KR20170115315A - Novel heterocyclic derivatives, and use thereof - Google Patents

Abstract

The present invention relates to novel heterocyclic derivatives, their tautomers, stereoisomers and mixtures thereof, or a pharmaceutically acceptable salt thereof; And a pharmaceutical composition for preventing or treating a cancer-related disease containing the same as an active ingredient.

Description

Novel heterocyclic derivatives, and uses thereof,

The present invention relates to novel heterocyclic derivatives, their tautomers, their stereoisomers or their pharmaceutically acceptable salts; A pharmaceutical composition for preventing or treating a cancer-related disease containing the same as an active ingredient; Its use; And a method for preventing or treating Tanzirase-related diseases using the same.

The human tankyrase belongs to the poly (ADP-ribose) polymerase (PARP) family of proteins consisting of 17 members sharing the catalytic PARP domain.

PARP family proteins are potential therapeutic targets; PARP1 and PARP2 act in DNA damage responses, while PARP inhibitors sensitize cancer cells to drugs and radiation therapy. PARP1 is also involved in diseases including inflammation, neuronal apoptosis and ischemia. Tancirase, which shares high sequence similarity with PARP1, is also attracting attention as a therapeutic target. Initially, tannicase is known to be a modulator of telomerase activity and is involved in DNA damage responses and Wnt signaling (Wahlbert et al. , 2012, Nat. Biotechnol. , 30 (3): 283- 288).

The TanKyraZine protein family consists of tankyrase 1 (TNKS1) and tankyrase 2 (TNKS2) sharing 85% amino acid identity. The biologic functions of the two types of mammalian cells were studied using genetically engineered mice lacking mouse mammalian 1 and / or mammalian 2. As a result, the TK2 deficient mice developed normally and no change in telomere length was detected, but showed a significant decrease in total body weight reflecting the role of TK2 in glucose or lipid metabolism. No defects were detected in retention of telomere length in TanKiraja 1 deficient mice. However, embryonic lethality was observed at 10 days of gestation in double-knockout mice lacking both Tancirase 1 and Tancirase 2 (Chiang et al. , 2008, PLoS One , 3 (7): e2639).

On the other hand, the main feature of the Wnt / β-catenin pathway is the controlled proteolysis of the downstream effector β-catenin by the β-catenin destruction complex. The major components of the β-catechin destruction complex are adenomatous polyposis coli (APC), axin and GSK3α / β. When the Wnt pathway is not activated, the cytoplasmic beta -catenin is constitutively phosphorylated and targeted for degradation. Upon Wnt stimulation, the β-catechin-destructive complex is isolated resulting in accumulation of β-catenin in the nucleus and transcription of the Wnt pathway reactive gene.

In the Wnt / [beta] -catenin pathway, it has been shown that the inhibitor of tannin inhibits beta-catenin degradation by stabilizing the lectin, thereby selectively inhibiting the transcription mediated by beta -catenin (Huang et al. , 2009, Nature , 461 (7264): 614-620).

Inadequate activation of the pathway, which is mediated by mutations that affect the overexpression of the Wnt protein or components of the beta -catenin-destroying complex, thus stabilizing [beta] -catenin, is associated with many cancers such as colon cancer, gastric cancer gastric cancer, hepatocellular carcinoma, breast cancer, medulloblastoma, melanoma, non-small cell lung cancer, pancreas adenocarcinoma, and prostate (Waaler et al. , 2012, Cancer Res. , 72 (11): 2822-2832). In particular, the tumor suppressor APC truncation mutation is the most common genetic change in colorectal carcinoma (Miyaki et al. , 1994, Cancer Res. , 54: 3011-3020). In addition, the mutation of axon 1 and axon 2 has been identified in patients with hepatocarcinoma and colorectal cancer, respectively (Taniguchi et al. , 2002, Oncogene , 21: 4863-4871; Liu et al. , 2000, Nat Genet. 26: 146-147). These somatic mutations induce Wnt-independent stabilization of β-catenin and constitutive activation of β-catenin-mediated transcription. In addition, deregulated Wnt pathway activity is also known to be associated with osteoporosis, osteoarthritis, polycystic kidney disease, pulmonary fibrosis, diabetes, schizophrenia, vascular disease, cardiac disease, But also other diseases other than the above-mentioned cancer diseases including non-oncogenic proliferative diseases and neurodegenerative diseases such as Alzheimer ' s disease.

Treatment strategies that target or ameliorate a Wnt signaling pathway disorder include bone density defects, coronary disease, late onset Alzheimer ' s disease, familial exudative vitreoretinopathy familial exudative vitreoretinopathy, retinal angiogenesis, tetramelia, Mullerian-duct regression and virilization, SERKAL syndrome, type 2 diabetes, perman syndrome (Fuhrmann syndrome, skeletal dysplasia, focal dennal hypoplasia, and neural tube defects. Although the introductory section focuses on the relevance of Wnt signaling in cancer, the Wnt signaling pathway is not limited to the example provided for the purposes of the above example, and has fundamental importance and potential impacts in a wide range of human diseases.

On the other hand, it has recently been shown that intracellular accessory levels are influenced by the poly (ADP-ribose) polymerase enzyme family members tankyrase-1 and tannin kinase-2 (also known as PARP5a and PARP5b) ( Nature Chemical Biology , 2009, 5: 100; Nature, 2009, 461: 614). The enzyme can be poly-ADP lyzed to the lecithin, so that the protein is displayed for subsequent ubiquitination and proteomic degradation. Thus, in the presence of inhibitors for the catalytic activity of tancirase, the lecithin protein concentration will increase, thereby increasing the concentration of destructive complexes, reducing intracellular beta-catenin and reducing Wnt signaling. Inhibitors of Tancirase-1 and -2 can also have an effect on other biological functions of the Tancirase protein (e.g., chromosomal terminal protection telomeric, insulin responsive and mitotic spindle assembly) (Chang et al. , 2005, Biochem. , 391: 177-184; Chi et al. , 2000, J. Biol. Chem. , 275: 38437-38444; Bae et al. , 2003, J. Biol . Chem . , 278: 5195-5204 ).

There is a continuing need for new therapeutic agents that can be used for cancer and hyperproliferative conditions, and there is a growing need for the development of antagonists that specifically regulate Wnt activity.

It is an object of the present invention to provide novel compounds exhibiting antitumor activity, tautomers thereof, stereoisomers thereof, or pharmaceutically acceptable salts thereof.

Another object of the present invention is to provide a method for producing the same.

Still another object of the present invention is to provide a pharmaceutical composition for preventing or treating a cancer-related disease comprising the compound of the present invention, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient .

It is another object of the present invention to provide a use thereof for the preparation of a medicament for the prophylactic or therapeutic treatment of a cancer-related disease.

It is yet another object of the present invention to provide a method for the prevention or treatment of a cancer-related disease comprising administering a therapeutically effective amount of the pharmaceutical composition of the present invention.

As a result of efforts made by the present inventors to achieve the above object, it was confirmed that newly designed and synthesized heterocyclic derivatives can inhibit or regulate the activity of Tancirase, and the present invention has been completed.

Heterocyclic  A derivative compound

The present invention provides a compound represented by the following general formula (1), a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[Chemical Formula 1]

In the above formulas,

X ₁ to X ₃ are C or N;

R ₁ is hydrogen, halo, cyano, nitro, carboxy, C _{1 -6} alkyl, C _{1 -6} alkyl, oxo, C _{2 -6} alkenyl, C _{1 -6} alkoxy, C _{1 -6} alkoxycarbonyl, C _{1 -6} hydroxyalkyl, C _{1 -6-dihydroxy} alkyl, halo C _{1 -6} alkyl unsubstituted or substituted by hydroxyl or C _{3 -7-cycloalkyl;}

A is A'-CH ₂ -CR ₂ R ₂ ';

A 'is CR ₃ R ₃ ', NR ₃ , O or S;

R ₂ and R ₂ 'are each independently hydrogen, halo, OH, CN, C _{1 -6} alkyl, or C _{3 -7-cycloalkyl;}

Y is C or N;

Z is O, CO or member;

W is Ar or Het;

Ar is phenyl {wherein the phenyl is unsubstituted or one to three hydrogen Beach _{halo, NO 2, CN, B,} OR 4, S (O) m R 4, NR 4 R 4 ', COB, COOR 4, Which may be substituted by a substituent selected from the group consisting of CONR ₄ R ₄ ', SO ₂ NR ₄ R ₄ ', NR ₄ COR ₅ , NR ₄ SO ₂ B, NR ₄ CONR ₅ R ₅ ', Ar' and Het ';

Het is selected from the group consisting of furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl and pyridazinyl one selected {wherein the Het is unsubstituted or one or two hydrogen are each independently selected from _{halo, NO 2, CN, B,} oR 4, NR 4 R 4 ', CONR 4 R 4', Ar ', Het' and Lt; RTI ID = 0.0 > = O; < / RTI >

Het 'is a group consisting of furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl and pyridazinyl Wherein the Het 'is unsubstituted or each one or two hydrogens is independently selected from halo, NO ₂ , CN, B, OR ₄ , NR ₄ R ₄ ', CONR ₄ R ₄ ', Ar'O;< / RTI >

Ar 'is phenyl {wherein the phenyl is unsubstituted or substituted with one to three hydrogen is _{halo, NO 2, CN, B,} OR 4, S (O) m R 4, NR 4 R 4', COB, COOR 4 , CONR ₄ R ₄ ', NR ₄ COR ₅ and NR ₄ SO ₂ B;

B is C _{1 -6} alkyl and {1 or 2 can be optionally substituted with one non-adjacent CH ₂ or CH groups are N or O atoms, which may be substituted by halo or hydroxy, each has one or more independently hydrogen};

R ₃ , R ₃ ', R _{4 ,} R ₄ ', R ₅ and R ₅ 'are each independently hydrogen or C _{1 -6} alkyl;

Halo is F, Cl, Br or I; And

m is 0, 1 or 2;

According to one embodiment of the present invention,

The compound of Formula 1 is a compound represented by Formula 1-1 or 1-2,

[Formula 1-1]

[Formula 1-2]

In the above formulas,

R ₁ is hydrogen, halo, cyano, nitro, carboxy, C _{1 -6} alkyl, C _{1 -6} alkyl, oxo, C _{2 -6} alkenyl, C _{1 -6} alkoxy, C _{1 -6} alkoxycarbonyl, C _{1 -6} hydroxyalkyl, C _{1 -6-dihydroxy} alkyl, halo C _{1 -6} alkyl unsubstituted or substituted by hydroxyl or C _{3 -7-cycloalkyl;}

A is A'-CH ₂ -CR ₂ R ₂ ';

A 'is CR ₃ R ₃ ', NR ₃ or S;

R ₂ and R ₂ 'are each independently hydrogen or methyl;

Y is C or N;

Z is CO;

W is Ar or Het;

Ar is phenyl {wherein the phenyl is unsubstituted or one to three hydrogen Beach _{halo, NO 2, CN, B,} OR 4, S (O) m R 4, NR 4 R 4 ', COB, COOR 4, Which may be substituted by a substituent selected from the group consisting of CONR ₄ R ₄ ', SO ₂ NR ₄ R ₄ ', NR ₄ COR ₅ , NR ₄ SO ₂ B, NR ₄ CONR ₅ R ₅ ', Ar' and Het ';

Het is selected from the group consisting of furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl and pyridazinyl one selected {wherein the Het is unsubstituted or one or two hydrogen are each independently selected from _{halo, NO 2, CN, B,} oR 4, NR 4 R 4 ', CONR 4 R 4', Ar ', Het' and Lt; RTI ID = 0.0 > = O; < / RTI >

Het 'is a group consisting of furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl and pyridazinyl Wherein the Het 'is unsubstituted or each one or two hydrogens is independently selected from halo, NO ₂ , CN, B, OR ₄ , NR ₄ R ₄ ', CONR ₄ R ₄ ', Ar'O;< / RTI >

Ar 'is phenyl {wherein the phenyl is unsubstituted or substituted with one to three hydrogen is _{halo, NO 2, CN, B,} OR 4, S (O) m R 4, NR 4 R 4', COB, COOR 4 , CONR ₄ R ₄ ', NR ₄ COR ₅ and NR ₄ SO ₂ B;

B is C _{1 -6} alkyl and {1 or 2 can be optionally substituted with one non-adjacent CH ₂ or CH groups are N or O atoms, which may be substituted by halo or hydroxy, each has one or more independently hydrogen};

R ₃ , R ₃ ', R _{4 ,} R ₄ ', R ₅ and R ₅ 'are each independently hydrogen or methyl;

Halo is F, Cl, Br or I; And

m is 0, 1 or 2;

According to a preferred embodiment of the present invention,

1) 5- (3- (4- (4-methoxybenzoyl) piperidin- 1 -yl) -3-oxopropylamino) -3-methyl-3H- [1,2,3] triazolo [ , 5-d] pyrimidin-7 (6H) -one;

2) Preparation of 5 - ((3- (4- (4-methoxybenzoyl) piperidin- 1 -yl) -3-oxopropyl) ] Triazolo [4,5-d] pyrimidin-7 (6H) -one;

3) Preparation of 5- (3- (4- (4-methoxybenzoyl) piperidin- 1 -yl) -3-oxopropylthio) -3-methyl- , 5-d] pyrimidin-7 (6H) -one;

4) Synthesis of 5- (3- (4- (4-methoxybenzoyl) piperazin-1-yl) -3-oxopropylamino) -3- 5-d] pyrimidin-7 (6H) -one;

5) 5- (3- (4- (4-methoxybenzoyl) piperidin-l-yl) -2,2- 3] triazolo [4,5-d] pyrimidin-7 (6H) -one;

6) 5- (3- (4- (4-methoxybenzoyl) piperazin-1-yl) -2,2-dimethyl-3-oxopropylamino) -3-methyl- ] Triazolo [4,5-d] pyrimidin-7 (6H) -one;

7) Preparation of 5- (4- (4- (4-methoxybenzoyl) piperidin- 1 -yl) -4-oxobutyl) -3-methyl- 5-d] pyrimidin-7 (6H) -one; And

8) 2- (3- (4- (4-methoxybenzoyl) piperidin-1-yl) -3-oxopropylamino) -7-methylimidazo [ , 4] triazin-4 (3H) -one;

≪ / RTI > However, it is not limited thereto.

The compounds of formula (I) of the present invention may exist in the form of pharmaceutically acceptable salts. Salts are useful as acid addition salts formed by pharmaceutically acceptable free acids. The term "pharmaceutically acceptable salt" of the present invention means a concentration that has a relatively non-toxic and harmless effective action in a patient, wherein the adverse effect due to the salt is an adverse effect of the compound Quot; means all organic acids or inorganic acid addition salts.

The acid addition salt is prepared by a conventional method, for example, by dissolving the compound in an excess amount of an acid aqueous solution, and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. The same molar amount of the compound and the acid or alcohol (e.g., glycol monomethyl ether) in water may be heated and then the mixture may be evaporated to dryness, or the precipitated salt may be subjected to suction filtration.

As the free acid, organic acids and inorganic acids can be used. As the inorganic acids, hydrochloric acid, phosphoric acid, sulfuric acid or nitric acid can be used. Examples of the organic acids include methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic (such as citric acid, lactic acid, glycollic acid, gluconic acid), succinic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, glutamic acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc. may be used. However, it is not limited thereto.

In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal salt or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the non-soluble salt salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically acceptable to produce sodium, potassium, or calcium salt, but not limited thereto. The corresponding silver salt can also be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

The pharmaceutically acceptable salts of the present invention include, unless otherwise indicated, salts of acidic or basic groups which may be present in the compounds of formula (1). For example, pharmaceutically acceptable salts may include sodium, calcium and potassium salts of hydroxy groups, and the other pharmaceutically acceptable salts of amino groups include hydrobromides, sulphates, sulphates, phosphates, hydrogen phosphates (Hydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts and the like, ≪ / RTI >

As salts of the heterocyclic derivatives of the present invention, pharmaceutically acceptable salts such as salts of heterocyclic derivatives exhibiting inhibitory activity against the inhibitors of the inhibitory activity against tyrosine kinase 1 and / or tyrosine kinase 2 equivalent to the heterocyclic derivative compounds All are available without restrictions.

Process for producing heterocyclic derivative compounds

The compounds of formula (I) of the present invention can be prepared by a series of reactions including the reaction of 7-isopropoxy-3-methyl-5- (methylsulfonyl) -3H- [1,2,3] triazolo [4,5- Methyl or 2-chloro-7-methylimidazo [l, 5- f] [1,2,4] triazine-4 (3H) -one. However, the following reaction formula is an exemplary method for preparing the compound of the present invention, and the method for preparing the compound of the present invention is not limited thereto, and can be carried out by using methods known in the art or by appropriately changing it.

As described above, the intermediate 7-isopropoxy-3-methyl-5- (methylsulfonyl) -3H- [1,2,3] triazolo [4,5- One or more of the reactions known in the art at the 2-chloro-7-methylimidazo [1,5- f] [1,2,4] triazine-4 (3H) (R) can be introduced in place of the methylsulfonyl group or chlorine by further performing a substitution reaction.

For example, when the substituent introduced in place of the methylsulfonyl group is an amine group or a mercaptan group, the reaction is carried out according to the following Reaction Scheme 1 or, if necessary, further deprotection reaction is carried out to obtain the intermediate 7-isopropoxy-3- A heterocyclic derivative compound ( 3 ) of the present invention can be obtained from methyl 5- (methylsulfonyl) -3H- [1,2,3] triazolo [4,5-d] pyrimidine .

[Reaction Scheme 1]

Preferably, the reaction can be carried out via reaction of the intermediate (1) with an amine or mercaptan compound containing a substituent suitable for the desired title compound in a THF / EtOH solvent. Preferably, the reaction is carried out at 70 to 80 ° C for 2 to 3 hours.

When the substituent introduced in place of the chlorine group is an amine group, the reaction is carried out according to the following Reaction Scheme 2 to obtain the intermediate 2-chloro-7-methylimidazo [1,5-f] Azine-4 (3H) -one (4), the heterocyclic derivative compound ( 5 ) of the present invention can be obtained.

[Reaction Scheme 2]

Preferably, the reaction can be carried out by reaction of the intermediate with an amine compound in a THF / EtOH solvent, containing a substituent suitable for the desired title compound. Preferably, the reaction is carried out at 90 to 100 < 0 > C for 20 to 24 hours.

Composition comprising a heterocyclic derivative compound, use thereof, and method for preventing or treating the same

The present invention provides a pharmaceutical composition for the treatment or prevention of a cancer-related disease comprising a compound of the following formula (1), a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[Chemical Formula 1]

Formula 1 is as defined above.

The compound of formula (I) of the present invention, its tautomer, its stereoisomer or pharmaceutically acceptable salt thereof may exhibit an activity of inhibiting the activity of Tancirase 1, Tancirase 2 or both.

Accordingly, the pharmaceutical composition comprising the compound of formula (I), a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as an active ingredient of the present invention is useful as an agent for inhibiting the activity of Tancirase 1 and / or Tancirase 2 Or proliferation of the cell, thereby preventing or treating a cancer-related disease by controlling the cell death, proliferation and / or metastasis by inhibiting the cell, thereby preventing or treating a disease caused by abnormality of the cancer cell line 1 and / Can be usefully used.

Specifically, the pharmaceutical composition of the present invention can be usefully used for the prevention or treatment of cancer, multiple sclerosis (MS), cardiovascular diseases, central nervous system injury or inflammatory diseases .

Wherein the cancer is selected from the group consisting of head, neck, eye, mouth, throat, esophagus, bronchus, larynx, pharynx, thorax, bone, lung, colon, rectum, stomach, prostate, bladder, uterus, cervix, And cancer diseases such as cancer of the reproductive organs, skin, thyroid, blood, lymph nodes, kidney, liver, pancreas, brain, central nervous system, solid tumors and blood infectious tumors. Preferably, the cancer-related disease that can be prevented or treated using the pharmaceutical composition of the present invention may be, but not limited to, colon cancer, rectal cancer, colon cancer, breast cancer, lung cancer or blood cancer.

In the present invention, the term "prevention" means any action that inhibits or delays the development, spread and recurrence of a cancer-related disease upon administration of the composition of the present invention. The term " The administration of the composition means any action that alleviates or alleviates the symptoms of the disease.

The pharmaceutical composition according to the present invention contains, as an active ingredient, a compound represented by the formula (1), a tautomer thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof in an amount of 0.1 to 75% by weight, By weight may be contained in an amount of 1 to 50% by weight.

In addition, the pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable carrier, diluent or excipient, and may be formulated into powders, granules, tablets, capsules, suspensions, The composition may be formulated into various forms such as oral formulations such as emulsions, syrups and aerosols, and injections of sterile injectable solutions, and may be administered by various routes including oral administration or intravenous, intraperitoneal, subcutaneous, rectal, . Examples of suitable carriers, excipients or diluents that may be included in such compositions include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. The composition of the present invention may further include a filler, an anti-coagulant, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent, an antiseptic, and the like.

Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose, lactose, gelatin, Are mixed and formulated. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used.

Examples of the oral liquid preparation include suspensions, solutions, emulsions and syrups. In addition to water and liquid paraffin which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like are included .

Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. 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. The supplements of suppositories are etwesol, macrogol, tween 61. Cacao butter, laurin, glycerogelatin and the like can be used. On the other hand, injecting agents may include conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers, preservatives and the like.

The composition of the present invention is administered in a pharmaceutically effective amount. In the present invention, the term "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment and not causing side effects, Factors well known in the art and other medical disciplines, including the health condition, the type of disease, the severity, the activity of the drug, the sensitivity to the drug, the manner of administration, the time of administration, the route of administration and rate of release, ≪ / RTI > The composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiply. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without side effects, which can be easily determined by those skilled in the art.

Specifically, the effective amount of the compound in the composition of the present invention may vary depending on the age, sex and body weight of the patient, and is generally 1 to 100 mg, preferably 5 to 60 mg per kg of body weight, It may be administered one to three times a day. However, the dosage may not be limited in any way because it may be increased or decreased depending on route of administration, severity of disease, sex, weight, age, and the like.

According to another embodiment of the present invention, the present invention provides a method for the treatment and / or prophylactic treatment of a subject, comprising administering to a subject in need thereof a compound represented by formula (I), a tautomer thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, A method for preventing or treating a cancer-related disease is provided.

In the present invention, the term "individual" means a monkey, a cow, a horse, a sheep, a pig, a chicken, a turkey, a quail, a cat, a dog, a mouse, Refers to all animals including mice, rabbits or guinea pigs, and the pharmaceutical composition of the present invention may be administered to an individual to effectively prevent or treat the disease. The pharmaceutical composition of the present invention can be administered in parallel with existing therapeutic agents.

In the present invention, the term "administration" means providing a predetermined substance to a patient by any suitable method, and the administration route of the composition of the present invention is administered through any conventional route ≪ / RTI > But are not limited to, intraperitoneal, intravenous, intramuscular, subcutaneous, intradermal, oral, topical, intranasal, intrathecal, rectal. In addition, the pharmaceutical composition of the present invention may be administered by any device capable of moving the active substance to the target cell. The preferred modes of administration and formulations are intravenous, subcutaneous, intradermal, intramuscular, and drip injections. The injectable solution may be a non-aqueous solvent such as an aqueous solvent such as a physiological saline solution or a ring gel solution, a vegetable oil, a higher fatty acid ester (e.g., oleic acid), an alcohol (e.g., ethanol, benzyl alcohol, propylene glycol, glycerin, etc.) (For example, ascorbic acid, sodium hydrogen sulfite, sodium pyrophosphate, BHA, tocopherol, EDTA and the like), an emulsifier, a buffer for pH control, a microbial growth inhibitor And a pharmaceutical carrier such as a preservative (e.g., mercury nitrate, thimerosal, benzalkonium chloride, phenol, cresol, benzyl alcohol, etc.).

The term "therapeutically effective amount " used in connection with the active ingredient in the present invention refers to an amount of a heterocyclic derivative compound, its tautomer, its stereoisomer or pharmaceutically acceptable salt thereof effective for preventing or treating a subject disease .

The pharmaceutical composition of the present invention can be administered orally or parenterally to prevent or treat any known disease other than a heterocyclic derivative compound, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient, Prophylactic or therapeutic agents of the present invention. For example, when it is used for the prophylactic or therapeutic treatment of cancer, it may further comprise, as an active ingredient, a known anticancer agent in addition to a heterocyclic derivative compound, a tautomer thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, May be used in combination with other therapies known for the treatment of diseases. Other treatments include, but are not limited to, chemotherapy, radiation therapy, hormone therapy, bone marrow transplantation, stem cell replacement therapy, other biological therapies, immunotherapy, and the like.

Examples of anticancer agents that can be included in the pharmaceutical composition of the present invention include DNA alkylating agents such as mechloethamine, chlorambucil, phenylalanine, mustard, cyclophosphate, Cyclophosphamide, ifosfamide, carmustine (BCNU), lomustine (CCNU), streptozotocin, busulfan, thiotepa, cisplatin cisplatin and carboplatin; The anticancer antibiotics include dactinomycin (actinomycin D), doxorubicin (adriamycin), daunorubicin, idarubicin, mitoxantrone, Plicamycin, mitomycin C, and bleomycin; And plant alkaloids such as vincristine, vinblastine, paclitaxel, docetaxel, etoposide, teniposide, topotecan, And iridotecan, but are not limited thereto.

The novel heterocyclic derivatives of the present invention are capable of inhibiting Tancirase 1 and / or Tancirase 2 and thus can be usefully used for the treatment or prevention of diseases caused by over-expression or excessive activity of Tancirase .

Hereinafter, the constitution and effects of the present invention will be described in more detail through examples. These examples are only for illustrating the present invention, and the scope of the present invention is not limited by these examples.

Preparation Example 1: Preparation of 3-amino-1- (4- (4-methoxybenzoyl) piperidin-1-yl) propan-1-one hydrochloride (I- 1-yl) -3- (methylamino) propan-1-one hydrochloride (I-2)

Step 1. Preparation of 3- (tert-butoxycarbonylamino) propionic acid

After dissolving 3-aminopropionic acid (891 mg, 10 mmol), di-tert-butyl-carbonate (2.756 ml, 12 mmol) and NaOH (480 mg, 12 mmol) in dioxane: distilled water = 1: Lt; / RTI > for 18 hours. The reaction mixture was concentrated under reduced pressure, and a 1N hydrochloric acid aqueous solution was slowly added thereto to adjust the pH to 4 to 5. The crystals formed were stirred for 10 minutes and filtered to give 1.26 g of the title compound as a white solid.

LC-MS (ESI, m / z) = 188.1 (MH ^< ⁺ &

Step 2. Preparation of tert-butyl-3- (4- (4-methoxybenzoyl) piperidin-1-yl) -3-oxopropylcarbamate

(555 mg, 2.932 mmol), PyBOP (1.525 g, 2.932 mmol), (4-methoxyphenyl) (piperidin-4-yl) Methanone hydrochloride (500 mg, 1.955 mmol) was dissolved in DMF, DIPEA (1.02 ml, 5.865 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with ethyl acetate and washed three times with water. Dehydrating the organic layer with Na ₂ SO _4, and then concentrated under reduced pressure and separated by column chromatography to give the title compound 735 mg as a yellow liquid.

LC-MS (ESI, m / z) = 391.0 (M + H ^& lt ^{; +} & gt ^; ).

Step 3. Preparation of 3-amino-1- (4- (4-methoxybenzoyl) piperidin-1-yl) propan-1-one hydrochloride

3- (4- (4-methoxybenzoyl) piperidin-1-yl) -3-oxopropylcarbamate (486 mg, 1.244 mmol) obtained in Step 2, 4M HCl in dioxane ml, 6.22 mmol) were dissolved in dichloromethane, and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure to give 406 mg of the titled compound as a yellow solid.

LC-MS (ESI, m / z) = 291.0 (M + H <^+> )

Step 4. Preparation of tert-butyl 3- (4- (4-methoxybenzoyl) piperidin-l-yl) -3-oxopropyl (methyl) carbamate

(247 mg, 0.632 mmol), NaH (37.92 mg, 0.948 &lt; RTI ID = 0.0 &gt; mmol) was diluted in DMF, MeI (0.06 ml, 0.948 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate and washed three times with water. Dehydrating the organic layer with Na ₂ SO _4, and then concentrated under reduced pressure and separated by column chromatography to give the title compound, 71 mg of a yellow liquid.

LC-MS (ESI, m / z) = 405.2 (M + H <^+> ).

Step 5. Preparation of l- (4- (4-methoxybenzoyl) piperidin-l-yl) -3- (methylamino) propan- 1-one hydrochloride

The compound obtained in Step 4 (71 mg, 0.175 mmol) was reacted in the same manner as in Step 3 to give 59 mg of the title compound as a yellow solid.

LC-MS (ESI, m / z) = 305.1 (M + H ^& lt ^{; +} &

Preparation Example 2: Preparation of 3-amino-1- (4- (4-methoxybenzoyl) piperidin-1-yl) propan-1-one hydrochloride (I-

Step 1. Preparation of tert-butyl 4- (4-methoxybenzoyl) piperazine-1-carboxylate

Butylpiperazine-1-carboxylate (0.98 g, 6.443 mmol) was reacted in the same manner as in Step 2 of Preparation Example 1 to obtain 1.72 g of the title compound. .

LC-MS (ESI, m / z) = 321.2 (M + H <^+> )

Step 2. Preparation of tert-butyl 3- (4- (4-methoxybenzoyl) piperazin-1-yl) -3-oxopropylcarbamate

(1.72 g, 5.369 mmol) obtained in Step 1 was reacted in the same manner as Step 3 of Preparation Example 1 to give 1.528 g of (4-methoxyphenyl) (piperazin-1-yl) methanone hydrochloride as a white solid &Lt; / RTI &gt; (500 mg, 1.948 mmol) and (4-methoxyphenyl) (piperazin-1-yl) methanone hydrochloride (442 mg, 2.338 mmol) obtained in step 1 of Preparation Example 1 were dissolved in step 2 To give 605 mg of the titled compound as a yellow solid.

LC-MS (ESI, m / z) = 392.1 (M + H ^& lt ^{; +} &

Step 3. Preparation of 3-amino-1- (4- (4-methoxybenzoyl) piperidin-1-yl) propan-1-one hydrochloride

The compound (605 mg, 1.545 mmol) obtained from Step 2 was reacted in the same manner as Step 3 of Production Example 1 to give 495 mg of the title compound as a yellow solid.

LC-MS (ESI, m / z) = 292.1 (M + H <^+> )

Preparation Example 3: Preparation of 3-amino-1- (4- (4-methoxybenzoyl) piperidin-1-yl) -2,2-dimethylpropan- - (4- (4-methoxybenzoyl) piperazin-1-yl) -2,2-dimethylpropan-1-

Step 1. Preparation of 3-chloro-1- (4- (4-methoxybenzoyl) piperidin-1-yl) -2,2-dimethylphan-1-

(100 mg, 0.391 mmol) was reacted with 3-chloro-2,2-dimethylpropanoic acid (64.1 mg, 0.469 mmol) and 4-methoxyphenyl (piperidin- To give 126 mg of the titled compound as a yellow liquid.

LC-MS (ESI, m / z) = 338.0 (M + H ^& lt ^{; +} &

Step 2. Preparation of 3-azido-1- (4- (4-methoxybenzoyl) piperidin-1-yl) -2,2-dimethylpropan-

The compound (126 mg, 0.373 mmol) and NaN ₃ (48.5mg, 0.746mmol) obtained in Step 1 was dissolved in DMF (1.24 ml). The mixture was stirred at 70 to 80 ° C for 3 hours and then cooled to room temperature. After dilution with ethyl acetate and concentrated washed with water three times, dried, filtered and reduced to Na ₂ SO _4. 100 mg of the title compound was obtained as a yellow liquid.

LC-MS (ESI, m / z) = 345.0 (M + H ^& lt ^{; +} &

Step 3. Preparation of 3-amino-1- (4- (4-methoxybenzoyl) piperidin-1-yl) -2,2-dimethylpropan-

The compound obtained in Step 2 (100 mg, 0.290 mmol) was dissolved in THF (0.49 ml) and water (0.49 ml), and then triphenylphosphine (91.3 mg, 0.348 mmol) was added. The mixture was stirred at room temperature for 4 hours and then concentrated under reduced pressure. A 1N hydrochloric acid aqueous solution was added dropwise to the obtained residue, the pH was adjusted to 1 to 2, and the mixture was extracted three times with ethyl acetate. The pH of the aqueous layer was adjusted to 7 to 8 by the dropwise addition of 2N aqueous NaOH solution, and the mixture was extracted 5 times with DCM / MeOH (9: 1), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. 82 mg of the title compound was obtained as a yellow solid.

LC-MS (ESI, m / z) = 319.1 (M + H <^+> )

Step 4. 3- Chloro -1- (4- (4- Methoxybenzoyl ) Piperazin-1-yl) -2,2-dimethylpropan-1-one

3-chloro-2,2-dimethylpropanoic acid (136.6 mg, 2.337 mmol) and the compound (500 mg, 1.948 mmol) obtained in the step 2 of Preparation Example 2 were reacted in the same manner as in Step 2 of Preparation Example 1 To give 646 mg of the title compound as a yellow liquid.

LC-MS (ESI, m / z) = 339.0 (M + H <^+> )

Step 5. 3- Azido -1- (4- (4- Methoxybenzoyl ) Piperazin-1-yl) -2,2-dimethylpropan-1-one

The compound (640 mg, 1.889 mmol) obtained from Step 4 was reacted in the same manner as in Step 2 to give 440 mg of the title compound as a white solid.

LC-MS (ESI, m / z) = 346.1 (M + H ^& lt ^{; +} &

Step 6. Preparation of 3-amino-1- (4- (4-methoxybenzoyl) piperazin-1-yl) -2,2-dimethylpropan-

The compound (440 mg, 1.274 mmol) obtained from Step 5 was reacted in the same manner as in Step 3 to obtain 200 mg of the title compound in the form of yellow liquid.

LC-MS (ESI, m / z) = 320.1 (M + H ^& lt ^{; +} &

Example 1: Preparation of 5- (3- (4- (4-methoxybenzoyl) piperidin- 1 -yl) -3-oxopropylamino) -3-methyl-3H- [1,2,3] [4,5-d] pyrimidin-7 (6H) -one

Step 1 : Compound ( I-1 ) (406 mg, 1.244 mmol) obtained in Production Example 1, 7-isopropoxy-3-methyl-5- (methylsulfonyl) triazole was stirred sol [4,5-d] pyrimidine (1) for 3 hours at (271.3 mg, 1.0 mmol), DIPEA 75 ~ 80 ℃ was dissolved (0.522 ml, 3.0 mmol) in ethanol. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, and washed twice with water. Dehydrating the organic layer with Na ₂ SO _4, and then concentrated under reduced pressure and separated by column chromatography to give the title compound 310 mg as a yellow solid.

LC-MS (ESI, m / z) = 482.1 (M + H <^+> )

Step 2 : The compound (150 mg, 0.311 mmol) obtained in Step 1 was dissolved in a sulfuric acid: acetic acid = 1: 4 solution and stirred at 45 to 55 ° C for 3 hours. After the reaction solution was concentrated under reduced pressure, 1N NaOH aqueous solution was added slowly to adjust the pH to 4-5 and extracted twice with ethyl acetate. Dehydrating the organic layer with Na ₂ SO _4, and then concentrated under reduced pressure and separated by column chromatography to give the title compound 71 mg as a white solid.

LC-MS (ESI, m / z) = 440.0 (M + H ^& lt ^{; +} & gt ^; ).

Example 2: Preparation of 5 - ((3- (4- (4-methoxybenzoyl) piperidin-1-yl) -3-oxopropyl) (methyl) amino) , 3] triazolo [4,5-d] pyrimidin-7 (6H) -one

( I-2 ) (59 mg, 0.25 mmol) obtained in Production Example 1 and 1- (4- (4-methoxybenzoyl) piperidin- 1 -yl) -3- (methylamino) propan- 3-methyl-5- (methylsulfonyl) -3H- [1,2,3] triazolo [4,5- d] pyrimidine ( 1 ) (47 mg, 0.175 mmol) mmol) were reacted in the same manner as in Example 1 to give 36 mg of the title compound as a white solid.

LC-MS (ESI, m / z) = 454.1 (M + H ^& lt ^{; +} & gt ^; ).

Example 3: Preparation of 5- (3- (4- (4-methoxybenzoyl) piperidin- 1 -yl) -3-oxopropylthio) -3-methyl- [4,5-d] pyrimidin-7 (6H) -one

Step 1 : 7-Isopropoxy-3-methyl-5- (methylsulfonyl) -3H- [1,2,3] triazolo [4,5- d] pyrimidine ( 1 ) (500 mg, 1.843 mmol ) And a mixture of methyl 3-mercaptopropionate (6.1 ml, 5.529 mmol) and Cs ₂ CO ₃ (1.8 g, 5.529 mmol) were stirred at 80-85 ° C for 1 hour. After cooling to room temperature, the mixture was diluted with ethyl acetate, and the organic layer was washed three times with water, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Separation by column chromatography gave 631 mg of the title compound as a yellow liquid.

LC-MS (ESI, m / z) = 312.0 (M + H ^& lt ^{; +} & gt ^; ).

Step 2 : To a solution of the compound obtained in Step 1 (315 mg, 1.014 mmol) by hydrolysis with LiOH.H ₂ O (212.7 mg, 5.07 mmol) to give 3- (7-isopropoxy- (64 mg, 0.215 mmol) was reacted in the same manner as in Step 2 of Preparation Example 1 to give 100 mg of the title compound as a yellow liquid. mg of the title compound were obtained.

LC-MS (ESI, m / z) = 499.1 (M + H ^& lt ^{; +} & gt ^; ).

Step 3 : The compound (100 mg, 0.201 mmol) obtained in Step 2 was reacted in the same manner as Step 2 of Example 1 to give 72 mg of the title compound as a white solid.

LC-MS (ESI, m / z) = 457.1 (M + H ^& lt ^{; +} & gt ^; ).

Example 4: Synthesis of 5- (3- (4- (4-methoxybenzoyl) piperazin-1-yl) -3-oxopropylamino) -3-methyl-3H- [1,2,3] triazolo [ 4,5-d] pyrimidin-7 (6H) -one

( I-3 ) (495 mg, 1.510 mmol) obtained in Preparation Example 2 and 7-isopropoxy-3-methyl-5- (methylsulfonyl) -3H- [1,2,3] triazolo [ 4,5-d] pyrimidine ( 1 ) (341 mg, 1.258 mmol) was reacted in the same manner as in Example 1 to give 455 mg of the title compound as a white solid.

LC-MS (ESI, m / z) = 441.2 (M + H ^& lt ^{; +} & gt ^; ).

Example 5: 5- (3- (4- (4-Methoxybenzoyl) piperidin-l-yl) -2,2- 2,3] triazolo [4,5-d] pyrimidin-7 (6H) -one

( I-4 ) (387.4 mg, 1.217 mmol) obtained in Production Example 3 and 7-isopropoxy-3-methyl-5- (methylsulfonyl) -3H- [1,2,3] triazolo [ 4,5-d] pyrimidine ( 1 ) (300 mg, 1.843 mmol) was reacted in the same manner as in Example 1 to obtain 166 mg of the title compound as a white solid.

LC-MS (ESI, m / z) = 468.1 (M + H ^& lt ^{; +} & gt ^; ).

Example 6: Preparation of 5- (3- (4- (4-methoxybenzoyl) piperazin-1-yl) -2,2-dimethyl-3-oxopropylamino) , 3] triazolo [4,5-d] pyrimidin-7 (6H) -one

( I-5 ) (200 mg, 0.627 mmol) obtained in Production Example 3 and 7-isopropoxy-3-methyl-5- (methylsulfonyl) -3H- [1,2,3] triazolo [ 4,5-d] pyrimidine ( 1 ) (170 mg, 0.627 mmol) was reacted in the same manner as in Example 1 to give 73 mg of the title compound as a white solid.

LC-MS (ESI, m / z) = 469.1 (M + H ^& lt ^{; +} & gt ^; ).

Example 7: Preparation of 5- (4- (4- (4-methoxybenzoyl) piperidin- 1 -yl) -4-oxobutyl) -3-methyl- 4,5-d] pyrimidin-7 (6H) -one

Step 1 : 2-Amino-2-cyanoacetamide (10 g, 100.918 mmol) was dissolved in 150 mL of 1N HCl and cooled to 0 &lt; 0 &gt; C. NaNO ₂ (7.66 g, 111.010 mmol) was dissolved in 40 ml of distilled water and slowly added thereto, followed by stirring at room temperature for 15 hours. The reaction solution was diluted with ethyl acetate and washed once with distilled water. Dehydrating the organic layer with Na ₂ SO _4, and then concentrated under reduced pressure to give a 2-amino-2-oxo-acetamide yimido yl cyanide of 7.24 g as a yellow solid.

¹ H NMR (300 MHz, DMSO- d ₆ ) ? 7.649 (brs, 2H).

Step 2 : After cooling the 40% methylamine aqueous solution to 0 占 폚, the compound obtained in Step 1 (7.24 g, 65.776 mmol) was slowly added and stirred for 1 hour. The reaction solution was filtered and washed once with methanol to obtain 2.615 g of 5-amino-1-methyl-1H-1,2,3-triazole-4-carboxamide as a yellow solid.

LC-MS (ESI, m / z) = 142.1 (M + H ^& lt ^{; +} & gt ^; ).

Step 3 : Monomethyl glutarate (0.293 ml, 2.346 mmol) and (4-methoxyphenyl) (piperidin-4-yl) methanone hydrochloride (500 mg, 1.955 mmol) To give 679 mg of the titled compound as a yellow liquid.

LC-MS (ESI, m / z) = 348.0 (M + H ^& lt ^{; +} & gt ^; ).

Step 4 : The compound obtained in Step 3 (679 mg, 1.955 mmol) and the compound obtained in Step 2 (276 mg, 1.955 mmol) were dissolved in EtOH and 21% NaOEt in EtOH (1.459 ml, 3.91 mmol) And the mixture was stirred at 75 to 80 DEG C for 22 hours. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, and washed twice with an aqueous ammonium chloride solution. Dehydrating the organic layer with Na ₂ SO _4, and then concentrated under reduced pressure and separated by column chromatography to give the title compound in 181 mg white solid.

LC-MS (ESI, m / z) = 439.1 (M + H ^& lt ^{; +} & gt ^; ).

Example 8: Preparation of 2- (3- (4- (4-methoxybenzoyl) piperidin-l-yl) -3-oxopropylamino) -7-methylimidazo [ , 2,4] triazin-4 (3H) -one

2-Chloro-7-methylimidazole crude [1,5-f] [1,2,4] triazine -4 (3H) - one (4) (200 mg, 1.084 mmol), obtained in Preparation Example 1 Compound ( I-1 ) (425 mg, 1.300 mmol) and DIPEA (0.57 ml, 3.251 mmol) were dissolved in ethanol (1.08 ml). Stirred at 90-100 &lt; 0 &gt; C for 22 h, then cooled to room temperature and diluted with ethyl acetate. The organic layer was washed three times with water and was concentrated to dryness, filtered, and reduced to Na ₂ SO _4. Separation by column chromatography gave 18.5 mg of the title compound as a white solid.

LC-MS (ESI, m / z) = 439.0 (M + H ^& lt ^{; +} & gt ^; ).

Example 9: Activity assay for Tancirase 1

The activity of the novel compounds synthesized according to Examples 1 to 8 for Tancirase 1 was analyzed using Trevigen kit (Cat. No. 4700-096-K). Absorbance was measured by ELISA using 96-well plates coated with poly PAR histone protein, anti-PAR monoclonal antibody and goat anti-mouse IgG-HRP. Specifically, water was added to 20X I-PAR assay buffer, diluted 1X, and 50 μl was added to each well of a 96-well plate. The histone coated on the bottom of each well was rehydrated at room temperature for 30 minutes. After removing the supernatant, 24 μl of the 1 × I-PAR assay buffer containing the assay substrate was added to each well. Then, the inhibitor to be tested, that is, the compounds of Examples 1 to 8 were prepared in 50 ×, And mixed. The 10 mMits / μl concentration of Tancylase 1 enzyme was diluted 50 fold in 1X I-PAR assay buffer and added to each well in an amount of 25 μl, followed by reaction at room temperature for 30 minutes with stirring. As a positive control to which no compound of the present invention was added, the same volume of 1X I-PAR assay buffer was added in place of the Tancirase I enzyme, and used as a negative control. After completion of the reaction, 200 μl of the solution was added to PBST prepared by adding 0.1% Triton X-100 to PBS, and the washing procedure was repeated twice. And then washed twice more with PBS in the same manner. The 5X anti-PAR monoclonal antibody was diluted 1-fold with distilled water, and then added in an amount of 50 μl per well, followed by reaction at room temperature for 30 minutes. After removing all anti-PAR monoclonal antibodies, washing with PBST and PBS was repeated twice. Finally, 50 μl of goat anti-mouse IgG-HRP diluted to 1/2000 was added to each well, followed by reaction at room temperature with stirring for 30 minutes. Washing with PBST and PBS was repeated twice as described above. 50 μl of TACS-sapphire was added, and the reaction was carried out for 10 to 15 minutes by shading so as not to enter the light. At this time, the reaction solution turned blue. To stop the reaction, 50 μl of 0.2 N HCl per well was added to change to yellow, and the absorbance of the reaction solution was finally measured at 450 nm (see Table 1).

[Table 1]

Claims (9)

A compound represented by the following formula (1), a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]

In the above formulas,
X ₁ to X ₃ are C or N;
R ₁ is hydrogen, halo, cyano, nitro, carboxy, C _{1 -6} alkyl, C _{1 -6} alkyl, oxo, C _{2 -6} alkenyl, C _{1 -6} alkoxy, C _{1 -6} alkoxycarbonyl, C _{1 -6} hydroxyalkyl, C _{1 -6-dihydroxy} alkyl, halo C _{1 -6} alkyl unsubstituted or substituted by hydroxyl or C _{3 -7-cycloalkyl;}
A is A'-CH ₂ -CR ₂ R ₂ ';
A 'is CR ₃ R ₃ ', NR ₃ , O or S;
R ₂ And R ₂ 'are each independently hydrogen, halo, OH, CN, C _{1 -6} alkyl, or C _{3 -7-cycloalkyl;}
Y is C or N;
Z is O, CO or member;
W is Ar or Het;
Ar is phenyl {wherein the phenyl is unsubstituted or one to three hydrogen Beach _{halo, NO 2, CN, B,} OR 4, S (O) m R 4, NR 4 R 4 ', COB, COOR 4, Which may be substituted by a substituent selected from the group consisting of CONR ₄ R ₄ ', SO ₂ NR ₄ R ₄ ', NR ₄ COR ₅ , NR ₄ SO ₂ B, NR ₄ CONR ₅ R ₅ ', Ar' and Het ';
Het is selected from the group consisting of furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl and pyridazinyl one selected {wherein the Het is unsubstituted or one or two hydrogen are each independently selected from _{halo, NO 2, CN, B,} oR 4, NR 4 R 4 ', CONR 4 R 4', Ar ', Het' and Lt; RTI ID = 0.0 &gt; = 0; &lt; / RTI &gt;
Het 'is a group consisting of furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl and pyridazinyl Wherein the Het 'is unsubstituted or each one or two hydrogens is independently selected from halo, NO ₂ , CN, B, OR ₄ , NR ₄ R ₄ ', CONR ₄ R ₄ ', Ar'O;&lt; / RTI &gt;
Ar 'is phenyl {wherein the phenyl is unsubstituted or substituted with one to three hydrogen is _{halo, NO 2, CN, B,} OR 4, S (O) m R 4, NR 4 R 4', COB, COOR 4 , CONR ₄ R ₄ ', NR ₄ COR ₅ and NR ₄ SO ₂ B;
B is C _{1 -6} alkyl and {1 or 2 can be optionally substituted with one non-adjacent CH ₂ or CH groups are N or O atoms, which may be substituted by halo or hydroxy, each has one or more independently hydrogen};
R ₃ , R ₃ ', R _{4 ,} R ₄ ', R ₅ and R ₅ 'are each independently hydrogen or C _{1 -6} alkyl;
Halo is F, Cl, Br or I; And
m is 0, 1 or 2; The method according to claim 1,
The compound of Formula 1 is a compound represented by Formula 1-1 or 1-2,
[Formula 1-1]

[Formula 1-2]

In the above formulas,
R ₁ is hydrogen, halo, cyano, nitro, carboxy, C _{1 -6} alkyl, C _{1 -6} alkyl, oxo, C _{2 -6} alkenyl, C _{1 -6} alkoxy, C _{1 -6} alkoxycarbonyl, C _{1 -6} hydroxyalkyl, C _{1 -6-dihydroxy} alkyl, halo C _{1 -6} alkyl unsubstituted or substituted by hydroxyl or C _{3 -7-cycloalkyl;}
A is A'-CH ₂ -CR ₂ R ₂ ';
B is CR ₃ R ₃ ', NR ₃ or S;
R ₂ and R ₂ 'are each independently hydrogen or methyl;
Y is C or N;
Z is CO;
W is Ar or Het;
Ar is phenyl {wherein the phenyl is unsubstituted or one to three hydrogen Beach _{halo, NO 2, CN, B,} OR 4, S (O) m R 4, NR 4 R 4 ', COB, COOR 4, Which may be substituted by a substituent selected from the group consisting of CONR ₄ R ₄ ', SO ₂ NR ₄ R ₄ ', NR ₄ COR ₅ , NR ₄ SO ₂ B, NR ₄ CONR ₅ R ₅ ', Ar' and Het ';
Het is selected from the group consisting of furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl and pyridazinyl one selected {wherein the Het is unsubstituted or one or two hydrogen are each independently selected from _{halo, NO 2, CN, B,} oR 4, NR 4 R 4 ', CONR 4 R 4', Ar ', Het' and Lt; RTI ID = 0.0 &gt; = 0; &lt; / RTI &gt;
Het 'is a group consisting of furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl and pyridazinyl Wherein the Het 'is unsubstituted or each one or two hydrogens is independently selected from halo, NO ₂ , CN, B, OR ₄ , NR ₄ R ₄ ', CONR ₄ R ₄ ', Ar'O;&lt; / RTI &gt;
Ar 'is phenyl {wherein the phenyl is unsubstituted or substituted with one to three hydrogen is _{halo, NO 2, CN, B,} OR 4, S (O) m R 4, NR 4 R 4', COB, COOR 4 , CONR ₄ R ₄ ', NR ₄ COR ₅ and NR ₄ SO ₂ B;
B is C _{1 -6} alkyl and {1 or 2 can be optionally substituted with one non-adjacent CH ₂ or CH groups are N or O atoms, which may be substituted by halo or hydroxy, each has one or more independently hydrogen};
R ₃ , R ₃ ', R _4, R ₄ ', R ₅ and R ₅ 'are each independently hydrogen or methyl;
Halo is F, Cl, Br or I; And
m is 0, 1 or 2;
A compound of formula (I), a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. The compound of claim 1, wherein the compound of formula (1)
1) 5- (3- (4- (4-methoxybenzoyl) piperidin- 1 -yl) -3-oxopropylamino) -3-methyl-3H- [1,2,3] triazolo [ , 5-d] pyrimidin-7 (6H) -one;
2) Preparation of 5 - ((3- (4- (4-methoxybenzoyl) piperidin- 1 -yl) -3-oxopropyl) ] Triazolo [4,5-d] pyrimidin-7 (6H) -one;
3) Preparation of 5- (3- (4- (4-methoxybenzoyl) piperidin- 1 -yl) -3-oxopropylthio) -3-methyl- , 5-d] pyrimidin-7 (6H) -one;
4) Synthesis of 5- (3- (4- (4-methoxybenzoyl) piperazin-1-yl) -3-oxopropylamino) -3- 5-d] pyrimidin-7 (6H) -one;
5) 5- (3- (4- (4-methoxybenzoyl) piperidin-l-yl) -2,2- 3] triazolo [4,5-d] pyrimidin-7 (6H) -one;
6) 5- (3- (4- (4-methoxybenzoyl) piperazin-1-yl) -2,2-dimethyl-3-oxopropylamino) -3-methyl- ] Triazolo [4,5-d] pyrimidin-7 (6H) -one;
7) Preparation of 5- (4- (4- (4-methoxybenzoyl) piperidin- 1 -yl) -4-oxobutyl) -3-methyl- 5-d] pyrimidin-7 (6H) -one; And
8) 2- (3- (4- (4-methoxybenzoyl) piperidin-1-yl) -3-oxopropylamino) -7-methylimidazo [ , 4] triazin-4 (3H) -one;
, The tautomers thereof, the stereoisomers thereof, or a pharmaceutically acceptable salt thereof. Use of a compound of formula (1) as defined in any one of claims 1 to 3, a tautomer thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient for the treatment or prevention of a cancer-related disease A pharmaceutical composition. 5. The method of claim 4,
Wherein the inhibitor inhibits the first, the second, the third or the third. 5. The method of claim 4,
Wherein said cancer-related disease is cancer, multiple sclerosis (MS), cardiovascular diseases, central nervous system injury or inflammatory disease. The method according to claim 6,
The cancer may be a cancer of the head, neck, eyes, mouth, throat, esophagus, bronchus, larynx, pharynx, thoracic cavity, lung, colon, rectum, large intestine, stomach, prostate, bladder, uterus, Wherein the cancer is selected from the group consisting of non-malignant reproductive organs, skin, thyroid, blood, lymph nodes, kidney, liver, pancreas, brain, central nervous system, solid tumors and blood infectious tumors. 8. The method of claim 7,
Wherein the cancer is colon cancer, rectal cancer, colon cancer, breast cancer, lung cancer or blood cancer. 5. The method of claim 4,
Wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, diluent or excipient.