KR20170022699A - Ureidobenzothiazole derivatives and pharmaceutical compositions for preventing or treating cancer containing the same - Google Patents

Abstract

The present invention relates to an ureidobenzothiazole compound showing excellent antiproliferative efficacy against cancer cells, a pharmaceutically allowable salt or a hydrate thereof, a manufacturing method thereof, a pharmaceutical composition for preventing or treating cancer metastasis and propagation diseases containing the same as an active ingredient, and an anticancer composition against cancer cells. According to the present invention, the compound, pharmaceutically allowable salt or hydrate thereof has excellent cancer cell inhibition activity and antiproliferative efficacy, thereby being used for inhibiting cancer cells, preventing cancer metastasis and propagation diseases or treating cancer.

Description

[0001] UREIDOBENZOTHIAZOLE DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS FOR PREVENTING OR TREATING CANCER CONTAINING THE SAME [0002]

 The present invention relates to a novel ureidobenzothiazole compound, a pharmaceutically acceptable salt or hydrate thereof, a process for preparing the same, and a pharmaceutical composition for preventing or treating cancer comprising the compound.

Protein kinase is an enzyme that catalyzes the phosphorylation of ATP to transfer the gamma-phosphate group of the protein to the hydroxy group of tyrosine, serine and threonine of the protein. It is responsible for cell metabolism, gene expression, cell growth, differentiation and cell division. It plays an important role in signal transduction.

Protein kinases account for about 2% of eukaryotic genomes and about 518 species in human genomes. Protein kinases are classified as tyrosine protein kinases that phosphorylate tyrosine and serine / threonine kinases that phosphorylate serine and threonine. More than 90 of them are tyrosine kinases, which are divided into receptor tyrosine kinase (RTK) and nonreceptor tyrosine kinase (NRTK). Receptor tyrosine kinase is a membrane protein that has a domain capable of accepting growth factors on the cell surface and has an active site capable of phosphorylating tyrosine residues in the cytoplasm. The nonreceptor tyrosine kinase is a single tyrosine kinase domain present in the nucleus and cytoplasm, which, although not in the form of a receptor, undergoes signaling to phosphorylate tyrosine residues.

Protein kinases are molecular switches that require smooth transitions between active and inactive states in the cell. Abnormal regulation can lead to uncontrolled cell division and proliferation by overexpressing intracellular signaling. In addition, abnormal activation by gene mutation, amplification and overexpression of monoclonal anti-cancer kinase plays a crucial role in the growth and metastasis of cancer cells due to the development and progression of various tumors. Representative protein kinases that are abnormally regulated include EGFR, VEGFR, PDGFRB, c-KIT, ABL1, SRC, BRAF, FGFR, BTK, SYK, ALK, MET, CDK, MEK, mTOR, JAK, LCK, PLK, , FMS, TIE2, RET, AKT, MAP, FAK, DDR, FLT3, and FES. In particular, receptor tyrosine kinase is mainly involved in signal transduction pathways to external signals and internal responses to cell growth, and thus inhibits and inhibits cancer cell growth.

The inhibition of kinase activity has been attracting attention as a major target for the development of anticancer drugs, and the development of low molecular organic compounds has been actively pursued by targeting various kinases.

The kinase inhibitors include Bcr-Abl and PDGFR tyrosine kinase inhibitors Gleevec® (imatinib, Novartis), Her-2 antibody Herceptin® (trastuzumab, Genentech), EGFR inhibitor Iressa® (gefitinib, AstraZeneca) Nexavar® (sorafenib, bayer), BRAF inhibitor Zelboraf® (vemurafenib, Roche), EGFR antibody (Erbitux®), Raf, VEGFR, KIT, RET, PDGFR-B and FLT-3 inhibitors (Eg, cetuximab, Imclone), the EGFR inhibitor Tarceva® (erlotinib, Genentech / Roche), and the KDR inhibitor Sutent® (sunitinib, Pfizer). These include leukemia, breast cancer, Liver cancer, malignant melanoma, colorectal cancer, etc. It is FDA-approved and widely used as the first standard therapy with excellent therapeutic efficacy. In addition, several compounds are in clinical trials.

However, many of these patients who received drug therapy for these anticancer drugs have side effects such as immunosuppression, gastrointestinal disorders, and other illnesses. Recently, mutants causing resistance to drugs have been identified. In particular, Gleevec resistance is caused by a point mutation in the active site of Bcr-Abl tyrosine kinase. The mutation (T315I) of the 315th threonine to isoleucine and the mutation (T253H) of the 253th tyrosine to histidine Is the most frequent. Among the Gleevec resistant point mutants, T315I-Bcr-Abl is the highest proportion. In addition, tolerance of gelbora is caused by a mutation (V600E) that changes to glutamic acid at the 600th amino acid of B-Raf kinase, and about 60% of melanomas have this mutation. Cells with this point mutation are no longer regulated by these drugs, and it is known that increasing the dose does not improve the therapeutic effect at all.

Although a second-generation anticancer drug capable of treating the inhibitory effect of cancer cells, reduction of side effects, and tolerance has been developed, it has been found that the ability to inhibit mutant species is very weak, and research on its drug development is more actively conducted . Therefore, it is time to develop a new anticancer drug that can prevent or treat side effects and tolerance of drugs.

 It is an object of the present invention to provide a novel ureidobenzothiazole compound, a pharmaceutically acceptable salt or hydrate thereof.

It is still another object of the present invention to provide a pharmaceutical composition for preventing or treating cancer or tumor comprising a novel ureidobenzothiazole compound, a pharmaceutically acceptable salt or hydrate thereof as an active ingredient.

As a result of continuing the study to solve the above problems, the present inventors have found that an anticancer compound exhibiting excellent inhibitory activity against cancer cells, particularly, a ureidobenzothiazole compound useful for the prevention or treatment of cancer as an inhibitor of selective kinase activity and mutagenic kinase activity , A pharmaceutically acceptable salt thereof, or a hydrate thereof, a process for producing the same, and a pharmaceutical composition for preventing or treating cancer comprising the same as an active ingredient.

An example of the present invention provides a ureidobenzothiazole compound represented by the following Formula 1, a pharmaceutically acceptable salt thereof, or a hydrate thereof:

[Chemical Formula 1]

In Formula 1,

X is O or S;

R1 is hydrogen; A C1-C6 alkyl group; A C3-C10 aryl group; A C3-C10 heteroaryl group; Or a C3-C10 heterocyclyl group;

Said C1-C6 alkyl group is selected from the group consisting of hydrogen; A halogen group; A C1-C6 alkyl group; A C1-C6 alkoxy group; Amino group (-NR2R3); An amide group (-CONR2R3); A C3-10 heteroaryl group; And a C3-10 heterocyclyl group;

The C3-C10 aryl group, the C3-C10 heteroaryl group or the C3-C10 heterocyclyl group is hydrogen; A halogen group; A carbonyl group; A C1-C3 alkyl group substituted or unsubstituted with halogen or a C3-C10 heterocyclyl group; A C1-C3 alkoxy group substituted or unsubstituted with halogen or a C3-C10 heterocyclyl group; A C3-C10 aryl group; Amino group (-NR2R3); An amide group (-CONR2R3); A C3-10 heteroaryl group and a C3-C10 heterocyclyl group;

And R 2 and R 3 include at least one member selected from the group consisting of hydrogen, a C 1-6 alkyl group, a C 1-6 alkenyl group, and a C 1-6 alkynyl group.

The C3-10 heteroaryl group and the C3-C10 heterocyclyl group may contain at least one heteroatom selected from the group consisting of N, O, and S.

In a preferred embodiment of the present invention,

X is O or S;

R1 is a C1-C6 alkyl group or a C3-C10 aryl group

Said C1-C6 alkyl group is selected from the group consisting of hydrogen; A hydroxy group; A C1-C6 alkyl group; A C1-C5 alkoxy group; Amino group -NR2R3; Amido group -CONR2R3; A C5-C6 heteroaryl group; And a C5-C6 heterocyclyl group;

The C3-C10 aryl group may be substituted with a halogen group; A C1-C3 alkyl group substituted or unsubstituted with halogen or a C5-C6 heterocyclyl group; A C5-C6 heterocyclyl group;

The C5-C6 heteroaryl group or the C5-C6 heterocyclyl group is substituted or unsubstituted with a C1-C3 alkyl group, an amino group -NR2R3;

And R 2 and R 3 may include at least one group selected from the group consisting of hydrogen, C 1-6 alkyl group, C 1-6 alkenyl group, and C 1-6 alkenyl group.

In a preferred embodiment of the present invention,

X is O or S;

R1 is a C1-6 alkyl group or a phenyl group,

Said C1-C6 alkyl group is selected from the group consisting of hydrogen; A hydroxy group; Amino group -NR2R3; And a C5-C6 heterocyclyl group;

The phenyl group is a C1-C3 alkyl group substituted or unsubstituted with a halogen or a C5-C6 heterocyclyl group; A halogen group; A C5-C6 heterocyclyl group;

The C5-C6 heterocyclyl group may be selected from the group consisting of pyrrolidine, piperidine, piperazine, and morpholine, and includes a C1-C3 alkyl group, an amino group- Substituted or unsubstituted with NR2R3;

And R < 2 > and R < 3 > may be substituted with a methyl group.

In a preferred embodiment of the present invention,

X is O;

R1 is a C1-6 alkyl group or a phenyl group,

The C1-C6 alkyl group comprises a piperazine substituent substituted with a C1-3 alkyl group;

The phenyl group may include a piperazine substituent substituted with a methyl group substituted with halogen and a C1-3 alkyl group.

In the definition of substituents in the present invention, the term " alkyl " means an aliphatic hydrocarbon radical. Alkyl may be a "saturated alkyl" containing no alkenyl or alkynyl moiety, or an "unsaturated alkyl" containing at least one alkenyl or alkynyl moiety. "Alkenyl" means a group comprising at least one carbon-carbon double bond, and "alkynyl" means a group comprising at least one carbon-carbon triple bond. Alkyl, when used alone or in combination, may be cyclic, branched or straight chain, respectively.

The term " aryl ", alone or in combination with other radicals, refers to a carbocyclic ring containing 6 carbon atoms which may be further fused with a second 5 or 6 membered carbocyclic group which may be aromatic, Aromatic monocyclic group. Examples of aryl include, but are not limited to, phenyl, indanyl, 1-naphthyl, 2-naphthyl, tetraphenylhydronaphthyl and the like. The aryl may be attached to another group at an appropriate position on the aromatic ring.

The term " alkoxy " means an alkyl group (i.e., -O-alkyl) attached to another group through an oxygen atom. The alkoxy group may be unsubstituted or substituted with one or more suitable substituents. Examples of the alkoxy group include a (C1-C6) alkoxy group such as -O-methyl, -O-ethyl, -O-propyl, -O-isopropyl, -O- Methyl-1-butyl, -O-2-methyl-3-butyl, -O-2,2-dimethyl- Propyl, -O-2-methyl-1-pentyl, -O-methyl-1-pentyl, Methyl-2-pentyl, -O-4-methyl-2-pentyl, -O-2,2-dimethyl-1-butyl, -O-3,3-dimethyl- But are not limited to, -butyl, -O-butyl, -O-isobutyl, -Ot-butyl, -O-pentyl, -O-isopentyl, -O-neopentyl and -O-hexyl.

 The term " amino group " means an alkyl group (i.e., -NH- or -N-alkyl) attached to another group through a nitrogen atom. The amine group may be unsubstituted or substituted with one or more suitable substituents. Examples of the alkoxy group include (C1-C6) amino groups such as -NH-methyl, -NH-ethyl, -NH-propyl, -NH-isopropyl, -NH- Methyl-1-butyl, -NH-2-methyl-3-butyl, -NH-2 Methyl-1-pentyl, -NH-2-methyl-1-pentyl, Methyl-2-pentyl, -NH-2-dimethyl-1-butyl, -NH-3,3-dimethyl-butyl, -NH-2 Butyl, -NH-butyl, -NH-pentyl, -NH-isopentyl, -NH-neopentyl, -NH-hexyl, -N, Methyl-N-ethyl, N-methyl-N-propyl, N-methyl-isopropyl, N-methyl-N-pentyl, N-methyl-N-isopentyl, N-methyl- Propyl, N-ethyl-N-isopropyl, N-ethyl-N-butyl, - Propyl-N-isopropyl, N-propyl-N-butyl, -N-propyl, Propyl-N-pentyl, N-propyl-N-iso-pentyl, N-propyl- Butyl-N-isobutyl, N-butyl-N-pentyl, N-butyl- -N, N-dipentyl, -N-pentyl-N-hexyl, -N-pentyl-N-isohexyl, -N, N-dihexyl.

The term " halogen group " means fluorine, chlorine, bromine or iodine.

The term " heterocycle group " means a heteroaromatic compound containing at least one heteroatom selected from the group consisting of N, O, and O, unless otherwise indicated. Preferably, the heterocyclyl group may include a pyrrolidine, a furan group, a morpholine group, a piperazine and a piperidine group, more preferably a pyrrolidine group, a piperidine group, a piperazine group, But are not limited thereto.

The term " heteroaryl group " means a heteroaromatic compound containing at least one heteroatom selected from the group consisting of N, O, and O, unless otherwise indicated. Preferably, the heteroaryl group is a group selected from the group consisting of a pyridine group, a pyrazine group, a pyrimidine group, a pyridazine group, a pyrazole group, an imidazole group, a triazole group, an indole group, an oxadiazole group, a thiadiazole group, a quinoline, Oxazoles, thiazoles, thiols, thiazoles, thiazoles, thiazoles, thiazoles, thiols, pyrroles, and the like.

The term " carbonyl group " means - (C = O) - and may be substituted with hydrogen, alkyl group, alkoxy group and amino group, but is not limited thereto.

Specific examples of preferred compounds as the compound according to the present invention are as follows:

[Compound 1: 4 - ((2- (3-ethylureido) benzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide];

[Compound 2: 4 - ((2- (3-isopropylureido) benzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide];

[Compound 3: 4 - ((2- (3-ethylthioureido) benzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide];

[Compound 4: 4 - ((2- (3- (2-hydroxyethyl) ureido) benzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide];

[Compound 5: 4 - ((2- (3- (2-Dimethylamino) ethyl) ureido) benzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide];

[Compound 6: N-methyl-4 - ((2- (3- (2- (pyrrolidin- 1 -yl) ethyl) ureido) benzo [d] thiazol- ];

[Compound 7: N-methyl-4 - ((2- (3- (2- (piperidin- 1 -yl) ethyl) ureido) benzo [d] thiazol-6-yl) oxy) picolinamide ];

[Compound 8: N-methyl-4 - ((2- (3- (2-morpholinoethyl) ureido) benzo [d] thiazol-6-yl) oxy) picolinamide];

[Compound 9: N-methyl-4 - ((2- (3- (2- (4-methylpiperazin-1-yl) ethyl) ureido) benzo [d] thiazol- Picoline amide];

[Compound 10: 4 - ((2- (3- (3-Hydroxypropyl) ureido) benzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide];

[Compound 11: 4 - ((2- (3- (3- (Dimethylamino) propyl) ureido) benzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide];

[Compound 12: N-methyl-4 - ((2- (3- (3- (pyrrolidin- 1 -yl) propyl) ureido) benzo [d] thiazol- Amide];

[Compound 13: N-methyl-4 - ((2- (3- (3- (piperidin- 1-yl) propyl) ureido) benzo [d] thiazol- Amide];

[Compound 14: N-methyl-4 - ((2- (3- (3 -morpholino propyl) ureido) benzo [d] thiazol-6-yl) oxy) picolinamide];

[Compound 15: N-methyl-4 - ((2- (3- (3- (4-methylpiperazin-1-yl) propyl) ureido) benzo [d] thiazol- Choline amide];

[Compound 16: 4 - ((2- (3- (4-Hydroxybutyl) ureido) benzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide];

[Compound 17: 4 - ((2- (3- (4- (Dimethylamino) butyl) ureido) benzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide];

[Compound 18: 4 - ((2- (3- (4-Chloro-3- (trifluoromethyl) phenyl) ureido) benzo [d] thiazol-6-yl) oxy) Amide];

[Compound 19: Synthesis of 4 - ((2- (3- (3,5-beads (trifluoromethyl) phenyl) ureido) benzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide ];

[Compound 20: 4 - ((2- (3- (2,4-Dichlorophenyl) ureido) benzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide];

[Compound 21: 4 - ((2- (3- (3,4-Dichlorophenyl) ureido) benzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide];

[Compound 22: 4 - ((2- (3- (4-Chlorophenyl) ureido) benzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide];

[Compound 23: N-methyl-4 - ((2- (3- (4- (trifluoromethyl) phenyl) ureido) benzo [d] thiazol-6-yl) oxy) picolinamide];

[Compound 24: 4 - ((2- (3- (4-Fluorophenyl) ureido) benzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide];

[Compound 25: 4 - ((2- (3- (4-bromophenyl) ureido) benzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide];

[Compound 26: 4 - ((2- (3- (2-Chloro-5- (trifluoromethyl) phenyl) ureido) benzo [d] thiazol-6-yl) oxy) Amide];

[Compound 27: 4 - ((2- (3- (2,4-Difluorophenyl) ureido) benzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide];

[Compound 28: N-methyl-4 - ((2- (3- (4 -morpholinophenyl) ureido) benzo [d] thiazol-6-yl) oxy) picolinamide];

[Compound 29: N-methyl-4 - ((2- (3- (4- (4-methylpiperazin-1-yl) phenyl) ureido) benzo [d] thiazol- Choline amide];

Yl) phenyl) ureido) benzo [d] thiazol-6-yl) oxy) - (4- N-methylpicolinamide];

[Compound 31: N-methyl-4 - ((2- (3- (4- (morpholinomethyl) -3- (trifluoromethyl) phenyl) ureido) benzo [d] thiazol- ) Oxy) picolinamide]; And

[Compound 32: 4 - ((2- (3- (4-Ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) ureido) benzo [d] thiazole -6-yl) oxy) -N-methylpicolinamide].

The compound of formula (I) according to the present invention can be used in the form of a pharmaceutically acceptable salt derived from an inorganic or organic acid. Preferred examples of the salt include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, , Malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, Methane sulfonic acid, benzene sulfonic acid, and toluene sulfonic acid.

The compounds of formula (I) or pharmaceutically acceptable salts thereof according to the present invention may include hydrates and solvates. The hydrate may mean that the compound of formula (1) is formed by bonding with water molecules.

The present invention provides a pharmaceutical composition for preventing or treating cancer, which comprises, as an active ingredient, a compound of the formula (1) according to the present invention or a pharmaceutically acceptable salt thereof. Preferably, the cancer is induced by a protein kinase, more preferably the protein kinase is selected from the group consisting of ABL, ABLT315I, B-RAF, C-RAF, FLT1 / VEGFR1, KDR / BEGFR2, LCK, And LYN. ≪ / RTI >

The pharmaceutical composition may be applied to an experimental animal such as a mouse, a rabbit, a rat, a guinea pig, or a hamster, or a primate including a human, but is not limited thereto, and is preferably applied to a primate including a human, more preferably a human.

 As used herein, " treatment " is intended to include alleviation or amelioration of symptoms, reduction in the extent of disease, delay or alleviation of disease progression, improvement, alleviation or stabilization of disease states, partial or complete recovery, May be used to mean both.

 As used herein, " treatment " is intended to include alleviation or amelioration of symptoms, reduction in the extent of disease, delay or alleviation of disease progression, improvement, alleviation or stabilization of disease states, partial or complete recovery, May be used to mean both.

 In the present specification, treatment of cancer means treatment for all cancer cells, and cancer includes angiogenesis of endothelial cells and mitosis thereof (solid tumors, tumor metastases and benign tumors). For example, the term "cancer" refers to a cancer, such as breast cancer, ovarian cancer, cervical cancer, prostate cancer, colon cancer, urinary tract organ cancer, esophageal cancer, laryngeal cancer, glioblastoma, gastric cancer, skin cancer, keratocellular carcinoma, lung cancer, Cancer of the liver, cancer of the kidney, lymphoid tissue, lymphoid tissue, lymphoid tissue, lymphoid tissue, lymphoid tissue, lymphoid tissue, endometrial cancer, Cancer, colon cancer, colorectal cancer, colorectal cancer, brain cancer, central nervous system cancer, leukemia, hemangioma, trachoma, or pyknotic sexually transmitted disease But is not limited thereto.

Depending on the use of the pharmaceutical composition of the present invention and the method of use, the content of the compound represented by the general formula (1), its pharmaceutically acceptable salt or hydrate thereof as an active ingredient may be appropriately adjusted according to the selection of a person skilled in the art.

For example, the pharmaceutical composition may contain 0.1 to 10% by weight, more preferably 0.5 to 5% by weight, of the compound represented by Formula 1, its pharmaceutically acceptable salt, or hydrate, based on the total weight of the total composition As shown in FIG.

 The pharmaceutically acceptable salts or hydrates of the compound represented by the above-mentioned formula (I) may be contained alone in the pharmaceutical composition, or may be contained together with other pharmacologically acceptable carriers, excipients, diluents or subcomponents.

Examples of the pharmaceutically acceptable carrier, excipient or diluent 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, propylhydroxybenzoate, talc, magnesium stearate and mineral oil , Dextrin, calcium carbonate, propylene glycol, liquid paraffin, and physiological saline. However, it is not limited to these, and any conventional carrier, excipient or diluent may be used. In addition, the pharmaceutical composition may further comprise at least one selected from the group consisting of conventional fillers, extenders, binders, disintegrants, anticoagulants, lubricants, wetting agents, pH adjusters, nutrients, vitamins, electrolytes, alginic acid and its salts, , Fragrances, emulsifiers, preservatives, and the like.

The compound of the formula (1) or a pharmaceutically acceptable salt thereof according to the present invention can enhance the therapeutic effect of the anticancer drug by co-administration with other anticancer drugs for treating cancer or tumors.

Specifically, the pharmaceutical composition may further include one or more other anticancer agents or other therapeutic agents known to be effective for the treatment or prevention of cancer, in addition to the above-mentioned effective ingredients, and may be used as a combination therapy applied simultaneously or at the same time. Other anticancer agents or other therapeutic agents that may be applied to the combination therapy include, for example, Gleevec (R), imatinib, Sutent (R), sunitinib, Herceptin (R), Trastuzumab, Velcade Bortezomib, dexamethasone, Nexavar (R), Sorafenib, aromatase inhibitors or kinase inhibitors, but are not limited thereto.

 The pharmaceutical composition may be administered orally or parenterally. For example, the pharmaceutical composition may be administered through various routes including oral, transdermal, subcutaneous, intravenous, or muscular. In addition, the formulations of the compositions may vary depending on the method of use and may be formulated using methods well known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to the mammal . In general, solid dosage forms for oral administration include tablets, pills, soft or hard capsules, pills, powders and granules, which may contain one or more Excipients such as starch, calcium carbonate, sucrose or lactose, gelatin, and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid preparations for oral use 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. Forms for parenteral administration include creams, looses, ONITMENTS, PLASTERS, LIQUIDS AND SOULTIONS, AEROSOLS, FRUIDEXTRACTS, Or may be in the form of an isotonic solution (ELIXIR), INFUSIONS, SACHET, PATCH or INJECTIONS, and in case of injectable form, it may preferably be in the form of an isotonic aqueous solution or suspension .

The pharmaceutical composition may further contain a sterilizing agent, an antiseptic, a stabilizer, a wetting agent or an emulsifying accelerator, an auxiliary agent such as a salt and / or a buffer for controlling osmotic pressure, and other therapeutically useful substances, Or coating method, and may be formulated using other appropriate methods known in the art.

 The dosage of the pharmaceutical composition may be determined in consideration of the administration method, the age and sex of the recipient, the severity of the patient, the condition, the degree of absorption of the active ingredient in the body, the inactivation rate, Can be administered separately. The active ingredient of the pharmaceutical composition is preferably administered orally or parenterally in an amount of 0.001 to 100 mg / kg body weight, preferably 0.01 to 35 mg / kg body weight per day, once or twice a day, May be administered via an old route.

 Another embodiment of the present invention provides a method for treating cancer, comprising administering a therapeutically effective amount of a compound represented by the following formula 1, a pharmaceutically acceptable salt thereof, or a hydrate thereof.

 Preferably, the method of treatment may further comprise identifying a patient in need of prevention or treatment of the cancer prior to the administration step.

&Quot; Therapeutically effective amount "of the present invention means the amount of the active ingredient for mammals effective for the prevention or treatment of cancer, and the therapeutically effective amount will depend on the type of disease, the severity of the disease, The type and amount of the active ingredient, the type and amount of the active ingredient, the type of the formulation and the age, body weight, general health condition, sex and diet of the patient, administration time, administration route and blood clearance of the composition, But preferably is administered orally or parenterally once or divided once a day in an amount of 0.001 to 100 mg / kg body weight, preferably 0.01 to 35 mg / kg body weight on a daily basis, as described above can do.

 The present invention also relates to a process for preparing a pharmaceutically acceptable salt or hydrate of the ureidobenzothiazole derivative represented by the above formula (1).

Production method 1: Ureidobenzothiazole  Production of derivatives

As illustrated below, the process for preparing a ureidobenzothiazole derivative of formula (I), a pharmaceutically acceptable salt or hydrate thereof, may comprise reacting a compound of formula (II) with a compound of formula (III).

[Chemical Formula 1]

(2)

(3)

In the above formulas (1) and (3)

X is O or S;

R1 is hydrogen; A C1-C6 alkyl group; A C3-C10 aryl group; And a C3-C10heteroaryl group and at least one heterocyclyl group including at least one member selected from the group consisting of N, O and S;

Said C1-C6 alkyl group is selected from the group consisting of hydrogen; A hydroxy group; A C1-C6 alkyl group; A C1-C5 alkoxy group; A C1-C5 amino group; A C1-C5 amide group; C3-10 heterocyclyl group; And a halogen group;

The C3-C10 aryl group and the C3-C10 hetero aryl group or the heterocyclic group containing at least one member selected from the group consisting of N, O and S is hydrogen; A C1-C3 alkyl group; A C1-C3 alkoxy group; A C3-C10 aryl group; A C1-C3 alkoxy group or a carbonyl group substituted with an alkyl group; A halogen group; A hydroxy group; A C1-C6 amino group; A C1-6 amide group and a C3-10 heterocyclyl group.

The above reaction is summarized in the following reaction formula 1.

[Reaction Scheme 1]

The process of Reaction Scheme 1 can be carried out by reacting NH 2 of Formula 2 with carbonyl carbon of Formula 3 using an amide or thioamide formation reaction (International Patent Application Publication Nos. 2003/0153568 and WO 2005/073224).

The compound of Formula 3 may be prepared by an O-aryl substitution reaction using 2-aminobenzo [d] thiazol-6-ol as in the following reference (International Patent Application Publication WO 2007/121484).

Production method 2: Ureidobenzothiazole  Production of derivatives

 In another embodiment, a process for preparing a ureidobenzothiazole derivative of formula (I), a pharmaceutically acceptable salt or hydrate thereof, as illustrated below, comprises reacting NH2-R1 with have.

[Chemical Formula 1]

[Chemical Formula 4]

[Chemical Formula 5]

In the above formulas (1) and (5)

X is O or S;

R1 is hydrogen; A C1-C6 alkyl group; A C3-C10 aryl group; And a C3-C10heteroaryl group and at least one heterocyclyl group including at least one member selected from the group consisting of N, O and S;

Said C1-C6 alkyl group is selected from the group consisting of hydrogen; A hydroxy group; A C1-C6 alkyl group; A C1-C5 alkoxy group; A C1-C5 amino group; A C1-C5 amide group; C3-10 heterocyclyl group; And a halogen group;

The C3-C10 aryl group and the C3-C10 hetero aryl group or the heterocyclic group containing at least one member selected from the group consisting of N, O and S is hydrogen; A C1-C3 alkyl group; A C1-C3 alkoxy group; A C3-C10 aryl group; A C1-C3 alkoxy group or a carbonyl group substituted with an alkyl group; A halogen group; A hydroxy group; A C1-C6 amino group; A C1-6 amide group and a C3-10 heterocyclyl group.

The above reaction is summarized in the following reaction formula 1.

 [Reaction Scheme 2]

The preparation method of Scheme 2 is an amide coupling reaction of H2N-R1 with carbonyl of formula 4 (International Patent Application Publication No. WO 2007/086584, WO 2012/176061, Collier, PN et al. J. Med. Chem. 2015, 58, 517).

The compound of formula (4) can be prepared by reacting a compound of formula (2) with 1,1'-carbonyldiimidazole (CDI) such as the following reference (Ozawa, T. et al. Bioorganic & Medicinal Chemistry, 2007, 15, 7325) To form an amide-forming reaction.

The pharmaceutical composition for prevention or treatment of the ureidobenzothiazole compound of the present invention, its pharmaceutically acceptable salt, or hydrate thereof and cancer comprising the same as an active ingredient, has low cytotoxicity and selectively inhibits high inhibitory activity against cancer cells And exhibits an anti-proliferative effect, it can be usefully used for prevention or treatment of cancer.

Hereinafter, the present invention will be described in detail with reference to examples. However, the following examples are illustrative of the present invention, and the contents of the present invention are not limited by the following examples.

Example 1: 4 -((2- (3-ethylureido) benzo [d] thiazole Yl) Oxy ) -N- Methylpicolinamide  (compound 1) of  Produce

Step (1) Preparation of 2-aminobenzo [d] thiazol-6-ol

2-Amino-6-methoxybenzothiazole (10.0 g, 55.50 mmol) was dissolved in a 48% aqueous solution of hydrogen bromide (240 mL) under argon atmosphere and refluxed for 13 hours. TLC (hexane: ethyl Acetate = 3: 1). The reaction solution was cooled to room temperature, neutralized with a sodium hydrogen carbonate solution, and the resulting precipitate was filtered with water to obtain the desired compound (9.2 g, quant. Yield).

7.00 (s, 1H), 7.20 (d, J = 8.8 Hz, 2H).

Step (2) Preparation of 4 - ((2-aminobenzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide

Aminobenzo [d] thiazol-6-ol (10.0 g, 60.25 mmol) prepared in the above step (1) was dissolved in a solvent of dimethylsulfoxide (100 mL) under an argon atmosphere and then cesium carbonate (49.0 mg, methylpicolinamide (10.25 g, 60.25 mmol) were added to the reaction mixture, and the mixture was stirred at room temperature. The reaction solution was heated to 135 ° C and stirred for 5 hours. The completion of the reaction was confirmed by TLC (hexane: ethyl acetate = 3: 1). The reaction mixture was poured into water (15 mL), and the organic solvent layer extracted with ethyl acetate (3 X 350 mL) was washed again with a saturated sodium chloride solution (1 L). The organic solvent layer was dried over anhydrous sodium sulfate, The solvent was removed by concentration. The concentrate was separated and purified by column chromatography (hexane: ethyl acetate = 1: 1, 1: 3) to obtain the desired compound (4.0 g, 23% yield).

(D, J = 2.4 Hz, 1 H), 8.51 (d, J = 5.6 Hz, J = 5.8 Hz, 1H), 7.57 (s, 2H, exchangeable with D2O), 7.42 (d, J = 8.4 Hz, 1H), 7.38 7.07 (dd, J = 8.8, 2.8 Hz, 1H), 2.80 (d, J = 4.8 Hz, 3H);

13 C NMR (100 MHz, DMSO-d 6)? 167.46, 166.79, 164.28, 152.88, 151.33, 150.80, 147.48, 132.82, 119.22, 119.01, 114.38, 114.36, 109.14, 26.45.

Step (3). Preparation of 4 - ((2- (3-ethylureido) benzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide

(2-aminobenzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide (30 mg, 0.10 mmol) prepared in the above step (2) Ethyl isocyanate (40 μL, 3.93 mmol) was added to the reaction mixture, which was then stirred at 90 ° C. for 15 hours. The completion of the reaction was confirmed by TLC (hexane: ethyl acetate = 3: 1) Respectively. The reaction solution was cooled to room temperature and concentrated under reduced pressure to remove the solvent. The concentrate was separated and purified by column chromatography (hexane: ethyl acetate = 1: 1, 1: 9) to obtain the desired compound (32 mg, 87% yield).

8.84 (br.s, 1H), 8.52 (d, J = 5.6 Hz, 1H), 7.84 (d, J = 2.4 Hz, 1H) 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 2.8 Hz, 1H), 7.237.17 = 6.8 Hz, 2H), 2.80 (d, J = 4.4 Hz, 3H), 1.11 (t, J = 7.2 Hz, 3H);

13 C NMR (100 MHz, DMSO-d 6)? 166.57, 164.27, 160.96, 158.43, 154.14, 152.89, 150.89, 148.90, 147.58, 133.51, 121.34, 119.76, 114.51, 109.29, 34.76, 26.45, 15.56;

HRMS (ESI-TOF) m / z calcd for C17H17N5O3SNa [M + Na] < + >: 394.0950, found: 394.0956.

Example  2. 4 - ((2- (3-isopropyl ureido) benzo [d] thiazole Yl) Oxy ) -N- Methylpicolinamide  (compound 2) of  Produce

(2-aminobenzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide prepared in step (2) of Example 1 in the same manner as in step (3) (34 mg, 88% yield) was obtained from the title compound (30 mg, 0.10 mmol) and isopropyl isocyanate (49 μL, 0.50 mmol).

8.84 (q, J = 4.4 Hz, 1H), 8.52 (d, J = 5.6 Hz, 1H), 7.84 (d, J = J = 8.8 Hz, 1 H), 7.28 (dd, J = 8.4, 2.4 Hz, J = 6.4 Hz, 1H), 6.66 (d, J = 7.6 Hz, 1H), 3.883.79 6H);

13C NMR (100 MHz, DMSO-d6)? 166.57, 164.29, 160.88, 153.45, 152.89, 150.91, 148.91, 147.58, 133.52, 121.37, 119.77, 114.53, 109.29, 42.04, 26.46,

Example  3. 4 - ((2- (3-ethylthioureido) benzo [d] thiazole Yl) Oxy ) -N- Methylpicolinamide  (compound 3) of  Produce

(2-aminobenzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide (40 mg, 0.13 mmol) prepared in step (2) of Example 1 was dissolved in pyridine (4 mL), and ethylisothiocyanate (50 μL, 0.67 mmol) was added dropwise. The reaction mixture was refluxed for 11 hours, and the completion of the reaction was confirmed by TLC (dichloromethane: methanol = 20: 1). The reaction mixture was poured into water (15 mL), and the organic solvent layer extracted with ethyl acetate (3 X 10 mL) was washed again with a saturated sodium chloride solution (30 mL). The organic solvent layer was dried over anhydrous sodium sulfate, The solvent was removed by concentration. The concentrate was separated and purified by column chromatography (dichloromethane: methanol = 50: 1) to obtain the desired compound (5 mg, 10% yield).

(D, J = 5.6, 0.4 Hz, 1H), 8.07 (d, J = 4.8 Hz, 1H) J = 2.4 Hz, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.73 (d, 7.2 Hz, 1H), 7.04 (dd, J = 5.6,2.4 Hz, 1H), 3.87 (q, J = 5.2 Hz, 2H), 3.05 3H);

HRMS (ESI-TOF) m / z calcd for C17H17N5O2S2Na [M + Na] +: 410.0722, found: 410.0718.

Example  4. 4 - ((2- (3- (2-hydroxyethyl) ureido) benzo [d] thiazol-6-yl) Oxy ) -N-methylpicolinamide (Compound 4)

(2-aminobenzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide (40 mg, 0.13 mmol) prepared in step (2) of Example 1 was dissolved in pyridine (4 mL), and ethylisothiocyanate (50 μL, 0.67 mmol) was added dropwise. The reaction mixture was refluxed for 11 hours, and the completion of the reaction was confirmed by TLC (dichloromethane: methanol = 20: 1). The reaction mixture was poured into water (15 mL), and the organic solvent layer extracted with ethyl acetate (3 X 10 mL) was washed again with a saturated sodium chloride solution (30 mL). The organic solvent layer was dried over anhydrous sodium sulfate, The solvent was removed by concentration. The concentrate was separated and purified by column chromatography (dichloromethane: methanol = 50: 1) to obtain the desired compound (5 mg, 10% yield).

(D, J = 5.6, 0.4 Hz, 1H), 8.07 (d, J = 4.8 Hz, 1H) J = 2.4 Hz, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.73 (d, 7.2 Hz, 1H), 7.04 (dd, J = 5.6,2.4 Hz, 1H), 3.87 (q, J = 5.2 Hz, 2H), 3.05 3H);

HRMS (ESI-TOF) m / z calcd for C17H17N5O2S2Na [M + Na] +: 410.0722, found: 410.0718.

Example  4. 4 - ((2- (3- (2-hydroxyethyl) ureido) benzo [d] thiazol-6-yl) Oxy ) -N-methylpicolinamide (Compound 4)

((2-aminobenzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide (50 mg, 0.17 mmol) prepared in step (2) of Example 1 was dissolved in N , And N, N-dimethylformamide (3 mL), 1,1'-carbonyldiimidazole (81 mg, 0.50 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 24 hours. 2-aminoethanol (50 μL, 0.83 mmol) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 24 hours. The completion of the reaction was confirmed by TLC (dichloromethane: methanol = 20: 1). The reaction mixture was poured into water (10 mL), and the organic solvent layer extracted with ethyl acetate (3 X 10 mL) was washed again with a saturated sodium chloride solution (30 mL). The organic solvent layer was dried over anhydrous sodium sulfate, The solvent was removed by concentration. The concentrate was added dropwise to dichloromethane and hexane (1: 4, 5 mL), and the precipitate formed was filtered with hexane to obtain the desired compound (29 mg, 44% yield).

8.84 (d, J = 4.6 Hz, 1H), 8.51 (d, J = 5.6 Hz, 1H), 7.84 (M, 2H), 6.85 (br.s, 1H), 4.85 (d, J = 2H), 3.48 (br.s, 2H), 3.25 (q, J = 5.7 Hz, 2H), 2.78 (d, J = 4.7 Hz, 3H);

HRMS (ESI-TOF) m / z calcd for C17H17N5O4SNa [M + Na] +: 410.0899, found: 410.0897.

Example  5. Preparation of 4 - ((2- (3- (2-dimethylamino) ethyl) ureido) benzo [d] thiazol- Oxy ) -N-methylpicolinamide (compound 5) of  Produce

((2-aminobenzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide (50 mg, 0.17 mmol) prepared in step (2) of Example 1 was dissolved in N , And N, N-dimethylformamide (3 mL), 1,1'-carbonyldiimidazole (81 mg, 0.50 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 24 hours. N, N-dimethyl-1,2-ethanediamine (91 μL, 0.83 mmol) was added dropwise to the reaction mixture and stirred at room temperature for 24 hours. The completion of the reaction was confirmed by TLC (ethyl acetate: methanol = 20: 1) Respectively. The reaction mixture was poured into water (15 mL), and the organic solvent layer extracted with ethyl acetate (3 X 15 mL) was washed again with a saturated sodium chloride solution (45 mL). The organic solvent layer was dried over anhydrous sodium sulfate, The solvent was removed by concentration. The concentrate was separated and purified by column chromatography (ethyl acetate: methanol = 9: 1, 2: 1) to obtain the desired compound (52 mg, 75% yield).

8.84 (q, J = 4.4 Hz, 1H), 8.52 (d, J = 5.6 Hz, 1H), 7.84 (d, J = J = 2.4 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.40 J = 6.0 Hz, 2H), 2.80 (d, J = 4.8 Hz, 3H), 2.38 (t, J = 6.0 Hz, , ≪ / RTI > 2H), 2.20 (s, 6H);

13C NMR (100 MHz, DMSO-d6)? 166.58, 164.24, 160.87, 154.20, 152.92, 150.86, 148.89, 147.59, 133.57, 121.35, 119.95, 114.51, 109.29, 58.50, 45.46, 37.65, 26.46.

Example  6. N- methyl -4 - ((2- (3- (2- (pyrrolidin-1-yl) ethyl) ureido ) Benzo [d] thiazole -6-yl) oxy) picolinamide (compound 6) of  Produce

(2-aminobenzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide (50 mg, 0.17 mmol) prepared in the step (2) of Example 1 The objective compound (16 mg, 22% yield) was prepared from 1,1'-carbonyldiimidazole (81 mg, 0.50 mmol) and N- (2- aminoethyl) pyrrolidine (106 μL, 0.83 mmol) .

1H NMR (300 MHz, CDCl3) [delta] 8.37 (d, J = 5.4 Hz, 1H), 8.02 (br.s, 1H), 7.687.57 (m, 3H), 7.42 2H), 3.00 (d, J = 4.6 Hz, 3H), 2.912.82 (m, 4H), 1.88 (brs, 4H), 1.25 (s, 2H).

Example  7. N- methyl 4 - ((2- (3- (2- (Piperidin-1-yl) ethyl) ureido) benzo [d] thiazol-6-yl) oxy) picolinamide 7) of  Produce

(2-aminobenzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide (50 mg, 0.17 mmol) prepared in the step (2) of Example 1 (24 mg, 32% yield) was obtained from 1,1'-carbonyldiimidazole (81 mg, 0.50 mmol) and N- (2- aminoethyl) piperidine (119 μL, 0.83 mmol) .

J = 4.8 Hz, 1H), 8.52 (d, J = 5.6 Hz, 1H), 7.84 (d, J = J = 8.8, 2.4 Hz, 1H), 7.18 (dd, J = 8.8 Hz, 1H), 7.22 (dd, J = J = 5.6 Hz, 2H), 2.79 (d, J = 4.8 Hz, 3H), 2.442 (m, 6H) 1.571.54 (m, 4 H), 1.41 (br s, 2 H);

(100 MHz, DMSO-d6) δ 166.58, 164.24, 161.03, 153.97, 152.91, 150.88, 148.88, 147.62, 133.52, 121.35, 119.77, 114.51, 112.97, 109.27, 57.84, 54.33, 36.97, 26.46, 25.88, 24.42 .

Example  8. N- methyl -4 - ((2- (3- (2-morpholinoethyl) ureido) benzo [d] Thiazol-6-yl) oxy) picolinamide (compound 8) of  Produce

(2-aminobenzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide (50 mg, 0.17 mmol) prepared in the step (2) of Example 1 (16 mg, 21% yield) was obtained from 1,1'-carbonyldiimidazole (81 mg, 0.50 mmol) and N- (2- aminoethyl) morpholine (111 μL, 0.83 mmol) .

J = 2.1 Hz, 1H), 7.47 (d, J = 2.1 Hz, 1H) (Dd, J = 5.6, 2.5 Hz, 1H), 3.86 (br.s, 4H), 3.55 (br.s, 2H) 3.00 (d, J = 5.1 Hz, 3H), 2.752.68 (m, 6H), 2.04 (br.s, 1H), 0.87 (br.s, 1H);

HRMS (ESI-TOF) m / z calcd for C21H25N6O4S [M + H] < + >: 457.1652, found: 457.1654.

Example  9. N- methyl -4-( (2- (3- (2- (4-methylpiperazin-1-yl) ethyl)) ureido ) Benzo [d] thiazole -6-yl) oxy) picolinamide (compound 9) of  Produce

(2-aminobenzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide (50 mg, 0.17 mmol) prepared in the step (2) of Example 1 (20 mg, 26 mmol) was obtained from 1,1'-carbonyldiimidazole (81 mg, 0.50 mmol) and 2- (4-methylpiperazin- % Yield).

8.84 (q, J = 4.8 Hz, 1H), 8.52 (d, J = 5.6 Hz, 1H), 7.84 (d, J = = 2.4 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.40 (d, J = 2.4 Hz, 1H), 7.22 J = 5.6 Hz, 2H), 2.80 (d, J = 4.8 Hz, 3H), 2.452.37 (m, 10H) , 2.18 (s, 3 H);

13C NMR (100 MHz, DMSO-d6)? 166.58, 164.25, 160.94, 154.17, 152.92, 150.87, 148.91, 147.61, 133.53, 121.34, 119.76, 114.52, 109.30, 57.22, 55.15, 52.96, 46.22, 36.99, 26.46.

Example  10. 4 - ((2- (3- (3-hydroxypropyl) ureido) benzo [d] thiazol-6-yl) Oxy ) -N-methylpiperazine Choline amide  (compound 10) of  Produce

(2-aminobenzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide (50 mg, 0.17 mmol) prepared in the step (2) of Example 1 (71 mg, 71%) was obtained from 1,1'-carbonyldiimidazole (81 mg, 0.50 mmol) and 3-aminopropanol (63 μL, 0.83 mmol).

J = 2.4 Hz, 1H), 8.51 (d, J = 5.6 Hz, 1H), 7.84 (d, J = 2.4 Hz, 1H) (Dd, J = 5.6, 2.6 Hz, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.39 J = 6.5 Hz, 2H), 7.02 (br.s, 1H), 6.83 (br.s, 1H), 4.57 2H), 2.79 (d, J = 4.8 Hz, 3H), 1.64 (p, J = 6.4 Hz, 2H);

13 C NMR (75 MHz, DMSO-d 6)? 166.58, 164.25, 161.46, 161.01, 154.32, 152.93, 150.86, 148.90, 147.56, 135.60, 133.53, 121.29, 119.73, 109.31, 58.95, 37.31, 32.89, 26.45;

HRMS (ESI-TOF) m / z calcd for C18H19N5O4SNa [M + Na] +: 424.1056, found: 424.1055.

Example  11. 4 - ((2- (3- (3- (dimethylamino) propyl) ureido) benzo [d] thiazole -6-yl) oxy) -N-methylpicolinamide (compound 11) of  Produce

(2-aminobenzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide (50 mg, 0.17 mmol) prepared in the step (2) of Example 1 (31 mg, 43%) was obtained from 1,1'-carbonyldiimidazole (81 mg, 0.50 mmol) and N, N-dimethyl-1,3-propanediamine (105 μL, ≪ / RTI >

J = 5.6 Hz, 1H), 7.84 (d, J = 4.8 Hz, 1H), 8.80 (q, J = J = 8.8 Hz, 1H), 7.18 (dd, J = 8.8 Hz, 1H), 7.32 J = 6.0 Hz, 2H), 2.79 (d, J = 4.8 Hz, 3H), 2.33 (t, J = 7.2 Hz, 2H), 2.21 (s, 6H), 1.63 (p, J = 6.8 Hz, 2H);

13C NMR (100 MHz, DMSO-d6)? 166.59, 164.24, 160.98, 152.91, 150.89, 148.87, 147.57, 133.51, 121.31, 119.77, 117.39, 114.54, 111.36, 109.26, 56.99, 45.40, 38.24, 27.43, 26.47.

Example  12. N- methyl -4-( (2- (3- (3- (pyrrolidin-1-yl) propyl) ) Ureido ) Benzo [d] thiazole -6-yl) oxy) picolinamide (compound 12) of  Produce

(2-aminobenzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide (50 mg, 0.17 mmol) prepared in the step (2) of Example 1 (48 mg, 63% yield) was obtained from 1,1'-carbonyldiimidazole (81 mg, 0.50 mmol) and N- (3- aminopropyl) pyrrolidine (105 μL, 0.83 mmol) .

(D, J = 4.8 Hz, 1H), 8.51 (d, J = 5.2 Hz, 1H), 8.33 (d, J = (D, J = 8.8 Hz, 1H), 7.18 (m, 1H), 6.91 (s, 1H) 1H), 3.23 (q, J = 6.4 Hz, 2H), 2.79 (d, J = 4.0 Hz, 3H), 2.522.47 (m, 6H), 1.701.64 (m, 6H);

13 C NMR (100 MHz, DMSO-d6) δ 166.58, 164.24, 161.04, 154.34, 152.93, 150.86, 148.87, 147.58, 133.53, 121.27, 119.72, 114.50, 109.29, 79.64, 54.04, 38.34, 28.92, 26.45, 23.55;

HRMS (ESI-TOF) m / z calcd for C22H26N6O3SNa [M + Na] +: 477.1685, found: 477.1689.

Example 13. Synthesis of N-methyl-4 - ((2- (3- (3- (piperidin-1-yl) propyl) ureido) benzo [d] thiazol- Amide (Compound 13)

(2-aminobenzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide (50 mg, 0.17 mmol) prepared in the step (2) of Example 1 (28 mg, 36% yield) was obtained from 1,1'-carbonyldiimidazole (81 mg, 0.50 mmol) and N- (3-aminopropyl) piperidine (133 μL, 0.83 mmol) .

J = 4.8 Hz, 1H), 8.53 (d, J = 5.6 Hz, 1H), 7.84 (d, J = J = 8.8 Hz, 1H), 7.18 (dd, J = 2.4 Hz, 1H), 7.72 J = 6.4 Hz, 2H), 2.79 (d, J = 4.8 Hz, 3H), 2.372 (m, 6H) 1.65 (p, J = 6.8 Hz, 2H), 1.53 (t, J = 5.2 Hz, 4H), 1.40 (d, J = 4.4 Hz, 2H).

Example  14. N- methyl -4 - ((2- (3- (3-morpholinopropyl) ureido) benzo [d] thiazol-6-yl) oxy) picolinamide (compound 14) of  Produce

(2-aminobenzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide (50 mg, 0.17 mmol) prepared in the step (2) of Example 1 (45 mg, 58% yield) was obtained from 1,1'-carbonyldiimidazole (81 mg, 0.50 mmol) and N- (3-aminopropyl) morpholine (121 μL, 0.83 mmol) .

8.84 (q, J = 4.8 Hz, 1 H), 8.52 (d, J = 5.6 Hz, 1 H), 7.84 (d, J = 2.4 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 2.8 Hz, 1H), 7.22 J = 6.4 Hz, 2H), 2.80 (d, J = 4.8 Hz, 2H) , 3H), 2.362.31 (m, 6H), 1.65 (p, J = 7.2 Hz, 2H);

13C NMR (100 MHz, DMSO-d6)? 166.58, 164.24, 161.03, 154.30, 152.94, 150.86, 148.91, 147.56, 133.52, 121.28, 119.73, 114.50, 109.31, 66.62, 56.23, 53.83, 38.30, 26.62, 26.45.

Example  15. N- methyl -4 - ((2- (3- (3- (4- Methylpiperazine -1-yl) propyl) Ureido ) Benzo [d] thiazole -6-yl) oxy) picolinamide (compound 15) of  Produce

(2-aminobenzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide (50 mg, 0.17 mmol) prepared in the step (2) of Example 1 (46.8 mg, 0.83 mmol) was obtained from 1,1'-carbonyldiimidazole (81 mg, 0.50 mmol) and 3- (4-methylpiperazin- 1 -yl) propan- mg, 58% yield).

J = 4.8 Hz, 1H), 8.52 (d, J = 5.6 Hz, 1H), 7.84 (d, J = (Dd, J = 2.4 Hz, 1H), 7.22 (dd, J = 8.8, 2.8 Hz, 1H), 7.71 2H), 2.80 (d, J = 4.8 Hz, 3H), 2.322.29 (m, 10H) 2.15 (s, 3H), 1.63 (p, J = 6.8 Hz, 2H);

(100 MHz, DMSO-d6) δ 166.59, 164.24, 161.14, 154.39, 152.91, 150.87, 148.84, 147.56, 133.52, 121.24, 119.73, 114.49, 109.28, 55.71, 55.16, 53.17, 46.20, 38.25, 31.42, 27.03 , 26.46, 22.53;

HRMS (ESI-TOF) m / z calcd for C23H30N7O3S [M + Na] +: 484.2125, found: 484.2134.

Example  16. Preparation of 4 - ((2- (3- (4-hydroxybutyl) ureido) benzo [d] thiazol-6-yl) Oxy ) -N-methylpicolinamide (compound 16)  Produce

(2-aminobenzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide (50 mg, 0.17 mmol) prepared in the step (2) of Example 1 (35.1 mg, 50.8% yield) was obtained from 1,1'-carbonyldiimidazole (81 mg, 0.50 mmol) and 4- amino-1-butanol (77 μL, 0.83 mmol).

J = 5.2 Hz, 1H), 8.52 (d, J = 5.6 Hz, 1H), 7.84 (d, J = J = 8.8, 2.4 Hz, 1H), 7.18 (dd, J = 8.8 Hz, 1H), 7.22 (dd, J = J = 5.6 Hz, 1H), 3.44 (q, J = 5.2 Hz, 2H), 3.19 (q, J = 5.6 Hz, 2H), 2.80 (d, J = 4.8 Hz, 3H), 1.531.45 (m, 4H);

13C NMR (100 MHz, DMSO-d6)? 166.58, 164.24, 160.94, 154.23, 152.93, 150.88, 148.90, 147.68, 133.56, 121.36, 119.75, 114.51, 109.51, 109.31, 60.86, 55.37, 30.26, 26.62, 26.46.

Example  17. 4 - ((2- (3- (4- (dimethylamino) butyl) ureido) benzo [d] thiazole -6-yl) oxy) -N-methylpicolinamide (compound 17)  Produce

(2-aminobenzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide (50 mg, 0.17 mmol) prepared in the step (2) of Example 1 (48.4 mg, 65.8%) was obtained from 1,1'-carbonyldiimidazole (81 mg, 0.50 mmol) and N, N-dimethyl-1,4-butanediamine (97 mg, 0.83 mmol) ≪ / RTI >

(D, J = 5.6, 2.4 Hz, 1H), 7.83 (d, J = 3.2 Hz, 1H), 8.57 (D, J = 8.4, 2.0 Hz, 1H), 7.40 (t, J = 2.0 Hz, 1H), 7.237.20 (m, 1H), 7.187 2H), 2.79 (d, J = 3.8 Hz, 3H), 2.26 (t, J = 6.4 Hz, 2H), 2.18 s, 6H), 1.491.44 (m, 4H);

13C NMR (100 MHz, DMSO-d6)? 166.58, 164.24, 161.01, 154.31, 152.92, 150.86, 148.88, 147.55, 133.53, 121.28, 119.73, 114.50, 109.30, 59.01, 45.43, 27.70, 26.45, 24.62;

HRMS (ESI-TOF) m / z calcd for C21H27N6O3S [M + H] +: 443.1859, found: 443.1865.

Example  18. 4 - ((2- (3- (4-chloro-3- (trifluoromethyl) Phenyl) Ureido ) Benzo [d] thiazole -6-yl) oxy) -N-methylpicolinamide (compound 18) of  Produce

(2-aminobenzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide (30 mg, 0.10 mmol) prepared in step (2) of Example 1 was dissolved in N And 4-chloro-3-fluoromethylphenyl isocyanate (24 mg, 0.11 mmol) were added to the reaction mixture, followed by stirring at room temperature for 16 hours. The completion of the reaction was confirmed by TLC (ethyl acetate: methanol = 9: 1). Dichloromethane (5 mL) was added to the reaction mixture, and the precipitate formed was filtered with dichloromethane to obtain the desired compound (39.8 mg, 76% yield).

(D, J = 5.6 Hz, 1 H), 8.79 (q, J = 4.8 Hz, 1 H), 8.54 , 8.16 (br.s, 1H), 7.89 (d, J = 2.0 Hz, 1H), 7.827.74 (m, 2H), 7.68 (d, J = 8.8 Hz, 1H) Hz, 1H), 7.28 (dd, J = 8.0, 2.8 Hz, 1H), 7.20 (dd, J = 5.6, 2.8 Hz, 1H), 2.80 (d, J = 5.2 Hz, 3H);

(100 MHz, DMSO-d6) δ 166.49, 164.23, 152.96, 150.93, 149.27, 138.82, 137.52, 134.70, 132.59, 127.41, 127.10, 124.30, 121.87, 120.57, 120.17, 118.06, 114.94, 114.58, 113.24, 109.83, 107.21, 26.46;

HRMS (ESI-TOF) m / z calcd for C22H16ClF3N5O3S [M + H] +: 522.0608, found: 522.0622.

Example  19. 4 - ((2- (3- (3,5-beads (trifluoromethyl) Phenyl) Ureido ) Benzo [d] thiazole -6-yl) oxy) -N-methylpicolinamide (compound 19)  Produce

(2-aminobenzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide (67 mg, 0.22 mmol) prepared in the step (2) of Example 1 was obtained in the same manner as in Example 18. (83 mg, 67% yield) was obtained from 3,5-bis (trifluoromethyl) phenyl isocyanate (57 mg, 0.22 mmol)

J = 4.9 Hz, 1H), 8.53 (d, J = 5.6 Hz, 1H), 8.79 (s, , 8.26 (s, 2H), 7.86 (d, J = 2.4 Hz, 1H), 7.747.71 (m, 2H), 7.42 Hz, 1H), 7.19 (dd, J = 5.6,2.6 Hz, 1H), 2.80 (d, J = 4.8 Hz, 3H);

(100 MHz, DMSO-d6) δ 166.46, 164.26, 152.94, 150.92, 149.35, 141.52, 131.72, 131.39, 131.07, 130.75, 127.79, 125.08, 122.37, 120.24, 119.11, 115.78, 115.01, 114.57, 109.36, 26.45.

Example  20. 4 - ((2- (3- (2,4-dichlorophenyl) ureido) benzo [d] thiazol-6-yl) Oxy ) -N-methylpicolinamide (compound 20)  Produce

(2-aminobenzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide (30 mg, 0.10 mmol) prepared in the step (2) of Example 1 was obtained in the same manner as in Example 18. (16 mg, 33% yield) was obtained from 2,4-dichlorophenyl isocyanate (21 mg, 0.11 mmol).

(D, J = 5.6 Hz, 1H), 8.79 (q, J = 5.2 Hz, 1H) 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.81 (d, J = , 7.47 (dd, J = 8.8,2.4 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.28 Hz, 1 H), 2.80 (d, J = 4.8 Hz, 3 H).

Example  21. 4 - ((2- (3- (3,4-dichlorophenyl) ureido) benzo [d] thiazol-6-yl) Oxy ) -N-methylpicolinamide (compound 21)  Produce

(2-aminobenzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide (30 mg, 0.10 mmol) prepared in the step (2) of Example 1 was obtained in the same manner as in Example 18. (34 mg, 70% yield) was obtained from 3,4-dichlorophenyl isocyanate (28 mg, 0.15 mmol).

J = 5.6 Hz, 1H), 8.52 (d, J = 5.6 Hz, 1H) , 7.91 (d, J = 15.1 Hz, 2H), 7.73 (s, 1H), 7.58 (d, J = 8.8 Hz, 1H), 7.48 J = 2.4 Hz, 1H), 7.27 (dd, J = 8.6, 2.4 Hz, 1H), 7.19 (d, J = 5.6, 2.6 Hz, 1H), 2.79 (d, J = 4.8 Hz, 3H);

HRMS (ESI-TOF) m / z calcd for C21H15Cl2N5O3SNa [M + Na] +: 510.0171, found: 510.0168.

Example  22. 4 - ((2- (3- (4-chlorophenyl) ureido) benzo [d] thiazole Yl) Oxy ) -N-methylpicolinamide (compound 22)  Produce

(2-aminobenzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide (30 mg, 0.10 mmol) prepared in the step (2) of Example 1 was obtained in the same manner as in Example 18. mmol) and 4-chlorophenyl isocyanate (23 mg, 0.15 mmol), the target compound (21 mg, 46% yield) was obtained.

J = 5.6 Hz, 1H), 8.78 (d, J = 4.8 Hz, 1H), 8.52 (d, J = 5.6 Hz, 1H) 2H), 7.47 (m, 3H), 7.26 (dd, J = 7.8 Hz, 1H) = 8.8, 2.4 Hz, 1H), 7.19 (dd, J = 5.6, 2.8 Hz, 1H), 2.79 (d, J = 4.8 Hz, 3H);

HRMS (ESI-TOF) m / z calcd for C21H16ClN5O3SNa [M + Na] +: 476.0560, found: 476.0563.

Example  23. N- methyl -4 - ((2- (3- (4-( Trifluoromethyl ) Phenyl) Ureido ) Benzo [d] thiazole -6-yl) oxy) picolinamide (compound 23)  Produce

(2-aminobenzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide (30 mg, 0.10 mmol) prepared in the step (2) of Example 1 was obtained in the same manner as in Example 18. (13 mg, 26% yield) was obtained from 3,4-dichlorophenyl isocyanate (17 μL, 0.20 mmol).

HRMS (ESI-TOF) m / z calcd for 2 (C22H16F3N5O3S) Na [2M + Na] +: 997.1750, found: 997.1743.

Example  24. 4 - ((2- (3- (4-fluorophenyl) ureido) benzo [d] Thiazol-6-yl) Oxy ) -N-methylpicolinamide (compound 24)  Produce

(2-aminobenzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide (40 mg, 0.13 mmol) prepared in step (2) of Example 1 was dissolved in acetone Nitrile (5 mL), and then 30 μL of 4-fluorophenyl isocyanate, 0.27 mmol) was added to the reaction mixture, followed by stirring at room temperature for 16 hours. The completion of the reaction was confirmed by TLC (ethyl acetate: methanol = 9: 1). Dichloromethane (5 mL) was added to the reaction mixture, and the precipitate formed was filtered with dichloromethane to obtain the desired compound (26 mg, 44% yield).

J = 5.6 Hz, 1 H), 8.52 (br.s, 1 H), 8.828.76 (m, (D, J = 8.8, 2.4 Hz, 1H), 7.89 (s, 1H), 7.77 (br.s, 1H), 7.607.47 , 7.227.12 (m, 3H), 2.80 (d, J = 4.8 Hz, 3H).

Example  25. 4 - ((2- (3- (4-bromophenyl) ureido) benzo [d] thiazole Yl) Oxy ) -N-methylpicolinamide (compound 25)  Produce

 In the same manner as in Example 24, 4 - ((2-aminobenzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide (50 mg, 0.17 (42 mg, 51% yield) was obtained from 4-bromophenyl isocyanate (33 mg, 0.17 mmol).

J = 4.8 Hz, 1H), 8.52 (d, J = 5.8 Hz, 1H), 7.87 (d, J = 2.0 Hz, 1H) (D, J = 8.8 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H) (dd, J = 5.6, 2.8 Hz, 1H), 2.79 (d, J = 4.8 Hz, 3H).

Example  26. 4 - ((2- (3- (2-chloro-5- (trifluoromethyl) Phenyl) Ureido ) Benzo [d] thiazole -6-yl) oxy) -N-methylpicolinamide (compound 26)  Produce

(2-aminobenzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide (30 mg, 0.10 mmol) prepared in the step (2) of Example 1 was obtained in the same manner as in Example 24. (26 mg, 51% yield) was obtained from 2-chloro-5-trifluoromethylphenyl isocyanate (22 L, 0.15 mmol)

Example  27. 4 - ((2- (3- (2,4-difluorophenyl) ureido) benzo [d] thiazol-6-yl) Oxy ) -N-methylpicolinamide (compound 27)  Produce

(2-aminobenzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide (40 mg, 0.13 mmol) prepared in the step (2) of Example 1 was obtained in the same manner as in Example 24. (27 mg, 45% yield) was obtained from 2,4-difluorophenyl isocyanate (31 L, 0.27 mmol).

J = 4.4 Hz, 1H), 8.54 (d, J = 5.2 Hz, 1H), 8.79 (q, , 8.07 (q, J = 8.4 Hz, 1H), 7.92 (d, J = 2.4 Hz, 1H), 7.80 (d, J = 8.9 Hz, 1H), 7.437 J = 8.8, 2.4 Hz, 1H), 7.20 (dd, J = 5.6, 2.4 Hz, 1H), 7.167.11 (m, 1H), 2.80 (d, J = 4.8 Hz, 3H);

HRMS (ESI-TOF) m / z calcd for C21H15F2N5O3SNa [M + Na] +: 478.0762, found: 478.0755.

Example  28. N- methyl -4 - ((2- (3- (4 -morpholinophenyl) ureido) benzo [d] Thiazol-6-yl) oxy) picolinamide (compound 28)  Produce

((2-aminobenzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide (50 mg, 0.17 mmol) prepared in step (2) of Example 1 was dissolved in N , And N, N-dimethylformamide (3 mL), 1,1'-carbonyldiimidazole (81 mg, 0.50 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 24 hours. 4-morpholinoaniline (30 mg, 0.17 mmol) dissolved in N, N-dimethylformamide (1 mL) was added dropwise to the reaction mixture, and the mixture was stirred at 100 ° C for 3 hours. TLC Hexane: ethyl acetate = 1: 1). The reaction mixture was poured into water (15 mL), and the organic solvent layer extracted with ethyl acetate (3 X 15 mL) was washed again with a saturated sodium chloride solution (45 mL). The organic solvent layer was dried over anhydrous sodium sulfate, The solvent was removed by concentration. The concentrate was separated and purified by column chromatography (hexane: ethyl acetate = 1: 1, 100% ethyl acetate) to obtain the desired compound (10 mg, 12% yield).

8.9 (br.s, 1H), 8.79 (q, J = 4.8 Hz, 1H), 8.53 (d, J = 5.6 Hz, 1H) (D, J = 8.8, 2.8 Hz, 1H), 7.19 (d, J = 7.2 Hz, 1H), 7.88 J = 5.6,2.8 Hz, 1H), 6.95 (d, J = 9.2 Hz, 2H), 3.75 (t, J = 5.2 Hz, 4H), 3.07 , ≪ / RTI > J = 5.2 Hz, 3H).

Example  29. N- methyl -4 - ((2- (3- (4- (4- Methylpiperazine -1-yl) phenyl) Ureido ) Benzo [d] thiazole -6-yl) oxy) picolinamide (compound 29)  Produce

(2-aminobenzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide (50 mg, 0.17 mmol) prepared in the step (2) of Example 1 24%) was obtained from 1,1'-carbonyldiimidazole (81 mg, 0.50 mmol) and 4- (4-methylpiperazin-1-yl) aniline (32 mg, Yield).

(D, J = 6.4 Hz, 1 H), 8.81 (q, J = 4.8 Hz, , 7.88 (d, J = 2.4 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.41 (dd, J = 8.4, 2.4 Hz, 1 H), 7.19 (dd, J = 5.6, 2.8 Hz, 1 H), 6.93 , 2.80 (d, J = 4.8 Hz, 3H), 2.46 (t, J = 5.2 Hz, 4H), 2.23 (s, 3H);

163.5, 164.24, 160.70, 152.93, 152.38, 150.90, 149.04, 147.75, 146.95, 133.42, 130.48, 121.25, 120.80, 119.93, 116.40, 114.68, 114.53, 109.32, 55.08, 49.01 (dd, , 46.20, 26.47.

Example  Yl) phenyl) ureido) benzo [d] thiazol-6-yl) oxy) -N- Methylpicoline amide (compound 30)  Produce

(2-aminobenzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide (50 mg, 0.17 mmol) prepared in the step (2) of Example 1 (37 mg, 0.17 mmol) was reacted with 1,1'-carbonyldiimidazole (81 mg, 0.50 mmol) and 1- (4-aminophenyl) -N, N-dimethylpiperidin- To obtain the title compound (24 mg, 27% yield).

J = 4.8 Hz, 1H), 8.53 (d, J = 5.2 Hz, 1H), 7.85 (d, J = J = 8.8 Hz, 2H), 7.24 (dd, J = 8.4Hz, 1H), 7.73 (d, J = J = 8.8 Hz, 2H), 3.70 (br.s, 1H), 3.64 (d, J = 12.8 Hz, 2H), 2.20 (s, 6H), 1.83 (d, J = 12.4Hz, 2H), 1.531.43 (d, J = m, 2H).

Example  31. N- methyl -4 - ((2- (3- (4-( Molopolymomethyl ) -3- ( Trifluoromethyl ) Phenyl) ureido) benzo [d] thiazol-6-yl) oxy) picolinamide 31)  Produce

(2-aminobenzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide (50 mg, 0.17 mmol) prepared in the step (2) of Example 1 (43 mg, 0.17 mmol) was reacted with 1,1'-carbonyldiimidazole (81 mg, 0.50 mmol) and 4- (morpholinomethyl) -3- (trifluoromethyl) aniline (16 mg, 17% yield).

J = 5.6 Hz, 1H), 8.54 (d, J = 5.6 Hz, 1H), 8.81 (q, J = ), 8.01 (s, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.777.72 (m, 3H), 7.41 2.4 Hz, 1H), 7.20 (dd, J = 5.6, 2.4 Hz, 1H), 3.613.57 (m, 6H), 2.80 (d, J = 5.2 Hz, 3H), 2.39 (br.s, 4H);

(100 MHz, DMSO-d6)? 166.52, 164.23, 161.12, 152.94, 150.92, 149.21, 138.28, 135.61, 133.02, 132.07, 131.25, 126.10, 123.37, 122.83, 120.81, 120.11, 116.29, 116.23, 114.84, 114.57, 109.32, 66.69, 58.25, 53.73, 26.47;

HRMS (ESI-TOF) m / z calcd for C27H25F3N6O4SNa [M + Na] < + >: 609.1508, found: 609.1508.

Example  32. 4 - ((2- (3- (4 - ((4-ethylpiperazin-1-yl) methyl ) -3- ( Trifluoromethyl ) Phenyl) ureido) benzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide 32)  Produce

(2-aminobenzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide (50 mg, 0.17 mmol) prepared in the step (2) of Example 1 3- (trifluoromethyl) aniline (48 mg, 0.50 mmol) and 1,1'-carbonyldiimidazole (81 mg, 0.50 mmol) 0.17 mmol) to obtain the title compound (17 mg, 16% yield).

8.00 (q, J = 4.8 Hz, 1H), 8.53 (d, J = 5.6 Hz, 1H), 8.00 (s, 1H) ), 7.88 (d, J = 2.4 Hz, 1H), 7.777.70 (m, 3H), 7.41 (d, J = 2.4 Hz, 1H) (d, J = 5.6,2.8 Hz, 1H), 3.56 (s, 2H), 3.51 (br.s, 1H), 2.80 (d, J = 4.8 Hz, 3H), 2.412.34 1.24 (br.s, 1H), 1.00 (t, J = 4.8 Hz, 3H);

166.54, 164.23, 155.96, 152.94, 150.92, 149.13, 140.35, 138.29, 131.91, 131.62, 131.31, 128.21, 123.39, 123.05, 122.76, 120.80, 120.04, 116.15, 114.77, 114.54 (100 MHz, DMSO-d6) , 109.34, 57.83, 53.13, 52.78, 52.01, 36.64, 26.47;

HRMS (ESI-TOF) m / z calcd for C29H31F3N7O3S [M + H] +: 614.2155, found: 614.2164.

Experimental Examples 1 and 2 showed the inhibition of kinase activity of the compounds of Examples 1 to 17 and the anticancer effect against cancer cells. Experiments on the inhibitory effect on the anti-cancer and kinase activity of the compounds of Examples 18 to 32 were performed in Experimental Examples 3 and 4 Respectively.

Experimental Example  1. Validation of inhibition of kinase activity ( ABL -1 and ABLT315I )

Kinase inhibition effects were measured for the compounds of Examples 1 to 17 and kinase assays were conducted in a "Hot Spot" assay platform method. Specific kinase / substrate pairs and cofactors were incubated in reaction buffer (20 mM HEPES (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.02% Brij35, 0.02 mg / mL BSA, 0.1 mM Na3VO4, 2 mM DTT and 1% DMSO). 10 μM of the compound was added to the reaction, and after 20 minutes, a mixture of ATP (Sigma) and 33P ATP (Perkin Elmer) was added. The reaction was carried out at 25 ° C for 120 minutes and the spotting of the reaction was filtered using P81 ion exchange filter paper (Whatman # 3698-915) and the unbound phosphate was filtered with 0.1% phosphoric acid Washed and removed.

The following Table 1 quantifies the activity of kinase by the addition concentration of the compound, assuming that the kinase activity of the kinase in the case where the compound is not treated (negative control, DMSO-treated kinase) is 100%. A positive control was prepared by adding imatinib (4- (4-methylpiperazin-1-yl) methyl-N- [4-methyl- (2-thienylcarbonyl) -1H-benzimidazol-2-yl] carbamate, an anticancer agent, Park, K. et al., Bioorganic & Medicinal Chemistry Letters 2012, 22, 5279.), Nocodazole (2-hydroxyethyl) -3- (6- (2-methoxyphenyl) benzo [d] thiazol-2-yl) -urea, Anticancer substances, Hong, S. et al., J. Med. Chem., 2013, 56, 3531.).

compound ABL -One ABLT315I % Inhibition,
10 μM IC50, nM % Inhibition,
10 μM IC50, nM One 99 33 91 82 2 95 115 - - 3 95 100 - - 4 97 55 87 192 5 96 285 - - 6 93 233 - - 7 94 199 - - 8 94 134 - - 9 98 48 92 67 10 97 70 89 151 11 98 80 - - 12 100 50 91 111 13 99 56 - - 14 97 79 - - 15 98 18 94 40 16 95 132 - - 17 100 25 94 56 Imatinib - 217 - - Nocodazole - 210 - 640 HS-438 - - - 0.064

As shown in Table 1 above, the compounds according to Examples 1 to 17 of the present invention showed an inhibitory effect of at least about 93% to about 100% at a concentration of 10 μM for ABL-1 kinase activity. IC50 values for these compounds were measured and found to be 80 nM at about 70 nM for compounds 10, 11 and 14, respectively. Compounds 4, 9, 12 and 13 showed 56 nM concentration at about 48 nM. Compounds 1 and 17 showed kinase activity inhibition 8 times higher than the reference compounds (imatinib and nocodazole) at a concentration of 33 nM at about 25 nM. Compound 15 showed a concentration of 18 nM, which is twice as high as compound 17 and 12 times higher kinase inhibitory effect than the positive control.

Compounds 9 and 17 inhibited 92% and 94% of the inhibitory effect of ABLT315I on compounds with high activity against ABL-1 kinase, respectively. As a result, nocodazole (inhibitor) (67 nM and 56 nM), respectively. Compound 15 showed 94% inhibition effect, which was twice as high as compound 9 and 16 times higher than nocodazole at an IC50 value of 40 nM. This resulted in the best inhibition of kinase activity against the ABL-1 and ABLT315I kinases among the synthesized compounds.

For reference, when the% inhibition value of the compounds having no IC50 value in the above Table 1 is obtained, the range of the maximum concentration and the minimum concentration is too narrow to find a value of 50%.

Experimental Example  2. Anticancer effect of cancer cell inhibitor (K-562)

The cell line used for the MTT assay was K-562 (Human leukemia cancer), which was cultured in a Korean cell line bank. The culture medium was RPMI 1640 medium containing 10% fetal bovine serum and incubated at 37 ° C in a humidified 5% CO 2 incubator. Cells were cultured in a 96-well microplate for 3 × 10 3 cells / well in a CO 2 incubator for 24 hours. Media was removed and 100 μl of diluted inhibitor solutions were added for 72 hours. 15 μl of MTT solution (Promega, CellTiter 96) was added and incubated for 4 hours. Stop solution (Promega, CellTiter 96) to dissolve blue formazan. After standing for 18 hours or longer, the absorbance was measured at 570 nm to obtain IC50 (concentration at which cancer cells were inhibited by 50%). The inhibitory activity and the IC50 for cancer cells were measured at 72 hours after treatment with or without 10 μM concentrations of the compounds 1, 9, 15 and 17, respectively, Respectively.

 The following Table 2 quantifies the activity of cancer cells at the addition concentration of the compound, assuming that the cancer cell activity in the case where the compound is not treated (negative control group) is 100%. As a positive control, Sorafenib (4- [4 - [[4-chloro-3- (trifluoromethyl) phenyl] carbamoylamino] phenoxy] -N-methyl-pyridine-2-carboxamide and anticancer agent were used. Sorafenib is a commercially available anticancer agent and was purchased from LC Laboratories.

compound K-562 % Inhibition, 10 μM One 92 9 90 15 90 17 88 Sorafenib 48

As shown in Table 2, when the cancer cells (%) of the negative control (control, DMSO-treated cells) were set at 100%, the inhibitory effects of the compounds according to Examples 1, 9, 15 and 17 As a result, the inhibitory effect of K-562 cancer cells was 88% or more at a concentration of 10 μM. It was shown that the compound of the present invention inhibited the activity of ABL-1 and ABLT315I to about 2-fold higher than that of the positive control (Sorafenib).

Experimental Example  3. Anticancer effect of cancer cell inhibitor HCT116 , MCF -7, SK-BR-3)

The cell lines used in the MTT assay were HCT116 (human colon carcinoma cancer), MCF-7 (human breat cancer) and SK-BR-3 (human breast cancer) The cells were cultured in Korean cell line. The% inhibitory activity and the IC50 for cancer cells were measured at 72 hours after treatment with or without each 10 μM concentration of the compounds 18 to 32, and the results are shown in Table 3 for each compound added .

compound HCT116 MCF -7 SK-BR-3 % Inhibition
10 μM GI50,
μM % Inhibition
10 μM GI50,
μM % Inhibition
10 μM GI50,
μM 18 83 2.38 ± 0.01 - - 80 3.72 ± 0.21 19 - - - - - - 20 32 - - - 22 - 21 70 3.93 + 0.17 - - 69 4.32 ± 0.08 22 57 7.07 ± 0.26 - - 51 11.83 + - 0.82 23 65 4.78 0.30 - - 70 4.92 ± 0.20 24 12 - - - 14 - 25 12 - 18 - 27 - 26 16 - - - 28 - 27 57 13.20 ± 0.07 - - 62 12.40 ± 0.89 28 2 - 14 - 14 - 29 25 - 16 - 31 - 30 68 5.26 ± 0.22 44 12.39 ± 0.19 45 6.81 + 0.13 31 2 - 8 - 30 - 32 93 2.05 ± 0.15 91 2.56 ± 0.06 78 2.67 ± 0.20 Sorafenib 48 6.18 ± 0.20 41 7.15 + 0.63 49 8.16 ± 0.18

In the experiment 3, when the cancer cells (%) of the negative control (control, DMSO-treated cells) were set to 100% as shown in Table 3, the inhibitory effect of the compounds according to Examples 18 to 32 , HCT116 cancer cells were inhibited from a minimum of about 2% to a maximum of 93% at a concentration of 10 μM, and MCF-7 cancer cells were inhibited from a minimum of about 8% up to a maximum of 91%. SK-BR-3 cancer cells were suppressed to a minimum of about 14% to 80%. Compounds 18, 21, 23 and 32 exhibited a concentration of 4.78 ± 0.30 μM at about 2.05 ± 0.15 μM in HCT116 cancer cells and a positive control (Sorafenib) at a concentration of more than 40% And about 1.3 to 3 times higher inhibitory activity. In the case of Compound 32 in MCF-7 cancer cells, the inhibitory activity was similar to that of MCF-7 at a concentration of 2.56 ± 0.06 μM, and was three times higher than that in the positive control. In SK-BR-3 cancer cells, compound 18, 21, 23 and 32 showed a concentration of 4.92 ± 0.20 μM at about 2.67 ± 0.20 μM and about 2 to 3 times higher inhibitory effect than the control substance.

Experimental Example  4. Validation of inhibition of kinase activity

The inhibitory effect of kinase activity on the compounds of Examples 18, 21 and 32 was measured, and Experimental Example 4 was carried out in the same manner as Experimental Example 1. The% inhibition effect on kinase and the IC50 were measured, respectively, and the results are shown in Table 4 for each of the added compounds, assuming that the kinase activity of the compound without treatment (negative control) is 100%.

As a positive control, sorafenib (4- [4- [[4-chloro-3- (trifluoromethyl) phenyl] carbamoylami no] phenoxy] -N-methyl- pyridine-2-carboxamide and anticancer agent were used.

compound BRAF ^V600E C- RAF % Inhibition,
10 μM IC50,
nM % Inhibition,
10 μM IC50,
nM 18 55 - 95 111 21 68 - 99 15 32 95 133 98 62 Sorafenib - 38 - 6

Compounds 18, 21 and 32, which exhibited high inhibitory activity against cancer cells, showed an inhibition effect of at least about 55% to a maximum of 95% at a concentration of 10 μM against BRAFV600E kinase activity, and the compound 32 having the highest activity inhibition was 133 lt; RTI ID = 0.0 > nM < / RTI > In the case of C-RAF kinase, compounds 18, 21 and 32 exhibited an activity inhibition of at least 95% up to 98%, and an IC50 of 111 nM at 62 nM.

Compound 32 showed an activity inhibitory effect on two kinases (BRAFV600E and C-RAF kinase), and various kinases (ABL-1, ABL-1T315I, BRAF, DDR1, FLT1 / VEGFR1, KDR / VEGFR2, LCK , LYN, RAF1) inhibitory effects were measured. % Inhibition effect on kinase and IC50 were measured in the same manner as in Experimental Example 1. The results are shown in Table 5 below.

Kinase
32 % Inhibition 10 μM IC50, nM ABL-1 94 53 ABL-1 (T315I) 93 53 BRAF 71 133 DDR1 99 57 FLT1 / VEGFR1 98 43 KDR / VEGFR2 99 43 LCK 99 7 LYN 100 20 RAF1 98 62

Compound 32 showed an inhibitory effect of at least 71% to a maximum of 100% for the nine kinases. IC50 values for these kinases were 20 nM for LYN kinase and 7 nM for LCK kinase, which was about 9-fold higher than that for C-RAF kinase. Respectively.

This showed high anti-cancer effect on all three cancer cells (HCT116, MCF-7 and SK-BR-3) and showed high activity inhibition effect on various kinases.

Thus, the compounds of the present invention are identified as anticancer compositions as selective kinase and mutant kinase activity inhibitors, and have shown the possibility of being used as the backbone of the compounds to be developed in the future.

Claims (13)

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

In Formula 1,
X is O or S;
R1 is hydrogen; A C1-C6 alkyl group; A C3-C10 aryl group; A C3-C10 heteroaryl group; And a C3-C10 heterocyclyl group;
Said C1-C6 alkyl group is selected from the group consisting of hydrogen; A hydroxy group; A C1-C6 alkyl group; A C1-C5 alkoxy group; Amino group -NR2R3; Amido group -CONR2R3; A C3-10 heteroaryl group; C3-10 heterocyclyl group; And a halogen group;
The C3-C10 aryl group, the C3-C10 heteroaryl group or the C3-C10 heterocyclyl group is hydrogen; A hydroxy group; A C1-C3 alkyl group substituted or unsubstituted with halogen or a C3-C10 heterocyclyl group; A C1-C3 alkoxy group substituted or unsubstituted with halogen or a C3-C10 heterocyclyl group; A C3-C10 aryl group; A carbonyl group; A halogen group; Amino group -NR2R3; Amide group CONR2R3; A C3-C10 heteroaryl group and a C3-C10 heterocyclyl group;
The C3-C10 heteroaryl group or the C3-C10 heterocyclyl group is substituted or unsubstituted with a C1-C3 alkyl group, an amino group -NR2R3;
And R 2 and R 3 include at least one group selected from the group consisting of hydrogen, C 1-6 alkyl group, C 1-6 alkenyl group, and C 1-6 alkenyl group. The method according to claim 1,
X is O or S;
R1 is at least one selected from the group consisting of a C1-C6 alkyl group and a C3-C10 aryl group
Said C1-C6 alkyl group is selected from the group consisting of hydrogen; A hydroxy group; A C1-C6 alkyl group; A C1-C5 alkoxy group; Amino group -NR2R3; Amido group -CONR2R3; A C3-10 heteroaryl group; And a C3-10 heterocyclyl group;
The C3-C10 aryl group is a C1-C3 alkyl group substituted or unsubstituted with halogen or a C3-C10 heterocyclyl group; A halogen group; And a C3-10 heterocyclyl group;
The C3-C10 heteroaryl group or the C3-C10 heterocyclyl group is substituted or unsubstituted with a C1-C3 alkyl group, an amino group -NR2R3;
Wherein R 2 and R 3 are each independently selected from the group consisting of hydrogen, a C 1-6 alkyl group, a C 1-6 alkenyl group, and a C 1-6 alkenyl group.
A ureidobenzothiazole compound, a pharmaceutically acceptable salt thereof, or a hydrate thereof. The method according to claim 1,
X is O or S;
R1 is a C1-6 alkyl group or a phenyl group,
Said C1-C6 alkyl group is selected from the group consisting of hydrogen; A hydroxy group; Amino group -NR2R3; And a C5-C6 heterocyclyl group;
The phenyl group is a C1-C3 alkyl group substituted or unsubstituted with a halogen or a C5-C6 heterocyclyl group; A halogen group; A C5-C6 heterocyclyl group;
The C5-C6 heterocyclyl group may be selected from the group consisting of pyrrolidine, piperidine, piperazine, and morpholine, and includes a C1-C3 alkyl group, an amino group- Substituted or unsubstituted with NR2R3;
Wherein R < 2 > and R < 3 &
A ureidobenzothiazole compound, a pharmaceutically acceptable salt thereof, or a hydrate thereof. The method according to claim 1,
X is O;
R1 is a C1-6 alkyl group or a phenyl group,
The C1-C6 alkyl group comprises a piperazine substituent substituted with a C1-3 alkyl group;
Wherein the phenyl group comprises a piperazine substituent substituted with a methyl group and a C1-3 alkyl group substituted with halogen
A ureidobenzothiazole compound, a pharmaceutically acceptable salt thereof, or a hydrate thereof. The method according to claim 1,
A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:
4 - ((2- (3-ethylureido) benzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide;
4 - ((2- (3-isopropylureido) benzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide;
4 - ((2- (3-ethylthioureido) benzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide;
4 - ((2- (3- (2-hydroxyethyl) ureido) benzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide;
4 - ((2- (3- (2-Dimethylamino) ethyl) ureido) benzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide;
N-methyl-4 - ((2- (3- (2- (pyrrolidin-1-yl) ethyl) ureido) benzo [d] thiazol-6-yl) oxy) picolinamide;
N-methyl-4 - ((2- (3- (2- (piperidin-1-yl) ethyl) ureido) benzo [d] thiazol-6-yl) oxy) picolinamide;
N-methyl-4 - ((2- (3- (2-morpholinoethyl) ureido) benzo [d] thiazol-6-yl) oxy) picolinamide;
N-methyl-4 - ((2- (3- (2- (4-methylpiperazin-1-yl) ethyl) ureido) benzo [d] thiazol-6-yl) oxy) picolinamide;
4 - ((2- (3- (3-hydroxypropyl) ureido) benzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide;
4 - ((2- (3- (3- (dimethylamino) propyl) ureido) benzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide;
N-methyl-4 - ((2- (3- (3- (pyrrolidin-1-yl) propyl)) ureido) benzo [d] thiazol-6-yl) oxy) picolinamide;
N-methyl-4 - ((2- (3- (3- (piperidin-1-yl) propyl)) ureido) benzo [d] thiazol-6-yl) oxy) picolinamide;
N-methyl-4 - ((2- (3- (3 -morpholino propyl) ureido) benzo [d] thiazol-6-yl) oxy) picolinamide;
N-methyl-4 - ((2- (3- (3- (4-methylpiperazin-1-yl) propyl) ureido) benzo [d] thiazol-6-yl) oxy) picolinamide;
4 - ((2- (3- (4-hydroxybutyl) ureido) benzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide;
4 - ((2- (3- (4- (dimethylamino) butyl) ureido) benzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide;
4 - ((2- (3- (4-chloro-3- (trifluoromethyl) phenyl) ureido) benzo [d] thiazol-6-yl) oxy) -N- methylpicolinamide;
4 - ((2- (3- (3,5-beads (trifluoromethyl) phenyl) ureido) benzo [d] thiazol-6-yl) oxy) -N- methylpicolinamide;
4 - ((2- (3- (2,4-Dichlorophenyl) ureido) benzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide;
4 - ((2- (3- (3,4-dichlorophenyl) ureido) benzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide;
4 - ((2- (3- (4-chlorophenyl) ureido) benzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide;
N-methyl-4 - ((2- (3- (4- (trifluoromethyl) phenyl) ureido) benzo [d] thiazol-6-yl) oxy) picolinamide;
4 - ((2- (3- (4-fluorophenyl) ureido) benzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide;
4 - ((2- (3- (4-bromophenyl) ureido) benzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide;
4 - ((2- (3- (2-Chloro-5- (trifluoromethyl) phenyl) ureido) benzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide;
4 - ((2- (3- (2,4-difluorophenyl) ureido) benzo [d] thiazol-6-yl) oxy) -N-methylpicolinamide;
N-methyl-4 - ((2- (3- (4 -morpholinophenyl) ureido) benzo [d] thiazol-6-yl) oxy) picolinamide;
N-methyl-4 - ((2- (3- (4- (4-methylpiperazin-1-yl) phenyl) ureido) benzo [d] thiazol-6-yl) oxy) picolinamide;
Phenyl) ureido) benzo [d] thiazol-6-yl) oxy) -N-methylpiperazin-1- Choline amide;
Dihydro-benzo [d] thiazol-6-yl) oxy) pyridin-2-yl) Choline amide; And
(4-ethylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) ureido) benzo [d] thiazol- ) Oxy) -N-methylpicolinamide. ≪ / RTI > A pharmaceutical composition for the prophylaxis or treatment of cancer, which comprises, as an active ingredient, a compound of the formula (1) according to claim 1 or a pharmaceutically acceptable salt thereof. The pharmaceutical composition for preventing or treating cancer according to claim 6, wherein the cancer is induced by protein kinase. The pharmaceutical composition according to claim 7, wherein the protein kinase is selected from one or more selected from ABL, ABLT315I, B-RAF, C-RAF, FLT1 / VEGFR1, KDR / BEGFR2, LCK and LYN. The method of claim 6, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, cervical cancer, prostate cancer, colon cancer, genitourinary cancer, esophageal cancer, laryngeal cancer, glioblastoma, stomach cancer, skin cancer, keratocytooma, lung cancer, Pancreatic cancer, adenocarcinoma, metastatic cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, normal carcinoma, melanoma, sarcoma, bladder cancer, liver cancer, bile duct cancer, kidney cancer, myeloid disease, lymphoma Colon cancer, colorectal cancer, rectal cancer, brain cancer, central nervous system cancer, leukemia, hemangioma, trachoma, and pyogenic granuloma. Lt; RTI ID = 0.0 > 1, < / RTI >
A pharmaceutical composition for preventing or treating cancer. The method according to claim 6,
The pharmaceutical composition according to claim 1, wherein the ureidobenzothiazole compound represented by the general formula (1), its pharmaceutically acceptable salt or hydrate thereof is contained in an amount of 0.5 to 10% by weight based on the total weight of the whole pharmaceutical composition.
A pharmaceutical composition for preventing or treating cancer. The method according to claim 1,
The pharmaceutically acceptable salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, Which is a salt of an inorganic or organic acid selected from the group consisting of ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid,
A ureidobenzothiazole compound, a pharmaceutically acceptable salt thereof, or a hydrate thereof. A process for preparing a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof, which comprises reacting a compound represented by the formula (2) and a compound represented by the formula (3)
[Chemical Formula 1]

(2)

(3)

In the above formulas (1) and (3)
X is O or S;
R1 is hydrogen; A C1-C6 alkyl group; A C3-C10 aryl group; A C3-C10 heteroaryl group; And a C3-C10 heterocyclyl group;
Said C1-C6 alkyl group is selected from the group consisting of hydrogen; A hydroxy group; A C1-C6 alkyl group; A C1-C5 alkoxy group; Amino group -NR2R3; Amido group -CONR2R3; A C3-10 heteroaryl group; C3-10 heterocyclyl group; And a halogen group;
The C3-C10 aryl group, the C3-C10 heteroaryl group or the C3-C10 heterocyclyl group is hydrogen; A hydroxy group; A C1-C3 alkyl group substituted or unsubstituted with halogen or a C3-C10 heterocyclyl group; A C1-C3 alkoxy group substituted or unsubstituted with halogen or a C3-C10 heterocyclyl group; A C3-C10 aryl group; A carbonyl group; A halogen group; Amino group -NR2R3; Amide group CONR2R3; A C3-10 heteroaryl group and a C3-C10 heterocyclyl group;
The C3-C10 heteroaryl group or the C3-C10 heterocyclyl group is substituted or unsubstituted with a C1-C3 alkyl group, an amino group -NR2R3;
And R 2 and R 3 include at least one group selected from the group consisting of hydrogen, C 1-6 alkyl group, C 1-6 alkenyl group, and C 1-6 alkenyl group. A process for preparing a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof, which comprises reacting a compound represented by the following formula (4) with a compound represented by the following formula (5)
[Chemical Formula 1]

[Chemical Formula 4]

[Chemical Formula 5]

In the above formulas (1) and (5)
X is O or S;
R1 is hydrogen; A C1-C6 alkyl group; A C3-C10 aryl group; A C3-C10 heteroaryl group; And a C3-C10 heterocyclyl group;
Said C1-C6 alkyl group is selected from the group consisting of hydrogen; A hydroxy group; A C1-C6 alkyl group; A C1-C5 alkoxy group; Amino group -NR2R3; Amido group -CONR2R3; A C3-10 heteroaryl group; C3-10 heterocyclyl group; And a halogen group;
The C3-C10 aryl group, the C3-C10 heteroaryl group or the C3-C10 heterocyclyl group is hydrogen; A hydroxy group; A C1-C3 alkyl group substituted or unsubstituted with halogen or a C3-C10 heterocyclyl group; A C1-C3 alkoxy group substituted or unsubstituted with halogen or a C3-C10 heterocyclyl group; A C3-C10 aryl group; A carbonyl group; A halogen group; Amino group -NR2R3; Amide group CONR2R3; A C3-10 heteroaryl group and a C3-C10 heterocyclyl group;
The C3-C10 heteroaryl group or the C3-C10 heterocyclyl group is substituted or unsubstituted with a C1-C3 alkyl group, an amino group -NR2R3;
And R 2 and R 3 include at least one group selected from the group consisting of hydrogen, C 1-6 alkyl group, C 1-6 alkenyl group, and C 1-6 alkenyl group.