KR101924801B1 - Composition for preventing or treating cancer comprising triazolopyridine derivatives - Google Patents

Abstract

The present invention relates to a composition for preventing or treating cancer comprising a triazolopyridine derivative or a pharmaceutically acceptable salt thereof as an active ingredient. The triazolopyridine derivative inhibits the activity of tankyrase enzyme and inhibits the expression of β-catenin, which is a tumor factor, to increase cancer cell death by apoptosis. When applied in combination with an anticancer agent or irradiation, excellent reduction of cell survival rate is exhibited. Accordingly, the triazolopyridine derivative may be useful as a pharmaceutical composition for preventing or treating cancer, a composition for promoting radiation therapy, or a health functional food for cancer prevention or alleviation.

Description

[0001] The present invention relates to a composition for preventing or treating cancer comprising, as an active ingredient, a triazolopyridine-based derivative,

The present invention relates to a pharmaceutical composition for preventing or treating cancer, a composition for promoting an anti-cancer effect, or a health food for cancer prevention or improvement, which comprises a triazolopyridine derivative as an active ingredient.

With the development of modern medicine, many diseases are being treated and prevented, but cancer is still one of the most difficult diseases to treat. Cancer is currently the number one cause of death, and it is increasing continuously.

Chemotherapy, surgery, and radiation therapy have been used to treat cancer. Of these, chemotherapy is the most commonly used method for treating cancer as an anticancer drug. Today, about 60 kinds of anticancer drugs are used in clinical practice. As knowledge of cancer development and characteristics of cancer cells is well known, new anticancer drugs are being developed. However, most of the anticancer drugs currently used in clinical practice are accompanied by side effects such as nausea, vomiting, ulcers in the mouth and small intestine, diarrhea, hair loss, and bone marrow suppression in which production of blood active ingredients is decreased. For example, mitomycin-C is known to cause renal insufficiency, and adriamycin has a side effect such as bone marrow suppression. In particular, cisplatin, which is the most useful anticancer drug developed so far, is widely used for the treatment of testicular cancer, ovarian cancer, lung cancer, head and neck cancer, bladder cancer, stomach cancer and cervical cancer, but hematopoietic toxicity such as anemia, vomiting, Such as kidney toxicity such as digestive tract toxicity, kidney tubular damage, hearing loss, internal electrolyte abnormality, shock, peripheral neuropathy, etc., have been a major problem. Therefore, it is urgently required to develop a novel anticancer drug having excellent safety.

In addition, as the number of cancer patients receiving radiation therapy increases year by year, the importance of radiation therapy for cancer treatment is also increasing.

However, it has been pointed out that the acquisition of radiation resistance of cancer cells and the damage of normal tissues during high-dose radiation therapy have been pointed out as a problem of reducing the efficiency of radiation therapy. Therefore, studies on radiation therapy sensitizers to improve the efficiency of radiation therapy have been made.

The radiation therapy sensitizers reported so far are mainly anticancer agents such as Taxol and cisplatin which can be used as radiation therapy sensitizers in solid tumors such as breast cancer, uterine cancer, lung cancer, stomach cancer and colon cancer have.

In addition, tirapazamine is a radiotherapeutic effect enhancer that is not used as an anticancer agent but only for radiation therapy. However, it is effective only for hypoxic tumor cells. Because of the pressure inside the tumor due to hypoxic conditions, It is known that the radiation therapy sensitizers have a low effect on clinical radiotherapy and their use is limited since they have high side effects.

Although there is a difference in sensitivity in the radiation therapy for cancer cells, if the sensitivity can be enhanced, the same therapeutic effect can be obtained while irradiating a smaller amount of radiation to the patient. Therefore, the cancer treatment effect is exhibited and the sensitivity of cancer cells to radiation Cancer drugs that can increase cancer risk.

Korean Patent Publication No. 2008-0047607 (Published May 29, 2008)

Disclosure of the Invention The present invention aims to provide a composition for enhancing an anticancer therapy effect which can solve the side effects of conventional anticancer therapy or radiation therapy and improve the anticancer treatment effect.

상기 화학식 1에 있어서,
상기 R¹ 및 R²는 각각 동일하거나 다를 수 있으며, 수소, CN, NO₂, CF₃, 할로겐 및 아세틸에서 선택되고,
상기 X는 질소 및 탄소에서 선택된 어느 하나임.
본 발명은 하기 화학식 1과 같이 표시되는 트리아졸로피리딘계 유도체 또는 이의 약제학적으로 허용가능한 염을 유효성분으로 함유하는 암 예방 또는 치료용 약학조성물을 제공한다.The present invention provides a triazolo pyridine-based derivative represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof.
[Chemical Formula 1]

In Formula 1,
R ¹ and R ² may be the same or different and are selected from hydrogen, CN, NO ₂ , CF ₃ , halogen and acetyl,
And X is any one selected from nitrogen and carbon.
The present invention provides a pharmaceutical composition for preventing or treating cancer comprising, as an active ingredient, a triazolo pyridine derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

In Formula 1,

R ¹ and R ² may be the same or different and are selected from hydrogen, CN, NO ₂ , CF ₃ , halogen and acetyl,

And X is any one selected from nitrogen and carbon.

The present invention provides a composition for enhancing an anticancer effect comprising, as an active ingredient, a triazolo pyridine derivative represented by the general formula (1) or a pharmaceutically usable salt thereof.

The present invention also provides a health food for preventing or ameliorating cancer comprising, as an active ingredient, a triazolopyridine-based derivative represented by the general formula (1) or a pharmaceutically usable salt thereof.

According to the present invention, the triazolo pyridine derivative represented by the formula (1) inhibits the enzyme activity of the tumor cell line and inhibits the expression of the tumor factor beta -catenin, thereby increasing the cancer cell death by apoptosis , An anticancer agent or a radiation irradiation, the triazole pyridine derivative can be used as a pharmaceutical composition for preventing and treating cancer, a composition for enhancing the effect of an anticancer agent or a radiation therapy, or a composition for preventing or improving cancer It can be usefully used as a health functional food.

FIG. 1 shows the result of confirming concentration-dependent inhibition of TNKS activity by treating Compound 1 or Compound 2, which is a triazolepyridine derivative, in a test tube by concentration.
FIG. 2 shows the results of confirming inhibition of β-catenin protein expression and increase of tumor suppressor AXIN2, respectively, after treating Compound 1 or Compound 2, which is a triazolepyridine derivative, with DLD-1 colon cancer cells.
FIG. 3 shows the results of confirming inhibition of expression of VEGF2 and Birc / Survivin, which are sub-genes of β-catenin, after treating DLD-1 colorectal cancer cells with Compound 1 or Compound 2, which is a triazolopyridine derivative.
FIG. 4 shows the result of confirming cell viability after treatment of DLD-1 colon cancer cells in which APC (mutant adenomatous polyposis coli) gene was mutagenized with Compound 1 or Compound 2, which is a triazolo pyridine derivative, upon irradiation.
FIG. 5 shows the results of confirming the decrease in cell survival rate after the combination treatment of the anticancer agent 5-FU and the triazolepyridine derivative, Compound 1 or Compound 2, into two colon cancer cell lines mutated with the APC gene.
FIG. 6 shows the results of confirming the decrease of CYR61 and CTGF, which are subgenera of tumor factor YAP / TAZ, after treatment of Compound 1 or Compound 2, which is a triazolo pyridine derivative, in DLD-1 colon cancer cell line.
FIG. 7 shows the results of confirming the decrease in cell viability after treatment of SKMEL28 melanoma cell line and SKMEL28 cell line, which is a BRAF inhibitory anticancer drug, with the compound 1 or 2, which is a triazolopyridine derivative, at various concentrations.

상기 화학식 1에 있어서,
상기 R¹ 및 R²는 각각 동일하거나 다를 수 있으며, 수소, CN, NO₂, CF₃, 할로겐 및 아세틸에서 선택되고,
상기 X는 질소 및 탄소에서 선택된 어느 하나일 수 있다.
상기 화합물의 R¹ 및 R²는 각각 동일하거나 다를 수 있으며, CN, NO₂, CF₃ 및 할로겐으로 이루어진 군에서 선택되고, 상기 X는 탄소일 수 있다.
상기 트리아졸로피리딘계 유도체는 N-([1,2,4,]트리아졸로[4,3-a]피리딘-3-일)-1-(2-시아노페닐)피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(2-니트로페닐)피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-페닐피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(4-니트로페닐)피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(2-니트로-4-(트리플루오로메틸)페닐)피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(4-(트리플루오로메틸)페닐)피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(4-플루오로-2-니트로페닐)피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(4-아세틸페닐)피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(4-클로로-2-니트로페닐)피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(4-시아노페닐)피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(5-니트로피리딘-2-일)피페리딘-4-카르복사마이드 및 N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(2-시아노-4-니트로페닐)피페리딘-4-카르복사마이드로 이루어진 군에서 선택될 수 있다.
본 발명은 하기 화학식 1과 같이 표시되는 트리아졸로피리딘계 유도체 또는 이의 약제학적으로 허용가능한 염을 유효성분으로 함유하는 암 예방 또는 치료용 약학조성물을 제공할 수 있다.The present invention can provide a triazolo pyridine-based derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.
[Chemical Formula 1]

In Formula 1,
R ¹ and R ² may be the same or different and are selected from hydrogen, CN, NO ₂ , CF ₃ , halogen and acetyl,
X may be any one selected from nitrogen and carbon.
R ¹ and R ² of the compound may be the same or different and are selected from the group consisting of CN, NO ₂ , CF _3, and halogen, and X may be carbon.
The above triazolo pyridine derivative may be obtained by reacting N - ([1,2,4,] triazolo [4,3- a] pyridin-3-yl) -1- (2-cyanophenyl) piperidine- (2, 3-a) pyridin-3-yl) -1- (2-nitrophenyl) piperidine-4-carboxamide, N- [1,2,4] triazolo [4,3-a] pyridin-3-yl) -1-phenylpiperidine-4-carboxamide, N- , [3-a] pyridin-3-yl) -1- (4-nitrophenyl) piperidine-4-carboxamide, N- Carboxamide, N - ([1,2,4] triazolo [4,3-c] pyridin-4-yl) a] pyridin-3-yl) -1- (4- (trifluoromethyl) phenyl) piperidine-4-carboxamide, N- Pyridin-3-yl) -1- (4-fluoro-2-nitrophenyl) piperidine-4-carboxamide, N- Carboxamide, N - ([1,2,4] triazolo [4,3-a] pyrimidin-4-yl) Carboxamide, N - ([1,2,4] triazolo [4,3-a] pyridin-3 Carboxamide, N - ([1,2,4] triazolo [4,3-a] pyridin-3-yl) - 1 (4-cyanophenyl) piperidine- Carboxamide and N - ([1,2,4] triazolo [4,3-a] pyridin-3-yl) -1- 2-cyano-4-nitrophenyl) piperidine-4-carboxamide.
The present invention can provide a pharmaceutical composition for preventing or treating cancer comprising, as an active ingredient, a triazolo pyridine derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

In Formula 1,

R ¹ and R ² may be the same or different and each is selected from hydrogen, CN, NO ₂ , CF ₃ , halogen and acetyl, and X may be any one selected from nitrogen and carbon.

More specifically, R ¹ and R ² of the compound may be the same or different and are selected from the group consisting of CN, NO ₂ , CF _3, and halogen, and X may be carbon.

The above triazolo pyridine derivative may be obtained by reacting N - ([1,2,4,] triazolo [4,3- a] pyridin-3-yl) -1- (2-cyanophenyl) piperidine- (2, 3-a) pyridin-3-yl) -1- (2-nitrophenyl) piperidine-4-carboxamide, N- [1,2,4] triazolo [4,3-a] pyridin-3-yl) -1-phenylpiperidine-4-carboxamide, N- , [3-a] pyridin-3-yl) -1- (4-nitrophenyl) piperidine-4-carboxamide, N- Carboxamide, N - ([1,2,4] triazolo [4,3-c] pyridin-4-yl) a] pyridin-3-yl) -1- (4- (trifluoromethyl) phenyl) piperidine-4-carboxamide, N- Pyridin-3-yl) -1- (4-fluoro-2-nitrophenyl) piperidine-4-carboxamide, N- Carboxamide, N - ([1,2,4] triazolo [4,3-a] pyrimidin-4-yl) Carboxamide, N - ([1,2,4] triazolo [4,3-a] pyridin-3 Carboxamide, N - ([1,2,4] triazolo [4,3-a] pyridin-3-yl) - 1 (4-cyanophenyl) piperidine- Carboxamide and N - ([1,2,4] triazolo [4,3-a] pyridin-3-yl) -1- 2-cyano-4-nitrophenyl) piperidine-4-carboxamide.

Said cancer is selected from the group consisting of lung cancer, acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, breast cancer, gastric cancer, liver cancer, colon cancer, skin cancer, head or neck cancer, uterine cancer, ovarian cancer, Cancer, bladder cancer, esophageal cancer, thyroid cancer, bladder cancer, kidney cancer, blood cancer, and rectal cancer.

More specifically, the triazolopyridine derivatives can be effectively used for the treatment of cancer cells in which β-catenin, which is a tumor factor, is overexpressed by inhibiting the activity of Tankyrase (TNKS) enzyme.

The TNKS is a telomeric repeat binding factor 1 (TRF1) which is a double-stranded telomer repeat protein; Nuclear Mitotic Associated Protein (NuMA), an essential protein in a mitotic spindle assembly; IRAP (aminopeptidase), an endogenous membrane protein involved in glucose uptake in response to insulin; And myeloid leukemia cell differentiation protein (Mcl-1), an apoptosis-promoting protein, and exhibits biological functions through their various interactions.

According to one embodiment of the present invention, the triazolo pyridine compounds 1-12 inhibited the activity of the TNKS-1 enzyme as shown in Table 1, while confirming that the PARP-1 activity was not inhibited, It was confirmed that the activity of the derivative was specific to the TNKS-1 enzyme.

From the above results, the triazolopyridine compounds 1 and 2 identified as TNKS enzyme activity inhibitors were treated with DLD-1 colon cancer cells mutated with the APC gene, and as a result, as shown in FIG. 2, , But the expression of AXIN2 protein was increased. Thus, the triazolepyridine derivative inhibited the activity of the Tankyrase (TNKS) enzyme and expressed β-catenin Can be provided as an anticancer agent that increases cancer cell death by apoptosis.

In one embodiment of the present invention, the pharmaceutical composition for preventing or treating cancer, which comprises the compound represented by Formula 1 or a pharmaceutically utilizable salt thereof as an active ingredient, may be administered orally, parenterally, , Pills, capsules, suppositories, gels, suspensions, emulsions, drops, or liquid preparations can be used.

In another embodiment of the present invention there is provided a pharmaceutical composition comprising a pharmaceutically acceptable carrier, excipient, disintegrant, sweetener, coating, swelling agent, lubricant, lubricant, flavoring agent, antioxidant, buffer, A dispersant, a surfactant, a binder, and a lubricant.

Specific examples of carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, Cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. Solid formulations for oral administration may be in the form of tablets, pills, powders, granules, capsules These solid preparations can be prepared by mixing at least one excipient, for example, starch, calcium carbonate, sucrose or lactose, gelatin, etc., into the composition. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, syrups and the like, and various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included in addition to water and liquid paraffin which are commonly used simple diluents. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, and the like. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. As the suppository base, witepsol, macrogol, tween 61, cacao paper, laurin, glycerogelatin and the like can be used.

According to one embodiment of the present invention, the pharmaceutical composition may be administered orally, intraarterally, intraperitoneally, intramuscularly, intraarterally, intraperitoneally, intrasternally, transdermally, nasally, inhaled, topically, rectally, ≪ / RTI > can be administered to the subject in a conventional manner.

The preferred dosage of the compound represented by Formula 1 may vary depending on the condition and body weight of the subject, the type and degree of disease, the drug form, the administration route and the period, and may be appropriately selected by those skilled in the art. According to one embodiment of the present invention, the daily dose may be 0.01 to 200 mg / kg, specifically 0.1 to 200 mg / kg, more specifically 0.1 to 100 mg / kg, though it is not limited thereto. The administration may be performed once a day or divided into several times, and thus the scope of the present invention is not limited thereto.

In the present invention, the 'subject' may be a mammal including a human, but is not limited thereto.

The present invention also provides a composition for enhancing an anticancer effect comprising a triazolopyridine derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

The anticancer effect enhancing composition may be treated with an anticancer agent or radiation.

The anticancer agent is selected from the group consisting of cisplatin, 5-fluorouracil, Paclitaxel, Doxorubicin, Daunorubicin, Vinblastine, Vincristine, Actinomycin D, Teniposide, Etoposide, cyclophosphamide, epirubicin, adriamycin, daunomycin, and mitomycin, And C (mitomycin-C).

The composition may comprise 1 to 99 parts by weight of an anticancer agent and 1 to 99 parts by weight of a triazolopyridine derivative represented by the general formula (1), based on 100 parts by weight of the total composition.

The composition for enhancing the anticancer effect may be used for the treatment of lung cancer, acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, breast cancer, gastric cancer, liver cancer, colon cancer, skin cancer, head or neck cancer, uterine cancer, , Cancer of the larynx, prostate cancer, bladder cancer, esophageal cancer, thyroid cancer, bladder cancer, kidney cancer, blood cancer and rectal cancer.

According to another embodiment of the present invention, the compound 1 and the compound 2 were treated with 20 μM of the DLD-1 colon cancer cells cultured, irradiated with 3 Gy of gamma irradiation, cultured for 3 days, As a result, when the triazolepyridine compound 1 or compound 2 was treated with irradiation with radiation as shown in Fig. 4, the survival rate of the cancer cells was confirmed to decrease. In addition, Compound 1 or Compound 2 was treated with DLT-1 cells and SW480 cells at a concentration of 20 μM for 48 hours in combination with 5-FU (10 μM), a colorectal cancer treatment anticancer agent, and MTT assay was performed to confirm cell viability As a result, the cell proliferation inhibitory effects of 5-FU and Compound 1 and Compound 2 in the experimental group treated with 5-FU alone and 5-FU alone were increased by 2-fold and 1.5-fold, respectively, as shown in FIG.

From the above results, it was confirmed that when the triazolopyridine compound is treated with an anticancer agent or radiation, the triazolopyridine compound can be used as an anticancer agent adjuvant.

The present invention also provides a health food for preventing or ameliorating cancer, which comprises a triazolopyridine derivative represented by the general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

Said cancer is selected from the group consisting of lung cancer, acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, breast cancer, gastric cancer, liver cancer, colon cancer, skin cancer, head or neck cancer, uterine cancer, ovarian cancer, Cancer, bladder cancer, esophageal cancer, thyroid cancer, bladder cancer, kidney cancer, blood cancer, and rectal cancer.

The health food may be used in combination with other food or food additives in addition to the triazolopyridine derivative represented by Formula 1 or its pharmaceutically usable salt, and may be suitably used according to a conventional method. The amount of the active ingredient to be mixed can be suitably determined according to its use purpose, for example, prevention, health or therapeutic treatment.

The effective dose of the compound contained in the above-mentioned health food may be used in accordance with the effective dose of the therapeutic agent, but may be less than the above range for health and hygiene purposes or for long-term intake for health control purposes, It is clear that the component can be used in an amount of more than the above range since there is no problem in terms of safety.

There is no particular limitation on the type of the health food, and examples thereof include meat, sausage, bread, chocolate, candy, snack, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream, Drinks, alcoholic beverages and vitamin complexes.

Also, the present invention provides a triazolopyridine derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the triazolopyridine derivative or a pharmaceutically acceptable salt thereof is an in vitro ( the present invention provides a reagent composition for inhibiting the activity of a Tancirase enzyme activity, which is characterized by inhibiting the activity of the Tankyrase (TNKS) enzyme in the cell in vitro.

The present invention also relates to a method for inhibiting the activity of a cell's tryptase enzyme activity in vitro, comprising the step of treating a cancer cell with a triazolo pyridine derivative represented by the formula 1 or a pharmaceutically acceptable salt thereof Can be provided.

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail with reference to the following examples. However, the following examples are intended to illustrate the contents of the present invention, but the scope of the present invention is not limited to the following examples. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.

< Synthetic example  1> Triazolopyridine-based  Derivative synthesis

The triazolepyridine derivative compounds 1 to 12, represented by the following Chemical Formulas 1 to 12, were synthesized as follows.

1. N- ( [1,2,4] triazolo [4,3-a] pyridine Yl) -1- (2- Cyanophenyl ) Piperidine-4-carboxamide {N- ( [1,2,4] triazolo [4,3-a] pyridine -3- yl ) -1- (2-cyanophenyl) piperidine-4-carboxamide; Compound 1}

[Reaction Scheme 1]

The starting material (1) and the carboxylic acid (2) are reacted with triethylamine and dichloromethane as a solvent in the same manner as in Scheme 1, by using an amide coupling reaction using dipyridinium chloride and halobutyl chloride in the presence of dichloromethane, 21 mg was obtained in a yield of 25%.

(1H, s), 7.96 (1H, d, J = 8.0 Hz), 7.73 (1H, t, J = 8.0 Hz), 7.4 (1H, ddd, J = 12.0, 4.0 and 0.8 Hz), 7.22 D, J = 12.0 Hz), 2.91 (2H, t, J = 12.0 Hz), 2.50 (1H, J = 6.0 Hz)

2. N- ( [L, 2,4] triazolo [4,3-a] pyridine Yl) -1- (2- Nitrophenyl ) Piperidine-4-carboxamide {N- ( [1,2,4] triazolo [4,3-a] pyridine -3- yl ) -1- (2-nitrophenyl) piperidine-4-carboxamide; Compound 2}

[Reaction Scheme 2]

The starting material (1) and the carboxylic acid (2) are reacted with triethylamine and dichloromethane as a solvent in the presence of diisocyanate and HOCI in the presence of an amide coupling reaction to obtain Compound 25 mg was obtained in a yield of 29%.

^{1 H NMR (DMSO-d6,} 400 MHz): δ 10.95 (1H, s), 7.95 (1H, d, J = 8.0Hz), 7.81 (1H, dd, J = 8.0 and 4.0Hz), 7.75 (1H, t, J = 8.0 Hz), 7.59 (1H, td, J = 8.0, and 4.0 Hz), 7.38 (2H, d, J = 12.0 Hz), 2.85 (2H, t, J = , m)

3. N- ( [L, 2,4] triazolo [4,3-a] pyridine Yl) -1- Phenylpiperidine -4- Carpama ({N- [1,2,4] triazolo [4,3-a] pyridine -3- yl )-One- 페 phenylpiperidine -4-carboxamide; Compound 3}

[Reaction Scheme 3]

The starting material (1) and the carboxylic acid (2) are reacted with triethylamine and dichloromethane as a solvent in the same manner as in Scheme 3 to give compound 3 (3) in an amide coupling reaction using dipyridinium chloride and H + 24 mg was obtained in a yield of about 28%.

_{^{1 H NMR (CDCl 3 -d,}} 400 MHz): δ 11.65 (1H, s), 7.91 (1H, d, J = 4.0Hz), 7.67 (1H, d, J = 8.0Hz), 7.27 (3H, m (2H, d, J = 8.0 Hz), 6.97 (2H, d, J = 8.0 Hz) (2H, dd, J = 14.0 and 2.0 Hz), 2.07 (2H, ddd, J = 24.0, 12.0 and 4.0 Hz)

4. N- ( [L, 2,4] triazolo [4,3-a] pyridine Yl) -1- (4- Nitrophenyl ) Piperidine-4-carboxamide {N- ( [1,2,4] triazolo [4,3-a] pyridine -3- yl ) -1- (4-nitrophenyl) piperidine-4-carboxamide; Compound 4}

[Reaction Scheme 4]

The starting material (1) and the carboxylic acid (2) are reacted with triethylamine and dichloromethane as a solvent in the presence of diisocyanate and H &lt; 22 mg was obtained in a yield of 25%.

^{1 H NMR (DMSO-d6,} 400 MHz): δ 10.96 (1H, s), 8.06 (2H, d, J = 8.0Hz), 7.93 (1H, d, J = 4.0Hz), 7.74 (1H, d, J = 8.0 Hz), 7.39 (1H, ddd, J = 8.4, 6.6 and 1.8 Hz), 7.07 d, J = 12.0 Hz), 3.14 (2H, t, J = 12.0 Hz), 2.89 (1H, m), 2.05

5. N- ( [L, 2,4] triazolo [4,3-a] pyridine Yl) -1- (2-nitro-4- ( Trifluoromethyl ) Phenyl) piperidine-4-carboxamide {N- ( [1,2,4] triazolo [4,3-a] pyridine -3- yl ) -1- (2-nitro-4- (trifluoromethyl) phenyl) piperidine-4-carboxamide; Compound 5}

[Reaction Scheme 5]

The starting material (1) and the carboxylic acid (2) are reacted with triethylamine and dichloromethane as a solvent in the same manner as in Scheme 5 to give compound (3) in the form of an amide coupling reaction using edicyl chloride and H- 28 mg was obtained in a yield of 27%.

^{1 H NMR (DMSO-d6,} 400 MHz): δ 10.97 (1H, s), 8.16 (1H, d, J = 4.0Hz), 7.87 (1H, d, J = 4.0Hz), 7.85 (1H, d, J = 2.0 Hz), 7.75 (1H, dt, J = 10.6 and 0.4 Hz), 7.49 (1H, d, J = 8.0 Hz), 7.40 T, J = 7.5, 7.5 and 3.2 Hz), 3.43 (2H, d, J = 16.0 Hz), 3.07 (2H, t, J = 12.0 Hz), 2.79 , J = 12.0 Hz), 1.85 (2H, t, J = 12.0 Hz)

6. N- ( [L, 2,4] triazolo [4,3-a] pyridine Yl) -1- (4- ( Trifluoromethyl ) Phenyl) piperidine-4-carboxamide {N- ( [1,2,4] triazolo [4,3-a] pyridine -3- yl ) -1- (4- (trifluoromethyl) phenyl) piperidine-4-carboxamide; Compound 6}

[Reaction Scheme 6]

As shown in Scheme 6, the starting material (1) and carboxylic acid (2) are reacted with triethylamine and dichloromethane in the presence of dichloromethane, 24 mg was obtained in a yield of 27%.

^{1 H NMR (DMSO-d6,} 400 MHz): δ 10.94 (1H, s), 7.93 (1H, d, J = 8.0Hz), 7.74 (1H, d, J = 12.0Hz), 7.50 (2H, d, D, J = 8.0 Hz), 6.97 (1H, t, J = 6.0 Hz), 3.97 (2H, M, 2.02 (2H, d, J = 12.0 Hz), 1.76 (2H, m)

7. N- ( [L, 2,4] triazolo [4,3-a] pyridine Yl) -1- (4- Fluoro -2- Nitrophenyl ) Piperidine-4-carboxamide {N- ( [1,2,4] triazolo [4,3-a] pyridine -3- yl ) -1- (4-fluoro-2-nitrophenyl) piperidine-4-carboxamide; Compound 7}

[Reaction Scheme 7]

As shown in Scheme 7, starting compound (1) and carboxylic acid (2) are reacted with triethylamine and dichloromethane as a solvent to give compound (3) in the form of an amide coupling reaction using epidichloride and H 28 mg was obtained in a yield of 27%.

^{1 H NMR (DMSO-d6,} 400 MHz): δ 10.94 (1H, s), 7.94 (1H, d, J = 4.0Hz), 7.83 (1H, dd, J = 8.0 and 4.0Hz), 7.75 (1H, d, J = 8.0 Hz), 7.52 (2H, m), 7.40 (1H, dd, J = 12.0 and 6.0 Hz), 6.99 (2H, m), 2.03 (2H, d, J = 8.0Hz), 2.82

8. N- ( [L, 2,4] triazolo [4,3-a] pyridine Yl) -1- (4- Acetylphenyl ) Piperidine-4-carboxamide {N- ( [1,2,4] triazolo [4,3-a] pyridine -3- yl ) -1- (4-acetylphenyl) piperidine-4-carboxamide; Compound 8}

[Reaction Scheme 8]

The starting material (1) and the carboxylic acid (2) are reacted with triethylamine and dichloromethane as a solvent to give compound (3) in the form of an amide coupling reaction using diisocyanate and H &lt; 24 mg was obtained in a yield of 28%.

^{1 H NMR (DMSO-d6,} 400 MHz): δ 10.95 (1H, s), 7.93 (1H, d, J = 8.0Hz), 7.81 (2H, d, J = 8.0Hz), 7.74 (1H, d, J = 12.0 Hz), 7.39 (1H, ddd, J = 8.4, 6.4 and 1.6 Hz), 6.99 (3H, m), 4.04 M), 2.45 (3H, s), 2.02 (2H, d, J = 12.0 Hz), 1.74

9. N- ( [L, 2,4] triazolo [4,3-a] pyridine Yl) -1- (4- Chloro -2- Nitrophenyl ) Piperidine-4-carboxamide {N- ( [1,2,4] triazolo [4,3-a] pyridine -3- yl ) -1- (4- chloro -2-nitrophenyl) piperidine-4-carboxamide; Compound 9}

[Reaction Scheme 9]

The starting material (1) and carboxylic acid (2) are reacted with triethylamine and dichloromethane as a solvent to give compound 9 (3) as an amide coupling reaction using epithichlorohydrate and H &lt; 28 mg was obtained in a yield of 26%.

^{1 H NMR (DMSO-d6,} 400 MHz): δ 10.95 (1H, s), 7.95 (2H, m), 7.75 (1H, d, J = 8.0Hz), 7.65 (1H, dd, J = 12.0 and 8.0 (2H, t, J = 12.0 Hz), 2.72 (1H, d, J = m), 2.03 (2H, d, J = 8.0 Hz), 1.83 (2H, m)

10. N- ( [L, 2,4] triazolo [4,3-a] pyridine Yl) -1- (4- Cyanophenyl ) Piperidine-4-carboxamide {N- ( [1,2,4] triazolo [4,3-a] pyridine -3- yl ) -1- (4-cyanophenyl) piperidine-4-carboxamide; Compound 10}

[Reaction Scheme 10]

As shown in Scheme 10, starting material (1) and carboxylic acid (2) were reacted with compound 10 (3) in the presence of triethylamine and dichloromethane as a solvent via an amide coupling reaction using edicyl chloride and H- Was obtained in a yield of about 23%.

^{1 H NMR (DMSO-d6,} 400MHz): δ 10,94 (1H, s), 7.93 (1H, d, J = 8.0Hz), 7.74 (1H, d, J = 8.0Hz), 7.58 (1H, d (2H, d, J = 8.0 Hz), 7.39 (1H, dd, J = 8.0 and 8.0 Hz), 7.06 ), 3.01 (2H, m), 2.83 (1H, m), 2.02 (2H,

11. N- ( [L, 2,4] triazolo [4,3-a] pyridine Yl) -1- (5- Nitropyridine -2-yl) piperidine-4-carboxamide {N- ( [1,2,4] triazolo [4,3-a] pyridine -3- yl ) -1- (5-nitropyridin-2-yl) piperidine-4-carboxamide; Compound 11}

[Reaction Scheme 11]

The starting material (1) and the carboxylic acid (4) are reacted with compound 11 (5) in the presence of triethylamine and dichloromethane as a solvent, using acetic acid chloride and HCl, 20 mg was obtained in a yield of about 26%.

^{1 H NMR (DMSO-d6,} 400MHz): δ 10,97 (1H, s), 8.98 (1H, d, J = 2.0Hz), 8.23 (1H, dd, J = 2.0 and 4.0Hz), 7.94 (1H d, J = 8.0 Hz), 7.74 (1H, d, J = 8.0 Hz), 7.39 M), 2.08 (2H, d, J = 12.0 Hz), 1.70 (2H, m)

12. N- ( [L, 2,4] triazolo [4,3-a] pyridine Yl) -1- (2- Cyano -4- Nitrophenyl ) Piperidine-4-carboxamide {N- ( [1,2,4] triazolo [4,3-a] pyridine -3- yl ) -1- (2- cyano -4-nitrophenyl) piperidine-4-carboxamide; Compound 12}

[Reaction Scheme 12]

The starting material (1) and the carboxylic acid (2) are reacted with triethylamine and dichloromethane as a solvent to give compound (12) (3) in the form of an amide coupling reaction using epichlorohydrin and H- 20 mg was obtained in a yield of 23%.

^{1 H NMR (DMSO-d6,} 400 MHz): δ 11.00 (1H, s), 8.54 (1H, d, J = 4.0Hz), 8.3 (1H, dd, J = 10.0 and 2.0Hz), 7.96 (1H, d, J = 4.0 Hz), 7.75 (1H, d, J = 8.0 Hz), 7.39 (1H, ddd, J = 6.6, 4.0 and 1.4 Hz) D, J = 12.0 Hz), 3.25 (2H, t, J = 12.0 Hz), 2.87 (1H, m), 2.13 Hz), 1.885 (2H, d, J = 12.0 Hz)

< Example  1> Tan kira ( TNKS ) Confirmation of inhibitory effect of enzyme activity

(Tankyrase 1 colorimetric activity assay kit, Cat # 4500-K) was used to confirm that the triazolo pyridine derivative compounds 1 to 12 can inhibit the activity of the enzyme tyrosylase (TNKS) (4-trifluoromethyl-phenyl) -3,5,7,8-tetrahydro-thiophene was used as a positive control. 4,3-d] pyrimidin-4-one &lt; / RTI &gt; , XAV939} was used.

PARP-1 colorimetric assay kit (Cat # 4677-096-K, Trevigen) was used to confirm that Compound 1 to Compound 12 could inhibit PARP (poly-ADP ribose polymerase) , RnD systmes) according to the manufacturer's instructions, and 1 μM olaparib was used as a positive control.

As a result, TNKS and PARP inhibitory activities of the compounds 1 to 12 were confirmed as shown in Table 1.

TNKS -One Inhibition
(Compared to 0% in the control group) PARP Inhibition density( μM )
10 10 Triazolopyridine
Compound 1 95.2 ± 0.5 0 Triazolopyridine
Compound 2 94.3 ± 1.3 0 Triazolopyridine
Compound 3 58.7 ± 2.4 0 Triazolopyridine
Compound 4 30.8 ± 4.7 1.5 ± 0.8 Triazolopyridine
Compound 5 70.4 ± 2.5 0 Triazolopyridine
Compound 6 51.7 ± 1.7 1.2 ± 0.4 Triazolopyridine
Compound 7 75.4 ± 1.2 0 Triazolopyridine
Compound 8 65.8 ± 2.3 0.8 ± 0.2 Triazolopyridine
Compound 9 72.9 ± 4.7 1.1 ± 0.5 Triazolopyridine
Compound 10 59.6 ± 5.2 0.8 ± 0.4 Triazolopyridine
Compound 11 47.4 ± 3.4 0.6 ± 0.1 Triazolopyridine
Compound 12 94.8 ± 0.8 0

The control group, XAV939 (10 μM), inhibited the activity of TNKS-1 enzyme by about 96% and Olafalp (10 μM) inhibited PARP enzyme activity by 98%. On the other hand, the triazolopyridine compounds 1 to 12 showed inhibition of the activity of the TNKS-1 enzyme as shown in Table 1, while the PARP-1 activity was not inhibited.

From the above results, it was confirmed that the activity of the triazolopyridine derivative was specific to the TNKS-1 enzyme.

In addition, Compound 1 and Compound 2, which were found to have the highest activity, were tested for inhibition concentration of TNKS-1 activity of 50% as shown in Table 2.

TNKS -1 activity 50% inhibitory concentration ( μM ) (IC ₅₀ ) Triazolopyridine
Compound 1 0.760 Triazolopyridine
Compound 2 0.863

< Example  2 > Catechin  Confirming expression suppression effect

1. Cell preparation

The DLD-1, SW480 and SKMEL28 cell lines were purchased from the American Type Culture Collection (ATCC). SKMEL28 cells were treated with 10% fetal bovine serum (FBS) and 100 μg / ml streptomycin and 100 units / ml streptomycin in DMEM (Dulbecco's modified Eagle's medium) medium for DLD-1 and SW480 cells, ml penicillin were added and cultured at 5% CO ₂ and 37 ° C, respectively.

The vemurafenib-resistant SKMEL28 cell line was treated with verumupenib 5 μM for one month and then treated with verapunem 40% cell proliferation inhibitor.

2. β- Catechin  Confirmation of expression inhibition

The triazolopyridine compounds 1 and 2 were confirmed by Western blotting to inhibit the expression of beta -catenin protein through TNKS inhibition and maintain the AXIN2 protein.

First, DLD-1 colon cancer cells mutated with APC gene were treated with 10 μM of Compound 1 or Compound 2, respectively, and then cultured for 24 hours at 5% CO ₂ and 37 ° C.

Cells treated with Compound 1 or Compound 2 were then obtained and a cytoplasmic fraction was obtained by a method commonly used in the art.

The fractions were separated by performing electrophoresis using 10% gradient SDS-PAGE and transferred to a nitrocellulose membrane (BioRad, Hercules, CA, USA). The membrane was blocked with 5% skim milk and reacted with primary anti-β-catenin (USA) and anti-AXIN2 antibody (Cell signaling, USA), followed by horseradish peroxidase ) Conjugated anti-mouse IgG antibody (Santa Cruz Biotechnology, USA) and visualized using an ECL system (GE, USA).

As a result, as shown in FIG. 2, the expression of the β-catenin protein was decreased by the TNKS inhibitors, Compound 1 and Compound 2, while the AXIN2 protein was increased.

3. β- Catechin  Confirmation of sub-gene expression inhibition

DLD-1 colon cancer cells mutated with APC gene were dispensed into 6 cm plates in a number of 5 × 10 ⁵ , treated with 10 μM each of the compound 1 and the compound 2, and incubated for 8 hours under the conditions of 5% CO ₂ and 37 ° C. Respectively.

Total RNA was extracted using RNeasy kit (Qiagen, USA) after obtaining Compound 1 or Compound 2-treated cells, and cDNA was synthesized using M-MLV reverse transcriptase (Enzynomics, Korea). Real-time PCR was performed using Cosmogentec (Korea) oligomer capable of binding to the β-catenin sub-genes VEGF2 and Birc5 / Survivin and labeled with SYBR-Green / fluorescein qPCR master mix (Thermo Scientific, USA) Followed by measurement on a Lightcycler 96 Real-time PCR system (Roche Diagnostics, Germany).

As a result, it was confirmed that expression of VEGF2 and Birc5 / Survivin was remarkably decreased in the cells treated with Compound 1 or Compound 2 as shown in Fig.

< Example  3> Confirmation of anticancer effect by combination treatment with irradiation

The cultured DLD-1 colorectal cancer cells were dispensed in a number of 3 × 10 ³ cells on a 96-well cell culture plate, and the compound 1 and the compound 2 were treated at a concentration of 20 μM, irradiated with 3 Gy of gamma irradiation, 5% CO ₂ and 37 ° C.

Then, 0.5 mg / mL MTT (3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide) solution was added to each well and further incubated at 37 ° C for 3 hours. After the incubation, the supernatant was removed and the formazan crystals formed were dissolved in DMSO and measured at 590 nm using a spectrophotometer (Lap Systems, USA). The control group was treated with DMSO and the cell viability was expressed as the relative growth rate relative to 100%.

As a result, it was confirmed that when the triazolepyridine compound 1 or compound 2 with a concentration of 20 [mu] M was treated with irradiation with radiation as shown in Fig. 4, the viability decreased.

From the above results, it was confirmed that the triazolopyridine compounds 1 and 2 can be used as a radiotherapy adjuvant which can increase the efficacy in radiotherapy.

< Example  4> Confirmation of anticancer effect by combination treatment with anticancer agent

DLD-1 cells and SW480 cells cultured in the same manner as in Example 3 were treated with 20 μM of Compound 1 or Compound 2 in combination with 5-FU (10 μM), a colorectal cancer treatment anticancer, for 48 hours and MTT assay was performed Cell viability was analyzed.

As a result, as shown in FIG. 5, it was confirmed that the cell proliferation inhibitory effects of the experimental group in which 5-FU and Compound 1 and Compound 2 were administered in combination were 2-fold and 1.5-fold higher, respectively, than those in the control group in which 5-FU alone was treated .

From the above results, it was confirmed that the triazolopyridine compound can be used as an anticancer agent adjuvant which can enhance the therapeutic effect of anticancer drugs.

< Example  5> Tumor factor  Identification of anticancer effect in resistant cancer cells by inhibition of YAP activity

1. YAP / TAZ  Confirm signaling inhibition effect

It was confirmed that TNKS activates the tumor factor YAP through Angiomotin. Therefore, in order to confirm the inhibitory effect of YAP / TAZ signaling by the TNKS inhibitor triazolopyridine compound, real-time PCR was performed in the same manner as in Example 2 Expression levels of YAP / TAZ subgenus CYR61 and CTGF were confirmed.

As a result, it was confirmed that the expression of CYR61 and CTGF was markedly decreased in the cells treated with Compound 1 or Compound 2 as shown in Fig.

From these results, it was confirmed that the triazolopyridine compound can target YAP / TAZ tumor factor.

2. Identification of anticancer effects of anti-cancer drugs and anti-cancer drugs in resistant cancer cells

According to EMBO J. 2016; 35 (5): 462), the B-RAF inhibiting anticancer drug verapunem (PLX4032) is reported to be involved in YAP / TAZ signaling. SKMEL28 melanoma cells cultured in the above- Mucopenib resistant SKMEL28 cells were treated with 10 μM, 20 μM and 30 μM of compound 1 or vemurafenib 10 μM and 20 μM, respectively, and cell viability was analyzed by MTT assay.

As a result, as shown in FIG. 7, the cell proliferation rate was decreased in the SKMEL28 cell line and the veramugenep resistant SKMEL28 cell line dependent on the compound 1 concentration. In particular, it was confirmed that cell proliferation was further reduced in veromucennep resistant SKMEL28 cells than in SKMEL28 cells, and thus it was confirmed that the triazolopyridine compound of the present invention can be used as a highly effective anticancer agent.

While the present invention has been particularly shown and described with reference to specific embodiments thereof, those skilled in the art will appreciate that such specific embodiments are merely preferred embodiments and that the scope of the present invention is not limited thereby. something to do. It is therefore intended that the scope of the invention be defined by the claims appended hereto and their equivalents.

Claims (15)

A triazolopyridine derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
[Chemical Formula 1]

In Formula 1,
Wherein one of R ¹ and R ² is CN or NO ₂ and the other is selected from the group consisting of hydrogen, CN and NO ₂ ,
X is carbon. delete [2] The compound according to claim 1, wherein the triazolo pyridine derivative is N - ([1,2,4,] triazolo [4,3-a] pyridin- Carboxamide, N - ([1,2,4] triazolo [4,3-a] pyridin-3-yl) -1- (2-nitrophenyl) piperidine- N - ([1,2,4] triazolo [4,3-a] pyridin-3-yl) 2, 4] triazolo [4,3-a] pyridin-3-yl) -1- (4-cyanophenyl) piperidine- 4- carboxamide and N- ] Triazolo [4,3-a] pyridin-3-yl) -1- (2-cyano-4-nitrophenyl) piperidine-4-carboxamide. A zolopyridine-based derivative or a pharmaceutically acceptable salt thereof. 1. A pharmaceutical composition for preventing or treating cancer comprising, as an active ingredient, a triazolo pyridine derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
[Chemical Formula 1]

In Formula 1,
R ¹ and R ² may be the same or different and are selected from hydrogen, CN, NO ₂ , CF ₃ , halogen and acetyl,
And X is any one selected from nitrogen and carbon. 5. The compound according to claim 4, wherein R ¹ and R ² of the compound may be the same or different and are selected from the group consisting of hydrogen, CN, NO ₂ , CF ₃ and halogen,
Wherein X is carbon, or a pharmaceutically acceptable salt thereof, as an active ingredient. [5] The method according to claim 4, wherein the triazolo pyridine derivative is at least one selected from the group consisting of N - ([1,2,4,] triazolo [4,3-a] pyridin- Carboxamide, N - ([1,2,4] triazolo [4,3-a] pyridin-3-yl) -1- (2-nitrophenyl) piperidine- Carboxamide, N - ([1,2,4] triazolo [4,3-a] pyridin-3-yl) N, N &apos; - [[1,2,4] triazolo [4,3-a] pyridin- Pyridine-4-carboxamide, N - ([l, 2,4] triazolyl) (4,3-a) pyridin-3-yl) -1- (4- (trifluoromethyl) phenyl) piperidine- 4-carboxamide, N - ([l, 2,4] triazolo [4,3-a] pyridin- , 3-a] pyridin-3-yl) -1- (4-acetylphenyl) piperidine- (4-chloro-2-nitrophenyl) piperidine-4-carboxamide, N - ([ (4,3-a) pyridin-3-yl) -1- (4-cyanophenyl) piperidine- a] pyridin-3-yl) -1- (5-nitropyridin-2-yl) piperidine- Pyridin-3-yl) -1- (2-cyano-4-nitrophenyl) piperidine-4-carboxamide. [Claim 4] The pharmaceutical composition for preventing or treating cancer according to claim 4, wherein the triazolo pyridine derivative represented by Formula 1 inhibits the enzyme activity of Tankyrase (TNKS). The method of claim 4, wherein the cancer is selected from the group consisting of lung cancer, acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, breast cancer, gastric cancer, liver cancer, colon cancer, skin cancer, head or neck cancer, uterine cancer, Wherein the composition is any one selected from the group consisting of brain cancer, laryngeal cancer, prostate cancer, bladder cancer, esophageal cancer, thyroid cancer, renal cancer, blood cancer and rectal cancer. 1. A composition for enhancing an anticancer effect comprising, as an active ingredient, a triazolopyridine derivative represented by the following formula (1) or a pharmaceutically usable salt thereof.
[Chemical Formula 1]

In Formula 1,
R ¹ and R ² may be the same or different and are selected from hydrogen, CN, NO ₂ , CF ₃ , halogen and acetyl,
And X is any one selected from nitrogen and carbon. [Claim 12] The composition for promoting anti-cancer activity according to claim 9, wherein the anti-cancer effect enhancing composition is treated with an anti-cancer agent or radiation. [Claim 11] The method of claim 10, wherein the anticancer agent is selected from the group consisting of cisplatin, 5-fluorouracil, Paclitaxel, Doxorubicin, Daunorubicin, Vinblastine, (Vincristine), Actinomycin D, Teniposide, Etoposide, cyclophosphamide, epirubicin, adriamycin, daunomycin, daunomycin, and mitomycin-C. &lt; RTI ID = 0.0 &gt; 25. &lt; / RTI &gt; [Claim 11] The anticancer composition according to claim 9, wherein the composition comprises 1 to 99 parts by weight of an anticancer agent and 1 to 99 parts by weight of a triazolopyridine derivative represented by the following formula . [12] The composition according to claim 9, wherein the composition for enhancing the anti-cancer effect is selected from lung cancer, acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, breast cancer, gastric cancer, liver cancer, colon cancer, The composition for enhancing an anticancer effect according to any one of claims 1 to 3, wherein the anticancer agent is selected from the group consisting of cancer, breast cancer, brain cancer, larynx cancer, prostate cancer, bladder cancer, esophageal cancer, thyroid cancer, kidney cancer, blood cancer, . 1. A health food for preventing or ameliorating cancer comprising, as an active ingredient, a triazolopyridine derivative represented by the following formula (1) or a pharmaceutically usable salt thereof:
[Chemical Formula 1]

In Formula 1,
R ¹ and R ² may be the same or different and are selected from hydrogen, CN, NO ₂ , CF ₃ , halogen and acetyl,
And X is any one selected from nitrogen and carbon. 15. The method of claim 14, wherein the cancer is selected from the group consisting of lung cancer, acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, breast cancer, gastric cancer, liver cancer, colon cancer, skin cancer, head or neck cancer, Wherein the cancer is any one selected from the group consisting of brain cancer, laryngeal cancer, prostate cancer, bladder cancer, esophageal cancer, thyroid cancer, kidney cancer, blood cancer and rectal cancer.

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