KR101796781B1 - Novel indazole derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating cancer containing the same as an active ingredient - Google Patents

Abstract

The present invention relates to a novel indazole derivative, a production method thereof, and a pharmaceutical composition for preventing or treating cancer containing the same as an active ingredient. According to the present invention, the compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof shows outstanding inhibitory activities on TRAIL-resistance regarding cancer which is resistant to tumor necrosis factor related apoptosis (TRAIL), and thus can be useful for preventing and treating cancer when used as a pharmaceutical composition containing the same as the active ingredient in conjunction with TRAIL.

Description

TECHNICAL FIELD [0001] The present invention relates to a novel indazole derivative, a process for producing the same, and a pharmaceutical composition for preventing or treating cancer diseases containing the same as an active ingredient. active ingredient}

The present invention relates to a novel indazole derivative, a process for producing the same, and a pharmaceutical composition for preventing or treating cancer diseases containing the same as an active ingredient.

Cancer is one of the greatest diseases that threatens the health of human beings. It is a disease that occurs when the cell line undergoes a series of mutagenic processes, multiplication and immortalization in an unlimited and uncontrolled manner. Causes of cancer include environmental or external factors such as chemicals, viruses, bacteria, and ionizing radiation, and internal factors such as congenital gene mutations (Non-Patent Document 1).

In the early stage of cancer, there are treatments such as surgery, radiation therapy, and chemotherapy, but the side effects are also a big problem. In the case of terminal cancer or metastatic cancer, life ends with a deadline without special treatment. In addition, various biochemical mechanisms related to cancer have been identified and therapies have been developed, but no fundamental treatment methods for cancer have yet been proposed.

TRAIL is a cytokine belonging to the tumor necrosis factor (TNF), which activates the death receptor pathway and induces apoptosis. TRAIL has four receptors, of which death receptor 4/5 (DR4 / 5) is a cancer cell line and decoy receptor (decoy receptor1 / 2, DcR1 / 2) . The decoy receptor does not have a death domain at the c-terminus, and cell death signaling is not transmitted to the cell. Therefore, TRAIL-based therapy is attracting attention as a next-generation anticancer therapy that has no side effects on normal cell lines.

Many anticancer agents and cancer inhibitors known so far have problems such as severe side effects due to non-specificity in normal tissues and acquisition of tolerance to cancer cells due to high mutation rate. However, in 1997, TRAIL was found not to act on normal cell lines but to act only on cancer cell lines, leading to apoptosis. TRAIL is not only a cancer cell-specific anticancer drug but also a therapeutic agent for cancer cells And the possibility of becoming. However, TRAIL resistance is evident in cancers such as breast cancer, prostate cancer, uterine cancer, lung cancer, liver cancer, brain tumor, and TRAIL is resistant to TRAIL, a cancer cell line that is susceptible to TRAIL.

The TRAIL resistance mechanism is expected to inhibit the action of 4/5 of death receptor due to overexpression of decoy receptors 1 and 2, and to inhibit intracellular apoptotic signal transduction. Among them, resistance to TRAIL This is perceived as a more convincing mechanism. These changes in signal transduction systems are known to be caused by overexpression of antiapoptotic proteins that inhibit the action of proapoptotic proteins. Accordingly, the development of a TRAIL sensor sensitizer that overcomes TRAIL resistance by promoting therapeutic agents to overcome tolerance of new TRAIL and thereby promotes cancer cell-specific cell death is an indispensable research field.

In addition to cancer, TRAIL-mediated apoptosis pathway is known to play an important role in diseases of rheumatoid arthritis, diabetic kidney disease, and degenerative brain disease. Various approaches using TRAIL have been attempted to induce the death of hyperactivated immune cells in arthritis, an autoimmune disease, and to alleviate and treat the disease. Therefore, TRAIL can be used not only for the treatment of various carcinomas mentioned above but also for the treatment of T-cell autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE), rheumatoid arthritis and type 1 diabetes .

Therefore, the inventors of the present invention studied a new TRAIL sensor sensitizer that can increase the cytotoxicity of TRAIL and increase the anticancer effect by TRAIL. In addition, when the compound of the present invention is administered in combination with TRAIL, Induced apoptosis in hepatocellular carcinoma cells showing hepatocellular carcinoma cells and that the compounds can be effectively used for the development of anticancer agents.

Klaunig & Kamendulis, Annu Rev Pharmacol Toxicol., (2004) 44: 239-267

It is an object of the present invention to provide a compound useful as an active ingredient of a pharmaceutical composition for preventing or treating cancer.

Another object of the present invention is to provide a process for producing the above compound.

It is still another object of the present invention to provide a pharmaceutical composition for preventing or treating cancer containing the above-mentioned compound as an active ingredient.

Another object of the present invention is to provide an anticancer adjuvant containing the above compound as an active ingredient.

In order to achieve the above object,

The present invention provides a compound represented by the following general formula (1): < EMI ID =

[Chemical Formula 1]

(In the formula 1,

X is a substituted or unsubstituted phenyl,

Wherein the substituted phenyl is C _1-5 linear or branched alkyl, substituted or unsubstituted C _1-5 straight or branched alkoxy, -CN, -NO ₂ , C _1-5 linear or branched alkylcarbonyl ≪ / RTI > nitro and halogen; And

Y is substituted or unsubstituted phenyl,

Wherein the substituted phenyl is C _1-5 linear or branched alkyl, substituted or unsubstituted C _1-5 straight or branched alkoxy, -CN, -NO ₂ , C _1-5 linear or branched alkylcarbonyl Lt; / RTI > may be substituted with one or more substituents selected from the group consisting of hydrogen, halogen and halogen.

The present invention also relates to a process for producing a compound represented by the formula (1)

Reacting a compound represented by the formula (2) with a compound represented by the formula (3) to prepare a compound represented by the formula (4) (step 1); And

A step of reacting a compound represented by the formula (4) prepared in the above step 1 with a compound represented by the formula (5) to prepare a compound represented by the formula (1) (step 2) Lt; / RTI >

[Reaction Scheme 1]

(In the above Reaction Scheme 1,

X and Y are independently as defined in Formula 1 above; And

A is a halogen).

Further, the present invention relates to a process for the preparation of

Reacting a compound represented by the formula (6) with a compound represented by the formula (7) to prepare a compound represented by the formula (8) (step 1);

Preparing a compound represented by the formula (9) from the compound represented by the formula (8) prepared in the step (1) (step 2);

Preparing a compound represented by the formula (4) from the compound represented by the formula (9) prepared in the step (2) (step 3); And

Reacting the compound represented by the formula (4) prepared in the above step 3 with the compound represented by the formula (5) to prepare a compound represented by the formula (1) (step 4) The method provides:

[Reaction Scheme 2]

(In the above Reaction Scheme 2,

X and Y are independently as defined in the above formula (1)).

The present invention also provides a pharmaceutical composition for preventing or treating cancer comprising as an active ingredient a compound represented by the above-mentioned formula (1) or a pharmaceutically acceptable salt thereof and a TRAIL (TNF-related apoptosis inducing ligand).

Furthermore, the present invention provides an anticancer adjuvant containing the above compound or a pharmaceutically acceptable salt thereof as an active ingredient.

The compound according to the present invention, its optical isomer or its pharmaceutically acceptable salt has excellent TRAIL resistance-inhibiting activity in a cancer having TRAIL resistance, and when it is used as a pharmaceutical composition containing it as an active ingredient, for example, When used in combination with TRAIL, there is a useful effect in the prevention and treatment of cancer.

FIG. 1 is a graph showing cancer cell survival rate by concentration (1.25 uM - 40 uM) of the compound of Example 1 alone or TRAIL simultaneously.
FIG. 2 is a graph showing tumor cell survival rates by concentration (1.25 uM-40 uM) of the compound of Example 3 alone or TRAIL simultaneously.
FIG. 3 is a graph showing tumor cell survival rates (1.25 uM - 40 uM) of the compound of Example 9 alone or in concurrent treatment with TRAIL.
FIG. 4 is a graph showing tumor cell survival rates (1.25 uM-40 uM) at the time of simultaneous treatment of the compound of Example 10 alone or TRAIL.
Figure 5a is a photograph of western blot for MKK7 and TIPRL of Example 1 compound via IP method.
6 (a) is a photograph showing a TIPRL expression vector, and FIG. 6 (b) is a photograph showing an MKK7 expression vector.
Figure 7a is a photograph showing the western blot of the compound of Example 1 via the GST pull-down method. Figure 7b is a photograph of western blot for MKK7 and TIPRL of Example 3 compound via GST pull down method.
FIG. 8A is an image and a chart showing the results of inhibition of mutual binding of MKK7 and TIPRL of Example 1 compound by immunofluorescence staining and optical focus microscopic observation. FIG. FIG. 8 (b) is an image and a diagram showing the result of inhibition of mutual binding of MKK7 and TIPRL of Example 3 compound by immunofluorescence staining and optical focus microscopic observation.

Hereinafter, the present invention will be described in detail.

The following description is provided to assist the understanding of the invention, and the present invention is not limited to the following description.

The present invention provides a compound represented by the following general formula (1): < EMI ID =

[Chemical Formula 1]

(In the formula 1,

X is a substituted or unsubstituted phenyl,

Wherein the substituted phenyl is C _1-5 linear or branched alkyl, substituted or unsubstituted C _1-5 straight or branched alkoxy, -CN, -NO ₂ , C _1-5 linear or branched alkylcarbonyl ≪ / RTI > nitro and halogen; And

Y is substituted or unsubstituted phenyl,

Wherein the substituted phenyl is C _1-5 linear or branched alkyl, substituted or unsubstituted C _1-5 straight or branched alkoxy, -CN, -NO ₂ , C _1-5 linear or branched alkylcarbonyl Lt; / RTI > may be substituted with one or more substituents selected from the group consisting of hydrogen, halogen and halogen.

Preferably,

X is a substituted or unsubstituted phenyl,

Wherein the substituted phenyl is C _1-3 straight or branched chain alkyl substituted with halogen, C _1-3 linear or branched alkoxy, -CN, C _1-3 straight or branched alkylcarbonyl and halogen ≪ RTI ID = 0.0 > and / or < / RTI > And

Y is substituted or unsubstituted phenyl,

Wherein the substituted phenyl is C _1-3 straight or branched chain alkyl substituted with halogen, C _1-3 linear or branched alkoxy, -CN, C _1-3 straight or branched alkylcarbonyl and halogen ≪ / RTI > may be substituted with one or more substituents selected from the group consisting of < RTI ID = 0.0 >

More preferably,

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또는

이고; 및X is

,

,

,

,

,

,

,

,

or

ego; And

,

,

,

,

또는

이다.Y is

,

,

,

,

or

to be.

Preferable examples of the compound represented by the formula (1) according to the present invention include the following compounds.

(1) N- (1- (5-acetyl-2,4-dichlorophenyl) -1H-indazol-5-yl) benzenesulfonamide;

(2) N- (1- (4-chlorophenyl) -1H-indazol-5-yl) -4-methoxybenzenesulfonamide;

(3) N- (1- (4-fluorophenyl) -1H-indazol-5-yl) -4-methoxybenzenesulfonamide;

(4) N- (1- (2-chlorophenyl) -1H-indazol-5-yl) -4-methoxybenzenesulfonamide;

(5) N- (1- (2,4-Difluorophenyl) -1H-indazol-5-yl) -4-methoxybenzenesulfonamide;

(6) N- (1- (2,4-Dichlorophenyl) -1H-indazol-5-yl) -2-fluorobenzenesulfonamide;

(7) N- (1- (2,4-dichlorophenyl) -1H-indazol-5-yl) -3-methylbenzenesulfonamide;

(8) 4-Fluoro-N- (1- (4-fluorophenyl) -1H-indazol-5-yl) benzenesulfonamide;

(9) N- (1- (4-fluorophenyl) -1H-indazol-5-yl) -3-methylbenzenesulfonamide;

(10) N- (1- (4-fluorophenyl) -1H-indazol-5-yl) -3- (trifluoromethyl) benzenesulfonamide;

(11) 4-Cyano-N- (1- (4-fluorophenyl) -1H-indazol-5-yl) benzenesulfonamide;

(12) N- (1- (2,4-Difluorophenyl) -1H-indazol-5-yl) -2-fluorobenzenesulfonamide;

(13) N- (1- (2,4-Difluorophenyl) -1H-indazol-5-yl) -4-methylbenzenesulfonamide;

(14) 4-Chloro-N- (1- (4-fluorophenyl) -1H-indazol-5-yl) benzenesulfonamide; And

(15) 3-Fluoro-N- (1- (4-fluorophenyl) -1H-indazol-5-yl) -4-methylbenzenesulfonamide.

The compound represented by the formula (1) of the present invention can be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid and the like, aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, Derived from organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid and the like. Examples of such pharmaceutically innocuous salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, But are not limited to, but are not limited to, but are not limited to, but are not limited to, but are not limited to, halides, halides, halides, halides, halides, halides, But are not limited to, lactose, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chloro Such as benzenesulfonate, benzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate,? -Hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1-sulfonate, naphthalene-2-sulfonate, mandelate and the like.

The acid addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the derivative of Chemical Formula 1 in an organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile and the like, Followed by filtration and drying, or by distillation of the solvent and excess acid under reduced pressure, followed by drying and crystallization in an organic solvent.

In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt. In addition, the corresponding salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable salt (such as silver nitrate).

Furthermore, the present invention encompasses the compounds represented by the formula (1) and pharmaceutically acceptable salts thereof as well as solvates, optical isomers and hydrates thereof which can be prepared therefrom.

The present invention also relates to a process for producing a compound represented by the formula (1)

Reacting a compound represented by the formula (2) with a compound represented by the formula (3) to prepare a compound represented by the formula (4) (step 1); And

A step of reacting a compound represented by the formula (4) prepared in the above step 1 with a compound represented by the formula (5) to prepare a compound represented by the formula (1) (step 2) Lt; / RTI >

[Reaction Scheme 1]

(In the above Reaction Scheme 1,

X and Y are independently as defined in Formula 1 above; And

A is a halogen).

Hereinafter, the process for preparing the compound represented by the formula (1) according to the present invention will be described in detail.

In the process for preparing a compound represented by the formula (1) according to the present invention, the compound represented by the formula (2) is reacted with the compound represented by the formula (3) .

At this time, H ₂ O, ethanol, tetrahydrofuran (THF), dichloromethane, toluene, acetonitrile, dimethylformamide and the like can be used as the solvent which can be used in the above step, and dimethylformamide is preferably used .

The reaction temperature in the above step is not particularly limited, but is preferably 90-130 ° C. The reaction time is not particularly limited, but is preferably 0.5-30 hours.

In step (2), the compound of formula (4) prepared in step (1) is reacted with a compound of formula (5) to obtain a compound of formula Is a step of preparing a compound represented by the formula

At this time, H ₂ O, ethanol, tetrahydrofuran (THF), dichloromethane, toluene, acetonitrile, dimethylformamide and the like can be used as the solvent in the above step, and dichloromethane can be preferably used.

The reaction temperature in the above step is not particularly limited, but is preferably 20-30 ° C. The reaction time is not particularly limited, but is preferably 0.5-20 hours.

In a preferred embodiment of the process for preparing the compound represented by the general formula (1) according to the present invention represented by the above-mentioned Reaction Scheme 1, there can be mentioned the process of Example 1 of the present invention and the process of Example 6 to 15, The scope of the present invention includes the range of changes or modifications that can be ordinarily performed by those skilled in the art.

Further, the present invention relates to a process for the preparation of

Reacting a compound represented by the formula (6) with a compound represented by the formula (7) to prepare a compound represented by the formula (8) (step 1);

Preparing a compound represented by the formula (9) from the compound represented by the formula (8) prepared in the step (1) (step 2);

Preparing a compound represented by the formula (4) from the compound represented by the formula (9) prepared in the step (2) (step 3); And

Reacting the compound represented by the formula (4) prepared in the above step 3 with the compound represented by the formula (5) to prepare a compound represented by the formula (1) (step 4) The method provides:

[Reaction Scheme 2]

(In the above Reaction Scheme 2,

X and Y are independently as defined in the above formula (1)).

Hereinafter, the process for preparing the compound represented by the formula (1) according to the present invention represented by the above-mentioned reaction formula 2 will be described in detail.

In the process for preparing a compound represented by the general formula (1) according to the present invention, the compound represented by the general formula (6) is reacted with the compound represented by the general formula (7) .

At this time, H ₂ O, ethanol, tetrahydrofuran (THF), dichloromethane, toluene, acetonitrile, dimethylformamide and the like can be used as the solvent in the above step, and ethanol can be preferably used.

In the above step, the reaction time is not particularly limited, but it is preferable that the reaction is carried out for 0.5 to 10 hours.

In the process for preparing the compound represented by the formula (1) according to the present invention represented by the above-mentioned reaction formula 2, the above step 2 is a step for preparing the compound represented by the formula (9) from the compound represented by the formula (8) .

At this time, H ₂ O, ethanol, tetrahydrofuran (THF), dichloromethane, toluene, acetonitrile, dimethylformamide and the like can be used as the solvent which can be used in the above step, and dimethylformamide is preferably used .

The reaction temperature in the above step is not particularly limited, but is preferably 90-110 ° C. The reaction time is not particularly limited, but it is preferably 10-20 hours.

In the process for preparing a compound represented by the general formula (1) according to the present invention represented by the above-mentioned Reaction Scheme 2, the above Step 3 is a step for preparing a compound represented by the general formula (4) from a compound represented by the general formula (9) .

At this time, H ₂ O, ethanol, tetrahydrofuran (THF), dichloromethane, toluene, acetonitrile, dimethylformamide and the like can be used as the solvent in the above step, and dichloromethane can be preferably used.

The reaction temperature in the above step is not particularly limited, but is preferably 20-30 ° C. The reaction time is not particularly limited, but is preferably 0.5-10 hours.

In the process for preparing a compound represented by the formula (1) according to the present invention, the compound represented by the formula (4) is reacted with a compound represented by the formula (5) 1 < / RTI >

At this time, H ₂ O, ethanol, tetrahydrofuran (THF), dichloromethane, toluene, acetonitrile, dimethylformamide and the like can be used as the solvent in the above step, and dichloromethane can be preferably used.

The reaction temperature in the above step is not particularly limited, but is preferably 20-30 ° C. The reaction time is not particularly limited, but is preferably 10-30 hours.

In a preferred embodiment of the process for preparing a compound represented by the general formula (1) according to the present invention represented by the above-mentioned Reaction Scheme 2, there can be mentioned the processes of Examples 2 to 5 of the present invention, And the scope of modification or modification that can be performed normally is also included in the manufacturing method of the present invention.

The present invention also provides a pharmaceutical composition for preventing or treating cancer comprising as an active ingredient a compound represented by the above-mentioned formula (1) or a pharmaceutically acceptable salt thereof and a TRAIL (TNF-related apoptosis inducing ligand).

Herein, the compound represented by the above formula (1) has an effect of inhibiting TRAIL resistance against cancer that is resistant to TRAIL and inducing cancer death. Therefore, when the compound of formula (I) or a pharmaceutically acceptable salt thereof according to the present invention is administered together with TRAIL, it can be confirmed through the present invention that it has a remarkable effect of killing cancer cells. Accordingly, the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof and TRAIL according to the present invention can be effectively used as a pharmaceutical composition for the prevention or treatment of cancer, wherein the compound represented by the formula The compound or a pharmaceutically acceptable salt thereof is useful as a cancer-preventing adjuvant. In addition, the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof according to the present invention can be used in combination with other pharmaceutical compositions such as anticancer drugs, anti-inflammatory drugs and rheumatoid arthritis drugs in addition to TRAIL It will be apparent to those skilled in the art that the present invention covers this. Further, applications involving modifications and changes from the compounds of the present invention are included in the present invention as far as they are ordinarily permitted to those skilled in the art.

The cancer may be, for example, colon cancer, liver cancer, stomach cancer, breast cancer, colon cancer, bone cancer, pancreatic cancer, head or neck cancer, uterine cancer, ovarian cancer, rectal cancer, esophageal cancer, small intestine cancer, One or more selected from the group consisting of endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, prostate cancer, bladder cancer, renal cancer, ureter cancer, kidney cell carcinoma, renal pelvic carcinoma central nervous system tumor and leukemia Can be.

The present invention also provides an anticancer adjuvant containing the above compound or a pharmaceutically acceptable salt thereof as an active ingredient.

The compound according to the present invention or its pharmaceutically acceptable salt has an effect of enhancing the TRAIL sensitivity as shown in the experimental example of the present invention, and thus, the cancer cell killing effect of TRAIL is markedly increased in cancer diseases such as liver cancer and the like Respectively. Accordingly, a compound according to the present invention or a pharmaceutically acceptable salt thereof may be useful as a TRAIL sensitivity enhancer of a chemotherapeutic adjuvant, TRAIL sensitivity enhancer or other pharmaceutical composition.

Further, the present invention provides a health functional food for preventing or ameliorating a cancer containing the compound represented by the above-mentioned formula (1) or a pharmaceutically acceptable salt thereof and TRAIL (TNF-related apoptosis inducing ligand) as an active ingredient.

Herein, the health functional food refers to a health functional food that can be used for prevention or improvement of cancer within a range applicable to any person skilled in the art. As can be seen from the experimental examples of the present invention, the compound of the present invention or a pharmaceutically acceptable salt thereof is based on the effects of enhancing the TRAIL sensitivity and enhancing the cancer cell killing effect.

The compound of formula (I) according to the present invention may be administered orally or parenterally in a variety of formulations at the time of clinical administration. In the case of formulation, the compound of the present invention may be used as a filler, an extender, a binder, a wetting agent, a disintegrant, Diluents or excipients.

Solid formulations for oral administration include tablets, pills, powders, granules, capsules, troches, and the like, which may contain one or more excipients such as starch, calcium carbonate, Sucrose, lactose, gelatin or the like. In addition to simple excipients, lubricants such as magnesium stearate talc are also used. Liquid preparations for oral administration include suspensions, solutions, emulsions or syrups. Various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like are included in addition to commonly used simple diluents such as water and liquid paraffin. .

Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, and the like. Examples of the non-aqueous solvent and suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. As a base for suppositories, witepsol, macrogol, tween 61, cacao paper, laurin, glycerol, gelatin and the like can be used.

The effective dose of the compound of the present invention on the human body may vary depending on the age, weight, sex, dosage form, health condition and disease severity of the patient, and is generally about 0.001-100 mg / kg / 0.0 > mg / kg / day. ≪ / RTI > It is generally from 0.07 to 7000 mg / day, preferably from 0.7 to 2500 mg / day, based on adult patients weighing 70 kg, and may be administered once a day It may be divided into several doses.

As indicated herein, a compound according to the invention, or a pharmaceutically acceptable salt thereof, inhibits the TRAIL-resistant mechanism of action in a cancer having TRAIL resistance, thereby enhancing TRAIL sensitivity, and concomitantly with TRAIL There is an effect of remarkably increasing the cancer cell killing effect.

The foregoing was confirmed through the following experimental examples,

As a result of the experiment to evaluate the effect of the compound according to the present invention on the TRAIL sensitivity of cancer, the compound according to the present invention showed excellent resistance to TRAIL of cancer cells (See Experimental Example 1). The results are shown in Table 1 below.

In addition, experiments for evaluating mutual binding inhibition of MKK7 and TIPRL by immunoprecipitation (IP), immunofluorescence staining and photomicroscopic observation, and GST pull-down method of the compounds according to the present invention were conducted. As shown in Example 2 (2-1 to 2-3), the compound according to the present invention has an effect of inhibiting the mutual binding of MKK7 and TIPRL, and thus has an effect of inhibiting TRAIL resistance of cancer And it can be used for prevention and treatment of cancer (see Experimental Examples 2-1 to 2-3).

Hereinafter, the present invention will be described in detail with reference to Examples and Experimental Examples.

However, the following examples and experimental examples are illustrative of the present invention, and the present invention is not limited thereto.

< Example  1 > N- (1- (5-acetyl-2,4- Dichlorophenyl ) -1H- Indazole -5 days) Benzenesulfonamide (TRT-0029)

step 1: 1 - (5- (5-amino-1H- Indazole -1-yl) -2, 4- Dichlorophenyl ) Ethane  Produce

1-one (10.0 g, 48.3 mmol), 1H-indazol-5-amine (6.40 g, 48.1 mmol) and K ₂ CO ₃ (66.8 g, 483 mmol) was dissolved in DMF (200 ml), and the mixture was stirred at 110 ° C for 20 hours. After the reaction was complete, the layers were separated with DCM and H ₂ O, the DCM layer was washed several times with H ₂ O and then concentrated. The concentrated residue was subjected to silica gel column chromatography (Hex: DCM: EA = 1: 5: 1) to obtain the desired compound (1.00 g, 6%).

^{1 H NMR (500 MHz, CDCl} 3): δ = 8.11 (s, 1H), 8.05 (s, 1H), 7.94 (s, 1H), 7.09 (d, J = 8.8 Hz, 1H), 6.87 (d, J = 8.1 Hz, 2H), 5.02 (s, 2H), 2.63 ppm (s, 3H). MS (ESI): m / z: 320 [M + H ^& lt ^{; +} & gt ^; ].

Step 2: N- (1- (5-Acetyl-2,4- Dichlorophenyl ) -1H- Indazole -5 days) Benzenesulfonamide Manufacturing

The compound (30 mg, 0.094 mmol) prepared in Step 1 and benzenesulfonyl chloride (0.014 ml, 0.11 mmol) were dissolved in DCM (2 ml), pyridine (0.011 ml, 0.14 mmol) Stir for 15 hours. After completion of the reaction, the reaction mixture was separated into DCM and H ₂ O and the DCM layer was concentrated. The concentrated residue was subjected to silica gel column chromatography (Hex: EA = 4: 1) to obtain the desired compound (25 mg, 58%).

^{1 H NMR (500 MHz, CDCl} 3): δ = 8.18 (s, 1H), 7.76 (t, J = 7.5 Hz, 3H), 7.72 (s, 1H), 7.57-7.54 (m, 2H), 7.46 ( t, J = 8.00 Hz, 2H), 7.13 (d, J = 1.5 Hz, 2H), 6.69 (s, 1H), 2.70 ppm (s, 3H). MS (ESI): m / z: 460 [M + H ^& lt ^{; +} & gt ^; ].

< Example  2 > N- (1- (4- Chlorophenyl ) -1H- Indazole -5-yl) -4- Methoxybenzenesulfonamide  Manufacturing (TRT-0172)

step 1: 1 -(4- Chlorophenyl ) -2- (2- Fluoro -5- Nitrobenzylidene ) Preparation of hydrazine

4-Chlorophenylhydrazine (42 mg, 0.29 mmol) and TSA.H ₂ O (3 mg, 0.02 mmol) were dissolved in EtOH (1 ml), followed by the addition of 2-fluoro-5-nitrobenzaldehyde ), And the mixture is refluxed for 1 hour. Concentration was followed by solidification to obtain the desired compound (67 mg, 84%).

^{1 H NMR (500 MHz, CDCl} 3): δ = 8.85 (dd, J = 2.8 Hz, 6.2Hz, 1H), 8.15 (m, 1H), 7.88 (s, 1H), 7.28 (d, J = 8.8Hz , 7.21 (t, J = 9.3 Hz, 1H), 7.10 (d, J = 8.7 Hz, 2H), 1.26 ppm (s, 1H). MS (ESI): m / z: 294 [M + H ^& lt ^{; +} & gt ^; ].

step 2: 1 -(4- Chlorophenyl ) -5-nitro-lH- Indazole  Produce

(47 mg, 0.16 mmol) and K ₂ CO ₃ (97 mg, 0.70 mmol) were added to DMF (2 ml), and the mixture was stirred at 100 ° C for 15 hours. The layers were separated with EA and H ₂ O and the EA layer was washed several times with water and then concentrated. The residue was subjected to silica gel column chromatography (Hex: EA = 1: 1) to give the desired compound (20 mg, 46%).

^{1 H NMR (300 MHz, CDCl} 3): δ = 8.80 (d, J = 1.9 Hz, 1H), 8.41 (s, 1H), 8.33 (dd, J = 2.1 Hz, 9.3 Hz, 1H), 7.70 (m , 3H), 7.56 ppm (dd, J = 2.1 Hz, 6.7 Hz, 2H). MS (ESI): m / z: 274 [M + H ^& lt ^{; +} & gt ^; ].

step 3: 1 -(4- Chlorophenyl ) -1H- Indazole -5- Amine  Produce

The compound (16 mg, 0.058 mmol) prepared in the above step 2 was dissolved in DCM (5 ml), followed by the addition of Pd / C (10% Time was shaken. After completion of the reaction, the reaction mixture was filtered on celite and evaporated under reduced pressure to obtain the desired compound (14 mg, 99%).

^{1 H NMR (500 MHz, CDCl} 3): δ = 8.8 (s, 1H), 7.77 (t, J = 7.0 Hz, 2H), 7.61 (m, 3H), 7.92 (dd, J = 2.1 Hz, 9.0 Hz , &Lt; / RTI &gt; 1H), 6.86 (d, J = 1.8 Hz, 1H), 5.06 ppm (s, 1H). MS (ESI): m / z: 244 [M + H ^& lt ^{; +} & gt ^; ].

Step 4: N- (1- (4- Chlorophenyl ) -1H- Indazole -5-yl) -4- Methoxybenzenesulfonamide  Produce

(8 mg, 0.03 mmol) and 4-methoxybenzenesulfonyl chloride (8 mg, 0.04 mmol) were dissolved in DCM (2 ml), pyridine (0.004 ml, 0.05 mmol) was added And then stirred at room temperature for 15 hours. After completion of the reaction, the reaction mixture was separated into DCM and H ₂ O and the DCM layer was concentrated. The concentrated residue was subjected to silica gel column chromatography (Hex: EA = 4: 1) to obtain the desired compound (6 mg, 48%).

^{1 H NMR (500 MHz, CDCl} 3): δ = 8.14 (s, 1H), 7.70-7.68 (m, 1H), 7.65 (d, J = 8.5 Hz, 3H), 7.59 (d, J = 9.0 Hz, 1H), 7.51 (d, J = 8.1 Hz, 3H), 7.19 (d, J = 7.5 Hz, 1H), 6.90 (d, J = 8.9 Hz, 2H), 3.84 ppm (s, 3H). MS (ESI): m / z: 414 [M + H ^& lt ^{; +} & gt ^; ].

< Example  3 > N- (1- (4- Fluorophenyl ) -1H- Indazole -5-yl) -4- Methoxybenzenesulfonamide ( TRT -0173)

step 1: 1 -(2- Fluoro -5- Nitrobenzylidene ) -2- (4- Fluorophenyl ) Preparation of hydrazine

(50 mg, 0.27 mmol) was dissolved in EtOH (1 ml), 4-fluorophenylhydrazine (37 mg, 0.29 mmol) and TSA.H ₂ O (3 mg, 0.02 mmol), and the mixture is refluxed for 1 hour. Concentrated and then solidified to obtain the desired compound (65 mg, 87%).

^{1 H NMR (300 MHz, CDCl} 3): δ = 8.84 (dd, J = 2.9 Hz, 6.2 Hz, 1H), 8.12 (m, 1H), 7.86 (s, 1H), 7.23 (t, J = 9.3 Hz , &Lt; / RTI &gt; 1H), 7.08 ppm (m, 4H). MS (ESI): m / z: 278 [M + H ^& lt ^{; +} & gt ^; ].

step 2: 1 -(4- Fluorophenyl ) -5-nitro-lH- Indazole  Produce

(61 mg, 0.22 mmol) and K ₂ CO ₃ (134 mg, 0.97 mmol) were added to DMF (2 ml), and the mixture was stirred at 100 ° C for 15 hours. The layers were separated with EA and H ₂ O and the EA layer was washed several times with water and then concentrated. The residue was subjected to silica gel column chromatography (Hex: EA = 1: 1) to obtain the desired compound (17 mg, 30%).

^{1 H NMR (300 MHz, CDCl} 3): δ = 8.80 (d, J = 2.0 Hz, 1H), 8.40 (s, 1H), 8.32 (dd, J = 2.1 Hz, 9.2 Hz, 1H), 7.68 (m , 3H), 7.30 ppm (t, J = 6.1 Hz, 2H). MS (ESI): m / z: 258 [M + H ^& lt ^{; +} & gt ^; ].

step 3: 1 -(4- Fluorophenyl ) -1H- Indazole -5- Amine  Produce

The compound (17 mg, 0.066 mmol) obtained in the above step 2 was dissolved in DCM (5 ml), Pd / C (10%) (10 mg) was added, and then hydrogen (60-70 psi) Time was shaken. After completion of the reaction, the mixture was filtered on celite and evaporated under reduced pressure to obtain the desired compound (14 mg, 93%).

^{1 H NMR (300 MHz, CDCl} 3): δ = 8.03 (s, 1H), 7.74 (dd, J = 5.2 Hz, 8.1 Hz, 2H), 7.55 (d, J = 8.9 Hz, 1H, 7.38 (t, J = 8.7 Hz, 2H), 6.88 (t, J = 8.2 Hz, 2H), 5.00 ppm (s, 1H). MS (ESI): m / z: 228 [M + H ⁺ ].

Step 4: N- (1- (4- Fluorophenyl ) -1H- Indazole -5-yl) -4- Methoxybenzenesulfonamide  Produce

(7 mg, 0.03 mmol) and 4-methoxybenzenesulfonyl chloride (8 mg, 0.04 mmol) were dissolved in DCM (2 ml), pyridine (0.004 ml, 0.05 mmol) And then stirred at room temperature for 15 hours. After the reaction was complete, the layers were separated with DCM and H ₂ O and the DCM layer was concentrated. The concentrated residue was subjected to silica gel column chromatography (Hex: EA = 4: 1) to obtain the desired compound (8 mg, 70%).

^{1 H NMR (500 MHz, CDCl} 3): δ = 8.13 (s, 1H), 7.69-7.64 (m, 4H), 7.61 (d, J = 9.0 Hz, 1H), 7.50 (d, J = 1.75 Hz, 1H), 7.25 (t, J = 8.6 Hz, 2H), 7.17 (dd, J = 2.0 Hz, 9.0 Hz, ), 3.85 ppm (s, 1 H). MS (ESI): m / z: 398 [M + H ^& lt ^{; +} & gt ^; ].

< Example  4 > N- (1- (2- Chlorophenyl ) -1H- Indazole -5-yl) -4- Methoxybenzenesulfonamide  Manufacturing (TRT-0176)

step 1: 1 -(2- Chlorophenyl ) -2- (2- Fluoro -5- Nitrobenzylidene ) Preparation of hydrazine

2-fluoro-5-nitrobenzaldehyde (50 mg, 0.27 mmol) was dissolved in EtOH (1 ml), and 2-chlorophenylhydrazine (42 mg, 0.29 mmol) and TSA.H ₂ O (3 mg, 0.02 mmol ), And the mixture is refluxed for 1 hour. After concentration and solidification, the desired compound (55 mg, 69%) was obtained.

^{1 H NMR (500 MHz, CDCl} 3): δ = 8.89 (dd, J = 2.9 Hz, 6.2 Hz, 1H), 8.44 (s, 1H), 8.19 (m, 1H), 8.03 (s, 1H), 7.68 (d, J = 1.4 Hz, 10 Hz, 1H), 7.29 (m, 2H), 7.31 (t, J = 5.0 Hz, 2H), 7.23 ). MS (ESI): m / z: 294 [M + H ^& lt ^{; +} & gt ^; ].

step 2: 1 -(2- Chlorophenyl ) -5-nitro-lH- Indazole  Produce

(51 mg, 0.17 mmol) and K ₂ CO ₃ (106 mg, 0.767 mmol) were added to DMF (2 ml), and the mixture was stirred at 100 ° C for 15 hours. The layers were separated with EA and H ₂ O and the EA layer was washed several times with water and concentrated. The residue was subjected to silica gel column chromatography (Hex: EA = 1: 1) to give the desired compound (18 mg, 38%).

^{1 H NMR (300 MHz, CDCl} 3): δ = 8.81 (d, J = 1.5 Hz, 1H), 8.44 (s, 1H), 8.29 (dd, J = 1.9 Hz, 9.2 Hz, 1H), 7.64 (m , &Lt; / RTI &gt; 1H), 7.53 (m, 3H), 7.30 ppm (d, J = 9.3 Hz, 1H). MS (ESI): m / z: 274 [M + H ^& lt ^{; +} & gt ^; ].

step 3: 1 -(2- Chlorophenyl ) -1H- Indazole -5- Amine  Produce

The compound (17 mg, 0.062 mmol) prepared in the above step 2 was dissolved in DCM (5 ml), Pd / C (10%) (10 mg) was added, and then hydrogen (60-70 psi) Time was shaken. After completion of the reaction, the reaction mixture was filtered on celite and evaporated under reduced pressure to obtain the desired compound (13 mg, 87%).

^{1 H NMR (300 MHz, CDCl} 3): δ = 8.04 (s, 1H), 7.72 (m, 1H), 7.54 (d, J = 3.1 Hz, 3H), 6.97 (d, J = 9.7 Hz, 1H) , 6.83 (m, 2H), 4.95 ppm (s, 2H). MS (ESI): m / z: 244 [M + H ^& lt ^{; +} & gt ^; ].

Step 4: Preparation of N- (1- (2- Chlorophenyl ) -1H- Indazole -5-yl) -4- Methoxybenzenesulfonamide  Produce

(7 mg, 0.03 mmol) and 4-methoxybenzenesulfonyl chloride (7 mg, 0.03 mmol) were dissolved in DCM (2 ml), pyridine (0.004 ml, 0.05 mmol) And then stirred at room temperature for 15 hours. After completion of the reaction, the reaction mixture was separated into DCM and H ₂ O and the DCM layer was concentrated. The concentrated residue was subjected to silica gel column chromatography (Hex: EA = 4: 1) to obtain the desired compound (10 mg, 83%).

^{1 H NMR (300 MHz, CDCl} 3): δ = 8.15 (s, 1H), 7.67 (d, J = 8.9 Hz, 2H), 7.59 (m, 1H), 7.45 (m, 4H), 7.11 (s, 1H), 6.88 (d, J = 8.9 Hz), 6.75 (s, 1H), 3.82 ppm (s, 1H). MS (ESI): m / z: 414 [M + H ^& lt ^{; +} & gt ^; ].

< Example  5 > N- (1- (2,4- Difluorophenyl ) -1H- Indazole -5-yl) -4- Methoxybenzenesulfonamide Manufacture of Mead ( TRT -0177)

step 1: 1 - (2,4- Difluorophenyl ) -2- (2- Fluoro -5- Nitrobenzylidene ) Preparation of hydrazine

(50 mg, 0.27 mmol) was dissolved in EtOH (1 ml), 2,4-difluorophenylhydrazine (43 mg, 0.30 mmol) and TSA.H ₂ O (3 mg, 0.02 mmol), and the mixture is refluxed for 1 hour. After concentration and solidification, the desired compound (70 mg, 88%) was obtained.

^{1 H NMR (300 MHz, CDCl} 3): δ = 8.85 (dd, J = 2.9 Hz, 6.2 Hz, 1H), 8.16 (m, 1H), 7.97 (s, 1H), 7.59 (m, 1H), 7.21 (m, 1 H), 6.89 ppm (m, 2 H). MS (ESI): m / z: 296 [M + H ^& lt ^{; +} & gt ^; ].

step 2: 1 - (2,4- Difluorophenyl ) -5-nitro-lH- Indazole  Produce

(65 mg, 0.22 mmol) and K ₂ CO ₃ (134 mg, 0.970 mmol) were added to DMF (2 ml), and the mixture was stirred at 100 ° C for 15 hours. The layers were separated with EA and H ₂ O and the EA layer was washed several times with water and then concentrated. The residue was subjected to silica gel column chromatography (Hex: EA = 1: 1) to give the desired compound (20 mg, 33%).

^{1 H NMR (300 MHz, CDCl} 3): δ = 8.80 (d, J = 2.0 Hz, 1H), 8.44 (s, 1H), 8.32 (dd, J = 2.1 Hz, 9.2 Hz, 1H), 7.65 (dd J = 5.9 Hz, 8.3 Hz, 1H), 7.40 (dd, J = 3.1 Hz, 9.2 Hz, 1H), 7.12 ppm (dd, J = 1.0 Hz, 16.3 Hz, 2H). MS (ESI): m / z: 276 [M + H ^& lt ^{; +} & gt ^; ].

step 3: 1 - (2,4- Difluorophenyl ) -1H- Indazole -5- Amine  Produce

(20 mg, 0.073 mmol) was dissolved in DCM (5 ml), Pd / C (10%) (10 mg) was added, and hydrogen (60-70 psi) Time was shaken. After completion of the reaction, the reaction mixture was filtered on celite and evaporated under reduced pressure to obtain the title compound (12 mg, 67%).

^{1 H NMR (300 MHz, CDCl} 3): δ = 8.07 (s, 1H), 7.63 (m, 2H), 7.30 (t, J = 0.8 Hz, 1H), 7.11 (m, 1H), 6.86 (d, J = 9.6 Hz, 2H), 4.98 ppm (s, 2H). MS (ESI): m / z: 246 [M + H ^& lt ^{; +} & gt ^; ].

Step 4: N- (1- (2,4- Difluorophenyl ) -1H- Indazole -5-yl) -4- Methoxybenzenesulfonamido Manufacture of de

(6 mg, 0.02 mmol) and 4-methoxybenzenesulfonyl chloride (6 mg, 0.03 mmol) were dissolved in DCM (2 ml), pyridine (0.004 ml, 0.05 mmol) And stirred at room temperature for 15 hours. After the reaction was complete, the layers were separated with DCM and H ₂ O and the DCM layer was concentrated. The concentrated residue was subjected to silica gel column chromatography (Hex: EA = 4: 1) to obtain the desired compound (6 mg, 60%).

^{1 H NMR (300 MHz, CDCl} 3): δ = 8.15 (s, 1H), 7.66 (d, J = 8.9 Hz, 2H), 7.55 (m, 2H), 7.22 (dd, J = 2.9 Hz, 8.9 Hz 1H), 7.09 (m, 3H), 6.88 (d, J = 8.9 Hz, 2H), 6.49 (s, 1H), 3.82 ppm (s, 3H). MS (ESI): m / z: 416 [M + H ^& lt ^{; +} & gt ^; ].

< Example  6 > N- (1- (2,4- Dichlorophenyl ) -1H- Indazole -5-yl) -2- Fluorobenzene sulfonate Manufacture of Mead ( TRT -0184)

step 1: 1 - (2,4- Dichlorophenyl ) -1H- Indazole -5- Amine  Produce

The reaction conditions set forth in WO 2008057857 were applied to obtain the desired compound as an intermediate.

^{1 H NMR (30 MHz, CDCl} 3): δ = 8.06 (s, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.60 (t, J = 5.0 Hz, 2H), 7.01 (d, J = 9.3 Hz, 1H), 6.85 (m, 2H), 4.97 ppm (s, 2H). MS (ESI): m / z: 278 [M + H ^& lt ^{; +} & gt ^; ].

Step 2: N- (1- (2,4- Dichlorophenyl ) -1H- Indazole -5-yl) -2- Fluorobenzenesulfonamido Manufacture of de

(20 mg, 0.072 mmol) and 2-fluorobenzenesulfonyl chloride (0.011 ml, 0.083 mmol) were dissolved in DCM (2 ml), pyridine (0.009 ml, 0.1 mmol) was added And stirred at room temperature for 15 hours. After completion of the reaction, the reaction mixture was separated into DCM and H ₂ O and the DCM layer was concentrated. The concentrated residue was subjected to silica gel column chromatography (Hex: EA = 4: 1) to obtain the desired compound (24 mg, 76%).

^{1 H NMR (500 MHz, CDCl} 3): δ = 8.16 (s, 1H), 7,79 (m, 1H), 7.58 (m, 3H), 7.41 (s, 2H), 7.22 (m, 3H), 7.12 (d, J = 8.9 Hz, 1 H), 6.90 ppm (s, 1 H). MS (ESI): m / z: 436 [M + H ^& lt ^{; +} & gt ^; ].

< Example  7 > N- (1- (2,4- Dichlorophenyl ) -1H- Indazole Yl) -3- Methylbenzenesulfonamide ( TRT -0190)

step 1: 1 - (2,4- Dichlorophenyl ) -1H- Indazole -5- Amine  Produce

The procedure of Step 1 of Example 6 was repeated to give the target compound.

Step 2: N- (1- (2,4- Dichlorophenyl ) -1H- Indazole Yl) -3- Methylbenzenesulfonamide  Produce

(20 mg, 0.072 mmol) and 3-methylbenzenesulfonyl chloride (0.013 ml, 0.090 mmol) were dissolved in DCM (2 ml), pyridine (0.009 ml, 0.1 mmol) was added And the mixture was stirred at room temperature for 15 hours. After completion of the reaction, the reaction mixture was separated into DCM and H ₂ O and the DCM layer was concentrated. The concentrated residue was subjected to silica gel column chromatography (Hex: EA = 4: 1) to obtain the desired compound (25 mg, 81%).

^{1 H NMR (500 MHz, CDCl} 3): δ = 8.18 (s, 1H), 7.63 (d, J = 1.4 Hz, 1H), 7.58 (s, 1H), 7.52 (m, 2H), 7.44 (t, J = 2.1 Hz, 2H), 7.33 (m, 2H), 7.13 (d, J = 0.75 Hz, 2H), 6.61 (s, 1H), 2.36 ppm (s, 3H). MS (ESI): m / z: 432 [M + H ^& lt ^{; +} & gt ^; ].

< Example  8> 4- Fluoro -N- (1- (4- Fluorophenyl ) -1H- Indazole -5 days) Benzenesulfonamide Manufacture of TRT -0204)

step 1: 1 -(4- Fluorophenyl ) -1H- Indazole -5- Amine  Produce

The procedure of Step 3 of Example 3 was repeated to give the target compound.

step 2: 4 - Fluoro -N- (1- (4- Fluorophenyl ) -1H- Indazole -5 days) Benzenesulfonamide Manufacturing

(20 mg, 0.088 mmol) and 4-fluorobenzenesulfonyl chloride (21 mg, 0.11 mmol) were dissolved in DCM (2 ml), pyridine (0.010 ml, 0.13 mmol) was added And stirred at room temperature for 15 hours. After completion of the reaction, the reaction mixture was separated into DCM and H ₂ O and the DCM layer was concentrated. The concentrated residue was subjected to silica gel column chromatography (Hex: EA = 4: 1) to obtain the desired compound (28 mg, 82%).

^{1 H NMR (300 MHz, CDCl} 3): δ = 8.12 (s, 1H), 7.73 (m, 2H), 7.63 (m, 2H), 7.55 (d, J = 8.9 Hz, 1H), 7.50 (d, J = 1.65, 1H), 7.21 (d, J = 8.7 Hz, 2H), 7.11 (m, 3H), 6.51 ppm (s, 1H). MS (ESI): m / z: 386 [M + H ^& lt ^{; +} & gt ^; ].

< Example  9> N- (1- (4- Fluorophenyl ) -1H- Indazole Yl) -3- Methylbenzenesulfonamide  Manufacturing (TRT-0208)

step 1: 1 -(4- Fluorophenyl ) -1H- Indazole -5- Amine  Produce

The procedure of Step 3 of Example 3 was repeated to give the target compound.

Step 2: N- (1- (4- Fluorophenyl ) -1H- Indazole Yl) -3- Methylbenzenesulfonamide  Produce

(20 mg, 0.088 mmol) and 3-methylbenzenesulfonyl chloride (0.016 ml, 0.11 mmol) were dissolved in DCM (2 ml), pyridine (0.010 ml, 0.13 mmol) was added And the mixture was stirred at room temperature for 15 hours. After the reaction was complete, the layers were separated with DCM and H ₂ O and the DCM layer was concentrated. The concentrated residue was subjected to silica gel column chromatography (Hex: EA = 4: 1) to obtain the desired compound (25 mg, 75%).

^{1 H NMR (500 MHz, CDCl} 3): δ = 8.13 (s, 1H), 7.65 (m, 3H), 7.53 (m, 3H), 7.33 (m, 2H), 7.22 (m, 2H), 7.16 ( d, J = 1.8 Hz, 1H), 6.62 (s, 1H), 2.38 ppm (s, 1H). MS (ESI): m / z: 382 [M + H ^& lt ^{; +} & gt ^; ].

< Example  10 > N- (1- (4- Fluorophenyl ) -1H- Indazole -5-yl) -3- ( Trifluoromethyl ) Benzenesulfonamide &lt; / RTI &gt; ( TRT -0211)

step 1: 1 -(4- Fluorophenyl ) -1H- Indazole -5- Amine  Produce

The procedure of Step 3 of Example 3 was repeated to give the target compound.

Step 2: N- (1- (4- Fluorophenyl ) -1H- Indazole -5-yl) -3- ( Trifluoromethyl ) Benzenesulfonamide  Produce

(20 mg, 0.088 mmol) and 3- (trifluoromethyl) benzenesulfonyl chloride (0.017 ml, 0.11 mmol) were dissolved in DCM (2 ml), and pyridine mmol) was added and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, the reaction mixture was separated into DCM and H ₂ O and the DCM layer was concentrated. The concentrated residue was subjected to silica gel column chromatography (Hex: EA = 4: 1) to obtain the desired compound (32 mg, 84%).

^{1 H NMR (500 MHz, CDCl} 3): δ = 8.13 (d, J = 0.6 Hz, 1H), 8.01 (s, 1H), 7.83 (m, 2H), 7.58 (m, 5H), 7.24 (m, 2H), 7.12 (dd, J = 2.0 Hz, 9.0 Hz, 1H), 6.61 ppm (s, 1H). MS (ESI): m / z: 436 [M + H ^& lt ^{; +} & gt ^; ].

< Example  11> 4- Cyano -N- (1- (4- Fluorophenyl ) -1H- Indazole -5 days) Benzenesulfonamide Manufacture of TRT -0215)

Step 1: Preparation of 1- (4-fluorophenyl) -lH-indazol-5-amine

The procedure of Step 3 of Example 3 was repeated to give the target compound.

step 2: 4 - Cyano -N- (1- (4- Fluorophenyl ) -1H- Indazole -5 days) Benzenesulfonamide  Produce

(20 mg, 0.088 mmol) and 4-cyanobenzenesulfonyl chloride (22 mg, 0.11 mmol) were dissolved in DCM (2 ml), pyridine (0.010 ml, 0.13 mmol) And stirred at room temperature for 15 hours. After completion of the reaction, the reaction mixture was separated into DCM and H ₂ O and the DCM layer was concentrated. The concentrated residue was subjected to silica gel column chromatography (Hex: EA = 4: 1) to obtain the desired compound (31 mg, 90%).

^{1 H NMR (500 MHz, CDCl} 3): δ = 8.14 (s, 1H), 7.83 (t, J = 6.9 Hz, 2H), 7.74 (dd, J = 1.8 Hz, 6.8 Hz, 2H), 7.64 (m 2H), 7.56 (d, J = 9.0 Hz, 1H), 7.52 (d, J = 1.8 Hz, 1H), 7.24 6.68 ppm (s, 1 H). MS (ESI): m / z: 393 [M + H ^& lt ^{; +} & gt ^; ].

< Example  12 > N- (1- (2,4- Difluorophenyl ) -1H- Indazole -5-yl) -2- Fluorobenzene &Lt; / RTI &gt; TRT -0269)

step 1: 1 - (2,4- Difluorophenyl ) -1H- Indazole -5- Amine  Produce

The procedure of Step 3 of Example 5 was repeated to obtain the target compound.

Step 2: N- (1- (2,4- Difluorophenyl ) -1H- Indazole -5-yl) -2- Fluorobenzene sulfonate Manufacture of Mead

(20 mg, 0.082 mmol) and 2-fluorobenzenesulfonyl chloride (0.013 ml, 0.098 mmol) were dissolved in DCM (2 ml), pyridine (0.010 ml, 0.12 mmol) was added And stirred at room temperature for 15 hours. After completion of the reaction, the reaction mixture was separated into DCM and H ₂ O and the DCM layer was concentrated. The concentrated residue was subjected to silica gel column chromatography (Hex: EA = 4: 1) to obtain the desired compound (28 mg, 85%).

^{1 H NMR (300 MHz, CDCl} 3): δ = 8.13 (s, 1H), 7.76 (m, 1H), 7.52 (m, 3H), 7.15 (m, 4H), 7.03 (m, 2H), 6.89 ppm (s, 1 H). MS (ESI): m / z: 404 [M + H ^& lt ^{; +} & gt ^; ].

< Example  13 > N- (1- (2,4- Difluorophenyl ) -1H- Indazole -5-yl) -4- Methylbenzenesulfonamide  Manufacturing (TRT-0276)

Step 1: Preparation of 1- (2,4-difluorophenyl) -1H-indazol-5-amine

The procedure of Step 3 of Example 5 was repeated to obtain the target compound.

Step 2: Preparation of N- (1- (2,4-difluorophenyl) -1H-indazol-5-yl) -4-methylbenzenesulfonamide

(20 mg, 0.082 mmol) and 4-methylbenzenesulfonyl chloride (19 mg, 0.10 mmol) were dissolved in DCM (2 ml), pyridine (0.010 ml, 0.12 mmol) was added And the mixture was stirred at room temperature for 15 hours. After completion of the reaction, the reaction mixture was separated into DCM and H ₂ O and the DCM layer was concentrated. The concentrated residue was subjected to silica gel column chromatography (Hex: EA = 4: 1) to obtain the desired compound (31 mg, 95%).

¹ H NMR (300 MHz, CDCl ₃ ):? = 8.14 (s, 1H), 7.56 (m, 4H), 7.13 (m, 6H), 6.64 (s, 1H), 2.38 ppm (s, 3H). MS (ESI): m / z: 400 [M + H ^& lt ^{; +} & gt ^; ].

< Example  14> 4- Chloro -N- (1- (4- Fluorophenyl ) -1H- Indazole -5 days) Benzenesulfonamide Manufacture of TRT -0332)

step 1: 1 -(4- Fluorophenyl ) -1H- Indazole -5- Amine  Produce

The procedure of Step 3 of Example 3 was repeated to produce the desired compound.

step 2: 4 - Chloro -N- (1- (4- Fluorophenyl ) -1H- Indazole -5 days) Benzenesulfonamide  Produce

(20 mg, 0.088 mmol) and 4-chlorobenzenesulfonyl chloride (23 mg, 0.11 mmol) were dissolved in DCM (2 ml), pyridine (0.010 ml, 0.13 mmol) was added And the mixture was stirred at room temperature for 15 hours. After completion of the reaction, the reaction mixture was separated into DCM and H ₂ O and the DCM layer was concentrated. The concentrated residue was subjected to silica gel column chromatography (Hex: EA = 4: 1) to obtain the desired compound (25 mg, 72%).

¹ H NMR (500 MHz, CDCl ₃ ):? = 8.13 (s, 1H), 7.64 (m, 4H), 7.56 (d, J = 8.9 Hz, , 7.24 (t, J = 8.6 Hz, 2H), 7.12 (dd, J = 1.7 Hz, 9.0 Hz, 1H), 6.53 ppm (1H). MS (ESI): m / z: 402 [M + H ^& lt ^{; +} & gt ^; ].

< Example  15> 3- Fluoro -N- (1- (4- Fluorophenyl ) -1H- Indazole -5-yl) -4- Methylbenzene Preparation of sulfonamide (TRT-0334)

Step 1: Preparation of 1- (4-fluorophenyl) -lH-indazol-5-amine

The procedure of Step 3 of Example 3 was repeated to produce the desired compound.

step 2: 4 - Chloro -N- (1- (4- Fluorophenyl ) -1H- Indazole -5 days) Benzenesulfonamide  Produce

(20 mg, 0.088 mmol) and 3-fluoro-4-methylbenzenesulfonyl chloride (23 mg, 0.11 mmol) were dissolved in DCM (2 ml), and pyridine mmol) was added and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, the reaction mixture was separated into DCM and H ₂ O and the DCM layer was concentrated. The concentrated residue was subjected to silica gel column chromatography (Hex: EA = 4: 1) to obtain the desired compound (23 mg, 65%).

^{1 H NMR (300 MHz, CDCl} 3): δ = 10.25 (s, 1H), 8.49 (s, 1H), 7.68 (m, 2H), 7.45 (m, 7H), 7.08 (d, J = 6.0 Hz, 1H), 2.24 ppm (s, 3H). MS (ESI): m / z: 400 [M + H ^& lt ^{; +} & gt ^; ].

Example constitutional formula Example constitutional formula One

9

2

10

3

11

4

12

5

13

6

14

7

15

8

< Experimental Example  1> TRAIL sensitivity assessment

< Experimental Example  1-1> TRAIL Sensitivity Assessment Example  Whole compound)

In order to evaluate the effect of the compounds according to the present invention on the TRAIL sensitivity of cancer, the following experiment was conducted.

Specifically, liver cancer cell line Huh-7 was cultured in DMEM medium containing 10% FBS and 1% streptomycin / penicillin under 5% carbon dioxide condition. For TRAIL sensitivity experiments, 20,000 Huh-7 cells were dispensed into each well of a 96-well plate. At this time, 100 ul / well was used for the volume to be dispensed. After 24 hours of incubation, the cells were completely adhered to the bottom of the plate. Cell culture medium was removed and replaced with serum-free media. In the subsequent experiments, serum-free medium was used. The compounds of each Example were sequentially diluted and processed into cells and added to a final concentration of TRAIL of 50 ng / well. Cells treated with the compound of Example and TRAIl were incubated for 24 hours in an incubator, and then treated with WST-1 to measure cell viability. The results are shown in Table 2.

At this time, as the control group, only the treatment group of TRAIl alone and the treatment group of the example compound alone were also performed under the same condition as the above experiment.

Example TRAIL-Sensitivity Assessment (% Cancer Cell Survival Rate) Only the compound of Example Compound + TRAIL treatment Cancer cell survival rate difference One 58.0 13.5 44.5 2 46.8 4.0 42.8 3 91.9 11.5 80.4 4 65.6 11.5 54.1 5 66.0 11.6 54.4 6 61.8 10.7 51.1 7 48.4 8.4 40.0 8 46.1 7.0 39.1 9 91.6 5.8 85.8 10 87.1 3.9 83.2 11 53.4 12.5 40.9 12 62.0 7.4 54.5 13 62.1 11.9 50.2 14 95.8 65.5 30.3 15 85.9 40.1 45.8 Treated only with TRAIL 93

The cancer cell survival rate difference is,

(Survival rate of cancer cells) = (survival rate of cancer cells at the time of treating only the compound of the present invention) - (survival rate of cancer cells at the compound + TRAIL treatment).

Table 2 shows that the compound according to the present invention alone had a certain cancer cell killing effect on its own, but when treated with TRAIL, TRAIL resistance-inhibiting activity was expected to be expected in the present invention, (Cancer cell survival rate of about 93%, cancer cell survival rate is about 10%, see table above). In particular, the cancer cell survival rate difference was calculated, and it was confirmed that the compound of the present invention had an excellent TRAIL resistance-inhibiting activity by a difference of 85.8% at most.

Therefore, as shown in the above experiment, the compound according to the present invention exhibits an activity of excellent inhibition of TRAIL resistance of cancer cells and can be used as a pharmaceutical composition for prevention and treatment of cancer containing the compound .

< Experimental Example  1-2> TRAIL Sensitivity Assessment Example  1, 3, 9 and 10 compounds)

From the results of Experimental Example 1-1, the compounds of Examples 1, 3, 9 and 10, which were found to be excellent in TRAIL resistance-inhibiting activity, (1.25 uM - 40 uM) cancer cell killing activity.

Specifically, experiments were carried out under the same conditions as those of Experimental Example 1-1, except that TRAIl sensitivity evaluation and cancer cell killing effect were evaluated by treating the compound of Example with different concentrations of 1.25 uM to 40 uM. The results are shown in Figs. 1 to 4 Respectively.

FIG. 1 is a graph showing cancer cell survival rate by concentration (1.25 uM - 40 uM) of the compound of Example 1 alone or TRAIL simultaneously.

FIG. 2 is a graph showing tumor cell survival rates by concentration (1.25 uM-40 uM) of the compound of Example 3 alone or TRAIL simultaneously.

FIG. 3 is a graph showing tumor cell survival rates (1.25 uM - 40 uM) of the compound of Example 9 alone or in concurrent treatment with TRAIL.

FIG. 4 is a graph showing tumor cell survival rates (1.25 uM-40 uM) at the time of simultaneous treatment of the compound of Example 10 alone or TRAIL.

1 to 4, there was an excellent cancer cell killing effect even in the case of the single treatment in Example 1, but when examined in the whole of Examples 1, 3, 9 and 10, when treated simultaneously with TRAIL, the cancer cell killing effect is remarkably excellent . From these results, it can be seen that the compounds of Examples 1, 3, 9 and 10 of the present invention have a TRAIL resistance-inhibiting activity of cancer cells and significantly increase TRAIL sensitivity.

Therefore, the compound according to the present invention exhibits an activity of excellent inhibition of TRAIL resistance of cancer cells, and thus can be effectively used as an active ingredient of a pharmaceutical composition for the prevention and treatment of cancer.

< Experimental Example  2> MKK7 and TIPRL's  Evaluation of Mutual Binding Inhibition

< Experimental Example  2-1> Immunoprecipitation method  through MKK7 and TIPRL's  Evaluation of Mutual Binding Inhibition

In order to evaluate the mutual binding inhibition of MKK7 and TIPRL by the immunoprecipitation method of the compound according to the present invention, the following experiment was conducted.

Specifically, in order to confirm binding inhibition of IP-based MKK7 and TIPRL by the compound of Example, 7 X 105 huh7 hepatocarcinoma cell lines were inoculated in a 60 mm culture dish and cultured for 24 hours. Then, 40 μM of the compound of Example 1 and 100 ng / ml of TRAIL, respectively, or simultaneously and cultured for 4 hours, and the cells were collected. To each sample was added 250 μl of dissolution buffer (Lysis buffer, 20 mM Tris (pH 7.4)), 150 mM NaCl, 1% Triton X-100, 2 mM NaF, 2 mM EDTA, 2 mM β-glycerophosphate, 5 mM sodium orthovanadate Sodium orthovanadate, 1 mM PMSF, leupeptin (10 ug / ml), and aprotinin (20 ug / ml) were injected and the cells were lysed. Each sample was quantitated to the same amount, and then 15 μl of protein G agarose (Roche) was added thereto, followed by stirring for 20 minutes. The supernatant was centrifuged at 12,000 rpm for 1 minute at 4 ° C, followed by addition of 2 μl of MKK7 antibody, followed by stirring for 16 hours. Each sample was washed three times with 200 μl of lysis buffer, followed by addition of 25 μl of dissolution buffer and 10 μl of sample buffer (for western blot) and reaction at 100 ° C. for 10 minutes. The samples were reacted on ice for 5 minutes and then subjected to Western blotting on SDS-PAGE gels, the results of which are shown in FIG.

Figure 5a is a photograph of western blot for MKK7 and TIPRL of Example 1 compound via IP method.

Referring to FIG. 5, it can be confirmed that the compound of Example 1 and TRAIL inhibited the binding of TIPRL and MKK7 during simultaneous treatment for 4 hours.

< Experimental Example  2-2> GST  pool Down method  through MKK7 and TIPRL's  Evaluation of Mutual Binding Inhibition

In order to evaluate the mutual binding inhibition of MKK7 and TIPRL by the GST pull-down method of the compound according to the present invention, the following experiment was conducted.

Step 1: HEK293T  Culture of cell line

The HEK293T cell line from Korean Cell Line Bank was cultured in Dulbecco's modified eagle's medium (DMEM) containing 10% fetal bovine serum at 37 ° C and 5% CO ₂ .

Step 2: TIPRL  Expression vectors and MKK7  Preparation of expression vector

To prepare a vector expressing TIPRL or MKK7 gene, total RNA (total RNA) was isolated from hepatocarcinoma cell line and used as a template, and a first cDNA was synthesized by a conventional method using a poly dT primer. To amplify the TIPRL or MKK7 gene, PCR was performed using the first cDNA solution synthesized above and a primer corresponding to each gene. As a primer of TIPRL, a forward primer (SEQ ID NO: 15: 5'-cg ggt acc aa atg atgac cac ggc ttc'-3 ') and a reverse primer (SEQ ID NO: 16: 5'-ccc gga tcc tta ttc Cac ttg tgt act (SEQ ID NO: 19: 5'-ccg ctc gag atg gcg gcg tcc tcc ctg-3 ') and the reverse primer (SEQ ID NO: 20: 5'-gg ggt acc cct gaa gaa ggg cag gtg-3 ') was used.

At this time, the conditions of the PCR were denatured at 95 ° C for 3 minutes, followed by repeating 30 cycles at 95 ° C for 1 minute, 58 ° C for 1 minute, and 72 ° C for 1 minute and 30 seconds, followed by extension at 72 ° C for 10 minutes Then, it was cooled to 4 캜.

In the case of the TTIPRL expression clone, the extracted PCR product (containing the KpnI and BamHI restriction sites in the used primers) was digested with KpnI and BamHI restriction enzymes, and then the pHA vector (pcDNA3.1; Invitrogen corpora vector In which the HA tag was inserted (Fig. 6 (a)). For the MKK7 expression clone, the pGST vector (pEBG vector) (Mayer et al., Supra), which was obtained by digesting the PCR products (BamHI and Not I restriction sites in the primers used) digested with Bam HI and Not I restriction enzymes, 1995 Current Biology 5 (3): 296-305) (Fig. 6 (b)).

6 (a) is a photograph showing a TIPRL expression vector, and FIG. 6 (b) is a photograph showing an MKK7 expression vector.

Step 3: Example  1 and Example  Of the three compounds MKK7 and TIPRL  Evaluation of Mutual Binding Inhibition

5X105 HEK293T cell lines were cultured in 6-well culture dishes for 24 hours to evaluate inhibition of binding of GST pull-down-based MKK7 and TIPRL by the compounds of the present invention. Then, 5 ul of Lipofectamine 2000R, The HEK293T cell line was transfected with 1 ug of the TIPRL expression vector and 1 ug of the MKK7 expression vector, and the MKK7 and TIPRL proteins were overexpressed. After 24 hours, the cells were harvested after co-treatment with the compound of Example (40uM of Example 1 or 20uM of Example 3) and 100 ng / ml of TRAIL, respectively, for 24 hours. Each sample was injected with 250 ul of lysis buffer (RIPA buffer) and the cells were lysed. After quantification so that the protein concentration of each sample was the same, 40 ul of GST-bead (BIORAD) was added and the mixture was stirred at 4 DEG C for 16 hours. The supernatant was removed by centrifugation at 12,000 rpm for 1 minute at 4 ° C, and each sample was washed three times with 1 ml of TBS, then 40 μl of 2 × sample buffer (for western blot) was added and incubated at 100 ° C. for 5 minutes Lt; / RTI &gt; After the sample was reacted on ice for 5 minutes, the supernatant was subjected to Western blotting on an SDS-PAGE gel, and the result is shown in FIG.

Figure 7a is a photograph showing the western blot of the compound of Example 1 via the GST pull-down method. Figure 7b is a photograph of western blot for MKK7 and TIPRL of Example 3 compound via GST pull down method.

Referring to FIG. 7, it can be confirmed that the mutual binding of MKK7 and TIPRL is inhibited when the compound of Example 1 or 3 is treated with TRAIL.

<Experimental Example 2-3> Immunofluorescent staining  And Light focus  Through microscopic observation MKK7 and TIPRL  Evaluation of Mutual Binding Inhibition

In order to evaluate the inhibition of mutual binding between MKK7 and TIPRL by immunofluorescence staining of the compound according to the present invention and observation with a photomicroscope, the following experiment was conducted.

Step 1: Huh7  Cell culture

Human Huh7 hepatocellular carcinoma cells from Korean Cell Line Bank were cultured in Dulbecco's modified eagle's medium (DMEM) supplemented with 10% fetal bovine serum in a cell incubator under the condition of 5% CO ₂ at 37 ° C.

Step 2: Immunofluorescent staining  And Confocal  Through microscopic observation MKK7 and TIPRL's  Evaluation of Mutual Binding Inhibition

In order to evaluate the inhibition of binding of MKK7 and TIPRL by immunofluorescent staining and confocal microscopy-based compounds, the Huh7 cell line cultured in step 1 was cultured by the simultaneous treatment of the compounds of Examples 1 and 3 and TRAIL, MKK7, and PP2Ac were investigated. Cells were seeded in an 8-well plate for confocal microscopy at 5 x 10 4 cells / ml for 24 hours and then incubated with the compound of Example (40 μM of Example 1 or 20 μM of Example 3) and 100 ng / ml of TRAIL Respectively. After culturing at various times (2 hours, 4 hours, 8 hours), the medium was removed, and the cells were fixed with methanol at room temperature for 15 minutes and subjected to permilylation using 2-mercaptoethanol. The cells were treated with PP2Ac diluted in a certain ratio (1: 100) to the blocking solution and reacted at 4 ° C. Twenty-four hours later, the cells were washed three times with PBS. Cells were treated with a goat secondary antibody diluted in a certain ratio (1: 250) in blocking solution under the dark condition, and reacted at room temperature for 2 hours. After washing with PBS three times, the cells were treated with MKK7 diluted at a predetermined ratio (1: 100) in the blocking solution, and reacted at 4 ° C. Twenty-four hours later, the cells were washed three times with PBS. The cells were treated with a rabbit secondary antibody diluted in a certain ratio (1: 250) to the blocking solution under the dark condition, and reacted at room temperature for 2 hours. After washing three times with PBS, the cells were treated with TIPRL diluted in a certain ratio (1: 100) in the blocking solution, and reacted at 4 ° C. After 4 hours, the cells were washed three times with PBS, and the cells were treated with a mouse secondary antibody diluted in a certain ratio (1: 250) in blocking solution under the dark condition, followed by reaction at room temperature for 2 hours. After three dilutions with PBS, DAPI staining followed by confocal fluorescence microscopy. The co-locality of PP2Ac, TIPRL, and MKK7 and the co-locality of TIPRL and MKK7 were evaluated.

Then, the values according to the three-dimensional positions of each protein obtained through the observation with a confocal fluorescence microscope were compared with Pearson's equation (-1, not in the same position; -1, same position) and mander's equation 1, present in the same position) method to evaluate the co-locality of TIPRL / MKK7, and the results are shown in FIG.

FIG. 8A is an image and a chart showing the result of inhibition of mutual binding of MKK7 and TIPRL of Example 1 compound by immunofluorescence staining and photomicroscopic observation. FIG. FIG. 8 (b) is an image and a diagram showing the result of inhibition of mutual binding of MKK7 and TIPRL of Example 3 compound by immunofluorescence staining and optical focus microscopic observation.

8, when the compound of Example 1 or the compound of Example 3 was treated with TRAIL, the co-locality of PP2Ac / TIPRL / MKK7 and the co-locality of TIPRL / MKK7 decreased, indicating that the mutual binding of MKK7 and TIPRL was inhibited .

Therefore, as shown in Experimental Example 2 (2-1 to 2-3), the compound according to the present invention has an effect of inhibiting the mutual binding between MKK7 and TIPRL, thereby inhibiting TRAIL resistance of cancer And it can be used for prevention and treatment of cancer.

Claims (10)

1. A compound represented by the following formula (1): &lt; EMI ID =
[Chemical Formula 1]

(In the formula 1,
X is a substituted or unsubstituted phenyl,
Wherein the substituted phenyl is C _1-5 linear or branched alkyl, substituted or unsubstituted C _1-5 straight or branched alkoxy, -CN, -NO ₂ , C _1-5 linear or branched alkylcarbonyl &Lt; / RTI &gt; nitro and halogen; And

Y is substituted or unsubstituted phenyl,
Wherein the substituted phenyl is C _1-5 linear or branched alkyl, substituted or unsubstituted C _1-5 straight or branched alkoxy, -CN, -NO ₂ , C _1-5 linear or branched alkylcarbonyl Lt; / RTI &gt; may be substituted with one or more substituents selected from the group consisting of hydrogen, halogen and halogen.
The method according to claim 1,
X is a substituted or unsubstituted phenyl,
Wherein the substituted phenyl is C _1-3 straight or branched chain alkyl substituted with halogen, C _1-3 linear or branched alkoxy, -CN, C _1-3 straight or branched alkylcarbonyl and halogen &Lt; RTI ID = 0.0 &gt; and / or &lt; / RTI &gt; And

Y is substituted or unsubstituted phenyl,
Wherein the substituted phenyl is C _1-3 straight or branched chain alkyl substituted with halogen, C _1-3 linear or branched alkoxy, -CN, C _1-3 straight or branched alkylcarbonyl and halogen &Lt; / RTI &gt; or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
X is

,

,

,

,

,

,

,

,

or

ego; And

Y is

,

,

,

,

or

&Lt; / RTI &gt; or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
Wherein the compound represented by the formula (1) is any one selected from the group consisting of the following compounds: or a pharmaceutically acceptable salt thereof:
(1) N- (1- (5-acetyl-2,4-dichlorophenyl) -1H-indazol-5-yl) benzenesulfonamide;
(2) N- (1- (4-chlorophenyl) -1H-indazol-5-yl) -4-methoxybenzenesulfonamide;
(3) N- (1- (4-fluorophenyl) -1H-indazol-5-yl) -4-methoxybenzenesulfonamide;
(4) N- (1- (2-chlorophenyl) -1H-indazol-5-yl) -4-methoxybenzenesulfonamide;
(5) N- (1- (2,4-Difluorophenyl) -1H-indazol-5-yl) -4-methoxybenzenesulfonamide;
(6) N- (1- (2,4-Dichlorophenyl) -1H-indazol-5-yl) -2-fluorobenzenesulfonamide;
(7) N- (1- (2,4-dichlorophenyl) -1H-indazol-5-yl) -3-methylbenzenesulfonamide;
(8) 4-Fluoro-N- (1- (4-fluorophenyl) -1H-indazol-5-yl) benzenesulfonamide;
(9) N- (1- (4-fluorophenyl) -1H-indazol-5-yl) -3-methylbenzenesulfonamide;
(10) N- (1- (4-fluorophenyl) -1H-indazol-5-yl) -3- (trifluoromethyl) benzenesulfonamide;
(11) 4-Cyano-N- (1- (4-fluorophenyl) -1H-indazol-5-yl) benzenesulfonamide;
(12) N- (1- (2,4-Difluorophenyl) -1H-indazol-5-yl) -2-fluorobenzenesulfonamide;
(13) N- (1- (2,4-Difluorophenyl) -1H-indazol-5-yl) -4-methylbenzenesulfonamide;
(14) 4-Chloro-N- (1- (4-fluorophenyl) -1H-indazol-5-yl) benzenesulfonamide; And
(15) 3-Fluoro-N- (1- (4-fluorophenyl) -1H-indazol-5-yl) -4-methylbenzenesulfonamide.
As shown in Scheme 1 below,
Reacting a compound represented by the formula (2) with a compound represented by the formula (3) to prepare a compound represented by the formula (4) (step 1); And
Reacting the compound represented by the formula (4) prepared in the above step 1 with the compound represented by the formula (5) to prepare a compound represented by the formula (1) (step 2) Manufacturing method:
[Reaction Scheme 1]

(In the above Reaction Scheme 1,
X and Y are independently as defined in formula 1 of claim 1; And
A is a halogen).
As shown in Reaction Scheme 2 below,
Reacting a compound represented by the formula (6) with a compound represented by the formula (7) to prepare a compound represented by the formula (8) (step 1);
Preparing a compound represented by the formula (9) from the compound represented by the formula (8) prepared in the step (1) (step 2);
Preparing a compound represented by the formula (4) from the compound represented by the formula (9) prepared in the step (2) (step 3); And
Reacting the compound represented by the general formula (4) with the compound represented by the general formula (5) to prepare the compound represented by the general formula (1) (step 4), and reacting the compound represented by the general formula Manufacturing method:
[Reaction Scheme 2]

(In the above Reaction Scheme 2,
X and Y are independently as defined in formula (1) of claim 1).
A pharmaceutical composition for preventing or treating cancer comprising as an active ingredient a compound represented by the general formula (1) of claim 1 or a pharmaceutically acceptable salt thereof and TRAIL (TNF-related apoptosis inducing ligand).
8. The method of claim 7,
Wherein the cancer is any one selected from the group consisting of liver cancer, breast cancer, prostate cancer, uterine cancer, lung cancer, colon cancer and brain tumor.
An anticancer adjuvant for TRAIL (TNF related apoptosis inducing ligand) comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
10. The method of claim 9,
The compound of claim 1 or a pharmaceutically acceptable salt thereof is an anticancer adjuvant for TRAIL, which has a TRAIL resistance-inhibiting activity specifically for a cancer having a TRAIL (TNF-related apoptosis inducing ligand) resistance.

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