RU2801811C1 - New compound and a pharmaceutical composition containing the compound for the prevention or treatment of cancer - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to a novel compound of formula 1, or a pharmaceutically acceptable salt thereof, which may find use in the prevention or treatment of resistant cancer. In the said formula, R₁ is hydrogen, linear or branched C₁~C₆alkyl, C₆~C₁₂aryl or C₁~C₆alkyl C₆~C₁₂aryl, each of which may be independently substituted with at least one substituent selected from halo, C₁~C₆alkyl, C₃~C₆cycloalkyl and C₆~C₁₂aryl; R₃ is hydrogen, C₁~C₆alkoxy, halogen, where C₁~C₆alkoxy can be substituted with C₁~C₆alkyl C₆~C₁₂aryl; L₁ is C₁~C₁₀alkylene, where alkylene may be substituted by oxo; Q is S, NR where R is hydrogen, linear or branched C₁~C₆alkyl, C₆~C₁₂aryl or C₁~C₆alkyl C₆~C₁₂aryl, each of which may be independently substituted with at least one substituent selected from C₃~C₇cycloalkyl and C₆~C₁₂aryl; R₂ is hydrogen, linear C₁~C₆alkyl, C₃~C₇cycloalkyl, C₆~C₁₂aryl, 3–12 membered heteroaryl containing a ring heteroatom selected from N, C₁~C₆alkyl C₆~C₁₂aryl, each of which may be independently substituted with at least one substituent selected from halo, C₁~C₆alkyl, C₁~C₆alkoxy, C₆~C₁₂aryl, nitro, cyano or trifluoromethyl; or R₂ is ; R₄ is hydrogen, linear or branched C₁~C₆alkyl, C₃~C₇cycloalkyl, C₂~C₆alkynyl, C₁~C₆alkylthio, C₆~C₁₂aryl, C₁~C₆alkyl-C₆~C₁₂aryl, each of which may be independently substituted with at least one substituent selected from halo, C₆~C₁₂aryl, C₆~C₁₂aryloxy, nitro, cyano or trifluoromethyl; R₂ and R₄ can be combined to form a 5–10 membered monocyclic or bicyclic ring, R₄' is hydrogen; m is an integer 1 and n is an integer with a value from 1 to 4; and X, Y and Z are each hydrogen, R₁ and R₂ are not simultaneously hydrogen or simultaneously linear alkyl. The invention also relates to a pharmaceutical composition containing a compound of formula 1 for the prevention or treatment of cancer or a resistant form of cancer, a method of treating cancer that is resistant to oncological therapies, the use of a compound of formula 1 for the production of a medicinal product for the treatment of cancer or a resistant form of cancer and cancer stem cells.

[Formula 1]

EFFECT: obtaining a new compound and a pharmaceutical composition containing the compound for the prevention or treatment of cancer.

11 cl, 37 dwg, 1 tbl, 92 ex

Description

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

This application claims the priority and benefit of U.S. Provisional Application No. 62/928398 filed with the U.S. Patent and Trademark Office (USPTO) on October 31, 2019.

The present invention relates to a novel compound and a pharmaceutical composition for the prevention or treatment of cancer, comprising the compound or a pharmaceutically acceptable salt thereof.

BACKGROUND OF THE INVENTION

Cancer is one of the most common causes of death worldwide, accounting for approximately 12% of deaths. Chemotherapy, which is a typical anti-cancer therapy, is currently used as the most effective therapeutic method for cancer treatment in the form of monotherapy or in combination with various therapeutic methods such as radiation therapy. However, when using chemotherapy, the effectiveness of the anti-cancer drug depends on its ability to kill cancer cells, but when using the drug, there is a problem of its effect not only on cancer cells, but also on normal cells.

It has been found that the administration of an anticancer drug causes, as a rule, excessive stress in cancer cells, calcium ions are excessively secreted from the endoplasmic reticulum (ER), and secreted calcium ions accumulate in mitochondria, which leads to the death of cancer cells, while cancer stem cells survive. , and at the same time, the concentration of calcium ions is regulated by an increase in the expression of SERCA (sarco/endoplasmic reticulum Ca ²⁺ -ATPase), which can reduce the secretion of excess calcium ions and simultaneously return excess secreted calcium ions to the ER when an anticancer agent is administered. That is, the SERCA protein may play a role in survival signaling in the process of ER stress signaling.

If a substance is developed to selectively suppress the growth of cancer stem cells that can act as an inhibitor targeting the SERCA protein, which causes resistance of cancer stem cells to the effects of anticancer drugs, a very high anticancer effect can be achieved due to an increase in the effectiveness of chemotherapy using an anticancer drug. , which can occur even when using a lower dose of the drug.

DESCRIPTION OF THE INVENTION

TECHNICAL PROBLEM

The objective of the present invention is to create a new connection.

It is also an object of the present invention to provide a pharmaceutical composition for the prevention or treatment of cancer which includes a novel compound.

It is also an object of the present invention to provide a pharmaceutical composition for the prevention or treatment of resistant cancer, which includes a novel compound.

It is also an object of the present invention to provide a method for using a novel compound in the prevention or treatment of resistant cancer.

However, the technical problems to be solved by the present invention are not limited to the problems described above, and other problems not yet mentioned will be fully understood by those skilled in the art upon reading the following descriptions.

SOLUTION OF THE TECHNICAL PROBLEM

According to one embodiment of the present invention, there is provided a compound represented by the following formula 1, or a pharmaceutically acceptable salt thereof:

[Formula 1]

Where:

R ₁ is hydrogen, linear or branched alkyl, alkoxy, haloalkyl, haloalkoxy, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, each of which may be independently substituted with at least one substituent selected from hydroxyl, halogen, C ₁ ~C ₆ alkyl, C ₁ ~C ₆ alkoxy, C ₃ ~C ₆ cycloalkyl, C ₁ ~C _{6 haloalkyl, C 1 ~C 6 haloalkoxy ,} oxo, cyano, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl;

R ₃ is hydrogen, linear or branched alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl, each of which may be independently substituted with at least one substituent selected from hydroxyl, halogen, C ₁ ~C ₆ alkyl , C ₁ ~C ₆ alkoxy, C ₁ ~C ₆ haloalkyl, C ₁ ~C ₆ haloalkoxy, oxo, cyano, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl;

L ₁ is C ₁ ~C ₁₀ alkylene, where alkylene may be substituted with at least one substituent selected from C ₁ ~C ₆ alkyl, C ₃ ~C ₆ cycloalkyl, C ₁ ~C ₆ alkoxy, hydroxyl , oxo or halo, and C ₁ ~C ₆ alkyl, C ₃ ~C ₆ cycloalkyl and C ₁ ~C ₆ alkoxy may be substituted with at least one substituent selected from unsubstituted or substituted aryl;

Q is S, Se, NR , P, P(O), P(O) ₂ or P(O)OR, where R is hydrogen, linear or branched alkyl, cycloalkyl, bi- or tricycloalkyl, alkoxy, haloalkyl, haloalkoxy, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, each of which may be independently substituted with at least one substituent selected from hydroxyl, halogen, C ₁ ~C ₆ alkyl, C ₁ ~C ₆ alkoxy, C ₁ ~ C ₆ haloalkyl, C ₁ ~C ₆ haloalkoxy, oxo, cyano, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl;

R ₂ is hydrogen, linear alkyl, cycloalkyl, alkoxy, haloalkoxy, haloalkyl, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, each of which may be independently substituted with at least one substituent selected from hydroxyl, halogen, C ₁ ~C ₆ alkyl, C ₁ ~C ₆ alkoxy, C ₁ ~C ₆ haloalkyl, C ₁ ~C ₆ haloalkoxy, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, oxo, nitro, cyano or trifluoromethyl;

R ₄ and R ₄ ' are each independently hydrogen, linear or branched alkyl, cycloalkyl, alkenyl, alkynyl, alkylthio, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, each of which may be independently substituted with at least one substituent selected from hydroxyl, halogen, C ₁ ~C ₆ alkyl, C ₁ ~C ₆ alkoxy, C ₁ ~C ₆ haloalkyl, C ₁ ~C ₆ haloalkoxy, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, oxo, nitro, cyano , or trifluoromethyl;

R ₂ and R ₄ can be connected to form a 5-10 membered monocyclic or bicyclic ring, where R ₄ ' represents hydrogen;

m is an integer 1 or 2, and n is an integer from 1 to 4; And

X, Y and Z are each independently hydrogen, linear or branched alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, each of which may be independently substituted with at least one substituent selected from hydroxyl, halogen, C ₁ ~C ₆ alkyl, C ₁ ~C ₆ alkoxy, C ₁ ~C ₆ haloalkyl, C ₁ ~C ₆ haloalkoxy, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, oxo, nitro, cyano or trifluoromethyl.

According to another embodiment of the present invention, there is provided a pharmaceutical composition for the prevention or treatment of cancer, which comprises one or more compounds selected from a compound of formula 1, or a pharmaceutically acceptable salt thereof.

According to another embodiment of the present invention, there is provided a pharmaceutical composition for the prevention or treatment of resistant cancer, which comprises one or more compounds selected from a compound of Formula 1, or a pharmaceutically acceptable salt thereof.

POSITIVE EFFECTS

A pharmaceutical composition comprising a compound of one embodiment of the present invention, or a pharmaceutically acceptable salt, may have a very high anti-cancer effect.

A composition comprising a compound of one embodiment of the present invention or a pharmaceutically acceptable salt can enhance the anti-cancer effect of an anti-cancer drug or radiation therapy, and can effectively treat cancer by inhibiting cancer cell proliferation and inducing cell death.

A composition comprising a compound of one embodiment of the present invention or a pharmaceutically acceptable salt makes it possible to overcome cancer resistance to the action of an anticancer drug or radiation therapy and, therefore, allows effective treatment of resistant cancer and reduces the side effects of cancer therapy.

A composition comprising a compound of one embodiment of the present invention, or a pharmaceutically acceptable salt, is effective in providing an anti-cancer effect on cancer stem cells.

It is intended that the effects of the present invention are not limited to those exemplified above, and various kinds of effects are included in the present invention.

DESCRIPTION OF THE DRAWINGS

Figure 1A shows the IC ₅₀ value for the anti-cancer drug paclitaxel for the ovarian adenocarcinoma cell line SKOV3, and Figure 1B shows the IC ₅₀ value for the anti-cancer drug paclitaxel for the paclitaxel-resistant ovarian carcinoma cell line SKOV3-TR.

Figure 2A shows the IC ₅₀ value for the anticancer drug doxetaxel for the SKOV3 cell line, and Figure 2B shows the IC ₅₀ value for the anticancer drug doxetaxel for the SKOV3-TR cell line.

Figures 3-10 show the results of the analysis of proliferation of SKOV3-TR and SKOV3c cells using the WST-1 kit compared with paclitaxel exposure.

Figures 11 and 12 show the results of a histochemical study with crystal violet staining of SKOV3-TR and SKOV3 cells treated with paclitaxel.

Figures 13-20 show the results of measuring the optical density of the SKOV3-TR and SKOV3 cell lines when treated with paclitaxel.

Figures 21-24 show the results of the analysis of the proliferation of SKOV3-TR and SKOV3c cells using the WST-1 kit when treated with doxetaxel.

Figures 25 and 26 show the results of a histochemical study with crystal violet staining of SKOV3-TR and SKOV3 cells treated with doxetaxel.

Figures 27-30 show the results of measuring the optical density of the SKOV3-TR and SKOV3 cell lines when treated with doxetaxel.

Figure 31 shows cell number changes after treatment of selected-MDA-MB231 cells and selected-MCF7 cells, which are cancer stem cells, with 100 nM, 50 nM, and 10 nM compound S101 in the absence of ER stress induced in cancer cells in the presence of glucose (G(+)), and in the presence of ER stress induced in cancer cells in the absence of glucose (G(-))

Figure 32 shows image fixations of selected-MDA-MB231 cells and selected-MCF7 cells stained with crystal violet stain.

Figure 33 shows the results of measurements of the effect of compound S101 on cancer cell death after glucose deprivation using the TUNEL fluorescence assay.

The figure 34 shows the changes in tumor volume when treating cancer cells with S101 and 2DG alone or in combination.

Figure 35 shows the mass and size of the resected tumor when treating cancer cells with S101 and 2DG alone or in combination.

Figure 36 shows changes in body weight between respective groups when evaluating anti-cancer effects in the case of treatment of cancer cells with S101 and 2DG alone or in combination in xenograft model s-231.

Figure 37 is an image showing whether liver tissue is degraded or not to determine the degree of cytotoxicity in the case of treatment of cancer cells with S101 and 2DG alone or in combination.

BEST MODE FOR CARRYING OUT THE INVENTION

The advantages and features of the present invention and methods for achieving them will become apparent upon review of the embodiments described in detail below with the accompanying drawings. However, the present invention is not limited to the embodiments disclosed below, and can be practiced in various forms. Therefore, it should be understood that the embodiments described in the invention are presented only to fully disclose the present invention and give full information to those of ordinary skill in the field of technology to which the present invention relates, the scope of the present invention, which is defined only by paragraphs invention formulas.

In this invention, the term "independently" indicates that independently applied variables vary regardless of one application or another. It follows that in compounds such as R ^a XYR ^a , when R ^a is "independently carbon or nitrogen", both R ^a can be carbon, both R ^a can be nitrogen, or one R ^a can be carbon and the other R ^a may be nitrogen.

Unless otherwise indicated in this invention, the term "alkyl" generally refers to a saturated straight or branched hydrocarbon chain C ₁ ~C ₁₀ alkyl, more specifically, a saturated straight or branched hydrocarbon chain C ₁ ~C ₆ alkyl. "C ₁ ~C ₁₀ alkyl" refers to straight or branched alkyl having 1 to 10 carbon atoms. Specifically, alkyl includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3-methylpentyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl, and others. similar alkyls. The term includes both substituted and unsubstituted alkyl groups. The alkyl group may be optionally 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 attached to alkyl carbon atoms may be, for example, substituted with one or more halogen atoms such as fluorine, chlorine, or both, resulting in trifluoromethyl, difluoromethyl, fluorochloromethyl, and the like. haloalkyls. A hydrocarbon chain may also include a heteroatom in the middle of it, such as N, O, or S.

The term "alkaryl" or "alkylaryl" refers to an alkyl group having an aryl substituent. The term "aralkyl" or "arylalkyl" refers to an aryl group having an alkyl substituent, eg, benzyl.

As used in this invention, the term "halogen" includes chlorine, bromine, iodine and fluorine.

Unless otherwise indicated in this invention, the term "alkyl" as used in the invention refers to "C ₁ ~C ₆ alkyl", and "C ₁ ~C ₆ alkyl" refers to a linear or branched alkyl having from 1 to 6 carbon atoms , and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl, hexyl, and the like, but the present invention is not limited to these alkyls. In the invention, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl are preferred.

Unless otherwise indicated in this invention, the term "alkoxy" as used in the invention refers to "C ₁ ~C ₆ alkoxy", and "C ₁ ~C ₆ alkoxy" refers to a linear or branched alkoxy having from 1 to 6 carbon atoms. , and includes methoxy, ethoxy, propoxy, isopropoxy, butoxy groups, and other similar alkoxy groups, but the present invention is not limited to these alkoxy groups.

Unless otherwise indicated in this invention, the term "alkenyl" as used in the invention refers to "C ₂ ~C ₆ alkenyl", and "C ₂ ~C ₆ alkenyl" refers to a linear or branched alkenyl having from 2 to 6 carbon atoms and containing one double bond, and includes vinyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl, and other similar alkenyls, but the present invention is not limited to these alkenyls.

Unless otherwise indicated in this invention, the term "alkynyl" as used in the invention refers to "C ₂ ~C ₆ alkynyl", and "C ₂ ~C ₆ alkynyl" refers to a linear or branched alkynyl having 2 to 6 carbon atoms. and containing one triple bond, and includes ethynyl, propynyl, butynyl, isobutynyl, pentynyl, hexynyl and other similar alkynyls, but the present invention is not limited to these alkynyls.

Unless otherwise indicated in this invention, the term "cycloalkyl" as used in the invention refers to "C ₃ ~C ₁₀ cycloalkyl", and "C ₃ ~C ₁₀ cycloalkyl" refers to cyclic alkyl having 3 to 10 carbon atoms in the ring , and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, and the like. The terms "C ₃ ~C ₈ cycloalkyl", "C ₃ ~C ₇ cycloalkyl" and "C ₃ ~C ₆ cycloalkyl" have similar meanings. A cycloalkyl group may have a ring substituted with an alkyl group, resulting in cyclopropylmethyl and other similar cycloalkyls.

Unless otherwise indicated in this invention, the term "aryl" as used in the invention refers to a "C ₆ -C ₁₂ aryl group", and "C ₆ -C ₁₂ aryl group" refers to a phenyl, biphenyl or naphthyl having 6 to 12 carbon atoms and does not contain a heteroatom in the ring. Preferably the aryl is phenyl. The term includes both substituted and unsubstituted moieties. "Substituted aryl" may be substituted with one or more substituents including unprotected or protected hydroxyl, halogen, amino, alkylamino, arylamino, C ₁ ~C ₆ alkyl, C ₁ ~C ₆ alkoxy, C ₃ ~C ₆ cycloalkyl, C ₁ ~C ₆ haloalkyl, C ₁ ~C ₆ haloalkoxy, oxo, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphoric acid, phosphate, or phosphonate as needed, but the present invention is not limited to these substituents. The term "C ₆ ~C ₁₀ aryl group" has a similar meaning.

As used in this invention, the term "heteroaryl" or "heterocyclic" refers to a "3-12 membered heterocyclic group", and the term "3-12 membered heterocyclic" refers to a saturated or unsaturated 3-12 membered ring group containing in the ring a heteroatom selected from oxygen, sulfur and nitrogen. For example, a heterocyclic group is dioxol. The term "3-10 membered heterocyclic" has a similar intended meaning. In this invention, "substituted heteroaryl" may be substituted with one or more substituents, including unsubstituted or substituted hydroxyl, halogen, amino, alkylamino, arylamino, C ₁ ~C ₆ alkyl, C ₁ ~C ₆ alkoxy, C ₃ ~C ₆ cycloalkyl, C ₁ ~C ₆ haloalkyl, C ₁ ~C ₆ haloalkoxy, oxo, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphoric acid, phosphate, or phosphonate as needed, but the present invention is not limited to these substituents.

As used in this invention, the term "alkylene" refers to a divalent hydrocarbyl group. In this case, the alkylene can be bonded to two other groups, since alkylene is divalent. In general, it is -(CH ₂ )n- where n ranges from 1 to 8, preferably when n ranges from 1 to 4. In specific cases, alkylene may also be substituted with other groups and may have different lengths, and the available valences do not have to be at opposite ends of the chain.

In general, any alkyl, alkenyl, alkynyl, aryl, alkylaryl, or arylalkyl used as a substituent may itself optionally be substituted with other additional substituents. Unless otherwise stated in the invention, the nature of these substituents is similar to that described for the primary substituents themselves.

As used in this invention, the term "heteroatom" refers to an atom that is not carbon or hydrogen, such as nitrogen, oxygen or sulfur. When a heteroatom is part of the backbone or backbone of a chain and ring, the heteroatom must be at least divalent, and can be selected, in most cases, from N, O, P, and S.

As used in this invention, the term "may be substituted" or "substituted" indicates that a particular group(s), which is referred to as optionally substituted, may have no non-hydrogen substituents, or that a particular group(s) may have one or more non-hydrogen substituents whose chemical and pharmacological activity corresponds to the activity of the resulting molecules. Unless otherwise indicated, the total number of these substituents that may be present in a particular group(s) is exactly the same as the total number of hydrogen atoms present in the unsubstituted form of the described group(s) and may be present in fewer than the maximum number of these substituents. . When an optional substituent is linked through a double bond, such as carbonyl oxygen (C=O), this group uses the two available valences on the carbon atoms to which the optional substituent is attached. Therefore, the total number of substituents that can be introduced into a group decreases depending on the number of available valences. In this invention, the term "substituted" indicates that one or more hydrogen atoms are each independently replaced by substituent(s) that are the same or different from each other, when the term is used in relation to the modification of said groups, moieties or radicals, or is used as part of the term "may be substituted" or otherwise.

Since the compounds described in this invention may have one or more chiral centers and/or double bonds, the compounds may exist as stereoisomers, for example, double bond isomers (i.e., geometric isomers, for example, E and Z), enantiomers, or diastereomers. In addition, the present invention includes each isolated individual stereoisomeric form (e.g., enantiomerically pure isomers, E and Z isomers, and other variants of stereoisomers) and mixtures of stereoisomers having different chiral purities and percentages of E and Z (unless they are specified as specific stereoisomers). ). Therefore, the chemical structures described herein encompass all possible enantiomers and stereoisomers of the compounds described, including pure stereoisomeric forms (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure forms), enantiomeric mixtures, and stereoisomeric mixtures. Enantiomeric mixtures and stereoisomeric mixtures can be separated into their respective enantiomeric or stereoisomeric components using separation techniques or chiral synthesis techniques well known in the art. The present invention also encompasses isolated individual stereoisomeric forms and mixtures of stereoisomers having different chiral purities, including a racemic mixture. The present invention also covers various diastereomers. Obviously, for the sake of convenience, other structures can be used to represent a particular isomer. Therefore, it should be understood that the present application is in no way limited as such to the particular isomers described. If the chemical name does not indicate the isomeric form of the compound, then this name refers to all possible isomeric forms of the compound or mixtures thereof.

In addition, as used in this specification and the following claims, the words "comprise", "comprising", "include", "comprising", "comprising", and "encompassing" are intended to indicate the presence of the claimed distinguishing features, integers , components, or steps, but does not preclude the presence or addition of one or more other distinguishing features, integers, components, steps, or groups.

Next, examples of embodiments of the present invention will be described.

According to one embodiment of the present invention, there is provided a compound represented by the following formula 1, or a pharmaceutically acceptable salt thereof.

[Formula 1]

A compound of formula 1 may be represented by the following formula 2.

[Formula 2]

A compound of formula 1 may be represented by the following formula 3, formula 4, formula 5, or formula 6.

[Formula 3]

[Formula 4]

[Formula 5]

[Formula 6]

In formulas 1-6, R ₁ is hydrogen, linear or branched alkyl, alkoxy, haloalkyl, haloalkoxy, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, each of which may be independently substituted with at least one substituent selected from hydroxyl, halogen, C ₁ ~C ₆ alkyl, C ₁ ~C ₆ alkoxy, C ₃ ~C ₆ cycloalkyl, C ₁ ~C ₆ haloalkyl, C ₁ ~C ₆ haloalkoxy, oxo, cyano, unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl.

Specifically, R ₁ is hydrogen, C ₁ ~C ₆ linear alkyl, C ₃ ~C ₆ branched alkyl, C ₁ ~C ₆ alkoxy, C ₁ ~C ₆ haloalkyl, C ₁ ~C ₆ haloalkoxy, aryl, heteroaryl, alkyl (C ₁ ~C ₆ ) aryl or alkyl(C ₁ ~C ₆ ) heteroaryl, each of which may be independently substituted with at least one substituent selected from hydroxyl, halogen, C ₁ ~C ₆ alkyl, C ₁ ~C ₆ alkoxy, C ₃ ~C ₆ cycloalkyl, C ₁ ~C ₆ haloalkyl, C ₁ ~C ₆ haloalkoxy, oxo, cyano, unsubstituted or substituted C ₆ ~C ₁₀ aryl or unsubstituted or substituted C ₅ ~C ₁₀ heteroaryl .

More specifically, R ₁ is hydrogen, unsubstituted or substituted C ₁ ~C ₆ linear alkyl, unsubstituted or substituted benzyl, or unsubstituted or substituted 2-phenylethyl, where substituted C ₁ ~C ₆ linear alkyl may be substituted with C ₃ ~C ₆ cycloalkyl, and substituted benzyl or substituted 2-phenylethyl may be substituted with halogen in at least one of the ortho, meta and para positions, or may be substituted with phenyl.

More specifically, R ₁ is hydrogen, C ₁ ~C ₆ linear alkyl, C ₃ ~C ₆ branched alkyl, C ₃ ~C ₆ cycloalkyl,

where X ₁ can be hydrogen, halogen, C ₁ ~C ₃ linear alkyl, CF ₃ , CN, NO ₂ or aryl.

In formulas 1-6, R ₃ is hydrogen, C ₁ ~C ₆ linear alkyl, C ₃ ~C ₆ branched alkyl, C ₃ ~C ₆ cycloalkyl, aryl, heteroaryl, alkyl(C ₁ ~C ₆ ) aryl, or alkyl (C ₁ ~C ₆ ) heteroaryl, each of which may be independently substituted with at least one substituent selected from hydroxyl, halogen, C ₁ ~C ₆ alkyl, C ₁ ~C ₆ alkoxy, C ₁ ~C ₆ haloalkyl, C ₁ ~C ₆ haloalkoxy, oxo, cyano, unsubstituted or substituted C ₆ ~C ₁₀ aryl, or unsubstituted or substituted C ₅ ~C ₁₀ heteroaryl.

Specifically, R ₃ is hydrogen, unsubstituted or substituted C ₁ ~C ₆ linear alkyl, unsubstituted or substituted C ₁ ~C ₆ alkoxy, halogen, or unsubstituted or substituted 2-phenylethyl, where substituted 2-phenylethyl may be substituted with halogen, at least one of the ortho, meta and para positions, and substituted C ₁ ~C ₆ alkoxy may be substituted with phenyl or benzyl.

More specifically, R ₃ is hydrogen, unsubstituted or substituted C ₁ ~C ₆ linear alkyl, unsubstituted or substituted C ₁ ~C ₆ alkoxy, halogen, or unsubstituted or substituted 2-phenylethyl, where substituted 2-phenylethyl may be substituted with halogen , at least one of the ortho, meta and para positions, and substituted C ₁ ~C ₆ alkoxy can be substituted with phenyl or benzyl.

More specifically, R ₃ is hydrogen, C ₁ ~C ₃ linear alkyl, unsubstituted or substituted C ₁ ~C ₃ alkoxy, halogen,

where X ₄ represents hydrogen or halogen, and substituted C ₁ ~C ₃ alkoxy may be substituted with phenyl or benzyl.

In formulas 1-6, R ₂ is hydrogen, linear alkyl, cycloalkyl, alkoxy, haloalkoxy, haloalkyl, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, each of which may be independently substituted with at least one substituent selected from hydroxyl, halogen, C ₁ ~C ₆ alkyl, C ₁ ~C ₆ alkoxy, C ₁ ~C ₆ haloalkyl, C ₁ ~C ₆ haloalkoxy, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, oxo, nitro, cyano or trifluoromethyl .

R ₂ specifically represents C ₁ ~C ₆ linear alkyl, C ₃ ~C ₆ cycloalkyl, C ₁ ~C ₆ alkoxy, C ₁ ~C ₆ haloalkoxy, C ₁ ~C ₆ haloalkyl, aryl, heteroaryl, alkyl(C ₁ ~ C ₆ ) aryl or alkyl(C ₁ ~C ₆ ) heteroaryl, each of which may be independently substituted with at least one substituent selected from hydroxyl, halogen, C ₁ ~C ₆ alkyl, C ₁ ~C ₆ alkoxy, C ₁ ~C ₆ haloalkyl, C ₁ ~C ₆ haloalkoxy, unsubstituted or substituted C ₆ ~C ₁₀ aryl, unsubstituted or substituted C ₅ ~C ₁₀ heteroaryl, oxo, nitro, cyano, or trifluoromethyl.

R ₂ is more specifically hydrogen, unsubstituted or substituted C ₁ ~C ₆ linear alkyl, unsubstituted or substituted benzyl, or unsubstituted or substituted 2-phenylethyl, where the substituted linear alkyl is substituted with halogen, the substituted benzyl is substituted with halogen, C ₁ ~ C ₃ linear alkyl, trifluoromethyl, cyano, nitro, C ₁ ~C ₃ alkoxy or aryl in at least one of the ortho, meta and para positions, and 2-phenylethyl is substituted with halogen in at least one of ortho, meta and a pair of positions.

More specifically, R ₂ is hydrogen, unsubstituted or substituted C ₁ ~C ₆ linear alkyl, unsubstituted or substituted C ₁ ~C ₃ alkoxy,

where substituted C ₁ ~C ₆ linear alkyl substituted with halogen.

In Formulas 1-6, R ₄ and R ₄ ' are each independently hydrogen, linear or branched alkyl, cycloalkyl, alkenyl, alkynyl, alkylthio, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, each of which may be independently substituted with, at least one substituent selected from hydroxyl, halogen, C ₁ ~C ₆ alkyl, C ₁ ~C ₆ alkoxy, C ₁ ~C ₆ haloalkyl, C ₁ ~C ₆ haloalkoxy, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, oxo, nitro, cyano or trifluoromethyl.

Specifically, R ₄ and R ₄ ' are each independently hydrogen, C ₁ ~C ₆ linear alkyl, C ₃ ~C ₆ branched alkyl, C ₃ ~C ₆ cycloalkyl, C ₂ ~C ₆ alkenyl, C ₂ ~C ₆ alkynyl , C ₁ ~C ₆ alkylthio, aryl, heteroaryl, alkyl(C ₁ ~C ₆ ) aryl, or alkyl(C ₁ ~C ₆ ) heteroaryl, each of which may be independently substituted with at least one substituent selected from hydroxyl, halogen, C ₁ ~C ₆ alkyl, C ₁ ~C ₆ alkoxy, C ₁ ~C ₆ haloalkyl, C ₁ ~C ₆ haloalkoxy, unsubstituted or substituted C ₆ ~C ₁₀ aryl, unsubstituted or substituted C ₅ ~C ₁₀ heteroaryl, oxo, nitro, cyano or trifluoromethyl.

More specifically, R ₄ and R ₄ ' are each independently hydrogen, unsubstituted or substituted C ₁ ~C ₆ linear alkyl, C ₃ ~C ₆ branched alkyl, C ₃ ~C ₆ cycloalkyl, C ₂ ~C ₆ alkynyl, C ₁ ~C ₆ alkylthio, unsubstituted or substituted benzyl, 2-naphthylmethyl or 1-naphthylmethyl, where the substituted linear alkyl may be substituted with methylthio, alkynyl, or benzyloxycarbonylamino, and the substituted benzyl may be substituted with halogen, aryl, nitro, cyano, C ₁ ~C ₃ alkoxy, trifluoromethyl, or benzyloxy in at least one of the ortho, meta, and para positions.

More specifically, R ₄ and R ₄ ' each independently represents hydrogen, unsubstituted or substituted C ₁ ~C ₄ linear alkyl, C ₃ ~C ₄ branched alkyl, C ₃ ~C ₆ cycloalkyl,

where substituted C ₁ ~C ₄ linear alkyl is substituted with C ₃ ~C ₆ cycloalkyl.

R ₂ and R ₄ can be connected to form a 5-10 membered monocyclic or bicyclic ring, where R ₄ ' can be hydrogen.

In formulas 1-6, L ₁ is C ₁ ~C ₁₀ alkylene, where alkylene can be substituted with at least one substituent selected from C ₁ ~C ₆ alkyl, C ₃ ~C ₆ cycloalkyl, C ₁ ~C ₆ alkoxy, hydroxyl, oxo or halogen, and C ₁ ~C ₆ alkyl, C ₃ ~C ₆ cycloalkyl and C ₁ ~C ₆ alkoxy may be substituted with unsubstituted or substituted aryl. Specifically, L ₁ is C ₁ ~C ₄ alkylene, where alkylene can be substituted with hydrogen, oxo, hydroxyl, C ₁ ~C ₄ alkoxy or C ₁ ~C ₄ alkyl, and C ₁ ~C ₄ alkoxy can be substituted with benzyl. More specifically, L ₁ is C ₁ ~C ₄ alkylene, where alkylene can be substituted with hydrogen, oxo, hydroxyl, C ₁ ~C ₄ alkyl, or .

In formula 1, Q may be S, Se, NR, P, P(O), P(O) ₂ or P(O)OR.

In Formulas 1-6, R is hydrogen, linear or branched alkyl, cycloalkyl, bi- or tricycloalkyl, alkoxy, haloalkyl, haloalkoxy, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, each of which may be independently substituted with at least , one substituent selected from hydroxyl, halogen, C ₁ ~C ₆ alkyl, C ₁ ~C ₆ alkoxy, C ₁ ~C ₆ haloalkyl, C ₁ ~C ₆ haloalkoxy, oxo, cyano, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl. Specifically, R may be hydrogen, unsubstituted or substituted C ₁ ~C ₄ linear alkyl,

In formulas 1-6, m may be an integer 1 or 2, and n may be an integer in the range of 1 to 4. Specifically, m and n may be 1.

In Formula 1, X, Y, and Z are each independently hydrogen, linear or branched alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, each of which may be independently substituted with at least one substituent selected from hydroxyl , halogen, C ₁ ~C ₆ alkyl, C ₁ ~C ₆ alkoxy, C ₁ ~C ₆ haloalkyl, C ₁ ~C ₆ haloalkoxy, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, oxo, nitro, cyano or trifluoromethyl.

The compound of the present invention may include one or more compounds selected from the group consisting of compounds whose formulas are presented in table 1 below.

[Table 1]

As used in this invention, the term "treatment" refers to a therapeutic, prophylactic or non-permanent method of treatment or method of prevention. As used in this invention, the term "prophylaxis" refers to any action of suppressing the onset of cancer or delaying the onset of cancer upon administration of a pharmaceutical composition. For the purposes of the present invention, beneficial or desirable clinical results include, but are not limited to, detectable or non-detectable relief of symptoms, reduction in disease severity, stable (i.e., unabated) disease state, slow progression or delay in disease progression, or mitigation, improvement, no need for permanent treatment, or alleviation of the course of the disease, or remission (partial or complete). "Treatment" can also mean an increase in survival compared to expected survival without any treatment. Subjects in need of treatment include subjects who are already suffering from a disease state or disorder, or subjects in whom the disease state or disorder has been prevented, as well as subjects who are predisposed to the occurrence of the disease state or disorder.

As used in this invention, the expression "therapeutically effective amount" or "effective amount" refers to an amount of a compound of formula I that is sufficient (i) to treat or prevent a particular disease, condition or disorder, (ii) to reduce, improve or alleviate one or more symptoms of a particular disease, condition or disorder, or (iii) to prevent or delay the onset of one or more symptoms of a particular disease, condition or disorder described in the invention, when a compound of Formula I is administered to a mammal in need of such treatment. The amount of compound corresponding to such an effective amount will depend on factors such as the particular compound, the condition of the disease and its severity, and the characteristic (eg, body weight) of the mammal in need of treatment. In this case, the amount of the compound can be determined in the usual way by a person skilled in the art.

Used in this invention, the terms "cancer" and "cancerous" usually refers to a physiological condition or expresses a physiological condition of a mammal, which is characterized by abnormal or uncontrolled cell growth. "Tumor" includes one or more cancer cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia, or malignant lymphoid tumor. More specific examples of such cancers include squamous cell carcinoma (eg, epithelial squamous cell carcinoma), lung cancer (including small cell lung cancer, non-small cell lung cancer (“NSCLC”), adenocarcinoma of the lung, and squamous cell carcinoma of the lung), peritoneal cancer, hepatocellular ulcer, cancer stomach or gastrointestinal tract, including gastric cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial carcinoma or uterus, salivary gland carcinoma, kidney cancer or nephritic syndrome, prostate cancer, vaginal cancer, thyroid cancer, hepatocarcinoma, anal carcinoma, penile carcinoma, skin cancer, including melanoma, and head and neck cancer.

As used in this invention, the term “pharmaceutically acceptable” indicates that the substance or composition is chemically and/or toxicologically compatible with the mammal being treated with it and/or with other components included in the medicinal product.

As used in this invention, the term “pharmaceutically acceptable salt” refers to a pharmaceutically acceptable organic or inorganic salt of a compound of the present invention.

Used in this invention "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt of the compounds described in this invention. Examples of this salt include, but are not limited to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate , bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate (mesylate), ethanesulfonate, ethanedisulfonate, benzenesulfonate, p- toluenesulfonate and pamoate (i.e. 1, 1'-methylene -bis-(2-hydroxy-3-naphthoate)) salts. A pharmaceutically acceptable salt contains an inclusion of another molecule, such as acetate ions, succinate ions, or other counterions. Counterions can be any organic or inorganic moiety that stabilizes the charge of the parent compound. In addition, a pharmaceutically acceptable salt may have more than one charged atom in its structure. In the case where a plurality of charged atoms are included in a pharmaceutically acceptable salt portion, the pharmaceutically acceptable salt may have a plurality of counterions. Therefore, a pharmaceutically acceptable salt may have one or more charged atoms and/or one or more counterions.

According to one embodiment of the present invention, there is provided a pharmaceutical composition for the prevention or treatment of cancer, which comprises a compound represented by formula 1, or a pharmaceutically acceptable salt, hydrate, solvate, structural isomer, optical isomer, or stereoisomer, or a combination thereof. The compound represented by Formula 1 or a pharmaceutically acceptable salt thereof has an effect of inhibiting cancer activity when used as a monotherapy.

According to one embodiment of the present invention, there is provided a pharmaceutical composition for the prevention or treatment of resistant cancer, which comprises a compound represented by formula 1, or a pharmaceutically acceptable salt, hydrate, solvate, structural isomer, optical isomer, or stereoisomer, or a combination thereof. The compound represented by Formula 1 or a pharmaceutically acceptable salt thereof has an effect of inhibiting cancer activity when used in combination with an anti-cancer drug or radiation therapy for a resistant cancer.

According to one embodiment of the present invention, the cancer or resistant cancer may include one or more types of cancer selected from the group consisting of ovarian cancer, colorectal cancer, pancreatic cancer, gastrointestinal cancer, liver cancer, breast cancer, 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, cancer skin, head and neck cancers, uterine cancer, rectal cancer, brain cancer, anal cancer, fallopian tube carcinoma, endometrial carcinoma, vaginal cancer, female vulvar carcinoma, esophageal cancer, small intestine cancer, endocrine gland carcinoma , adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, ureteral cancer, renal cell carcinoma, renal pelvis carcinoma, leukemia, central nervous system (CNS) tumor, spinal cord tumor, brainstem glioma, and pituitary adenoma.

According to one embodiment of the present invention, the anticancer agent may include one or more anticancer agents selected from the group consisting of nitrogen mustard, imatinib, oxaliplatin, rituximab, erlotinib, neratinib, lapatinib, gefitinib, vandetanib, nilotinib, semaxanib, bosutinib, axitinib, masitinib, cediranib, lestaurtinib, trastuzumab, gefitinib, bortezomib, sunitinib, pazopanib, toceranib, nintedanib, regorafenib, semaxanib, tivozanib, ponatinib, cabozantinib, carboplatin, sorafenib, lenvatinib, bevacizumab, cisplatin, cetuximab, viscum album, asparaginase, tretinoin, hydroxyurea , dasatinib, estramustine, gemtuzumab ozogamicin, ibritumomab tiuxetan, heptaplatin, methylaminolevulinic acid, amsacrine, alemtuzumab, procarbazine, alprostadil, chitosan holmium nitrate, gemcitabine, doxifluridine, pemetrexed, tegafur, capecitabine a, gimeracil, oteracil, azacitidine, methotrexate, uracil, cicitarabin, fluorouracil, fludarabine, enocytabin, flutamide, capecitabine, decitabine, mercaptopurine, thioguanine, cladribine, carmofur, raltitrexed, doxetaxel, paclitaxel, cabazitaxel, irinotecan, belotecan, topotecan, vinorelbine, etoposide, vincristine, vinblastine, teniposide, doxorubicin, idarubicin, epirubicin, mitoxantrone, mitomycin, bleomycin, daunorubicin, dactinomycin, pyrarubicin, aclarubicin, pepromycin, temsirolimus, temozolomide, busulfan, ifosfamide, cyclophosphamide, melphalan, altretamine, dacabazine, thiotepa, nimustine, chlorambucil, mitolactol, leucovore ina, tretonin, exmestan, aminoglutethimide, anagrelide, olaparib, navelbine, padrazole, tamoxifen, toremifene, testolactone, anastrozole, letrozole, borozol, bicalutamide, lomustine, vorinostat, entinostat, and carmustine.

The pharmaceutical composition according to one embodiment of the present invention may include a compound represented by formula 1 or a pharmaceutically acceptable salt thereof and an anticancer drug in a concentration ratio of 1:0.001 to 1:1000 moles, 1:0.01 to 1:100 moles, 1:0.1 to 1:50 moles or 1:0.1 to 1:20 moles.

The pharmaceutical composition according to one embodiment of the present invention may be in the form of a capsule, tablet, granule, injection, ointment, powder, or beverage.

The pharmaceutical composition according to one embodiment of the present invention may be formulated and administered in an oral form (such as powder, granule, capsule, tablet, aqueous suspension, and the like), in an external preparation, in a suppository form. and injection solution.

The pharmaceutical composition according to one embodiment of the present invention may include a pharmaceutically acceptable carrier. A pharmaceutically acceptable carrier may be mixed and used with a binder, lubricant, disintegrant, excipient, solubilizer, dispersing agent, stabilizer, suspending agent, pigment or flavoring agent in the case of oral administration, and in the case of injectable preparations, with a buffer, preservative, analgesic agent, solubilizer, isotonic agent or stabilizer, and in the case of topical application, with a base, excipient, lubricant or preservative. The composition of the pharmaceutical composition according to one embodiment of the present invention may be mixed with a pharmaceutically acceptable carrier and prepared in various forms. For example, for oral administration, the pharmaceutical composition of the present invention may be in the form of a tablet, lozenge, capsule, elixir, suspension, syrup, wafer, or the like, and may be in the form of a single dose ampoule or dosage form for repeated administration in case of injection. In addition, the pharmaceutical composition of the present invention can be prepared in the form of a solution, suspension, tablet, capsule, sustained release preparation, and the like.

The carrier, excipient and diluent for preparing the dosage form may include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, mineral oil, bulking agent, anticoagulant, lubricant, humectant, fragrance, emulsifier, preservative, or the like.

One embodiment of the present invention relates to a pharmaceutical composition comprising a compound represented by formula 1 of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient in combination with a pharmaceutically acceptable adjuvant and/or excipient.

In the present invention, the term "adjuvant" refers to a substance that can cause, increase or modify a specific reaction with the active ingredient of the present invention when administered simultaneously or sequentially. For example, known injectable adjuvants include aluminum compounds (eg, aluminum hydroxide or aluminum phosphate), saponins (eg, QS21), muramyl dipeptide or muramyl tripeptide, proteins (eg, gamma interferon or TNF), M59, squalene, or polyol.

The route of administration of the pharmaceutical composition according to one embodiment of the present invention may include oral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, intracardial, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, sublingual or rectal administration, but the present invention is not limited to these methods. .

The pharmaceutical composition according to one embodiment of the present invention may be administered orally or parenterally. For parenteral administration, administration methods such as external application to the skin, intraperitoneal injection, rectal administration, subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection can be selected.

The dosage of the pharmaceutical composition according to one embodiment of the present invention may vary depending on the patient's condition and body weight, disease severity, drug type, route of administration, and duration of administration period, and may be appropriately selected by one of ordinary skill in the art. For example, a pharmaceutical composition according to one embodiment of the present invention may be administered daily at a dose of 0.0001 to 1000 mg/kg or 0.001 to 500 mg/kg. The pharmaceutical composition of the present invention may be administered once daily or in divided doses. It is intended that the values of this dose in no way limit the scope of the present invention.

In addition, the present invention provides the use of a compound represented by formula 1, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

In addition, the present invention provides the use of a compound represented by formula 1, or a pharmaceutically acceptable salt thereof, for use in the treatment of resistant cancer.

In addition, the present invention provides the use of a compound represented by formula 1, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer stem cells.

The resistant cancer and the compound represented by formula 1 or a pharmaceutically acceptable salt thereof are the same as those described above and, therefore, their detailed description will be omitted hereinafter.

In addition, the present invention provides a method for treating cancer or a resistant form of cancer, which comprises: administering a therapeutically effective amount of a compound represented by Formula 1, or a pharmaceutically acceptable salt, hydrate, solvate, structural isomer, optical isomer, or stereoisomer, or a combination thereof, to a subject with resistant cancer. When administered, the chemotherapeutic agents used to treat cancer or a proliferative disease may be administered simultaneously, separately or sequentially.

The term "administration" refers to the administration of a predetermined substance to a subject using a suitable method.

"Subject with resistant cancer" refers to a subject who has developed a resistant form of cancer or who has a high probability of developing a resistant form of cancer and therefore needs appropriate treatment, and may be a subject who has already received anticancer therapy , for example, surgical removal of a tumor, chemotherapy using an anti-cancer drug, radiation therapy, or immunotherapy, but who has been found to relapse due to resistance to the therapies mentioned above.

The resistant cancer subject may be a human, a cow, a dog, a guinea pig, a rabbit, a chicken, an insect, or the like. Specifically, the cancer-resistant subject may be a mammal such as a human, a cow, a horse, a dog, a sheep, a goat, a cat, or other similar mammal. The subject may be a subject who has developed cancer or is highly likely to develop cancer.

In addition, the present invention provides a method of radiation therapy, which includes: administering the above-described compound represented by formula 1, or a pharmaceutically acceptable salt thereof, to a subject with resistant cancer, and irradiating the subject with radioactive radiation.

The resistant cancer, the subject with the resistant cancer, and the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof are the same as those described above and, therefore, their detailed description will be omitted hereinafter.

For radiation irradiation, any irradiation method conventionally used for cancer radiation therapy or a radiation irradiation method that may be developed in the future can be applied.

When the administration of the compound represented by formula 1 of the present invention or a pharmaceutically acceptable salt thereof is used in combination with radiation irradiation, a synergistic effect of inhibiting the growth of cancer cells or cancer stem cells and/or inducing cell death can be achieved, whereby not only effective prevention or treatment of cancer is achieved, but also prevention of resistance to radiation therapy or metastasis or recurrence of cancer.

METHOD FOR CARRYING OUT THE INVENTION

Synthesis examples

The compounds shown in Table 1 were prepared using the method described in the Synthesis Example below.

[Formula 7]

2-((2-ethylbenzothiophen-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione was prepared by carrying out the 10-step reaction described below. The synthesis method for each step was described in detail as follows.

1) Stage 1

[Diagram 1]

As shown in Scheme 1, benzothiophene (1.0 equivalent) was cooled to -78°C in the presence of tetrahydrofuran solvent, and a solution of 2.5M n-butyllithium (1.2 equivalent) was added. The resulting mixture was stirred for one hour while maintaining the temperature at -78°C, and ethyl iodide (2.0 equivalents) was added dropwise and stirred at 0°C for one hour. The completion of the reaction was confirmed, and the reaction was terminated by using an aqueous solution of ammonium chloride and ethyl acetate. The organic layer was washed with distilled water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 2-ethyl benzothiophene.

2) Stage 2

[Diagram 2]

2-ethyl benzothiophene (1.0 equivalent) was added to methylene chloride (MC) and cooled to 0°C, and while maintaining the temperature at 0°C, tin(IV) chloride (1.5 equivalents) and dichloromethyl methyl ether (1, 5 equivalents), and then stirred for one hour. The completion of the reaction was confirmed, and the reaction was terminated by using an aqueous solution of ammonium chloride and methylene chloride. 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 give 2-ethyl-1-benzothiophene-3-carbaldehyde.

3) Stage 3

[Diagram 3]

Added piperazine-2-carboxylic acid (1.0 equivalent), dioxane and distilled water and cooled to 5°C or below. Ditert-butyl dicarbonate (1.1 equivalents) was then added while maintaining the temperature at 10° C. or lower. The resulting mixture was stirred at room temperature for 5 hours and then sodium carbonate (1.1 equivalents) was added and stirred for 5 minutes. 9-fluorenylmethyl chloroformate (1.2 equivalents) was added, stirred overnight, and then concentrated under reduced pressure. Ethyl acetate and 1 M hydrochloric acid were added to the residue, and the pH of the resulting mixture was adjusted to pH 2-3. The mixture was then vigorously stirred until the residue was completely dissolved. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. Recrystallization was carried out in the organic layer with EA to give 1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid.

4) Stage 4

[Diagram 4]

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 methylene chloride was cooled to 0°C in a stream of nitrogen. Diethyl azodicarboxylate (DEAD) (1.02 equivalents) was added and stirred for one hour while maintaining the temperature at 0°C or below. Water was added and the resulting mixture was vigorously stirred for 20 minutes. Then, the organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 1-((9H-fluoren-9-yl)methyl)2-benzyl 4-(tert-butyl)piperazine-1,2,4-tricarboxylate.

5) Stage 5

[Diagram 5]

As shown in Scheme 5, trifluoroacetic acid (TFA) (2.0 volumes) was added to a solution of 1-((9H-fluoren-9-yl)methyl) 2-benzyl 4-(tert-butyl)piperazin-1,2,4- tricarboxylate in methylene chloride (5.0 volumes) at room temperature and stirred at room temperature for 30 minutes. The resulting mixture was neutralized with sodium bicarbonate and then extracted with methylene chloride, and the organic layer was washed with brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give 1-((9H-fluoren-9-yl)methyl) 2-benzyl piperazine-1,2-dicarboxylate.

6) Stage 6

[Diagram 6]

2-ethyl-1-benzothiophene-3-carbaldehyde (1.0 equivalent) obtained in step 2 and 1-((9H-fluoren-9-yl)methyl) 2-benzyl piperazine-1,2-dicarboxylate (1 2 equivalents) obtained in step 5 was added to 1,2-dichloroethane (DCE) at room temperature and then stirred for 30 minutes. Sodium triacetoxyborohydride (3.0 equivalents) was added and the resulting mixture was stirred overnight at room temperature. Methylene chloride 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 give 1-((9H-fluoren-9-yl)methyl)2-benzyl 4-((2-ethylbenzothiophen-3-yl)-methyl)piperazin- 1,2-dicarboxylate.

7) Stage 7

[Diagram 7]

At room temperature, 1-((9H-fluoren-9-yl)methyl) 2-benzyl 4-((2-ethylbenzothiophen-3-yl)methyl)piperazin-1,2-di-carboxylate (1.0 equivalent) was dissolved in dimethylformamide and then piperidine (10 equivalents; 25% piperidine in solvent) was added and stirred for one hour. Then, ethyl acetate, piperidine in solution were added to the reaction mixture, washed with an aqueous solution of ammonium chloride. The resulting reaction solution was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was then purified by silica gel chromatography to obtain benzyl 4-((2-ethylbenzothiophen-3-yl)methyl)piperazine-2-carboxylate.

8) Stage 8

[Diagram 8]

At room temperature, benzyl 4-((2-ethylbenzofuran-3-yl)methyl)piperazine-2-carboxylate (1.0 equivalent), N-(tert-butoxycarbonyl)glycine (1.1 equivalent) and (benzotriazole-1 -yloxy)tripyrrolidinophosphonium hexafluorophosphate (1.2 equivalents) was dissolved in dimethylformamide and N,N-diisopropyl-ethylamine (1.5 equivalents) was added and stirred overnight at room temperature. The reaction was terminated by using an aqueous solution of ammonium chloride and ethyl acetate. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel chromatography to give benzyl 1-((tert-butoxycarbonyl)glycyl)-4-((2-ethylbenzothiophen-3-yl)methyl)piperazine-2-carboxylate.

9) Stage 9

[Diagram 9]

As shown in Scheme 9, benzyl 1-((tert-butoxycarbonyl)-glycyl)-4-((2-ethylbenzothiophen-3-yl)methyl)piperazine-2-carboxylate obtained in step 8 was dissolved in methylene chloride (5.0 volumes ) at room temperature, and then trifluoroacetic acid (2.0 vol) was added and stirred at room temperature for 30 minutes. After the reaction was completed, the reaction solution was neutralized with an aqueous sodium bicarbonate solution and extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give benzyl 4-((2-ethylbenzothiophen-3-yl)methyl)-1-glycylpiperazine-2-carboxylate.

10) Stage 10

[Diagram 10]

Benzyl 4-((2-ethylbenzothiophen-3-yl)methyl)-1-glycylpiperazine-2-carboxylate obtained in step 9 was dissolved in isopropanol (5.0 vol) and then acetic acid (1.5 vol) was added, heated and stirred for one hour. After completion of the reaction, the resulting reaction solution was neutralized with an aqueous sodium bicarbonate solution. The reaction solution was extracted with methylene chloride and dried over anhydrous magnesium sulfate. After the reaction solution was concentrated under reduced pressure, the residue was purified by silica gel chromatography to obtain 2-((2-ethylbenzothiophen-3-yl)methyl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6,9-dione (S101 ).

[Formula 7]

S101

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.82 (d, J=8.0 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.34-7.31 (m, 1H), 7.29-7.25 (m, 1H), 4.50-4.46 (m, 1H), 4.07 (d, J=10.0 Hz, 1H), 4, 00 (s, 2H), 3.81-3.67 (m, 2H), 3.48 (d, J=10.5 Hz, 1H), 2.94 (q, J=7.5 Hz, 2H ), 2.86 (d, J=11.5 Hz, 1H), 2.74-2.69 (m, 1H), 2.17 (t, J=11.0 Hz, 1H), 2.10 -2.05 (m, 1H), 1.33 (t, J=7.5 Hz, 3H).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 166.10, 161.85, 146.58, 140.52, 138.09, 125.68, 124.02, 123.78, 122.22, 122.19 , 56.99, 56.38, 53.28, 51.39, 44.61, 41.59, 22.13, 16.20.

MS (ESI) m/z for C ₁₈ H ₂₁ N ₃ O ₂ S [M+H] ⁺ : calculated 344.1427, found 344.1423.

[Formula 8]

S102

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.83 (d, J=8.0 Hz, 1H), 7.76 (d, J=8.0 Hz, 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(kv, J=7.5Hz, 2H), 2.86-2.82 (m, 1H), 2.72-2.67 (m, 1H), 2.13 (q, J=11.0 Hz, 1H), 2.08-2 .02 (m, 1H), 1.48 (dd, J=7.0 Hz, 19.0 Hz, 3H), 1.33 (t, J=7.5 Hz, 3H).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 166.06, 165.96, 165.49, 165.41, 146.44, 140.56, 138.09, 125.83, 123.99, 123.75 , 122.26, 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.

MS (ESI) m/z for C ₁₉ H ₂₃ N ₃ O ₂ S [M+H] ⁺ : calculated 358.1584, found 358.1579.

[Formula 9]

S103

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.82 (d, J=8.0 Hz, 1H), 7.75 (d, J=8.0 Hz, 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 (kv, J=7.5 Hz, 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=7.5 Hz, 3H), 0.97-0.90 (m, 6H).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 165.93, 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.

MS (ESI) m/z for C ₂₂ H ₂₉ N ₃ O ₂ S [M+H] ⁺ : calculated 400.2053, found 400.4056.

[Formula 10]

S105

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.82 (d, J=8.0 Hz, 1H), 7.76 (d, J=8.0 Hz, 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, 1H), 3.55-3.49 (m, 1H), 2.94 (kv, J=7.5 Hz, 2H), 2.85-2.83 (m, 1H), 2.68-2.63 (m, 1H), 2.14-2.00 (m, 2H), 1.85-1.57 (m, 4H), 1.56-1.40 (m, 1H ), 1.35-1.05 (m, 9H).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 166.71, 166.08, 164.96, 163.41, 146.42, 140.54, 138.09, 128.59, 127.62, 127.04 , 125.83, 124.00, 123.76, 122.24, 122.17, 60.21, 59.81, 57.40, 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.

MS (ESI) m/z for C ₂₄ H ₃₁ N ₃ O ₂ S [M+H] ⁺ : calculated 426.2210, found 426.2210.

[Formula 11]

S106

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.83-7.76 (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=7.5 Hz, 2H), 2.88-2.70 (m, 4H), 2.24-2.02 (m, 3H), 1.34 (t, J=7, 5 Hz, 3H).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 165.73, 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.

MS (ESI) m/z for C ₂₁ H ₂₃ N ₃ O ₂ S [M+H] ⁺ : calculated 382.1584, found 382.1594.

[Formula 12]

S107

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.84-7.82 (m, 1H), 7.76 (d, J=8.0 Hz, 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=10.5 Hz, 1H), 2.95 (kv, J=7.5 Hz, 2H), 2.85 (d, J=10.5 Hz, 1H), 2.72-2.66 (m, 1H), 2.61 (t, J= 7.5 Hz, 1H), 2.60-2.55 (m, 1H), 2.25-2.11 (m, 3H), 2.09-2.02 (m, 4H), 1.33 (t, J=7.5 Hz, 3H).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 166.13, 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.

MS (ESI) m/z for C ₂₁ H ₂₇ N ₃ O ₂ S ₂ [M+H] ⁺ : calculated 418.1618, found 418.1618.

[Formula 13]

S108

¹ H NMR ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.82-7.75 (m, 2H), 7.32-7.25 (m, 7H), 6.56-6.52 (m, 1H), 4.46 (t, J=11.5 Hz, 1H), 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).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 163.43, 162.88, 140.38, 138.02, 137.42, 128.94, 128.79, 128.77, 128.57, 127.52 , 127.46, 127.00, 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.

MS (ESI) m/z for C ₂₆ H ₂₉ N ₃ O ₂ S ₂ [M+H] ⁺ : calculated 480.1774, found 480.1782.

[Formula 14]

S109

¹ H NMR (500 MHz, CDCl ₃ ) 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)

¹³ C NMR (126 MHz, CDCl ₃ ) δ 167.03, 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, 122.22, 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.

MS (ESI) m/z for C ₂₁ H ₂₅ N ₃ O ₂ S [M+H] ⁺ : calculated 384.1740, found 384.1746.

[Formula 15]

S111

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.76-7.71 (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=13.0 Hz, 65.5 Hz, 1H), 3.44 (dd, J=13.0 Hz, 27 .5 Hz, 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).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 166.56, 165.99, 164.52, 162.74, 146.41, 146.22, 140.55, 140.52, 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.

MS (ESI) m/z for C ₂₅ H ₂₇ N ₃ O ₂ S [M+H] ⁺ : calculated 434.1897, found 434.1895.

[Formula 16]

S112

¹ H-NMR (500 MHz, CDCl ₃ ) δ 7.78-7.72 (m, 2H), 7.39 (d, J=8.0 Hz, 1H), 7.34-7.25 (m , 3H), 7.18 (d, J=8.5 Hz, 1H), 7.09 (d, J=8.5 Hz, 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) .

¹³ C NMR (126 MHz, CDCl ₃ ) δ 164.18, 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.

MS (ESI) m/z for C ₂₅ H ₂₆ ClN ₃ O ₂ S [M+H] ⁺ : calculated 468.1507, found 468.1507.

[Formula 17]

S113

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.79-7.72 (m, 2H), 7.54 (d, J=8.0 Hz, 1H), 7.44 (d, J=8, 5 Hz, 1H), 7.36-7.23 (m, 2H), 7.13 (d, J=8.0 Hz, 1H), 7.03 (d, J=8.0 Hz, 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).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 164.16, 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.

MS (ESI) m/z for C ₂₅ H ₂₆ BrN ₃ O ₂ S [M+H] ⁺ : calculated 512.1002, found 512.1002.

[Formula 18]

S114

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.77-7.72 (m, 2H), 7.37-7.24 (m, 2H), 7.22-7.19 (m, 1H), 7.13-7.08 (m, 2H), 7.00 (t, J=8.5 Hz, 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).

¹³ C NMR (126 MHz, CDCl3) δ 164.19, 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, 123.88, 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.

MS (ESI) m/z for C ₂₅ H ₂₆ FN ₃ O ₂ S [M+H] ⁺ : calculated 452.1803, found 452.1798.

[Formula 19]

S115

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.78-7.72 (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).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 163.79, 162.28, 146.43, 140.39, 140.35, 137.98, 137.95, 132.03, 131.96, 128.56 127.64 127.01 126.01 123.96 123.92 123.69 122.07 119.82 119.69 118.95 118.81 117.60 117 .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.

MS (ESI) m/z for C ₂₅ H ₂₅ F ₂ N ₃ O ₂ S [M+H] ⁺ : calculated 470.1708, found 470.1702.

[Formula 20]

S116

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.77-7.71 (m, 2H), 7.68-7.65 (m, 1H), 7.58-7.55 (m, 1H), 7.38-7.35 (m, 1H), 7.31-7.21 (m, 3H), 4.43-4.31 (m, 2H), 3.85-3.82 (m, 0 .5H), 3.65 (dd, J=13.0 Hz, 65.0 Hz, 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).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 166.34, 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.

MS (ESI) m/z for C ₂₆ H ₂₆ F ₃ N ₃ O ₂ S [M+H] ⁺ : calculated 502.1771, found 502.1758.

[Formula 21]

S117

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.77-7.70 (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=13.0 Hz, 54.0 Hz, 1H), 3.53-3.43 (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).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 166.19, 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.

MS (ESI) m/z for C ₂₆ H ₂₆ N ₄ O ₂ S [M+H] ⁺ : calculated 459.1849, found 459.1833.

[Formula 22]

S118

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.26-8.23 (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=13.0 Hz, 52.5 Hz, 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).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 166.24, 165.90, 163.51, 162.06, 147.58, 147.54, 146.51, 146.47, 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.

MS (ESI) m/z for C ₂₅ H ₂₆ N ₄ O ₄ S [M+H] ⁺ : calculated 479.1748, found 479.1732.

[Formula 23]

S119

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.74-7.18 (m, 13H), 4.47-4.30 (m, 2H), 3.86-3.80 (m, 0.5H ), 3.63 (dd, J=13.0 Hz, 71.0 Hz, 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=7.5 Hz, 1.5H), 1.07 (t, J=7.5 Hz, 1, 5H).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 166.68, 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.

MS (ESI) m/z for C ₃₁ H ₃₁ N ₃ O ₂ S [M+H] ⁺ : calculated 510.2210, found 510.2193.

[Formula 24]

S120

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.77-7.71 (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=13.0 Hz, 68.5 Hz, 1H), 3.45 (dd, J=13.0 Hz, 45.5 Hz, 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=7.5 Hz, 1.5H), 1.25 (t, J=7.5 Hz, 1.5H).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 166.61, 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.

MS (ESI) m/z for C ₃₂ H ₃₃ N ₃ O ₃ S [M+H] ⁺ : calculated 540.2315, found 540.2292.

[Formula 25]

S121

¹ H-NMR (500 MHz, CDCl ₃ ) δ 8.18 (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).

¹³ C-NMR (126 MHz, CDCl ₃ ) δ165.62, 165.56, 164.56, 163.23, 146.28, 146.09, 140.45, 140.42,

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

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

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.

MS (ESI) m/z for C ₂₉ H ₂₉ N ₃ O ₂ S [M+H] ⁺ : calculated 484.2053, found 484.2047

[Formula 26]

S122

¹ H-NMR (500 MHz, CDCl ₃ ) δ 7.94-7.89 (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), 2.75-2.57( m, 3H), 2.48-2.38 (m, 2H), 2.00-1.92 (m, 1H), 1.27-1.22 (m, 3H);

¹³ C-NMR (126 MHz, CDCl ₃ ) δ 166.20, 165.90, 164.42, 162.50, 146.27, 145.95, 140.42, 140.33, 137.93, 137, 85, 133.70, 133.42, 132.68, 132.57, 132.51, 132.42, 129.74, 129.18, 128.90, 128.42, 128.13, 127.93, 127.73 127.61 127.60 126.50 126.47 126.11 125.70 125.66 123.83 123.67 123.57 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.

MS (ESI) m/z for C ₂₉ H ₂₉ N ₃ O ₂ S [M+H] ⁺ : calculated 484.2053, found 484.2044

[Formula 27]

S126

¹ H-NMR (500 MHz, CDCl ₃ ) δ 7.83 (d, J=8.0 Hz, 1H), 7.77 (d, J=8.0 Hz, 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=11.0 Hz, 1H), 3.80 (d, J=13.0 Hz, 1H), 3.70-3.3.63 (m, 2H), 3. 51 (d, J=11.0 Hz, 1H), 2.94 (q, J=7.5 Hz, 2H), 2.85 (d, J=11.5 Hz, 1H), 2.69- 2.62 (m, 1H), 2.18 (t, J=11.0 Hz, 1H), 2.01-1.95 (m, 1H), 1.33 (t, J=7.5 Hz , 3H), 1.09 (s, 9H);

¹³ C-NMR (126 MHz, CDCl ₃ ) δ165.63, 162.11, 146.27, 140.48, 138.01, 125.81, 123.90, 123.65, 122.16, 122.07 , 63.52, 57.83, 56.32, 53.18, 51.81, 41.76, 36.62, 29.69, 26.71, 22.02, 16.10.

MS (ESI) m/z for C ₂₂ H ₂₉ N ₃ O ₂ S [M+H] ⁺ : calculated 400.2053, found 400.2053.

[Formula 28]

S127

¹ H-NMR (500 MHz, CDCl ₃ ) δ 7.81 (d, J=8.0 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.40-7, 31 (m, 6H), 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=13.0 Hz, 1H), 3.67-3.59 (m, 1H), 3.56-3.49 (m, 1H) , 2.97-2.89 (m, 2H), 2.83-2.75 (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);

¹³ C-NMR (126 MHz, CDCl ₃ ) δ 166.10, 165.36, 163.45, 162.75, 146.35, 140.46, 140.44, 138.01, 137.98, 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.

MS (ESI) m/z for C ₂₄ H ₂₅ N ₃ O ₂ S [M+H] ⁺ : calculated 420.1740, found 420.1740.

[Formula 29]

S128

¹ H-NMR (500 MHz, CDCl ₃ ) δ 7.82 (d, J=8.0 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.32-7, 23 (m, 2H), 4.66 (d, J=13.0 Hz, 1H), 4.48-4.43 (m, 1H), 4.03 (d, J=10.5 Hz, 1H ), 3.83-3.76 (m, 2H), 3.62 (d, J=13.0 Hz, 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=13.0 Hz, 1H), 2.10-1.97 (m, 3H), 1.70 (t, J=13.0 Hz, 1H), 1.61 -1.52(m, 1H), 1.43-1.37(m, 2H), 1.32-1.29(m, 3H);

¹³ C-NMR (126 MHz, CDCl ₃ ) δ 164.20, 163.98, 162.15, 162.09, 146.28, 146.27, 140.52, 140.49, 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.

MS (ESI) m/z for C ₂₂ H ₂₇ N ₃ O ₂ S [M+H] ⁺ : calculated 398.1897, found 398.1891.

[Formula 30]

S135

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.84 (d, J=7.5 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.34-7.26 (m, 2H), 7.24-7.13 (m, 4H), 5.46 (d, J=17.0 Hz, 1H), 4.53-4.53 (m, 1H), 4, 24-4.19 (m, 2H), 4.16-4.11 (m, 1H), 3.84 (d, J=13.0 Hz, 1H), 3.67 (d, J=13, 0 Hz, 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=11.0 Hz, 1H), 2.10-2.04 (m, 1H), 1.34 (t, J=7.5 Hz, 3H).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 163.56, 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.

MS (ESI) m/z for C ₂₆ H ₂₇ N ₃ O ₂ S [M+H] ⁺ : calculated 446.1896, found 446.1889.

[Formula 31]

S136

¹ H-NMR (500 MHz, CDCl ₃ ) δ 7.83-7.81 (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=13.0 Hz, 1H), 3.64 (d, J=13.0 Hz, 1H), 3, 57-3.54 (m, 1H), 3.34 (d, J=13.0 Hz, 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=11.5 Hz, 1H), 2.04-1 .96 (m, 2H), 1.32 (t, J=7.5 Hz, 3H), 1.17 (s, 9H).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 167.28, 162.95, 146.28, 140.52, 138.00, 125.93, 123.87, 123.61, 122.24, 122.03 , 74.48, 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.

MS (ESI) m/z for C ₂₅ H ₃₃ N ₃ O ₃ S [M+H] ⁺ : calculated 456.2315, found 465.2308.

[Formula 32]

S141

¹ H NMR (700 MHz, CDCl ₃ ) δ 7.75-7.68 (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), 1.89-1.83 (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).

¹³ C NMR (176 MHz, CDCl ₃ ) 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.

MS (ESI) m/z for C ₃₂ H ₃₉ N ₃ O ₂ S [M+H] ⁺ : calculated 530.2836, found 530.2824.

[Formula 33]

S142

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.75-7.68 (m, 2H), 7.40-7.22 (m, 10H), 7.13 (d, J=8.0 Hz, 1H), 7.02 (d, J=7.5 Hz, 1H), 5.69 (d, J=14.5 Hz, 0.5H), 5.53 (d, J=14.5 Hz, 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=13.0 Hz, 81.0 Hz, 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).

¹³ C NMR (176 MHz, CDCl ₃ ) 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, 127.50, 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.

MS (ESI) m/z for C ₃₂ H ₃₃ N ₃ O ₂ S [M+H] ⁺ : calculated 524.2366, found 524.2364.

[Formula 34]

S151

¹ H NMR (700 MHz, CDCl ₃ ) δ 7.85 (d, J=5.5 Hz, 1H), 7.76 (d, J=6.0 Hz, 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=9.5 Hz, 1H), 3.71 (d, J=3.0 Hz, 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=5.5 Hz, 3H), 1.22-1.10 (m, 7H), 0.98-0.87 (m, 2H).

¹³ C NMR (176 MHz, CDCl ₃ ) δ 165.49, 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 .

MS (ESI) m/z for C ₃₁ H ₄₃ N ₃ O ₂ S [M+H] ⁺ : calculated 522.3154, found 522.3143.

[Formula 35]

S152

¹ H NMR (700 MHz, CDCl ₃ ) δ 7.86-7.83 (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).

¹³ C NMR (176 MHz, CDCl ₃ ) δ165.34, 165.00, 164.24, 162.08, 146.27, 146.21, 140.53, 140.48, 138.02, 137.99, 135.77, 135.53, 128.92, 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.

MS (ESI) m/z for C ₃₁ H ₃₇ N ₃ O ₂ S [M+H] ⁺ : calculated 516.2679, found 516.2677.

[Formula 36]

S201

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.83 (d, J=7.5 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.32 (t, J =7.5 Hz, 1H), 7.26 (t, J=7.5 Hz, 1H), 4.47 (d, J=13.0 Hz, 1H), 4.05 (d, J=11 .0 Hz, 1H), 3.97 (s, 2H), 3.79 (d, J=13.0 Hz, 1H), 3.65 (d, J=13.0 Hz, 1H), 3, 54 (d, J=11.5 Hz, 1H), 2.97-2.91 (m, 5H), 2.82 (d, J=11.5 Hz, 1H), 2.69 (dt, J =3.5, 12.5 Hz, 1H), 2.11 (d, J=11.3 Hz, 1H), 2.03 (dt, J=3.5, 12.0 Hz, 1H), 1 .33 (t, J=7.5 Hz, 3H).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 163.75, 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.

MS (ESI) m/z for C ₁₉ H ₂₃ N ₃ O ₂ S [M+H] ⁺ : calculated 358.1584, found 358.1576.

[Formula 37]

S202

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.83 (d, J=8.0 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.32 (t, J =7.5 Hz, 1H), 7.26 (t, J=7.5 Hz, 1H), 4.46 (d, J=13.5 Hz, 1H), 4.04 (d, 11.0 Hz, 1H), 3.96 (d, J=3.0 Hz, 2H), 3.79 (d, J=13.0 Hz, 1H), 3.65 (d, J=13.0 Hz, 1H), 3.54 (d, J=11.0 Hz, 1H), 3.43 (m, 2H), 2.94 (q, J=7.5 Hz, 2H), 2.82 (d, J=11.5 Hz, 1H), 2.69 (dt, J=3.0, 12.5 Hz, 1H), 2.11 (d, J=11.5 Hz, 1H), 2.03 ( dt, J=3.0, 11.5 Hz, 1H), 1.33 (t, J=7.5 Hz, 3H), 1.15 (t, J=7.3 Hz, 3H).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 163.21, 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.

MS (ESI) m/z for C ₂₀ H ₂₅ N ₃ O ₂ S [M+H] ⁺ : calculated 372.1740, found 372.1734.

[Formula 38]

S203

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.83 (d, J=8.0 Hz, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.32 (t, J =7.5 Hz, 1H), 7.26 (t, J=7.5 Hz, 1H), 4.45 (d, J=13.0 Hz, 1H), 4.05 (d, 11.0 Hz, 1H), 3.96 (s, 2H), 3.80 (d, J=13.0 Hz, 1H), 3.65 (d, J=13.0 Hz, 1H), 3.55 ( d, J=11.5 Hz, 1H), 3.37 (t, J=7.5 Hz, 2H), 2.94 (m, 2H), 2.82 (d, J=11.0 Hz, 1H), 2.69 (dt, J=3.5, 12.5 Hz, 1H), 2.11 (d, J=11.0 Hz, 1H), 2.03 (dt, J=3.0 , 11.0 Hz, 1H), 1.54 (m, J=3.6 Hz, 2H), 1.33 (t, J=7.5 Hz, 5H), 0.94 (t, J=7 .5 Hz, 3H).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 163.45, 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.

MS (ESI) m/z for C ₂₂ H ₂₉ N ₃ O ₂ S [M+H] ⁺ : calculated 400.2053, found 400.2042.

[Formula 39]

S204

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.83 (d, J=8.0 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.32 (t, J =7.5 Hz, 1H), 7.26 (t, J=7.5 Hz, 1H), 4.46 (d, J=13.0 Hz, 1H), 4.04 (d, 11.0 Hz, 1H), 3.96 (s, 2H), 3.79 (d, J=13.0 Hz, 1H), 3.65 (d, J=13.0 Hz, 1H), 3.55 ( d, J=11.0 Hz, 1H), 3.39-3.34 (m, 2H), 2.97-2.91 (m, 2H), 2.82 (d, J=11.5 Hz , 1H), 2.69 (dt, J=3.5, 12.5 Hz, 1H), 2.11 (t, J=11.3 Hz, 1H), 2.03 (dt, J=3, 5, 12.0 Hz, 1H), 1.58-1.51 (m, 2H), 1.33 (t, J=7.5 Hz, 3H), 1.29 (s, 6H) 0.89 (t, J=6.5 Hz, 3H).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 163.42, 162.09, 146.51, 140.69, 138.20, 126.01, 124.10, 123.85, 122.42, 122.26 , 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.

MS (ESI) m/z for C ₂₄ H ₃₃ N ₃ O ₂ S [M+H] ⁺ : calculated 428.2366, found 428.2352.

[Formula 40]

S206

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.84 (d, J=8.0 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.37-7.23 (m, 7H), 4.57 (dd, J=14.5, 32.0 Hz, 2H), 4.43 (d, J=13.0 Hz, 1H), 4.12 (d, J= 11.0 Hz, 1H), 3.86 (s, 2H), 3.81 (d, J=13.0 Hz, 1H), 3.66 (d, J=13.0 Hz, 1H), 3 .61 (d, J=11.0 Hz, 1H), 2.94 (q, J=7.5 Hz, 2H), 2.81 (d, J=11.0 Hz, 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=7.5 Hz, 3H).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 163.70, 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.

MS (ESI) m/z for C ₂₅ H ₂₇ N ₃ O ₂ S [M+H] ⁺ : calculated 434.1897, found 434.1892.

[Formula 41]

S207

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.84 (d, J=8.0 Hz, 1H), 7.76 (d, J=8.0 Hz, 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=13.0 Hz, 1H), 4.11 (d, J=11 Hz, 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(kv, J=7 .5 Hz, 2H), 2.81 (d, J=10.0 Hz, 1H), 2.67 (dt, J=3.5, 12.5 Hz, 1H), 2.33 (s, 3H ), 2.15 (t, J=11.0 Hz, 1H), 2.02 (dt, J=3.5, 11.5 Hz, 1H), 1.33 (t, J=7.5 Hz , 3H).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 163.61, 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.

MS (ESI) m/z for C ₂₆ H ₂₉ N ₃ O ₂ S [M+H] ⁺ : calculated 448.2053, found 448.2055.

[Formula 42]

S208

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.84 (d, J=8.0 Hz, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.35-7.30 (m, 3H), 7.27 (t, J=7.5 Hz, 1H), 7.20 (d, J=8.5 Hz, 2H), 4.53 (dd, J=14.5, 27.0 Hz, 2H), 4.44 (d, J=13.0 Hz, 1H), 4.12 (d, J=11.0 Hz, 1H), 3.86 (s, 2H), 3 .81 (d, J=13.0 Hz, 1H), 3.67 (d, J=13.0 Hz, 1H), 3.59 (d, J=11.5 Hz, 1H), 2.98 -2.91 (m, 2H), 2.82 (d, J=11.5 Hz, 1H), 2.69 (dt, J=3.0, 12.5 Hz, 1H), 2.15 ( t, J=11.5 Hz, 1H), 2.04 (dt, J=3.0, 11.5 Hz, 1H), 1.34 (t, J=7.5 Hz, 3H).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 163.79, 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.

MS (ESI) m/z for C ₂₅ H ₂₆ ClN ₃ O ₂ S [M+H] ⁺ : calculated 468.1507, found 468.1477.

[Formula 43]

S209

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.83 (d, J=8.0 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.47 (d, J =8.0 Hz, 2H), 7.33 (t, J=7.5 Hz, 1H), 7.27 (t, J=7.5 Hz, 1H), 7.13 (d, J=8 .0 Hz, 2H), 4.51 (dd, J=14.5, 24.0 Hz, 2H), 4.43 (d, J=13.5 Hz, 1H), 4.11 (d, J =10.5 Hz, 1H), 3.85 (s, 2H), 3.81 (d, J=13.0 Hz, 1H), 3.67 (d, J=13.0 Hz, 1H), 3.59 (d, J=11.0 Hz, 1H), 2.98-2.91 (m, 2H), 2.82 (d, J=11.5 Hz, 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=7.5 Hz, 3H).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 163.80, 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.

MS (ESI) m/z for C ₂₅ H ₂₆ BrN ₃ O ₂ S [M+H] ⁺ : calculated 512.1002, found 512.0997.

[Formula 44]

S210

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.84 (d, J=8.0 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.33 (t, J =7.5 Hz, 1H), 7.29-7.22 (m, 3H), 7.03 (t, J=8.5 Hz, 2H), 4.53 (dd, J=14.5, 36.0 Hz, 2H), 4.43 (d, J=13.0 Hz, 1H), 4.11 (d, J=11.0 Hz, 1H), 3.85 (s, 2H), 3 .81 (d, J=13.0 Hz, 1H), 3.67 (d, J=13.0 Hz, 1H), 3.59 (d, J=11.5 Hz, 1H), 2.94 (kv, J=7.0 Hz, 2H), 2.82 (d, J=11.5 Hz, 1H), 2.68 (dt, J=3.0, 12.5 Hz, 1H), 2 .15 (t, J=11.0 Hz, 1H), 2.03 (dt, J=3.5, 12.0 Hz, 1H), 1.33 (t, J=7.5 Hz, 3H) .

¹³ C NMR (126 MHz, CDCl ₃ ) 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.

MS (ESI) m/z for C ₂₅ H ₂₆ FN ₃ O ₂ S [M+H] ⁺ : calculated 452.1803, found 452.1781.

[Formula 45]

S211

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.84 (d, J=7.5 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.61 (d, J =8.0 Hz, 2H), 7.38 (d, J=8.0 Hz, 2H), 7.33 (t, J=7.5 Hz, 1H), 7.27 (t, J=7 .5 Hz, 1H), 4.62 (s, 2H), 4.44 (d, J=13.0 Hz, 1H), 4.14 (d, J=11.0 Hz, 1H), 3, 87 (s, 2H), 3.81 (d, J=13.0 Hz, 1H), 3.68 (d, J=13.0 Hz, 1H), 3.60 (d, J=11.0 Hz, 1H), 2.98-2.92 (m, 2H), 2.83 (d, J=11.5 Hz, 1H), 2.60 (dt, J=3.0, 12.5 Hz , 1H), 2.16 (t, J=11.0 Hz, 1H), 2.04 (dt, J=3.0, 12.0 Hz, 1H), 1.34 (t, J=7, 5 Hz, 3H).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 163.94, 161.55, 146.60, 140.67, 139.29, 138.24, 131.13, 130.87, 130.61, 130.35 128.92 127.38 126.22 126.19 126.16 126.13 125.92 125.21 124.13 123.90 123.05 122.40 122 .32, 57.54, 57.04, 53.43, 51.32, 49.20, 49.03, 41.68, 22.27, 16.35.

MS (ESI) m/z for C ₂₆ H ₂₆ F ₃ N ₃ O ₂ S [M+H] ⁺ : calculated 502.1771, found 502.1766.

[Formula 46]

S212

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.83 (d, J=8.0 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.64 (d, J =8.5 Hz, 2H), 7.36 (d, J=8.5 Hz, 2H), 7.33 (t, J=7.5 Hz, 1H), 7.30-7.25 (m , 1H), 4.61 (d, J=3.0 Hz, 2H), 4.44 (d, J=13.5 Hz, 1H), 4.14 (d, J=8.5 Hz, 1H ), 3.88 (s, 2H), 3.81 (d, J=13.0 Hz, 1H), 3.68 (d, J=13.0 Hz, 1H), 3.58 (d, J =11.0 Hz, 1H), 2.98-2.92 (m, 2H), 2.84 (d, J=11.0 Hz, 1H), 2.71 (dt, J=3.0, 12.5 Hz, 1H), 2.16 (t, J=11.0 Hz, 1H), 2.06 (dt, J=3.0, 12.5 Hz, 1H), 1.34 (t, J=7.5 Hz, 3H).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 164.06, 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.

MS (ESI) m/z for C ₂₆ H ₂₆ N ₄ O ₂ S [M+H] ⁺ : calculated 459.1849, found 459.1828.

[Formula 47]

S213

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.20 (d, J=8.5 Hz, 2H), 7.84 (d, J=8.0 Hz, 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 .5 Hz, 1H), 4.66 (s, 2H), 4.45 (d, J=13.0 Hz, 1H), 4.16 (d, J=11.0 Hz, 1H), 3, 91 (s, 2H), 3.82 (d, J=13.0 Hz, 1H), 3.69 (d, J=13.0 Hz, 1H), 3.59 (d, J=11.0 Hz, 1H), 2.98-2.92 (m, 2H), 2.85 (d, J=11.5 Hz, 1H), 2.71 (dt, J=3.0, 12.5 Hz , 1H), 2.17 (t, J=11.5 Hz, 1H), 2.06 (dt, J=3.0, 12.0 Hz, 1H), 1.34 (t, J=7, 5 Hz, 3H).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 164.11, 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.

MS (ESI) m/z for C ₂₅ H ₂₆ N ₄ O ₄ S [M+H] ⁺ : calculated 479.1748, found 479.1727.

[Formula 48]

S214

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.84 (d, J=8.0 Hz, 1H), 7.76 (d, J=8.0 Hz, 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, 31.5 Hz, 2H), 4.44 (d, J=13.0 Hz, 1H), 4.13 (d, J=11.0 Hz, 1H), 3.90 (s, 2H), 3 .82 (d, J=13.0 Hz, 1H), 3.67 (d, J=13.0 Hz, 1H), 3.62 (d, J=11.0 Hz, 1H), 2.98 -2.92 (m, 2H), 2.82 (d, J=11.0 Hz, 1H), 2.68 (dt, J=3.0, 12.5 Hz, 1H), 2.18 ( t, J=11.3 Hz, 1H), 2.04 (dt, J=3.0, 12.0 Hz, 1H), 1.33 (t, J=7.5 Hz, 3H).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 163.75, 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.

MS (ESI) m/z for C ₃₁ H ₃₁ N ₃ O ₂ S [M+H] ⁺ : calculated 510.2210, found 510.2210.

[Formula 49]

S215

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.83 (d, J=8.0 Hz, 1H), 7.76 (d, J=7.5 Hz, 1H), 7.35-7.21 (m, 5H), 7.19 (d, J=7.0 Hz, 2H), 4.42 (d, J=13.0, 1H), 4.01 (d, J=11.0 Hz, 1H), 3.81-3.75 (m, 3H), 3.66-3.55 (m, 4H), 3.51 (d, J=11.0 Hz, 1H), 2.97-2 .86 (m, 3H), 2.81 (d, J=11.5 Hz, 1H), 2.67 (dt, J=3.0, 12.5 Hz, 1H), 2.04-1, 97 (m, 2H), 1.33 (t, J=7.5 Hz, 3H).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 163.54, 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.

MS (ESI) m/z for C ₂₆ H ₂₉ N ₃ O ₂ S [M+H] ⁺ : calculated 448.2053, found 448.2026.

[Formula 50]

S216

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.82 (d, J=8.0 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.33 (t, J =7.5Hz, 1H), 7.27(kv, J=7.5Hz, 1H), 7.15(dd, J=5.5, 8.0Hz, 2H), 6.99(t , J=8.5 Hz, 2H), 4.43 (d, J=13.0 Hz, 1H), 4.01 (d, J=11.0 Hz, 1H), 3.83 (s, 2H ), 3.78 (d, J=13.5 Hz, 1H), 3.65 (d, J=13.5 Hz, 1H), 3.63-3.52 (m, 2H), 3.50 (d, J=11.5 Hz, 1H), 2.97-2.91 (m, 2H), 2.88-2.80 (m, 3H), 2.68 (dt, J=3.5 , 12.5 Hz, 1H), 2.05-1.98 (m, 2H), 1.33 (t, J=7.5 Hz, 3H).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 163.58, 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.

MS (ESI) m/z for C ₂₆ H ₂₈ FN ₃ O ₂ S [M+H] ⁺ : calculated 466.1959, found 466.1935.

[Formula 51]

S218

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.83 (d, J=8.0 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.34-7.25 (m, 2H), 4.45 (d, J=13.0 Hz, 1H), 4.07 (d, J=11.0 Hz, 1H), 3.96 (s, 2H), 3.80 (d, J=13.0 Hz, 1H), 3.65 (d, J=13.0 Hz, 1H), 3.56 (d, J=11.0 Hz, 1H), 3.30-3 .15 (m, 2H), 2.94 (q, J=7.5 Hz, 2H), 2.82 (d, J=11.5 Hz, 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=7.5 Hz, 3H), 1.26-1.14 (m, 3H), 1.00-0.93 (m, 2H).

¹³ C NMR (176 MHz, CDCl ₃ ) δ 163.61, 161.95, 146.27, 140.48, 138.01, 125.81, 123.88, 123.63, 122.21, 122.04 , 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.

MS (ESI) m/z for C ₂₅ H ₃₃ N ₃ O ₂ S [M+H] ⁺ : calculated 440.2366, found 440.2360.

[Formula 52]

S221

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.06-8.03 (m, 1H), 7.91-7.89 (m, 1H), 7.85 (t, J=8.0 Hz, 2H), 7.78 (d, J=8.0 Hz, 1H), 7.76-7.52 (m, 2H), 7.45-7.39 (m, 2H), 7.34 (t , J=7.2 Hz, 1H), 7.29 (t, J=7.2 Hz, 1H), 5.12 (d, J=14.5, 1H), 5.06 (d, J= 14.5, 1H), 4.40 (d, J=13.0 Hz, 1H), 4.15 (d, J=11.0 Hz, 1H), 3.82 (d, J=13.0 Hz, 1H), 3.73 (s, 2H), 3.68-3.65 (m, 2H), 2.98-2.93 (m, 2H), 2.80 (d, J=11, 5 Hz, 1H), 2.69-2.63 (m, 1H), 2.15 (t, J=11.0 Hz, 1H), 2.02-1.97 (m, 1H), 1, 35 (t, J=7.5 Hz, 3H).

¹³ C NMR (176 MHz, CDCl ₃ ) δ 163.04, 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.

MS (ESI) m/z for C ₂₉ H ₂₉ N ₃ O ₂ S [M+H] ⁺ : calculated 484.2053, found 484.2053.

[Formula 53]

S222

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.86-7.80 (m, 4H), 7.77 (d, J=8.0 Hz, 1H), 7.71 (s, 1H), 7 .54-7.47 (m, 2H), 7.38-7.32 (m, 2H), 7.28 (t, J=7.5 Hz, 1H), 4.80 (d, J=14 .5, 1H), 4.70 (d, J=14.5, 1H), 4.44 (d, J=13.5 Hz, 1H), 4.16 (d, J=9.0 Hz, 1H), 3.91 (s, 2H), 3.83 (d, J=13.0 Hz, 1H), 3.68 (d, J=13.0 Hz, 1H), 3.64 (d, J=11.0 Hz, 1H), 2.98-2.93 (m, 2H), 2.83 (d, J=11.0 Hz, 1H), 2.72-2.67 (m, 1H ), 2.19 (t, J=11.3 Hz, 1H), 2.06-2.01 (m, 1H), 1.34 (t, J=7.5 Hz, 3H).

¹³ C NMR (176 MHz, CDCl ₃ ) δ 163.56, 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.

MS (ESI) m/z for C ₂₉ H ₂₉ N ₃ O ₂ S [M+H] ⁺ : calculated 484.2053, found 484.2041.

[Formula 55]

S224

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.84 (d, J=8.0 Hz, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.33 (t, J =7.5 Hz, 1H), 7.29 (d, J=7.5 Hz, 1H), 7.19 (d, J=8.5 Hz, 2H), 6.87 (d, J=8 .5 Hz, 2H), 4.57 (d, J=14.5 Hz, 1H), 4.47 (d, J=14.5 Hz, 1H), 4.44 (d, J=16.0 Hz, 1H), 4.11 (d, J=8.5 Hz, 1H), 3.85 (s, 2H), 3.82 (d, J=13.0 Hz, 1H), 3.80 ( s, 3H), 3.66 (d, J=13.0 Hz, 1H), 3.60 (d, J=11.0 Hz, 1H), 2.98-2.93 (m, 2H), 2.82 (d, J=11.5 Hz, 1H), 2.71-2.65 (m, 1H), 2.15 (t, J=11.3 Hz, 1H), 2.05-2 .00 (m, 1H), 1.34 (t, J=7.5 Hz, 3H).

¹³ C NMR (176 MHz, CDCl ₃ ) δ 163.35, 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.

MS (ESI) m/z for C ₂₆ H ₂₉ N ₃ O ₃ S [M+H] ⁺ : calculated 464.2002, found 464.1991.

[Formula 56]

S225

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.84 (d, J=8.0 Hz, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.33 (t, J =7.5 Hz, 1H), 7.28 (t, J=8.0 Hz, 1H), 6.39 (s, 3H), 4.56 (d, J=14.5 Hz, 1H), 4.48-4.42 (m, 2H), 4.13 (d, J=11.0 Hz, 1H), 3.88 (s, 2H), 3.81 (d, J=13.0 Hz , 1H), 3.78 (s, 6H), 3.67 (d, J=13.0 Hz, 1H), 3.60 (d, J=11.0 Hz, 1H), 2.97-2 .93 (m, 2H), 2.83 (d, J=11.5 Hz, 1H), 2.72-2.66 (m, 1H), 2.16 (t, J=11.3 Hz, 1H), 2.07-2.02 (m, 1H), 1.34 (t, J=7.8 Hz, 3H).

¹³ C NMR (176 MHz, CDCl ₃ ) δ 163.46, 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.

MS (ESI) m/z for C ₂₇ H ₃₁ N ₃ O ₄ S [M+H] ⁺ : calculated 494.2108, found 494.2101.

[Formula 58]

S301

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.95 (d, J=7.0 Hz, 1H), 7.86 (d, J=7.0 Hz, 1H), 7.40-7.35 (m, 2H), 7.30 (s, 1H), 6.25 (s, 1H), 4.52 (d, J=13.0 Hz, 1H), 4.12 (d, J=12, 5 Hz, 1H), 4.06 (s, 2H), 3.89 (d, J=13.5 Hz, 1H), 3.77 (d, J=13.5 Hz, 1H), 3.53 (d, J=11.0 Hz, 1H), 2.93 (d, J=11.5 Hz, 1H), 2.82-2.76 (m, 1H), 2.17 (t, J= 11.3 Hz, 1H), 2.12-2.07 (m, 1H).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 166.12, 161.93, 140.93, 138.87, 132.20, 125.27, 124.72, 124.23, 123.02, 122.83 , 57.12, 56.55, 56.49, 51.81, 44.81, 41.75.

MS (ESI) m/z for C ₁₆ H ₁₇ N ₃ O ₂ S [M+H] ⁺ : calculated 316.112, found 316.1115.

[Formula 59]

S302

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.81 (d, J=7.5 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.33 (t, J =7.5 Hz, 1H), 7.28 (d, J=7.5 Hz, 1H), 6.21 (s, 1H), 4.49 (d, J=13.0 Hz, 1H), 4.08 (d, J=11.0 Hz, 1H), 4.06 (s, 2H), 3.79 (d, J=13.0 Hz, 1H), 3.67 (d, J=13 .0 Hz, 1H), 3.50 (d, J=10.5 Hz, 1H), 2.86 (d, J=11.5 Hz, 1H), 2.76-2.70 (m, 1H ), 2.54 (s, 3H), 2.18 (t, J=11.3 Hz, 1H), 2.11-2.06 (m, 1H).

¹³ C NMR (176 MHz, CDCl ₃ ) δ 166.05, 161.70, 140.47, 138.58, 137.99, 126.71, 123.94, 123.69, 121.99, 121.89 , 56.96, 56.29, 53.25, 51.33, 44.54, 41.53, 14.07.

MS (ESI) m/z for C ₁₇ H ₁₉ N ₃ O ₂ S [M+H] ⁺ : calculated 330.1276, found 330.1273.

[Formula 60]

S303

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.84 (d, J=8.0 Hz, 1H), 7.76 (d, J=7.5 Hz, 1H), 7.33 (t, J =7.2 Hz, 1H), 7.28 (d, J=7.0 Hz, 1H), 6.23 (s, 1H), 4.49 (d, J=13.0 Hz, 1H), 4.09 (d, J=11.0 Hz, 1H), 4.06 (s, 2H), 3.80 (d, J=13.0 Hz, 1H), 3.67 (d, J=13 .0 Hz, 1H), 3.51 (d, J=12.0 Hz, 1H), 2.91 (t, J=7.8 Hz, 2H), 2.85 (d, J=11.5 Hz, 1H), 2.74-2.68 (m, 1H), 2.18 (t, J=11.3 Hz, 1H), 2.09-2.04 (m, 1H), 1.72 -1.66 (m, 2H), 1.46-1.38 (m, 2H), 0.95 (t, J=7.5 Hz, 3H).

¹³ C NMR (176 MHz, CDCl ₃ ) δ 166.09, 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.

MS (ESI) m/z for C ₂₀ H ₂₅ N ₃ O ₂ S [M+H] ⁺ : calculated 372.1746, found 372.1748.

[Formula 61]

S304

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.84 (d, J=8.0 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.32 (t, J =7.5 Hz, 1H), 7.27 (t, J=6.8 Hz, 1H), 6.71 (s, 1H), 4.49 (d, J=13.0 Hz, 1H), 4.08 (d, J=11.0 Hz, 1H), 4.05 (s, 2H), 3.80 (d, J=13.0 Hz, 1H), 3.66 (d, J=13 .0 Hz, 1H), 3.50 (d, J=11.0 Hz, 1H), 2.90 (t, J=7.5 Hz, 2H), 2.84 (d, J=11.5 Hz, 1H), 2.73-2.68 (m, 1H), 2.18 (t, J=11.0 Hz, 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 ).

¹³ C NMR (176 MHz, CDCl ₃ ) δ 166.06, 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.

MS (ESI) m/z for C ₂₂ H ₂₉ N ₃ O ₂ S [M+H] ⁺ : calculated 400.2059, found 400.2070.

[Formula 62]

S306

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.86 (d, J=8.0 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.35-7.31 (m, 2H), 7.30-7.26 (m, 3H), 7.25-7.22 (m, 2H), 4.45 (d, J=13.0 Hz, 1H), 4, 26 (d, J=3.5 Hz, 2H), 4.02-4.01 (m, 1H), 4.00 (s, 2H), 3.83 (d, J=13.0 Hz, 1H ), 3.71 (d, J=13.0 Hz, 1H), 3.46 (d, J=10.5 Hz, 1H), 2.82 (d, J=11.5 Hz, 1H), 2.68-2.62 (m, 1H), 2.12 (t, J=11.3 Hz, 1H), 2.04-1.99 (m, 1H).

¹³ C NMR (176 MHz, CDCl ₃ ) δ 166.07, 161.80, 142.67, 140.37, 139.55, 138.66, 128.63, 128.60, 127.25, 126.72 , 124.06, 124.01, 122.31, 122.16, 56.94, 56.34, 53.42, 51.35, 44.57, 41.52, 34.54.

MS (ESI) m/z for C ₂₃ H ₂₃ N ₃ O ₂ S [M+H] ⁺ : calculated 406.1589, found 406.1605.

[Formula 63]

S307

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.85 (d, J=8.0 Hz, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.35-7.30 (m, 2H), 7.27 (t, J=7.2 Hz, 1H), 7.11 (q, J=7.7 Hz, 3H), 4.46 (d, J=13.0 Hz , 1H), 4.22 (d, J=4.0 Hz, 2H), 4.03 (d, J=11.0 Hz, 1H), 4.00 (s, 2H), 3.83 (d , J=13.0 Hz, 1H), 3.71 (d, J=13.0 Hz, 1H), 3.47 (d, J=11.0 Hz, 1H), 2.83 (d, J =11.5 Hz, 1H), 2.70-2.64 (m, 1H), 2.31 (s, 3H), 2.13 (t, J=11.3 Hz, 1H), 2.05 -2.00 (m, 1H).

¹³ C NMR (176 MHz, CDCl ₃ ) δ 166.05, 161.77, 143.19, 140.39, 138.65, 136.48, 136.31, 129.32, 128.50, 127.02 , 124.01, 123.94, 122.29, 122.15, 56.96, 56.35, 53.42, 51.36, 44.57, 41.54, 34.15, 21.08.

MS (ESI) m/z for C ₂₄ H ₂₅ N ₃ O ₂ S [M+H] ⁺ : calculated 420.1746, found 420.1740.

[Formula 64]

S308

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.86 (d, J=8.0 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.34 (t, J =7.2 Hz, 1H), 7.29 (t, J=7.2 Hz, 1H), 7.24 (d, J=7.0 Hz, 2H), 7.16 (d, J=8 .0 Hz, 2H), 4.47 (d, J=13.0 Hz, 1H), 4.23 (d, J=3.5 Hz, 2H), 4.01 (s, 2H), 3, 99 (d, J=2.5 Hz, 1H), 3.80 (d, J=13.0 Hz, 1H), 3.71 (d, J=13.5 Hz, 1H), 3.43 ( d, J=10.5 Hz, 1H), 2.84 (d, J=11.5 Hz, 1H), 2.70-2.64 (m, 1H), 2.11-2.02 (m , 2H).

¹³ C NMR (176 MHz, CDCl ₃ ) δ 165.81, 162.58, 161.80, 141.87, 140.23, 138.57, 137.99, 132.47, 129.90, 128.71 , 127.48, 124.14, 122.30, 122.15, 56.89, 56.20, 53.36, 51.47, 44.54, 41.45, 33.82.

MS (ESI) m/z for C ₂₃ H ₂₂ ClN ₃ O ₂ S [M+H] ⁺ : calculated 440.12, found 440.1199.

[Formula 65]

S309

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.86 (d, J=7.5 Hz, 1H), 7.74 (d, J=7.5 Hz, 1H), 7.40 (d, J =8.0 Hz, 2H), 7.34 (t, J=7.2 Hz, 1H), 7.29 (t, J=7.2 Hz, 1H), 7.11 (d, J=8 .5 Hz, 2H), 4.47 (d, J=13.0 Hz, 1H), 4.22 (d, J=3.5 Hz, 2H), 4.03-3.97 (m, 3H ), 3.79 (d, J=13.0 Hz, 1H), 3.71 (d, J=13.0 Hz, 1H), 3.42 (d, J=11.0 Hz, 1H), 2.84 (d, J=11.5 Hz, 1H), 2.70-2.64 (m, 1H), 2.10-2.02 (m, 2H).

¹³ C NMR (176 MHz, CDCl ₃ ) δ 165.79, 162.57, 161.79, 141.72, 140.22, 138.56, 138.51, 131.65, 130.28, 127.52 , 124.14, 122.30, 122.15, 120.51, 56.88, 56.19, 53.36, 51.48, 44.53, 41.45, 33.88.

MS (ESI) m/z for C ₂₃ H ₂₂ BrN ₃ O ₂ S [M+H] ⁺ : calculated 484.0694, found 484.0660.

[Formula 66]

S310

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.87 (d, J=8.0 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.36-7.28 (m, 2H), 7.20 (dd, J=8.5, 5.5 Hz, 2H), 6.98 (t, J=8.5 Hz, 2H), 4.48 (d, J= 13.0 Hz, 1H), 4.24 (d, J=3.5 Hz, 2H), 4.01 (s, 3H), 3.82 (d, J=13.0 Hz, 1H), 3 .72 (d, J=13.0 Hz, 1H), 3.45 (d, J=11.0 Hz, 1H), 2.84 (d, J=11.5 Hz, 1H), 2.70 -2.65 (m, 1H), 2.12 (t, J=11.5 Hz, 1H), 2.08-2.02 (m, 1H).

¹³ C NMR (176 MHz, CDCl ₃ ) δ 165.94, 162.35, 161.74, 160.96, 142.42, 140.27, 138.56, 135.20, 135.19, 130.04 , 129.99, 127.28, 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.

MS (ESI) m/z for C ₂₃ H ₂₂ FN ₃ O ₂ S [M+H] ⁺ : calculated 424.1495, found 424.1490.

[Formula 67]

S314

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.87 (d, J=8.0 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.56 (d, J =7.0 Hz, 2H), 7.52 (d, J=8.0 Hz, 2H), 7.41 (t, J=7.8 Hz, 2H), 7.36-7.27 (m , 5H), 4.47 (d, J=13.0 Hz, 1H), 4.30 (d, J=3.0 Hz, 2H), 4.02-3.96 (m, 3H), 3 .84 (d, J=13.0 Hz, 1H), 3.74 (d, J=13.5 Hz, 1H), 3.45 (d, J=11.0 Hz, 1H), 2.88 -2.83(m, 1H), 2.70-2.65(m, 1H), 2.12-2.03(m, 2H).

¹³ C NMR (176 MHz, CDCl ₃ ) δ 165.92, 162.59, 161.72, 142.46, 140.68, 140.33, 139.57, 138.62, 138.57, 128.97 , 128.74, 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.

MS (ESI) m/z for C ₂₉ H ₂₇ N ₃ O ₂ S [M+H] ⁺ : calculated 482.1902, found 482.1898.

[Formula 68]

S318

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.85 (d, J=8.0 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.32 (t, J =7.5 Hz, 1H), 7.27 (t, J=7.5 Hz, 1H), 4.48 (d, J=13.0 Hz, 1H), 4.06 (d, J=10 .0 Hz, 1H), 4.02 (s, 2H), 3.79 (d, J=13.0 Hz, 1H), 3.66 (d, J=13.0 Hz, 1H), 3, 48 (d, J=10.0 Hz, 1H), 2.84 (d, J=11.5 Hz, 1H), 2.78 (d, J=7.5 Hz, 2H), 2.72- 2.67 (m, 1H), 2.17 (t, J=11.0 Hz, 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).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 166.33, 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.

MS (ESI) m/z for C ₂₃ H ₂₉ N ₃ O ₂ S [M+H] ⁺ : calculated 412.2059, found 412.2052.

[Formula 69]

N101

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.68 (d, J=8.0 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.22 (t, J =7.5 Hz, 1H), 7.11 (t, J=7.5 Hz, 1H), 6.96 (s, 1H), 4.47 (d, J=13.0 Hz, 1H), 4.05 (d, J=9.5 Hz, 1H), 3.94 (s, 2H), 3.81 (d, J=13.5 Hz, 1H), 3.74-3.72 (m , 4H), 3.48 (d, J=10.5 Hz, 1H), 2.94 (d, J=11.5 Hz, 1H), 2.79-2.73 (m, 1H), 2 .15-2.10 (m, 1H), 2.07-2.02 (m, 1H).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 166.49, 162.08, 137.36, 128.84, 128.41, 122.01, 119.74, 119.42, 109.97, 109.53 , 57.20, 56.17, 53.44, 51.60, 44.71, 41.80, 32.97.

MS (ESI) m/z for C ₁₇ H ₂₀ N ₄ O ₂ [M+H] ⁺ : calculated 313.1659, found 313.1651. [M+Na] ⁺ : calculated 335.1478, found 335.1473.

[Formula 70]

N102

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.69 (d, J=8.0 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.21 (t, J =7.5 Hz, 1H), 7.10 (t, J=7.5 Hz, 1H), 6.98 (s, 1H), 6.60 (s, 1H), 4.49 (d, J =13.0 Hz, 1H), 4.13-4.08 (m, 1H), 4.03-4.00 (m, 1H), 3.90 (d, J=7.5 Hz, 2H) , 3.86 (d, J=13.5 Hz, 1H), 3.72 (d, J=13.5 Hz, 1H), 3.53 (d, J=11.5 Hz, 1H), 2 .92-2.98 (m, 1H), 2.81-2.75 (m, 1H), 2.12 (t, J=11.3 Hz, 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).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 166.44, 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.

MS (ESI) m/z for C ₂₃ H ₃₀ N ₄ O ₂ [M+H] ⁺ : calculated 395.2441, found 395.2438. [M+Na] ⁺ : calculated 417.2261, found 417.2272.

[Formula 71]

N103

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.72 (d, J=7.5 Hz, 1H), 7.32-7.20 (m, 4H), 7.17 (t, J=7, 5 Hz, 1H), 7.13-7.09 (m, 3H), 7.03 (s, 1H), 5.27 (s, 2H), 4.49 (d, J=13.0 Hz, 1H), 4.07 (d, J=11.0 Hz, 1H), 3.96 (s, 2H), 3.84 (d, J=13.5 Hz, 1H), 3.73 (d, J=13.5 Hz, 1H), 3.51 (d, J=11.0 Hz, 1H), 2.95 (d, J=11.5 Hz, 1H), 2.79-2.74 ( m, 1H), 2.10 (t, J=11.5 Hz, 1H), 2.07-2.01 (m, 1H).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 166.45, 162.00, 137.64, 137.09, 129.03, 128.63, 128.17, 127.90, 127.06, 122.25 , 119.96, 119.70, 110.84, 110.03, 57.23, 56.34, 53.59, 51.57, 50.22, 44.77, 41.84.

MS (ESI) m/z for C ₂₃ H ₂₄ N ₄ O ₂ [M+H] ⁺ : calculated 389.1972, found 389.1971. [M+Na] ⁺ : calculated 411.1791, found 411.1798.

[Formula 72]

N104

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.80-7.72 (m, 3H), 7.54 (s, 1H), 7.46-7.42 (m, 2H), 7.30 ( d, J=8.0 Hz, 1H), 7.22 (d, J=8.5 Hz, 1H), 7.18-7.11 (m, 2H), 7.12 (t, J=7 .5 Hz, 1H), 7.06 (s, 1H), 5.41 (s, 2H), 4.48 (d, J=13.5 Hz, 1H), 4.06 (d, J=11 .0 Hz, 1H), 3.94 (s, 2H), 3.84 (d, J=13.5 Hz, 1H), 3.73 (d, J=13.5 Hz, 1H), 3, 52 (d, J=10.0 Hz, 1H), 2.95 (d, J=11.5 Hz, 1H), 2.79-2.73 (m, 1H), 2.10 (t, J =11.5 Hz, 1H), 2.06-2.01 (m, 1H).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 166.46, 162.02, 137.19, 135.08, 133.55, 133.09, 128.96, 128.70, 128.22, 128.07 , 127.97, 126.66, 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.

MS (ESI) m/z for C ₂₇ H ₂₆ N ₄ O ₂ [M+H] ⁺ : calculated 439.2128, found 439.2129. [M+Na] ⁺ : calculated 461.1948, found 461.1957.

[Formula 73]

N105

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.91-7.74 (m, 2H), 7.77 (dd J=8.0 Hz, 19.5 Hz, 2H), 7.52-7, 48 (m, 2H), 7.34-7.30 (m, 2H), 7.18-7.23 (m, 2H), 7.15 (t, J=7.5 Hz, 1H), 6 .92 (s, 1H), 5.70 (s, 2H), 4.46 (d, J=12.0 Hz, 1H), 4.04 (d, J=11.0 Hz, 1H), 3 .95 (s, 2H), 3.81 (d, J=13.5 Hz, 1H), 3.68 (d, J=13.0 Hz, 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).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 166.31, 161.95, 137.25, 133.92, 132.50, 131.12, 129.18, 128.74, 128.65, 128.12 , 126.91, 126.28, 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.

MS (ESI) m/z for C ₂₇ H ₂₆ N ₄ O ₂ [M+H] ⁺ : calculated 439.2128, found 439.2128. [M+Na] ⁺ : calculated 461.1948, found 461.1957.

[Formula 74]

N106

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.73 (d, J=8.0 Hz, 1H), 7.52 (dd, J=8.0 Hz, 11.0 Hz, 4H), 7, 40 (t, J=7.5 Hz, 2H), 7.28-7.33 (m, 2H), 7.15-7.22 (m, 3H), 7.13 (t, J=7, 5 Hz, 1H), 7.05 (s, 1H), 5.30 (s, 2H), 4.49 (d, J=13.0 Hz, 1H), 4.07 (d, J=9, 0 Hz, 1H), 3.95 (s, 2H), 3.85 (d, J=13.5 Hz, 1H), 3.74 (d, J=13.5 Hz, 1H), 3.52 (d, J=11.0 Hz, 1H), 2.95 (d, J=10.0 Hz, 1H), 2.79-2.73 (m, 1H), 2.11 (t, J= 11.3 Hz, 1H), 2.07-2.02 (m, 1H).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 166.33, 161.96, 140.87, 140.76, 137.09, 136.61, 129.04, 128.67, 128.20, 127.75 , 127.64, 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.

MS (ESI) m/z for C ₂₉ H ₂₈ N ₄ O ₂ [M+H] ⁺ : calculated 465.2285, found 465.2291. [M+Na] ⁺ : calculated 487.2104, found 487.2109.

[Formula 75]

N107

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.66-7.64 (m, 1H), 7.27-7.20 (m, 4H), 7.13-7.08 (m, 2H), 6.95 (d, J=7.0 Hz, 2H), 5.30 (s, 2H), 4.48 (d, J=11.0 Hz, 1H), 4.08-4.04 (m , 1H), 3.97 (s, 2H), 3.83 (d, J=13.0 Hz, 1H), 3.70 (d, J=13.0 Hz, 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 =11.3 Hz, 1H), 2.07-2.01 (m, 1H);

¹³ C NMR (126 MHz, CDCl ₃ ) δ 166.33, 161.82, 137.87, 136.61, 135.44, 128.90, 128.57, 127.41,126.05, 121.25, 119 .58, 118.71, 109.19, 107.21, 57.19, 56.34, 52.51, 51.36, 46.65, 44.64, 41.74,10.59.

MS (ESI) m/z for C ₂₄ H ₂₆ N ₄ O ₂ [M+Na] ⁺ : calculated 425.1948, found 425.1949.

[Formula 76]

N108

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.85 (d, J=2.0 Hz, 1H), 7.32-7.23 (m, 4H), 7.12-7.04 (m, 4H), 5.25 (s, 2H), 4.51 (d, J=13.5 Hz, 1H), 4.10 (d, J=10.5 Hz, 1H), 4.01 (s, 2H), 3.77-3.66 (m, 2H), 3.49 (d, J=11.0 Hz, 1H), 2.94 (d, J=11.5 Hz, 1H), 2, 82-2.77 (m, 1H), 2.10-2.02 (m, 2H);

¹³ C NMR (126 MHz, CDCl ₃ ) NMR (126 MHz, ) δ 166.09, 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 .

MS (ESI) m/z for C ₂₃ H ₂₃ BrN ₄ O ₂ [M+H] ⁺ : calculated 467.1077, found 467.1079.

[Formula 77]

N109

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.31-7.26 (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=13.0 Hz, 1H), 3.69 (d, J=13.5 Hz, 1H), 3.55-3.52 (m, 1H), 2.97 (d, J=11.5 Hz, 1H), 2.82-2.76 (m, 1H), 2.13 (t, J=11.5 Hz, 1H), 2, 07-2.02 (m, 1H);

¹³ C NMR (126 MHz, CDCl ₃ ) δ 166.18, 161.83, 154.13, 137.55, 132.25, 128.87, 128.85, 128.74, 127.74, 126.83 , 112.11, 110.68, 109.97, 101.78, 57.02, 56.21, 56.06, 53.50, 51.31, 50.28, 44.65, 41.66

MS (ESI) m/z for C ₂₄ H ₂₆ N ₄ O ₃ [M+H] ⁺ : calculated 419.2078, found 419.2070.

[Formula 78]

N111

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.05-8.02 (m, 1H), 7.90-7.87 (m, 1H), 7.85 (d, J=8.5 Hz, 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=14.5 Hz, 1H), 5.03 (d, J=14.5 Hz, 1H), 4.43-4.40 (m, 1H), 4.20-4, 17 (m, 1H), 3.89 (d, J=13.0 Hz, 1H), 3.75 (d, J=13.5 Hz, 1H), 3.72-3.69 (m, 3H ), 2.93-2.90 (m, 1H), 2.76-2.70 (m, 1H), 2.11 (t, J=11.0 Hz, 1H), 2.02-1, 96 (m, 1H).

¹³ C NMR (126 MHz, CDCl ₃ ) NMR (126 MHz, ) δ 163.31, 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, 127.98, 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.

MS (ESI) m/z for C ₁₈ H ₂₁ N ₃ O ₂ S [M+H] ⁺ : calculated 529.2598, found 529.2598.

[Formula 79]

N112

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.82-7.78 (m, 3H), 7.74 (d, J=8.0 Hz, 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 (dd, J=14.5 Hz, 37.0 Hz, 2H), 4.46-4.43(m, 1H), 4.19-4.16(m, 1H), 3.90-85(m, 3H), 3.74(d, J=13, 0 Hz, 1H), 3.68-3.65 (m, 1H), 2.94-2.92 (m, 1H), 2.78-2.72 (m, 1H), 2.13 (t , J=11.0 Hz, 1H), 2.05-1.99 (m, 1H).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 163.80, 161.73, 137.52, 136.98, 133.33, 133.13, 132.48, 129.12, 128.90, 128.52 128.09 128.04 127.98 127.88 127.83 126.95 126.91 126.63 126.44 126.14 126.11 122.13 119 .85, 119.58, 110.76, 109.90, 57.58, 56.77, 53.44, 51.26, 50.09, 49.59, 48.68, 41.52.

MS (ESI) m/z for C ₁₈ H ₂₁ N ₃ O ₂ S [M+H] ⁺ : calculated 529.2598, found 529.2605.

[Formula 80]

N113

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.74-7.72 (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=13.5 Hz, 1H), 3.84-3, 83 (m, 2H), 3.73 (d, J=13.5 Hz, 1H), 3.66-3.63 (m, 1H), 2.95-2.92 (m, 1H), 2 .78-2.72 (m, 1H), 2.11 (t, J=11.0 Hz, 1H), 2.05-1.99 (m, 1H).

¹³ C NMR (126 MHz, CDCl ₃ ) NMR (126 MHz, ) δ 163.70, 161.76, 137.52, 136.98, 135.07, 129.05, 129.02, 128.94, 128 .67, 128.57, 128.51, 128.29, 128.10, 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.

MS (ESI) m/z for C ₁₈ H ₂₁ N ₃ O ₂ S [M+H] ⁺ : calculated 479.2442, found 479.2446.

[Formula 81]

N114

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.75 (d, J=8.0 Hz, 1H), 7.58-7.76 (m, 4H), 7.45 (t, J=8, 0 Hz, 2H), 7.38-7.25 (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=14.5 Hz, 23.5 Hz, 2H), 4.50-4.46 (m, 1H), 4.20 -4.17 (m, 1H), 3.90-3.88 (m, 3H), 3.76 (d, J=13.0 Hz, 1H), 3.69-3.66 (m, 1H ), 2.97-2.94 (m, 1H), 2.81-2.75 (m, 1H), 2.15 (t, J=11.0 Hz, 1H), 2.08-2, 02 (m, 1H).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 163.68, 161.77, 154.49, 141.31, 140.60, 137.48, 136.96, 134.02, 129.09, 128.94 128.91 128.51 128.16 127.79 127.61 127.20 126.93 122.14 119.79 119.61 110.47 109.91 57 .44, 56.64, 53.39, 51.20, 50.11, 49.14, 48.71, 41.43.

MS (ESI) m/z for C ₁₈ H ₂₁ N ₃ O ₂ S [M+H] ⁺ : calculated 555.2755, found 555.2752.

[Formula 82]

N122

¹ H NMR (500 MHz, CD ₃ OD) δ 8.12 (d, J=8.5 Hz, 1H), 8.02 (d, J=8.5 Hz, 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=8.5 Hz, 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=14.5 Hz, 25.5 Hz, 2H), 4.51-4.48 (m, 1H), 4.22-4.15 (m, 3H), 3.88 (d, J=13.5 Hz, 1H), 3.75 (d, J=13.5 Hz, 1H), 3, 66-3.63 (m, 1H), 2.97-2.94 (m, 1H), 2.82-2.76 (m, 1H), 2.17 (t, J=11.0 Hz, 1H), 2.09-2.03 (m, 1H).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 164.01, 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.

MS (ESI) m/z for C ₁₈ H ₂₁ N ₃ O ₂ S [M+H] ⁺ : calculated 530.2551, found 530.2549.

[Formula 83]

N162

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.49-7.46 (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=2.5 Hz, 9, 0 Hz, 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=13.5 Hz, 1H), 3.65 (d, J=13.0 Hz, 1H), 3.50-3.47 (m, 1H), 2.92-2 .88 (m, 1H), 2.71-2.65 (m, 1H), 2.08 (t, J=11.0 Hz, 1H), 2.01-1.95 (m, 1H).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 166.11, 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.

MS (ESI) m/z for C ₃₀ H ₃₀ N ₄ O ₃ [M+H] ⁺ : calculated 495.2390, found 495.2386.

[Formula 84]

N163

¹ H NMR (500 MHz, CDCl ₃ )δ 7.84-7.82 (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), 3.49 (d, J=10.5 Hz, 1H), 2.87 (d, J=11.0 Hz, 1H), 2.75-2, 73 (m, 1H), 2.07-1.96 (m, 2H).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 165.99, 161.61, 140.37, 138.16, 136.90, 131.44, 130.83, 128.70, 128.53, 128.43 , 127.22, 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.

MS (ESI) m/z for C ₁₈ H ₂₁ N ₃ O ₂ S [M+H] ⁺ : calculated 465.2285, found 465.2281.

[Formula 85]

N164

¹ H NMR (500 MHz, DMSO) δ 8.13 (s, 1H), 7.88-7.86 (m, 1H), 7.41 (t, J=11.0 Hz, 2H), 7, 34-7.28 (m, 5H), 7.23 (t, J=7.5 Hz, 2H), 7.19-7.15 (m, 3H), 4.27 (d, J=12, 5 Hz, 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=11.5 Hz, 1H), 2.68-2.62 (m, 1H), 1.99-1.86 (m, 2H).

¹³ C NMR (126 MHz, DMSO) δ 165.32, 162.97, 139.54, 138.21, 137.84, 131.56, 131.26, 131.13, 131.04, 129.82, 128.75, 128.51, 128.27, 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.

MS (ESI) m/z for C ₁₈ H ₂₁ N ₃ O ₂ S [M+H] ⁺ : calculated 451.2129, found 451.2129.

[Formula 86]

SN611

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.39 (d, J=7.5 Hz, 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).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 193.68, 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.

MS (ESI) m/z for C ₁₈ H ₂₁ N ₃ O ₂ S [M+H] ⁺ : calculated 431.2078, found 431.2072.

[Formula 87]

SN612

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.89-7.77 (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).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 169.05, 164.35, 162.19, 140.32, 138.48, 128.60, 124.76, 124.49, 122.91, 122.17 , 121.71, 56.38, 54.61, 48.89, 44.59, 41.00, 34.82.

MS (ESI) m/z for C ₁₇ H ₁₇ N ₃ O ₃ S [M+H] ⁺ : calculated 344.1063, found 344.1061.

[Formula 88]

N199

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.68-7.66 (m, 1H), 7.39-7.37 (m, 1H), 7.19-7.13 (m, 2H), 7.12-7.07 (m, 1H), 4.45 (d, J=13.5 Hz, 1H), 4.08 (d, J=11.0 Hz, 1H), 3.96-3 .77 (m, 4H), 3.49 (d, J=11.0 Hz, 1H), 2.98 (d, J=11.5 Hz, 1H), 2.79 (t, J=12, 5 Hz, 1H), 2.15-2.04 (m, 2H).

¹³ C NMR (126 MHz, CDCl ₃ ) δ 169.79, 166.51, 140.46, 131.63, 128.55, 125.70, 123.22, 122.92, 115.31, 113.92 , 60.80, 59.65, 57.06, 55.17, 48.11, 45.41.

MS (ESI) m/z for C ₁₆ H ₁₆ N ₄ O ₂ [M+H] ⁺ : calculated 299.1502, found 299.1502.

Examples of conducting studies on biological activity

1. Preparation of SKOV3 and SKOV3-TR cell lines

The cell experiment was carried out on the ovarian epithelial cancer cell line SKOV3 and SKOV3-TR, which is obtained and produced as a resistant cancer cell line with resistance to the anticancer drug paclitaxel. In the invention, Figure 1A shows the IC ₅₀ value for the anti-cancer drug paclitaxel against SKOV3 cells, and Figure 1B shows the IC ₅₀ value for the anti-cancer drug paclitaxel against SKOV3-TR cells. Figure 2A shows the IC ₅₀ value for the anti-cancer drug doxetaxel against SKOV3 cells and a figure 2B shows the IC ₅₀ value for the anti-cancer drug doxetaxel against SKOV3-TR cells.

Two cancer cell lines cultured in a 12-well plate were pretreated with 102 S-forms at low concentration (0.5 μM) and at high concentration (2 μM) for 4 hours, and then SKOV3-TR cells were treated with with 4 μM paclitaxel, and SKOV3 cells were treated with 0.05 μM paclitaxel. For cell morphological analysis, cells were untreated (nothing treated group), treated with DMSO (solvent for paclitaxel), ethanol (EtOH) (solvent for S-form), DMSO+EtOH, paclitaxel, paclitaxel+ethanol (Pacli+ EtOH), and 102 S-forms, and analyzed after 1, 2 and 3 days, and recorded images. For cell metabolism analysis, cell proliferation assay was performed using the WST-1 kit 3 days after the combined treatment of cells with paclitaxel and S-forms. The results are presented in figures 3-10. The percentage of cell survival in the same experimental groups was assessed by staining with crystal violet dye. The results are presented in figures 13-20.

Two cancer cell lines cultured in a 12-well plate were pre-treated with S-form at low concentration (0.5 μM) and high concentration (2 μM) for 4 hours, and then SKOV3-TR cells were treated with 0.9 μM doxetaxel and SKOV3 cells were treated with 0.5 μM doxetaxel. For cell morphological analysis, cells were untreated (nothing treated group), treated with DMSO (solvent for doxetaxel), ethanol (EtOH) (solvent for S-form), DMSO+EtOH, doxetaxel, doxetaxel+ethanol (doxetaxel+ EtOH), and S-forms, and analyzed after 1, 2 and 3 days, and recorded images. For cell metabolism analysis, cell proliferation assay was performed using the WST-1 kit 3 days after the combined treatment of cells with doxetaxel and S-forms. The results are presented in figures 21-24. The percentage of cell survival in the same experimental groups was assessed by staining with crystal violet dye. The results are presented in figures 27-30.

Figures 3, 4, 13 and 14 graphically represent the results in case of no treatment, in case of treatment with DMSO, ethanol (EtOH), DMSO+ethanol, paclitaxel, paclitaxel+ethanol, 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), S110 (2 µM), S111 (0.5 µM), S111 (2 µM) , S112 (0.5 µM), S112 (2 µM), S113 (0.5 µM), S113 (2 µM), S114 (0.5 µM), S114 (2 µM), S115 (0.5 µM) , S115 (2 µM), S116 (0.5 µM), S116 (2 µM), S117 (0.5 µM), S117 (2 µM), S118 (0.5 µM), S118 (2 µM), S119 (0.5 µM), S119 (2 µM), S120 (0.5 µM), S120 (2 µM), S201 (0.5 µM), S201 (2 µM), S202 (0.5 µM), S202 (2 μM), S203 (0.5 μM), S203 (2 μM), S204 (0.5 μM), S204 (2 μM), S206 (0.5 μM), S206 (2 μM), S207 (0 .5 µM), S207 (2 µM), S208 (0.5 µM), S208 (2 µM), S209 (0.5 µM), S209 (2 µM), S210 (0.5 µM), S210 (2 µM), S211 (0.5 µM), S211 (2 µM), S212 (0.5 µM), S212 (2 µM), S213 (0.5 µM), S213 (2 µM), S214 (0.5 μM), S214 (2 μM), S215 (0.5 μM), S215 (2 μM), S216 (0.5 μM), and S216 (2 μM) in that order.

Figures 5, 6, 15 and 16 graphically represent the results in case of no treatment, in case of treatment with 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), S225 (2 µM), S301 (0.5 µM), S301 (2 µM), S302 (0.5 µM), S302 (2 µM), S303 (0.5 µM) , S303 (2 µM), S304 (0.5 µM), S304 (2 µM), S306 (0.5 µM), S306 (2 µM), S307 (0.5 µM), S307 (2 µM), S309 (0.5 µM), S309 (2 µM), S310 (0.5 µM), S310 (2 µM), S314 (0.5 µM), S314 (2 µM), S318 (0.5 µM) and S318 (2 µM) in that order.

Figures 7, 8, 17 and 18 graphically represent the results in case of no treatment, in case of treatment with DMSO, ethanol (EtOH), DMSO + ethanol, paclitaxel, paclitaxel + ethanol, 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 (25 µM), S128 (0.5 µM), S128 (2 µM), N101 (0.5 µM), N101 (2 µM) , N102 (0.5 µM), N102 (2 µM), N103 (0.5 µM), N103 (2 µM), N104 (0.5 µM), N104 (2 µM), N105 (0.5 µM) , N105 (2 µM), N106 (0.5 µM), N106 (2 µM) in that order.

Figures 9, 10, 19 and 20 graphically show the results in case of no treatment, in case of treatment with 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 (0.5 µM), N163 (2 µM) , N108 (0.5 µM), N108 (2 µM), N109 (0.5 µM), N109 (2 µM), S135 (0.5 µM), S135 (2 µM), N162 (0.5 µM) , N162 (2 µM), SN612 (0.5 µM), SN612 (2 µM), N199 (0.5 µM), N199 (2 µM), S136 (0.5 µM), S136 (2 µM), SN611 (0.5 µM), SN611 (2 µM) in that order.

Figures 21, 22, 27 and 28 graphically show the results in case of no treatment, in case of treatment with DMSO, ethanol (EtOH), DMSO+ethanol, doxetaxel, doxetaxel+ethanol, 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), S109 (0.5 µM), S109 (2 µM) , S110 (0.5 µM), S110 (2 µM), S111 (0.5 µM), S111 (2 µM), S112 (0.5 µM), S112 (2 µM), S113 (0.5 µM) , S113 (2 µM), S114 (0.5 µM), S114 (2 µM), S115 (0.5 µM), S115 (2 µM), S116 (0.5 µM), S116 (2 µM), S117 (0.5 µM), S117 (2 µM), S118 (0.5 µM), S118 (2 µM), S119 (0.5 µM), S119 (2 µM), S120 (0.5 µM), S120 (2 μM), S201 (0.5 μM), S201 (2 μM), S202 (0.5 μM), S202 (2 μM), S203 (0.5 μM), S203 (2 μM), S204 (0 .5 µM), S204 (2 µM), S206 (0.5 µM), S206 (2 µM), S207 (0.5 µM), S207 (2 µM), S208 (0.5 µM), S208 (2 µM), S209 (0.5 µM), S209 (2 µM), S210 (0.5 µM), S210 (2 µM), S211 (0.5 µM), S211 (2 µM), S212 (0.5 µM), S212 (2 µM), S213 (0.5 µM), S213 (2 µM), S214 (0.5 µM), S214 (2 µM), S215 (0.5 µM), S215 (2 µM) , S216 (0.5 µM), S216 (2 µM) in that order.

Figures 23, 24, 29 and 30 graphically represent the results in case of no treatment, in case of treatment with DMSO, ethanol (EtOH), DMSO+ethanol, doxetaxel, doxetaxel+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), S225 (2 µM), S301 (0.5 µM), S301 (2 µM), S302 (0.5 µM), S302 (2 µM), S303 (0.5 µM) , S303 (2 µM), S304 (0.5 µM), S304 (2 µM), S306 (0.5 µM), S306 (2 µM), S307 (0.5 µM), S307 (2 µM), S308 (0.5 µM), S308 (2 µM), S309 (0.5 µM), S309 (2 µM), S310 (0.5 µM), S310 (2 µM), S314 (0.5 µM), S314 (2 μM), S318 (0.5 μM), S318 (2 μM) in that order.

2. WST-1 analysis

Based on the results of the WST-1 assay, which assessed cellular metabolism, a decrease in metabolism in SKOV3-TR and SKOV3 cells induced by treatment with paclitaxel was found. The results of the WST-1 analysis of the effect of 102 S forms on SKOV3-TR cells and the results of the WST-1 analysis of the effect of 102 S forms on SKOV3 cells in the presence of paclitaxel are shown in Figures 3-10.

That is, optical densities at 450 nm decreased in paclitaxel-treated groups due to the phenomenon of cell death induction and cell growth inhibition in the SKOV3-TR and SKOV3 cell lines compared to untreated or DMSO-treated groups. When cell lines were treated with S-forms in combination with paclitaxel, S-forms enhanced the anti-cancer effect of paclitaxel on SKOV3-TR cells, which is a cancer-resistant cell line, which was manifested in lower optical densities compared to the group treated with paclitaxel+ethanol (Pacli+EtOH), but did not enhance the anti-cancer effect of paclitaxel on SKOV3 cells. In addition, an acceptable dose-response relationship should be noted in that the reduction in metabolism in SKOV3-TR cells by paclitaxel was further promoted in the presence of 2 μM S-forms compared to 0.5 μM S-forms. As a comparative example, the optical density value for the group treated with paclitaxel+ethanol (Pacli+EtOH) was taken as the baseline. With respect to enhancing the anti-cancer effect of paclitaxel, optical densities (OD values at 450 nm) were significantly reduced in the WST-1 assay when cell lines were treated with paclitaxel+S-form compared to the paclitaxel+ethanol treated group. (Pacli+EtOH).

Based on the results of the WST-1 assay, which assessed cellular metabolism, a decrease in metabolism in SKOV3-TR and SKOV3 cells induced by doxetaxel treatment was found. The results of the WST-1 analysis of the effects of S-forms on SKOV3-TR cells and the results of the WST-1 analysis of the effects of S-forms on SKOV3 cells in the presence of doxetaxel are shown in Figures 21-24.

That is, optical densities at 450 nm decreased in doxetaxel-treated groups due to the phenomenon of cell death induction and cell growth inhibition in SKOV3-TR and SKOV3 cell lines compared to untreated or DMSO-treated groups. When cell lines were treated with S-forms in combination with doxetaxel, S-forms enhanced the anti-cancer effect of doxetaxel on SKOV3-TR cells, which is a cancer-resistant cell line, which was manifested in lower optical densities compared to the group treated with doxetaxel+ethanol (doxetaxel+EtOH), but did not enhance the anticancer effect of doxetaxel on SKOV3 cells. In addition, an acceptable dose-response relationship should be noted in view of the fact that the decrease in metabolism in SKOV3-TR cells when SKOV3-TR cells were exposed to doxetaxel was additionally promoted in the presence of 2 μM S-forms compared to 0.5 μM S-forms. . As a comparative example, the optical density value for the group treated with doxetaxel+ethanol (doxetaxel+EtOH) was taken as the baseline. With respect to enhancing the anti-cancer effect of doxetaxel, optical densities (OD values at 450 nm) were significantly reduced in the WST-1 assay when cell lines were treated with doxetaxel+S-form compared to the doxetaxel+ethanol treated group. (doxetaxel+EtOH).

3. Percent Cell Survival Analysis and Cell Line Analysis

Based on crystal violet staining, cell survival percentage analysis was performed and cell counts were performed, whereby a decrease in the number of SKOV3-TR and SKOV3 cells was found due to paclitaxel treatment due to a decrease in cell survival percentage. Namely, SKOV3-TR and SKOV3 cell lines were imaged after the cell lines were treated with paclitaxel and doxetaxel alone for 3 days or treated with S101 and S105, resulting in enhanced anticancer activity of paclitaxel and doxetaxel in combination of S101 and S105 with paclitaxel or doxetaxel for 3 days. The results of crystal violet staining of SKOV3-TR cells after paclitaxel treatment are shown in Figure 11, and the results of crystal violet staining of SKOV3 cells are shown in Figure 12. The results of crystal violet staining of SKOV3-TR cells after doxetaxel treatment are shown in Figure 25, and the staining results stained with crystal violet SKOV3 cells are shown in Figure 26.

Optical densities at 570 nm decreased with a decrease in the counted number of cells in the groups treated with paclitaxel, due to the phenomenon of cell death induction and inhibition of cell growth of SKOV3-TR and SKOV3 cells, compared with untreated or treated with DMSO. When resistant cancer cell lines were treated with S-forms in combination with paclitaxel, S-forms enhanced the anti-cancer effect of paclitaxel on SKOV3-TR cells, which is a resistant cancer cell line, which was manifested in lower optical values. densities compared to the paclitaxel+ethanol (Pacli+EtOH) treated group, but did not enhance the anti-cancer effect of paclitaxel on SKOV3 cells. In addition, an acceptable dose-response relationship should be noted in view of the fact that the decrease in the survival rate of SKOV3-TR cells under the influence of paclitaxel was additionally promoted at a high concentration (2 μM) of S-forms compared with a low concentration (0.5 μM) of S -forms. For analysis, images of cell lines stained with crystal violet dye were recorded 3 days after treatment with compound 102. The degree of staining was determined by ELISA by measuring optical densities at 570 nm eluting the dye as in the WST-1 assay. In the ELISA assay, the absorbance value of the group treated with paclitaxel+ethanol (Pacli+EtOH) as a control group was taken as the baseline. The absorbance results of SKOV3-TR cells treated with 102 S-forms and the absorbance results of SKOV3 cells treated with 102 S-forms are shown in Figures 13-20.

Optical densities at 570 nm decreased with a decrease in the number of cells counted in the doxetaxel-treated groups due to the phenomenon of cell death induction and cell growth inhibition of SKOV3-TR and SKOV3 cells compared to untreated or treated with DMSO. When resistant cancer cell lines were treated with S-forms in combination with doxetaxel, the S-forms enhanced the anti-cancer effect of doxetaxel on SKOV3-TR cells, which is a resistant cancer cell line, which was manifested in lower optical values. densities compared to the doxetaxel+ethanol (doxetaxel+EtOH) treated group, but did not enhance the anti-cancer effect of paclitaxel on SKOV3 cells. In addition, an acceptable dose-response relationship should be noted in view of the fact that the decrease in the survival rate of SKOV3-TR cells under the influence of doxetaxel was additionally promoted at a high concentration (2 μM) of S-forms compared to a low concentration (0.5 μM) of S -forms. For analysis, images of cell lines stained with crystal violet dye were recorded 3 days after treatment with compound 102. The degree of staining was determined by ELISA by measuring optical densities at 570 nm by eluting the dye as in the WST-1 assay. In the ELISA assay, the absorbance value of the group treated with doxetaxel+ethanol (doxetaxel+EtOH) as a control group was taken as the baseline. Absorbance results of SKOV3-TR cells treated with S-forms, absorbance results of SKOV3 cells treated with S-forms are shown in Figures 27-30.

4. Measurement of anti-cancer efficacy

1) Analysis of cell number changes ( in vitro )

Cell number changes after selected-MDA-MB231 and selected-MCF7 cells, which are cancer stem cells, were treated with 100 nM, 50 nM, and 10 nM Compound S101 without applying ER stress to cancer cells in the presence of glucose ( G(+)) and applying ER stress to cancer cells in the absence (G(-)), are shown in Figure 31, and the imaging results of crystal violet stained selected-MDA-MB231 and selected-MCF7 cells are shown in Figure 32. In addition, the effect of S101 on cancer cell death after glucose deprivation was measured by the TUNEL method. The results are shown in figure 33.

2) In vivo verification of the mouse model

Selected-MDA-MB231 cells, verified as cancer stem cells, were cultured in vitro and harvested. Following this, an in vivo mouse model was created to verify the anticancer effect. In Comparative Example 1 (2DG), test animals induced with severe ER stress were used as a control group, and 2-deoxy-d-glucose was used instead of an anticancer drug. In Example 2, test animals were administered 2 mg of S101 as monotherapy (S101 only), and in Example 3, test animals were administered 10 mg of 2-deoxy-d-glucose and 2 mg of S101 (S101+2DG, 2 mg: 10 mg) in order to verify the anticancer effect. Tumor volume change results are shown in Figure 34. Results obtained by comparing masses and sizes of resected tumors between respective groups are shown in Figures 35A and 35B, respectively. In a xenograft model of selected-MDA-MB231 cells, changes in body weight between respective groups were measured in assessing the anti-cancer effect after combined treatment with S101 and 2DG. The results are presented in figure 36.

To determine the degree of cytotoxicity when cells were treated with S101 and 2DG alone or when treated together with S101 and 2DG, livers were removed from each group to prepare paraffin-embedded tissue blocks. Then, the tissue blocks were cut with a microtome to prepare microscopic preparations, and then stained with hematoxylin-eosin (H&E) to determine whether pathological degradation of the liver tissue occurred, as a result of which the degree of toxicity could be inferred. Figure 37 shows an image of liver tissue at 400x magnification.

While the present invention has been described in detail with reference to examples of embodiments of the present invention, it will nevertheless be apparent to one of ordinary skill in the art to which the present invention pertains that this specific description is merely a description of the preferred embodiment, and it does not limit the scope of the present invention in any way. Therefore, it should be understood that the scope of the present invention is defined by the appended claims and their equivalents.

Claims (48)

1. The compound represented by the following formula 1, or a pharmaceutically acceptable salt thereof: [Formula 1] where R ₁ represents hydrogen, linear or branched C ₁ ~C ₆ alkyl, C ₆ ~C ₁₂ aryl or C ₁ ~C ₆ alkyl C ₆ ~C ₁₂ aryl, each of which can be independently substituted with at least one a substituent selected from halogen, C ₁ ~C ₆ alkyl, C ₃ ~C ₆ cycloalkyl and C ₆ ~C ₁₂ aryl; R ₃ is hydrogen, C ₁ ~C ₆ alkoxy, halogen, where C ₁ ~C ₆ alkoxy may be substituted by C ₁ ~C ₆ alkyl C ₆ ~C ₁₂ aryl; L ₁ is C ₁ ~C ₁₀ alkylene, where alkylene may be substituted by oxo; Q is S, NR where R is hydrogen, linear or branched C ₁ ~C ₆ alkyl, C ₆ ~C ₁₂ aryl, or C ₁ ~C ₆ alkyl C ₆ ~C ₁₂ aryl, each of which may be independently substituted with at least one substituent selected from C ₃ ~C ₇ cycloalkyl and C ₆ ~C ₁₂ aryl; R ₂ is hydrogen, linear C ₁ ~C ₆ alkyl, C ₃ ~C ₇ cycloalkyl, C ₆ ~C ₁₂ aryl, 3-12 membered heteroaryl containing a ring heteroatom selected from N, C ₁ ~C ₆ alkyl C ₆ ~C ₁₂ aryl, each of which may be independently substituted with at least one substituent selected from halogen, C ₁ ~C ₆ alkyl, C ₁ ~C ₆ alkoxy, C ₆ ~C ₁₂ aryl, nitro, cyano or trifluoromethyl, or R ₂ is ; R ₄ is hydrogen, linear or branched C ₁ ~C ₆ alkyl, C ₃ ~C ₇ cycloalkyl, C ₂ ~C ₆ alkynyl, C ₁ ~C ₆ alkylthio, C ₆ ~C ₁₂ aryl, C ₁ ~C ₆ alkyl -C ₆ -C ₁₂ aryl, each of which may be independently substituted with at least one substituent selected from halo, C ₆ -C ₁₂ aryl, C ₆ -C ₁₂ aryloxy, nitro, cyano, or trifluoromethyl; R ₂ and R ₄ can be connected to form a 5-10-membered monocyclic or bicyclic ring; R ₄ ' represents hydrogen; m is an integer 1 and n is an integer from 1 to 4; And X, Y and Z are each independently hydrogen, R ₁ and R ₂ are neither hydrogen nor linear alkyl at the same time. 2. A compound or a pharmaceutically acceptable salt thereof according to claim 1, where R ₁ is hydrogen, C ₁ ~C ₆ linear alkyl, benzyl, where C ₁ ~C ₆ linear alkyl can be substituted with C ₃ ~C ₆ cycloalkyl and benzyl can be substituted with halogen or substituted with phenyl at at least one of the ortho, meta, and para positions; R ₃ is hydrogen, C ₁ ~C ₆ alkoxy, halogen, where C ₁ ~C ₆ alkoxy is substituted with benzyl; L ₁ is C ₁ ~C ₄ alkylene, where alkylene may be substituted with oxo; R ₂ is hydrogen, linear C ₁ ~C ₆ alkyl or 2-phenylethyl, where linear alkyl may be substituted with tert-butoxy, cyclohexyl, benzyl, naphthyl, quinoline, where substituted benzyl may be substituted with halogen, C ₁ ~C ₃ linear alkyl, trifluoromethyl, cyano, nitro, C ₁ ~C ₃ alkoxy or phenyl in at least one of the ortho, meta and para positions and where 2-phenylethyl can be substituted with halogen in at least one of the ortho , meta and a couple of positions; R ₄ is hydrogen, C ₁ ~C ₆ linear alkyl, C ₃ ~C ₆ branched alkyl, C ₃ ~C ₆ cycloalkyl, C ₂ ~C ₆ alkynyl, C ₁ ~C ₆ alkylthio, benzyl, phenyl, 2-naphthylmethyl or 1-naphthylmethyl, where linear alkyl may be substituted with methylthio or C ₂ ~C ₆ alkynyl and benzyl may be substituted with halogen, C ₆ ~C ₁₂ aryl, nitro, cyano, trifluoromethyl, or benzyloxy in at least one of ortho, meta and para positions, C ₁ ~C ₆ alkylthio can be substituted with benzyl; And R ₂ and R ₄ can be connected to form a 5-10-membered monocyclic or bicyclic ring; And R ₄ ' is hydrogen. 3. A compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula 1 comprises a compound represented by the following formula 3 or formula 4, or a pharmaceutically acceptable salt thereof: [Formula 3] , [Formula 4] , where R₁ is hydrogen, C₁~C₆ linear alkyl, where X₁ is hydrogen, halogen, C₁~C₃ linear alkyl or phenyl; R ₃ is hydrogen, methoxy, halogen, where methoxy may be substituted with benzyl; L ₁ is C ₁ ~C ₄ alkylene, where alkylene may be substituted with oxo; R ₂ is hydrogen, C ₁ ~C ₆ linear alkyl, , , , , , , , , , , , , , , , , , , or , where C ₁ ~C ₆ linear alkyl can be substituted with tert-butoxy; R ₄ is hydrogen, C ₁ ~C ₄ linear alkyl, C ₃ ~C ₄ branched alkyl, C ₃ ~C ₆ cycloalkyl, , , , , , , , , , , , , , , or ; R ₂ and R ₄ can be connected to form a 5-10 membered monocyclic or bicyclic ring, R ₄ ' represents hydrogen; And R is hydrogen, , , , , or . 4. A compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of Formula 1 is selected from the group consisting of: No. Chemical structure No. Chemical structure 7 8 9 10 eleven 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 thirty 31 32 33 34 35 40 41 42 43 44 45 46 47 48 49 50 51 52 53 55 56 59 60 61 62 63 64 65 66 67 68 75 78 79 80 81 82 84 85 - - 5. Pharmaceutical composition for the prevention or treatment of cancer or a resistant form of cancer, comprising a compound according to any one of paragraphs. 1-4 or a pharmaceutically acceptable salt thereof, wherein the cancer or resistant cancer includes one or more resistant cancers selected from the group consisting of ovarian cancer, colorectal cancer, pancreatic cancer, gastrointestinal cancer, liver cancer, breast cancer, cervical cancer, thyroid cancer , parathyroid cancer, lung cancer, non-small cell lung cancer, prostate cancer, bladder cancer, melanoma, colon cancer, head and neck cancers, rectal cancer, endometrial carcinoma, esophageal cancer, and cancer stem cells. 6. The pharmaceutical composition according to claim 5, wherein the resistant form of cancer is resistant to an anticancer drug or resistant to radiation therapy. 7. The pharmaceutical composition according to claim 6, wherein the anti-cancer drug comprises one or more anti-cancer drugs selected from the group consisting of nitrogen mustard, imatinib, oxaliplatin, rituximab, erlotinib, neratinib, lapatinib, gefitinib, vandetanib, nilotinib, semaxanib, bosutinib, axitinib, masitinib, cediranib, lestaurtinib, trastuzumab, gefitinib, bortezomib, sunitinib, pazopanib, toceranib, nintedanib, regorafenib, semaxanib, tivozanib, ponatinib, cabozantinib, carboplatin, sorafeniba, lenvatinib, beva cizumab, cisplatin, cetuximab, viscum album, asparaginase , tretinoin, hydroxycarbamide, dasatinib, estramustine, gemtuzumab ozogamicin, ibritumomab tiuxetan, heptaplatin, methylaminolevulinic acid, amsacrine, alemtuzumab, procarbazine, alprostadil, chitosan holmium nitrate, gemcitabine, doxifluridine, pemetrexe yes, tegafur, capecitabine, gimeracil, oteracil, azacitidine, methotrexate, uracil, cicitarabin, fluorouracil, fludarabine, enocytabine, flutamide, capecitabine, decitabine, mercaptopurine, thioguanine, cladribine, carmofur, raltitrexed, doxetaxel, paclitaxel, cabazitaxel, irinotecan, belotecan, topotecan, vinorelbine, etoposide, vincristine, vinblastine, teniposide, doxorubicin, idarubicin, epirubicin, mitoxantrone, mitomycin, bleomycin, daunorubicin, dactinomycin, pyrarubicin, aclarubicin, pepromycin, temsirolimus, temozolomide, busulfan, ifosfamide, cyclophosphamide, melphalan, altretamine, dacabazine, thiotepa, nimustine, chlorambu cila, mitolactol, leucovorin, tretonin, exmestane, aminoglutethimide, anagrelide, olaparib, navelbine, padrazole, tamoxifen, toremifene, testolactone, anastrozole, letrozole, borozol, bicalutamide, lomustine, vorinostat, entinostat, and carmustine. 8. A method for treating cancer that is resistant to oncological therapies, including: administration of a therapeutically effective amount of a compound according to any one of paragraphs. 1-4 or a pharmaceutically acceptable salt thereof to a subject with a resistant form of cancer, wherein the cancer that is resistant to oncological therapies includes one or more resistant cancers selected from the group consisting of ovarian cancer, colorectal cancer, pancreatic cancer, gastrointestinal cancer, liver cancer, breast cancer, cervical cancer, thyroid cancer, parathyroid cancer, lung cancer, non-small cell lung cancer, prostate cancer, bladder cancer, melanoma, colon cancer, head and neck cancers, rectal cancer, endometrial carcinoma, esophageal cancer, and cancer stem cells. 9. The method of claim 8, wherein the chemotherapeutic agents used to treat cancer or a proliferative disease are administered simultaneously, separately, or sequentially. 10. The use of a compound according to any one of paragraphs. 1-4 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of cancer or a resistant form of cancer, wherein the cancer or resistant cancer includes one or more resistant cancers selected from the group consisting of ovarian cancer, colorectal cancer, pancreatic cancer, gastrointestinal cancer, liver cancer, breast cancer, cervical cancer, thyroid cancer , parathyroid cancer, lung cancer, non-small cell lung cancer, prostate cancer, bladder cancer, melanoma, colon cancer, head and neck cancers, rectal cancer, endometrial carcinoma, and esophageal cancer. 11. The use of a compound according to any one of paragraphs. 1-4 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of cancer stem cells.