, methods for preparing the benzoselenophene compounds, pharmaceutical compositions containing the benzoselenophene compounds, and antibody-drug conjugates. [Background technology]

[0002] Duocarmycin is known as a highly effective anti-cancer therapeutic substance. However, during animal testing, duocarmycin also acts as a toxin on normal cells, resulting in the death of some experimental animals. Therefore, the substance itself cannot be used in humans. Active research is being conducted to develop a substance that specifically acts on tumor cells, kills only tumor cells, and maintains stability and high activity in the blood.

[0003] Antibody therapy has been used to target the treatment of patients with cancer, immunological disorders, and angiogenic disorders. In cancer treatment, antibody-drug conjugates (ADCs), or immunoconjugates, are used to locally deliver drugs, such as cytotoxic or cytostatic agents, that kill or inhibit tumor cells [see Payne, G. (2003) Cancer Cell 3:207-212; Trail et al. (2003) Cancer Immunol. Immunother. 52:328-337; Syrigos and Epenetos (1999) Anticancer Research 19:605-614; Niculescu-Duvaz and Springer (1997) Adv. Drug Del. Rev. 26:151-172; US 4,975,278]. Theoretically, this allows targeted delivery of the drug moiety to tumors, resulting in the accumulation of the drug within tumor cells.

[0004] However, existing derivatives with excellent activity have limited water solubility and can aggregate when bound to targeting proteins such as antibodies, making it difficult to synthesize stable antibody-drug conjugates. Summary of the Invention [Problem to be solved by the invention]

[0005] The present application aims to provide benzoselenophene compounds, methods for preparing the benzoselenophene compounds, pharmaceutical compositions containing the benzoselenophene compounds, and antibody-drug conjugates.

[0006] In particular, the present application relates to the preparation of novel benzoselenophene derivatives with significantly increased water solubility and activity by introducing a novel water-soluble group into benzoselenophene, and the use of the benzoselenophene derivatives as anticancer drugs. The novel water-soluble benzoselenophene derivatives of the present application can be used as antibody-drug conjugates and can function as prodrugs. Furthermore, the water-soluble benzoselenophene derivatives can be conjugated to targeting agents such as antibodies, proteins, ligands, nanoparticles, and aptamers, and can function as prodrugs.

[0007] However, the problems to be solved by the present application are not limited to those described above, and other problems not mentioned will be clearly understood by those skilled in the art from the following description. [Means for solving the problem]

[0008] A first aspect of the present application provides a benzoselenophene-based compound represented by the following formula 1: [ka] In the above Chemical Formula 1, R 1 is a substituted or unsubstituted amino group or a substituted or unsubstituted linear or branched C 1-6 is an alkylamino group, R 2 and R 3are each independently hydrogen, fluorine, chlorine, bromine, iodine, or substituted or unsubstituted C 1-5 is an alkyl group, R 4 and R 5 are each independently hydrogen or a substituted or unsubstituted C 1-5 is an alkyl group, X is a halogen element.

[0009] A second aspect of the present application provides a method for producing a benzoselenophene-based compound, comprising: (a) reacting a carboxylic acid represented by the following Chemical Formula 2 with an amine represented by the following Chemical Formula 3 to produce an intermediate product; and (b) reacting the intermediate product with an amine represented by the following Chemical Formula 4 to obtain a benzoselenophene-based compound represented by the following Chemical Formula 1: [ka] In the chemical formula 1, the chemical formula 2, the chemical formula 3, and the chemical formula 4, R 1 is a substituted or unsubstituted amino group or a substituted or unsubstituted linear or branched C 1-6 is an alkylamino group, R 2 and R 3 are each independently hydrogen, fluorine, chlorine, bromine, iodine, or substituted or unsubstituted C 1-5 is an alkyl group, R 4 and R 5 are each independently hydrogen or a substituted or unsubstituted C 1-5 is an alkyl group, R 6 is a substituted or unsubstituted C 1-5 is an alkyl group, X is a halogen element.

[0010] A third aspect of the present application provides a pharmaceutical composition for preventing or treating a proliferative disease, comprising a benzoselenophene compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof: [ka] In the above Chemical Formula 1, R 1 is a substituted or unsubstituted amino group or a substituted or unsubstituted linear or branched C 1-6 is an alkylamino group, R 2 and R 3 are each independently hydrogen, fluorine, chlorine, bromine, iodine, or substituted or unsubstituted C 1-5 is an alkyl group, R 4 and R 5 are each independently hydrogen or a substituted or unsubstituted C 1-5 is an alkyl group, X is a halogen element.

[0011] A fourth aspect of the present application provides an antibody-drug conjugate, or a pharmaceutically acceptable salt thereof, comprising an antibody, a linker, and a benzoselenophene compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof: [ka] In the above Chemical Formula 1, R 1 is a substituted or unsubstituted amino group, or a substituted or unsubstituted linear or branched alkylamino group, R 2 and R 3 are each independently hydrogen, fluorine, chlorine, bromine, iodine, or substituted or unsubstituted C 1-5 is an alkyl group, R 4 and R 5 are each independently hydrogen or a substituted or unsubstituted C 1-5 is an alkyl group, X is a halogen element.

[0012] A fifth aspect of the present application provides an anti-cancer composition comprising the antibody-drug conjugate according to the fourth aspect or a pharmaceutically acceptable salt thereof. [Effects of the Invention]

[0013] According to embodiments of the present application, novel benzoselenophene derivatives with significantly increased water solubility and activity can be prepared by introducing a novel water-soluble group, such as an amino group or an alkylamino group, and the benzoselenophene derivatives can be used as anticancer drugs. The novel water-soluble benzoselenophene derivatives of the present application can be used as antibody-drug conjugates and can function as prodrugs. Furthermore, the water-soluble benzoselenophene derivatives can be conjugated to targeting agents such as antibodies, proteins, ligands, nanoparticles, and aptamers, and can function as prodrugs.

[0014] The benzoselenophene compounds according to the present invention have IC activity against cancer cells. 50 It is a substance with very strong anti-cancer effects at the nM or pM level, and can be used in the development of new drugs using antibody-drug conjugates.

[0015] According to an embodiment of the present application, a DNA alkylating derivative containing a benzoselenophene-based compound having excellent water solubility and activity can be synthesized and used as an anticancer agent or its precursor. [Brief explanation of the drawings]

[0016] [Figure 1] 1 is a graph showing the results of in vitro cytotoxicity evaluation of the substances according to Example 1 and Comparative Example 1 of the present application. [Figure 2a] 1 shows the results of verifying the individual cytotoxicity of the substances according to Example 1 and Comparative Example 1 on NCI-N87 cells. [Figure 2b] 1 shows the results of verifying the individual cytotoxicity of the substances according to Example 1 and Comparative Example 1 on NCI-N87 cells. [Figure 3a]1 shows the results of verifying the individual cytotoxicity of the substances according to Example 1 and Comparative Example 1 on SK-OV-3 cells. [Figure 3b] 1 shows the results of verifying the individual cytotoxicity of the substances according to Example 1 and Comparative Example 1 on SK-OV-3 cells. DETAILED DESCRIPTION OF THE INVENTION

[0017] Hereinafter, with reference to the accompanying drawings, embodiments and examples of the present application will be described in detail so that those skilled in the art can easily carry out the present application. However, the present application may be embodied in various different forms and is not limited to the embodiments and examples described herein. In the drawings, parts that are not relevant to the description are omitted in order to clearly explain the present invention, and similar parts are designated by similar reference numerals throughout the specification.

[0018] Throughout the specification of this application, when a part is said to be "coupled" to another part, this includes not only "directly coupled" but also "electrically coupled" with another element in between.

[0019] Throughout this specification, when a member is said to be "on" another member, this includes not only when the member is in contact with the other member, but also when there is another member between the two members.

[0020] Throughout this specification, when a part is said to "comprise" a certain element, this means that it may further include other elements, but not to the exclusion of other elements, unless otherwise specified.

[0021] As used herein, terms of degree such as "about," "substantially," and the like are used to mean a numerical value or a value close to the numerical value when inherent manufacturing and material tolerances are given, and are used to prevent unscrupulous infringers from unfairly exploiting disclosures in which precise or absolute numerical values are recited to aid in the understanding of the present application.

[0022] As used throughout this specification, the terms "steps for" or "steps of" do not mean "steps for."

[0023] Throughout the specification of this application, the term "combination(s) of these" contained in a Markush expression means a mixture or combination of one or more selected from the group of elements set forth in the Markush expression, and means including one or more selected from the group of elements.

[0024] Throughout the specification of this application, the phrase "A and / or B" means "A or B, or A and B."

[0025] Throughout this specification, the term "alkyl" or "alkyl group" includes linear or branched alkyl groups having 1 to 12 carbon atoms, 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 5 carbon atoms, and all possible isomers thereof. For example, the alkyl or alkyl group may include methyl (Me), ethyl (Et), n-propyl (N-propyl), ... n Pr), isopropyl group ( i Pr), n-butyl group ( n Bu), iso-butyl group ( i Bu), tert-butyl group (tert-Bu, t Bu), sec-butyl group (sec-Bu, sec Bu), n-pentyl group ( n Pe), iso-pentyl group ( iso Pe), sec-pentyl group ( sec Pe), tert-pentyl group ( tPe), neo-pentyl group ( neo Pe), 3-pentyl, n-hexyl, iso-hexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and isomers thereof, but are not limited to these.

[0026] Hereinafter, specific examples of the present application will be described in detail, but the present application is not limited thereto.

[0027] A first aspect of the present application provides a benzoselenophene-based compound represented by the following formula 1: [ka] In the above Chemical Formula 1, R 1 is a substituted or unsubstituted amino group or a substituted or unsubstituted linear or branched C 1-6 is an alkylamino group, R 2 and R 3 are each independently hydrogen, fluorine, chlorine, bromine, iodine, or substituted or unsubstituted C 1-5 is an alkyl group, R 4 and R 5 are each independently hydrogen or a substituted or unsubstituted C 1-5 is an alkyl group, X is a halogen element.

[0028] In one embodiment of the present application, when the functional group is substituted, the substituent may be an acyl group, an amino group (including a simple amino group, a mono- and di-alkylamino group, a mono- and diarylamino group, and an alkylarylamino group), an acylamino group (including a carbamoyl group and a ureido group), an alkylcarbonyloxy group, an arylcarbonyloxy group, an alkoxycarbonyl group, an alkoxycarbonyl group, a carboxyl group, a carboxylate group, an aminocarbonyl group, a mono- and di-alkylaminocarbonyl group, a cyano group, an azide group, a halogen group, a hydroxy group, a nitro group, a trifluoromethyl group, a thiol group, an alkylthiol group, an aryl ... The alkyl group may include, but is not limited to, one or more selected from an arylthiol group, an alkylthiocarbonyl group, a thiocarboxylate group, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a lower alkoxy group, an aryloxy group, an aryloxycarbonyloxy group, a benzyloxy group, a benzyl group, a sulfinyl group, an alkylsulfinyl group, a sulfonyl group, a sulfate group, a sulfonate group, a sulfonamide group, a phosphate group, a phosphonate group, a phosphinate group, an oxo group, a guanidine group, an imino group, and a formyl group.

[0029] In one embodiment of the present application, R 1 is a dialkylamino group containing a tertiary nitrogen, and R 4 and R 5 may each independently be hydrogen, a methyl group, or an ethyl group, but are not limited thereto.

[0030] In one embodiment, X may be, but is not limited to, F, Cl, Br, or I. In another embodiment, X may be Cl.

[0031] In one embodiment of the present disclosure, the benzoselenophene-based compound of the present disclosure comprises a —CHR 2 CHR 1 R 3 The main skeleton is composed of two sp3 By including carbon, the flexibility of the molecule itself may be increased. 1 Preferably, R comprises a tertiary amine with a small substituent. For example, R 1 If is a tertiary nitrogen, pK a It acts as a weak base with a pH of about 6 and can exist in the form of a salt under physiological conditions, greatly increasing its water solubility.

[0032] In one embodiment of the present application, R 1 may include, but is not limited to, a dimethylamino group, an ethylmethylamino group, a diethylamino group, a methylpropylamino group, an ethylpropylamino group, or a dipropylamino group.

[0033] In one embodiment of the present application, R 1 may be a dimethylamine group, a methylethylamine group, or a diethylamine group.

[0034] In one embodiment of the present application, R 2 and R 3 may all be hydrogen.

[0035] In one embodiment of the present application, R 5 and R 6 may each independently be hydrogen, a methyl group, an ethyl group, or a propyl group.

[0036] In one embodiment, the benzoselenophene-based compound may include: [ka]

[0037] A second aspect of the present application provides a method for producing a benzoselenophene-based compound, comprising: (a) reacting a carboxylic acid represented by the following Chemical Formula 2 with an amine represented by the following Chemical Formula 3 to produce an intermediate product; and (b) reacting the intermediate product with an amine represented by the following Chemical Formula 4 to obtain a benzoselenophene-based compound represented by the following Chemical Formula 1: [ka] In the chemical formula 1, the chemical formula 2, the chemical formula 3, and the chemical formula 4, R 1 is a substituted or unsubstituted amino group or a substituted or unsubstituted linear or branched C 1-6 is an alkylamino group, R 2 and R 3 are each independently hydrogen, fluorine, chlorine, bromine, iodine, or substituted or unsubstituted C 1-5 is an alkyl group, R 4 and R 5 are each independently hydrogen or a substituted or unsubstituted C 1-5 is an alkyl group, R 6 is a substituted or unsubstituted C 1-5 is an alkyl group, X is a halogen element.

[0038] Detailed explanations of parts that overlap with the first aspect of the present application are omitted, but the contents explained in the first aspect of the present application may be applied in the same manner even if the explanation is omitted in the second aspect of the present application.

[0039] In one embodiment of the present application, when the functional group is substituted, the substituent may be an acyl group, an amino group (including a simple amino group, a mono- and di-alkylamino group, a mono- and diarylamino group, and an alkylarylamino group), an acylamino group (including a carbamoyl group and a ureido group), an alkylcarbonyloxy group, an arylcarbonyloxy group, an alkoxycarbonyl group, an alkoxycarbonyl group, a carboxyl group, a carboxylate group, an aminocarbonyl group, a mono- and di-alkylaminocarbonyl group, a cyano group, an azide group, a halogen group, a hydroxy group, a nitro group, a trifluoromethyl group, a thiol group, an alkylthiol group, an aryl ... The alkyl group may include, but is not limited to, one or more selected from an arylthiol group, an alkylthiocarbonyl group, a thiocarboxylate group, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a lower alkoxy group, an aryloxy group, an aryloxycarbonyloxy group, a benzyloxy group, a benzyl group, a sulfinyl group, an alkylsulfinyl group, a sulfonyl group, a sulfate group, a sulfonate group, a sulfonamide group, a phosphate group, a phosphonate group, a phosphinate group, an oxo group, a guanidine group, an imino group, and a formyl group.

[0040] In one embodiment of the present application, R 1 is a dialkylamino group containing a tertiary nitrogen, and R 4 and R 5 may each independently be hydrogen, a methyl group, or an ethyl group, but are not limited thereto.

[0041] In one embodiment, X may be, but is not limited to, F, Cl, Br, or I. In another embodiment, X may be Cl.

[0042] In one embodiment of the present disclosure, the benzoselenophene-based compound of the present disclosure comprises a —CHR 2 CHR 1 R 3 The main skeleton is composed of two sp3 By including carbon, the flexibility of the molecule itself may be increased. 1 Preferably, R comprises a tertiary amine with a small substituent. For example, R 1 If is a tertiary nitrogen, pK a It acts as a weak base with a pH of about 6 and can exist in the form of a salt under physiological conditions, greatly increasing its water solubility.

[0043] In one embodiment of the present application, R 1 may include, but is not limited to, a dimethylamino group, an ethylmethylamino group, a diethylamino group, a methylpropylamino group, an ethylpropylamino group, or a dipropylamino group.

[0044] In one embodiment of the present application, R 1 may be a dimethylamine group, a methylethylamine group, or a diethylamine group.

[0045] In one embodiment of the present application, R 2 and R 3 may all be hydrogen.

[0046] In one embodiment of the present application, R 5 and R 6 may each independently be hydrogen, a methyl group, an ethyl group, or a propyl group.

[0047] In one embodiment of the present application, the intermediate product produced in (a) can be converted to R 6 may be substituted with hydrogen and may be in the form of a carboxylic acid or a carboxylate salt, but is not limited thereto.

[0048] In one embodiment of the present application, the amine compound represented by Formula 4 may be obtained by subjecting the conventionally known seco-MCBI represented by the following formula to an acid treatment, but is not limited thereto: [ka]

[0049] In one embodiment, the benzoselenophene-based compound may include: [ka]

[0050] A third aspect of the present application provides a pharmaceutical composition for preventing or treating a proliferative disease, comprising a benzoselenophene compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof: [ka] In the above Chemical Formula 1, R 1 is a substituted or unsubstituted amino group or a substituted or unsubstituted linear or branched C 1-6 is an alkylamino group, R 2 and R 3 are each independently hydrogen, fluorine, chlorine, bromine, iodine, or substituted or unsubstituted C 1-5 is an alkyl group, R 4 and R 5 are each independently hydrogen or a substituted or unsubstituted C 1-5 is an alkyl group, X is a halogen element.

[0051] Detailed explanations of parts that overlap with the first and second aspects of the present application are omitted, but the contents explained for the first and second aspects of the present application may be similarly applied even if the explanation is omitted in the third aspect of the present application.

[0052] In an embodiment of the present application, the benzoselenophene compound or a pharmaceutically acceptable salt thereof may be, but is not limited to, a prodrug.

[0053] In one embodiment of the present application, the benzoselenophene compound or a pharmaceutically acceptable salt thereof may form an active form when administered in a solvent or into the body, but is not limited thereto.

[0054] In one embodiment of the present application, the proliferative disease may include, but is not limited to, one or more selected from neoplasms, tumors, cancers, leukemia, psoriasis, bone diseases, fibroproliferative disorders, and atherosclerosis.

[0055] In one embodiment of the present application, the cancer may include, but is not limited to, one or more selected from solid tumors, blood cancers, colorectal cancer, uterine cancer, uterine fibroids, meningioma, lung cancer, small cell lung cancer, gastrointestinal cancer, colon cancer, intestinal cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, and melanoma. The pharmaceutical composition according to one embodiment of the present application may be applicable to diseases other than carcinoma as the target of prevention or treatment.

[0056] In one embodiment of the present application, when the functional group is substituted, the substituent may be an acyl group, an amino group (including a simple amino group, a mono- and di-alkylamino group, a mono- and diarylamino group, and an alkylarylamino group), an acylamino group (including a carbamoyl group and a ureido group), an alkylcarbonyloxy group, an arylcarbonyloxy group, an alkoxycarbonyl group, an alkoxycarbonyl group, a carboxyl group, a carboxylate group, an aminocarbonyl group, a mono- and di-alkylaminocarbonyl group, a cyano group, an azide group, a halogen group, a hydroxy group, a nitro group, a trifluoromethyl group, a thiol group, an alkylthiol group, an aryl ... The alkyl group may include, but is not limited to, one or more selected from an arylthiol group, an alkylthiocarbonyl group, a thiocarboxylate group, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a lower alkoxy group, an aryloxy group, an aryloxycarbonyloxy group, a benzyloxy group, a benzyl group, a sulfinyl group, an alkylsulfinyl group, a sulfonyl group, a sulfate group, a sulfonate group, a sulfonamide group, a phosphate group, a phosphonate group, a phosphinate group, an oxo group, a guanidine group, an imino group, and a formyl group.

[0057] In one embodiment of the present application, R 1 is a dialkylamino group containing a tertiary nitrogen, and said R 4 and R 5 may each independently be hydrogen, a methyl group, or an ethyl group, but are not limited thereto.

[0058] In one embodiment, X may be, but is not limited to, F, Cl, Br, or I. In another embodiment, X may be Cl.

[0059] In one embodiment of the present disclosure, the benzoselenophene-based compound of the present disclosure comprises a —CHR 2 CHR 1 R 3The main skeleton is composed of two sp 3 By including carbon, the flexibility of the molecule itself may be increased. 1 Preferably, R comprises a tertiary amine with a small substituent. For example, R 1 If is a tertiary nitrogen, pK a It acts as a weak base with a pH of about 6 and can exist in the form of a salt under physiological conditions, greatly increasing its water solubility.

[0060] In one embodiment of the present application, R 1 may include, but is not limited to, a dimethylamino group, an ethylmethylamino group, a diethylamino group, a methylpropylamino group, an ethylpropylamino group, or a dipropylamino group.

[0061] In one embodiment of the present application, R 1 may be a dimethylamine group, a methylethylamine group, or a diethylamine group.

[0062] In one embodiment of the present application, R 2 and R 3 may all be hydrogen.

[0063] In one embodiment of the present application, R 5 and R 6 may each independently be hydrogen, a methyl group, an ethyl group, or a propyl group.

[0064] In one embodiment, the benzoselenophene-based compound may include: [ka]

[0065] A fourth aspect of the present application provides an antibody-drug conjugate, or a pharmaceutically acceptable salt thereof, comprising an antibody, a linker, and a benzoselenophene compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof: [ka] In the above Chemical Formula 1, R 1 is a substituted or unsubstituted amino group, or a substituted or unsubstituted linear or branched alkylamino group, R 2 and R 3 are each independently hydrogen, fluorine, chlorine, bromine, iodine, or substituted or unsubstituted C 1-5 is an alkyl group, R 4 and R 5 are each independently hydrogen or a substituted or unsubstituted C 1-5 is an alkyl group, X is a halogen element.

[0066] Detailed explanations of parts that overlap with the first to third aspects of the present application are omitted, but the contents explained in the first to third aspects of the present application may be similarly applied even if the explanation is omitted in the fourth aspect of the present application.

[0067] In one embodiment of the present application, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be, but is not limited to, a prodrug.

[0068] In one embodiment of the present application, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may form an active form in a solvent or when administered to the body, but is not limited thereto.

[0069] In one embodiment of the present application, the antibody may include, but is not limited to, an antibody capable of immunospecifically acting against a proliferative disease, a modified antibody, or an antigen-binding fragment thereof. Here, the term "antibody" encompasses both polyclonal and monoclonal antibodies, and is preferably a monoclonal antibody, or may be in the form of a complete whole antibody. The whole antibody has a structure comprising two full-length light chains and two full-length heavy chains, including a constant region, and each light chain is linked to a heavy chain by a disulfide bond. In one embodiment of the present application, the antibody includes, but is not limited to, a monoclonal antibody, a multispecific antibody, a human antibody, a humanized antibody, a chimeric antibody, a single-chain Fvs (scFv), a single-chain antibody, a Fab fragment, a F(ab') fragment, a disulfide-linked Fvs (sdFv), and an anti-idiotype (anti-Id) antibody, or an epitope-binding fragment thereof. The whole antibody of the anti-c-Met antibody according to an embodiment of the present application is a concept that includes IgA, IgD, IgE, IgM, and IgG forms, and IgG subtypes include IgG1, IgG2, IgG3, and IgG4. Furthermore, the term "modified antibody" herein includes a double antibody, which refers to a single-substance antibody having antibodies or antibody-binding fragments that recognize different antigens, and the corresponding antibody refers to a form including an antibody specific to a cancer-associated antigen or an immune checkpoint protein antigen, or an antibody that specifically binds to an immune effector cell-associated antigen, or an antigen-binding fragment thereof, and is not limited to a specific antibody structure. Furthermore, the term "antigen-binding fragment" herein refers to a fragment that retains the function of binding to an antigen, and is a concept that includes Fab, Fab', F(ab')2, scFv (scFv)2, scFv-Fc, Fv, etc.

[0070] In one embodiment of the present application, the proliferative disease may include, but is not limited to, one or more selected from neoplasms, tumors, cancers, leukemia, psoriasis, bone diseases, fibroproliferative disorders, and atherosclerosis.

[0071] In one embodiment of the present application, the proliferative disease may be cancer, which may include, but is not limited to, one or more selected from solid tumors, blood cancers, colorectal cancer, uterine cancer, uterine fibroids, meningioma, lung cancer, small cell lung cancer, gastrointestinal cancer, colon cancer, intestinal cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, and melanoma. The pharmaceutical composition according to one embodiment of the present application may be applicable to diseases other than carcinoma as the target of prevention or treatment.

[0072] In one embodiment of the present application, the antibody may be an antibody that binds to one or more tumor-associated antigens or cell surface receptors selected from the following, but is not limited to these. The antibody may also bind to various antigens known in the art, but is not limited to these: (1) BMPR1B (bone morphogenetic protein receptor-type 1B); (2) E16 (LAT1, SLC7A5); (3) STEAP1 (six transmembrane epithelial antigen of prostate); (4) 0772P (CA125, MUC16); (5) MPF (MPF, MSLN, SMR, megakaryocyte potentiating factor, mesothelin); (6) Napi3b [NAPI-3B, NPTIIb, SLC34A2, solute carrier family 34 (sodium phosphate), member 2, type II sodium-dependent phosphate transporter 3b]; (7) Sema 5b (FLJ10372, KIAA1445, Mm.42015, SEMA5B, SEMAG, Semaphorin 5b H log, sema domain, seven thrombospondin repeats (type 1 and type 1-like), transmembrane domain (TM) and short cytoplasmic domain, (semaphorin)5B; (8) PSCA hlg (2700050C12Rik, C530008O16Rik, RIKEN cDNA 2700050C12, RIKEN cDNA 2700050C12 gene); (9) ETBR (Endothelin type B receptor); (10) MSG783 (RNF24, hypothetical protein FLJ20315); (11) STEAP2 [HGNC_8639, IPCA-1, PCANAP1, STAMP1, STEAP2, STMP, prostate cancer associated gene 1, prostate cancer associated protein 1, six transmembrane epithelial antigen of prostate 2, six transmembrane prostate protein];(12) TrpM4 [BR22450, FLJ20041, TRPM4, TRPM4B, transient receptor potential cation channel, subfamily M, member 4]; (13) CRIPTO [CR, CR1, CRGF, CRIPTO, TDGF1, teratocarcinoma-derived growth factor]; (14) CD21 (CR2 (complement receptor 2) or C3DR [C3d / Epstein-Barr virus receptor] or Hs 73792); (15) CD79b (CD79B, CD79P, IGb (immunoglobulin-associated beta), B29); (16) FcRH2 (IFGP4, IRTA4, SPAP1A (phosphatase anchor protein 1a, SH-12 domain containing phosphatase anchor protein 1a, SPAP1B, SPAP1C); (17) HER2; (18) NCA; (19) MDP; (20) IL20Rα; (21) Brevican; (22) EphB2R; (23) ASLG659; (24) PSCA; (25) GEDA; (26) BAFF-R (B cell-activating factor receptor, BLyS receptor 3, BR3); (27) CD22 (B cell receptor CD22-B isoform); (28) CD79a (CD79A, CD79α, immunoglobulin-associated alpha); (29) CXCR5 (Burkitt's lymphoma receptor 1). 1); (30) HLA-DOB (Beta subunit of MHC class II molecule (Ia antigen));(31) P2X5 (Purinergic receptor P2X ligand-gated ion channel 5); (32) CD72 (B-cell differentiation antigen CD72, Lyb-2); (33) LY64 (Lymphocyte antigen 64 (RP105), a type I membrane protein of the LRR family); (34) FcRH1 (Fc receptor-like protein 1); (35) IRTA2 (Immunoglobulin superfamily receptor translocation associated 2); and (36) TENB2 (putative transmembrane proteoglycan). proteoglycan); (37) Other HGF, EGFR, EGFRvIII, Her2, Her3, IGF-1R, VEGF, VEGFR-1, VEGFR-2, VEGFR-3, Ang2, Dll4, NRP1, FGFR, FGFR2, FGFR3, c-Kit, MUC1, MUC16, CD20, CD22, CD27, CD30, CD33, CD40, CD52, CD70, CD79, DDL3, Folate R1, and Nectin 4, Trop2, gpNMB, Axl, BCMA, PD-1, PD-L1, PD-L2, CTLA4, BTLA, 4-1BB, ICOS, GITR, OX40, VISTA, TIM-3, LAG-3, KIR, B7. 1, B7.2, B7-H2, B7-H3, B7-H4, B7-H6, B7-H7, EphA2, EphA4, EphB2, E-selectin, EpCam, CEA, PSMA, PSA, c-MET and (38) TCR / CD3, CD16 (Fcγ RIIIa) CD44, CD56, CD69, CD64 (Fcγ RI), CD89, CD11b / CD18 (CR3) as immune competent cell-related antigens. ;

[0073] In one embodiment of the present application, the antibody may be used without limitation as long as it is an antibody that can be used for the prevention and treatment of proliferative diseases, particularly for anti-cancer treatment, and examples thereof include alemtuzumab, apolizumab, aselizumab, atlizumab, bapineuzumab, bevacizumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, and certolizumab pegol. pegol, cetuximab, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, ertumaxomab, felvizumab, fontolizumab, gemtuzumab, gemtuzumab ozogamicin, ibritumomab tiuxetan, inotuzumab ozogamicinozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, panitumumab, and pascolizumab. , pecfusituzumab, pectuzumab, pertuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resyvizumab, rituximab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan The therapeutic agent may include, but is not limited to, those selected from tetraxetan, tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, tositumomab, trastuzumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab, urtoxazumab, and visilizumab.

[0074] In one embodiment of the present application, the linker is a linker commonly used in the art. Linkers useful for antibody-drug conjugates may be used without limitation and may include, but are not limited to, those selected from the following:

[0075] Bis-maleimidopolyethyleneglycol (BMPEO), N-(β-maleimidopropyloxy) succinimide ester (BMPS), ε-maleimidocaproic acid N-hydroxysuccinimide ester (EMCS), γ-maleimidobutyric acid N-succinimidyl ester (GMBS), HBVS, LC-N-succinimidyl-4-(N-maleimidomethyl)cyclohexanecarboxylate (SMCC), m-maleimidobenzoyl-N-hydroxysuccinimide ester (m-maleimidobenzoyl-N-hydroxysuccinimide ester (MBS), 4-(4-N-maleimidophenyl)-butyric acid hydrazide (MPBH), N-succinimidyl 3-(bromoacetamido)propionate (SBAP), N-succinimidyl iodoacetate (SIA), N-succinimidyl-4-(iodoacetyl)-aminobenzoate (SIAB), N-succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (N-succinimidyl 4-(maleimidomethyl)cyclohexanecarboxylate, SMCC], N-succinimidyl-4-(p-maleimidophenyl)butyrate [N-succinimidyl4-(p-maleimidophenyl)butyrate, SMPB], succinimidyl-6-(maleimidopropionamido)hexanoate, SMPH], N-(e-maleimidocaproyloxy)sulfosuccinimide ester, sulfo-EMCS], N-(y-maleimidobutryloxy)sulfosuccinimide ester, sulfo-GMBS], N-(κ-maleimidoundecanoyloxy)sulfosuccinimide ester, sulfo-GMBS] ester, sulfo-KMUS], m-maleimidobenzoyl-N-hydroxysulfosuccinimide ester (sulfo-MBS), sulfosuccinimidyl(4-iodo-acetyl)aminobenzoate (sulfo-SIAB), sulfosuccinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (sulfo-SMCC), sulfosuccinimidyl 4-(p-maleimidophenyl)butyrate (sulfosuccinimidyl 4-(p-maleimidophenyl)butyrate, sulfo-SMPB, succinimidyl-(4-vinylsulfone)benzoate, SVSB, and bis-maleimide reagents.reagents): dithiobis-maleimidoethane (DTME), 1,4-bis-maleimidobutane (BMB), 1,4-bismaleimidyl-2,3-dihydroxybutane (BMDB), bis-maleimidohexane (BMH), bis-maleimidoethane (BMOE), 1,8-bis-maleimidodiethylene glycol [1,8-bis-maleimidodiethyleneglycol, BM(PEO)2], and 1,11-bis-maleimidotriethyleneglycol [1,11-bis-maleimidotriethyleneglycol, BM(PEO)3]; and [ka]

[0076] In the linker, the dashed line indicates a covalent bond to the antibody or the benzoselenophene compound, and n is a number from about 1 to about 1,000.

[0077] In one embodiment, n may be, but is not limited to, about 1 to about 1,000, about 1 to about 900, about 1 to about 800, about 1 to about 700, about 1 to about 600, about 1 to about 500, about 1 to about 400, about 1 to about 300, about 1 to about 200, about 1 to about 100, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 1 to about 5, or about 1 to about 3. In one embodiment, n may be about 1 to about 5 or about 1 to about 3.

[0078] In one embodiment of the present application, the n number of the polyethylene glycol (PEG) moiety in the linker may be adjusted to have a molecular weight of, for example, about 1,000 or about 2,000, or a 4-arm or 8-arm branched PEG may be formed to synthesize a DNA alkylation derivative containing a benzoselenophene-based compound with increased water solubility, and the DNA alkylation derivative may be used as an anticancer agent or a precursor thereof, but is not limited thereto.

[0079] In one embodiment of the present application, the antibody-drug conjugate of the present application is an IC 50 The substance may be, but is not limited to, a substance having a very strong anti-cancer effect in the nM or pM range.

[0080] In an embodiment of the present application, the linker and the benzoselenophene-based compound may be connected by, but are not limited to, a peptide bond.

[0081] In one embodiment of the present application, when the functional group is substituted, the substituent may be an acyl group, an amino group (including a simple amino group, a mono- and di-alkylamino group, a mono- and diarylamino group, and an alkylarylamino group), an acylamino group (including a carbamoyl group and a ureido group), an alkylcarbonyloxy group, an arylcarbonyloxy group, an alkoxycarbonyl group, an alkoxycarbonyl group, a carboxyl group, a carboxylate group, an aminocarbonyl group, a mono- and di-alkylaminocarbonyl group, a cyano group, an azide group, a halogen group, a hydroxy group, a nitro group, a trifluoromethyl group, a thiol group, an alkylthiol group, an aryl ... The alkyl group may include, but is not limited to, one or more selected from an arylthiol group, an alkylthiocarbonyl group, a thiocarboxylate group, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a lower alkoxy group, an aryloxy group, an aryloxycarbonyloxy group, a benzyloxy group, a benzyl group, a sulfinyl group, an alkylsulfinyl group, a sulfonyl group, a sulfate group, a sulfonate group, a sulfonamide group, a phosphate group, a phosphonate group, a phosphinate group, an oxo group, a guanidine group, an imino group, and a formyl group.

[0082] In one embodiment of the present application, R 1 is a dialkylamino group containing a tertiary nitrogen, and R 4 and R 5 may each independently be hydrogen, a methyl group, or an ethyl group, but are not limited thereto.

[0083] In one embodiment, X may be, but is not limited to, F, Cl, Br, or I. In another embodiment, X may be Cl.

[0084] In one embodiment of the present disclosure, the benzoselenophene-based compound of the present disclosure comprises a —CHR 2 CHR 1 R 3 The main skeleton is composed of two sp3 By including carbon, the flexibility of the molecule itself may be increased. 1 Preferably, R comprises a tertiary amine with a small substituent. For example, R 1 If is a tertiary nitrogen, pK a It acts as a weak base with a pH of about 6 and can exist in the form of a salt under physiological conditions, greatly increasing its water solubility.

[0085] In one embodiment of the present application, R 1 may include, but is not limited to, a dimethylamino group, an ethylmethylamino group, a diethylamino group, a methylpropylamino group, an ethylpropylamino group, or a dipropylamino group.

[0086] In one embodiment of the present application, R 1 may be a dimethylamine group, a methylethylamine group, or a diethylamine group.

[0087] In one embodiment of the present application, R 2 and R 3 may all be hydrogen.

[0088] In one embodiment of the present application, R 5 and R 6 may each independently be hydrogen, a methyl group, an ethyl group, or a propyl group.

[0089] In one embodiment, the benzoselenophene-based compound may include: [ka]

[0090] In one embodiment of the present application, the bond between the benzoselenophene compound and the linker of the present application may be prepared by, for example, but not limited to, the following method: [ka]

[0091] In one embodiment of the present application, the drug-to-antibody ratio (DAR) in the antibody-drug conjugate may be, but is not limited to, about 1 to about 8. In one embodiment of the present application, the drug-to-antibody ratio (DAR) in the antibody-drug conjugate may be, but is not limited to, about 1 to about 8, about 1 to about 6, about 1 to about 5, about 2 to about 8, about 2 to about 6, about 2 to about 5, about 3 to about 8, about 3 to about 6, or about 3 to about 5. Furthermore, in one embodiment of the present application, the drug-to-antibody ratio (DAR) in the antibody-drug conjugate may be about 2 to about 5.

[0092] A fifth aspect of the present application provides an anti-cancer composition comprising the antibody-drug conjugate according to the fourth aspect or a pharmaceutically acceptable salt thereof.

[0093] Detailed descriptions of parts that overlap with the first to fourth aspects of the present application are omitted, but the contents described for the first to fourth aspects of the present application may be similarly applied even if the description is omitted in the fifth aspect of the present application.

[0094] In one embodiment of the present application, the anti-cancer composition may have anti-cancer activity against one or more diseases selected from, but not limited to, solid tumors, blood cancers, colorectal cancer, uterine cancer, uterine fibroids, meningioma, lung cancer, small cell lung cancer, gastrointestinal cancer, colon cancer, intestinal cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, and melanoma. The pharmaceutical composition according to one embodiment of the present application may be applicable to diseases other than carcinoma as the target for prevention or treatment.

[0095] The present application will be described in more detail below using examples. However, the following examples are merely illustrative examples to aid in understanding the present application, and the contents of the present application are not limited to the following examples.

[0096] [Example] 1. Example 1 (Preparation of Compound 2, DS-26) (1) Synthesis of intermediate product: Production of 5-(3-(dimethylamino)propanamido)benzo[b]selenophene-2-carboxylic acid (compound 6) [ka] 3-(Dimethylamino)propanoic acid (3 equivalents), EDC (3 equivalents), and DMAP (2 equivalents) were dissolved in DMF and stirred for 15 minutes. Then, (Ethyl)(5-Amino-benzo[b]selenophene-2-carboxylate) (Compound 5, 1 eq) was added and the mixture was allowed to react for 24 hours. After the reaction was completed, the methylene chloride (MC) layer was separated using a separatory funnel with MC / water, dried over MgSO4, and filtered. The filtered solution was then subjected to a rotary evaporator to remove the solvent and then column-eluted. Yield: 71%.

[0097] 1 H NMR (500.1MHz, CDCl3) ∂1.39(t, 3H, J=7.2), 2.42(s, 6H), 2.56(t, 2H, J=5.8), 2.71(t, 2H, J= 5.7), 4.37(q, 2H, J=7.1), 7.39(d, 1H, J=8.6), 7.77(d, 1H, J=8.6), 8.23(s, 1H), 8.25(s, 1H); 13 C NMR(125.7MHz, CDCl3)∂13.3, 32.3, 43.4, 54.1, 60.6, 116.8, 119.1, 124.9, 133.3, 135.4, 136.4, 137.6, 140.8, 162.9, 169.7;HRMS(ESI);m / z calcd for C 16 H 20 N2O3Se[M+]:368.06;found:369.0718 [M+H]+

[0098] (Ethyl)(5-(3-(dimethylamino)propanamido)benzo[b]selenophene-2-carboxylate) (1 equivalent) obtained in the above process was dissolved in methanol, and then 2 mL of 3N NaOH was added and the reaction was allowed to proceed for 24 hours. After the reaction was completed, 20% HCl was added to adjust the pH to acidic, and the solvent was removed using a rotary evaporator and the resulting mixture was subjected to column chromatography. Yield: 88%.

[0099] 1 H NMR (500.1MHz, MeOD-d4) ∂2.88-2.91(m, 8H), 3.42(t, 2H, J=6.4), 7.38(d, 1H, J=8.6), 7.72(d, 1H, J=8.6), 7.85(s, 1H), 8.05(s, 1H); 13 C NMR(125.7MHz, MeOD-d4)∂30.9, 42.1, 52.5, 117.1, 119.6, 126.4, 133.4, 136.6, 137.7, 139.8, 141.6, 168.0, 171.4;HRMS(ESI);m / z calcd for C 14 H 16 N2O3Se[M+]:340.03;found:341.0406[M+H]+

[0100] (2) Reaction of the intermediate product with seco-MCBI to produce the final product The seco-MCBI (compound 1) used in the synthesis was synthesized using a known method. The process of coupling benzoselenophene carboxylic acid with the intermediate obtained by acid treatment to synthesize compound 2 was carried out as follows: [ka]

[0101] A round-bottom flask containing seco-MCBI (compound 1, 30 mg, 0.09 mmol) was charged with 4 mL of saturated HCl solution in ethyl acetate at −78°C to prepare a reaction mixture. The reaction mixture was stirred at −78°C for 30 minutes and then at room temperature for 1 hour. After salt formation was confirmed by TLC, the ethyl acetate was evaporated under a nitrogen stream and then completely dried under high vacuum for 1 hour. The resulting residue was dissolved in anhydrous DMF (0.2 mL) and added to a mixture of the carboxylic acid (compound 6) (1.1 equivalents) and EDC (52 mg, 0.27 mmol) in anhydrous DMF (0.5 mL) at 0°C. The mixture was stirred at 0°C for 3 hours and then at room temperature for 5 hours. After the reaction was complete, the resulting mixture was diluted with water and extracted with ethyl acetate (3 × 15 mL). The resulting organic layer was washed with brine, dried over MgSO4, filtered and concentrated to produce a crude product which was purified by column chromatography to give the desired product.

[0102] (3) Analysis results of compound 2: (S)-N-(2-(1-(chloromethyl)-5-hydroxy-8-methoxy-2,3-dihydro-1H-benzo[e]indole-3-carbonyl)benzo[b]selenophen-5-yl)-3-(dimethylamino)propanamide (compound 2, DS-26) [ka] 1H NMR (500.1MHz, Acetone-d6) δ10.37(s, 1H), 8.46(s, 1H), 8.21(d, J=6.9Hz, 1H), 8.15(d, J=9.2 Hz, 1H), 7.98(d, J=8.6Hz, 1H), 7.75(brs, 1H), 7.52(d, J=7.1Hz, 1H), 7.21(s, 1H), 7.03(d, J=9 .2Hz, 1H), 4.75(t, J=9.9Hz, 1H), 4.66(d, J=11.0Hz, 1H), 4.21(m, 1H), 4.06(dd, J=11.0, 3.0Hz HRMS Calcd for(C 28 H 28 ClN3O4Se)586.1006[M+H]+,Observed 586.1006.

[0103] 2. Anticancer activity analysis of compound 2 Cytotoxicity experiments were carried out on Compound 2 (DS-26) according to Example 1 and Comparative Example 1 (DS-28) having the same backbone.

[0104] Example 1 [Compound 2](DS-26) [ka]

[0105] <Comparative example 1> (DS-28) [ka]

[0106] (1)Cell cytotoxicity assay To evaluate the cytotoxicity of a substance, the inventors treated cancer cell lines with the drug and then measured cell growth. NCI-N87 gastric cancer cells were cultured in 96-well plates at 3 × 10 4After 4 hours, the cells were treated with DS-26 (Example 1) and DS-28 (Comparative Example 1) at concentrations of 833.8 nM, 277.8 nM, 92.6 nM, 30.9 nM, and 10.3 nM in triplicate. After 72 hours of drug treatment, cell growth was measured using the Ez-Cytox assay kit.

[0107] As a result, as shown in FIG. 1, it was found that DS-26 (Example 1) had strong cytotoxicity, and it was confirmed that it had relatively strong cytotoxicity compared to other drugs.

[0108] (2) High-throughput screening (HTS) The inventors further tested the cytotoxicity of DS-26 (Example 1) and DS-28 (Comparative Example 1) using an HTS system capable of simultaneously testing various drugs and substances. Gastric cancer cells NCI-N87 and ovarian cancer cells SK-OV-3 were cultured in a 384-well plate, treated with drugs at different concentrations, and then cultured for 72 hours. The cell growth was then measured using an ATPlite assay. The measured data were analyzed using GraphPad Prism 5.0 software to calculate IC 50 The AUC (area under the curve) was converted to analyze the potency of each drug.

[0109] The experimental results, as can be seen from Table 1 below, Figures 2a, 2b, 3a, and 3b, show that the DS-26 50 The solubility of DS-26 is about 40 pM to about 50 pM, which means that it exhibits strong cytotoxicity. In addition, DS-26 has stable solubility and stability due to its chemical structure, making it valuable for drug development.

[0110] [Table 1]

[0111] The above description of the present application is for illustrative purposes only, and those skilled in the art will understand that the present application may be easily modified into other specific forms without changing the technical concept or essential features of the present application. Therefore, it should be understood that the above-described embodiments are illustrative in all respects and not limiting. For example, each component described as a single component may be implemented in a distributed form, and similarly, each component described as a distributed component may be implemented in a combined form.

[0112] The scope of the present application is indicated by the claims that follow rather than by the above detailed description, and all modifications or variations that fall within the meaning and scope of the claims and their equivalents should be interpreted as being included within the scope of the present application.

Claims

1. A benzoselenophene-based compound represented by the following chemical formula 1: 【Chemical 1】 In the above Chemical Formula 1, R １ is a dialkylamino group, R ２ and R ３ are each independently hydrogen, fluorine, chlorine, bromine, iodine, or substituted or unsubstituted C １－５ is an alkyl group, R ４ and R ５ are each independently hydrogen or substituted or unsubstituted C １－５ is an alkyl group, X is a halogen element.

2. R ４ and R ５ The benzoselenophene compound according to claim 1 , wherein each of is independently hydrogen, a methyl group, or an ethyl group.

3. R １ 2. The benzoselenophene compound according to claim 1, wherein the dialkylamino group comprises a dimethylamino group, an ethylmethylamino group, a diethylamino group, a methylpropylamino group, an ethylpropylamino group, or a dipropylamino group.

4. The benzoselenophene compound according to claim 1 is Compound 2: 【Chemistry 2】

5. The present invention includes a benzoselenophene compound represented by the following formula 1 or a pharmaceutically acceptable salt thereof: Pharmaceutical compositions for the prevention or treatment of proliferative disorders: 【Chemistry 3】 In the above Chemical Formula 1, R １ is a dialkylamino group, R ２ and R ３ are each independently hydrogen, fluorine, chlorine, bromine, iodine, or substituted or unsubstituted C １－５ is an alkyl group, R ４ and R ５ are each independently hydrogen or substituted or unsubstituted C １－５ is an alkyl group, X is a halogen element.

6. The pharmaceutical composition according to claim 5, wherein the benzoselenophene compound or a pharmaceutically acceptable salt thereof is used as a prodrug.

7. 6. The pharmaceutical composition of claim 5, wherein the proliferative disease comprises one or more selected from neoplasms, tumors, cancer, leukemia, psoriasis, bone diseases, fibroproliferative disorders, and atherosclerosis.

8. 8. The pharmaceutical composition of claim 7, wherein the cancer comprises one or more selected from solid tumors, blood cancers, colorectal cancer, uterine cancer, uterine fibroids, meningioma, lung cancer, small cell lung cancer, gastrointestinal cancer, colon cancer, intestinal cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, and melanoma.

9. R ４ and R ５ The pharmaceutical composition of claim 5 , wherein each independently is hydrogen, a methyl group, or an ethyl group.

10. R １ The pharmaceutical composition of claim 5 , wherein the dialkylamino group comprises a dimethylamino group, an ethylmethylamino group, a diethylamino group, a methylpropylamino group, an ethylpropylamino group, or a dipropylamino group.

11. An antibody, A benzoselenophene compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof; A linker for connecting the antibody and the benzoselenophene compound or a pharmaceutically acceptable salt thereof, R ５ a linker attached to the oxygen atom of the O group; or a pharmaceutically acceptable salt thereof, comprising: 【Chemistry 4】 In the above Chemical Formula 1, R １ is a dialkylamino group, R ２ and R ３ are each independently hydrogen, fluorine, chlorine, bromine, iodine, or substituted or unsubstituted C １－５ is an alkyl group, R ４ and R ５ are each independently hydrogen or substituted or unsubstituted C １－５ is an alkyl group, X is a halogen element.

12. The antibody-drug conjugate or pharmaceutically acceptable salt thereof according to claim 11, wherein the benzoselenophene compound or pharmaceutically acceptable salt thereof is used as a prodrug in the antibody-drug conjugate or pharmaceutically acceptable salt thereof.

13. The antibody-drug conjugate or a pharmaceutically acceptable salt thereof according to claim 11, wherein the antibody comprises an antibody, a modified antibody, or an antigen-binding fragment thereof that can act immunospecifically against a proliferative disease.

14. The antibody-drug conjugate or a pharmaceutically acceptable salt thereof according to claim 13, wherein the proliferative disease comprises one or more selected from the group consisting of neoplasms, tumors, cancers, leukemia, psoriasis, bone diseases, fibroproliferative disorders, and atherosclerosis.

15. The antibody-drug conjugate or a pharmaceutically acceptable salt thereof according to claim 14, wherein the cancer comprises one or more selected from solid tumors, blood cancers, colorectal cancer, uterine cancer, uterine fibroids, meningioma, lung cancer, small cell lung cancer, gastrointestinal cancer, colon cancer, intestinal cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, and melanoma.

16. The antibody may be alemtuzumab, apolizumab, aselizumab, atlizumab, bapineuzumab, bevacizumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, or the like. pegol), cetuximab, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, ertumaxomab, felvizumab, fontolizumab, gemtuzumab, gemtuzumab ozogamicin ozogamicin, ibritumomab tiuxetan, inotuzumab ozogamicinozogamicin), ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motavizumab, natalizumab b), nimotuzumab, nolovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, panitumumab, pascolizumab , pecfusituzumab, pectuzumab, pertuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab ), resivizumab, rituximab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan tetraxetan, tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, tositumomab, trastuzumab, tucotuzumab The antibody-drug conjugate or a pharmaceutically acceptable salt thereof according to claim 11, comprising an antibody selected from the group consisting of celmoleukin, tucusituzumab, umavizumab, urtoxazumab, and visilizumab.

17. The antibody-drug conjugate or a pharmaceutically acceptable salt thereof according to claim 11, wherein the linker comprises one selected from the following: Bis-maleimidopolyethyleneglycol (BMPEO), N-(β-maleimidopropyloxy)succinimide ester (BMPS), ε-maleimidocaproic acid N-hydroxysuccinimide ester (EMCS), γ-maleimidobutyric acid N-succinimidyl ester (γ-maleimidobutylic acid N-succinimidyl ester, GMBS), HBVS, LC-N-succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate [long chain N-succinimidyl 4-(maleimidomethyl)cyclohexanecarboxylate, SMCC], m-maleimidobenzoyl-N-hydroxysuccinimide ester (m-maleimidobenzoyl-N-hydroxysuccinimide ester, MBS), 4-(4-N-maleimidophenyl)-butyric acid hydrazide [4-(4-N-maleimidophenyl)-butyric acid hydrazide, MPBH], N-succinimidyl 3-(bromoacetamido)propionate [N-succinimidyl 3-(bromoacetamido)propionate, SBAP], N-succinimidyl iodoacetate (N-succinimidyl iodoacetate, SIA), N-succinimidyl-4-(iodoacetyl)-aminobenzoate [N-succinimidyl-4-(iodoacetyl)-aminobenzoate, SIAB], N-succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate [N-succinimidyl 4-(maleimidomethyl)cyclohexanecarboxylate, SMCC], N-succinimidyl-4-(p-maleimidophenyl)butyrate [N-succinimidyl4-(p-maleimidophenyl)butyrate, SMPB], succinimidyl-6-(maleimidopropionamido)hexanoate, SMPH], N-(e-maleimidocaproyloxy)sulfosuccinimide ester, sulfo-EMCS], N-(y-maleimidobutryloxy)sulfosuccinimide ester, sulfo-EMCS], ester, sulfo-GMBS], N-(κ-maleimidoundecanoyloxy)sulfosuccinimide ester [N-(κ-maleimidoundecanoyloxy)sulfosuccinimide ester, sulfo-KMUS], m-maleimidobenzoyl-N-hydroxysulfosuccinimide ester (m-maleimidobenzoyl-N-hydroxysulfosuccinimide ester, sulfo-MBS), sulfosuccinimidyl (4-iodo-acetyl)aminobenzoate [sulfosuccinimidyl(4-iodo-acetyl)aminobenzoate, sulfo-SIAB], sulfosuccinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate [sulfosuccinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate, sulfo-SMCC], sulfosuccinimidyl 4-(p-maleimidophenyl)butyrate [sulfosuccinimidyl 4-(p-maleimidophenyl)butyrate (sulfo-SMPB), succinimidyl-(4-vinylsulfone)benzoate (SVSB), and bis-maleimide reagentsReagents: dithiobis-maleimidoethane (DTME), 1,4-bis-maleimidobutane (BMB), 1,4-bismaleimidyl-2,3-dihydroxybutane (BMDB), bis-maleimidohexane (bis-maleimidohexane), bis-maleimidohexane (BMH), bis-maleimidoethane (BMOE), 1,8-bis-maleimidodiethylene glycol [1,8-bis-maleimidodiethyleneglycol, BM(PEO)2], and 1,11-bis-maleimidotriethyleneglycol [1,11-bis-maleimidotriethyleneglycol, BM(PEO)3]; and 【Chemistry 5】 In the linker, The dashed line indicates a covalent bond to the antibody or the benzoselenophene compound; The n is a number from 1 to 1,000.

18. R ４ and R ５ and each independently represent a hydrogen atom, a methyl group, or an ethyl group, or a pharmaceutically acceptable salt thereof.

19. R １ The antibody-drug conjugate or a pharmaceutically acceptable salt thereof according to claim 11, wherein the dialkylamino group comprises a dimethylamino group, an ethylmethylamino group, a diethylamino group, a methylpropylamino group, an ethylpropylamino group, or a dipropylamino group.

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