Novel compound, pharmaceutical composition containing the same and use thereof

Abstract

The present invention relates to a novel compound, a pharmaceutical composition for preventing or treating resistant cancer comprising the novel compound or a pharmaceutically acceptable salt thereof, and use thereof. When the composition of the present invention is administered together with an anticancer agent, it can exhibit an excellent anticancer effect.

Description

Technical Field

[0001] This application claims the benefit of the filing date of Provisional Application No. 62 / 928,398, filed in the U.S. Patent Office on October 31, 2019, the entire contents of which are incorporated herein by reference.

[0002] The present application relates to novel compounds, pharmaceutical compositions for preventing or treating cancer comprising the compounds or pharmaceutically acceptable salts thereof, and uses thereof. Background Art

[0003] Cancer is one of the most common causes of death worldwide, accounting for about 12% of deaths. Chemotherapy, a representative anticancer therapy, is currently used as the most effective treatment for cancer, and it can be used alone or in combination with other therapies such as radiotherapy. However, the efficacy of cancer therapeutic drugs in chemotherapy depends on their ability to kill cancer cells, but there is a problem that when using drugs, they can act not only on cancer cells but also on normal cells.

[0004] It is reported that, for ordinary cancer cells, when anticancer drugs are administered, excessive stress is induced, calcium ions are excessively secreted from the endoplasmic reticulum (ER), and the secreted calcium ions accumulate in the mitochondria, leading to apoptosis of cancer cells, while for cancer stem cells, when anticancer drugs are administered, the secretion of excessive calcium ions is reduced, and the expression of sarcoplasmic reticulum calcium pump (SERCA) that can return excessive secreted calcium ions to the endoplasmic reticulum is increased to control the calcium ion concentration, thereby achieving survival. In other words, SERCA protein can play a role in survival signal transduction in the endoplasmic reticulum stress signal transduction process.

[0005] If the growth of cancer stem cells can be selectively inhibited by developing a substance that can be used as an inhibitor targeting the SERCA protein (the reason why cancer stem cells have resistance to anticancer drugs), the efficacy of chemotherapy by anticancer drugs can be improved, and excellent anticancer effects can be exhibited even with lower doses of drugs. Summary of the invention

[0006] Technical Problems to be Solved by the Invention

[0007] One aspect of the present application provides a novel compound.

[0008] Furthermore, another aspect of the present application provides a pharmaceutical composition for preventing or treating cancer comprising the novel compound.

[0009] Furthermore, another aspect of the present application provides a pharmaceutical composition comprising a novel compound for preventing or treating resistant cancer.

[0010] Furthermore, another aspect of the present application provides a method for preventing or treating resistant cancer comprising the novel compound.

[0011] The technical problems to be solved by the present application are not limited to those described above. Other problems not mentioned above can be clearly understood by those skilled in the art through the following description.

[0012] Technical Solution

[0013] According to one embodiment of the present application, a compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof is provided.

[0014] [Chemical formula 1]

[0015]

[0016] In the above chemical formula 1,

[0017] R1 is hydrogen, straight or branched alkyl, alkoxy, haloalkyl, haloalkoxy, aryl, heteroaryl, alkylaryl or alkylheteroaryl, each of which can be independently substituted by at least one of hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, oxo, cyano, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl;

[0018] R3 is hydrogen, a straight or branched alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, an alkylaryl group or an alkylheteroaryl group, each of which can be independently substituted by at least one of a hydroxyl group, a halogen group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, an oxo group, a cyano group, an unsubstituted or substituted aryl group, or an unsubstituted or substituted heteroaryl group;

[0019] L1 is C1~C 10 Alkylene, in this case, the alkylene can be substituted by at least one of C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, hydroxy, oxo or halogen, and the C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy can be substituted by unsubstituted or substituted aryl;

[0020] Q is S, Se, NR, P, P(O), P(O)2 or P(O)OR, in which case R is hydrogen, a linear or branched alkyl, a cycloalkyl, a bicycloalkyl or tricycloalkyl, an alkoxy, a haloalkyl, a haloalkoxy, an aryl, a heteroaryl, an alkylaryl or an alkylheteroaryl, each of which can be independently substituted with at least one of hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, oxo, cyano, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl;

[0021] R2 is hydrogen, straight-chain alkyl, cycloalkyl, alkoxy, haloalkoxy, haloalkyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl, each of which can be independently substituted by at least one of hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, oxo, nitro, cyano or trifluoromethyl;

[0022] R4 and R4' are each independently hydrogen, a straight or branched alkyl, a cycloalkyl, an alkenyl, an alkynyl, an alkylthio, an aryl, a heteroaryl, an alkylaryl or an alkylheteroaryl, each of which can be independently substituted by at least one of hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, oxo, nitro, cyano or trifluoromethyl;

[0023] R2 and R4 can be connected to form a 5- to 10-membered monocyclic or bicyclic ring, in which case R4' is hydrogen;

[0024] m is an integer of 1 or 2, and n is an integer of 1 to 4;

[0025] X, Y, and Z are each independently hydrogen, a straight-chain or branched alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, an alkylaryl group, or an alkylheteroaryl group, each of which can be independently substituted with at least one of hydroxyl, halogen, C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 haloalkyl group, C1-C6 haloalkoxy group, unsubstituted or substituted aryl group, unsubstituted or substituted heteroaryl group, oxo group, nitro group, cyano group, or trifluoromethyl group.

[0026] According to one embodiment of the present application, a pharmaceutical composition for treating or preventing cancer is provided, comprising at least one of the above Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

[0027] According to one embodiment of the present application, a pharmaceutical composition for treating or preventing resistant cancer is provided, comprising at least one of the above Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

[0028] Beneficial Effects

[0029] The pharmaceutical composition comprising the compound according to one embodiment of the present application or a pharmaceutically acceptable salt thereof can exhibit excellent anti-cancer effects.

[0030] The composition comprising the compound according to one embodiment of the present application or a pharmaceutically acceptable salt thereof can enhance the anticancer activity of anticancer agents or radiation, and can effectively treat cancer by inhibiting the proliferation of cancer cells and inducing cell apoptosis.

[0031] The composition comprising the compound according to one embodiment of the present application or a pharmaceutically acceptable salt thereof can effectively treat resistant cancer by overcoming the resistance of cancer resistant to anticancer agents or radiation, and can reduce the side effects of anticancer treatment.

[0032] The composition comprising the compound according to one embodiment of the present application or a pharmaceutically acceptable salt thereof can effectively treat stem cell cancer.

[0033] The effects according to the present application are not limited to the above-exemplified contents, and more various effects are included in this specification. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 Part (a) shows the paclitaxel anticancer agent IC50 value of SKOV3, and part (b) shows the paclitaxel anticancer agent IC50 value of SKOV3-TR.

[0035] Figure 2 Part (a) shows the docetaxel anticancer agent IC50 value of SKOV3, and part (b) shows the docetaxel anticancer agent IC50 value of SKOV3-TR.

[0036] Figures 3 to 10 The results of WST-1 analysis of SKOV3-TR and SKOV3 with respect to paclitaxel are shown.

[0037] Figure 11 to Figure 12 The crystal violet staining results of SKOV3-TR and SKOV3 with respect to paclitaxel are shown.

[0038] Figures 13 to 20 The absorbance results of SKOV3-TR and SKOV3 with respect to paclitaxel are shown.

[0039] Figure 21 to Figure 24 The results of WST-1 analysis of SKOV3-TR and SKOV3 with respect to docetaxel are shown.

[0040] Figure 25 to Figure 26The crystal violet staining results of SKOV3-TR and SKOV3 with respect to docetaxel are shown.

[0041] Figures 27 to 30 Shown are the absorbance results of SKOV3-TR and SKOV3 with respect to docetaxel.

[0042] Fig.31 The graph shows changes in the number of cells after treatment with S101 compound at 100 nM, 50 nM, and 10 nM in the presence of glucose (G(+)) and in the absence of glucose (G(-)) under ER stress for selected-MDA-MB231 cells and selected-MCF7, which are stem cell cancer cells.

[0043] Fig.32 The results of capturing images stained with crystal violet are shown.

[0044] Fig.33 The apoptotic effect of S101 on cancer cells after glucose deprivation was detected by TUNEL assay.

[0045] Fig.34 The graph shows the changes in tumor volume when S101 and 2DG were treated alone or in combination.

[0046] Fig.35 The weight and size of dissected tumors are shown when S101 and 2DG were treated alone or in combination.

[0047] Fig.36 The figure shows the changes in body weight between groups when the anticancer effect of the combination of S101 and 2DG was measured in the s-231 xenograft model.

[0048] Fig.37 The figure shows the presence or absence of liver tissue degradation for analyzing the degree of cytotoxicity when S101 and 2DG are treated alone or in combination. DETAILED DESCRIPTION

[0049] The advantages and features of the present application and the methods for realizing them will become more clear through the embodiments described in detail below. However, the application is not limited to the embodiments disclosed below, but can be implemented in a variety of different forms. The present embodiment is provided only to make the disclosure of the present application complete, and to fully inform those of ordinary skill in the art that the application belongs to the scope of the present invention, and the application is limited by the scope of the claims.

[0050] In this specification, the term "independently" means that the variables applied independently vary independently at each application. a XY a For compounds such as a "are independently carbon or nitrogen", then the two R a Both can be carbon, two R a can be nitrogen, or an R a It can be carbon, another R a It may be nitrogen.

[0051] In this specification, unless otherwise specified, "alkyl" generally refers to C1-C 10 The term "C1-C6 alkyl" refers to a saturated straight or branched hydrocarbon chain, more specifically, a saturated straight or branched hydrocarbon chain of a C1-C6 alkyl group. 10 "Alkyl" refers to a straight or branched alkyl group having 1 to 10 carbon atoms, specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3-methylpentyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl. The above term includes all substituted and unsubstituted alkyl groups. Optionally, the alkyl group may be substituted with one or more moieties selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphoric acid, phosphate, or phosphonate. One or more hydrogen atoms connected to the carbon atoms of the alkyl group may be substituted with one or more halogen atoms, such as fluorine or chlorine or both, such as trifluoromethyl, difluoromethyl, fluorochloromethyl, etc. The above hydrocarbon chain may also contain heteroatoms such as N, O or S in the middle.

[0052] The term "alkaryl group" or "alkylaryl group" refers to an alkyl group having an aryl substitution product. The term "aralkyl group" or "arylalkyl group" refers to an aryl group having an alkyl substitution product, for example, having a benzyl group.

[0053] The term "halo" as used in this specification includes chlorine, bromine, iodine and fluorine.

[0054] Unless otherwise specified, the term "alkyl" used in this specification refers to "C1~C6 alkyl", and "C1~C6 alkyl" refers to a straight chain or branched alkyl group having 1 to 6 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl and hexyl, but not limited thereto, preferably ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

[0055] Unless otherwise specified, the term "alkoxy" used in this specification refers to "C1~C6 alkoxy", and "C1~C6 alkoxy" refers to a straight chain or branched alkoxy group having 1 to 6 carbon atoms, including methoxy, ethoxy, propoxy, isopropoxy and butoxy, etc., but not limited thereto.

[0056] Unless otherwise specified, the term "alkenyl" used in this specification refers to "C2-C6 alkenyl", and "C2-C6 alkenyl" refers to a straight chain or branched alkenyl group having 2 to 6 carbon atoms and one double bond, including vinyl, propenyl, butenyl, isobutenyl, pentenyl and hexenyl, etc., but not limited thereto.

[0057] Unless otherwise specified, the term "alkynyl" used in this specification refers to "C2-C6 alkynyl", and "C2-C6 alkynyl" refers to a straight or branched alkynyl group having 2 to 6 carbon atoms and containing a tricyclic group, including ethynyl, propynyl, butynyl, isobutynyl, pentynyl and hexynyl, but not limited thereto.

[0058] Unless otherwise specified, the term "cycloalkyl" used in this specification refers to "C3-C 10 Cycloalkyl", "C3~C 10 "Cycloalkyl" refers to a cyclic alkyl group having 3 to 10 carbon atoms in the ring, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclodecyl, but not limited thereto. The terms "C3-C8 cycloalkyl", "C3-C7 cycloalkyl" and "C3-C6 cycloalkyl" have similar meanings. The ring of the above cycloalkyl group may be substituted by an alkyl group, such as cyclopropylmethyl.

[0059] Unless otherwise specified, the term "aryl" used in this specification refers to "C6 to C 12 Aryl", "C6~C 12 The term "aryl" refers to a phenyl, biphenyl or naphthyl group having 6 to 12 carbon atoms and containing no heteroatoms in the ring, preferably a phenyl group. The above term includes all substituted and unsubstituted parts. The above "substituted aryl" can be substituted with one or more substituents including unprotected or protected hydroxyl, halogen, amino, alkylamino, arylamino, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, oxo, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphoric acid, phosphate, or phosphonate, as needed, but is not limited thereto. The term "C6-C 10 "Aryl" has a similar meaning.

[0060] The term "heteroaryl" or "heterocycle" used in this specification refers to a "3- to 12-membered heterocycle". "3- to 12-membered heterocycle" refers to a saturated or unsaturated 3- to 12-membered ring group containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen in the ring, for example, dioxol. The term "3- to 10-membered heterocycle" has a similar meaning. In this specification, "substituted heteroaryl" can be substituted as needed with one or more substituents including unprotected or protected hydroxyl, halogen, amino, alkylamino, arylamino, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, oxo, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphoric acid, phosphate, or phosphonate, but is not limited thereto.

[0061] As used herein, "alkylene" refers to a divalent hydrocarbon radical; this is because it is divalent and can be linked together with two other groups. Typically, it is -(CH2)n-, where n is 1-8, preferably n is 1-4, but in certain cases, the alkylene group can also be substituted with other groups and can also have different lengths, and the open valences do not necessarily have to be on opposite sides of the chain.

[0062] In general, all alkyl, alkenyl, alkynyl groups contained in the substituent, or aryl, alkylaryl or arylalkyl groups themselves may be optionally substituted with other additional substituents. Unless otherwise specified for these substituents, the properties of these substituents are similar to those listed for the primary substituents themselves.

[0063] The term "heteroatom" as used in this specification refers to atoms other than hydrogen, such as nitrogen, oxygen and sulfur. If it is part of the main chain or skeleton of a chain or ring, the heteroatom must be at least divalent and is usually selected from N, O, P and S.

[0064] The term "substitutable" or "substituted" as used in this specification means that the specific group or groups referred to as being optionally substituted do not have non-hydrogen substituents, or the above group or groups may have more than one non-hydrogen substituent that is consistent with the chemical and pharmacological activity of the final molecule. Unless otherwise specified, the total number of these substituents that may be present is equal to the total number of hydrogen atoms present in the unsubstituted form of the group; there may be less than the maximum number of these substituents. When the optional substituent is bonded by a double bond such as carbonyl oxygen (C=O), the group takes the two valences available on the carbon atom to which the optional substituent is attached, so the total number of substituents that can be included decreases with the number of available valences. In this application, when used to modify a specific group, part or base, whether the term "substituted" is used as part of the term "substitutable" or used in other ways, it means that more than one hydrogen atom is replaced by the same or different substituents or multiple substituents, each independently of each other.

[0065] In this specification, since the compound may contain more than one chiral center and / or double bond, it may exist in the form of stereoisomers, for example, double bond isomers (i.e., geometric isomers, such as E and Z), enantiomers or diastereoisomers. The present application also includes separately separated stereoisomer forms (e.g., enantiomerically pure isomers, E and Z isomers, and other substitutes of stereoisomers) and mixtures of stereoisomers with different chiral purity and E and Z percentages (unless limited to specific stereoisomers). Therefore, the chemical structure described in the present application includes all possible enantiomers and stereoisomers of the compound, including pure forms from the perspective of stereoisomers (e.g., pure forms from the perspective of geometric isomers, pure forms from the perspective of enantiomers, or pure forms from the perspective of diastereoisomers) and mixtures of enantiomers and mixtures of stereoisomers, etc. Separation techniques well known in the art or chiral synthesis techniques can be used to separate enantiomeric mixtures and stereoisomer mixtures into their corresponding enantiomers or stereoisomer components. The application not only includes the stereoisomer forms separated separately, but also includes the mixtures (including racemic mixtures) of stereoisomers of different chiral purities. The application also includes multiple diastereomers. Although other structures may appear to describe specific isomers, this is just for convenience and is not intended to limit the application to the isomers specifically described. When the chemical name does not specify the isomeric form of a compound, it refers to all possible isomeric forms or mixtures thereof of the isomeric form of the compound.

[0066] As used herein and in the preceding claims, the words "comprising," "including," "include," and "comprising" are intended to specify the features, integers, components, or steps mentioned, but do not exclude the presence or addition of one or more other features, integers, components, or steps, or combinations thereof.

[0067] Next, embodiments of the present application are described.

[0068] According to one embodiment of the present application, a compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof is provided.

[0069] [Chemical formula 1]

[0070]

[0071] The above Chemical Formula 1 can be represented by the following Chemical Formula 2.

[0072] [Chemical formula 2]

[0073]

[0074] The above Chemical Formula 1 may be represented by the following Chemical Formula 3, Chemical Formula 4, Chemical Formula 5 or Chemical Formula 6.

[0075] [Chemical formula 3]

[0076]

[0077] [Chemical formula 4]

[0078]

[0079] [Chemical formula 5]

[0080]

[0081] [Chemical formula 6]

[0082]

[0083] In Chemical Formulae 1 to 6, R1 is hydrogen, a linear or branched alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, an aryl group, a heteroaryl group, an alkylaryl group or an alkylheteroaryl group, each of which can be independently substituted by at least one of a hydroxyl group, a halogen group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, an oxo group, a cyano group, an unsubstituted or substituted aryl group, or an unsubstituted or substituted heteroaryl group.

[0084] Specifically, the above R1 is hydrogen, C1-C6 straight-chain alkyl, C3-C6 branched alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, aryl, heteroaryl, alkyl (C1-C6) aryl or alkyl (C1-C6) heteroaryl, each of which can be independently replaced by hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, oxo, cyano, unsubstituted or substituted C6-C 10 Aryl, or unsubstituted or substituted C5~C 10 At least one of the heteroaryl groups is substituted.

[0085] More specifically, the above R1 is hydrogen, unsubstituted or substituted C1~C6 straight-chain alkyl, unsubstituted or substituted benzyl, or unsubstituted or substituted 2-phenylethyl. In this case, the above substituted C1~C6 straight-chain alkyl may be substituted by a C3~C6 cycloalkyl, and the above substituted benzyl or the above substituted 2-phenylethyl may be substituted by a halide or by a phenyl group in at least one of the ortho, meta and para positions.

[0086] More specifically, the above R1 is hydrogen, C1-C6 straight chain alkyl, C3-C6 branched chain alkyl, C3-C6 cycloalkyl, In this case, the X1 may be hydrogen, a halo group, a C1-C3 straight-chain alkyl group, CF3, CN, NO2 or an aryl group.

[0087] In Chemical Formulae 1 to 6, R3 is hydrogen, C1-C6 straight-chain alkyl, C3-C6 branched-chain alkyl, C3-C6 cycloalkyl, aryl, heteroaryl, alkyl (C1-C6) aryl or alkyl (C1-C6) heteroaryl, each of which can be independently replaced by hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, oxo, cyano, unsubstituted or substituted C6-C 10 Aryl, or unsubstituted or substituted C5~C 10 At least one of the heteroaryl groups is substituted.

[0088] Specifically, the above R3 is hydrogen, unsubstituted or substituted C1~C6 straight-chain alkyl, unsubstituted or substituted C1~C6 alkoxy, halogen, or unsubstituted or substituted 2-phenethyl. In this case, in the above-mentioned substituted 2-phenethyl, at least one of the ortho, meta and para positions may be substituted by a halo group, and the above-mentioned substituted C1~C6 alkoxy may be substituted by a phenyl or benzyl group.

[0089] More specifically, the above R3 is hydrogen, unsubstituted or substituted C1~C6 straight-chain alkyl, unsubstituted or substituted C1~C6 alkoxy, halogen, or unsubstituted or substituted 2-phenethyl. In this case, in the above-mentioned substituted 2-phenethyl, at least one of the ortho, meta and para positions may be substituted by a halo group, and the above-mentioned substituted C1~C6 alkoxy may be substituted by a phenyl or benzyl group.

[0090] More specifically, the above R3 is hydrogen, C1-C3 straight chain alkyl, unsubstituted or substituted C1-C3 alkoxy, halogen, or In this case, the above X4 is hydrogen or a halogenated group, and the substituted C1-C3 alkoxy group may be substituted by a phenyl group or a benzyl group.

[0091] In Chemical Formulae 1 to 6, R2 is hydrogen, a linear alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a haloalkyl group, an aryl group, a heteroaryl group, an alkylaryl group or an alkylheteroaryl group, each of which can be independently substituted with at least one of a hydroxyl group, a halogen group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, an unsubstituted or substituted aryl group, an unsubstituted or substituted heteroaryl group, an oxo group, a nitro group, a cyano group or a trifluoromethyl group.

[0092] Specifically, the above R2 is hydrogen, C1-C6 straight-chain alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 haloalkyl, aryl, heteroaryl, alkyl (C1-C6) aryl or alkyl (C1-C6) heteroaryl, each of which can be independently replaced by hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, unsubstituted or substituted C6-C 10 Aryl, unsubstituted or substituted C5~C 10 The substituted amino group is at least one of heteroaryl, oxo, nitro, cyano or trifluoromethyl.

[0093] More specifically, the above-mentioned R2 is hydrogen, unsubstituted or substituted C1~C6 straight-chain alkyl, unsubstituted or substituted benzyl, or unsubstituted or substituted 2-phenylethyl, in which case the above-mentioned substituted straight-chain alkyl is substituted by a halo group, at least one of the ortho, meta and para positions of the above-mentioned substituted benzyl is substituted by a halo group, a C1~C3 straight-chain alkyl, a trifluoromethyl group, a cyano group, a nitro group, a C1~C3 alkoxy group or an aryl group, and at least one of the ortho, meta and para positions of the above-mentioned 2-phenylethyl is substituted by a halo group.

[0094] More specifically, the above R2 is hydrogen, unsubstituted or substituted C1-C6 straight chain alkyl, unsubstituted or substituted C1-C3 alkoxy, In this case, the above-mentioned substituted C1-C6 straight-chain alkyl group is substituted with a halogenated group.

[0095] In Chemical Formulae 1 to 6, R4 and R4' are each independently hydrogen, a linear or branched alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an alkylthio group, an aryl group, a heteroaryl group, an alkylaryl group or an alkylheteroaryl group, each of which can be independently substituted by at least one of a hydroxyl group, a halogen group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, an unsubstituted or substituted aryl group, an unsubstituted or substituted heteroaryl group, an oxo group, a nitro group, a cyano group or a trifluoromethyl group.

[0096] Specifically, the above R4 and R4' are each independently hydrogen, C1-C6 straight-chain alkyl, C3-C6 branched alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkylthio, aryl, heteroaryl, alkyl (C1-C6) aryl or alkyl (C1-C6) heteroaryl, each of which can be independently substituted by hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, unsubstituted or substituted C6-C 10 Aryl, unsubstituted or substituted C5~C 10 The substituted amino group is at least one of heteroaryl, oxo, nitro, cyano or trifluoromethyl.

[0097] More specifically, the above R4 and R4' are each independently hydrogen, unsubstituted or substituted C1~C6 straight-chain alkyl, C3~C6 branched alkyl, C3~C6 cycloalkyl, C2~C6 alkynyl, C1~C6 alkylthio, unsubstituted or substituted benzyl, 2-naphthylmethyl or 1-naphthylmethyl, in which case the above-mentioned substituted straight-chain alkyl is substituted by methylthio, alkynyl or benzyloxycarbonylamino, and at least one of the ortho, meta and para positions of the above-mentioned substituted benzyl can be substituted by a halide, an aryl, a nitro, a cyano, a C1~C3 alkoxy, a trifluoromethyl or a benzyloxy group.

[0098] More specifically, the above R4 and R4' are each independently hydrogen, unsubstituted or substituted C1-C4 straight chain alkyl, C3-C4 branched chain alkyl, C3-C6 cycloalkyl, The above-mentioned substituted C1-C4 straight-chain alkyl group is substituted with a C3-C6 cycloalkyl group.

[0099] The above R2 and R4 can be linked to form a 5- to 10-membered monocyclic or bicyclic ring, in which case, R4' can be hydrogen.

[0100] In Chemical Formulae 1 to 6, L1 is C1 to C 10Alkylene, in this case, the alkylene can be substituted by at least one of C1~C6 alkyl, C3~C6 cycloalkyl, C1~C6 alkoxy, hydroxyl, oxo or halogen, and the C1~C6 alkyl, C3~C6 cycloalkyl, C1~C6 alkoxy can be substituted by unsubstituted or substituted aryl. Specifically, L1 is C1~C4 alkylene, in this case, the alkylene is substituted by hydrogen, oxo, hydroxyl, C1~C4 alkoxy or C1~C4 alkyl, and the C1~C4 alkoxy can be substituted by benzyl. More specifically, L1 is C1~C4 alkylene, in this case, the alkylene can be substituted by hydrogen, oxo, hydroxyl, C1~C4 alkyl, or halogen. replace.

[0101] In Chemical Formula 1, Q may be S, Se, NR, P, P(O), P(O)2, or P(O)OR.

[0102] In Chemical Formulae 1 to 6, R is hydrogen, a linear or branched alkyl, a cycloalkyl, a bicyclic alkyl or tricyclic alkyl, an alkoxy, a haloalkyl, a haloalkoxy, an aryl, a heteroaryl, an alkylaryl or an alkylheteroaryl, each of which can be independently substituted by at least one of a hydroxyl, a halogen, a C1-C6 alkyl, a C1-C6 alkoxy, a C1-C6 haloalkyl, a C1-C6 haloalkoxy, an oxo, a cyano, an unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl. Specifically, R can be hydrogen, an unsubstituted or substituted C1-C4 linear alkyl,

[0103] In Chemical Formulae 1 to 6, m is an integer of 1 or 2, and n is an integer of 1 to 4; specifically, m and n may be 1.

[0104] In Chemical Formula 1, X, Y, and Z are each independently hydrogen, a linear or branched alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, an alkylaryl group, or an alkylheteroaryl group, each of which can be independently substituted by at least one of a hydroxyl group, a halogen group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, an unsubstituted or substituted aryl group, an unsubstituted or substituted heteroaryl group, an oxo group, a nitro group, a cyano group, or a trifluoromethyl group.

[0105] The compound of the present application may be at least one compound selected from the group consisting of the chemical formulas in Table 1 below, but is not limited thereto.

[0106] [Table 1]

[0107]

[0108]

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126]

[0127] As used in this specification, the term "treatment-" or "treatment" refers to a therapeutic agent, a preventive, temporary prescription method or a preventive method. The term "prevention" used in this specification refers to all actions to suppress cancer or delay the onset of cancer by administering the above-mentioned pharmaceutical composition. For the present application, beneficial or desired clinical results are non-restrictive, which may be detected or undetectable, and may include symptom relief, reduction in disease severity, a stable (i.e., unmitigated) state of the disease, a delay or gradual progression of the disease, an improvement in the disease state or a temporary prescription and improvement (whether partial or complete). "Treatment" can also refer to sustained survival compared to the expected survival without treatment. Those who need treatment include not only those who are prone to a condition or disorder, but also those who already have a condition or disorder, or a condition or disorder that is prevented.

[0128] The expression "therapeutically effective amount" or "effective amount" used in this specification refers to an amount sufficient to produce the following effects when the compound of Formula I described herein is administered to a mammal: (i) treating or preventing a specific disease, condition or disorder; (ii) reducing, improving or alleviating one or more symptoms of a specific disease, condition or disorder; or (iii) preventing or delaying one or more symptoms of a specific disease, condition or disorder. The amount of the compound equivalent to this amount will vary depending on factors such as the specific compound, the disease state and its severity, the common characteristics of the mammal in need of treatment (e.g., weight), but can nevertheless be routinely determined by a person of ordinary skill in the art.

[0129] As used herein, the terms "cancer" and "cancerous" refer to or express a physiological condition in mammals that is generally characterized by abnormal or unregulated cell growth. A "tumor" includes more than one type of cancerous cell. Without limitation, examples of cancer include carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More specific examples of such cancers include squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), lung cancer (including small cell lung cancer, non-small cell lung cancer ("NSCLC"), lung adenocarcinoma, and lung squamous cell carcinoma), peritoneal cancer, hepatocellular carcinoma, stomach or gastric cancer (including gastrointestinal cancer), pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, liver tumors, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine cancer, salivary gland cancer, kidney or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, liver tumors, anal cancer, penile cancer, skin cancer (including melanoma), and head and neck cancer.

[0130] As used herein, "pharmaceutically acceptable" means that the above-mentioned substance or composition is chemically and / or toxicologically compatible with the mammals and / or other ingredients (including dosage forms) to be treated thereby.

[0131] The "pharmaceutically acceptable salt" used in the present specification refers to a pharmaceutically acceptable organic salt or inorganic salt of the compound of the present application.

[0132] As used in this specification, "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt of a compound described in this specification. In a non-limiting manner, exemplary salts may include sulfates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, bisulfates, phosphates, acid phosphates, isonicotinates, lactates, salicylates, acid citrates, tartrates, oleates, tannates, pantothenates, bitartrates, ascorbates, succinates, maleates, gentisinates, fumarates, gluconates, glucuronates, saccharates, formates, benzoates, glutamates, methanesulfonates, ethanolates, ethanesulfonates, edisylate, benzenesulfonates, p-toluenesulfonates, and pamoates (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphtonate)). A pharmaceutically acceptable salt may contain inclusion bodies of another molecule, such as acetate ions, succinate ions, or other counterions. Counterions may be any organic or inorganic moiety that stabilizes the charge of the parent compound. Also, a pharmaceutically acceptable salt may have more than one filling atom in its structure. In the case where multiple filling atoms are part of a pharmaceutically acceptable salt, there may be multiple counterions. Thus, a pharmaceutically acceptable salt may have more than one charged atom and / or more than one counterion.

[0133] One embodiment of the present application provides a pharmaceutical composition for preventing or treating cancer, comprising a compound represented by Chemical Formula 1, a pharmaceutically acceptable salt, hydrate, solvate, structural isomer, optical isomer, stereoisomer, or a combination thereof. When the compound represented by the above Chemical Formula 1 or a pharmaceutically acceptable salt thereof is administered alone, it has the effect of inhibiting cancer activity.

[0134] One embodiment of the present application provides a pharmaceutical composition for preventing or treating resistant cancer, comprising a compound represented by Chemical Formula 1, a pharmaceutically acceptable salt, hydrate, solvate, structural isomer, optical isomer, stereoisomer, or a combination thereof. When the compound represented by the above Chemical Formula 1 or a pharmaceutically acceptable salt thereof is administered in combination with an anticancer drug or radiotherapy for resistant cancer, it has the effect of inhibiting cancer activity.

[0135] In one embodiment of the present application, the above-mentioned cancer or resistant cancer can be at least one selected from the group consisting of ovarian cancer, colorectal cancer, pancreatic cancer, gastric cancer, liver cancer, breast cancer, cervical cancer, thyroid cancer, parathyroid cancer, lung cancer, non-small cell lung cancer, prostate cancer, gallbladder cancer, bile duct cancer, blood cancer, bladder cancer, kidney cancer, melanoma, colon cancer, bone cancer, skin cancer, head and neck cancer, uterine cancer, rectal cancer, brain cancer, perianal cancer, fallopian tube cancer, endometrial cancer, vaginal cancer, vulvar cancer, esophageal cancer, small intestine cancer, endocrine gland cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, ureteral cancer, renal cell carcinoma, renal pelvis cancer, leukemia, central nervous system (CNS) tumors, spinal cord tumors, brain stem gliomas and pituitary adenomas.

[0136] In one embodiment of the present application, the above-mentioned anticancer drug can be selected from nitrogen mustard, imatinib, oxaliplatin, rituximab, erlotinib, neratinib, lapatinib, gefitinib, vandetanib, nilotinib, semasanib, bosutinib, axitinib, masitinib, cediranib, lestaurtinib, trastuzumab, gefitinib, bortezomib, sunitinib, pazopanib, tocitanib, nintedanib, regorafenib, semasanib, tivozanib, ponatinib, cabozantinib, abdine, carboplatin, sorafenib, lenvatinib, bevacizumab, cisplatin, cetuximab, mistletoe, asparaginase, retinoic acid, hydroxyurea, dasatinib, estramustine, gemtuzumab, ibritumomab tiuxetan, heptaplatin, methylaminolevulinic acid, amsacrine, alemtuzumab, procarbazine, alprostadil, holmium nitrate chitosan, gemcitabine, doxifluridine, pemetrexed, tegafur, capecitabine, gimeracil, otracil, azacitidine, methotrexate, uracil, cytarabine , 5-fluorouracil, fludarabine, enocitabine, flutamide, capecitabine, decitabine, mercaptopurine, thioguanine, cladribine, carmofur, raltitrexed, docetaxel, paclitaxel, cabazitaxel, irinotecan, belotecan, topotecan, vinorelbine, etoposide, vincristine, vinblastine, teniposide, doxorubicin, idarubicin, epirubicin, mitoxantrone, mitomycin, bleomycin, daunorubicin, actinomycin, pirarubicin, aclarubicin, peclozuryl At least one of the group consisting of oxazolidinone, temsirolimus, temozolomide, busulfan, ifosfamide, cyclophosphamide, melphalan, altretinoin, dacarbazine, thiotepa, nimustine, chlorambucil, dibromodulin, folinic acid, retinoic acid, exemestane, aminoglutethimide, anagrelide, olaparib, navelbine, fadrozole, tamoxifen, toremifene, testolactone, anastrozole, letrozole, vorozole, bicalutamide, lomustine, vorinostat, entinostat and carmustine.

[0137] The drug combination according to an embodiment of the present application may include the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof and the anticancer agent at a molar concentration ratio of 1:0.001 to 1:1000, 1:0.01 to 1:100, 1:0.1 to 1:50 or 1:0.1 to 1:20.

[0138] The pharmaceutical composition according to one embodiment of the present application may be in the form of capsules, tablets, granules, injections, ointments, powders and beverages.

[0139] The pharmaceutical composition according to one embodiment of the present application can be formulated into oral dosage forms (such as powders, granules, capsules, tablets, aqueous suspensions, etc.); external preparations; suppositories; and injection forms.

[0140] The pharmaceutical composition according to one embodiment of the present application may include a pharmaceutically acceptable carrier. As for pharmaceutically acceptable carriers, binders, lubricants, disintegrants, excipients, solubilizers, dispersants, suspending agents, pigments, spices, etc. may be used for oral administration, and buffers, preservatives, pain-relieving agents, solubilizers, isotonic agents, stabilizers may be mixed for use in injections, and bases, excipients, lubricants, etc. may be used for topical administration.

[0141] The dosage form of the pharmaceutical composition according to one embodiment of the present application can be prepared in various ways by mixing with a pharmaceutically acceptable carrier, for example, it can be prepared into tablets, lozenges, capsules, elixirs, suspensions, syrups, tablets, etc. for oral administration, and can be prepared into unit dose ampoules or multiple administration forms for injection. In addition, the dosage form of the pharmaceutical composition of the present application can be prepared into solutions, suspensions, tablets, capsules, sustained-release preparations, etc.

[0142] The carriers, excipients and diluents used for formulation may include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, mineral oil, fillers, anticoagulants, lubricants, wetting agents, flavors, emulsifiers or preservatives, etc.

[0143] One embodiment of the present application relates to a pharmaceutical composition comprising a pharmaceutically applicable adjuvant and / or excipient and a compound represented by Chemical Formula 1 of the present invention or a pharmaceutically acceptable salt thereof as active ingredients.

[0144] In this application, "adjuvant" refers to any substance that can produce, intensify or modify a specific response to the active ingredient of the present invention if administered simultaneously, in the same time period or continuously. Well-known adjuvants are used for injection solutions, for example, aluminum compositions, such as aluminum hydroxide or aluminum phosphate; saponins, such as QS21, muramyl dipeptide or muramyl tripeptide; proteins, such as gamma-interferon or tumor necrosis factor (TNF); M59; squalene; polyols.

[0145] The administration route of the pharmaceutical composition according to one embodiment of the present application includes but is not limited to oral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, sublingual or rectal.

[0146] The pharmaceutical composition according to one embodiment of the present application can be administered orally or parenterally. When administered parenterally, it can be applied externally or injected intraperitoneally, intrarectally, subcutaneously, intravenously, intramuscularly or intrathoracically.

[0147] The dosage of the pharmaceutical composition according to one embodiment of the application is different according to the patient's state and body weight, disease components, drug form, route of administration and time, but can be appropriately selected by those skilled in the art. For example, the pharmaceutical composition according to one embodiment of the application can be administered 0.0001mg / kg to 1000mg / kg or 0.001mg / kg to 500mg / kg per day. The administration of the pharmaceutical composition according to one embodiment of the application can be administered once a day or several times. The above dosage does not limit the scope of the application in any way.

[0148] Furthermore, the present application provides a use of a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof in treating cancer.

[0149] Furthermore, the present application provides a use of a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof in treating resistant cancer.

[0150] Furthermore, the present application provides a use of a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof in treating stem cell cancer.

[0151] The resistant cancer and the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof are the same as those described above, and thus detailed description is omitted.

[0152] Furthermore, the present application provides a method for treating cancer or resistant cancer, comprising administering to an individual suffering from resistant cancer a therapeutically effective amount of the aforementioned compound represented by Chemical Formula 1, its pharmaceutically acceptable salt, hydrate, solvate, structural isomer, optical isomer, stereoisomer, or a combination thereof. With respect to the above-mentioned administration, it can be administered simultaneously, separately or sequentially with a chemotherapeutic agent that can be used to treat cancer or proliferative diseases.

[0153] The term "administering" refers to introducing a predetermined substance into a subject by an appropriate method.

[0154] A "subject with resistant cancer" refers to an individual who has developed or is likely to develop resistant cancer and is in need of appropriate treatment, and may be an individual who has received anti-cancer treatment (e.g., surgical resection, chemotherapy using anti-cancer agents, radiotherapy, or immunotherapy) but has relapsed due to resistance to the treatment.

[0155] Subjects with resistant cancer may include humans, cattle, dogs, guinea pigs, rabbits, chickens, or insects, etc. Specifically, they may be mammals such as humans, cattle, horses, pigs, dogs, sheep, goats, cats, etc. The above individuals may be individuals who have or may have a high risk of developing cancer.

[0156] Furthermore, the present application provides a radiation therapy method, comprising the steps of administering a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof to a subject suffering from resistant cancer; and irradiating radiation.

[0157] The resistant cancer, the subject having the resistant cancer, the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof are the same as those described above, and thus a detailed description thereof is omitted.

[0158] As the radiation irradiation, any radiation method generally used for radiation therapy of cancer or any radiation method for cancer developed later can be applied.

[0159] When the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof of the present application is administered in combination with radiation irradiation, a synergistic effect of growth inhibition and / or death induction on cancer cells or cancer stem cells is provided, thereby effectively preventing or treating cancer and further preventing radiation resistance, cancer metastasis or cancer recurrence. Specific embodiments

[0161] Preparation Example

[0162] The compounds in Table 1 were prepared by the methods of the following Preparation Examples.

[0163] [Chemical formula 7]

[0164] 2-((2-ethylbenzothiophene-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione was prepared by the following 10 steps. The synthesis method in each step will be described in detail below.

[0165] 1) Step 1

[0166] [Reaction 1]

[0167]

[0168] As shown in reaction formula 1, benzothiophene (1.0 equivalent) is cooled to -78 ° C under tetrahydrofuran solvent, and 2.5M n-butyl lithium (1.2 equivalent) solution is added. Stir for 1 hour while maintaining -78 ° C, add iodoethane (2.0 equivalents) dropwise, and stir at 0 ° C for 1 hour. Confirm that the reaction is complete, and use ammonium chloride aqueous solution and ethyl acetate to terminate the reaction. The organic layer is washed with distilled water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel chromatography to obtain 2-ethylbenzothiophene (2-Ethylbenzothiophene).

[0169] 2) Step 2

[0170] [Reaction 2]

[0171]

[0172] After 2-ethylbenzothiophene (1.0 equivalent) was added to dichloromethane (MC), it was cooled to 0°C, maintained at 0°C, and tin chloride (IV) (1.5 equivalents) and dichloromethyl methyl ether (1.5 equivalents) were added in sequence, and then stirred for 1 hour. Confirm that the reaction is complete, and terminate the reaction with aqueous ammonium chloride and dichloromethane. The organic layer was washed with distilled water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain 2-ethyl-1-benzothiophene-3-carbaldehyde.

[0173] 3) Step 3

[0174] [Reaction 3]

[0175]

[0176] Add piperazine-2-carboxylic acid (1.0 equivalent), dioxane and distilled water, and cool to below 5°C. Subsequently, add di-tert-butyl dicarbonate (1.1 equivalent) while maintaining below 10°C. After stirring at room temperature for 5 hours, add sodium carbonate (1.1 equivalent) and stir for 5 minutes. Add 9-fluorenylmethyl chloroformate (1.2 equivalent), stir overnight, and concentrate under reduced pressure. Add ethyl acetate and 1M hydrochloric acid to the residue, adjust the pH to 2-3, and stir vigorously until the residue is completely dissolved. Wash the organic layer with brine, dry over anhydrous magnesium sulfate, and concentrate under reduced pressure. Recrystallization from ethyl acetate (EA) gave 1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid.

[0177] 4) Step 4

[0178] [Reaction 4]

[0179]

[0180] Under nitrogen flow, a solution of 1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid, benzyl alcohol (1.02 equivalents) and triphenylphosphine (1.02 equivalents) in anhydrous dichloromethane was cooled to 0°C. Diethyl azodicarboxylate (DEAD) (1.02 equivalents) was added while maintaining the temperature below 0°C and stirred for 1 hour. After adding water and stirring vigorously for 20 minutes, the organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain 1-((9H-fluoren-9-yl)methyl)2-benzyl 4-(tert-butyl)piperazine-1,2,4-tricarboxylate.

[0181] 5) Step 5

[0182] [Reaction 5]

[0183]

[0184] As shown in reaction formula 5, trifluoroacetic acid (TFA) (2.0 volumes) was added to a dichloromethane (5.0 volumes) solution of 1-((9H-fluoren-9-yl)methyl)2-benzyl 4-(tert-butyl)piperazine-1,2,4-tricarboxylate at room temperature, and stirred at room temperature for 30 minutes. After neutralization with sodium bicarbonate, extraction was performed with dichloromethane, and the organic layer was washed with brine. Drying was performed with anhydrous magnesium sulfate, and concentration was performed to obtain 1-((9H-fluoren-9-yl)methyl)2-benzyl piperazine-1,2-dicarboxylate.

[0185] 6) Step 6

[0186] [Reaction 6]

[0187]

[0188] At room temperature, 2-ethyl-1-benzothiophene-3-carboxaldehyde (1.0 equivalent) obtained in step 2 and 1-((9H-fluoren-9-yl)methyl)2-benzylpiperazine-1,2-dicarboxylate (1.2 equivalent) obtained in step 5 were added to 1,2-dichloroethane (DCE), and stirred for 30 minutes. Sodium triacetoxyborohydride (3.0 equivalent) was added, and stirred at room temperature overnight. Dichloromethane and water were added to the reaction solution, and stirred vigorously for 20 minutes. The separated organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated to obtain 1-((9H-fluoren-9-yl)methyl)2-benzyl 4-((2-ethylbenzothiophen-3-yl)methyl)piperazine-1,2-dicarboxylate.

[0189] 7) Step 7

[0190] [Reaction 7]

[0191]

[0192] 1-((9H-fluoren-9-yl)methyl)2-benzyl 4-((2-ethylbenzothiophene-3-yl)methyl)piperazine-1,2-dicarboxylate (1.0 equivalent) was dissolved in dimethylformamide at room temperature, and piperidine (10 equivalents, 25% piperidine in the solvent) was added and stirred for 1 hour. Ethyl acetate was added to the reaction solution, and the piperidine in the solution was washed with an aqueous ammonium chloride solution. After drying over anhydrous magnesium sulfate, the residue obtained by concentrating under reduced pressure was purified by silica gel chromatography to obtain benzyl 4-((2-ethylbenzothiophene-3-yl)methyl)piperazine-2-carboxylate.

[0193] 8) Step 8

[0194] [Reaction formula 8]

[0195]

[0196] At room temperature, benzyl 4-((2-ethylbenzothiophene-3-yl)methyl)piperazine-2-carboxylate (1.0 equivalent), N-(tert-Butoxycarbonyl)glycine (1.1 equivalent), and (Benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (1.2 equivalent) were dissolved in dimethylformamide, and N,N-diisopropylethylamine (1.5 equivalent) was added, followed by stirring at room temperature overnight. The reaction was terminated with aqueous ammonium chloride and ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give benzyl 1-((tert-butoxycarbonyl)glycyl)-4-((2-ethylbenzothiophene-3-yl)methyl)piperazine-2-carboxylate.

[0197] 9) Step 9

[0198] [Reaction formula 9]

[0199]

[0200] As shown in reaction formula 9, at room temperature, 1-((tert-butyloxycarbonyl) glycyl)-4-((2-ethylbenzothiophene-3-yl) methyl) piperazine-2-carboxylic acid benzyl ester obtained by step 8 is dissolved in dichloromethane (5.0 volumes), trifluoroacetic acid (2.0 volumes) is added and stirred for 30 minutes at room temperature. After the reaction is completed, the reaction solution is neutralized with sodium bicarbonate aqueous solution and extracted with dichloromethane. Anhydrous magnesium sulfate is used for drying, and reduced pressure concentration obtains 4-((2-ethylbenzothiophene-3-yl) methyl) 1-glycylpiperazine-2-carboxylic acid benzyl ester (benzyl 4-((2-ethylbenzothiophene-3-yl)methyl)-1-glycylpiperazine-2-carboxylate).

[0201] 10) Step 10

[0202] [Reaction formula 10]

[0203]

[0204] After the 4-((2-ethylbenzothiophene-3-yl)methyl)1-glycylpiperazine-2-carboxylic acid benzyl ester obtained in step 9 was dissolved in isopropanol (5.0 volumes), acetic acid (1.5 volumes) was added and stirred for 1 hour under heating conditions. After the reaction was completed, sodium bicarbonate aqueous solution was used for neutralization. The reactant was extracted with dichloromethane and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography to obtain 2-((2-ethylbenzothiophene-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (2-((2-ethylbenzothiophene-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione) (S101).

[0205] [Chemical formula 7]

[0206] S101

[0207]

[0208] 1H NMR(500MHz, CDCl3)δ7.82(d,J=8.0Hz,1H),7.76(d,J=8.0Hz,1H),7.34-7.31(m,1H ),7.29-7.25(m,1H),4.50-4.46(m,1H),4.07(d,J=10.0Hz,1H),4.00(s,2H),3.81- 3.67(m,2H),3.48(d,J=10.5Hz,1H),2.94(q,J=7.5Hz,2H),2.86(d,J=11.5Hz,1H), 2.74-2.69(m,1H),2.17(t,J=11.0Hz,1H),2.10-2.05(m,1H),1.33(t,J=7.5Hz,3H).

[0209] 13 C NMR (126MHz, CDCl3) δ166.10,161.85,146.58,140.52,138.09,125.68,124.02,1 23.78,122.22,122.19,56.99,56.38,53.28,51.39,44.61,41.59,22.13,16.20.

[0210] MS (ESI) m / z for C 18 H 21 N3O2S[M+H] + : Calculated value 344.1427, measured value 344.1423.

[0211] [Chemical formula 8]

[0212] S102

[0213]

[0214] 1H NMR(500MHz, CDCl3)δ7.83(d,J=8.0Hz,1H),7.76(d,J=8.0Hz,1H),7.52-7.49(m,1H),7.34 -7.25(m,2H),4.49-4.44(m,1H),4.10-4.03(m,2H),3.70(d,J=13.0Hz,1H),3.68-3.65(m, 1H),3.50-3.46(m,1H),2.94(q,J=7.5Hz,2H),2.86-2.82(m,1H),2.72-2.67(m,1H),2.13( q,J=11.0Hz,1H),2.08-2.02(m,1H),1.48(dd,J=7.0Hz,19.0Hz,3H),1.33(t,J=7.5Hz,3H).

[0215] 13 C NMR (126MHz, CDCl3) δ166.06,165.96,165.49,165.41,146.44,140.56,138.09,125.83,123.99,123.75,122.2 6,122.17,57.45,57.16,56.74,56.53,53.31,51.59,51.46,50.92,50.62,41.75,22.11,21.56,21.48,16.20.

[0216] MS (ESI) m / z for C 19 H 23 N3O2S[M+H] + : Calculated value 358.1584, measured value 358.1579.

[0217] [Chemical formula 9]

[0218] S103

[0219]

[0220] 1H NMR(500MHz, CDCl3)δ7.82(d,J=8.0Hz,1H),7.75(d,J=8.0Hz,1H),7.33-7.30(m ,1H),7.28-7.25(m,1H),4.78-4.44(m,1H),4.05-3.98(m,2H),3.80-3.66(m,2H) ,3.50-3.48(m,1H),2.94(q,J=7.5Hz,2H),2.88-2.82(m,1H),2.71-2.65(m,1H) ,2.15-2.02(m,2H),1.89-1.60(m,3H),1.32(t,J=7.5Hz,3H),0.97-0.90(m,6H).

[0221] 13 C NMR (126MHz, CDCl3) δ165.93,165.71,165.52,164.98,146.45,140.51,138.09,125.81,124.02,123.77,122.21,122.18, 57.48,56.65,56.35,53.60,53.23,51.60,51.43,44.21,44.09,41.81,24.13,23.44,23.22,22.14,21.39,21.35,16.18.

[0222] MS (ESI) m / z for C 22 H 29 N3O2S[M+H] + : Calculated value 400.2053, measured value 400.4056.

[0223] [Chemical formula 10]

[0224] S105

[0225]

[0226] 1H NMR(500MHz, CDCl3)δ7.82(d,J=8.0Hz,1H),7.76(d,J=8.0Hz,1H),7.35-7.25( m,2H),4.52-4.48(m,1H),4.07-4.01(m,1H),3.89-3.75(m,2H),3.69-3.62(m,1 H),3.55-3.49(m,1H),2.94(q,J=7.5Hz,2H),2.85-2.83(m,1H),2.68-2.63(m,1 H),2.14-2.00(m,2H),1.85-1.57(m,4H),1.56-1.40(m,1H),1.35-1.05(m,9H).

[0227] 13 C NMR (126MHz, CDCl3) δ166.71,166.08,164.96,163.41,146.42,140.54,138.09,1 28.59,127.62,127.04,125.83,124.00,123.76,122.24,122.17,60.21,59.81,5 7.40,57.07,56.59,56.38,53.36,53.22,51.80,51.39,43.56,42.00,41.80,41.38,29.36,29.17,26.69,26.46,26.40,26.24,25.96,25.85,25.73,22.12,16.20.

[0228] MS (ESI) m / z for C 24 H 31 N3O2S[M+H] + : Calculated value 426.2210, measured value 426.2210.

[0229] [Chemical formula 11]

[0230] S106

[0231]

[0232] 1H NMR (500MHz, CDCl3) δ7.83-7.76(m,2H),7.37-7.28(m,2H),6.66(s,1H),4.51-4.48(m,1H),4.15-4.13(m,2H),3.81 -3.66(m,2H),3.53-3.49(m,1H),2.95(q,J=7.5Hz,2H),2.88-2.70(m,4H),2.24-2.02(m,3H),1.34(t,J=7.5Hz,3H).

[0233] 13 C NMR (126MHz, CDCl3) δ165.73,165.32,163.17,162.57,146.48,140.52,138.09,128.64,127.07,125.76,124.01,123.77, 122.19,78.95,78.53,72.91,57.28,56.55,53.75,53.28,51.40,41.74,31.66,25.95,25.45,22.73,22.13,16.18,14.20.

[0234] MS (ESI) m / z for C 21 H 23 N3O2S[M+H] + : Calculated value 382.1584, measured value 382.1594.

[0235] [Chemical formula 12]

[0236] S107

[0237]

[0238] 1H NMR (500MHz, CDCl3) δ7.84-7.82(m,1H),7.76(d,J=8.0Hz,1H),7.48-7.41(m,1H),7.34-7.31(m, 1H),7.29-7.25(m,1H),4.50-4.44(m,1H),4.18-4.16(m,1H),4.07-4.05(m,1H),3.81-3.66(m,2H ),3.49(d,J=10.5Hz,1H),2.95(q,J=7.5Hz,2H),2.85(d,J=10.5Hz,1H),2.72-2.66(m,1H),2.61 (t,J=7.5Hz,1H),2.60-2.55(m,1H),2.25-2.11(m,3H),2.09-2.02(m,4H),1.33(t,J=7.5Hz,3H).

[0239] 13 C NMR (126MHz, CDCl3) δ166.13,166.01,164.70,164.06,146.43,140.53,138.09,125.79,124.01,123.76,122.23,122.17,57. 43,56.84,56.71,56.33,53.92,53.82,53.25,51.57,51.35,41.82,33.62,33.31,29.42,29.28,22.13,16.19,15.25,15.09.

[0240] MS (ESI) m / z for C 21 H 27 N3O2S2[M+H] + : Calculated value 418.1618, measured value 418.1618.

[0241] [Chemical formula 13]

[0242] S108

[0243]

[0244] 1 H NMR 1H NMR (500MHz, CDCl3) δ7.82-7.75(m,2H),7.32-7.25(m,7H),6.56-6.52(m,1H),4.46(t,J=11.5Hz,1 H),4.19-4.02(m,2H),3.80-3.53(m,5H),3.03-2.69(m,6H),2.28-2.06(m,2H),1.34-1.31(m,3H).

[0245] 13 C NMR (126MHz, CDCl3) δ163.43,162.88,140.38,138.02,137.42,128.94,128.79,128.77,128.57,127.52,127.46,127.0 0,124.01,123.77,122.15,57.26,56.59,54.52,53.89,53.18,51.22,46.19,41.58,37.41,36.84,36.78,22.10,16.09.

[0246] MS (ESI) m / z for C 26 H 29 N3O2S2[M+H] + : Calculated value 480.1774, measured value 480.1782.

[0247] [Chemical formula 14]

[0248] S109

[0249]

[0250] 1 H NMR (500MHz, CDCl3) δ7.85-7.75(m,2H),7.34-7.25(m,2H),4.51-4.36(m,1H),4.12-4.00(m,2H),3.81-3.65(m,3H),3.60-3.38(m,2H),2.98-2 .91(m,2H),2.88-2.79(m,1H),2.77-2.68(m,1H),2.49-2.43(m,1H),2. 19-2.10(m,1H),2.09-1.99(m,2H),1.97-1.83(m,2H),1.36-1.31(m,3H)

[0251] 13C NMR (126MHz, CDCl3) δ167.03,164.35,163.16,162.69,146.41,146.37,140.61,140. 54,138.09,138.06,126.04,125.78,124.00,123.93,123.73,123.68,122.33,122.2 2,122.14,122.11,61.02,58.96,58.59,56.99,56.22,55.84,53.47,53.18,51.81,51.26,45.35,45.28,41.93,41.60,29.99,29.80,22.11,21.90,21.76,16.19,16.16.

[0252] MS (ESI) m / z for C 21 H 25 N3O2S[M+H] + : Calculated value 384.1740, measured value 384.1746.

[0253] [Chemical formula 15]

[0254] S111

[0255]

[0256] 1 H NMR (500MHz, CDCl3) δ7.76-7.71(m,2H),7.41-7.03(m,8H),4.48-4.25(m,2H),3 .84-3.78(m,0.5H),3.70(dd,J=13.0Hz,65.5Hz,1H),3.44(dd,J=13.0Hz,27.5Hz ,1H),3.35-3.27(m,1H),3.21-3.16(m,0.5H),3.08-2.83(m,4H),2.77-2.62(m, 1H),2.58-2.37(m,1H),2.01-1.92(m,1H),1.87-1.65(m,1H),1.34-1.27(m,3H).

[0257] 13C NMR (126MHz, CDCl3) δ166.56,165.99,164.52,162.74,146.41,146.22,140.55,1 40.52,138.07,135.17,134.88,131.05,130.09,128.85,128.82,127.73,127.49, 125.84,123.92,123.71,122.23,122.19,122.13,57.51,56.27,56.23,55.98,55.83,55.59,53.25,52.91,51.19,51.14,41.71,41.36,40.76,22.09,22.03,16.18.

[0258] MS (ESI) m / z for C 25 H 27 N3O2S[M+H] + : Calculated value 434.1897, measured value 434.1895.

[0259] [Chemical formula 16]

[0260] S112

[0261]

[0262] 1 H-NMR (500MHz, CDCl3) δ7.78-7.72(m,2H),7.39(d,J=8.0Hz,1H),7.34-7.25(m,3H),7.18(d,J=8.5Hz,1H),7.09 (d,J=8.5Hz,1H),4.45-4.28(m,2H),3.83-2.83(m,8H),2.83-2.37(m,2H),2.05-1.68(m,2H),1.35-1.27(m,3H).

[0263] 13 C NMR (126MHz, CDCl3) δ164.18,162.30,146.47,140.48,138.05,133.81,133.60,133.43,132.54,131.40,128.94,125.75,124.05,123. 96,123.76,122.16,56.21,56.07,55.84,55.65,53.17,53.08,51.21,51.05,41.65,41.39,40.57,39.97,22.13,22.06,16.26,16.16.

[0264] MS (ESI) m / z for C 25 H 26 ClN3O2S[M+H] + : Calculated value 468.1507, measured value 468.1507.

[0265] [Chemical formula 17]

[0266] S113

[0267]

[0268] 1 H NMR (500MHz, CDCl3) δ7.79-7.72(m,2H),7.54(d,J=8.0Hz,1H),7.44(d,J=8.5Hz,1H),7.36-7.23(m,2H),7.13(d,J=8.0Hz, 1H),7.03(d,J=8.0Hz,1H),4.45-4.28(m,2H),3.90-2.85(m,8H),2.78-2.41(m,2H),2.05-1.65(m,2H),1.35-1.28(m,3H).

[0269] 13 C NMR (126MHz, CDCl3) δ164.16,162.24,146.43,140.48,138.06,134.87,134 .05,133.95,132.93,131.89,131.75,125.75,124.06,123.96,123.76,122 .15,121.87,121.70,57.68,56.20,56.15,56.01,55.90,55.58,53.21,53.13,52.47,51.13,51.04,41.68,41.42,40.69,40.11,22.13,16.31,16.18.

[0270] MS (ESI) m / z for C 25 H 26 BrN3O2S[M+H] + : Calculated value 512.1002, measured value 512.1002.

[0271] [Chemical formula 18]

[0272] S114

[0273]

[0274] 1 H NMR (500MHz, CDCl3) δ7.77-7.72(m,2H),7.37-7.24(m,2H),7.22-7.19(m,1H),7.13-7.08(m,2H),7.00(t,J=8.5Hz,1H),4.48- 4.27(m,2H),3.84-3.47(m,2H),3.36-3.18(m,2H),3.03-3.86(m,4H),2.77-2.43(m,2H),2.04-1.68(m,2H),1.34-1.28(m,3H).

[0275] 13 C NMR (126MHz, CDCl3) δ164.19,163.33,162.45,161.39,146.43,140.41,140. 36,137.98,132.55,132.49,131.57,131.52,130.81,130.52,123.93,123.8 8,123.67,122.07,115.72,115.68,115.55,115.52,56.12,56.00,55.69,55.62,53.12,52.97,51.01,41.55,41.28,40.34,39.69,22.04,21.93,16.06.

[0276] MS (ESI) m / z for C 25 H 26 FN3O2S[M+H] + : Calculated value 452.1803, measured value 452.1798.

[0277] [Chemical formula 19]

[0278] S115

[0279]

[0280] 1H NMR (500MHz, CDCl3) δ7.78-7.72(m,2H),7.37-7.24(m,3H),7.21-7.06(m,1H),6.95-6.86(m,1H),4.49-4.27(m,2H),3.86-3. 49(m,2H),3.38-3.30(m,1H),3.23-2.98(m,2H),2.94-2.83(m,3H),2.78-2.48(m,2H),2.04-1.68(m,2H),1.33-1.30(m,3H).

[0281] 13 C NMR (126MHz, CDCl3) δ163.79,162.28,146.43,140.39,140.35,137.98,137.95,13 2.03,131.96,128.56,127.64,127.01,126.01,123.96,123.92,123.69,122.07,1 19.82,119.69,118.95,118.81,117.60,117.44,117.31,56.16,55.88,55.44,53.09,53.02,51.40,51.04,41.55,41.36,40.11,39.54,22.05,21.90,16.05,16.03.

[0282] MS (ESI) m / z for C 25 H 25 F2N3O2S[M+H] + : Calculated value 470.1708, measured value 470.1702.

[0283] [Chemical formula 20]

[0284] S116

[0285]

[0286] 1H NMR (500MHz, CDCl3) δ7.77-7.71(m,2H),7.68-7.65(m,1H),7.58-7.55(m,1H),7.38-7.35(m,1H),7.31-7.2 1(m,3H),4.43-4.31(m,2H),3.85-3.82(m,0.5H),3.65(dd,J=13.0Hz,65.0Hz,1H),3.50-3.41(m,1H),3.35- 3.29(m,1H),3.28-3.23(m,0.5H),3.14-3.09(m,0.5H),3.08-3.03(m,1H),3.02-2.96(m,0.5H),2.92-2.80 (m,2H),2.78-2.60(m,1H),2.56-2.37(m,1H),2.04-1.80(m,1.5H),1.53-1.44(m,0.5H),1.31-1.26(m,3H).

[0287] 13 C NMR (126MHz, CDCl3) δ166.34,165.91,163.97,162.11,146.43,146.31,140.48,140.46 ,139.31,139.26,138.03,131.44,130.46,128.63,127.09,125.70,125.66,125.61,125 .58,123.99,123.91,123.75,123.69,122.18,122.12,57.37,56.22,56.18,56.10,55.96,55.53,53.21,52.83,51.10,51.01,41.68,41.51,40.97,40.35,22.07,21.87,16.09.

[0288] MS (ESI) m / z for C 26 H 26 F3N3O2S[M+H] + : Calculated value 502.1771, measured value 502.1758.

[0289] [Chemical formula 21]

[0290] S117

[0291]

[0292] 1H NMR (500MHz, CDCl3) δ7.77-7.70(m,2H),7.68-7.64(m,1H),7.59-7.56(m,1H),7.38-7.32(m,2H) ,7.29-7.23(m,2H),4.46-4.29(m,2H),3.85-3.78(m,0.5H),3.66(dd,J=13.0Hz,54.0Hz,1H),3.5 3-3.43(m,1H),3.42-3.37(m,0.5H),3.32-3.24(m,1H),3.13-2.96(m,2H),2.93-2.86(m,2H),2. 81-2.68(m,1H),2.61-2.36(m,1H),2.02-1.92(m,1.5H),1.59-1.51(m,0.5H),1.35-1.28(m,3H).

[0293] 13 C NMR (126MHz, CDCl3) δ166.19,165.77,163.62,162.08,146.50,146.44,140.86,140.74,140.46 ,140.39,138.04,132.39,132.33,131.85,130.89,128.63,127.70,127.09,125.63,125.44,124 .07,123.98,123.81,123.75,122.15,118.49,118.45,111.73,111.55,65.30,57.31,56.29,56.15,56.04,55.77,55.37,53.20,51.52,51.15,41.70,41.51,41.09,40.47,22.09,16.23,16.17.

[0294] MS (ESI) m / z for C 26 H 26 N4O2S[M+H] + : Calculated value 459.1849, measured value 459.1833.

[0295] [Chemical formula 22]

[0296] S118

[0297]

[0298] 1H NMR (500MHz, CDCl3) δ8.26-8.23(m,1H),8.16-8.13(m,1H),7.75-7.67(m,2H),7.42-7.39(m,1H),7.36- 7.21(m,3H),4.48-4.33(m,2H),3.85-3.80(m,0.5H),3.65(dd,J=13.0Hz,52.5Hz,1H),3.50-3.45(m,0. 5H),3.44-3.26(m,2H),3.22-3.10(m,1H),3.08-3.01(m,1H),2.89(q,J=7.5Hz,1H),2.84-2.76(m,1.5H ),2.72-2.67(m,0.5H),2.60-2.42(m,1H),2.03-1.89(m,1.5H),1.61-1.51(m,0.5H),1.31-1.27(m,3H).

[0299] 13 C NMR (126MHz, CDCl3) δ166.24,165.90,163.51,162.06,147.58,147.54,146.51,146.4 7,142.89,140.45,140.37,138.04,138.01,131.93,131.00,128.64,127.10,125.61, 125.36,124.02,123.97,123.79,123.72,122.13,122.09,57.28,56.36,56.17,55.75,55.35,53.20,53.11,51.45,51.18,41.74,41.54,40.74,40.16,22.09,21.99,16.13.

[0300] MS (ESI) m / z for C 25 H 26 N4O4S[M+H] + : Calculated value 479.1748, measured value 479.1732.

[0301] [Chemical formula 23]

[0302] S119

[0303]

[0304] 1H NMR (500MHz, CDCl3) δ7.74-7.18(m,13H),4.47-4.30(m,2H),3.86-3.80(m,0.5H),3.63(dd,J =13.0Hz,71.0Hz,1H),3.45-3.39(m,0.5H),3.36-3.15(m,2H),3.13-3.07(m,0.5H),3.02-2. 96(m,1.5H),2.89-2.83(m,1H),2.75-2.70(m,0.5H),2.57-2.47(m,2H),2.46-2.38(m,0.5H) ,2.03-1.86(m,1.5H),1.61-1.53(m,0.5H),1.26(t,J=7.5Hz,1.5H),1.07(t,J=7.5Hz,1.5H).

[0305] 13 C NMR (126MHz, CDCl3) δ166.68,166.12,164.63,162.50,146.36,146.12,140.75,140.53,140.48,140.41 ,138.03,137.96,134.07,133.94,131.68,130.57,129.15,128.95,127.79,127.60,127.42,127.32,127 .13,126.93,125.83,125.69,123.95,123.84,123.67,123.62,122.22,122.10,122.03,57.47,56.29,56.26,56.09,55.88,53.26,53.04,51.03,50.88,41.68,41.45,41.06,40.45,22.08,21.75,16.14,16.04.

[0306] MS (ESI) m / z for C 31 H 31 N3O2S[M+H] + : Calculated value 510.2210, measured value 510.2193.

[0307] [Chemical formula 24]

[0308] S120

[0309]

[0310] 1H NMR (500MHz, CDCl3) δ7.77-7.71(m,2H),7.44-7.20(m,7H),7.18-7.14(m,1H),7.06-7.00(m,2H),6.92-6.88(m,1H),5.09 (s,1H),5.04-4.99(m,1H),4.70-4.34(m,1H),4.31-4.22(m,1H),3.86-3.80(m,0.5H),3.65(dd,J=13.0Hz,68.5Hz,1H),3. 45(dd,J=13.0Hz,45.5Hz,1H),3.34-3.30(m,0.5H),3.29-3.24(m,0.5H),3.17-3.12(m,0.5H),3.05-2.81(m,4H),2.77-2. 60(m,1H),2.57-2.35(m,1H),2.03-1.82(m,1.5H),1.73-1.66(m,0.5H),1.29(t,J=7.5Hz,1.5H),1.25(t,J=7.5Hz,1.5H).

[0311] 13 C NMR (126MHz, CDCl3) δ166.61,166.00,164.58,162.84,158.44,146.40,146.29,140.57,140.52,138.08 ,138.05,136.84,136.77,132.07,131.17,128.73,128.68,128.19,128.08,127.51,127.49,127.37,126 .97,125.87,125.83,123.97,123.94,123.71,122.22,122.13,115.24,115.20,70.28,70.12,57.49,56.37,56.05,55.98,55.82,53.30,53.08,51.20,51.11,41.68,41.34,40.52,39.97,22.10,21.99,16.17.

[0312] MS (ESI) m / z for C 32 H 33 N3O3S[M+H] + : Calculated value 540.2315, measured value 540.2292.

[0313] [Chemical formula 25]

[0314] S121

[0315]

[0316] 1 H-NMR(500MHz, CDCl3)δ8.18(m,1H),7.93-7.85(m,1H),7.81-7.69(m,2H),7.59-7.35(m,4H),7.33-7.24(m,3H),4.44-4.27(m,2H), 3.91-3.77(m,1H),3.73-3.57(m,2H),3.43-3.23(m,3H),2.97-2.74(m,3H),2.50-2.31(m,2H),2.05-1.96(m,1H),1.35-1.27(m,3H).

[0317] 13 C-NMR (126MHz, CDCl3) δ165.62,165.56,164.56,163.23,146.28,146.09,140.45,140.42,

[0318] 137.99,137.94,134.14,134.06,132.44,131.67,131.42,131.30,129.58,128.90,128.75,128.68,

[0319] 128.48,128.36,126.63,126.62,126.13,126.09,125.74,125.73,125.40,125.34,124.32,123.84,

[0320] 123.79,123.64,123.61,123.59,122.14,122.04,122.01,57.45,56.39,56.23,55.56,55.42,55.31,53.14,52.75,51.08,50.64,41.66,41.55,38.48,37.71,21.99,21.93,16.10,16.08.

[0321] MS (ESI) m / z for C 29 H 29 N3O2S[M+H] + :Calculated value 484.2053, measured value 484.2047

[0322] [Chemical formula 26]

[0323] S122

[0324]

[0325] 1 H-NMR(500MHz, CDCl3)δ7.94-7.89(m,1H),7.82-7.73(m,2H),7.70-7.65 (m,1H),7.60-7.46(m,3H),7.42-7.29(m,1H),7.32-7.12(m,3H),4.45-4 .37(m,2H),3.76-3.52(m,2H),3.34-3.12(m,2H),2.98-2.83(m,2H),2.7 5-2.57(m,3H),2.48-2.38(m,2H),2.00-1.92(m,1H),1.27-1.22(m,3H);

[0326] 13 C-NMR (126MHz, CDCl3) δ166.20,165.90,164.42,162.50,146.27,145.95,140.42,140.33,137.93,137.85,133.70,1 33.42,132.68,132.57,132.51,132.42,129.74,129.18,128.90,128.42,128.13,127.93,127.73,127.61,127.60,12 6.50,126.47,126.11,125.70,125.66,123.83,123.67,123.57,123.50,122.12,122.10,122.00,121.93,57.32,56.27,56.15,56.02,56.01,55.43,53.07,52.40,50.94,50.64,41.55,41.48,41.36,40.85,21.97,21.70,16.13,16.02.

[0327] MS (ESI) m / z for C 29 H 29 N3O2S[M+H] + :Calculated value 484.2053, measured value 484.2044

[0328] [Chemical formula 27]

[0329] S126

[0330]

[0331] 1H-NMR (500MHz, CDCl3) δ7.83(d,J=8.0Hz,1H),7.77(d,J=8.0Hz,1H),7.33(t,J=7.5Hz,1H),7.27 (t,J=7.5Hz,1H),7.62(s,1H),4.48(d,J=13.0Hz,1H),4.07(d,J=11.0Hz,1H),3.80(d,J=13.0Hz, 1H),3.70-3.3.63(m,2H),3.51(d,J=11.0Hz,1H),2.94(q,J=7.5Hz,2H),2.85(d,J=11.5Hz,1H), 2.69-2.62(m,1H),2.18(t,J=11.0Hz,1H),2.01-1.95(m,1H),1.33(t,J=7.5Hz,3H),1.09(s,9H);

[0332] 13 C-NMR (126MHz, CDCl3) δ165.63,162.11,146.27,140.48,138.01,125.81,123.90,123.65,12 2.16,122.07,63.52,57.83,56.32,53.18,51.81,41.76,36.62,29.69,26.71,22.02,16.10.

[0333] MS (ESI) m / z for C 22 H 29 N3O2S[M+H] + : Calculated value 400.2053, measured value 400.2053.

[0334] [Chemical formula 28]

[0335] S127

[0336]

[0337] 1H-NMR (500MHz, CDCl3) δ7.81(d,J=8.0Hz,1H),7.75(d,J=8.0Hz,1H),7.40-7.31(m,6 H),7.28-7.24(m,1H),5.00-5.04(m,1H),4.42-4.32(m,1H),4.15-4.09(m,1H),3.78( d,J=13.0Hz,1H),3.67-3.59(m,1H),3.56-3.49(m,1H),2.97-2.89(m,2H),2.83-2.7 5(m,1H),2.69-2.61(m,1H),2.21-2.12(m,1H),2.07-1.90(m,1H),1.34-1.30(m,3H);

[0338] 13 C-NMR (126MHz, CDCl3) δ166.10,165.36,163.45,162.75,146.35,140.46,140.44,138.01,13 7.98,137.75,129.00,128.95,128.79,128.75,128.51,127.56,127.08,126.96,126.65,125 .72,125.70,123.91,123.89,123.67,123.65,122.17,122.16,122.08,65.21,59.20,59.17,57.68,57.07,56.50,56.48,53.27,53.14,51.37,51.32,41.96,41.80,22.01,16.11,16.10.

[0339] MS (ESI) m / z for C 24 H 25 N3O2S[M+H] + : Calculated value 420.1740, measured value 420.1740.

[0340] [Chemical formula 29]

[0341] S128

[0342]

[0343] 1H-NMR (500MHz, CDCl3) δ7.82(d,J=8.0Hz,1H),7.74(d,J=8.0Hz,1H),7.32-7.23(m,2H),4.66(d,J=13.0Hz ,1H),4.48-4.43(m,1H),4.03(d,J=10.5Hz,1H),3.83-3.76(m,2H),3.62(d,J=13.0Hz,1H),3.54(d,J=11.0 Hz,1H),2.95-2.89(m,2H),2.79(d,J=11.5Hz,1H),2.68-2.61(m,1H),2.49-2.41(m,1H),2.33(d,J=13.0H z,1H),2.10-1.97(m,3H),1.70(t,J=13.0Hz,1H),1.61-1.52(m,1H),1.43-1.37(m,2H),1.32-1.29(m,3H);

[0344] 13 C-NMR (126MHz, CDCl3) δ164.20,163.98,162.15,162.09,146.28,146.27,140.52,14 0.49,138.00,125.84,125.79,123.90,123.87,123.63,123.61,122.22,122.20,122 .04,59.03,58.78,57.59,57.57,57.19,57.03,53.22,53.20,51.42,51.19,42.60,42.43,41.38,41.34,32.28,31.67,24.69,24.57,24.48,24.44,22.02,16.10,16.09.

[0345] MS (ESI) m / z for C 22 H 27 N3O2S[M+H] + : Calculated value 398.1897, measured value 398.1891.

[0346] [Chemical formula 30]

[0347] S135

[0348]

[0349] 1H NMR (500MHz, CDCl3) δ7.84(d,J=7.5Hz,1H),7.76(d,J=8.0Hz,1H),7.34-7.26(m,2H),7.24-7.13( m,4H),5.46(d,J=17.0Hz,1H),4.53-4.53(m,1H),4.24-4.19(m,2H),4.16-4.11(m,1H),3.84(d,J= 13.0Hz,1H),3.67(d,J=13.0Hz,1H),3.63-3.59(m,1H),3.45-3.40(m,1H),2.99-2.93(m,3H),2.87 -2.84(m,1H),2.77-2.71(m,1H),2.18(t,J=11.0Hz,1H),2.10-2.04(m,1H),1.34(t,J=7.5Hz,3H).

[0350] 13 C NMR (126MHz, CDCl3) δ163.56,162.52,146.36,140.49,138.01,132.13,131.00,128.92,127.07,126.95,126.29, 125.76,123.90,123.65,122.20,122.07,57.10,57.05,55.51,53.23,51.18,44.07,41.47,34.42,22.04,16.13.

[0351] MS (ESI) m / z for C 26 H 27 N3O2S[M+H] + : Calculated value 446.1896, measured value 446.1889.

[0352] [Chemical formula 31]

[0353] S136

[0354]

[0355] 1H-NMR (500MHz, CDCl3) δ7.83-7.81(m,1H),7.75-7.73(m,1H),7.32-7.29(m,1H),7.26-7.23(m,1H),4.37 -4.32(m,2H),4.24-4.20(m,1H),4.04-4.01(m,1H),3.91-3.86(m,1H),3.78(d,J=13.0Hz,1H),3.64(d,J= 13.0Hz,1H),3.57-3.54(m,1H),3.34(d,J=13.0Hz,1H),2.96-2.91(m,2H),2.86-2.82(m,1H),2.78-2.72 (m,1H),2.36-2.31(m,1H),2.09(t,J=11.5Hz,1H),2.04-1.96(m,2H),1.32(t,J=7.5Hz,3H),1.17(s,9H).

[0356] 13 C NMR (126MHz, CDCl3) δ167.28,162.95,146.28,140.52,138.00,125.93,123.87,123.61,122.24,122.03,74.4 8,67.09,56.97,56.80,55.78,54.49,53.41,51.14,41.52,38.85,33.98,28.23,25.64,24.95,22.03,16.11.

[0357] MS (ESI) m / z for C 25 H 33 N3O3S[M+H] + : Calculated value 456.2315, measured value 465.2308.

[0358] [Chemical formula 32]

[0359] S141

[0360]

[0361] 1H NMR (700MHz, CDCl3) δ7.75-7.68(m,2H),7.30-7.26(m,4H),7.26-7.25(m,1H),7.10-6.99( m,2H),4.43-4.20(m,2H),4.16-4.07(m,1H),3.70-3.49(m,1H),3.38-3.28(m,2H),3.23-3. 13(m,1H),3.10-2.95(m,1H),2.89-2.83(m,2H),2.81-2.50(m,3H),2.27-2.17(m,1H),1.8 9-1.83(m,1H),1.77-1.60(m,8H),1.33-1.26(m,3H),1.24-1.15(m,2H),1.04-0.91(m,2H).

[0362] 13 C NMR (176MHz, CDCl3) δ165.42,165.21,164.20,162.52,146.16,145.92,140.49,140.45,137.98,137.94,134.83,134 .41,131.10,130.02,128.92,128.62,127.83,127.45,125.92,125.91,123.74,123.55,123.52,122.22,122.12,121 .98,60.97,60.35,57.62,56.92,55.16,54.78,53.09,52.57,50.71,50.42,49.82,49.62,41.37,40.88,37.39,36.55,35.71,35.26,31.12,31.06,30.53,30.51,26.33,26.28,25.83,25.74,25.65,25.60,21.99,21.93,16.07,16.07.

[0363] MS (ESI) m / z for C 32 H 39 N3O2S[M+H] + : Calculated value 530.2836, measured value 530.2824.

[0364] [Chemical formula 33]

[0365] S142

[0366]

[0367] 1H NMR (500MHz, CDCl3) δ7.75-7.68(m,2H),7.40-7.22(m,10H),7.13(d,J=8.0Hz,1H),7.02(d,J=7.5Hz,1H),5.69(d,J=14.5H z,0.5H),5.53(d,J=14.5Hz,0.5H),4.41-4.36(m,0.5H),4.26-4.21(m,0.5H),4.20-4.13(m,1H),4.01-3.93(m,1H),3.87-3 .83(m,0.5H),3.60(dd,J=13.0Hz,81.0Hz,1H),3.39-3.28(m,2H),3.24-3.18(m,1H),3.14-3.09(m,0.5H),2.95-2.82(m,3H ),2.66(d,J=11.5,0.5H),2.58-2.47(m,1H),2.31-2.23(m,1H),1.94-1.84(m,1H),1.65-1.58(m,0.5H),1.33-1.26(m,3H).

[0368] 13 C NMR (176MHz, CDCl3) δ165.40,165.13,164.12,162.37,146.20,145.97,140.49,140.44,137.99,137.95,135.41 ,135.05,134.89,134.50,131.01,129.92,129.01,128.97,128.69,128.59,128.32,128.26,128.14,127.88,12 7.50,125.89,125.84,123.77,123.75,123.58,123.54,122.19,122.11,122.00,59.34,58.54,57.85,56.48,55.06,55.03,53.12,52.60,50.75,50.49,46.75,46.39,41.41,40.97,37.01,35.98,22.01,21.95,16.09,16.07.

[0369] MS (ESI) m / z for C 32 H 33 N3O2S[M+H] + : Calculated value 524.2366, measured value 524.2364.

[0370] [Chemical formula 34]

[0371] S151

[0372]

[0373] 1 H NMR(700MHz, CDCl3)δ7.85(d,J=5.5Hz,1H),7.76(d,J=6.0Hz,1H),7.36-7.31(m,1H),7.28-7.25(m,1H), 4.44-4.41(m,1H),4.01-3.98(m,2H),3.81(d,J=9.5Hz,1H),3.71(d,J=3.0Hz,1H),3.64-3.61(m,2H),2. 98-2.93(m,2H),2.83-2.80(m,1H),2.70-2.66(m,1H),2.49-2.46(m,1H),2.04-1.99(m,2H),1.82-1.72( m,5H),1.70-1.60(m,7H),1.43-1.38(m,1H),1.33(t,J=5.5Hz,3H),1.22-1.10(m,7H),0.98-0.87(m,2H).

[0374] 13 C NMR (176MHz, CDCl3) δ165.49,165.37,146.23,140.54,138.01,128.51,127.54,126.94,125.95,123.86,123.60,122.27,122.03,65.63,65.25 ,57.52,56.33,53.37,51.58,51.00,43.22,40.86,35.78,30.99,30.53 ,30.05,28.24,26.42,26.35,26.23,25.82,25.77,25.66,22.02,16.10.

[0375] MS (ESI) m / z for C 31 H 43 N3O2S[M+H] + : Calculated value 522.3154, measured value 522.3143.

[0376] [Chemical formula 35]

[0377] S152

[0378]

[0379] 1H NMR (700MHz, CDCl3) δ7.86-7.83(m,1H),7.77-7.74(m,1H),7.35-7.25(m,5H),7.23-7.19(m,2H),5. 39-5.34(m,1H),4.45-4.40(m,1H),4.16-4.08(m,1H),3.99-3.93(m,1H),3.84-3.81(m,1H),3.75-3. 70(m,1H),3.67-3.57(m,2H),2.98-2.93(m,2H),2.83-2.81(m,1H),2.71-2.61(m,1H),2.25-2.06(m ,1H),2.05-1.97(m,1H),1.87-1.55(m,7H),1.35-1.32(m,3H),1.21-1.06(m,3H),1.00-0.87(m,1H).

[0380] 13 C NMR (176MHz, CDCl3) δ165.34,165.00,164.24,162.08,146.27,146.21,140.53,140.48,138.02,137.99,135.77,135.53,1 28.92,128.87,128.50,128.34,128.01,127.95,127.93,127.54,126.93,125.93,125.88,123.89,123.87,123.63,123.61, 122.25,122.21,122.05,65.26,63.77,63.29,58.26,57.16,56.77,56.20,53.39,53.14,51.68,51.03,47.98,47.61,42.84,41.42,40.97,40.86,30.44,30.02,28.30,28.04,26.87,26.50,26.44,26.25,25.92,25.75,22.04,22.02,16.12,16.10.

[0381] MS (ESI) m / z for C 31 H 37 N3O2S[M+H] + : Calculated value 516.2679, measured value 516.2677.

[0382] [Chemical formula 36]

[0383] S201

[0384]

[0385] 1 H NMR (500MHz, CDCl3) δ7.83(d,J=7.5Hz,1H),7.76(d,J=8.0Hz,1H),7.32(t,J=7.5Hz,1H),7.26(t, J=7.5Hz,1H),4.47(d,J=13.0Hz,1H),4.05(d,J=11.0Hz,1H),3.97(s,2H),3.79(d,J=13.0Hz,1H), 3.65(d,J=13.0Hz,1H),3.54(d,J=11.5Hz,1H),2.97-2.91(m,5H),2.82(d,J=11.5Hz,1H),2.69(d t,J=3.5,12.5Hz,1H),2.11(d,J=11.3Hz,1H),2.03(dt,J=3.5,12.0Hz,1H),1.33(t,J=7.5Hz,3H).

[0386] 13 C NMR (126MHz, CDCl3) δ163.75,161.59,146.55,140.70,138.21,125.99,124.12,123. 86,122.41,122.28,57.51,57.08,53.43,51.46,51.42,41.60,33.62,22.26,16.35.

[0387] MS (ESI) m / z for C 19 H 23 N3O2S[M+H] + : Calculated value 358.1584, measured value 358.1576.

[0388] [Chemical formula 37]

[0389] S202

[0390]

[0391] 1H NMR (500MHz, CDCl3) δ7.83(d,J=8.0Hz,1H),7.75(d,J=8.0Hz,1H),7.32(t,J=7.5Hz,1H),7.26(t,J=7.5Hz,1H ),4.46(d,J=13.5Hz,1H),4.04(d,11.0Hz,1H),3.96(d,J=3.0Hz,2H),3.79(d,J=13.0Hz,1H),3.65(d,J=13.0 Hz,1H),3.54(d,J=11.0Hz,1H),3.43(m,2H),2.94(q,J=7.5Hz,2H),2.82(d,J=11.5Hz,1H),2.69(dt,J=3.0,1 2.5Hz,1H),2.11(d,J=11.5Hz,1H),2.03(dt,J=3.0,11.5Hz,1H),1.33(t,J=7.5Hz,3H),1.15(t,J=7.3Hz,3H).

[0392] 13 C NMR (126MHz, CDCl3) δ163.21,162.04,146.52,140.70,138.21,126.02,124.11,123.85, 122.42,122.27,57.55,57.05,53.44,51.37,48.81,41.60,41.12,22.26,16.35,11.84.

[0393] MS (ESI) m / z for C 20 H 25 N3O2S[M+H] + : Calculated value 372.1740, measured value 372.1734.

[0394] [Chemical formula 38]

[0395] S203

[0396]

[0397] 1H NMR (500MHz, CDCl3) δ7.83(d,J=8.0Hz,1H),7.75(d,J=7.5Hz,1H),7.32(t,J=7.5Hz,1H),7.26(t,J=7.5Hz,1H),4 .45(d,J=13.0Hz,1H),4.05(d,11.0Hz,1H),3.96(s,2H),3.80(d,J=13.0Hz,1H),3.65(d,J=13.0Hz,1H),3.55(d, J=11.5Hz,1H),3.37(t,J=7.5Hz,2H),2.94(m,2H),2.82(d,J=11.0Hz,1H),2.69(dt,J=3.5,12.5Hz,1H),2.11(d, J=11.0Hz,1H),2.03(dt,J=3.0,11.0Hz,1H),1.54(m,J=3.6Hz,2H),1.33(t,J=7.5Hz,5H),0.94(t,J=7.5Hz,3H).

[0398] 13 C NMR (126MHz, CDCl3) δ163.45,162.09,146.51,140.69,138.21,126.01,124.10,123.85,122.42 ,122.27,57.53,57.11,53.44,51.35,49.35,45.98,41.61,28.63,22.25,20.13,16.34,13.96.

[0399] MS (ESI) m / z for C 22 H 29 N3O2S[M+H] + : Calculated value 400.2053, measured value 400.2042.

[0400] [Chemical formula 39]

[0401] S204

[0402]

[0403] 1H NMR (500MHz, CDCl3) δ7.83(d,J=8.0Hz,1H),7.75(d,J=8.0Hz,1H),7.32(t,J=7.5Hz,1H),7.26(t,J=7.5Hz,1H),4.4 6(d,J=13.0Hz,1H),4.04(d,11.0Hz,1H),3.96(s,2H),3.79(d,J=13.0Hz,1H),3.65(d,J=13.0Hz,1H),3.55(d,J=11 .0Hz,1H),3.39-3.34(m,2H),2.97-2.91(m,2H),2.82(d,J=11.5Hz,1H),2.69(dt,J=3.5,12.5Hz,1H),2.11(t,J=11 .3Hz,1H),2.03(dt,J=3.5,12.0Hz,1H),1.58-1.51(m,2H),1.33(t,J=7.5Hz,3H),1.29(s,6H)0.89(t,J=6.5Hz,3H).

[0404] 13 C NMR (126MHz, CDCl3) δ163.42,162.09,146.51,140.69,138.20,126.01,124.10,123.85,122.42,122.2 6,57.53,57.10,53.43,51.37,49.35,46.24,41.60,31.63,26.55,26.52,22.73,22.25,16.34,14.23.

[0405] MS (ESI) m / z for C 24 H 33 N3O2S[M+H] + : Calculated value 428.2366, measured value 428.2352.

[0406] [Chemical formula 40]

[0407] S206

[0408]

[0409] 1H NMR (500MHz, CDCl3) δ7.84(d,J=8.0Hz,1H),7.76(d,J=8.0Hz,1H),7.37-7.23(m,7H),4.57(dd,J=14 .5,32.0Hz,2H),4.43(d,J=13.0Hz,1H),4.12(d,J=11.0Hz,1H),3.86(s,2H),3.81(d,J=13.0Hz,1H) ,3.66(d,J=13.0Hz,1H),3.61(d,J=11.0Hz,1H),2.94(q,J=7.5Hz,2H),2.81(d,J=11.0Hz,1H),2.68 (dt,J=3.5,12.5Hz,1H),2.16(t,J=11.0Hz,1H),2.03(dt,J=3.0,11.5Hz,1H),1.33(t,J=7.5Hz,3H).

[0410] 13 C NMR (126MHz, CDCl3) δ163.70,161.90,146.55,140.70,138.24,135.16,129.19,128.73,128.45,126. 00,124.13,123.89,122.43,122.31,57.61,57.14,53.46,51.33,49.55,48.77,41.62,22.28,16.37.

[0411] MS (ESI) m / z for C 25 H 27 N3O2S[M+H] + : Calculated value 434.1897, measured value 434.1892.

[0412] [Chemical formula 41]

[0413] S207

[0414]

[0415] 1H NMR (500MHz, CDCl3) δ7.84(d,J=8.0Hz,1H),7.76(d,J=8.0Hz,1H),7.33(t,J=7.5Hz,1H),7.27(t,J=7.5Hz,1H), 7.14(s,4H),4.53(dd,J=14.5,35.5Hz,2H),4.43(d,J=13.0Hz,1H),4.11(d,J=11Hz,1H),3.84(s,2H),3.81(d,J= 13.0Hz,1H),3.66(d,J=13.0Hz,1H),3.60(d,J=11.5Hz,1H),2.94(q,J=7.5Hz,2H),2.81(d,J=10.0Hz,1H),2.67( dt,J=3.5,12.5Hz,1H),2.33(s,3H),2.15(t,J=11.0Hz,1H),2.02(dt,J=3.5,11.5Hz,1H),1.33(t,J=7.5Hz,3H).

[0416] 13 C NMR (126MHz, CDCl3) δ163.61,161.97,146.54,140.70,138.24,138.23,132.11,129.84,128.77,126.01, 124.13,123.88,122.43,122.30,57.62,57.14,53.46,51.34,49.28,48.67,41.60,22.27,21.37,16.37.

[0417] MS (ESI) m / z for C 26 H 29 N3O2S[M+H] + : Calculated value 448.2053, measured value 448.2055.

[0418] [Chemical formula 42]

[0419] S208

[0420]

[0421] 1H NMR (500MHz, CDCl3) δ7.84(d,J=8.0Hz,1H),7.77(d,J=8.0Hz,1H),7.35-7.30(m,3H),7.27(t,J=7.5Hz,1H),7. 20(d,J=8.5Hz,2H),4.53(dd,J=14.5,27.0Hz,2H),4.44(d,J=13.0Hz,1H),4.12(d,J=11.0Hz,1H),3.86(s,2H) ,3.81(d,J=13.0Hz,1H),3.67(d,J=13.0Hz,1H),3.59(d,J=11.5Hz,1H),2.98-2.91(m,2H),2.82(d,J=11.5Hz, 1H), 2.69 (dt, J = 3.0, 12.5Hz, 1H), 2.15 (t, J = 11.5Hz, 1H), 2.04 (dt, J = 3.0, 11.5Hz, 1H), 1.34 (t, J = 7.5Hz, 3H).

[0422] 13 C NMR (126MHz, CDCl3) δ163.79,161.68,146.57,140.67,138.24,134.42,133.72,130.09,129.38,125. 93,124.13,123.89,122.40,122.31,57.57,57.07,53.44,51.32,48.97,48.83,41.65,22.27,16.36.

[0423] MS (ESI) m / z for C 25 H 26 ClN3O2S[M+H] + : Calculated value 468.1507, measured value 468.1477.

[0424] [Chemical formula 43]

[0425] S209

[0426]

[0427] 1H NMR (500MHz, CDCl3) δ7.83(d,J=8.0Hz,1H),7.76(d,J=8.0Hz,1H),7.47(d,J=8.0Hz,2H),7.33(t,J=7.5Hz,1H),7.27 (t,J=7.5Hz,1H),7.13(d,J=8.0Hz,2H),4.51(dd,J=14.5,24.0Hz,2H),4.43(d,J=13.5Hz,1H),4.11(d,J=10.5Hz,1H) ,3.85(s,2H),3.81(d,J=13.0Hz,1H),3.67(d,J=13.0Hz,1H),3.59(d,J=11.0Hz,1H),2.98-2.91(m,2H),2.82(d,J=1 1.5Hz,1H),2.68(dt,J=3.0,12.5Hz,1H),2.14(t,J=11.5Hz,1H),2.03(dt,J=3.0,11.5Hz,1H),1.33(t,J=7.5Hz,3H).

[0428] 13 C NMR (126MHz, CDCl3) δ163.80,161.66,146.57,140.67,138.23,134.25,132.33,130.41,125.94,124. 13,123.89,122.52,122.40,122.31,57.56,57.06,53.44,51.32,49.03,48.84,41.65,22.27,16.37.

[0429] MS (ESI) m / z for C 25 H 26 BrN3O2S[M+H] + : Calculated value 512.1002, measured value 512.0997.

[0430] [Chemical formula 44]

[0431] S210

[0432]

[0433] 1H NMR (500MHz, CDCl3) δ7.84(d,J=8.0Hz,1H),7.76(d,J=8.0Hz,1H),7.33(t,J=7.5Hz,1H),7.29-7.22(m,3H),7. 03(t,J=8.5Hz,2H),4.53(dd,J=14.5,36.0Hz,2H),4.43(d,J=13.0Hz,1H),4.11(d,J=11.0Hz,1H),3.85(s,2H), 3.81(d,J=13.0Hz,1H),3.67(d,J=13.0Hz,1H),3.59(d,J=11.5Hz,1H),2.94(q,J=7.0Hz,2H),2.82(d,J=11.5Hz ,1H),2.68(dt,J=3.0,12.5Hz,1H),2.15(t,J=11.0Hz,1H),2.03(dt,J=3.5,12.0Hz,1H),1.33(t,J=7.5Hz,3H).

[0434] 13 C NMR (126MHz, CDCl3) δ163.79,163.73,161.83,161.76,146.57,140.68,138.24,131.07,131.04,130.56,130.50,125. 96,124.13,123.89,122.41,122.31,116.21,116.04,57.58,57.07,53.44,51.32,48.88,48.74,41.64,22.27,16.36.

[0435] MS (ESI) m / z for C 25 H 26 FN3O2S[M+H] + : Calculated value 452.1803, measured value 452.1781.

[0436] [Chemical formula 45]

[0437] S211

[0438]

[0439] 1H NMR (500MHz, CDCl3) δ7.84(d,J=7.5Hz,1H),7.76(d,J=8.0Hz,1H),7.61(d,J=8.0Hz,2H),7.38(d,J=8.0Hz,2H), 7.33(t,J=7.5Hz,1H),7.27(t,J=7.5Hz,1H),4.62(s,2H),4.44(d,J=13.0Hz,1H),4.14(d,J=11.0Hz,1H),3.87(s ,2H),3.81(d,J=13.0Hz,1H),3.68(d,J=13.0Hz,1H),3.60(d,J=11.0Hz,1H),2.98-2.92(m,2H),2.83(d,J=11.5H z,1H),2.60(dt,J=3.0,12.5Hz,1H),2.16(t,J=11.0Hz,1H),2.04(dt,J=3.0,12.0Hz,1H),1.34(t,J=7.5Hz,3H).

[0440] 13 C NMR (126MHz, CDCl3) δ163.94,161.55,146.60,140.67,139.29,138.24,131.13,130.87,130.61,130.35,128.92,127.38,126.22,126.19, 126.16,126.13,125.92,125.21,124.13,123.90,123.05,122.40,12 2.32,57.54,57.04,53.43,51.32,49.20,49.03,41.68,22.27,16.35.

[0441] MS (ESI) m / z for C 26 H 26 F3N3O2S[M+H] + : Calculated value 502.1771, measured value 502.1766.

[0442] [Chemical formula 46]

[0443] S212

[0444]

[0445] 1H NMR (500MHz, CDCl3) δ7.83(d,J=8.0Hz,1H),7.76(d,J=8.0Hz,1H),7.64(d,J=8.5Hz,2H),7.36(d,J=8.5Hz,2H),7 .33(t,J=7.5Hz,1H),7.30-7.25(m,1H),4.61(d,J=3.0Hz,2H),4.44(d,J=13.5Hz,1H),4.14(d,J=8.5Hz,1H),3.88 (s,2H),3.81(d,J=13.0Hz,1H),3.68(d,J=13.0Hz,1H),3.58(d,J=11.0Hz,1H),2.98-2.92(m,2H),2.84(d,J=11.0 Hz,1H),2.71(dt,J=3.0,12.5Hz,1H),2.16(t,J=11.0Hz,1H),2.06(dt,J=3.0,12.5Hz,1H),1.34(t,J=7.5Hz,3H).

[0446] 13 C NMR (126MHz, CDCl3) δ164.06,161.42,146.61,140.65,140.64,138.24,132.98,129.16,125.87,124.13, 123.91,122.38,122.32,118.57,112.43,57.50,56.98,53.42,51.31,49.34,49.20,41.71,22.27,16.37.

[0447] MS (ESI) m / z for C 26 H 26 N4O2S[M+H] + : Calculated value 459.1849, measured value 459.1828.

[0448] [Chemical formula 47]

[0449] S213

[0450]

[0451] 1H NMR (500MHz, CDCl3) δ8.20(d,J=8.5Hz,2H),7.84(d,J=8.0Hz,1H),7.76(d,J=7.5Hz,1H),7.43(d,J=8.5Hz,2H), 7.33(t,J=7.5Hz,1H),7.28(t,J=7.5Hz,1H),4.66(s,2H),4.45(d,J=13.0Hz,1H),4.16(d,J=11.0Hz,1H),3.91(s ,2H),3.82(d,J=13.0Hz,1H),3.69(d,J=13.0Hz,1H),3.59(d,J=11.0Hz,1H),2.98-2.92(m,2H),2.85(d,J=11.5H z,1H),2.71(dt,J=3.0,12.5Hz,1H),2.17(t,J=11.5Hz,1H),2.06(dt,J=3.0,12.0Hz,1H),1.34(t,J=7.5Hz,3H).

[0452] 13 C NMR (126MHz, CDCl3) δ164.11,161.36,148.01,146.62,142.63,140.65,138.24,129.30,125.87,124. 39,124.13,123.91,122.38,122.32,57.50,56.98,53.42,51.32,49.27,49.10,41.72,22.27,16.36.

[0453] MS (ESI) m / z for C 25 H 26 N4O4S[M+H] + : Calculated value 479.1748, measured value 479.1727.

[0454] [Chemical formula 48]

[0455] S214

[0456]

[0457] 1H NMR (500MHz, CDCl3) δ7.84(d,J=8.0Hz,1H),7.76(d,J=8.0Hz,1H),7.56(d,J=8.0Hz,4H),7.43(t,J=7.5Hz,2H) ,7.37-7.24(m,5H),4.61(dd,J=14.5,31.5Hz,2H),4.44(d,J=13.0Hz,1H),4.13(d,J=11.0Hz,1H),3.90(s,2H) ,3.82(d,J=13.0Hz,1H),3.67(d,J=13.0Hz,1H),3.62(d,J=11.0Hz,1H),2.98-2.92(m,2H),2.82(d,J=11.0Hz, 1H), 2.68 (dt, J = 3.0, 12.5Hz, 1H), 2.18 (t, J = 11.3Hz, 1H), 2.04 (dt, J = 3.0, 12.0Hz, 1H), 1.33 (t, J = 7.5Hz, 3H).

[0458] 13 C NMR (126MHz, CDCl3) δ163.75,161.91,146.56,141.47,140.71,138.25,134.14,129.22,129.08,127.93,127.76, 127.33,126.01,124.15,123.90,122.44,122.32,57.64,57.14,53.47,51.35,49.30,48.85,41.64,22.29,16.38.

[0459] MS (ESI) m / z for C 31 H 31 N3O2S[M+H] + : Calculated value 510.2210, measured value 510.2210.

[0460] [Chemical formula 49]

[0461] S215

[0462]

[0463] 1H NMR(500MHz, CDCl3)δ7.83(d,J=8.0Hz,1H),7.76(d,J=7.5Hz,1H),7.35-7.21(m,5 H),7.19(d,J=7.0Hz,2H),4.42(d,J=13.0,1H),4.01(d,J=11.0Hz,1H),3.81-3.75 (m,3H),3.66-3.55(m,4H),3.51(d,J=11.0Hz,1H),2.97-2.86(m,3H),2.81(d,J=1 1.5Hz,1H),2.67(dt,J=3.0,12.5Hz,1H),2.04-1.97(m,2H),1.33(t,J=7.5Hz,3H).

[0464] 13 C NMR (126MHz, CDCl3) δ163.54,161.88,146.54,140.71,138.23,138.15,128.98,128.94,127.06,126.00, 124.12,123.88,122.42,122.30,57.49,57.01,53.45,51.41,50.14,48.13,41.62,33.09,22.28,16.37.

[0465] MS (ESI) m / z for C 26 H 29 N3O2S[M+H] + : Calculated value 448.2053, measured value 448.2026.

[0466] [Chemical formula 50]

[0467] S216

[0468]

[0469] 1H NMR (500MHz, CDCl3) δ7.82(d,J=8.0Hz,1H),7.76(d,J=8.0Hz,1H),7.33(t,J=7.5Hz,1H),7.27(q,J=7.5Hz ,1H),7.15(dd,J=5.5,8.0Hz,2H),6.99(t,J=8.5Hz,2H),4.43(d,J=13.0Hz,1H),4.01(d,J=11.0Hz,1H),3 .83(s,2H),3.78(d,J=13.5Hz,1H),3.65(d,J=13.5Hz,1H),3.63-3.52(m,2H),3.50(d,J=11.5Hz,1H),2.9 7-2.91(m,2H),2.88-2.80(m,3H),2.68(dt,J=3.5,12.5Hz,1H),2.05-1.98(m,2H),1.33(t,J=7.5Hz,3H).

[0470] 13 C NMR (126MHz, CDCl3) δ163.58,162.96,161.78,161.01,146.57,140.69,138.23,133.74,133.72,130.41,130.35,125.96, 124.12,123.87,122.40,122.30,115.88,115.72,57.45,56.96,53.43,51.41,50.00,47.93,41.63,32.21,22.26,16.35.

[0471] MS (ESI) m / z for C 26 H 28 FN3O2S[M+H] + : Calculated value 466.1959, measured value 466.1935.

[0472] [Chemical formula 51]

[0473] S218

[0474]

[0475] 1H NMR (500MHz, CDCl3) δ7.83(d,J=8.0Hz,1H),7.76(d,J=8.0Hz,1H),7.34-7.25(m,2H),4.45(d,J=13.0Hz,1 H),4.07(d,J=11.0Hz,1H),3.96(s,2H),3.80(d,J=13.0Hz,1H),3.65(d,J=13.0Hz,1H),3.56(d,J=11.0Hz ,1H),3.30-3.15(m,2H),2.94(q,J=7.5Hz,2H),2.82(d,J=11.5Hz,1H),2.72-2.67(m,1H),2.12(t,J=11.5 Hz,1H),2.06-2.01(m,1H),1.74-1.60(m,6H),1.32(t,J=7.5Hz,3H),1.26-1.14(m,3H),1.00-0.93(m,2H).

[0476] 13 C NMR (176MHz, CDCl3) δ163.61,161.95,146.27,140.48,138.01,125.81,123.88,123.63,122.21,122.0 4,57.29,57.01,53.22,52.01,51.08,49.91,41.40,35.17,30.60,30.57,26.24,25.67,22.02,16.09.

[0477] MS (ESI) m / z for C 25 H 33 N3O2S[M+H] + : Calculated value 440.2366, measured value 440.2360.

[0478] [Chemical formula 52]

[0479] S221

[0480]

[0481] 1H NMR (500MHz, CDCl3) δ8.06-8.03(m,1H),7.91-7.89(m,1H),7.85(t,J=8.0Hz,2H),7.78(d,J=8.0Hz,1H),7.76-7.52 (m,2H),7.45-7.39(m,2H),7.34(t,J=7.2Hz,1H),7.29(t,J=7.2Hz,1H),5.12(d,J=14.5,1H),5.06(d,J=14.5,1H), 4.40(d,J=13.0Hz,1H),4.15(d,J=11.0Hz,1H),3.82(d,J=13.0Hz,1H),3.73(s,2H),3.68-3.65(m,2H),2.98-2.93( m,2H),2.80(d,J=11.5Hz,1H),2.69-2.63(m,1H),2.15(t,J=11.0Hz,1H),2.02-1.97(m,1H),1.35(t,J=7.5Hz,3H).

[0482] 13 C NMR (176MHz, CDCl3) δ163.04,161.51,146.32,140.49,138.02,133.99,131.50,130.12,129.48,128.88,128.56,126.90,126. 25,125.77,125.13,123.90,123.65,123.60,122.18,122.07,57.47,56.89,53.21,51.09,48.16,47.25,41.28,22.02,16.11.

[0483] MS (ESI) m / z for C 29 H 29 N3O2S[M+H] + : Calculated value 484.2053, measured value 484.2053.

[0484] [Chemical formula 53]

[0485] S222

[0486]

[0487] 1H NMR (500MHz, CDCl3) δ7.86-7.80(m,4H),7.77(d,J=8.0Hz,1H),7.71(s,1H),7.54-7.47(m,2H),7.38-7.32(m, 2H),7.28(t,J=7.5Hz,1H),4.80(d,J=14.5,1H),4.70(d,J=14.5,1H),4.44(d,J=13.5Hz,1H),4.16(d,J=9.0H z,1H),3.91(s,2H),3.83(d,J=13.0Hz,1H),3.68(d,J=13.0Hz,1H),3.64(d,J=11.0Hz,1H),2.98-2.93(m,2H) ,2.83(d,J=11.0Hz,1H),2.72-2.67(m,1H),2.19(t,J=11.3Hz,1H),2.06-2.01(m,1H),1.34(t,J=7.5Hz,3H).

[0488] 13 C NMR (176MHz, CDCl3) δ163.56,161.64,146.32,140.49,138.03,133.23,133.04,132.34,129.02,127.77,127.75,127.72,126. 54,126.36,125.99,125.77,123.90,123.65,122.20,122.07,57.43,56.92,53.23,51.10,49.52,48.58,41.38,22.03,16.11.

[0489] MS (ESI) m / z for C 29 H 29 N3O2S[M+H] + : Calculated value 484.2053, measured value 484.2041.

[0490] [Chemical formula 55]

[0491] S224

[0492]

[0493] 1H NMR (500MHz, CDCl3) δ7.84(d,J=8.0Hz,1H),7.77(d,J=8.0Hz,1H),7.33(t,J=7.5Hz,1H),7.29(d,J=7.5Hz,1H),7.19(d ,J=8.5Hz,2H),6.87(d,J=8.5Hz,2H),4.57(d,J=14.5Hz,1H),4.47(d,J=14.5Hz,1H),4.44(d,J=16.0Hz,1H),4.11(d,J =8.5Hz,1H),3.85(s,2H),3.82(d,J=13.0Hz,1H),3.80(s,3H),3.66(d,J=13.0Hz,1H),3.60(d,J=11.0Hz,1H),2.98-2. 93(m,2H),2.82(d,J=11.5Hz,1H),2.71-2.65(m,1H),2.15(t,J=11.3Hz,1H),2.05-2.00(m,1H),1.34(t,J=7.5Hz,3H).

[0494] 13 C NMR (176MHz, CDCl3) δ163.35,161.75,159.56,146.31,140.49,138.02,129.96,127.01,125.79,123.89, 123.64,122.20,122.07,114.32,57.41,56.90,55.31,53.23,51.11,48.75,48.36,41.36,22.03,16.10.

[0495] MS (ESI) m / z for C 26 H 29 N3O3S[M+H] + : Calculated value 464.2002, measured value 464.1991.

[0496] [Chemical formula 56]

[0497] S225

[0498]

[0499] 1H NMR (500MHz, CDCl3) δ7.84(d,J=8.0Hz,1H),7.77(d,J=8.0Hz,1H),7.33(t,J=7.5Hz,1H),7.28(t,J=8.0 Hz,1H),6.39(s,3H),4.56(d,J=14.5Hz,1H),4.48-4.42(m,2H),4.13(d,J=11.0Hz,1H),3.88(s,2H),3.8 1(d,J=13.0Hz,1H),3.78(s,6H),3.67(d,J=13.0Hz,1H),3.60(d,J=11.0Hz,1H),2.97-2.93(m,2H),2.8 3(d,J=11.5Hz,1H),2.72-2.66(m,1H),2.16(t,J=11.3Hz,1H),2.07-2.02(m,1H),1.34(t,J=7.8Hz,3H).

[0500] 13 C NMR (176MHz, CDCl3) δ163.46,161.66,161.24,146.32,140.48,138.01,137.17,125.77,123.89,123.64 ,122.18,122.06,106.46,99.89,57.39,56.88,55.36,53.21,51.13,49.39,48.57,41.37,22.02,16.10.

[0501] MS (ESI) m / z for C 27 H 31 N3O4S[M+H] + : Calculated value 494.2108, measured value 494.2101.

[0502] [Chemical formula 58]

[0503] S301

[0504]

[0505] 1H NMR(500MHz, CDCl3)δ7.95(d,J=7.0Hz,1H),7.86(d,J=7.0Hz,1H),7.40-7.35(m,2 H),7.30(s,1H),6.25(s,1H),4.52(d,J=13.0Hz,1H),4.12(d,J=12.5Hz,1H),4.06 (s,2H),3.89(d,J=13.5Hz,1H),3.77(d,J=13.5Hz,1H),3.53(d,J=11.0Hz,1H),2. 93(d,J=11.5Hz,1H),2.82-2.76(m,1H),2.17(t,J=11.3Hz,1H),2.12-2.07(m,1H).

[0506] 13 C NMR (126MHz, CDCl3) δ166.12,161.93,140.93,138.87,132.20,125.27,12 4.72,124.23,123.02,122.83,57.12,56.55,56.49,51.81,44.81,41.75.

[0507] MS (ESI) m / z for C 16 H 17 N3O2S[M+H] + : Calculated value 316.112, measured value 316.1115.

[0508] [Chemical formula 59]

[0509] S302

[0510]

[0511] 1H NMR (500MHz, CDCl3) δ7.81(d,J=7.5Hz,1H),7.75(d,J=8.0Hz,1H),7.33(t,J=7.5Hz,1H) ,7.28(d,J=7.5Hz,1H),6.21(s,1H),4.49(d,J=13.0Hz,1H),4.08(d,J=11.0Hz,1H),4.06 (s,2H),3.79(d,J=13.0Hz,1H),3.67(d,J=13.0Hz,1H),3.50(d,J=10.5Hz,1H),2.86(d,J =11.5Hz,1H),2.76-2.70(m,1H),2.54(s,3H),2.18(t,J=11.3Hz,1H),2.11-2.06(m,1H).

[0512] 13 C NMR (176MHz, CDCl3) δ166.05,161.70,140.47,138.58,137.99,126.71,123.9 4,123.69,121.99,121.89,56.96,56.29,53.25,51.33,44.54,41.53,14.07.

[0513] MS (ESI) m / z for C 17 H 19 N3O2S[M+H] + : Calculated value 330.1276, measured value 330.1273.

[0514] [Chemical formula 60]

[0515] S303

[0516]

[0517] 1H NMR (500MHz, CDCl3) δ7.84(d,J=8.0Hz,1H),7.76(d,J=7.5Hz,1H),7.33(t,J=7.2Hz,1H),7.28(d,J=7.0Hz ,1H),6.23(s,1H),4.49(d,J=13.0Hz,1H),4.09(d,J=11.0Hz,1H),4.06(s,2H),3.80(d,J=13.0Hz,1H),3.6 7(d,J=13.0Hz,1H),3.51(d,J=12.0Hz,1H),2.91(t,J=7.8Hz,2H),2.85(d,J=11.5Hz,1H),2.74-2.68(m,1 H),2.18(t,J=11.3Hz,1H),2.09-2.04(m,1H),1.72-1.66(m,2H),1.46-1.38(m,2H),0.95(t,J=7.5Hz,3H).

[0518] 13 C NMR (176MHz, CDCl3) δ166.09,161.72,144.96,140.42,138.11,126.12,123.86,123.65, 122.16,122.01,56.97,56.38,53.31,51.28,44.53,41.56,33.70,28.31,22.46,13.91.

[0519] MS (ESI) m / z for C 20 H 25 N3O2S[M+H] + : Calculated value 372.1746, measured value 372.1748.

[0520] [Chemical formula 61]

[0521] S304

[0522]

[0523] 1H NMR (500MHz, CDCl3) δ7.84(d,J=8.0Hz,1H),7.76(d,J=8.0Hz,1H),7.32(t,J=7.5Hz,1H),7.27(t,J=6.8Hz,1H) ,6.71(s,1H),4.49(d,J=13.0Hz,1H),4.08(d,J=11.0Hz,1H),4.05(s,2H),3.80(d,J=13.0Hz,1H),3.66(d,J=13 .0Hz,1H),3.50(d,J=11.0Hz,1H),2.90(t,J=7.5Hz,2H),2.84(d,J=11.5Hz,1H),2.73-2.68(m,1H),2.18(t,J= 11.0Hz,1H),2.09-2.03(m,1H),1.73-1.67(m,2H),1.40-1.37(m,2H),1.33-1.31(m,4H),0.89(t,J=7.0Hz,3H).

[0524] 13 C NMR (176MHz, CDCl3) δ166.06,161.69,145.03,140.44,138.13,126.11,123.86,123.65,122.17 ,122.02,56.99,56.41,53.32,51.27,44.56,41.57,31.61,31.58,29.06,28.63,22.56,14.08.

[0525] MS (ESI) m / z for C 22 H 29 N3O2S[M+H] + : Calculated value 400.2059, measured value 400.2070.

[0526] [Chemical formula 62]

[0527] S306

[0528]

[0529] 1H NMR(500MHz, CDCl3)δ7.86(d,J=8.0Hz,1H),7.73(d,J=8.0Hz,1H),7.35-7.31(m,2H),7.3 0-7.26(m,3H),7.25-7.22(m,2H),4.45(d,J=13.0Hz,1H),4.26(d,J=3.5Hz,2H),4.02-4.0 1(m,1H),4.00(s,2H),3.83(d,J=13.0Hz,1H),3.71(d,J=13.0Hz,1H),3.46(d,J=10.5Hz, 1H),2.82(d,J=11.5Hz,1H),2.68-2.62(m,1H),2.12(t,J=11.3Hz,1H),2.04-1.99(m,1H).

[0530] 13 C NMR (176MHz, CDCl3) δ166.07,161.80,142.67,140.37,139.55,138.66,128.63,128.60,127.2 5,126.72,124.06,124.01,122.31,122.16,56.94,56.34,53.42,51.35,44.57,41.52,34.54.

[0531] MS (ESI) m / z for C 23 H 23 N3O2S[M+H] + : Calculated value 406.1589, measured value 406.1605.

[0532] [Chemical formula 63]

[0533] S307

[0534]

[0535] 1H NMR (500MHz, CDCl3) δ7.85(d,J=8.0Hz,1H),7.72(d,J=8.0Hz,1H),7.35-7.30(m,2H),7.27(t,J =7.2Hz, 1H), 7.11 (q, J = 7.7Hz, 3H), 4.46 (d, J = 13.0Hz, 1H), 4.22 (d, J = 4.0Hz, 2H), 4.03 (d, J = 11. 0Hz,1H),4.00(s,2H),3.83(d,J=13.0Hz,1H),3.71(d,J=13.0Hz,1H),3.47(d,J=11.0Hz,1H),2. 83(d,J=11.5Hz,1H),2.70-2.64(m,1H),2.31(s,3H),2.13(t,J=11.3Hz,1H),2.05-2.00(m,1H).

[0536] 13 C NMR (176MHz, CDCl3) δ166.05,161.77,143.19,140.39,138.65,136.48,136.31,129.32,128.50,1 27.02,124.01,123.94,122.29,122.15,56.96,56.35,53.42,51.36,44.57,41.54,34.15,21.08.

[0537] MS (ESI) m / z for C 24 H 25 N3O2S[M+H] + : Calculated value 420.1746, measured value 420.1740.

[0538] [Chemical formula 64]

[0539] S308

[0540]

[0541] 1H NMR (500MHz, CDCl3) δ7.86(d,J=8.0Hz,1H),7.74(d,J=8.0Hz,1H),7.34(t,J=7.2Hz,1H),7.2 9(t,J=7.2Hz,1H),7.24(d,J=7.0Hz,2H),7.16(d,J=8.0Hz,2H),4.47(d,J=13.0Hz,1H),4.23 (d,J=3.5Hz,2H),4.01(s,2H),3.99(d,J=2.5Hz,1H),3.80(d,J=13.0Hz,1H),3.71(d,J=13.5 Hz,1H),3.43(d,J=10.5Hz,1H),2.84(d,J=11.5Hz,1H),2.70-2.64(m,1H),2.11-2.02(m,2H).

[0542] 13 C NMR (176MHz, CDCl3) δ165.81,162.58,161.80,141.87,140.23,138.57,137.99,132.47,129.9 0,128.71,127.48,124.14,122.30,122.15,56.89,56.20,53.36,51.47,44.54,41.45,33.82.

[0543] MS (ESI) m / z for C 23 H 22 ClN3O2S[M+H] + : Calculated value 440.12, measured value 440.1199.

[0544] [Chemical formula 65]

[0545] S309

[0546]

[0547] 1H NMR(500MHz, CDCl3) δ7.86(d,J=7.5Hz,1H),7.74(d,J=7.5Hz,1H),7.40(d,J=8.0Hz,2H) ,7.34(t,J=7.2Hz,1H),7.29(t,J=7.2Hz,1H),7.11(d,J=8.5Hz,2H),4.47(d,J=13.0Hz,1 H),4.22(d,J=3.5Hz,2H),4.03-3.97(m,3H),3.79(d,J=13.0Hz,1H),3.71(d,J=13.0Hz,1 H),3.42(d,J=11.0Hz,1H),2.84(d,J=11.5Hz,1H),2.70-2.64(m,1H),2.10-2.02(m,2H).

[0548] 13 C NMR (176MHz, CDCl3) δ165.79,162.57,161.79,141.72,140.22,138.56,138.51,131.65,130.2 8,127.52,124.14,122.30,122.15,120.51,56.88,56.19,53.36,51.48,44.53,41.45,33.88.

[0549] MS (ESI) m / z for C 23 H 22 BrN3O2S[M+H] + : Calculated value 484.0694, measured value 484.0660.

[0550] [Chemical formula 66]

[0551] S310

[0552]

[0553] 1H NMR (500MHz, CDCl3) δ7.87(d,J=8.0Hz,1H),7.74(d,J=8.0Hz,1H),7.36-7.28(m,2H),7. 20(dd,J=8.5,5.5Hz,2H),6.98(t,J=8.5Hz,2H),4.48(d,J=13.0Hz,1H),4.24(d,J=3.5H z,2H),4.01(s,3H),3.82(d,J=13.0Hz,1H),3.72(d,J=13.0Hz,1H),3.45(d,J=11.0Hz,1 H),2.84(d,J=11.5Hz,1H),2.70-2.65(m,1H),2.12(t,J=11.5Hz,1H),2.08-2.02(m,1H).

[0554] 13 C NMR (176MHz, CDCl3) δ165.94,162.35,161.74,160.96,142.42,140.27,138.56,135.20,135.19,130.04,129.99,1 27.28,124.93,124.10,124.09,122.28,122.15,115.46,115.34,56.89,56.24,53.36,51.42,44.51,41.47,33.68.

[0555] MS (ESI) m / z for C 23 H 22 FN3O2S[M+H] + : Calculated value 424.1495, measured value 424.1490.

[0556] [Chemical formula 67]

[0557] S314

[0558]

[0559] 1H NMR (500MHz, CDCl3) δ7.87(d,J=8.0Hz,1H),7.74(d,J=8.0Hz,1H),7.56(d,J=7.0Hz,2H ),7.52(d,J=8.0Hz,2H),7.41(t,J=7.8Hz,2H),7.36-7.27(m,5H),4.47(d,J=13.0Hz,1 H),4.30(d,J=3.0Hz,2H),4.02-3.96(m,3H),3.84(d,J=13.0Hz,1H),3.74(d,J=13.5Hz ,1H),3.45(d,J=11.0Hz,1H),2.88-2.83(m,1H),2.70-2.65(m,1H),2.12-2.03(m,2H).

[0560] 13 C NMR (176MHz, CDCl3) δ165.92,162.59,161.72,142.46,140.68,140.33,139.57,138.62,138.57,128.97,128.7 4,127.27,127.22,126.96,124.04,124.01,122.29,122.14,56.88,56.20,53.40,51.43,44.50,41.47,34.13.

[0561] MS (ESI) m / z for C 29 H 27 N3O2S[M+H] + : Calculated value 482.1902, measured value 482.1898.

[0562] [Chemical formula 68]

[0563] S318

[0564]

[0565] 1H NMR (500MHz, CDCl3) δ7.85(d,J=8.0Hz,1H),7.75(d,J=8.0Hz,1H),7.32(t,J=7.5Hz,1H),7.27(t,J=7. 5Hz,1H),4.48(d,J=13.0Hz,1H),4.06(d,J=10.0Hz,1H),4.02(s,2H),3.79(d,J=13.0Hz,1H),3.66(d, J=13.0Hz,1H),3.48(d,J=10.0Hz,1H),2.84(d,J=11.5Hz,1H),2.78(d,J=7.5Hz,2H),2.72-2.67(m,1H ),2.17(t,J=11.0Hz,1H),2.08-2.03(m,1H),1.79-1.64(m,5H),1.27-1.14(m,4H),2.08-2.03(m,2H).

[0566] 13 C NMR (126MHz, CDCl3) δ166.33,161.93,143.80,140.62,138.50,127.14,124.04,123.91,122.49 ,122.16,57.21,56.64,53.66,51.50,44.78,41.80,40.54,36.52,33.53,33.51,26.61,26.44.

[0567] MS (ESI) m / z for C 23 H 29 N3O2S[M+H] + : Calculated value 412.2059, measured value 412.2052.

[0568] [Chemical formula 69]

[0569] N101

[0570]

[0571] 1H NMR (500MHz, CDCl3) δ7.68(d,J=8.0Hz,1H),7.31(d,J=8.0Hz,1H),7.22(t,J=7.5H z,1H),7.11(t,J=7.5Hz,1H),6.96(s,1H),4.47(d,J=13.0Hz,1H),4.05(d,J=9.5Hz ,1H),3.94(s,2H),3.81(d,J=13.5Hz,1H),3.74-3.72(m,4H),3.48(d,J=10.5Hz,1H ),2.94(d,J=11.5Hz,1H),2.79-2.73(m,1H),2.15-2.10(m,1H),2.07-2.02(m,1H).

[0572] 13 C NMR (126MHz, CDCl3) δ166.49,162.08,137.36,128.84,128.41,122.01,119.7 4,119.42,109.97,109.53,57.20,56.17,53.44,51.60,44.71,41.80,32.97.

[0573] MS (ESI) m / z for C 17 H 20 N4O2[M+H] + : Calculated value 313.1659, measured value 313.1651.[M+Na] + : Calculated value 335.1478, measured value 335.1473.

[0574] [Chemical formula 70]

[0575] N102

[0576]

[0577] 1H NMR (500MHz, CDCl3) δ7.69(d,J=8.0Hz,1H),7.31(d,J=8.0Hz,1H),7.21(t,J=7.5Hz,1H),7.10(t,J=7.5Hz,1H),6. 98(s,1H),6.60(s,1H),4.49(d,J=13.0Hz,1H),4.13-4.08(m,1H),4.03-4.00(m,1H),3.90(d,J=7.5Hz,2H),3.86( d,J=13.5Hz,1H),3.72(d,J=13.5Hz,1H),3.53(d,J=11.5Hz,1H),2.92-2.98(m,1H),2.81-2.75(m,1H),2.12(t,J= 11.3Hz,1H),2.07-2.02(m,1H),1.87-1.80(m,1H)1.73-1.59(m,5H),1.28-1.13(m,1H),1.17(m,3H),0.99(m,2H).

[0578] 13 C NMR (126MHz, CDCl3) δ166.44,161.99,137.00,128.67,128.37,121.79,119.75,119.27,109 .98,109.48,57.14,56.25,53.50,53.14,51.43,44.76,41.77,38.97,31.33,26.53,25.95.

[0579] MS (ESI) m / z for C 23 H 30 N4O2[M+H] + : Calculated value 395.2441, measured value 395.2438.[M+Na] + : Calculated value 417.2261, measured value 417.2272.

[0580] [Chemical formula 71]

[0581] N103

[0582]

[0583] 1H NMR(500MHz, CDCl3)δ7.72(d,J=7.5Hz,1H),7.32-7.20(m,4H),7.17(t,J=7.5Hz,1H),7 .13-7.09(m,3H),7.03(s,1H),5.27(s,2H),4.49(d,J=13.0Hz,1H),4.07(d,J=11.0Hz, 1H),3.96(s,2H),3.84(d,J=13.5Hz,1H),3.73(d,J=13.5Hz,1H),3.51(d,J=11.0Hz,1H ),2.95(d,J=11.5Hz,1H),2.79-2.74(m,1H),2.10(t,J=11.5Hz,1H),2.07-2.01(m,1H).

[0584] 13 C NMR (126MHz, CDCl3) δ166.45,162.00,137.64,137.09,129.03,128.63,128.17,127.90,127.0 6,122.25,119.96,119.70,110.84,110.03,57.23,56.34,53.59,51.57,50.22,44.77,41.84.

[0585] MS (ESI) m / z for C 23 H 24 N4O2[M+H] + : Calculated value 389.1972, measured value 389.1971.[M+Na] + : Calculated value 411.1791, measured value 411.1798.

[0586] [Chemical formula 72]

[0587] N104

[0588]

[0589] 1H NMR (500MHz, CDCl3) δ7.80-7.72(m,3H),7.54(s,1H),7.46-7.42(m,2H),7.30(d,J=8.0Hz,1H),7.22 (d,J=8.5Hz,1H),7.18-7.11(m,2H),7.12(t,J=7.5Hz,1H),7.06(s,1H),5.41(s,2H),4.48(d,J=13.5 Hz,1H),4.06(d,J=11.0Hz,1H),3.94(s,2H),3.84(d,J=13.5Hz,1H),3.73(d,J=13.5Hz,1H),3.52(d, J=10.0Hz,1H),2.95(d,J=11.5Hz,1H),2.79-2.73(m,1H),2.10(t,J=11.5Hz,1H),2.06-2.01(m,1H).

[0590] 13 C NMR (126MHz, CDCl3) δ166.46,162.02,137.19,135.08,133.55,133.09,128.96,128.70,128.22,128.07,127.97,126.6 6,126.35,125.93,125.12,122.32,120.01,119.77,110.95,110.08,57.23,56.35,53.60,51.60,50.43,44.77,41.84.

[0591] MS (ESI) m / z for C 27 H 26 N4O2[M+H] + : Calculated value 439.2128, measured value 439.2129.[M+Na] + : Calculated value 461.1948, measured value 461.1957.

[0592] [Chemical formula 73]

[0593] N105

[0594]

[0595] 1H NMR(500MHz,CDCl3)δ7.91-7.74(m,2H),7.77(dd J=8.0Hz,19.5Hz,2H),7.52-7.48(m,2H),7.34-7.30(m,2H),7.18-7.23(m,2H),7.15( t,J=7.5Hz,1H),6.92(s,1H),5.70(s,2H),4.46(d,J=12.0Hz,1H),4.04(d,J=11.0Hz,1 H),3.95(s,2H),3.81(d,J=13.5Hz,1H),3.68(d,J=13.0Hz,1H),3.49(d,J=10.0Hz,1H) ,2.91(d,J=11.5Hz,1H),2.76-2.70(m,1H),2.17(t,J=11.5Hz,1H),2.02-1.97(m,1H).

[0596] 13 C NMR (126MHz, CDCl3) δ166.31,161.95,137.25,133.92,132.50,131.12,129.18,128.74,128.65,128.12,126.91,126.2 8,125.79,125.45,122.83,122.35,120.04,119.85,110.81,109.97,57.15,56.26,53.54,51.47,48.04,44.79,41.76.

[0597] MS (ESI) m / z for C 27 H 26 N4O2[M+H] + :Calculated value 439.2128, measured value 439.2128.[M+Na] + : Calculated value 461.1948, measured value 461.1957.

[0598] [Chemical formula 74]

[0599] N106

[0600]

[0601] 1H NMR(500MHz, CDCl3) δ7.73(d,J=8.0Hz,1H),7.52(dd,J=8.0Hz,11.0Hz,4H),7.40(t,J=7.5Hz,2H),7 .28-7.33(m,2H),7.15-7.22(m,3H),7.13(t,J=7.5Hz,1H),7.05(s,1H),5.30(s,2H),4.49(d,J=13.0 Hz,1H),4.07(d,J=9.0Hz,1H),3.95(s,2H),3.85(d,J=13.5Hz,1H),3.74(d,J=13.5Hz,1H),3.52(d, J=11.0Hz,1H),2.95(d,J=10.0Hz,1H),2.79-2.73(m,1H),2.11(t,J=11.3Hz,1H),2.07-2.02(m,1H).

[0602] 13 C NMR (126MHz, CDCl3) δ166.33,161.96,140.87,140.76,137.09,136.61,129.04,128.67,128.20,127.75,127.6 4,127.52,127.27,122.31,119.98,119.77,110.84,110.06,57.19,56.31,53.58,51.55,49.97,44.79,41.81.

[0603] MS (ESI) m / z for C 29 H 28 N4O2[M+H] + : Calculated value 465.2285, measured value 465.2291. [M+Na] + : Calculated value 487.2104, measured value 487.2109.

[0604] [Chemical formula 75]

[0605] N107

[0606]

[0607] 1H NMR (500MHz, CDCl3) δ7.66-7.64(m,1H),7.27-7.20(m,4H),7.13-7.08(m,2H),6.9 5(d,J=7.0Hz,2H),5.30(s,2H),4.48(d,J=11.0Hz,1H),4.08-4.04(m,1H),3.97(s, 2H),3.83(d,J=13.0Hz,1H),3.70(d,J=13.0Hz,1H),3.51-3.49(m,1H),2.94-2.89 (m,1H),2.77-2.71(m,1H),2.32(s,3H),2.13(t,J=11.3Hz,1H),2.07-2.01(m,1H);

[0608] 13 C NMR (126MHz, CDCl3) δ166.33,161.82,137.87,136.61,135.44,128.90,128.57,127.41,126.05,1 21.25,119.58,118.71,109.19,107.21,57.19,56.34,52.51,51.36,46.65,44.64,41.74,10.59.

[0609] MS (ESI) m / z for C 24 H 26 N4O2[M+Na] + : Calculated value 425.1948, measured value 425.1949.

[0610] [Chemical formula 76]

[0611] N108

[0612]

[0613] 1 H NMR (500MHz, CDCl3) δ7.85(d,J=2.0Hz,1H),7.32-7.23(m,4H),7.12-7.04(m,4H),5.25(s,2H),4.51(d,J=13.5Hz,1H),4.10(d,J= 10.5Hz,1H),4.01(s,2H),3.77-3.66(m,2H),3.49(d,J=11.0Hz,1H),2.94(d,J=11.5Hz,1H),2.82-2.77(m,1H),2.10-2.02(m,2H);

[0614] 13C NMR(126MHz,CDCl3)NMR(126MHz,)δ166.09,161.79,136.91,135.58,130.01,129.02,128.91,127.88 ,126.75,124.95,122.39,112.92,111.37,110.45,56.90,56.03,53.31,51.49,50.22,44.60,41.56.

[0615] MS (ESI) m / z for C 23 H 23 BrN4O2[M+H] + : Calculated value 467.1077, measured value 467.1079.

[0616] [Chemical formula 77]

[0617] N109

[0618]

[0619] 1 H NMR(500MHz, CDCl3)δ7.31-7.26(m,2H),7.17-7.08(m,5H),7.02(s,1H),6.85- 6.82(m,1H),5.24(s,2H),4.52-4.48(m,1H),4.11(m,1H),3.99(s,2H),3.85(s ,3H),3.83(d,J=13.0Hz,1H),3.69(d,J=13.5Hz,1H),3.55-3.52(m,1H),2.97( d,J=11.5Hz,1H),2.82-2.76(m,1H),2.13(t,J=11.5Hz,1H),2.07-2.02(m,1H);

[0620] 13 C NMR (126MHz, CDCl3) δ166.18,161.83,154.13,137.55,132.25,128.87,128.85,128.74,127.74,1 26.83,112.11,110.68,109.97,101.78,57.02,56.21,56.06,53.50,51.31,50.28,44.65,41.66.

[0621] MS (ESI) m / z for C 24 H 26 N4O3[M+H] +: Calculated value 419.2078, measured value 419.2070.

[0622] [Chemical formula 78]

[0623] N111

[0624]

[0625] 1 H NMR (500MHz, CDCl3) δ8.05-8.02(m,1H),7.90-7.87(m,1H),7.85(d,J=8.5Hz,1H),7.76-7.74(m,1H),7.53-7.49( m,2H),7.44-7.37(m,2H),7.32-7.26(m,4H),7.22-7.19(m,1H),7.16-7.12(m,3H),7.06(s,1H),5.30(s,2H),5.11 (d,J=14.5Hz,1H),5.03(d,J=14.5Hz,1H),4.43-4.40(m,1H),4.20-4.17(m,1H),3.89(d,J=13.0Hz,1H),3.75(d,J =13.5Hz,1H),3.72-3.69(m,3H),2.93-2.90(m,1H),2.76-2.70(m,1H),2.11(t,J=11.0Hz,1H),2.02-1.96(m,1H).

[0626] 13 C NMR(126MHz,CDCl3)NMR(126MHz,)δ163.31,161.65,137.51,136.97,134.08, 131.62,130.25,129.56,128.98,128.91,128.62,128.54,128.08,128.03,12 7.98,127.77,127.02,126.94,126.36,125.26,123.72,122.12,119.83,119.59,110.73,109.90,57.62,56.76,53.40,51.17,50.10,48.28,47.33,41.42.

[0627] MS (ESI) m / z for C 18 H 21 N3O2S[M+H] + : Calculated value 529.2598, measured value 529.2598.

[0628] [Chemical formula 79]

[0629] N112

[0630]

[0631] 1 H NMR (500MHz, CDCl3) δ7.82-7.78(m,3H),7.74(d,J=8.0Hz,1H),7.68(s,1H),7.50-7.45(m,2H),7.37-7 .35(m,1H),7.30-7.23(m,4H),7.20-7.17(m,1H),7.14-7.10(m,3H),7.04(s,1H),5.28(s,2H),4.71(d d,J=14.5Hz,37.0Hz,2H),4.46-4.43(m,1H),4.19-4.16(m,1H),3.90-85(m,3H),3.74(d,J=13.0Hz,1H ),3.68-3.65(m,1H),2.94-2.92(m,1H),2.78-2.72(m,1H),2.13(t,J=11.0Hz,1H),2.05-1.99(m,1H).

[0632] 13 C NMR (126MHz, CDCl3) δ163.80,161.73,137.52,136.98,133.33,133.13,13 2.48,129.12,128.90,128.52,128.09,128.04,127.98,127.88,127.83,1 26.95,126.91,126.63,126.44,126.14,126.11,122.13,119.85,119.58, 110.76,109.90,57.58,56.77,53.44,51.26,50.09,49.59,48.68,41.52.

[0633] MS (ESI) m / z for C 18 H 21 N3O2S[M+H] + : Calculated value 529.2598, measured value 529.2605.

[0634] [Chemical formula 80]

[0635] N113

[0636]

[0637] 1 H NMR (500MHz, CDCl3) δ7.74-7.72(m,1H),7.35-7.22(m,9H),7.19-7.16(m,1H),7.14-7.10( m,3H),7.04(s,1H),5.28(s,2H),4.56(dd,J=14.5Hz,27.5Hz,2H),4.47-4.43(m,1H),4.16 -4.13(m,1H),3.87(d,J=13.5Hz,1H),3.84-3.83(m,2H),3.73(d,J=13.5Hz,1H),3.66-3.6 3(m,1H),2.95-2.92(m,1H),2.78-2.72(m,1H),2.11(t,J=11.0Hz,1H),2.05-1.99(m,1H).

[0638] 13 C NMR(126MHz,CDCl3)NMR(126MHz,)δ163.70,161.76,137.52,136.98,135.07,129.05,129.02,128.94,128.67,128.57,128.51,128.29,12 8.10,127.96,127.81,126.99,126.88,122.13,119.85,119.62,110. 77,109.91,57.54,56.78,53.44,51.32,50.09,49.39,48.65,41.53.

[0639] MS (ESI) m / z for C 18 H 21 N3O2S[M+H] + : Calculated value 479.2442, measured value 479.2446.

[0640] [Chemical formula 81]

[0641] N114

[0642]

[0643] 1H NMR(500MHz, CDCl3)δ7.75(d,J=8.0Hz,1H),7.58-7.76(m,4H),7.45(t,J=8.0Hz,2H),7.38-7.2 5(m,7H),7.21-7.18(m,1H),7.16-7.12(m,3H),7.06(s,1H),5.30(s,2H),4.61(dd,J=14.5Hz,23 .5Hz,2H),4.50-4.46(m,1H),4.20-4.17(m,1H),3.90-3.88(m,3H),3.76(d,J=13.0Hz,1H),3.6 9-3.66(m,1H),2.97-2.94(m,1H),2.81-2.75(m,1H),2.15(t,J=11.0Hz,1H),2.08-2.02(m,1H).

[0644] 13 C NMR (126MHz, CDCl3) δ163.68,161.77,154.49,141.31,140.60,137.48,136.96,134.02,129.09,128.94,128.91,128.51,128.16,1 27.79,127.61,127.20,126.93,122.14,119.79,119.61,110.47,109.91,57.44,56.64,53.39,51.20,50.11,49.14,48.71,41.43.

[0645] MS (ESI) m / z for C 18 H 21 N3O2S[M+H] + : Calculated value 555.2755, measured value 555.2752.

[0646] [Chemical formula 82]

[0647] N122

[0648]

[0649] 1H NMR (500MHz, CD3OD) δ8.12(d,J=8.5Hz,1H),8.02(d,J=8.5Hz,1H),7.80-7.78(m,1H),7.75-7.73(m,1H),7.72-7.69( m,1H),7.55-7.51(m,1H),7.37(d,J=8.5Hz,1H),7.31-7.25(m,4H),7.20-7.17(m,1H),7.14-7.10(m,3H),7.05(s,1H ),5.28(s,2H),4.85(dd,J=14.5Hz,25.5Hz,2H),4.51-4.48(m,1H),4.22-4.15(m,3H),3.88(d,J=13.5Hz,1H),3.75( d,J=13.5Hz,1H),3.66-3.63(m,1H),2.97-2.94(m,1H),2.82-2.76(m,1H),2.17(t,J=11.0Hz,1H),2.09-2.03(m,1H).

[0650] 13 C NMR (126MHz, CDCl3) δ164.01,161.98,155.41,147.76,137.45,137.41,136.93,129.94,129.31,128.89,128.49,128.21,127.75,127. 68,127.54,126.92,126.80,122.13,120.18,119.75,119.62,110.32,109.91,57.33,56.55,53.36,51.64,51.19,50.10,49.92,41.40.

[0651] MS (ESI) m / z for C 18 H 21 N3O2S[M+H] + : Calculated value 530.2551, measured value 530.2549.

[0652] [Chemical formula 83]

[0653] N162

[0654]

[0655] 1H NMR(500MHz, CDCl3)δ7.49-7.46(m,2H),7.39-7.36(m,2H),7.31-7.27(m,3H),7.25-7.24(m, 1H),7.15-7.09(m,4H),7.00(s,1H),6.92(dd,J=2.5Hz,9.0Hz,1H),5.23(s,2H),5.12(s,2H) ,4.47-4.44(m,1H),4.02-3.94(m,3H),3.80(d,J=13.5Hz,1H),3.65(d,J=13.0Hz,1H),3.50- 3.47(m,1H),2.92-2.88(m,1H),2.71-2.65(m,1H),2.08(t,J=11.0Hz,1H),2.01-1.95(m,1H).

[0656] 13 C NMR (126MHz, CDCl3) δ166.11,161.72,153.11,137.77,137.44,132.32,128.77,128.68,128.50,127.69,127. 64,127.41,126.76,112.75,110.54,110.16,103.36,70.83,56.90,56.05,53.46,51.19,50.15,44.53,41.56.

[0657] MS (ESI) m / z for C 30 H 30 N4O3[M+H] + : Calculated value 495.2390, measured value 495.2386.

[0658] [Chemical formula 84]

[0659] N163

[0660]

[0661] 1H NMR (500MHz, CDCl3) δ7.84-7.82(m,1H),7.40-7.39(m,3H),7.33-7.32(m,2H),7. 25-7.15(m,5H),6.93(d,J=7.5Hz,2H),6.65(s,1H),5.22(s,2H),4.46-4.44(m,1H ),4.10-4.08(m,1H),4.03-3.95(m,2H),3.85-3.83(m,1H),3.69-3.67(m,1H),3.4 9(d,J=10.5Hz,1H),2.87(d,J=11.0Hz,1H),2.75-2.73(m,1H),2.07-1.96(m,2H).

[0662] 13 C NMR (126MHz, CDCl3) δ165.99,161.61,140.37,138.16,136.90,131.44,130.83,128.70,128.53,128.43,1 27.22,126.13,122.28,119.99,119.96,110.41,109.20,57.20,56.32,52.74,51.17,47.68,44.69,41.80.

[0663] MS (ESI) m / z for C 18 H 21 N3O2S[M+H] + : Calculated value 465.2285, measured value 465.2281.

[0664] [Chemical formula 85]

[0665] N164

[0666]

[0667] 1H NMR (500MHz, DMSO) δ8.13(s,1H),7.88-7.86(m,1H),7.41(t,J=11.0Hz,2H),7.34-7.28(m,5H),7.23(t,J=7.5Hz,2H),7.19-7.15(m,3H),4.27(d,J =12.5Hz,1H),3.95-3.92(m,1H),3.86-3.77(m,2H),3.69(s,2H),3.28-3 .26(m,1H),2.89(d,J=11.5Hz,1H),2.68-2.62(m,1H),1.99-1.86(m,2H).

[0668] 13 C NMR (126MHz, DMSO) δ165.32,162.97,139.54,138.21,137.84,131.56,131.26,131.13,131.04,129.82,128.75,128.51,12 8.27,127.74,123.19,123.01,120.94,120.76,120.44,111.18,110.78,110.59,56.92,55.99,52.77,52.00,44.41,41.38.

[0669] MS (ESI) m / z for C 18 H 21 N3O2S[M+H] + : Calculated value 451.2129, measured value 451.2129.

[0670] [Chemical formula 86]

[0671] SN611

[0672]

[0673] 1 H NMR (500MHz, CDCl3) δ8.39 (d, J = 7.5Hz, 1H), 7.81 (s, 1H), 7.35-7.24 (m, 5H), 7.18-7.15 (m, 3H), 5.34 (s, 2H), 4.52-4.48 (m, 1H), 4.01-3.99 (m, 3H),3.48-3.46(m,1H),3.07(t,J=7.5Hz,2H),3.02-2.96(m,1H),2.94 -2.92(m,1H),2.89-2.83(m,1H),2.79-2.73(m,1H),2.17-2.08(m,2H).

[0674] 13 C NMR (126MHz, CDCl3) δ193.68,165.94,161.82,137.19,135.81,134.79,129.16,128.36,127.14,126. 50,123.72,122.93,122.72,117.11,110.30,56.84,55.95,53.27,52.27,50.84,44.64,41.46,37.31.

[0675] MS (ESI) m / z for C 18 H 21 N3O2S[M+H] + : Calculated value 431.2078, measured value 431.2072.

[0676] [Chemical formula 87]

[0677] SN612

[0678]

[0679] 1 H NMR (500MHz, CDCl3) δ7.89-7.77(m,2H),7.41-7.20(m,3H),4.66-4.44(m,2H),4.09-3. 85(m,5H),3.68-3.56(m,1H),3.18-3.02(m,1H),2.74-2.63(m,1H),2.62-2.38(m,1H).

[0680] 13 C NMR (126MHz, CDCl3) δ169.05,164.35,162.19,140.32,138.48,128.60,124.7 6,124.49,122.91,122.17,121.71,56.38,54.61,48.89,44.59,41.00,34.82.

[0681] MS (ESI) m / z for C 17 H 17 N3O3S[M+H] + : Calculated value 344.1063, measured value 344.1061.

[0682] [Chemical formula 88]

[0683] N199

[0684]

[0685] 1 H NMR (500MHz, CDCl3) δ7.68-7.66(m,1H),7.39-7.37(m,1H),7.19-7.13(m,2H),7.12-7.07(m,1H),4.45(d,J=13.5Hz,1H),4.08( d,J=11.0Hz,1H),3.96-3.77(m,4H),3.49(d,J=11.0Hz,1H),2.98(d,J=11.5Hz,1H),2.79(t,J=12.5Hz,1H),2.15-2.04(m,2H).

[0686] 13 C NMR (126MHz, CDCl3) δ169.79,166.51,140.46,131.63,128.55,125.70,12 3.22,122.92,115.31,113.92,60.80,59.65,57.06,55.17,48.11,45.41.

[0687] MS (ESI) m / z for C 16 H 16 N4O2[M+H] + : Calculated value 299.1502, measured value 299.1502.

[0688] Experimental example

[0689] 1. Preparation of SKOV3 and SKOV3-TR

[0690] Cell experiments were conducted using epithelial ovarian cancer cell lines SKOV3 and SKOV3-TR. SKOV3-TR is a cancer cell line derived from SKOV3 and made resistant to the anticancer drug paclitaxel. Figure 1 Part (a) shows the paclitaxel anticancer agent IC50 value of SKOV3, and part (b) shows the paclitaxel anticancer agent IC50 value of SKOV3-TR. Figure 2 Part (a) shows the docetaxel anticancer agent IC50 value of SKOV3, and part (b) shows the docetaxel anticancer agent IC50 value of SKOV3-TR.

[0691] Two cancer cell lines grown in 12-wells were pretreated with 102 types of S-forms at low concentrations (0.5μM) and high concentrations (2μM) for 4 hours, and then the SKOV3-TR cell line was treated with 4μM paclitaxel and the SKOV3 cell line was treated with 0.05μM paclitaxel. For cell morphology analysis, the cells that were not treated (None) and treated with DMSO (paclitaxel solvent), ethanol (EtOH) (S-form solvent), DMSO+EtOH, paclitaxel, paclitaxel+ethanol (Pacli+EtOH), and 102 types of S-forms were analyzed and images were captured after 1 day, 2 days, and 3 days. For cell metabolism analysis, WST-1 analysis was performed after 3 days of combined treatment with paclitaxel and S-forms and is shown in Figures 3 to 10 , using the same experimental groups, cell viability was analyzed by crystal violet staining and is shown in Figures 13 to 20 .

[0692] For docetaxel, two cell lines grown in 12-wells were pretreated with S-form at low concentrations (0.5 μM) and high concentrations (2 μM) for 4 hours, and then 0.9 μM docetaxel was treated for SKOV3-TR cell line and 0.5 nM docetaxel was treated for SKOV3 cell line. For cell morphology analysis, cells treated with DMSO (docetaxel solvent), ethanol (ethanol, EtOH) (S-form solvent), DMSO + EtOH, docetaxel, doxetaxel + ethanol (Doxetaxel + EtOH), and S-form were analyzed and images were captured after 1, 2, and 3 days. For cell material metabolism analysis, WST-1 analysis was performed after 3 days of combined treatment with docetaxel and S-form and is shown in Figure 21 to Figure 24 , using the same experimental groups, cell viability was analyzed by crystal violet staining and is shown in Figures 27 to 30 .

[0693] Figure 3 , Figure 4 , Fig.13 and Fig.14The cells were treated with untreated, DMSO, ethanol (EtOH), DMSO + EtOH, paclitaxel, paclitaxel + EtOH, S101 (0.5 μM), S101 (2 μM), S102 (0.5 μM), S102 (2 μM), S105 (0.5 μM), S105 (2 μM), S106 (0.5 μM), S106 (2 μM), S108 (0.5 μM), S108 (2 μM), S109 (0.5 μM), S109 (2 μM), S110 (0.5 μM), S111 0(2μM), S111(0.5μM), S111(2μM), S112(0.5μM), S112(2μM), S113(0.5μM), S113(2μM), S114(0.5μM), S114(2μM ), S115(0.5μM), S115(2μM), S116(0.5μM), S116(2μM), S117(0.5μM), S117(2μM), S118(0.5μM), S118(2μM), S119 (0.5μM), S119 (2μM), S120 (0.5μM), S120 (2μM), S201 (0.5μM), S201 (2μM), S202 (0.5μM), S202 (2μM), S203 (0.5μ M), S203 (2μM), S204 (0.5μM), S204 (2μM), S206 (0.5μM), S206 (2μM), S207 (0.5μM), S207 (2μM), S208 (0.5μM), S20 8(2μM), S209(0.5μM), S209(2μM), S210(0.5μM), S210(2μM), S211(0.5μM), S211(2μM), S212(0.5μM), S212(2μM), S213(0.5μM), S213(2μM), S214(0.5μM), S214(2μM), S215(0.5μM), S215(2μM), S216(0.5μM), S216(2μM).

[0694] Figure 5 , Figure 6 , Fig.15 and Fig.16The cells were treated with untreated, DMSO, ethanol (EtOH), DMSO + ethanol, paclitaxel, paclitaxel + ethanol, S121 (0.5 μM), S121 (2 μM), S122 (0.5 μM), S122 (2 μM), S126 (0.5 μM), S126 (2 μM), S127 (0.5 μM), S127 (2 μM), S128 (0.5 μM), S128 (2 μM), S221 (0.5 μM), S221 (2 μM), S222 (0.5 μM), S222 (2 μM), S224 (0.5 μM), S224 (2 μM), S225 (0.5 μM), S226 (2 μM). The order of S305(2μM), S301(0.5μM), S301(2μM), S302(0.5μM), S302(2μM), S303(0.5μM), S303(2μM), S304(0.5μM), S304(2μM), S306(0.5μM), S306(2μM), S307(0.5μM), S307(2μM), S309(0.5μM), S309(2μM), S310(0.5μM), S310(2μM), S314(0.5μM), S314(2μM), S318(0.5μM), S318(2μM).

[0695] Figure 7 , Figure 8 , Fig.17 and Fig.18 The cells were treated with untreated, DMSO, ethanol (EtOH), DMSO + EtOH, paclitaxel, paclitaxel + EtOH, S101 (0.5 μM), S101 (2 μM), S206 (0.5 μM), S206 (2 μM), S142 (0.5 μM), S142 (2 μM), S121 (0.5 μM), S121 (2 μM), S122 (0.5 μM), S122 (2 μM), S127 (0.5 μM), S127 (25μM), S128 (0.5μM), S128 (2μM), N101 (0.5μM), N101 (2μM), N102 (0.5μM), N102 (2μM), N103 (0.5μM), N103 (2μM), N104 (0.5μM), N104 (2μM), N105 (0.5μM), N105 (2μM), N106 (0.5μM), N106 (2μM).

[0696] Fig. 9 , Fig.10 , Fig.19 and Fig. 20The cells were treated with untreated, DMSO, ethanol (EtOH), DMSO + ethanol, paclitaxel, paclitaxel + ethanol, N107 (0.5 μM), N107 (2 μM), N111 (0.5 μM), N111 (2 μM), N112 (0.5 μM), N112 (2 μM), N113 (0.5 μM), N113 (2 μM), N114 (0.5 μM), N114 (2 μM), N122 (0.5 μM), N122 (2 μM), N164 (0.5 μM), N164 (2 μM), N163 (0 .5μM), N163 (2μM), N108 (0.5μM), N108 (2μM), N109 (0.5μM), N109 (2μM), S135 (0.5μM), S135 (2μM), N162 (0.5μM), N162 (2μM), SN612 (0.5μM), SN612 (2μM), N199 (0.5μM), N199 (2μM), S136 (0.5μM), S136 (2μM), SN611 (0.5μM), SN611 (2μM).

[0697] Fig.21 , Fig. 22 , Fig. 27 and Fig.28The cells were treated with untreated, DMSO, ethanol (EtOH), DMSO + EtOH, docetaxel, docetaxel + EtOH, S101 (0.5 μM), S101 (2 μM), S102 (0.5 μM), S102 (2 μM), S103 (0.5 μM), S103 (2 μM), S105 (0.5 μM), S105 (2 μM), S106 (0.5 μM), S106 (2 μM), S107 (2 μM), S107 (0.5 μM), S108 (0.5 μM), S108 (2 μM), S1 09(0.5μM), S109(2μM), S110(0.5μM), S110(2μM), S111(0.5μM), S111(2μM), S112(0.5μM), S112(2μM), S113(0.5μM), S 113(2μM), S114(0.5μM), S114(2μM), S115(0.5μM), S115(2μM), S116(0.5μM), S116(2μM), S117(0.5μM), S117(2μM), S11 8(0.5μM), S118(2μM), S119(0.5μM), S119(2μM), S120(0.5μM), S120(2μM), S201(0.5μM), S201(2μM), S202(0.5μM), S2 02(2μM), S203(0.5μM), S203(2μM), S204(0.5μM), S204(2μM), S206(0.5μM), S206(2μM), S207(0.5μM), S207(2μM), S208 (0.5μM), S208(2μM), S209(0.5μM), S209(2μM), S210(0.5μM), S210(2μM), S211(0.5μM), S211(2μM), S212(0.5μM), S212(2μM), S213(0.5μM), S213(2μM), S214(0.5μM), S214(2μM), S215(0.5μM), S215(2μM), S216(0.5μM), S216(2μM).

[0698] Fig.23 , Fig.24 , Fig.29 and Fig.30The cells were treated with untreated, DMSO, ethanol (EtOH), DMSO + EtOH, docetaxel, docetaxel + EtOH, S121 (0.5 μM), S121 (2 μM), S122 (0.5 μM), S122 (2 μM), S126 (0.5 μM), S126 (2 μM), S127 (0.5 μM), S127 (2 μM), S128 (0.5 μM), S128 (2 μM), S221 (0.5 μM), S221 (2 μM), S222 (0.5 μM), S222 (2 μM), S224 (0.5 μM), S224 (2 μM), S225 (0.5 μM), S225 (2 μM), S30 1(0.5μM), S301(2μM), S302(0.5μM), S302(2μM), S303(0.5μM), S303(2μM), S304(0.5μM), S304(2μM), S306(0.5μM), S306(2μM), S307(0.5μM), S307(2μM), S308(0.5μM), S308(2μM), S309(0.5μM), S309(2μM), S310(0.5μM), S310(2μM), S314(0.5μM), S314(2μM), S318(0.5μM), S318(2μM).

[0699] 2. WST-1 analysis

[0700] According to the results of WST-1 analysis for analyzing the metabolism of cells, paclitaxel treatment induced a decrease in the metabolism of SKOV3-TR and SKOV3. The results of WST-1 analysis of paclitaxel on 102 types of SKOV3-TR and 102 types of SKOV3 are shown in Figures 3 to 10 .

[0701] That is, in the paclitaxel-treated group, the absorbance at 450 nm decreased due to the phenomenon of apoptosis induction and cell growth inhibition in SKOV3-TR and SKOV3, compared with the untreated (None) or DMSO-treated group. When the S-type and paclitaxel were treated in combination, the anticancer effect of paclitaxel was enhanced in SKOV3-TR, which is a resistant cancer cell line, and a lower absorbance was shown compared with the paclitaxel + ethanol (Pacli + EtOH) treatment group, but the anticancer effect of paclitaxel was not enhanced in SKOV3. In addition, in SKOV3-TR, since 2 μM of the S-type promoted the reduction of the substance metabolism based on paclitaxel more than 0.5 μM of the S-type, it was found that a dose-response relationship was established. The absorbance of the paclitaxel + ethanol (Pacli + EtOH) treatment group as a comparative example was added with a baseline. As for the anticancer enhancing effect of paclitaxel, the absorbance (OD value at 450 nm) in the WST-1 assay was significantly decreased when paclitaxel+S-form was treated compared to the paclitaxel+ethanol treatment group (Pacli+EtOH).

[0702] According to the results of WST-1 analysis for analyzing the metabolism of cells, docetaxel treatment induced a decrease in the metabolism of SKOV3-TR and SKOV3. The results of WST-1 analysis of docetaxel on the S-type of SKOV3-TR and the results of WST-1 analysis of docetaxel on the S-type of SKOV3 are shown in Figure 21 to Figure 24 .

[0703] That is, in the docetaxel-treated group, the absorbance at 450 nm decreased due to the phenomenon of apoptosis induction and cell growth inhibition in SKOV3-TR and SKOV3, compared with the untreated (None) or DMSO-treated group. When the S-type and docetaxel were treated in combination, the anticancer efficacy of docetaxel was enhanced in SKOV3-TR, which is a resistant cancer cell line, and a lower absorbance was shown compared with the docetaxel + ethanol (Doxetaxel + EtOH) treatment group, but the anticancer efficacy of docetaxel was not enhanced in SKOV3. In addition, in SKOV3-TR, since 2 μM of the S-type promoted the reduction of paclitaxel-based substance metabolism more than 0.5 μM of the S-type, it was found that a dose-response relationship was established. The absorbance of the docetaxel + ethanol (Doxetaxel + EtOH) treatment group as a comparative example was added with a baseline. As for the anticancer enhancing effect of docetaxel, the absorbance (OD value at 450 nm) in the WST-1 assay was significantly decreased when docetaxel+S-form was treated compared to the docetaxel+ethanol treatment group (Doxetaxel+EtOH).

[0704] 3. Cell survival rate and cell line analysis

[0705] According to crystal violet staining for analyzing cell viability and cell number, paclitaxel treatment induced a decrease in cell number by reducing cell viability in SKOV3-TR and SKOV3. Representatively, images were captured after 3 days of treatment with paclitaxel and docetaxel alone or in combination with paclitaxel and docetaxel in SKOV3-TR and SKOV3 cell lines. The crystal violet staining results of SKOV3-TR for paclitaxel are shown in Fig.11 The crystal violet staining results of SKOV3 are shown in Fig.12 The results of crystal violet staining of SKOV3-TR for docetaxel are shown in Fig.25 The crystal violet staining results of SKOV3 are shown in Fig.26 .

[0706] Compared with the untreated or DMSO-treated groups, in the paclitaxel-treated group, the number of cells decreased due to phenomena such as apoptosis induction and cell growth inhibition in SKOV3-TR and SKOV3, so the absorbance at 570 nm decreased. When S-type and paclitaxel were treated in combination, the anticancer effect of paclitaxel was enhanced in SKOV3-TR, which is a resistant cancer cell line, and a lower absorbance was shown compared with the paclitaxel + ethanol (Pacli + EtOH) treatment group, but the anticancer effect of paclitaxel was not enhanced in SKOV3. In addition, in SKOV3-TR, since the high concentration of 2 μM S-type promoted the reduction of cell survival rate by paclitaxel more than the low concentration of 0.5 μM S-type, it was found that a dose-response relationship was established. For analysis, 102 experimental groups were treated for 3 days, and images stained with crystal violet were captured. The degree of staining was measured by dye elution, and the absorbance at 570 nm was measured by ELISA in the same manner as the WST-1 analysis. In the ELISA analysis, a baseline was added to the absorbance of the Pacli+EtOH treatment group as a comparison object. The absorbance results for 102 SKOV3-TR and 102 SKOV3 are shown in Figures 13 to 20 .

[0707] Compared with the untreated or DMSO-treated group, in the docetaxel-treated group, the number of cells decreased due to phenomena such as apoptosis induction and cell growth inhibition in SKOV3-TR and SKOV3, so the absorbance at 570 nm decreased. When S-type and docetaxel were treated in combination, the anticancer effect of docetaxel was enhanced in SKOV3-TR, which is a resistant cancer cell line, and a lower absorbance was shown compared with the docetaxel + ethanol (Doxetaxel + EtOH) treatment group, but the anticancer effect of docetaxel was not enhanced in SKOV3. In addition, in SKOV3-TR, since the high concentration of 2 μM S-type promoted the decrease in cell survival rate by docetaxel more than the low concentration of 0.5 μM S-type, it was found that a dose-responserelationship was established. For analysis, 102 experimental groups were treated for 3 days, and images stained with crystal violet were captured. The degree of staining was measured by dye elution, and the absorbance at 570 nm was measured by ELISA in the same manner as the WST-1 analysis. In the ELISA analysis, a baseline was added to the absorbance of the docetaxel + ethanol (Doxetaxel + EtOH) treatment group as a comparison object. The absorbance results for the S-type of SKOV3-TR and the absorbance results for the S-type of SKOV3 are shown in Figures 27 to 30 .

[0708] 4. Measuring anticancer efficacy

[0709] 1) Analysis of cell number changes (in vitro)

[0710] The changes in the number of cells after treatment with 100 nM, 50 nM, and 10 nM of the S101 compound in the absence of endoplasmic reticulum stress G(+): glucose and the absence of endoplasmic reticulum stress G(-): glucose are shown in Figure 2. Fig.31 The results of capturing crystal violet stained images are shown in Fig.32 Furthermore, the apoptotic effect of S101 on cancer cells after glucose deprivation was measured by TUNEL method and is shown in Fig.33 .

[0711] 2) Mouse in vivo model validation

[0712] After culturing and harvesting the selected MDA-MB231 cells verified as cancer stem cells in vitro, the anti-cancer effect was verified by constructing an in vivo mouse model. A control group and a severe ER stress were induced, and 2-deoxy-d-glucose was used as a substitute for the anticancer agent as Comparative Example 1 (2DG). The group using 2 mg of S101 alone was used as Example 2 (S101 alone), and the group using 10 mg of 2-deoxy-d-glucose and 2 mg of S101 was used as Example 3 (S101+2DG, 2 mg:10 mg), and verification was performed. The results of tumor volume changes are shown in Fig.34 The weight and size of the dissected tumors were compared between each group and are shown in Fig.35 In the selected-MDA-MB231 cell xenograft model, when measuring the anticancer effect of S101 and 2DG combined, the weight change between each group was measured and shown in Fig.36 .

[0713] In order to determine the degree of cytotoxicity when S101 or 2DG was used alone or in combination, livers were extracted from each group to prepare paraffin embedded tissue blocks. After being cut into slides, H&E staining was performed, and liver tissue degradation was analyzed pathologically to infer the degree of cytotoxicity. Fig.37 The image is shown at a magnification of x 400.

[0714] Those skilled in the art to which this application belongs will be able to understand that this application can be implemented in other specific forms without changing its technical spirit or essential features. Therefore, it should be understood that the above embodiments are exemplary in all aspects and not restrictive. The scope of this application is represented by the attached claims rather than the above detailed description, and the changes or modifications made by the meaning and scope of the claims and their equivalents should be understood to be included in the scope of this application.

Claims

1. A compound represented by the following chemical formula 3 or a pharmaceutically acceptable salt thereof, wherein: [Chemical formula 3] In the chemical formula 3, R1 is hydrogen, linear alkyl, unsubstituted or substituted benzyl, or unsubstituted or substituted 2-phenylethyl, in which case at least one of the ortho, meta, and para positions of the substituted benzyl or the substituted 2-phenylethyl is substituted with a halide; L1 is C1 alkylene; R2 is hydrogen, linear alkyl, unsubstituted or substituted benzyl, or unsubstituted or substituted 2-phenylethyl, in which case the linear alkyl is substituted with a halide, the substituted benzyl is substituted with a halide, a C1 linear alkyl, a trifluoromethyl, a cyano, a nitro, or an aryl in at least one of the ortho, meta, and para positions, and the 2-phenylethyl is substituted with a halide in at least one of the ortho, meta, and para positions; R4' is hydrogen; R4 is hydrogen, straight-chain alkyl, branched alkyl, cycloalkyl, alkynyl, unsubstituted or substituted benzyl, 2-naphthylmethyl or 1-naphthylmethyl, in which case the straight-chain alkyl is substituted with methylthio, alkynyl or benzyloxycarbonylamino, and at least one of the ortho, meta and para positions of the substituted benzyl can be substituted with at least one of halo, aryl, nitro, cyano, trifluoromethyl or benzyloxy; m is 1; R1 and R2 are not hydrogen or linear alkyl at the same time.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen, straight chain alkyl, In this case, X1 is hydrogen, halo or C1 straight chain alkyl; The L1 is a C1 alkylene group; R2 is hydrogen, straight chain alkyl, In this case, the linear alkyl group is substituted with a halide; The R4 are each independently hydrogen, straight chain alkyl, branched chain alkyl, cycloalkyl, 3. Any one of the following compounds or their pharmaceutically acceptable salts, 。 4. A pharmaceutical composition for preventing or treating cancer, wherein: The pharmaceutical composition comprises the compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, or the compound according to claim 3, or a pharmaceutically acceptable salt thereof.

5. The pharmaceutical composition for preventing or treating cancer according to claim 4, wherein: The cancer is a resistant cancer.

6. The pharmaceutical composition for preventing or treating cancer according to claim 5, wherein: The resistant cancer is resistant to anticancer drugs or to radiation.

7. The pharmaceutical composition for preventing or treating cancer according to claim 5, wherein: The resistant cancer is at least one selected from the group consisting of ovarian cancer, colorectal cancer, pancreatic cancer, gastric cancer, liver cancer, breast cancer, cervical cancer, thyroid cancer, parathyroid cancer, lung cancer, prostate cancer, gallbladder cancer, bile duct cancer, blood cancer, bladder cancer, kidney cancer, melanoma, colon cancer, bone cancer, skin cancer, head and neck cancer, uterine cancer, rectal cancer, brain cancer, perianal cancer, fallopian tube cancer, endometrial cancer, vaginal cancer, vulvar cancer, esophageal cancer, small intestine cancer, endocrine gland cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, ureteral cancer, renal cell carcinoma, renal pelvis cancer, central nervous system tumors, spinal cord tumors, brain stem gliomas and pituitary adenomas.

8. The pharmaceutical composition for preventing or treating cancer according to claim 6, wherein: The anticancer drug is selected from the group consisting of nitrogen mustard, imatinib, oxaliplatin, rituximab, erlotinib, neratinib, lapatinib, gefitinib, vandetanib, nilotinib, semasanib, bosutinib, axitinib, masitinib, cediranib, lestaurtinib, trastuzumab, gefitinib, bortezomib, sunitinib, pazopanib, tocitanib, nintedanib, regorafenib, semasanib, tivozanib, ponatinib, cabozantinib, carboplatin, sorafil Azithromycin, lenvatinib, bevacizumab, cisplatin, cetuximab, mistletoe, asparaginase, retinoic acid, hydroxyurea, dasatinib, estramustine, gemtuzumab, ibritumomab tiuxetan, heptaplatin, methylaminolevulinic acid, amsacrine, alemtuzumab, procarbazine, alprostadil, holmium nitrate chitosan, gemcitabine, doxifluridine, pemetrexed, tegafur, capecitabine, gimeracil, otracil, azacitidine, methotrexate, uracil, cytarabine, 5-fluorouracil Uracil, fludarabine, enocitabine, flutamide, capecitabine, decitabine, mercaptopurine, thioguanine, cladribine, carmofur, raltitrexed, docetaxel, paclitaxel, irinotecan, belotecan, topotecan, vinorelbine, etoposide, vincristine, vinblastine, teniposide, doxorubicin, idarubicin, epirubicin, mitoxantrone, mitomycin, bleomycin, daunorubicin, actinomycin, pirarubicin, aclarubicin, pecloramycin, teciloxime At least one of the group consisting of lomustine, temozolomide, busulfan, ifosfamide, cyclophosphamide, melphalan, altretinoin, dacarbazine, thiotepa, nimustine, chlorambucil, dibromodulin, folinic acid, retinoic acid, exemestane, aminoglutethimide, anagrelide, olaparib, navelbine, fadrozole, tamoxifen, toremifene, testolactone, anastrozole, letrozole, vorozole, bicalutamide, lomustine, vorinostat, entinostat and carmustine.

9. Use of the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, or the compound according to claim 3 or a pharmaceutically acceptable salt thereof, in the preparation of a drug for treating cancer.

10. The use according to claim 9, wherein The cancer is a resistant cancer.

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