Composition for preventing or treating malignant neoplasm

Abstract

The present invention relates to a pharmaceutical composition useful for preventing or treating malignant tumors and, to a composition for preventing or treating malignant neoplasm, comprising, as an active ingredient, at least one selected from the group consisting of a compound represented by chemical formula (1), a pharmaceutically acceptable salt, a hydrate, a solvate, and a prodrug of the compound, and a combination thereof.

Description

Composition for the prevention or treatment of malignant tumors

[0001] The present invention relates to a pharmaceutical composition useful for the prevention or treatment of malignant tumors. Specifically, it relates to a novel compound or a pharmaceutical composition containing the same that inhibits the growth and survival of cancer cells and simultaneously activates immune and inflammatory responses to exhibit an anticancer effect. Furthermore, it relates to a pharmaceutical composition for the prevention, inhibition, or treatment of malignant tumors containing the said compound and its use.

[0002]

[0003] Malignant tumors arise from the abnormal proliferation of cells and the evasion of apoptosis, and are known to progress due to various biological factors such as genetic factors, exposure to carcinogens, chronic inflammation, and immune evasion.

[0004] Currently, clinically used anticancer drugs are primarily classified into DNA synthesis inhibitors, microtubule inhibitors, tyrosine kinase inhibitors, and immune checkpoint inhibitors. While these drugs exhibit short-term tumor suppression effects, side effects such as damage to normal cells due to non-specific toxicity, the development of drug resistance, and cardiotoxicity and hepatotoxicity are frequently reported. In particular, although targeted therapies have a selective inhibitory effect on specific mutated genes, long-term administration leads to the activation of compensatory signaling pathways and the induction of acquired mutations in tumor cells, resulting in a problem of low sustainability of therapeutic effects.

[0005] Meanwhile, immunotherapy is attracting attention as a new approach to eliminate tumors by activating immune cells; however, it has limitations in applying to all patient groups due to immune-related adverse events or responsiveness limited to specific cancer types. Furthermore, chemotherapy and radiotherapy present problems such as difficulty in long-term treatment due to severe side effects and low selectivity, as well as the inability to completely suppress the recurrence and metastasis of cancer cells.

[0006] Therefore, there is an urgent need to develop anticancer compositions with a new mechanism of action that can overcome the problems of resistance and toxicity of existing anticancer drugs and selectively inhibit the survival mechanisms of cancer cells while minimizing toxicity to normal cells.

[0007]

[0008] One embodiment of the present invention aims to provide a composition for the prevention or treatment of malignant tumors with a novel mechanism of action capable of selectively inhibiting the survival mechanism of cancer cells, while overcoming the limitations of non-specific toxicity, drug resistance, and treatment persistence of existing anticancer drugs.

[0009]

[0010] In one embodiment of the present invention, a composition for the prevention or treatment of malignant neoplasm is provided, comprising one or more active ingredients selected from the group consisting of a compound represented by the following chemical formula (1), a pharmaceutically acceptable salt, hydrate, sorbate, prodrug, and combinations thereof.

[0011]

[0012] In the above chemical formula (1), X1, X2, and X3 are identical or different from each other and are each independently N or C(R2); X4 is selected from the group consisting of direct bond, N(R3), C(R4)(R5), oxygen (O), and sulfur (S); and R1 to R5 are identical or different from each other and are each independently hydrogen, cyano group, nitro group, halogen group, amino group, hydroxyl group, substituted or unsubstituted straight-chain or branched alkyl group having 1 to 30 carbon atoms, substituted or unsubstituted straight-chain or branched alkenyl group having 2 to 30 carbon atoms, substituted or unsubstituted straight-chain or branched alkynyl group having 2 to 24 carbon atoms, substituted or unsubstituted cycloalkyl group having 3 to 30 carbon atoms, substituted or unsubstituted cycloalkenyl group having 3 to 30 carbon atoms, substituted or unsubstituted carbon atoms One is selected from the group consisting of a cycloheteroalkyl group of 30, a substituted or unsubstituted alkylthio group of 1 to 4 carbon atoms, a substituted or unsubstituted haloalkyl group of 1 to 30 carbon atoms, a substituted or unsubstituted alkoxy group of 1 to 10 carbon atoms, a substituted or unsubstituted arylalkyl group of 7 to 30 carbon atoms, a substituted or unsubstituted aryl group of 5 to 30 carbon atoms, a substituted or unsubstituted heteroaryl group of 5 to 30 carbon atoms, and a substituted or unsubstituted alkylaryl group of 7 to 30 carbon atoms, wherein n is an integer from 0 to 9, and if n is 2 or more, a plurality of R1s are identical or different from each other, and ring A is a substituted or unsubstituted monocyclic aromatic ring of 5 to 30 carbon atoms, a substituted or unsubstituted polycyclic aromatic ring of 5 to 30 carbon atoms, or a substituted or unsubstituted monocyclic ring of 5 to 30 carbon atoms It is one selected from the group consisting of a heteroaromatic ring and a polycyclic heteroaromatic ring having 5 to 30 carbon atoms that is substituted or unsubstituted.

[0013] In one embodiment, the compound of the above formula (1) may include the compound of the following formula (2).

[0014]

[0015] In the above chemical formula (2), the details regarding R1, n and ring A are the same as those described above in the above chemical formula (1).

[0016] In one embodiment, the composition for preventing or treating malignant tumors may comprise a compound having a structure selected from the group consisting of the following chemical formulas (4) to (14) in which ring A is formed; or a combination of two or more of the said compounds.

[0017]

[0018] In one embodiment, the composition for preventing or treating malignant tumors may comprise one selected from the group consisting of pharmaceutically acceptable carriers, excipients, pH adjusters, stabilizers, preservatives, sweeteners, flavoring agents, and combinations thereof.

[0019] In one embodiment, the malignant tumor may be hematologic cancer.

[0020] In one embodiment, the hematologic cancer may be at least one of acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), and lymphoma.

[0021] In one embodiment, the malignant tumor may be cervical cancer.

[0022]

[0023] The composition for preventing or treating malignant tumors according to one embodiment may exhibit an inhibitory effect on cell proliferation in various cancer cell lines, such as blood cancer (AML, CML, ALL, etc.) and cervical cancer, by including a compound of a specific chemical structure. In particular, it can significantly reduce the survival rate of cancer cells even at lower concentrations compared to conventional anticancer drugs such as imatinib or vincristine.

[0024] In addition, the above composition for the prevention or treatment of malignant tumors can achieve selective activity against cancer cells, a reduction in cardiotoxicity, and excellent in vivo antitumor efficacy.

[0025] In addition, the above composition for the prevention or treatment of malignant tumors can express a complex anticancer mechanism by promoting apoptosis through the induction of intracellular stress, while simultaneously activating immune and inflammatory pathways.

[0026] In addition, the above-mentioned composition for the prevention or treatment of malignant tumors is highly likely to exhibit a synergistic effect when combined with existing chemotherapy agents, targeted anticancer agents, or immunotherapy agents, in addition to being administered alone, making it possible to apply it to the treatment of various types of cancer.

[0027]

[0028] Figures 1 to 3 show the cell proliferation inhibitory effect on a blood cancer cell line according to Example 1.

[0029] Figure 4 shows the results of the cytotoxicity evaluation on normal cells according to Example 3.

[0030] Figure 5 shows the results of the cardiotoxicity evaluation according to Example 4.

[0031] Figure 6 shows the tumor growth inhibitory effect according to Example 5.

[0032] Figure 7 shows the results of confirming the mechanism through RNA analysis according to Example 6.

[0033]

[0034] A composition for the prevention or treatment of malignant neoplasm is provided, comprising one or more active ingredients selected from the group consisting of a compound represented by the following chemical formula (1), pharmaceutically acceptable salts, hydrates, sorbates, prodrugs of said compound, and combinations thereof.

[0035]

[0036] In the above chemical formula (1),

[0037] The above X1, X2, and X3 are identical or different from each other, and each is independently N or C(R2), and

[0038] The above X4 is selected from the group consisting of direct bonding, N(R3), C(R4)(R5), oxygen(O), and sulfur(S), and

[0039] The above R1 to R5 are identical or different from one another and each independently comprise hydrogen, a cyano group, a nitro group, a halogen group, an amino group, a hydroxyl group, a substituted or unsubstituted straight-chain or branched alkyl group having 1 to 30 carbon atoms, a substituted or unsubstituted straight-chain or branched alkenyl group having 2 to 30 carbon atoms, a substituted or unsubstituted straight-chain or branched alkynyl group having 2 to 24 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 30 carbon atoms, a substituted or unsubstituted cycloalkenyl group having 3 to 30 carbon atoms, a substituted or unsubstituted cycloheteroalkyl group having 3 to 30 carbon atoms, a substituted or unsubstituted alkylthio group having 1 to 4 carbon atoms, a substituted or unsubstituted haloalkyl group having 1 to 30 carbon atoms, a substituted or unsubstituted alkoxy group having 1 to 10 carbon atoms, a substituted or unsubstituted One selected from the group consisting of an arylalkyl group having 7 to 30 carbon atoms, a substituted or unsubstituted aryl group having 5 to 30 carbon atoms, a substituted or unsubstituted heteroaryl group having 5 to 30 carbon atoms, and a substituted or unsubstituted alkylaryl group having 7 to 30 carbon atoms, and

[0040] The above n is an integer from 0 to 9, and

[0041] If n is 2 or greater, the plurality of R1s are identical or different from each other, and

[0042] The above ring A is one selected from the group consisting of a substituted or unsubstituted monocyclic aromatic ring having 5 to 30 carbon atoms, a substituted or unsubstituted polycyclic aromatic ring having 5 to 30 carbon atoms, a substituted or unsubstituted monocyclic heteroaromatic ring having 5 to 30 carbon atoms, and a substituted or unsubstituted polycyclic heteroaromatic ring having 5 to 30 carbon atoms.

[0043]

[0044] The advantages and features of the present invention, and the methods for achieving them, will become clearer through the embodiments specifically described below. However, the present invention is not limited to the following embodiments, but can be modified and implemented in various ways within the scope equivalent to the technical concept of the present invention. The following embodiments are merely illustrative descriptions to provide a sufficient understanding of the content of the present invention, and the scope of the rights of the present invention is limited by the claims.

[0045] Unless specifically defined otherwise, the terms used in this specification and claims shall be interpreted in the sense generally understood by those skilled in the art of pharmacy, biotechnology, chemistry and related technical fields.

[0046] In this specification and claims, expressions such as 'include,' 'contain,' and 'have' mean that specific components or components are present, but are not limited to these and may include other components or components.

[0047] In this specification, the content, concentration, ratio, etc., of compounds, pharmaceutical compositions, or physiologically active substances are expressed on a weight basis (w / w) unless otherwise noted. When a numerical range is described as 'A to B', 'A or greater', or 'A or less', it refers to all values ​​including the values ​​at both ends (A, B). Furthermore, unless explicitly stated otherwise, it is interpreted to include a conventional analytical error range (±10%).

[0048] In this specification, the term "pharmaceuticalally acceptable" refers to a component that does not cause adverse effects, such as toxicity, irritation, or allergic reactions, upon administration in vivo, and does not inhibit or cause loss of the pharmacological activity of the active ingredient.

[0049] In this specification, "prevention" means any act of suppressing or delaying the onset of a disease.

[0050] In this specification, "treatment" refers to any act that improves the symptoms of a disease or changes them in a beneficial direction.

[0051] In this specification, the term 'Compound' is not limited to a structure depicted by a specific chemical formula and is interpreted to include all forms of racemic mixtures, enantiomers, diastereomers, or mixtures thereof.

[0052] In this specification, "direct bond" means that two adjacent atoms are directly bonded without any separate atoms at the corresponding positions.

[0053]

[0054] Hereinafter, embodiments according to the present invention will be described in detail.

[0055] In one embodiment of the present invention, a composition for the prevention or treatment of malignant neoplasm (hereinafter referred to as the 'composition') is provided, comprising one or more active ingredients selected from the group consisting of a compound represented by the following chemical formula (1), a pharmaceutically acceptable salt, hydrate, sorbate, prodrug of said compound, and combinations thereof.

[0056]

[0057] In the above chemical formula (1), X1, X2 and X3 may be identical or different from each other, and each may independently be N or C(R2).

[0058] The above X4 can be selected from the group consisting of direct bonding, N(R3), C(R4)(R5), oxygen(O), and sulfur(S).

[0059] The above R1 to R5 are identical or different from one another and each independently comprise hydrogen, a cyano group, a nitro group, a halogen group, an amino group, a hydroxyl group, a substituted or unsubstituted straight-chain or branched alkyl group having 1 to 30 carbon atoms, a substituted or unsubstituted straight-chain or branched alkenyl group having 2 to 30 carbon atoms, a substituted or unsubstituted straight-chain or branched alkynyl group having 2 to 24 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 30 carbon atoms, a substituted or unsubstituted cycloalkenyl group having 3 to 30 carbon atoms, a substituted or unsubstituted cycloheteroalkyl group having 3 to 30 carbon atoms, a substituted or unsubstituted alkylthio group having 1 to 4 carbon atoms, a substituted or unsubstituted haloalkyl group having 1 to 30 carbon atoms, a substituted or unsubstituted alkoxy group having 1 to 10 carbon atoms, a substituted or unsubstituted It may be one selected from the group consisting of an arylalkyl group having 7 to 30 carbon atoms, a substituted or unsubstituted aryl group having 5 to 30 carbon atoms, a substituted or unsubstituted heteroaryl group having 5 to 30 carbon atoms, and a substituted or unsubstituted alkylaryl group having 7 to 30 carbon atoms.

[0060] In this specification, the R1 group represents a substituent that can be bonded to a chemically acceptable position in the fused ring constituting the core structure of the formula (1). Here, "chemically acceptable position" means a substitutable carbon atom within a range that does not significantly impair the π-electron donating or accepting properties of the polycyclic structure.

[0061] The above n may be an integer from 0 to 9.

[0062] If n is 2 or more, the plurality of R1s may be identical or different from each other.

[0063] The above ring A may be one selected from the group consisting of a substituted or unsubstituted monocyclic aromatic ring having 5 to 30 carbon atoms, a substituted or unsubstituted polycyclic aromatic ring having 5 to 30 carbon atoms, a substituted or unsubstituted monocyclic heteroaromatic ring having 5 to 30 carbon atoms, and a substituted or unsubstituted polycyclic heteroaromatic ring having 5 to 30 carbon atoms.

[0064] In one embodiment, the compound of the above formula (1) may include the compound of the following formula (2).

[0065]

[0066] In the above chemical formula (2), the details regarding R1, n, and ring A are the same as those described above in the above chemical formula (1).

[0067] In one embodiment, the compound of the above formula (1) may include the compound of the following formula (3).

[0068]

[0069] In the above chemical formula (3), the details regarding ring A are the same as those described above in the above chemical formula (1).

[0070] The composition according to one embodiment may include a compound having a structure selected from the group consisting of the following chemical formulas (4) to (14) in which ring A is ring A; or a combination of two or more of the above compounds.

[0071]

[0072] In the above chemical formulas (4) to (14), the above Z1 to Z 14 Each can be independently selected from the group consisting of nitrogen (N), N-oxide [N(+)-O(-)], oxygen (O), and C (R7).

[0073] In one embodiment, the above Z1 to Z 14 Each can be independently selected from the group consisting of nitrogen (N), N-oxide [N(+)-O(-)] and C (R7).

[0074] In the above chemical formulas (4) to (14), Y1 to Y5 can each be independently selected from the group consisting of nitrogen (N), N-oxide [N(+)-O(-)], oxygen (O), sulfur (S), and C (R7).

[0075] In one embodiment, Y1 to Y5 can each be independently selected from the group consisting of oxygen (O), sulfur (S), and C (R7).

[0076] In the above formulas (4) to (14), R6 and R7 are each independently hydrogen, a cyano group, a nitro group, a halogen group, an amino group, a hydroxyl group, a substituted or unsubstituted straight-chain or branched alkyl group having 1 to 30 carbon atoms, a substituted or unsubstituted straight-chain or branched alkenyl group having 2 to 30 carbon atoms, a substituted or unsubstituted straight-chain or branched alkynyl group having 2 to 24 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 30 carbon atoms, a substituted or unsubstituted cycloalkenyl group having 3 to 30 carbon atoms, a substituted or unsubstituted cycloheteroalkyl group having 3 to 30 carbon atoms, a substituted or unsubstituted alkylthio group having 1 to 4 carbon atoms, a substituted or unsubstituted haloalkyl group having 1 to 30 carbon atoms, or a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms It may be one selected from the group consisting of an alkoxy group, a substituted or unsubstituted arylalkyl group having 7 to 30 carbon atoms, a substituted or unsubstituted aryl group having 5 to 30 carbon atoms, a substituted or unsubstituted heteroaryl group having 5 to 30 carbon atoms, and a substituted or unsubstituted alkylaryl group having 7 to 30 carbon atoms.

[0077] In one embodiment, R6 and R7 may each independently be one selected from the group consisting of hydrogen, a halogen group, a hydroxyl group, a substituted or unsubstituted straight-chain or branched alkyl group having 1 to 30 carbon atoms, a substituted or unsubstituted haloalkyl group having 1 to 30 carbon atoms, and a substituted or unsubstituted alkoxy group having 1 to 10 carbon atoms.

[0078] In this specification, the R6 group represents a substituent capable of being bonded to a chemically acceptable position on ring A. Here, "chemically acceptable position" means a substitutable carbon atom within a range that does not significantly impair the π-electron donating or accepting properties of ring A of the monocyclic or polycyclic structure. The R6 group may be present not only at the position shown in the formulas (4) to (14), but also at a chemically acceptable position on another fused adjacent ring. Additionally, the R6 group is Z1 to Z 14 and can be bonded at chemically possible positions among the atoms indicated by Y1 to Y5, and the specific bonding positions are Z1 to Z 14 and may vary depending on the specific examples of Y1 to Y5 atoms.

[0079] In the above chemical formulas (4) to (14), m may be an integer from 0 to 7.

[0080] In the above chemical formulas (4) to (14), when m is 2 or more, the plurality of R6 may be the same or different from each other.

[0081] In the above chemical formulas (4) to (14), the asterisk (*) indicates a bonding point in which the above chemical formulas (4) to (14) bond with a residue of the above chemical formula (1) as the ring A, and the bonding point may include any chemically permissible position within the ring A.

[0082] In one embodiment, where ring A is a polycyclic aromatic ring or a polycyclic heteroaromatic ring, the asterisk (*) indicator may be present at a chemically acceptable location on an adjacent fused ring as well as at the location where the asterisk (*) indicator is shown in the chemical formulas (8) to (14). Additionally, the asterisk (*) indicator may be present at the Z1 to Z 14and can be bonded at chemically possible positions among the atoms indicated by Y1 to Y5, and the specific bonding positions are Z1 to Z 14 and may vary depending on the specific examples of Y1 to Y5 atoms.

[0083] The composition according to one embodiment may comprise a compound having a structure selected from the group consisting of the following chemical formulas (4A) to (4B); the following chemical formulas (5A) to (5C); and the following chemical formulas (6A) to (6B); or a combination of two or more of the said compounds.

[0084]

[0085] In the above formulas (4A) to (4B), (5A) to (5C) and (6A) to (6B), Z1 to Z6 may each be independently selected from the group consisting of nitrogen (N), N-oxide [N(+)-O(-)] and C (R7), R7 is the same as described above with respect to formulas (4) to (14), and R6 may be one selected from the group consisting of hydrogen, a halogen group, a hydroxyl group, a substituted or unsubstituted haloalkyl group having 1 to 30 carbon atoms, and a substituted or unsubstituted alkoxy group having 1 to 10 carbon atoms, and m may be an integer from 0 to 4.

[0086] In the above chemical formulas (4A) to (4B), (5A) to (5C) and (6A) to (6B), if m is 2 or more, the plurality of R6 may be the same or different from each other.

[0087] In the above chemical formulas (4A) to (4B), (5A) to (5C) and (6A) to (6B), the asterisk (*) indicates a bonding point where the above chemical formulas (4A) to (4B), (5A) to (5C) and (6A) to (6B) are bonded to the residue of the above chemical formula (1) as ring A.

[0088] The composition according to one embodiment may include a compound having a structure selected from the group consisting of the following chemical formulas (7A) to (7B) in which ring A has a structure selected from the group consisting of the following chemical formulas; or a combination of two or more of the said compounds.

[0089]

[0090] In the above chemical formulas (7A) to (7B), Y1 is selected from the group consisting of nitrogen (N), N-oxide [N(+)-O(-)], oxygen (O) and sulfur (S), R6 is selected from the group consisting of hydrogen, a halogen group, a hydroxyl group, a substituted or unsubstituted haloalkyl group having 1 to 30 carbon atoms, and a substituted or unsubstituted alkoxy group having 1 to 10 carbon atoms, and m may be an integer from 0 to 3.

[0091] In the above chemical formulas (7A) to (7B), if m is 2 or more, the plurality of R6 may be the same or different from each other.

[0092] In the above chemical formulas (7A) to (7B), the asterisk (*) indicates a bonding point where the above chemical formulas (7A) to (7B) are bonded to the residue of the above chemical formula (1) as ring A.

[0093] The composition according to one embodiment may include a compound having a structure selected from the group consisting of the following chemical formulas (8A) to (8G) in which ring A is ring A; or a combination of two or more of the above compounds.

[0094]

[0095] In the above chemical formulas (8A) to (8G), Y2 is selected from the group consisting of nitrogen (N), N-oxide [N(+)-O(-)], oxygen (O) and sulfur (S), R6 is selected from the group consisting of hydrogen, a halogen group, a hydroxyl group, a substituted or unsubstituted haloalkyl group having 1 to 30 carbon atoms, and a substituted or unsubstituted alkoxy group having 1 to 10 carbon atoms, and m may be an integer from 0 to 5.

[0096] In the above chemical formulas (8A) to (8G), if m is 2 or more, the plurality of R6 may be the same or different from each other.

[0097] In the above chemical formulas (8A) to (8G), the asterisk (*) indicates a bonding point where the above chemical formulas (8A) to (8G) are bonded to a residue of the above chemical formula (1) as ring A.

[0098] The composition according to one embodiment may include a compound having a structure selected from the group consisting of the following chemical formulas (9A) to (9C), wherein the ring A has a structure selected from one of the following chemical formulas; or a combination of two or more of the said compounds.

[0099]

[0100] In the above chemical formulas (9A) to (9C), Y3 is selected from the group consisting of nitrogen (N), N-oxide [N(+)-O(-)], oxygen (O) and sulfur (S), R6 is selected from the group consisting of hydrogen, a halogen group, a hydroxyl group, a substituted or unsubstituted haloalkyl group having 1 to 30 carbon atoms, and a substituted or unsubstituted alkoxy group having 1 to 10 carbon atoms, and m may be an integer from 0 to 5.

[0101] In the above chemical formulas (9A) to (9C), if m is 2 or more, the plurality of R6 may be the same or different from each other.

[0102] In the above chemical formulas (9A) to (9C), the asterisk (*) indicates a bonding point where the above chemical formulas (9A) to (9C) are bonded to a residue of the above chemical formula (1) as ring A.

[0103] The composition according to one embodiment may include a compound having a structure selected from the group consisting of the following chemical formulas (10A) to (10C) in which the ring A has a structure selected from the group consisting of the following chemical formulas; or a combination of two or more of the said compounds.

[0104]

[0105] In the above chemical formulas (10A) to (10C), Y4 and Y4 are each independently selected from the group consisting of nitrogen (N), N-oxide [N(+)-O(-)], oxygen (O) and sulfur (S), R6 is one selected from the group consisting of hydrogen, a halogen group, a hydroxyl group, a substituted or unsubstituted haloalkyl group having 1 to 30 carbon atoms, and a substituted or unsubstituted alkoxy group having 1 to 10 carbon atoms, and m may be an integer from 0 to 4.

[0106] In the above chemical formulas (10A) to (10C), if m is 2 or more, the plurality of R6 may be the same or different from each other.

[0107] In the above chemical formulas (10A) to (10C), the asterisk (*) indicates a bonding point where the above chemical formulas (10A) to (10C) are bonded to a residue of the above chemical formula (1) as ring A.

[0108] The composition according to one embodiment may include a compound having a structure selected from the group consisting of the following chemical formulas (11A) to (11H) in which the ring A has a structure selected from the group consisting of the following chemical formulas (11A) to (11H); or a combination of two or more of the said compounds.

[0109]

[0110] In the above chemical formulas (11A) to (11H), Z7 and Z8 are each independently selected from the group consisting of nitrogen (N), N-oxide [N(+)-O(-)] and C (R7), and R6 and R7 are each independently selected from the group consisting of hydrogen, a halogen group, a hydroxyl group, a substituted or unsubstituted haloalkyl group having 1 to 30 carbon atoms, and a substituted or unsubstituted alkoxy group having 1 to 10 carbon atoms, and m may be an integer from 0 to 6.

[0111] In the above chemical formulas (11A) to (11H), if m is 2 or more, the plurality of R6 may be the same or different from each other.

[0112] In the above chemical formulas (11A) to (11H), the asterisk (*) indicates a bonding point where the above chemical formulas (11A) to (11H) are bonded to the residue of the above chemical formula (1) as ring A.

[0113] The composition according to one embodiment may include a compound having a structure selected from the group consisting of the following chemical formulas (12A) to (12G) in which ring A is ring A; or a combination of two or more of the above compounds.

[0114]

[0115] In the above chemical formulas (12A) to (12G), Z9 is selected from the group consisting of nitrogen (N) and N-oxide [N(+)-O(-)], and R6 is each independently selected from the group consisting of hydrogen, a halogen group, a hydroxyl group, a substituted or unsubstituted haloalkyl group having 1 to 30 carbon atoms, and a substituted or unsubstituted alkoxy group having 1 to 10 carbon atoms, and m may be an integer from 0 to 6.

[0116] In the above chemical formulas (12A) to (12G), if m is 2 or more, the plurality of R6 may be the same or different from each other.

[0117] In the above chemical formulas (12A) to (12G), the asterisk (*) indicates a bonding point where the above chemical formulas (12A) to (12G) are bonded to the residue of the above chemical formula (1) as ring A.

[0118] The composition according to one embodiment may comprise a compound having a structure selected from the group consisting of the following chemical formulas (13A) to (13F); and the following chemical formulas (14A) to (14C); or a combination of two or more of the said compounds.

[0119]

[0120] In the above chemical formulas (13A) to (13F) and (14A) to (14C), the Z 11 To Z 14 Each is independently selected from the group consisting of nitrogen (N) and N-oxide [N(+)-O(-)], and each R6 is independently selected from the group consisting of hydrogen, a halogen group, a hydroxyl group, a substituted or unsubstituted haloalkyl group having 1 to 30 carbon atoms, and a substituted or unsubstituted alkoxy group having 1 to 10 carbon atoms, and m may be an integer from 0 to 5.

[0121] In the above chemical formulas (13A) to (13F) and (14A) to (14C), if m is 2 or more, the plurality of R6 may be the same or different from each other.

[0122] In the above chemical formulas (13A) to (13F) and (14A) to (14C), the asterisk (*) indicates a bonding point where the above chemical formulas (13A) to (13F) and (14A) to (14C) bond with the residue of the above chemical formula (1) as ring A.

[0123] A composition according to one embodiment may comprise a compound having a structure selected from the group consisting of the ring A, which is composed of formulas (4A) to (4B); formulas (5A) to (5C); formulas (6A) to (6B); formulas (7A) to (7B); formulas (8A) to (8G); and formulas (11A) to (11H); or a combination of two or more of the compounds.

[0124] A composition according to one embodiment may comprise a compound having a structure selected from the group consisting of the following chemical formulas (4-1) to (4-27); the following chemical formulas (5-1) to (5-3); the following chemical formulas (6-1) to (6-3); the following chemical formulas (7-1) to (7-2); the following chemical formulas (8-1) to (8-8); the following chemical formulas (9-1) to (9-2); the following chemical formulas (10-1) to (10-3); the following chemical formulas (11-1) to (11-12); the following chemical formulas (12-1) to (12-7); the following chemical formulas (13-1) to (13-6); and the following chemical formulas (14-1) to (14-3); or a combination of two or more of the said compounds.

[0125]

[0126]

[0127]

[0128]

[0129] The composition according to one embodiment may comprise a compound having a structure selected from the group consisting of the ring A, which is composed of the formulas (4-1) to (4-27); the formulas (5-1) to (5-2); the formula (6-1); the formulas (7-1) to (7-2); the formula (8-1); and the formulas (11-1) to (11-2); or a combination of two or more of the compounds.

[0130] The composition according to one embodiment may comprise a compound having a structure selected from the group consisting of the formulas (4-1), (4-3), (4-6), (4-8), (4-10), (4-12), (4-14), (4-16), (4-17), (4-19), (4-23), (4-24), (4-25), (5-1), (7-1), (7-2), (8-1), and (11-2); or a combination of two or more of the above compounds.

[0131] The composition according to one embodiment may comprise one or more active ingredients selected from the group consisting of the aforementioned compound, pharmaceutically acceptable salts, hydrates, sorbates, prodrugs, and combinations thereof.

[0132] In this specification, the term "pharmaceuticalally acceptable salt" refers to a salt used by a person skilled in the art in the pharmaceutical field for the purpose of improving the physiological water solubility, solubility, stability, or bioavailability of the compound. For example, hydrochloride, sulfate, phosphate, acetate, citrate, maleate, or sodium salt, potassium salt, calcium salt, etc. may be included.

[0133] In this specification, the terms "hydrate" and "solvate" each refer to a form in which the compound is combined with water or other solvent molecules, and may include partial hydrate and mixed solvate forms.

[0134] In this specification, the term "prodrug" refers to a compound that can be converted into said compound by chemical or enzymatic action in vivo.

[0135] In one embodiment, the active ingredient may be included alone or in combination of two or more, and each of the components may be formulated in a solid, liquid, or semi-solid form.

[0136] The composition according to one embodiment may further comprise one selected from the group consisting of pharmaceutically acceptable carriers, exipients, pH adjusters, stabilizers, preservatives, sweeteners, flavoring agents, and combinations thereof.

[0137] The above-mentioned pharmaceutically acceptable carrier refers to an inactive substance that facilitates the delivery or administration of the above-mentioned active ingredient, and can be used in various formulation forms such as solid, liquid, or semi-solid.

[0138] In one embodiment, the carrier comprises a solid carrier selected from the group consisting of lactose, starch, microcrystalline cellulose, sucrose, mannitol, sorbitol, povidone, kaolin, talc, magnesium stearate, stearic acid and salts thereof, colloidal silica, sodium starch glycolate, croscarmellose sodium, crospovidone and combinations thereof; A liquid carrier comprising one selected from the group consisting of purified water, vegetable oil (e.g., castor oil, corn oil, sunflower oil, soybean oil), mineral oil, glycerin, polyethylene glycol, propylene glycol, ethanol, butanol, benzyl alcohol, polysorbate, sorbitan ester, and combinations thereof; a semi-solid carrier comprising one selected from the group consisting of vaseline, lanolin, polyethylene wax, carbopol, glyceryl monostearate, cetyl alcohol, stearyl alcohol, fatty acid ester, fatty acid triglycerides, and combinations thereof; and may comprise one selected from the group consisting of combinations thereof.

[0139] The above-mentioned pharmaceutically acceptable exipient refers to an additive intended to dilute the active ingredient to an appropriate amount or to impart physical stability to the formulation without inhibiting or causing loss of the active ingredient's efficacy.

[0140] The above excipients may be selected in various ways depending on the type of formulation (e.g., oral, injectable, topical, eye drops, etc.) and may include all substances commonly used by a person skilled in the art in the field of pharmaceutical formulations.

[0141] In one embodiment, the excipient may include one selected from the group consisting of lactose, starch, cellulose, dextrin, dextrose, mannitol, sorbitol, calcium phosphate, kaolin, precipitated silica, and combinations thereof.

[0142] The above-mentioned pharmaceutically acceptable pH adjuster refers to an additive for improving stability or solubility by adjusting the acidity or alkalinity of the composition without inhibiting or causing loss of the efficacy of the above-mentioned active ingredient.

[0143] In one embodiment, the pH adjuster is potassium phosphate, sodium phosphate, citric acid, lactic acid, tartaric acid, acetic acid, malic acid, oxalic acid, ethylenediaminetetraacetic acid, fumaric acid, palmitic acid, propanoic acid, sorbic acid, stearic acid, succinic acid, ascorbic acid, erythoribic acid, methanesulfonic acid, nitric acid, formic acid, adipic acid, alginic acid, Tris, tromethamine, sodium hydroxide, It may include one selected from the group consisting of potassium hydroxide, hydrochloric acid, sulfuric acid, and combinations thereof.

[0144] The above-mentioned pharmaceutically acceptable stabilizer refers to an additive that maintains the stability of the active ingredient by preventing oxidation, hydrolysis, or photodegradation, without inhibiting or causing loss of the active ingredient's efficacy.

[0145] In one embodiment, the stabilizer may comprise one selected from the group consisting of butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), sodium metabisulfite, ascorbic acid, tocopherol, EDTA, sodium citrate, lactose, sucrose, and combinations thereof.

[0146] The above-mentioned pharmaceutically acceptable preservative refers to an additive for inhibiting microbial contamination or proliferation without impairing or causing loss of the efficacy of the above-mentioned active ingredient.

[0147] In one embodiment, the preservative may include one selected from the group consisting of parabens (such as methylparaben and propylparaben), benzyl alcohol, chlorobutanol, phenol, sorbic acid, benzoic acid, dehydroacetic acid, benzalkonium chloride, benzethonium chloride, cresols, cetylpyridinium chloride, and combinations thereof.

[0148] The above pharmaceutically acceptable sweetener refers to an additive for improving the palatability of the composition without inhibiting or losing the efficacy of the active ingredient, and may include, for example, one selected from the group consisting of sucrose, glucose, fructose, aspartame, acesulfame potassium, saccharin, sucralose, sorbitol, mannitol, xylitol, stevioside, erythritol, and combinations thereof.

[0149] The above pharmaceutically acceptable flavoring agent is an additive for improving palatability when administering the composition without inhibiting or losing the medicinal effect of the active ingredient, and may include natural or synthetic flavorings, for example, one selected from the group consisting of vanillin, menthol, orange oil, peppermint oil, lemon oil, eucalyptus oil, cinnamon oil, cherry flavor, cocoa flavor, and combinations thereof.

[0150] The above composition may include one or more of the above active ingredients and additives in a pharmaceutically acceptable ratio and may be applied to various formulations such as oral, injectable, topical, inhalant, ophthalmic, and nasal preparations.

[0151] The above composition is a composition for the prevention or treatment of malignant neoplasms and can be applied to various types of malignant tumors through the inhibition of cancer cell proliferation, induction of apoptosis, regulation of the cell cycle, and regulation of immune responses within the tumor microenvironment.

[0152] In one embodiment, the malignant tumor may be a hematologic cancer. Hematologic cancer is a malignant disease caused by the abnormal proliferation of hematopoietic cells and generally includes leukemia, lymphoma, and multiple myeloma. The composition according to one embodiment of the present invention may exhibit a therapeutic or preventive effect by inhibiting the proliferation of such hematologic cancer cells or inducing their death.

[0153] In one embodiment, the malignant tumor may be at least one of lymphoma, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and acute lymphoblastic leukemia (ALL).

[0154] In one embodiment, the composition may exhibit at least one of a decrease in cell viability, an increase in the activity of apoptotic enzyme protein (Caspase-3); and the induction of poly(ADP-ribose) polymerase (PARP) cleavage for each of the AML cell line (HL-60), CML cell line (K-562), ALL cell line (Reh), and lymphoma cell line (U937).

[0155] In another embodiment, the malignant tumor may be cervical cancer. Cervical cancer is a representative epithelial malignant tumor caused by persistent infection with human papillomavirus (HPV), and is characterized by abnormal cell cycle progression of tumor cells and overexpression of anti-apoptosis proteins. The composition according to one embodiment of the present invention can inhibit the proliferation of cervical cancer cells (e.g., HeLa, SiHa, CaSki, etc.) by regulating abnormal intracellular signaling, and can exhibit anticancer activity against cervical cancer by regulating apoptosis-related proteins (Bax / Bcl-2 ratio, cleaved caspase-3, etc.).

[0156]

[0157] Specific embodiments of the present invention are presented below. However, the embodiments described below are merely for the purpose of specifically illustrating or explaining the present invention, and the scope of the present invention is not to be interpreted as limited by this, and the scope of the present invention is determined by the claims.

[0158]

[0159] <Synthetic Example>

[0160] Unless otherwise noted, all starting materials and reagents in the synthesis examples described below were commercially available products purchased from TCI (Tokyo Chemical Industry), Sigma-Aldrich, Merck, Combi-Blocks, and Alfa Aesar (Thermo Fisher), all of which are readily available through ordinary means. Furthermore, unless otherwise noted, they were used as is without any additional purification process.

[0161] All solvents used for product separation and chromatography were reagent grade and purified through glass distillation.

[0162] The reaction flask was thoroughly dried at 100°C before use.

[0163] Reactions sensitive to air or moisture were performed under an argon (Ar) atmosphere.

[0164] Flash column chromatography was performed using silica gel 60 (230-400 mesh, Merck) under specified solvent conditions.

[0165] Thin-layer chromatography (TLC) was performed using 0.25 mm thick silica gel plates (Merck).

[0166] 1 H Nuclear Magnetic Resonance ( 1 ¹H NMR spectra were measured using JEOL 400 MHz and Agilent FT-NMR 600 MHz spectrometers on samples dissolved in the specified solvent.

[0167] The chemical shift was expressed as a downward (ppm, δ) value from tetramethylsilane (TMS) and was based on the signal of the deuteration solvent used for measurement.

[0168] 1 1H NMR data were described in the order of chemical shift, multiplicity (single-line (s), double-line (d), triple-line (t), quadruple-line (q), quint-line (quint), multiple-line (m) or complex resonance), number of hydrogens, and coupling constant (Hz).

[0169]

[0170] Synthesis Example 1: Compounds of Formulas GX-24001 to 24013 and GX-25001 to 25019

[0171]

[0172] Synthesis method (a): While stirring an N,N-dimethylformamide (DMF) solution containing the above compound (R-1), the carboxylic acid (about 3.0 equivalents) of the above compound (R-2), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl, 3.0 equivalents), 1-hydroxybenzotriazole monohydrate (HOBt·H2O, 2.0 equivalents), 4-(dimethylamino)pyridine (DMAP, 0.1 equivalents), and N,N-diisopropylethylamine (DIPEA, 3.5 equivalents) were added sequentially.

[0173] Next, the reaction was terminated by adding water (H2O) after stirring at room temperature for about 10 hours (Overnight). Afterward, the product containing the compound (P-1) was extracted with ethyl acetate (EtOAc), the organic layer was collected, dried with anhydrous magnesium sulfate (MgSO4), and then concentrated under reduced pressure. The residue was purified by flash column chromatography using a column packed with silica gel.

[0174] The chemical structure of the compound (P-1) is determined according to the ring B structure of the compound (R-2), and specific examples thereof are described in detail in Synthesis Examples 1-1 to 1-32 below.

[0175]

[0176] Synthesis Example 1-1: Chemical formula GX-24001

[0177]

[0178] As a result of reacting according to the synthesis method (a) using the above compound (R-1) (100 mg, 0.404 mmol) and isonicotinic acid (149 mg, 1.21 mmol) as the above compound (R-2), an ivory solid (77.0 mg, yield 54%) of the N-(9H-dibenzo[c,f]imidazo[1,5-a]azepine-3-yl)isonicotinamide compound having the chemical formula GX-24001 structure was obtained as the above compound (P-1). The obtained product was purified by flash column chromatography (MeOH : CH2Cl2 = 1 : 100) using a column packed with silica gel.

[0179] 1 H-NMR (CDCl3, 600 MHz) δ 12.97 (s, 1H), 8.68 (d, 2H, J = 4.9 Hz), 8.05 (d, 1H, J = 8.1 Hz), 8.01 (d, 2H, J = 4.9 Hz), 7.46 (d, 1H, J = 7.5) Hz), 7.43 (td, 1H, J = 7.7, 1.6 Hz), 7.40 (dd, 1H, J = 7.6, 1.6 Hz), 7.36 (m, 1H), 7.34 (m, 2H), 7.30 (m, 1H), 7.01 (s, 1H), 4.12 (d, 1H, J = 13.8 Hz), 3.67 (d, 1H, J = 13.8 Hz).

[0180]

[0181] Synthesis Example 1-2: Chemical Formula GX-24002

[0182]

[0183] As a result of reacting according to the synthesis method (a) using the above compound (R-1) (100 mg, 0.404 mmol) and picolinic acid (149 mg, 1.21 mmol) as the above compound (R-2), the above compound (P-1) was obtained as a white solid (57.0 mg, yield 40%) of N-(9H-dibenzo[c,f]imidazo[1,5-a]azepine-3-yl)picolinamide with the above chemical formula GX-24002 structure. The obtained product was purified by flash column chromatography (MeOH : CH2Cl2 = 1 : 100) using a column packed with silica gel.

[0184] 1 H-NMR (CDCl3, 600 MHz) δ 10.24 (s, 1H), 8.58 (d, 1H, J = 4.8 Hz), 8.16 (d, 1H, J = 7.8 Hz), 7.85 (td, 1H, J = 7.7, 1.7 Hz), 7.56 (m, 1H), 7.47 (dd, 1H, J = 7.6, 4.7 Hz), 7.42 (dd, 2H, J = 7.6, 1.5 Hz), 7.34 (s, 1H), 7.32 (m, 1H), 7.28 (m, 4H), 7.24 (td, 3H, J = 7.7, 1.3 Hz), 7.16 (t, 1H, J = 7.7 Hz), 4.13 (d, 1H, J = 13.5 Hz), 3.69 (d, 1H, J = 13.5 Hz).

[0185]

[0186] Synthesis Example 1-3: Chemical Formula GX-24003

[0187]

[0188] As a result of reacting according to the synthesis method (a) using the above compound (R-1) (100 mg, 0.404 mmol) and 2-naphthoic acid (2-naphthoic acid, 209 mg, 1.21 mmol) as the above compound (R-2), the above compound (P-1) was obtained as a pale yellow solid (80.6 mg, yield 50%) of the N-(9H-dibenzo[c,f]imidazo[1,5-a]azepine-3-yl)-2-naphtamide compound having the chemical formula GX-24003 structure. The obtained product was purified by flash column chromatography (MeOH : CH2Cl2 = 1 : 40) using a column packed with silica gel.

[0189] 1 H-NMR (CDCl3, 600 MHz) δ 8.73 (s, 1H), 8.26 (d, 1H, J = 8.6 Hz), 8.11 (d, 1H, J = 8.1 Hz), 7.93 (d, 1H, J = 7.9 Hz), 7.84 (m, 2H), 7.52 (m, 2H), 7.46 (m, 2H), 7.42 (d, 1H, J = 8.0 Hz), 7.39 (s, 1H), 7.35 (d, 1H, J = 2.5 Hz), 7.33 (m, 2H), 7.30 (m, 1H), 7.05 (s, 1H), 4.15 (d, 1H, J = 13.7 Hz), 3.67 (d, 1H, J = 13.7 Hz).

[0190]

[0191] Synthesis Example 1-4: Chemical Formula GX-24004

[0192]

[0193] As a result of reacting according to the synthesis method (a) using the above compound (R-1) (100 mg, 0.404 mmol) and 4-chlorobenzoic acid (190 mg, 1.21 mmol) as the above compound (R-2), a 4-chloro-N-(9H-dibenzo[c,f]imidazo[1,5-a]azepine-3-yl)benzamide compound having the chemical formula GX-24004 structure was obtained as the above compound (P-1) as a light brown solid (66.0 mg, yield 42%). The obtained product was purified by flash column chromatography (MeOH : CH2Cl2 = 1 : 40) using a column packed with silica gel.

[0194] 1 H-NMR (CDCl3, 600 MHz) δ 8.13 (d, 2H, J = 8.2 Hz), 8.01 (d, 1H, J = 8.0 Hz), 7.45 (d, 1H, J = 7.4 Hz), 7.38 (dd, 2H, J = 7.5, 1.7 Hz), 7.35 (m, 2H), 7.33 (m, 3H), 7.29 (m, 1H), 7.01 (s, 1H), 4.12 (d, 1H, J = 13.8 Hz), 3.65 (d, 1H, J = 13.8 Hz).

[0195]

[0196] Synthesis Examples 1-5: Chemical Formula GX-24005

[0197]

[0198] As a result of reacting according to the synthesis method (a) using the above compound (R-1) (100 mg, 0.404 mmol) and benzoic acid (148 mg, 1.21 mmol) as the above compound (R-2), an N-(9H-dibenzo[c,f]imidazo[1,5-a]azepine-3-yl)benzamide compound with the chemical formula GX-24005 structure was obtained as the above compound (P-1) as a gray solid (22.0 mg, yield 15%). The obtained product was purified by flash column chromatography (MeOH : CH2Cl2 = 1 : 100) using a column packed with silica gel.

[0199] 1 H-NMR (CDCl3, 600 MHz) δ 8.18 (d, 2H, J = 7.5 Hz), 8.03 (s, 1H), 7.47 (d, 1H, J = 7.2 Hz), 7.44 (d, 1H, J = 7.2 Hz), 7.40 (d, 2H, J = 7.4 Hz), 7.38 (d, 2H, J = 7.6 Hz), 7.33 (m, 2H), 7.29 (m, 2H), 7.02 (s, 1H), 4.13 (d, 1H, J = 13.7 Hz), 3.66 (d, 1H, J = 13.7 Hz).

[0200]

[0201] Synthesis Example 1-6: Chemical Formula GX-24006

[0202]

[0203]

[0204] As a result of reacting according to the synthesis method (a) using the above compound (R-1) (100 mg, 0.404 mmol) and 2-methoxybenzoic acid (184 mg, 1.21 mmol) as the above compound (R-2), an ivory solid (135 mg, yield 88%) of the N-(9H-dibenzo[c,f]imidazo[1,5-a]azepine-3-yl)-2-methoxybenzamide compound having the chemical formula GX-24006 structure was obtained as the above compound (P-1). The obtained product was purified by flash column chromatography (MeOH : CH2Cl2 = 1 : 100) using a column packed with silica gel.

[0205] 1 H-NMR (CDCl3, 600 MHz) δ 10.01 (s, 1H), 8.09 (d, 1H, J = 7.8 Hz), 7.55 (m, 1H), 7.49 (m, 1H), 7.42 (m, 2H), 7.31 (m, 2H), 7.27 (d, 1H, J = 0.9 Hz), 7.25 (s, 1H), 7.23 (td, 1H, J = 7.5, 1.3 Hz), 7.15 (td, 1H, J = 7.7, 1.5 Hz), 7.05 (t, 1H, J = 7.5 Hz), 7.00 (d, 1H, J) = 8.3 Hz), 4.13 (d, 1H, J = 13.5 Hz), 3.93 (s, 3H), 3.68 (d, 1H, J = 13.5 Hz).

[0206]

[0207] Synthesis Example 1-7: Chemical Formula GX-24007

[0208]

[0209] As a result of reacting according to the synthesis method (a) using the above compound (R-1) (100 mg, 0.404 mmol) and 3-methoxybenzoic acid (184 mg, 1.21 mmol) as the above compound (R-2), the above compound (P-1) was obtained as a gray solid (69.0 mg, yield 45%) of the N-(9H-dibenzo[c,f]imidazo[1,5-a]azepine-3-yl)-3-methoxybenzamide compound having the above chemical formula GX-24007 structure. The obtained product was purified by flash column chromatography (MeOH : CH2Cl2 = 1 : 100) using a column packed with silica gel.

[0210] 1 H-NMR (CDCl3, 600 MHz) δ 13.05 (s, 1H), 8.02 (s, 1H), 7.77 (d, 1H, J = 7.2 Hz), 7.74 (s, 1H), 7.45 (d, 1H, J = 7.4 Hz), 7.36 (t, 2H, J = 8.0 Hz), 7.33 (m, 2H), 7.29 (m, 3H), 7.00 (s, 1H), 6.99 (d, 1H, J = 2.5 Hz), 4.13 (m, 1H), 3.83 (s, 3H), 3.65 (d, 1H, J = 13.7 Hz).

[0211]

[0212] Synthesis Example 1-8: Chemical Formula GX-24008

[0213]

[0214] As a result of reacting according to the synthesis method (a) using the above compound (R-1) (100 mg, 0.404 mmol) and 4-fluorobenzoic acid (170 mg, 1.21 mmol) as the above compound (R-2), an ivory solid (92.0 mg, yield 62%) of the N-(9H-dibenzo[c,f]imidazo[1,5-a]azepine-3-yl)-4-fluorobenzamide compound having the chemical formula GX-24008 structure was obtained as the above compound (P-1). The obtained product was purified by flash column chromatography (EtOAc : n-hexane = 1 : 2) using a column packed with silica gel.

[0215] 1 H-NMR (CDCl3, 400 MHz) δ 8.20 (dd, 2H, J = 8.5, 5.7 Hz), 8.03 (d, 1H, J = 8.0 Hz), 7.45 (dd, 1H, J = 7.0, 1.4 Hz), 7.41 (m, 1H), 7.38 (m, 1H), 7.31 (m, 4H), 7.05 (m, 2H), 6.99 (s, 1H), 4.13 (d, 1H, J = 13.7 Hz), 3.65 (d, 1H, J = 13.7 Hz).

[0216]

[0217] Synthesis Example 1-9: Chemical Formula GX-24009

[0218]

[0219] As a result of reacting according to the synthesis method (a) using the above compound (R-1) (100 mg, 0.404 mmol) and 2-furoic acid (136 mg, 1.21 mmol) as the above compound (R-2), the above compound (P-1) was obtained as a gray solid (56.0 mg, yield 41%) of the N-(9H-dibenzo[c,f]imidazo[1,5-a]azepine-3-yl)furan-2-carboxamide compound having the chemical formula GX-24009 structure. The obtained product was purified by flash column chromatography ((MeOH : CH2Cl2 = 1 : 100) using a column packed with silica gel.

[0220] 1 H-NMR (CDCl3, 400 MHz) δ 7.93 (s, 1H), 7.51 (m, 1H), 7.46 (m, 1H), 7.36 (m, 2H), 7.32 (m, 2H), 7.29 (m, 2H), 7.08 (m, 1H), 7.04 (s, 1H), 6.46 (m, 1H), 4.11 (d, 1H, J = 13.6 Hz), 3.64 (d, 1H, J = 13.6 Hz).

[0221]

[0222] Synthesis Example 1-10: Chemical formula GX-24010

[0223]

[0224] As a result of reacting according to the synthesis method (a) using the above compound (R-1) (100 mg, 0.404 mmol) and 3-chlorobenzoic acid (190 mg, 1.21 mmol) as the above compound (R-2), a 3-chloro-N-(9H-dibenzo[c,f]imidazo[1,5-a]azepine-3-yl)benzamide compound having the chemical formula GX-24010 structure was obtained as the above compound (P-1) as a gray solid (85.0 mg, yield 55%). The obtained product was purified by flash column chromatography (MeOH : CH2Cl2 = 1 : 100) using a column packed with silica gel.

[0225] 1 H-NMR (CDCl3, 600 MHz) δ 12.98 (s, 1H), 8.18 (s, 1H), 8.08 (d, 1H, J = 7.7 Hz), 8.05 (d, 1H, J = 8.1 Hz), 7.46 (d, 1H, J = 7.4 Hz), 7.43 (m, 1H), 7.40 (m, 1H), 7.38 (m, 1H), 7.33 (m, 4H), 7.29 (m, 1H), 7.00 (s, 1H), 4.12 (d, 1H, J = 13.7 Hz), 3.66 (d, 1H, J = 13.8 Hz).

[0226]

[0227] Synthesis Example 1-11: Chemical formula GX-24011

[0228]

[0229] As a result of reacting according to the synthesis method (a) using the above compound (R-1) (100 mg, 0.404 mmol) and 2-fluorobenzoic acid (170 mg, 1.21 mmol) as the above compound (R-2), the above compound (P-1) was obtained as a gray solid (54.0 mg, yield 36%) of the N-(9H-dibenzo[c,f]imidazo[1,5-a]azepine-3-yl)-2-fluorobenzamide compound having the chemical formula GX-24011 structure. The obtained product was purified by flash column chromatography ((MeOH : CH2Cl2 = 1 : 100) using a column packed with silica gel.

[0230] 1 H-NMR (CDCl3, 600 MHz) δ 7.98 (s, 1H), 7.77 (s, 1H), 7.50 (d, 1H, J = 7.3 Hz), 7.44 (m, 1H), 7.37 (d, 1H, J = 7.6 Hz), 7.32 (m, 2H), 7.28 (m, 3H), 7.18 (t, 1H, J = 7.5 Hz), 7.13 (m, 2H), 4.11 (d, 1H, J = 13.5 Hz), 3.66 (d, 1H, J = 13.6 Hz).

[0231]

[0232] Synthesis Example 1-12: Chemical formula GX-24012

[0233]

[0234] As a result of reacting according to the synthesis method (a) using the above compound (R-1) (100 mg, 0.404 mmol) and 3-fluorobenzoic acid (170 mg, 1.21 mmol) as the above compound (R-2), the above compound (P-1) was obtained as a gray solid (101 mg, yield 68%) of the N-(9H-dibenzo[c,f]imidazo[1,5-a]azepine-3-yl)-3-fluorobenzamide compound having the chemical formula GX-24012 structure. The obtained product was purified by flash column chromatography ((MeOH : CH2Cl2 = 1 : 100) using a column packed with silica gel.

[0235] 1 H-NMR (CDCl3, 600 MHz) δ 13.01 (s, 1H), 8.04 (d, 1H, J = 8.0 Hz), 7.99 (d, 1H, J = 7.6 Hz), 7.88 (d, 1H, J = 10.0 Hz), 7.46 (d, 1H, J = 7.5) Hz), 7.41 (t, 1H, J = 7.7 Hz), 7.38 (d, 1H, J = 7.5 Hz), 7.33 (m, 4H), 7.29 (m, 1H), 7.13 (t, 1H, J = 8.2 Hz), 7.00 (s, 1H), 4.12 (d, 1H, J = 13.7 Hz), 3.66 (d, 1H, J = 13.8 Hz).

[0236]

[0237] Synthesis Example 1-13: Chemical formula GX-24013

[0238]

[0239] As a result of reacting according to the synthesis method (a) using the above compound (R-1) (100 mg, 0.404 mmol) and nicotinic acid (149 mg, 1.21 mmol) as the above compound (R-2), the above compound (P-1) was obtained as a gray solid (71.0 mg, yield 50%) of the N-(9H-dibenzo[c,f]imidazo[1,5-a]azepine-3-yl)nicotinamide compound having the chemical formula GX-24013 structure. The obtained product was purified by flash column chromatography (MeOH : CH2Cl2 = 1 : 100) using a column packed with silica gel.

[0240] 1 H-NMR (CDCl3, 600 MHz) δ 12.95 (s, 1H), 9.41 (s, 1H), 8.65 (s, 1H), 8.44 (d, 1H, J = 7.8 Hz), 8.06 (d, 1H, J = 8.0 Hz), 7.46 (d, 1H, J = 7.5 Hz), 7.41 (td, 1H, J = 7.7, 1.6 Hz), 7.38 (d, 1H, J = 7.0 Hz), 7.33 (m, 3H), 7.32 (m, 2H), 7.00 (s, 1H), 4.12 (d, 1H, J = 13.8 Hz), 3.66 (d, 1H, J = 13.8 Hz).

[0241]

[0242] Synthesis Example 1-14: Chemical Formula GX-25001

[0243]

[0244] As a result of reacting according to the synthesis method (a) using the above compound (R-1) (100 mg, 0.404 mmol) and 2,4-dichlorobenzoic acid (2,4-dichlorobenzoic acid, 231 mg, 1.21 mmol) as the above compound (R-2), an ivory solid (66.0 mg, yield 40%) of the 2,4-dichloro-N-(9H-dibenzo[c,f]imidazo[1,5-a]azepine-3-yl)benzamide compound having the chemical formula GX-25001 structure was obtained as the above compound (P-1). The obtained product was purified by flash column chromatography (EtOAc : n-hexane = 1 : 3) using a column packed with silica gel.

[0245] 1 H-NMR (CDCl3, 600 MHz) δ 7.96 (d, 1H, J = 7.4 Hz), 7.81 (s, 1H), 7.46 (d, 1H, J = 7.4 Hz), 7.40 (s, 1H), 7.34 (m, 4H), 7.29 (m, 2H), 7.22 (d, 1H, J = 7.5 Hz), 7.03 (s, 1H), 4.09 (d, 1H, J = 13.7 Hz), 3.65 (d, 1H, J = 13.5 Hz).

[0246]

[0247] Synthesis Example 1-15: Chemical formula GX-25002

[0248]

[0249] As a result of reacting according to the synthesis method (a) using the above compound (R-1) (100 mg, 0.404 mmol) and 3,5-dichlorobenzoic acid (231 mg, 1.21 mmol) as the above compound (R-2), the above compound (P-1) was obtained as an ivory solid (69.0 mg, yield 41%) of the 3,5-dichloro-N-(9H-dibenzo[c,f]imidazo[1,5-a]azepine-3-yl)benzamide compound having the above chemical formula GX-25002 structure. The obtained product was purified by flash column chromatography (EtOAc : n-hexane = 1 : 3) using a column packed with silica gel.

[0250] 1 H-NMR (CDCl3, 600 MHz) δ 12.95 (s, 1H), 9.41 (s, 1H), 8.65 (d, 1H, J = 3.7 Hz), 8.44 (d, 1H, J = 7.8 Hz), 8.06 (d, 1H, J = 8.0 Hz), 7.46 (d, 1H, J = 7.5 Hz), 7.41 (td, 1H, J = 7.7, 1.6 Hz), 7.38 (d, 1H, J = 7.0 Hz), 7.33 (m, 3H), 7.30 (m, 2H), 7.00 (s, 1H), 4.12 (d, 1H, J = 13.8 Hz), 3.66 (d, 1H, J = 13.8 Hz).

[0251]

[0252] Synthesis Example 1-16: Chemical Formula GX-25003

[0253]

[0254] As a result of reacting according to the synthesis method (a) using the above compound (R-1) (100 mg, 0.404 mmol) and 2,3-dimethoxybenzoic acid (2,3-dimethoxybenzoic acid, 220 mg, 1.21 mmol) as the above compound (R-2), the above compound (P-1) was obtained as a white solid N-(9H-dibenzo[c,f]imidazo[1,5-a]azepine-3-yl)-2,3-dimethoxybenzamide compound having the above chemical formula GX-25003 structure. The obtained product was purified by flash column chromatography (EtOAc : n-hexane = 1 : 3) using a column packed with silica gel.

[0255] 1 H-NMR (CDCl3, 600 MHz) δ 10.12 (s, 1H), 7.59 (s, 1H), 7.55 (m, 1H), 7.40 (d, 2H, J = 7.5, 1.5 Hz), 7.32 (m, 2H), 7.27 (m, 2H), 7.22 (td, 1H, J = 7.5, 1.3 Hz), 7.15 (m, 1H), 7.12 (m, 1H), 7.08 (dd, 1H, J = 8.1, 1.7 Hz), 4.13 (d, 1H, J = 13.5 Hz), 3.93 (s, 3H), 3.90 (s, 3H), 3.68 (d, 1H, J = 13.5 Hz).

[0256]

[0257] Synthesis Example 1-17: Chemical formula GX-25004

[0258]

[0259] As a result of reacting according to the synthesis method (a) using the above compound (R-1) (100 mg, 0.404 mmol) and 2-chlorobenzoic acid (190 mg, 1.21 mmol) as the above compound (R-2), a 2-chloro-N-(9H-dibenzo[c,f]imidazo[1,5-a]azepine-3-yl)benzamide compound having the chemical formula GX-25004 structure was obtained as the above compound (P-1) as a gray solid (19.0 mg, yield 12%). The obtained product was purified by flash column chromatography (EtOAc : n-hexane = 1 : 3) using a column packed with silica gel.

[0260] 1 H-NMR (CDCl3, 400 MHz) δ 7.91 (s, 1H), 7.79 (s, 1H), 7.47 (m, 1H), 7.39 (d, 1H, J = 7.8 Hz), 7.35 (m, 2H), 7.31 (m, 3H), 7.29 (m, 3H), 7.04 (s, 1H), 4.11 (d, 1H, J = 13.6 Hz), 3.64 (d, 1H, J = 13.6 Hz).

[0261]

[0262] Synthesis Example 1-18: Chemical formula GX-25005

[0263]

[0264] As a result of reacting according to the synthesis method (a) using the above compound (R-1) (100 mg, 0.404 mmol) and 2-fluoro-4-(trifluoromethyl)benzoic acid (252 mg, 1.21 mmol) as the above compound (R-2), an ivory solid (85.0 mg, yield 48%) of the N-(9H-dibenzo[c,f]imidazo[1,5-a]azepine-3-yl)-2-fluoro-4-(trifluoromethyl)benzamide compound having the chemical formula GX-25005 structure was obtained as the above compound (P-1). The obtained product was purified by flash column chromatography (EtOAc : n-hexane = 1 : 3) using a column packed with silica gel.

[0265] 1 H-NMR (CDCl3, 400 MHz) δ 12.92 (s, 1H), 8.12 (t, 1H, J = 7.7 Hz), 7.98 (d, 1H, J = 8.0 Hz), 7.47 (d, 1H, J = 7.3 Hz), 7.41 (d, 1H, J = 8.0 Hz), 7.38 (m, 2H), 7.34 (m, 3H), 7.30 (m, 2H), 7.06 (s, 1H), 4.10 (d, 1H, J = 13.7 Hz), 3.65 (d, 1H, J = 13.7 Hz).

[0266]

[0267] Synthesis Example 1-19: Chemical formula GX-25006

[0268]

[0269] As a result of reacting according to the synthesis method (a) using the above compound (R-1) (100 mg, 0.404 mmol) and 4-methoxybenzoic acid (184 mg, 1.21 mmol) as the above compound (R-2), the above compound (P-1) was obtained as a gray solid (62.7 mg, yield 41%) of N-(9H-dibenzo[c,f]imidazo[1,5-a]azepine-3-yl)-4-methoxybenzamide with the above chemical formula GX-25006 structure. The obtained product was purified by flash column chromatography (MeOH : CH2Cl2 = 1 : 100) using a column packed with silica gel.

[0270] 1 H-NMR (CDCl3, 600 MHz) δ 8.12 (d, 2H, J = 8.3 Hz), 7.99 (s, 1H), 7.46 (d, 1H, J = 7.3 Hz), 7.37 (m, 2H), 7.32 (m, 2H), 7.28 (t, 2H, J = 7.2, 1.5 Hz), 7.02 (s, 1H), 6.90 (d, 2H, J = 8.8 Hz), 4.13 (d, 1H, J = 13.7 Hz), 3.84 (s, 3H), 3.65 (d, 1H, J = 13.7 Hz).

[0271]

[0272] Synthesis Example 1-20: Chemical Formula GX-25007

[0273]

[0274] As a result of reacting according to the synthesis method (a) using the above compound (R-1) (100 mg, 0.404 mmol) and 1-naphthoic acid (209 mg, 1.21 mmol) as the above compound (R-2), an ivory solid (55.0 mg, yield 34%) of the N-(9H-dibenzo[c,f]imidazo[1,5-a]azepine-3-yl)-1-naphtamide compound having the chemical formula GX-25007 structure was obtained as the above compound (P-1). The obtained product was purified by flash column chromatography (EtOAc : n-hexane = 1 : 3) using a column packed with silica gel.

[0275] 1 H-NMR (CDCl3, 600 MHz) δ 8.48 (s, 1H), 8.02 (s, 1H), 7.92 (d, 1H, J = 8.0 Hz), 7.83 (d, 1H, J = 8.0 Hz), 7.76 (s, 1H), 7.47 (m, 3H), 7.40 (d, 2H, J = 7.3 Hz), 7.32 (m, 2H), 7.28 (m, 3H), 7.00 (s, 1H), 4.17 (s, 1H), 3.68 (s, 1H).

[0276]

[0277] Synthesis Example 1-21: Chemical formula GX-25008

[0278]

[0279] As a result of reacting according to the synthesis method (a) using the above compound (R-1) (100 mg, 0.404 mmol) and benzofuran-2-carboxylic acid (196 mg, 1.21 mmol) as the above compound (R-2), an N-(9H-dibenzo[c,f]imidazo[1,5-a]azepine-3-yl)benzofuran-2-carboxamide compound having the chemical formula GX-25008 structure was obtained as the above compound (P-1) as a yellow solid (59.0 mg, yield 37%). The obtained product was purified by flash column chromatography (EtOAc : n-hexane = 1 : 2) using a column packed with silica gel.

[0280] 1 H-NMR (CDCl3, 600 MHz) δ 12.84 (s, 1H), 8.02 (d, 1H, J = 7.9 Hz), 7.62 (d, 1H, J = 7.7 Hz), 7.57 (d, 1H, J = 8.3 Hz), 7.47 (d, 1H, J = 7.5 Hz), 7.42 (s, 1H), 7.39 (m, 2H), 7.36 (t, 1H, J = 7.7 Hz), 7.32 (m, 3H), 7.28 (m, 1H), 7.24 (t, 1H, J = 7.4 Hz), 7.07 (s, 1H), 4.13 (d, 1H, J = 13.8 Hz), 3.66 (d, 1H, J = 13.8 Hz).

[0281]

[0282] Synthesis Example 1-22: Chemical Formula GX-25009

[0283]

[0284] As a result of reacting according to the synthesis method (a) using the above compound (R-1) (100 mg, 0.404 mmol) and 2-fluoro-5-(trifluoromethyl)benzoic acid (252 mg, 1.21 mmol) as the above compound (R-2), the above compound (P-1) was obtained as a pale yellow solid (86.0 mg, yield 49%) of the N-(9H-dibenzo[c,f]imidazo[1,5-a]azepine-3-yl)-2-fluoro-5-(trifluoromethyl)benzamide compound having the above chemical formula GX-25009 structure. The obtained product was purified by flash column chromatography (EtOAc : n-hexane = 1 : 3) using a column packed with silica gel.

[0285] 1 H-NMR (CDCl3, 600 MHz) δ 8.36 (s, 1H), 8.00 (s, 1H), 7.63 (d, 1H, J = 7.3 Hz), 7.47 (d, 1H, J = 7.5 Hz), 7.38 (m, 2H), 7.34 (d, 2H, J = 4.1 Hz), 7.30 (m, 2H), 7.19 (t, 1H, J = 9.4 Hz), 7.07 (s, 1H), 4.10 (d, 1H, J = 13.7 Hz), 3.66 (d, 1H, J = 13.8 Hz).

[0286]

[0287] Synthesis Example 1-23: Chemical formula GX-25010

[0288]

[0289] As a result of reacting according to the synthesis method (a) using the above compound (R-1) (100 mg, 0.404 mmol) and pyrazine-2-carboxylic acid (150 mg, 1.21 mmol) as the above compound (R-2), an N-(9H-dibenzo[c,f]imidazo[1,5-a]azepine-3-yl)pyrazine-2-carboxamide compound with the chemical formula GX-25010 structure was obtained as the above compound (P-1) as a yellow solid (74.0 mg, yield 52%). The obtained product was purified by flash column chromatography (EtOAc : n-hexane = 1 : 2) using a column packed with silica gel.

[0290] 1 H-NMR (CDCl3, 600 MHz) δ 9.92 (s, 1H), 9.40 (s, 1H), 8.73 (s, 1H), 8.62 (s, 1H), 7.52 (d, 1H, J = 6.8 Hz), 7.42 (d, 1H, J = 7.3 Hz), 7.34 (d, 1H, J = 7.0 Hz), 7.29 (m, 4H), 4.12 (d, 1H, J = 13.6 Hz), 3.69 (d, 1H, J = 13.7 Hz).

[0291]

[0292] Synthesis Example 1-24: Chemical Formula GX-25011

[0293]

[0294] As a result of reacting according to the synthesis method (a) using the above compound (R-1) (100 mg, 0.404 mmol) and pyridazine-3-carboxylic acid (150 mg, 1.21 mmol) as the above compound (R-2), an ivory solid (85.0 mg, yield 60%) of the N-(9H-dibenzo[c,f]imidazo[1,5-a]azepine-3-yl)pyridazine-3-carboxamide compound having the chemical formula GX-25011 structure was obtained as the above compound (P-1). The obtained product was purified by flash column chromatography (EtOAc : n-hexane = 1 : 2) using a column packed with silica gel.

[0295] 1 H-NMR (CDCl3, 600 MHz) δ 10.38 (s, 1H), 9.32 (dd, 1H, J = 5.1, 1.7 Hz), 8.29 (dd, 1H, J = 8.4, 1.7 Hz), 7.66 (m, 1H), 7.56 (m, 1H), 7.48 (s, 1H), 7.41 (d, 1H, J = 7.4 Hz), 7.35 (s, 1H), 7.32 (m, 1H), 7.29 (m, 2H), 7.24 (d, 1H, J = 7.4 Hz), 7.19 (t, 1H, J = 7.5 Hz), 4.11 (d, 1H, J = 13.6 Hz), 3.70 (d, 1H, J = 13.6 Hz).

[0296]

[0297] Synthesis Example 1-25: Chemical formula GX-25012

[0298]

[0299] As a result of reacting according to the synthesis method (a) using the above compound (R-1) (100 mg, 0.404 mmol) and thiophene-2-carboxylic acid (155 mg, 1.21 mmol) as the above compound (R-2), an ivory solid (84.0 mg, yield 58%) of the N-(9H-dibenzo[c,f]imidazo[1,5-a]azepine-3-yl)thiophene-2-carboxamide compound having the chemical formula GX-25012 structure was obtained as the above compound (P-1). The obtained product was purified by flash column chromatography (EtOAc : n-hexane = 1 : 6) using a column packed with silica gel.

[0300] 1 H-NMR (CDCl3, 600 MHz) δ 12.71 (s, 1H), 8.07 (d, 1H, J = 8.0 Hz), 7.76 (d, 1H, J = 3.6 Hz), 7.44 (d, 1H, J = 7.5 Hz), 7.40 (m, 2H), 7.36 (d, 1H, J = 7.6, 1.6 Hz), 7.33 (m, 2H), 7.29 (m, 2H), 7.06 (m, 1H), 6.97 (s, 1H), 4.12 (d, 1H, J = 13.8 Hz), 3.64 (d, 1H, J = 13.8 Hz).

[0301]

[0302] Synthesis Example 1-26: Chemical formula GX-25013

[0303]

[0304] As a result of reacting according to the synthesis method (a) using the above compound (R-1) (100 mg, 0.404 mmol) and 2,4-dimethoxybenzoic acid (2,4-dimethoxybenzoic acid, 220 mg, 1.21 mmol) as the above compound (R-2), the above compound (P-1) was obtained as a white solid N-(9H-dibenzo[c,f]imidazo[1,5-a]azepine-3-yl)-2,4-dimethoxybenzamide compound having the chemical formula GX-25013 structure (119 mg, yield 72%). The obtained product was purified by flash column chromatography (EtOAc : n-hexane = 1 : 2) using a column packed with silica gel.

[0305] 1 H-NMR (CDCl3, 600 MHz) δ 9.85 (s, 1H), 8.07 (d, 1H, J = 8.8 Hz), 7.54 (m, 1H), 7.42 (d, 1H, J = 7.9 Hz), 7.40 (dd, 1H, J = 7.5, 1.5 Hz), 7.31 (m, 2H), 7.25 (m, 2H), 7.22 (td, 1H, J = 7.6, 1.3 Hz), 7.14 (m, 1H), 6.57 (dd, 1H, J = 8.8, 2.3 Hz), 6.49 (d, 1H, J = 2.3 Hz), 4.13 (d, 1H, J = 13.5 Hz), 3.90 (s, 3H), 3.85 (s, 3H), 3.67 (d, 1H, J = 13.5 Hz).

[0306]

[0307] Synthesis Example 1-27: Chemical formula GX-25014

[0308]

[0309] As a result of reacting according to the synthesis method (a) using the above compound (R-1) (100 mg, 0.404 mmol) and 2,5-dimethoxybenzoic acid (220 mg, 1.21 mmol) as the above compound (R-2), the above compound (P-1) was obtained as a white solid, N-(9H-dibenzo[c,f]imidazo[1,5-a]azepine-3-yl)-2,5-dimethoxybenzamide compound having the above chemical formula GX-25014 structure (115 mg, yield 69%). The obtained product was purified by flash column chromatography (EtOAc : n-hexane = 1 : 2) using a column packed with silica gel.

[0310] 1 H-NMR (CDCl3, 400 MHz) δ 10.12 (s, 1H), 7.61 (d, 1H, J = 3.2 Hz), 7.55 (m, 1H), 7.42 (m, 1H), 7.40 (m, 1H), 7.31 (m, 2H), 7.27 (m, 1H), 7.26 (m, 1H), 7.23 (m, 1H), 7.15 (td, 1H, J = 7.7, 1.6 Hz), 7.04 (dd, 1H, J = 9.0, 3.3 Hz), 6.94 (d, 1H, J = 9.0 Hz), 4.13 (d, 1H, J = 13.4 Hz), 3.90 (s, 3H), 3.77 (s, 3H), 3.68 (d, 1H, J = 13.5 Hz).

[0311]

[0312] Synthesis Example 1-28: Chemical formula GX-25015

[0313]

[0314] As a result of reacting according to the synthesis method (a) using the above compound (R-1) (100 mg, 0.404 mmol) and isonicotinic acid N-oxide (169 mg, 1.21 mmol) as the above compound (R-2), a 4-(9H-dibenzo[c,f]imidazo[1,5-a]azepine-3-yl)carbamoyl)pyridine 1-oxide compound having the chemical formula GX-25015 structure was obtained as the above compound (P-1) as a yellow solid (33.0 mg, yield 22%). The obtained product was purified by flash column chromatography (EtOAc : n-hexane = 1 : 2) using a column packed with silica gel.

[0315] 1 H-NMR (CDCl3, 600 MHz) δ 12.85 (s, 1H), 8.18 (d, 2H, J = 6.3 Hz), 8.03 (d, 2H, J = 6.2 Hz), 7.97 (d, 1H, J = 7.9 Hz), 7.46 (d, 1H, J = 7.5) Hz), 7.43 (m, 1H), 7.40 (d, 1H, J = 6.1 Hz), 7.35 (m, 3H), 7.30 (m, 1H), 7.01 (s, 1H), 4.11 (d, 1H, J = 13.8 Hz), 3.67 (d, 1H, J = 13.9 Hz).

[0316]

[0317] Synthesis Example 1-29: Chemical formula GX-25016

[0318]

[0319] As a result of reacting according to the synthesis method (a) using the above compound (R-1) (100 mg, 0.404 mmol) and pyrimidine-2-carboxylic acid (150 mg, 1.21 mmol) as the above compound (R-2), an N-(9H-dibenzo[c,f]imidazo[1,5-a]azepine-3-yl)pyrimidine-2-carboxamide compound having the chemical formula GX-25016 structure was obtained as the above compound (P-1) as a pale yellow solid (58.0 mg, yield 41%). The obtained product was purified by flash column chromatography (EtOAc : n-hexane = 1 : 2) using a column packed with silica gel.

[0320] 1 H-NMR (CDCl3, 400 MHz) δ 10.12 (s, 1H), 8.89 (d, 2H, J = 4.9 Hz), 7.54 (m, 1H), 7.46 (t, 1H, J = 4.9 Hz), 7.39 (dd, 1H, J = 7.4, 1.6 Hz), 7.32 (m, 2H), 7.28 (m, 2H), 7.26 (m, 1H), 7.23 (td, 1H, J = 7.6, 1.4 Hz), 7.17 (t, 1H, J = 7.7 Hz), 4.13 (d, 1H, J = 13.5 Hz), 3.67 (d, 1H, J = 13.6 Hz.

[0321]

[0322] Synthesis Example 1-30: Chemical formula GX-25017

[0323]

[0324] As a result of reacting according to the synthesis method (a) using the above compound (R-1) (100 mg, 0.404 mmol) and picolinic acid N-oxide (169 mg, 1.21 mmol) as the above compound (R-2), the compound 2-((9H-dibenzo[c,f]imidazo[1,5-a]azepine-3-yl)carbamoyl)pyridine 1-oxide with the chemical formula GX-25017 structure was obtained as the above compound (P-1) as a yellow solid (36.0 mg, yield 24%). The obtained product was purified by flash column chromatography (EtOAc : n-hexane = 1 : 2) using a column packed with silica gel.

[0325] 1 H-NMR (CDCl3, 600 MHz) δ 8.43 (dd, 1H, J = 8.0, 2.3 Hz), 8.26 (dd, 1H, J = 6.4, 1.3 Hz), 7.55 (m, 1H), 7.49 (m, 1H), 7.46 (m, 1H), 7.44 (m, 1H), 7.41 (m, 1H), 7.37 (s, 1H), 7.31 (m, 1H), 7.28 (m, 1H), 7.27 (m, 2H), 7.25 (m, 1H), 4.06 (d, 1H, J = 13.5 Hz), 3.67 (d, 1H, J = 13.5 Hz).

[0326]

[0327] Synthesis Example 1-31: Chemical formula GX-25018

[0328]

[0329] As a result of reacting according to the synthesis method (a) using the above compound (R-1) (100 mg, 0.404 mmol) and pyrimidine-4-carboxylic acid (150 mg, 1.21 mmol) as the above compound (R-2), an N-(9H-dibenzo[c,f]imidazo[1,5-a]azepine-3-yl)pyrimidine-4-carboxamide compound having the chemical formula GX-25018 structure was obtained as the above compound (P-1) as a yellow solid (56.0 mg, yield 39%). The obtained product was purified by flash column chromatography (EtOAc : n-hexane = 1 : 2) using a column packed with silica gel.

[0330] 1 H-NMR (CDCl3, 600 MHz) δ 9.30 (s, 1H), 8.93 (d, 1H, J = 5.0 Hz), 8.07 (d, 1H, J = 5.6 Hz), 7.61 (s, 1H), 7.53 (m, 1H), 7.42 (dd, 1H, J = 7.5 Hz), 7.34 (m, 2H), 7.30 (m, 3H), 7.25 (m, 1H), 4.11 (d, 1H, J = 13.6 Hz), 3.70 (d, 1H, J = 13.6 Hz).

[0331]

[0332] Synthesis Example 1-32: Chemical formula GX-25019

[0333]

[0334] As a result of reacting according to the synthesis method (a) using the above compound (R-1) (100 mg, 0.404 mmol) and nicotinic acid N-oxide (169 mg, 1.21 mmol) as the above compound (R-2), the compound 3-((9H-dibenzo[c,f]imidazo[1,5-a]azepine-3-yl)carbamoyl)pyridine 1-oxide with the chemical formula GX-25019 structure was obtained as the above compound (P-1) as an ivory solid (62.0 mg, yield 42%). The obtained product was purified by flash column chromatography (EtOAc : n-hexane = 1 : 2) using a column packed with silica gel.

[0335] 1 H-NMR (CDCl3, 600 MHz) δ 12.85 (s, 1H), 9.00 (s, 1H), 8.31 (d, 1H, J = 6.3 Hz), 8.09 (d, 1H, J = 7.9 Hz), 7.94 (d, 1H, J = 8.0 Hz), 7.46 (d, 1H, J = 7.5 Hz), 7.43 (m, 1H), 7.39 (m, 1H), 7.35 (m, 3H), 7.30 (m, 2H), 7.03 (s, 1H), 4.10 (d, 1H, J = 13.8 Hz), 3.67 (d, 1H, J) = 13.8 Hz).

[0336]

[0337] Synthesis Example 2: Compound of Formula GX-25000

[0338]

[0339] Synthesis method (b): A compound of the chemical formula GX-24006 (90.0 mg, 0.236 mmol) prepared in Synthesis Examples 1-6 was dissolved in a dichloromethane (CH2Cl2) solution being stirred, and then boron tribromide (BBr3, 236 μL of 1.0 M CH2Cl2 solution) was slowly added at 0°C. Subsequently, the mixture was stirred for approximately 3 hours at room temperature. After the reaction was complete, water (H2O) was added to stop the reaction, and the product was extracted with dichloromethane (CH2Cl2). The organic layer was collected, dried with anhydrous magnesium sulfate (MgSO4), and then concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc : n-hexane = 1 : 3) using a column packed with silica gel to obtain N-(9H-dibenzo[c,f]imidazo[1,5-a]azepine-3-yl)-2-hydroxybenzamide of the chemical formula GX-25000 structure as a gray solid compound 15 (31.0 mg, yield 35%).

[0340] 1 H-NMR (CDCl3, 600 MHz) δ 13.38 (s, 1H), 13.02 (s, 1H), 8.11 (dd, 1H, J = 7.9, 1.8 Hz), 7.91 (d, 1H, J = 8.0 Hz), 7.46 (m, 2H), 7.41 (dd, 1H, J = 7.6, 1.6 Hz), 7.37 (d, 1H, J = 7.5, 1.2 Hz), 7.34 (m, 3H), 7.30 (m, 1H), 7.00 (s, 1H), 6.89 (m, 1H), 6.86 (m, 1H), 4.11 (d, 1H, J = 13.8 Hz), 3.67 (d, 1H, J = 13.8 Hz)

[0341]

[0342] Synthesis Example 3: Compounds of Formulas GX-25020 and GX-25021

[0343]

[0344] Synthesis method (c): Oxalyl chloride (5.0 equivalents) and one drop of dimethylformamide (DMF) were added at room temperature to a dichloromethane (CH2Cl2) solution containing the carboxylic acid (2.5 equivalents) of the compound (R-3). Subsequently, the mixture was stirred for 1 hour, concentrated in vacuum, and diluted with dichloromethane (CH2Cl2). Then, a dichloromethane (CH2Cl2) solution containing the compound (R-1) was added, and the mixture was stirred for an additional 4 hours at room temperature. After the reaction was complete, water (H2O) was added to stop the reaction, and the mixture was extracted with dichloromethane (CH2Cl2). The organic layer was collected, dried with anhydrous magnesium sulfate (MgSO4), and then concentrated under vacuum. The residue was purified by flash column chromatography using a silica gel column.

[0345] Synthesis method (d): Tetra-n-butylammonium fluoride (TBAF, 1.5 equivalents) was added at room temperature to a tetrahydrofuran (THF) solution containing the compound (P-2) obtained by synthesis method (c). Then, after stirring for 15 minutes, water (H2O) was added to terminate the reaction. Afterward, the product containing a compound of the structure of the compound (P-3) was extracted with dichloromethane (CH2Cl2), the organic layer was collected, dried with anhydrous magnesium sulfate (MgSO4), and concentrated under reduced pressure. The residue was purified by flash column chromatography using a silica gel column.

[0346] The chemical structure of the compound (P-2) is determined according to the structure of ring C of the compound (R-3), and the structure of ring D of the compound (P-3) is determined according to the structure of ring C of the compound (P-2). Specific examples of these are described in detail in Synthesis Examples 3-1 to 3-2 below.

[0347]

[0348] Synthesis Example 3-1: Chemical formula GX-25020

[0349]

[0350] As a result of reacting according to the synthesis method (c) using the above compound (R-1) (100 mg, 0.404 mmol) and 3-((tert-butyldimethylsilyl)oxy)benzoic acid (255 mg, 1.01 mmol) as the above compound (R-3), 3-((tert-butyldimethylsilyl)oxy)-N-(9H-dibenzo[c,f]imidazo[1,5-a]azepine-3-yl)benzamide as the above compound (P-2) was obtained as a purple solid compound (83.0 mg, yield 43%). Purification was performed by silica gel column chromatography (MeOH : CH2Cl2 = 1 : 30).

[0351] 1 H-NMR (CDCl3, 400 MHz) δ 7.96 (s, 1H), 7.80 (d, 1H, J = 8.0 Hz), 7.63 (s, 1H), 7.46 (dd, 1H, J = 7.0, 1.3 Hz), 7.38 (dd, 1H, J = 7.3, 1.8 Hz), 7.34 (m, 3H), 7.31 (m, 1H), 7.28 (m, 2H), 7.07 (s, 1H), 6.94 (m, 1H), 4.14 (d, 1H, J = 13.7 Hz), 3.67 (d, 1H, J = 13.7 Hz), 0.98 (s, 9H), 0.19 (d, 6H, J = 0.8 Hz).

[0352] Using 3-((tert-butyldimethylsilyl)oxy)-N-(9H-dibenzo[c,f]imidazo[1,5-a]azepine-3-yl)benzamide (70.0 mg, 0.145 mmol) obtained as compound (P-2), the reaction was carried out according to the synthesis method (d) above. After the reaction was completed, the product was purified to obtain N-(9H-dibenzo[c,f]imidazo[1,5-a]azepine-3-yl)-3-hydroxybenzamide with the chemical formula GX-250020 structure as compound (P-3) as a pale purple solid compound 37 (50.0 mg, yield 93%). Purification was performed by silica gel column chromatography (MeOH : CH2Cl2 = 1 : 30).

[0353] 1 H-NMR (DMSO-d6, 600 MHz) δ 10.72 (s, 1H), 9.75 (s, 1H), 7.57 (m, 1H), 7.50 (d, 1H, J = 7.4 Hz), 7.43 (m, 2H), 7.35 (s, 1H), 7.31 (m, 3H), 7.23 (m, 4H), 6.96 (s, 1H), 3.86 (d, 1H, J = 12.7 Hz), 3.77 (s, 1H).

[0354]

[0355] Synthesis Example 3-2: Chemical Formula GX-25021

[0356]

[0357] As a result of reacting according to the synthesis method (c) using the above compound (R-1) (100 mg, 0.404 mmol) and 4-((tert-butyldimethylsilyl)oxy)benzoic acid (255 mg, 1.01 mmol) as the above compound (R-3), 4-((tert-butyldimethylsilyl)oxy)-N-(9H-dibenzo[c,f]imidazo[1,5-a]azepine-3-yl)benzamide as the above compound (P-2) was obtained as a white solid compound (62.7 mg, yield 32%). Purification was performed by silica gel column chromatography (EtOAc : n-hexane = 1 : 3).

[0358] 1 H-NMR (CDCl3, 600 MHz) δ 8.06 (d, 2H, J = 8.2 Hz), 7.96 (s, 1H), 7.45 (d, 1H, J = 7.2 Hz), 7.37 (dd, 1H, J = 7.6, 1.6 Hz), 7.33 (m, 3H), 7.30 (m, 3H), 7.27 (m, 3H), 7.04 (s, 1H), 6.83 (m, 2H), 4.13 (d, 1H, J = 13.7 Hz), 3.65 (d, 1H, J = 13.8 Hz), 0.98 (s, 9H), 0.20 (s, 6H).

[0359] Using 4-((tert-butyldimethylsilyl)oxy)-N-(9H-dibenzo[c,f]imidazo[1,5-a]azepine-3-yl)benzamide (52.7 mg, 0.109 mmol) obtained as compound (P-2), the reaction was carried out according to the synthesis method (d) above. After the reaction was completed, the product was purified to obtain N-(9H-dibenzo[c,f]imidazo[1,5-a]azepine-3-yl)-4-hydroxybenzamide with the chemical formula GX-250021 structure as compound (P-3) as a dark purple solid compound (41.0 mg, yield 97%). Purification was performed by silica gel column chromatography (MeOH : CH2Cl2 = 1 : 30).

[0360] 1H-NMR (DMSO-d6, 600 MHz) δ 10.56 (s, 1H), 10.17 (s, 1H), 7.74 (s, 2H), 7.56 (m, 1H), 7.49 (d, 1H, J = 7.6 Hz), 7.43 (m, 2H), 7.34 (s, 1H), 7.30 (m, 2H), 7.20 (m, 2H), 6.81 (d, 2H, J = 7.8 Hz), 3.85 (d, 1H, J = 13.2 Hz), 3.77 (s, 1H).

[0361]

[0362] <Examples and Comparative Examples>

[0363] Example 1: Inhibitory effect on cell proliferation of blood cancer cell lines

[0364] Each of the following human-derived cell lines was stabilized by culturing them in RPMI medium, a cell culture medium, for one week, and then 10,000 cells were seeded into each group.

[0365] HL-60: Acute myeloid leukemia (AML) cell line

[0366] K-562: Chronic Myeloid Leukemia (CML) cell line

[0367] Reh: Acute lymphoblastic leukemia (ALL) cell line

[0368] U937: Lymphoma cell line

[0369] Each of the 35 compounds of the chemical formulas GC-24001 to GX-24013 and GX-25000 to GX-25021 prepared through Synthesis Examples 1-1 to 1-32, Synthesis Example 2, and Synthesis Examples 3-1 to 3-2 were used as Examples 1-1 to 1-35, and each of the blood cancer cell lines was treated with 10 μM and cultured for 4 days to confirm the cell proliferation inhibitory effect.

[0370] In addition, comparative examples were composed as follows, and the cell proliferation inhibitory effect was confirmed for each:

[0371] Comparative Example 1-1: DMSO 0.1% treated control group,

[0372] Comparative Example 1-2: Polyethylene Glycol (Polyethylene Glycol 400, PEG-400) treated control group,

[0373] Comparative Examples 1-3: Group treated with the existing CML treatment Imatinib 10μM, and

[0374] Comparative Examples 1-4: Group treated with 10μM of the existing ALL treatment Vincristine.

[0375] The quantitative results of some of the above examples and each of the above comparative examples are shown in Table 1 below.

[0376] In addition, as an example of the above examples, photographs of the culture results at different concentrations for each cell line of Examples 1-22 (compound of chemical formula GX-250008) are shown in Figure 2.

[0377] In addition, graphs of the cell proliferation inhibitory effects at different concentrations on H-60 ​​cell lines for each of the above Examples 1-1 to 1-31 (chemical formulas GX-24001 to 24013; and chemical formulas GX-25000 to 25017) are shown in FIG. 3. Specifically, FIG. 3(a) shows the results for the treatment group at a concentration of 1 μM of each example, (b) shows the results for the treatment group at a concentration of 5 μM of each example, and (c) shows the results for the treatment group at a concentration of 10 μM of each example.

[0378]

[0379] Classification Cell Line K-562HL-60RehU937 Unit %%%% Comparative Example 1-1 DMSO 100 100 100 100 Comparative Example 1-2 PEG 4 00 100 100 100 100 Comparative Example 1-3 Imatinib 5.40 --- Comparative Example 1-4 Vincristine 2.40 --- Example 1-1 GX-2400 127.8 30.00 2.05 4.95 Example 1-3 GX-2400 320.29 1.21 0.21 2.94 Example 1-5 GX-2400 526.38 1.8 21.03 3.12 Example 1-7 GX-2400 76 1.16 1.8 20.8 36.79 Example 1-8GX-2400830.312.424.744.02 Example 1-9GX-2400924.640.003.081.28 Example 1-10GX-240101002.123.3922.03 Example 1-11GX-240111001.8212.42100 Example 1-14GX-2500026.091.071.642.75 Example 1-15GX-2500127.831.781.644.04 Example 1-17GX-2500372.171.071.442.39 Example 1-20GX-250061002.492.7119.16 Example 1-22GX-2500822.381.070.234.02 Example 1-23GX-2500934.282.142.935.94 Example 1-26GX-2501223.480.001.231.65 Example 1-29GX-2501510099.64100100 Example 1-30GX-2501633.9910042.66100 Example 1-31GX-2501710095.73100100

[0380]

[0381] Example 2: Inhibitory effect on cell proliferation of cervical cancer cell lines

[0382] The inhibitory effect on cell proliferation of human-derived cervical cancer cell lines (HeLa) was confirmed for some of the compounds of Examples 1-1 to 1-35, specifically the compounds of Examples 1-3, 1-5, 1-7, 1-11, 1-14, and 1-22.

[0383] Specifically, the above HeLa cell line was stabilized by subculturing in DMEM cell culture medium for one week, and then 90,000 cells were seeded into a 35 mm cell culture dish.

[0384] Comparative Example 1-1: The control group treated with 0.1% DMSO and the groups treated with 10 μM of the compounds of Examples 1-3, 1-5, 1-7, 1-11, 1-14 and 1-22 were cultured for 4 days, and the number of cells was measured.

[0385] As a result, in the case of Comparative Example 1-1 above, more than 1.8 million cells proliferated, but in the case of each of the above Examples above, a proliferation inhibition effect of more than 80% compared to Comparative Example 1-1 was observed. The results are described in [Table 2] below.

[0386]

[0387] Classification Cell Line HeLa Unit % Comparative Example 1-1 DMSO 100 Example 1-3 GX-2400 3 10.64 Example 1-5 GX-2400 5 12.50 Example 1-7 GX-2400 7 13.83 Example 1-11 GX-240 1 118.35 Example 1-14 GX-2500 24.47 Example 1-22 GX-2500 8 11.44

[0388]

[0389] Referring to [Table 2] above, it was confirmed that the compounds of Examples 1-3, 1-5, 1-7, 1-11, 1-14 and 1-22 exhibited anticancer effects not only in blood cancer but also in solid tumors such as cervical cancer.

[0390]

[0391] Example 3: Evaluation of cytotoxicity against normal cells

[0392] To confirm the non-specific cytotoxicity of the compounds of Examples 1-3, 1-5, 1-7, 1-11, 1-14, and 1-22 on normal cells, normal human epithelial cell lines, WISH cells, Normal Stomach Epithelial Cells (NSC), and human embryonic kidney cells (HEK 293) were cultured, respectively. The results for the WISH cells treated with Comparative Example 1-1: 0.1% DMSO control group and the 10 μM treatment groups of each of the compounds of Examples 1-3, 1-5, 1-7, 1-11, 1-14, and 1-22 are shown in the graph (a) and culture dish photograph (b) of Figure 4.

[0393] In addition, as a graph of the number of cells over time of treatment results for the WISH cells, the results for Comparative Example 1-4: the group treated with 10 μM of the existing acute myeloid leukemia (ALL) treatment drug Vincristine, and the group treated with 10 μM of the compounds of Comparative Example 1-1 and Example 1-14 are shown in FIG. 4 (c).

[0394] In addition, as a graph of the results of the toxicity evaluation on the NSC cells and HEK 293 cells, the results for Comparative Example 1-4: the group treated with 10 μM of the existing acute myeloid leukemia (ALL) treatment vincristine, and the group treated with 10 μM of the compounds of Comparative Example 1-1 and Example 1-14 (GX-25000) are shown in FIG. 4 (d).

[0395] Referring to FIG. 4 (a) to (d), it was found that the compounds of Examples 1-3, 1-5, 1-7, 1-11, 1-14 and 1-22 according to one embodiment of the present invention are not toxic to normal cells and have an anticancer effect that induces apoptosis that selectively acts on cancer cells.

[0396]

[0397] Example 4: Cardiotoxicity Evaluation

[0398] Cardiotoxicity was evaluated by assessing whether the compounds of Examples 1-3, 1-5, 1-7, 1-9, 1-11, 1-14, and 1-22 inhibited hERG transport pathways. When quinidine was used as the most standard positive control in the hERG inhibition test, the half maximal inhibitory concentration (IC10) 50 It was confirmed to be 1.2 μM, which was consistent with the literature value.

[0399] The inhibitory effect of the compounds of Examples 1-3, 1-5, 1-7, 1-9, 1-11, 1-14, and 1-22 on the hERG migration pathway is shown in the graph of Figure 5.

[0400] Referring to FIG. 5, the compound of each of the above examples has a mild to moderate inhibitory effect on the hERG migration pathway, i.e., IC 50 It was confirmed that all of these exceeded 20 μM, and in particular, in the case of Examples 1-3, 1-14, and 1-22, IC 50 All of these were found to be 100 μM or higher, confirming that they are very safe in terms of cardiotoxicity.

[0401]

[0402] Example 5: Tumor growth inhibitory effect

[0403] As a representative compound according to one embodiment, the tumor growth inhibitory effect of the compound of Examples 1-14 (GX-25000) was evaluated in an HL-60 cell xenograft model using BALB / c mice. Specifically, after inducing tumor formation by subcutaneously injecting the HL-60 cells into the BALB / c mice, the tumor size was approximately 300 mm 3 At the point of growth above this level, the test group and control group were distinguished and evaluated.

[0404] The above test group was prepared by dissolving the compound of Example 1-14 (GX-25000) in a polyethylene glycol (PEG400) solvent to make a 150 μM solution and administering it, and the above control group was the polyethylene glycol (Polyethylene Glycol 400, PEG-400) treatment group of Comparative Example 1-2.

[0405] 200 μL was administered intraperitoneally to mice of each of the above test group and control group at 1-day intervals. The sample size (n) for each test group and control group was set to 4. The results are as shown in Figure 6.

[0406] Referring to Fig. 6, in the case of the control group, the tumor volume increased by 437.3±64.3% (n=4) on the 7th day of administration, whereas in the case of the test group, the increase in tumor volume was only 146.7±24.6% (n=4). That is, it can be seen that the compound of Example 1-14 (GX-25000) according to one embodiment clearly demonstrates a tumor growth inhibitory effect in an in vivo model.

[0407]

[0408] Example 6: Confirmation of mechanism through RNA analysis

[0409] As a representative compound according to one embodiment, the molecular mechanism of action of anticancer activity was elucidated through transcriptome (RNA-seq) analysis in cells treated with the compound of Example 1-14 (GX-25000). Specifically, the compound of Example 1-14 (GX-25000) was subjected to transcriptome analysis (RNA sequencing, RNA-seq) on HL-60 cells, a human acute myeloid leukemia (AML) cell line.

[0410] The above HL-60 cells were treated with 10 μM of the compound of Examples 1-14 (GX-25000), and the control group was treated with DMSO (0.1%) under the same conditions. After 24 hours of treatment, total RNA was extracted and sequenced using the 150 bp paired-end method with the Illumina platform.

[0411] Differentially expressed genes (DEG; padj < 0.05) were identified using DESeq2 and subsequently evaluated using Gene Set Enrichment Analysis (GSEA). The specific analysis items were categorized into Hallmark gene set, Gene Ontology: Biological Process (GO:BP), Gene Ontology: Molecular Function (GO:MF), Gene Ontology: Cellular Component (GO:CC), Chemical & Genetic Perturbation, and Transcription Factor Target (C3:TFT).

[0412] Each result is shown in Figures 7 (a) to (f).

[0413]

[0414] (1) Hallmark analysis results

[0415] When treated with the compound of Examples 1-14 (GX-25000) above, immune and inflammation-related pathways such as TNFα signaling, interferon response (IFN), and the IL6 / JAK / STAT3 pathway were significantly activated: (NES > 0, padj < 0.01),

[0416] On the other hand, pathways related to cell proliferation signals, such as MYC targets and E2F targets, were inhibited, and it was confirmed that the compound of Examples 1-14 (GX-25000) exhibited an action accompanied by cell proliferation inhibition and immune activation.

[0417] In addition, it was confirmed that the Unfolded Protein Response (UPR) related pathway is activated, leading to increased intracellular protein stress and inducing apoptosis caused by endoplasmic reticulum stress (ER stress).

[0418] Through these results, it can be confirmed that the compound of Example 1-14 (GX-25000) inhibits the growth and division of cancer cells while simultaneously exhibiting anticancer activity through immune and stress responses.

[0419]

[0420] (2) GO Analysis Results

[0421] GO: Biological Process (BP) analysis results confirmed that biological processes related to stress, immunity, and inflammation, such as acute-phase response, T cell-mediated cytotoxicity, and inflammatory response, were significantly activated in the group treated with the compounds of Examples 1-14 (GX-25000).

[0422] GO: As a result of Molecular Function (MF) analysis, it was confirmed that immune-related signaling functions, such as immune receptor activity and cytokine receptor binding, were increased in the treatment group of the compounds of Examples 1-14 (GX-25000), while the functions of ATP-dependent protein folding chaperone and RNA splicing factor activity were inhibited.

[0423] GO: Cellular Component (CC) analysis results showed that in the group treated with the compounds of Examples 1-14 (GX-25000), genes related to cellular organelles involved in protein synthesis, such as cytosolic ribosomes and ribosomal subunits, were relatively increased, and inhibition of the protein folding chaperone complex and spliceosomal complex gene groups was observed.

[0424] Through these results, it can be confirmed that the compound of Examples 1-14 (GX-25000) increases the expression of genes related to protein synthesis at the ribosome level, but reduces the efficiency of subsequent protein folding and splicing quality control processes, thereby inducing the accumulation of protein stress within the cell and consequently reducing the viability of cancer cells.

[0425]

[0426] (3) Analysis results of chemical and genetic perturbation

[0427] When treated with the compound of Examples 1-14 (GX-25000), the EIF2AK4 / GCN2 signaling pathway and the ATF4 activation pathway were significantly activated (NES > 0, p.adj < 0.01). This means that the compound of Examples 1-14 (GX-25000) detects intracellular amino acid deficiency or abnormal protein synthesis conditions, activates GCN2 (EIF2AK4) signaling, and selectively activates the ATF4 transcription factor (activating transcription factor 4) through eIF2α phosphorylation, thereby inducing stress response gene expression. In other words, it means that it induces amino acid deficiency-like signaling and apoptotic ER stress centered on the GCN2 (eIF2AK4)-eIF2α-ATF4-CHOP axis. In particular, the selective activation of the ATF4 / CHOP axis indicates that a terminal UPR, i.e., an apoptosis-inducing UPR, is being induced rather than a restorative UPR (ATF6 / XBP1 pathway).

[0428] Through these results, it can be confirmed that the compound of Examples 1-14 (GX-25000) increases protein folding load, inhibits recovery UPR (ATF6 / XBP1 axis), and induces terminal UPR (ATF4-CHOP axis), thereby blocking the survival pathway of cancer cells and promoting apoptosis.

[0429]

[0430] (4) Transcription factor target gene set (C3:TFT) analysis results

[0431] In the group treated with the compound of Examples 1-14 (GX-25000), both the CHOP_01 and CEBPB_01 gene sets were activated (NES > 0, p.adj < 0.01). This means that the compound of Examples 1-14 (GX-25000) strongly induces a transcriptional stress program centered on the PERK-eIF2α-ATF4-CHOP axis. The simultaneous activation of CHOP and C / EBPβ is known to be a key indicator of the apoptotic ER stress program.

[0432] Therefore, it can be confirmed that the compound of Example 1-14 (GX-25000) induces an imbalance in protein synthesis and quality control, thereby activating ER stress and inducing selective death of leukemia cells through an ATF4-CHOP-centered apoptotic UPR.

[0433]

[0434] When combining the results of (1) to (4) above, as summarized in [Table 3] below, it can be seen that the compound according to one embodiment exhibits selective activation of the GCN2-eIF2α-ATF4-CHOP axis; inhibition of the ATF6 / XBP1-related recovery type UPR; induction of nutrient deficiency-based endoplasmic reticulum stress and conversion to a death type UPR; and simultaneous activation of immune and inflammatory response pathways. As a result, it can be confirmed that it acts as a protein stress-based apoptosis-inducing anticancer candidate substance and is a new therapeutic candidate substance with a complex anticancer mechanism that is differentiated from existing compounds.

[0435]

[0436] Analysis Items Major Activation Pathways Inhibition Pathways Results Hallmarks TNFα IFN, IL6 / JAK / STAT3MYC, E2F Inhibition of proliferation signaling, activation of stress response GO Immune / inflammatory proteins Stress proteins Folding RNS Fragmentation proteins Quality Control Inhibition ER Stress Induction Chemical disturbance GCN2(eIF2AK4)-eIF2α-ATF4-CHOP-Nutrient-deficient ER Stress Induction C3:TFTCHOP, C / EBPβATF6 / XBP1 Apoptotic UPR Mild Action

Claims

1. A compound represented by the following chemical formula (1), comprising one or more active ingredients selected from the group consisting of pharmaceutically acceptable salts, hydrates, sorbates, prodrugs, and combinations thereof, said compound, said compound, said compound, said compound, said compound, said compound, said compound, said compound, and one or more active ingredients selected from the group consisting of said compound, and one or more active ingredients selected thereof, said compound Composition for the prevention or treatment of malignant neoplasms: In the above chemical formula (1), The above X1, X2, and X3 are identical or different from each other, and each is independently N or C(R2), and The above X4 is selected from the group consisting of direct bonding, N(R3), C(R4)(R5), oxygen(O), and sulfur(S), and The above R1 to R5 are identical or different from one another and each independently comprise hydrogen, a cyano group, a nitro group, a halogen group, an amino group, a hydroxyl group, a substituted or unsubstituted straight-chain or branched alkyl group having 1 to 30 carbon atoms, a substituted or unsubstituted straight-chain or branched alkenyl group having 2 to 30 carbon atoms, a substituted or unsubstituted straight-chain or branched alkynyl group having 2 to 24 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 30 carbon atoms, a substituted or unsubstituted cycloalkenyl group having 3 to 30 carbon atoms, a substituted or unsubstituted cycloheteroalkyl group having 3 to 30 carbon atoms, a substituted or unsubstituted alkylthio group having 1 to 4 carbon atoms, a substituted or unsubstituted haloalkyl group having 1 to 30 carbon atoms, a substituted or unsubstituted alkoxy group having 1 to 10 carbon atoms, a substituted or unsubstituted One selected from the group consisting of an arylalkyl group having 7 to 30 carbon atoms, a substituted or unsubstituted aryl group having 5 to 30 carbon atoms, a substituted or unsubstituted heteroaryl group having 5 to 30 carbon atoms, and a substituted or unsubstituted alkylaryl group having 7 to 30 carbon atoms, and The above n is an integer from 0 to 9, and If n is 2 or greater, the plurality of R1s are identical or different from each other, and The above ring A is one selected from the group consisting of a substituted or unsubstituted monocyclic aromatic ring having 5 to 30 carbon atoms, a substituted or unsubstituted polycyclic aromatic ring having 5 to 30 carbon atoms, a substituted or unsubstituted monocyclic heteroaromatic ring having 5 to 30 carbon atoms, and a substituted or unsubstituted polycyclic heteroaromatic ring having 5 to 30 carbon atoms.

2. In Paragraph 1, The compound of the above chemical formula (1) comprises the compound of the following chemical formula (2). Composition for the prevention or treatment of malignant neoplasms: In the above chemical formula (2), the details regarding R1, n and ring A are the same as those described above in the above chemical formula (1).

3. In Paragraph 1 or 2, The above ring A comprises a compound having a structure selected from the group consisting of the following chemical formulas (4) to (14); or a combination of two or more of the above compounds. Composition for the prevention or treatment of malignant neoplasms: In the above chemical formulas (4) to (14), The above Z1 to Z 14 Each is independently selected from the group consisting of nitrogen (N), N-oxide [N(+)-O(-)], oxygen (O), and C(R7), and The above Y1 to Y5 are each independently selected from the group consisting of nitrogen (N), N-oxide [N(+)-O(-)], oxygen (O), sulfur (S), and C (R7). The above R6 and R7 are each independently hydrogen, a cyano group, a nitro group, a halogen group, an amino group, a hydroxyl group, a substituted or unsubstituted straight-chain or branched alkyl group having 1 to 30 carbon atoms, a substituted or unsubstituted straight-chain or branched alkenyl group having 2 to 30 carbon atoms, a substituted or unsubstituted straight-chain or branched alkynyl group having 2 to 24 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 30 carbon atoms, a substituted or unsubstituted cycloalkenyl group having 3 to 30 carbon atoms, a substituted or unsubstituted cycloheteroalkyl group having 3 to 30 carbon atoms, a substituted or unsubstituted alkylthio group having 1 to 4 carbon atoms, a substituted or unsubstituted haloalkyl group having 1 to 30 carbon atoms, a substituted or unsubstituted alkoxy group having 1 to 10 carbon atoms, a substituted or unsubstituted alkoxy group having 7 to One selected from the group consisting of a 30-carbon arylalkyl group, a substituted or unsubstituted aryl group having 5 to 30 carbon atoms, a substituted or unsubstituted heteroaryl group having 5 to 30 carbon atoms, and a substituted or unsubstituted alkylaryl group having 7 to 30 carbon atoms, and The above m is an integer from 0 to 7, and If the above m is 2 or greater, the plurality of the above R6s are identical or different from each other, and The asterisk (*) above indicates a bonding point where the above chemical formulas (4) to (14) bond with a residue of the above chemical formula (1) as the above ring A, and the bonding point includes any chemically permissible position within the above ring A.

4. In Paragraph 3, The above ring A comprises a compound having a structure selected from the group consisting of the following chemical formulas (4A) to (4B); the following chemical formulas (5A) to (5C); and the following chemical formulas (6A) to (6B); or a combination of two or more of the above compounds. Composition for the prevention or treatment of malignant neoplasms: In the above chemical formulas (4A) to (4B), (5A) to (5C) and (6A) to (6B), The above Z1 to Z6 are each independently selected from the group consisting of nitrogen (N), N-oxide [N(+)-O(-)] and C (R7), and The above R7 is the same as described above in Paragraph 3, and The above R6 is one selected from the group consisting of hydrogen, a halogen group, a hydroxyl group, a substituted or unsubstituted haloalkyl group having 1 to 30 carbon atoms, and a substituted or unsubstituted alkoxy group having 1 to 10 carbon atoms, and The above m is an integer from 0 to 4, and If the above m is 2 or greater, the plurality of the above R6s are identical or different from each other, and The asterisk (*) above indicates a bonding point where the above chemical formulas (4A) to (4B), (5A) to (5C) and (6A) to (6B) are bonded to the residue of the above chemical formula (1) as ring A.

5. In Paragraph 3, The above ring A comprises a compound having a structure selected from the group consisting of the following chemical formulas (7A) to (7B); or a combination of two or more of the above compounds. Composition for the prevention or treatment of malignant neoplasms: In the above chemical formulas (7A) to (7B), The above Y1 is selected from the group consisting of nitrogen (N), N-oxide [N(+)-O(-)], oxygen (O), and sulfur (S), and The above R6 is one selected from the group consisting of hydrogen, a halogen group, a hydroxyl group, a substituted or unsubstituted haloalkyl group having 1 to 30 carbon atoms, and a substituted or unsubstituted alkoxy group having 1 to 10 carbon atoms, and The above m is an integer from 0 to 3, and If the above m is 2 or greater, the plurality of the above R6s are identical or different from each other, and The asterisk (*) above indicates a bonding point where the above chemical formulas (7A) to (7B) are bonded to the residue of the above chemical formula (1) as ring A.

6. In Paragraph 3, A compound having a structure selected from the group consisting of the following chemical formulas (8A) to (8G), wherein the above ring A comprises a compound having a structure selected from the group consisting of the following chemical formulas (8A) to (8G); or a combination of two or more of the above compounds, Composition for the prevention or treatment of malignant neoplasms: In the above chemical formulas (8A) to (8G), The above Y2 is selected from the group consisting of nitrogen (N), N-oxide [N(+)-O(-)], oxygen (O), and sulfur (S), and The above R6 is one selected from the group consisting of hydrogen, a halogen group, a hydroxyl group, a substituted or unsubstituted haloalkyl group having 1 to 30 carbon atoms, and a substituted or unsubstituted alkoxy group having 1 to 10 carbon atoms, and The above m is an integer from 0 to 5, and If the above m is 2 or greater, the plurality of the above R6s are identical or different from each other, and The asterisk (*) above indicates a bonding point where the above chemical formulas (8A) to (8G) are bonded to the residue of the above chemical formula (1) as ring A.

7. In Paragraph 3, A compound having a structure selected from the group consisting of the following chemical formulas (9A) to (9C), wherein the above ring A comprises a compound having a structure selected from the group consisting of the following chemical formulas (9A) to (9C); or a combination of two or more of the above compounds, Composition for the prevention or treatment of malignant neoplasms: In the above chemical formulas (9A) to (9C), The above Y3 is selected from the group consisting of nitrogen (N), N-oxide [N(+)-O(-)], oxygen (O), and sulfur (S), and The above R6 is one selected from the group consisting of hydrogen, a halogen group, a hydroxyl group, a substituted or unsubstituted haloalkyl group having 1 to 30 carbon atoms, and a substituted or unsubstituted alkoxy group having 1 to 10 carbon atoms, and The above m is an integer from 0 to 5, and If the above m is 2 or greater, the plurality of the above R6s are identical or different from each other, and The asterisk (*) above indicates a bonding point where the above chemical formulas (9A) to (9C) are bonded to the residue of the above chemical formula (1) as ring A.

8. In Paragraph 3, A compound having a structure selected from the group consisting of the following chemical formulas (10A) to (10C), wherein the above ring A comprises a compound having a structure selected from the group consisting of the following chemical formulas (10A) to (10C); or a combination of two or more of the above compounds, Composition for the prevention or treatment of malignant neoplasms: In the above chemical formulas (10A) to (10C), The above Y4 and Y4 are each independently selected from the group consisting of nitrogen (N), N-oxide [N(+)-O(-)], oxygen (O), and sulfur (S). The above R6 is one selected from the group consisting of hydrogen, a halogen group, a hydroxyl group, a substituted or unsubstituted haloalkyl group having 1 to 30 carbon atoms, and a substituted or unsubstituted alkoxy group having 1 to 10 carbon atoms, and The above m is an integer from 0 to 4, and If the above m is 2 or greater, the plurality of the above R6s are identical or different from each other, and The asterisk (*) above indicates a bonding point where the above chemical formulas (10A) to (10C) are bonded to the residue of the above chemical formula (1) as ring A.

9. In Paragraph 3, A compound having a structure selected from the group consisting of the following chemical formulas (11A) to (11H), wherein the above ring A is a compound having a structure selected from the group consisting of the following chemical formulas (11A) to (11H); or a combination of two or more of the above compounds, Composition for the prevention or treatment of malignant neoplasms: In the above chemical formulas (11A) to (11H), The above Z7 and Z8 are each independently selected from the group consisting of nitrogen (N), N-oxide [N(+)-O(-)] and C(R7), and The above R6 and R7 are each independently selected from the group consisting of hydrogen, a halogen group, a hydroxyl group, a substituted or unsubstituted haloalkyl group having 1 to 30 carbon atoms, and a substituted or unsubstituted alkoxy group having 1 to 10 carbon atoms, and The above m is an integer from 0 to 6, and If the above m is 2 or greater, the plurality of the above R6s are identical or different from each other, and The asterisk (*) above indicates a bonding point where the above chemical formulas (11A) to (11H) are bonded to the residue of the above chemical formula (1) as ring A.

10. In Paragraph 3, A compound having a structure selected from the group consisting of the following chemical formulas (12A) to (12G), wherein the above ring A comprises a compound having a structure selected from the group consisting of the following chemical formulas (12A) to (12G); or a combination of two or more of the above compounds, Composition for the prevention or treatment of malignant neoplasms: In the above chemical formulas (12A) to (12G), The above Z9 is selected from the group consisting of nitrogen (N) and N-oxide [N(+)-O(-)], and The above R6 is each independently selected from the group consisting of hydrogen, a halogen group, a hydroxyl group, a substituted or unsubstituted haloalkyl group having 1 to 30 carbon atoms, and a substituted or unsubstituted alkoxy group having 1 to 10 carbon atoms, and The above m is an integer from 0 to 6, and If the above m is 2 or greater, the plurality of the above R6s are identical or different from each other, and The asterisk (*) above indicates a bonding point where the above chemical formulas (12A) to (12G) are bonded to the residue of the above chemical formula (1) as ring A.

11. In Paragraph 3, The above ring A comprises a compound having a structure selected from the group consisting of the following chemical formulas (13A) to (13F); and the following chemical formulas (14A) to (14C); or a combination of two or more of the above compounds. Composition for the prevention or treatment of malignant neoplasms: In the above chemical formulas (13A) to (13F) and (14A) to (14C), The above Z 11 To Z 14 Each is independently selected from the group consisting of nitrogen (N) and N-oxide [N(+)-O(-)], and The above R6 is each independently selected from the group consisting of hydrogen, a halogen group, a hydroxyl group, a substituted or unsubstituted haloalkyl group having 1 to 30 carbon atoms, and a substituted or unsubstituted alkoxy group having 1 to 10 carbon atoms, and The above m is an integer from 0 to 5, and If the above m is 2 or greater, the plurality of the above R6s are identical or different from each other, and The asterisk (*) above indicates a bonding point where the above chemical formulas (13A) to (13F) and (14A) to (14C) are bonded to the residue of the above chemical formula (1) as ring A.

12. In any one of paragraphs 3 through 11, The above ring A comprises a compound having a structure selected from the group consisting of the above formulas (4A) to (4B); the above formulas (5A) to (5C); the above formulas (6A) to (6B); the above formulas (7A) to (7B); the above formulas (8A) to (8G); and the above formulas (11A) to (11H); or a combination of two or more of the above compounds. Composition for the prevention or treatment of malignant neoplasms.

13. In Paragraph 3, The above ring A, The following chemical formulas (4-1) to (4-27); The following chemical formulas (5-1) to (5-3); The following chemical formulas (6-1) to (6-3); The following chemical formulas (7-1) to (7-2); The following chemical formulas (8-1) to (8-8); The following chemical formulas (9-1) to (9-2); The following chemical formulas (10-1) to (10-3); The following chemical formulas (11-1) to (11-12); The following chemical formulas (12-1) to (12-7); The following chemical formulas (13-1) to (13-6); and A compound having a structure selected from the group consisting of the following chemical formulas (14-1) to (14-3); or a combination of two or more of the above compounds, Composition for the prevention or treatment of malignant neoplasms:

14. In Paragraph 13, The above ring A, The above chemical formulas (4-1) to (4-27); The above chemical formulas (5-1) to (5-2); The above chemical formula (6-1); The above chemical formulas (7-1) to (7-2); The above chemical formula (8-1); and A compound having a structure selected from the group consisting of the above chemical formulas (11-1) to (11-2); or a combination of two or more of the above compounds, Composition for the prevention or treatment of malignant neoplasms.

15. In Paragraph 1, Comprising one selected from the group consisting of pharmaceutically acceptable carriers, excipients, pH adjusters, stabilizers, preservatives, sweeteners, flavorings, and combinations thereof, Composition for the prevention or treatment of malignant neoplasms.

16. In Paragraph 1, The above malignant tumor is hematologic cancer, Composition for the prevention or treatment of malignant neoplasms.

17. In Paragraph 16, The above hematologic cancer, At least one of acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), and lymphoma, Composition for the prevention or treatment of malignant neoplasms.

18. In Paragraph 1, The above malignant tumor is cervical cancer, Composition for the prevention or treatment of malignant neoplasms.

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