KR20180032784A - Novel imidazolyl pyrimidine derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating cancer containing the same as an active ingredient - Google Patents

Abstract

The present invention relates to a novel imidazolium pyrimidine derivative, a preparation method thereof, and a pharmaceutical composition for preventing or treating cancer containing the same as an active ingredient. The imidazolium pyrimidine derivatives, optical isomers thereof or pharmaceutically acceptable salts thereof according to the present invention are useful not only for an activity of a Wee1 kinase, but also has an excellent effect in inhibiting cell proliferation of liver cancer cell line such that the present invention can be usefully used as a pharmaceutical composition for preventing or treating Wee1 kinase related diseases such as liver cancer preferably, and solid cancer such as liver cancer, lung cancer, colorectal cancer, stomach cancer, breast cancer, colon cancer, bone cancer, pancreatic cancer, head or neck cancer, uterine cancer, ovarian cancer, rectal cancer, esophageal cancer, small bowel cancer, cancer nearby an anus, fallopian tube cancer, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, prostate cancer, bladder cancer, renal cancer, ureter cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system tumor cancer, and the like.

Description

TECHNICAL FIELD The present invention relates to a novel imidazolyl pyrimidine derivative, a process for preparing the same, and a pharmaceutical composition for preventing or treating cancer containing the same as an active ingredient. same as an active ingredient}

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

Human hepatocellular carcinoma (HCC) is a disease caused by long term liver inflammation.

Although surgical and percutaneous radiofrequency ablation surgery improves the survival rate of patients, it has been shown that a new treatment for advanced hepatocellular carcinoma (HCC) Treatment alternatives are needed. Therefore, chemotherapy and induction of apoptosis by low molecular weight substance transport are emerging alternatives.

Transforming growth factor-b1 (TGF-β1) strongly inhibits human hepatocellular carcinoma (HCC) cell growth. Particularly, it promotes cell growth in non-epithelial cells such as fibroblasts and stellate cells, while it promotes cell growth by cell apoptosis or cell cycle arrest, Inhibits cell growth in both human hepatocellular carcinoma (HCC) cells.

Induction of TGF-β1-induced apoptosis in human hepatocellular carcinoma (HCC) cells is mediated by dephosphorylation of cdc2 Tyr15 (active form of cdc2), ie, decreased cdc2 phosphorylation. The cdc2 activity is induced by Wee1 kinase downregulation, and cdc2 activity by reduction of Tyr15 phosphorylation is very important for TGF- [beta] -induced cell death in human hepatocellular carcinoma (HCC) cells. A decrease in Wee1 kinase expression was observed after TGF-beta treatment, and cdc2 phosphorylation was modulated by Wee1 kinase. From this, it can be said that TGF-β1 mediated cell death is induced in the Wee1 / cdc2 axis.

In surgically resected specimens, Wee1 kinase is overexpressed in human hepatocellular carcinoma (HCC), but no kinase expression is observed in non-cancerous tissues including cirrhotic tissue. Overexpression of Wee1 kinase has been reported in other tumor types including brain tumors and leukemia (Non-Patent Document 1). In brain tumors, expression of Wee1 kinase is upregulated only in tumor cells, and elevated kinase plays an important role in cancer cell survival.

Wee1 kinase is a negative regulator of cdc2. Since TGF-β1 is a multifunctional cytokine, it can not be a practical treatment alternative. Wee1 kinase inhibits premature mitotic entry and subsequent apoptosis by negatively regulating the G2 / M stage by inhibiting the early stages of mitosis before DNA damage is restored It is being considered. Certain inhibitors or siRNAs can be used to inhibit Wee1 kinase and induce apoptosis in human hepatocellular carcinoma (HCC) cells. Thus, Wee1 kinase inhibitors may be a novel therapeutic strategy and alternative in Wee1 kinase-overexpressing carcinomas such as human hepatocellular carcinoma (HCC), and this type of inhibitor is a realistic therapeutic alternative to advanced solid tumors .

Accordingly, the inventors of the present invention have been studying compounds which inhibit Wee1 kinase, and the imidazolium pyrimidine derivatives, its optical isomers or pharmaceutically acceptable salts thereof according to the present invention are remarkably excellent in inhibiting the activity of Wee1 kinase, And can be useful as a preventive or therapeutic agent for Wee1 kinase-related diseases, for example, liver cancer. The present invention has been completed based on this finding.

Harris PS et al., (2014) Integrated genomic analysis identifies the mitotic checkpoint kinase WEE1 as a novel therapeutic target in medulloblastoma. Mol Cancer 13: 72

It is an object of the present invention to provide an imidazolium pyrimidine derivative, an optical isomer thereof or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a process for preparing the imidazolium pyrimidine derivative.

It is still another object of the present invention to provide a pharmaceutical composition for preventing or treating Wee1 kinase-related diseases, which comprises the imidazolium pyrimidine derivative, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

Another object of the present invention is to provide a health functional food composition for preventing or ameliorating Wee1 kinase-related diseases, which comprises the imidazolium pyrimidine derivative, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

In order to achieve the above object,

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

[Chemical Formula 1]

(In the formula 1,

X is hydrogen, halogen, unsubstituted or substituted C _1-3 straight chain or branched C ₃ alkyl,

The substituted straight chain or branched chain alkyl may be substituted with halogen;

R ¹ and R ² are each independently an unsubstituted or substituted C _1-5 straight chain or C _3-5 branched chain alkoxy,

The substituted straight chain or branched alkoxy may be substituted with dimethylamino; And

R ³ is -NR ⁴ R ⁵ , unsubstituted or substituted C _6-10 cycloalkyl, or an unsubstituted or substituted 5 to 10 membered heteroaromatic ring containing one or more heteroatoms selected from the group consisting of N, O, and S Lt; RTI ID = 0.0 >

Wherein R ⁴ and R ⁵ are each independently an unsubstituted or substituted C _1-5 straight chain or C _3-5 branched chain alkyl and the substituted straight chain or branched chain alkyl may be substituted with dimethylamino However,

Said substituted cycloalkyl or substituted heterocycloalkyl is selected from the group consisting of C _1-10 straight chain or C _3-10 branched chain alkyl, halogen, amino, C _1-3 alkylcarbonyl or N, O, S Which may be unsubstituted or substituted with 5 to 10 atoms of unsubstituted or substituted heterocycloalkyl containing one or more heteroatoms selected,

Wherein said substituted heterocycloalkyl may be substituted with a C _1-5 straight chain or C _3-5 branched chain alkyl.

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

A step of preparing a compound represented by the formula (3) from the compound represented by the formula (2) (step 1); And

Reacting the compound represented by the formula (3) and the compound represented by the formula (4) to prepare the compound represented by the formula (1) (step 2), and reacting the compound represented by the formula A method of manufacturing is provided:

[Reaction Scheme 1]

(In the above Reaction Scheme 1,

X, R ¹ , R ² and R ³ are as defined in the compound represented by the formula (1)).

Further, the present invention provides a pharmaceutical composition for preventing or treating a Wee1 kinase-related disease, which comprises the compound represented by the above-mentioned formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention also provides a health functional food composition for preventing or ameliorating a Wee1 kinase-related disease, which comprises the compound represented by the formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

The imidazolium pyrimidine derivative, its optical isomer or pharmaceutically acceptable salt thereof according to the present invention is excellent in the activity of inhibiting the cell proliferation of the liver cancer cell line as well as the activity of the Wee1 kinase, The present invention relates to a method for the treatment and prophylaxis of cancer such as liver cancer, lung cancer, colon cancer, gastric cancer, breast cancer, colon cancer, pancreatic cancer, head or neck cancer, uterine cancer, ovarian cancer, rectal cancer, esophageal cancer, small intestine cancer, fallopian tube carcinoma, endometrial carcinoma, Can be usefully used as a pharmaceutical composition for the prevention or treatment of solid tumors, preferably hepatocellular carcinoma such as vaginal cancer, vulvar carcinoma, prostate cancer, bladder cancer, kidney cancer, ureter cancer, kidney cell carcinoma, renal pelvic carcinoma, .

Hereinafter, the present invention will be described in detail.

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

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

[Chemical Formula 1]

(In the formula 1,

X is hydrogen, halogen, unsubstituted or substituted C _1-3 straight chain or branched C ₃ alkyl,

The substituted straight chain or branched chain alkyl may be substituted with halogen;

R ¹ and R ² are each independently an unsubstituted or substituted C _1-5 straight chain or C _3-5 branched chain alkoxy,

The substituted straight chain or branched alkoxy may be substituted with dimethylamino; And

R ³ is -NR ⁴ R ⁵ , unsubstituted or substituted C _6-10 cycloalkyl, or an unsubstituted or substituted 5 to 10 membered heteroaromatic ring containing one or more heteroatoms selected from the group consisting of N, O, and S Lt; RTI ID = 0.0 >

Wherein R ⁴ and R ⁵ are each independently an unsubstituted or substituted C _1-5 straight chain or C _3-5 branched chain alkyl and the substituted straight chain or branched chain alkyl may be substituted with dimethylamino However,

Said substituted cycloalkyl or substituted heterocycloalkyl is selected from the group consisting of C _1-10 straight chain or C _3-10 branched chain alkyl, halogen, amino, C _1-3 alkylcarbonyl or N, O, S Which may be unsubstituted or substituted with 5 to 10 atoms of unsubstituted or substituted heterocycloalkyl containing one or more heteroatoms selected,

Wherein said substituted heterocycloalkyl may be substituted with a C _1-5 straight chain or C _3-5 branched chain alkyl.

Preferably,

Wherein X is iodo (I)

Preferably,

,

,

,

,

,

또는

이고,R ³ is

,

,

,

,

,

or

ego,

Most preferably,

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

(1) 4- (1H-imidazol-1-yl)) - 5-iodo-N- (4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-2-amine;

(2) 4- (1H-Imidazol-1-yl) -5-iodo-N- (4-morpholinophenyl) pyrimidin-2-amine;

(3) Synthesis of 4- (1H-imidazol-1-yl) -5-iodo-N- (3-methoxy- ;

(4) N- (4- (4- (Dimethylamino) piperidin-1-yl) phenyl) -4- (1H-imidazol-1-yl) -5-iodopyrimidin-2-amine;

(5) 4- (lH-imidazol-l-yl) -5-iodo-N- (4- Pyrimidin-2-amine;

(6) 4- (1H-imidazol-1-yl) -5-iodo-N- (3-methoxy- Yl) phenyl) pyrimidin-2-amine;

(7) 4- (1H-Imidazol-1-yl) -5-iodo-N- (4- (4 -morpholinopiperidin-1-yl) phenyl) pyrimidin-2-amine;

(8) Synthesis of N1- (4- (1H-imidazol-1-yl) -5-iodopyridin-2-yl) -N4- (2- (dimethylamino) ethyl) - diamines;

(9) Synthesis of 1- (4- (4 - ((4- (1H-imidazol-1-yl) -5-iodopyrimidin- 1-one;

(10) N- (3- (2- (Dimethylamino) ethoxy) phenyl) -4- (1H-imidazol-1-yl) -5-iodopyrimidin-2-amine;

(11) 4- (1H-imidazol-1-yl) -5-iodo-N- (2-methoxy- Amine;

(12) 4- (1H-Imidazol-1-yl) -5-iodo-N- (2-methoxy-4-morpholino) phenyl) pyrimidin-2-amine;

(13) 4- (lH-imidazol-l-yl) -5-iodo-N- (2-methoxy- Yl) phenyl) pyrimidin-2-amine;

(14) Synthesis of N- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -4- (lH-imidazol- Amine;

(15) 4- (1H-Imidazol-1-yl)) - N- (4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-2-amine;

(16) 4- (1H-Imidazol-1-yl)) - 5-methyl-N- (4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-2-amine;

(17) 4- (1H-Imidazol-1-yl)) - 5-fluoro-N- (4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-2-amine;

(18) 4- (1H-Imidazol-1-yl)) - 5-chloro-N- (4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-2-amine;

(19) 4- (1H-imidazol-1-yl)) - 5-bromo-N- (4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-2-amine;

(20) 4- (1 H-imidazol-1-yl) - N- (4- (4-methylpiperazin- 1 -yl) phenyl) -5- (trifluoromethyl) pyrimidin- ; And

(21) 4- (1H-Imidazol-1-yl) -5-methyl-N- (4- (4 -morpholinopiperidin-1-yl) phenyl) pyrimidin-2-amine.

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

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

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

Furthermore, the present invention includes all the solvates, stereoisomers, hydrates, and the like, which can be prepared therefrom, as well as the compound represented by Formula 1 and pharmaceutically acceptable salts thereof.

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

A step of preparing a compound represented by the formula (3) from the compound represented by the formula (2) (step 1); And

Reacting the compound represented by the formula (3) and the compound represented by the formula (4) to prepare the compound represented by the formula (1) (step 2), and reacting the compound represented by the formula A method of manufacturing is provided:

[Reaction Scheme 1]

(In the above Reaction Scheme 1,

X, R ¹ , R ² and R ³ are as defined in the compound represented by the formula (1)).

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

In the process for preparing the compound represented by the general formula (1) according to the present invention, the step 1 of Scheme 1 is a step for preparing the compound represented by the general formula (3) from the compound represented by the general formula (2).

In this case, the step 1 may be understood as a reaction for introducing an imidazole substituent, and there is no particular limitation therefor, but the reaction temperature may preferably be 40 - 90 ° C, and the reaction time may be 5 - 20 hours .

Further, as a solvent usable in the step 1, tetrahydrofuran (THF); Dioxane; Ether solvents including ethyl ether, 1,2-dimethoxyethane and the like; Lower alcohols including methanol, ethanol, propanol and butanol; But are not limited to, dimethylformamide (DMF), dimethylsulfoxide (DMSO), dichloromethane (DCM), dichloroethane, water, acetonazenesulfonate, toluene sulfonate, chlorobenzene sulfonate, xylenesulfonate, phenylacetate, Naphthalene-2-sulphonate, mandelate, and naphthalene-2-sulphonate, and salts and esters thereof, such as phenylbutyrate, chitrate, lactate, A mixture thereof, and it is preferable to use dimethylformamide (DMF).

In the process for preparing a compound represented by the general formula (1) according to the present invention, step 2 of the above reaction scheme 1 is a step for preparing a compound represented by the general formula (1) by reacting a compound represented by the general formula (4) with a compound represented by the general formula .

In this case, the step 2 can be understood as a reaction for introducing an aniline derivative, and there is no particular limitation therefor. However, the addition of the imidazolium pyrimidine derivative, the aniline derivative and K ₂ CO ₃ and the addition of Pd ₂ (dab ₃ ) and The compound of the present invention can be prepared by reacting with Xphos. The reaction temperature may be preferably 60-100 ° C, and the reaction time may be 5-20 hours.

The solvent used in step 2 may be H ₂ O, ethanol, sec-BuOH, tetrahydrofuran (THF), dichloromethane, toluene, acetonitrile, dimethylformamide, -BuOH is preferably used.

The present invention also provides a pharmaceutical composition for preventing or treating a Wee1 kinase-related disease, which comprises the compound represented by the formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

The Wee1 kinase-related disease is solid cancer, and the solid cancer is liver cancer, lung cancer, colon cancer, stomach cancer, breast cancer, colon cancer, bone cancer, pancreatic cancer, head or neck cancer, uterine cancer, ovarian cancer, rectum cancer, , Pancreatic cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, prostate cancer, bladder cancer, renal cancer, ureter cancer, renal cell carcinoma, renal pelvic carcinoma and central nervous system tumor.

Furthermore, the present invention provides a health functional food composition for preventing or ameliorating diseases caused by activity of Wee1 kinase containing the compound represented by the formula (1), its optical isomer or its pharmaceutically acceptable salt as an active ingredient do.

In general, Wee1 kinase negatively regulates the G2 / M stage by inhibiting the early stages of mitosis before DNA damage is restored, leading to premature mitotic entry and subsequent apoptosis .

Thus, in order to evaluate the inhibitory activity against the Wee1 kinase of the compound represented by the formula 1 according to the present invention, the compound 1-21 according to the present invention showed an excellent inhibitory activity against the Wee1 kinase , And particularly effectively inhibited the activity of Wee1 kinase at very low concentrations of 1 μM or less (see Table 2 in Experimental Example 1).

As a result, the compound 1-21 according to the present invention inhibited cell proliferation of hepatocellular carcinoma cells Hep3B and Huh7 cells, Inhibited cell proliferation at low concentrations, and effectively inhibited cell proliferation at very low concentrations of < RTI ID = 0.0 > M < / RTI > units (see Table 3 in Experimental Example 2).

Therefore, the imidazolium pyrimidine derivative, its optical isomer or pharmaceutically acceptable salt thereof according to the present invention has an excellent effect of inhibiting cell proliferation of a cancer cell line, preferably a liver cancer cell line, as well as the activity of a Wee1 kinase, Can be usefully used as a pharmaceutical composition for the prevention or treatment of kinase-related diseases, for example, the above-described solid cancer, preferably liver cancer.

Meanwhile, the compound represented by the formula (1) according to the present invention can be administered in various formulations of oral and parenteral administration at the time of clinical administration, and when it is formulated, it is possible to use a compound such as fillers, extenders, binders, wetting agents, , ≪ / RTI > and the like.

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

Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, and the like.

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

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

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

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

In the following example compounds,

Each analysis condition is as follows.

HPLC analysis conditions

Device name: Shimadzu

Column: YMC-pack pro C18, 150 x 4.6 mm I.D., 5 μm, 40 ° C

Mobile phase: 5% -> 100% acetonitrile / H ₂ O + 0.1% TFA,

Analysis time: 9 minutes, flow rate: 1 ml / min

UV detector: 254nm

SFC purification conditions

Device name: Waters

Column: Viridis®Prep Silica 2-EP OBD ^™ 5 μm, 19 × 150 mm

Mobile phase: 10 -> 15% Methanol

Analysis time: 10 minutes, flow rate: 80 ml / min

UV detector: 254nm

LC-MS analysis conditions

Device name: Shimadzu LCMS-2020

Column: ACE Excel2 C18, 75 x 2.1 mm

Mobile phase: acetonitrile / H ₂ O + 0.1% TFA

Flow rate: 1 ml / min

UV detector: 254nm

¹ H NMR

Device name: Brucler Avance (400 MHz)

Hereinafter, the method for preparing the compound of the present invention will be described in detail.

< Example  1> 4- (1H-imidazol-1-yl)) - 5- Iodo -N- (4- (4- Methylpiperazine -1-yl) phenyl) pyrimidin-2-amine

step 1: 2 - Chloro -4- (1H-imidazol-1-yl) -5- Iodopyrimidine  Produce

After adding 2,4-dichloro-5-iodopyrimidine (1 eq.) To DMF (0.3 M) and dissolving, imidazole (2 eq.) Was added at room temperature and reacted at 65 ° C for 14 hours. After the reaction mixture was cooled to room temperature, water was poured to induce precipitation, which was filtered to give the target compound as a white solid (yield: 60%).

step 2: 4 - (1H-imidazol-1-yl)) - 5- Iodo -N- (4- (4- Methylpiperazine -1-yl) phenyl) pyrimidin-2-amine

Cheokga to a compound (1.2 equivalents), 4- (4-methylpiperazin-1-yl) aniline (1.0 eq.) And K ₂ CO ₃ a sec-BuOH (5.0 eq) (0.1 M) prepared in Step 1, After dissolving, the gas was removed by sonication for 1 minute. To the reaction mixture were added Pd ₂ (dab ₃ ) (0.1 eq) and Xphos (0.1 eq) at 80 ° C and reacted for 14 hours. After the reaction, the reaction mixture was filtered through celite, washed with EtOAc and MeOH. The obtained filtrate was concentrated, and then purified by SFC to obtain the target compound as a yellow solid (yield: 9%).

HPLC t _R min: 4.23; ^{1 H NMR (400 MHz, Methanol} -d4) δ 8.78 (s, 3H), 8.41 (s, 3H), 7.81 (s, 1H), 7.51 (d, J = 9.1 Hz, 2H), 7.15 (s, 1H ), 6.98 (d, J = 9.1 Hz, 2H), 3.19-3.16 (m, 4H), 2.64-2.62 (m, 4H), 2.36 (s, 3H); 462 [M + H].

< Example  2> 4- (1H-Imidazol-1-yl) -5- Iodo -N- (4- Morpholinophenyl ) Pyrimidin-2-amine

The procedure of Example 1 was repeated except for using 4-morpholinoaniline instead of 4- (4-methylpiperazin-1-yl) aniline used in Step 2 of Example 1 to obtain the desired compound .

HPLC t _R min: 4.20; ^{1 H NMR (400 MHz, CDCl3} ) δ 8.72 (s, 1H), 8.39 (s, 1H), 7.75 (s, 1H), 7.44 (d, J = 6.8 Hz, 2H), 7.14 (s, 1H), 7.12 (s, 1H), 6.94 (d, J = 6.8 Hz, 2H), 3.89 (m, 4H), 3.15 (m, 4H); 448 [M + H].

< Example  3> 4- (1H-Imidazol-1-yl) -5- Iodo -N- (3- Methoxy -4- (4- Methylpiperazine -1-yl) phenyl) pyrimidin-2-amine

Except that 4- (3-methoxy-4-methylpiperazin-1-yl) aniline was used instead of 4- (4-methylpiperazin-1-yl) aniline used in step 2 of Example 1 And the procedure of Example 1 was repeated to produce the target compound.

HPLC t _R min: 4.03; ^{1 H NMR (400 MHz, DMSO} -d 6) δ 8.72 (s, 1H), 8.39 (s, 1H), 7.75 (s, 1H), 7.44 (d, J = 6.8 Hz, 2H), 7.14 (s, 1H), 7.12 (s, 1H), 6.94 (d, J = 6.8 Hz, 2H), 3.89 (m, 4H), 3.15 (m, 4H); 492 [M + H].

< Example  4 Preparation of N- (4- (4- (dimethylamino) piperidin-1-yl) phenyl) -4- (lH- imidazol- l-yl) -5-iodopyrimidin-

(4-aminophenyl) -N, N-dimethipiperidin-4-amine instead of 4- (4-methylpiperazin-1-yl) aniline used in step 2 of Example 1 The procedure of Example 1 was repeated to produce the target compound.

HPLC t _R min: 3.94; ^{1 H NMR (400 MHz, MeOH} -d 4) δ 8.67 (s, 1H), 8.30 (s, 1H), 7.71 (s, 1H), 7.40 (d, J = 9.0 Hz, 2H), 7.05 (s, 1H), 6.89 (d, J = 9.0 Hz, 2H), 3.61 (m, 2H), 2.61 (t, J = 10.4 Hz, 2H) m, 2H); 489 [M + H].

< Example  5> 4- (1H-Imidazol-1-yl) -5- Iodo -N- (4- (4- (4- &lt; / RTI &gt; Methylpiperazine Yl) piperidin-1-yl) phenyl) pyrimidin-2-amine

(4- (4-methylpiperazin-1-yl) piperidin-1-yl) aniline was used in the place of 4- (4-methylpiperazin- ) &Lt; / RTI &gt; aniline, the target compound was prepared.

HPLC t _R min: 3.87; ^{1 H NMR (400 MHz, Methanol} -d 4) δ 8.78 (s, 1H), 8.40 (s, 1H), 7.82 (s, 1H), 7.50 (d, J = 9.0 Hz, 2H), 7.15 (s, 1H), 6.99 (d, J = 9.0 Hz, 2H), 3.73-3.70 (m, 2H), 3.38-3.33 (m, 2H), 2.72-2.80 -2.01 (m, 2H), 1.73-1.68 (m, 2H); 545 [M + H].

< Example  6> 4- (1H-Imidazol-1-yl) -5- Iodo -N- (3- Methoxy -4- (4- (4- Methylpiper 1-yl) piperidin-1-yl) phenyl) pyrimidin-2-amine

(4-methylpiperazin-1-yl) piperidine was used in the place of 4- (4-methylpiperazin-1-yl) Pyridin-1-yl) aniline was used in place of the compound obtained in Example 1, the target compound was prepared.

HPLC t _R min: 3.56; ¹ H NMR (400 MHz, MeOH-d ₄ )? 8.71 (s, IH), 8.32 (s, IH), 7.81 2H), 3.75 (s, 3H), 3.32 (m, 2H), 2.50 (m, 7H) 2.47 (t, J = 11.2 Hz, 4H), 1.91 (m, 2H), 1.64 (m, 2H); 575 [M + H].

< Example  7> 4- (1H-Imidazol-1-yl) -5- Iodo -N- (4- (4- Morpholinopiperidine -1-yl) phenyl) pyrimidin-2-amine

Except that 4- (4-morpholinopiperidin-1-yl) aniline was used in place of 4- (4-methylpiperazin-1-yl) aniline used in step 2 of Example 1, The procedure of Example 1 was repeated to produce the desired compound.

HPLC t _R min: 4.10; ^{1 H NMR (400 MHz, MeOH} -d 4) δ 9.49 (s, 1H), 8.91 (s, 1H), 8.14 (s, 1H), 7.75 (s, 1H), 7.57 (d, J = 9.0 Hz, 2H), 7.08 (d, J = 9.0 Hz, 2H), 4.14 (m, 2H), 3.87 (m, Hz, &lt; / RTI &gt; 2H), 2.05 (m, 2H), 1.91 (m, 2H); 531 [M + H].

< Example  8> N1- (4- (1H-Imidazol-1-yl) -5- Iodopyridine -2-yl) -N4- (2- (dimethylamino) ethyl) -N4-methylbenzene-1,4-diamine

Except that 4- (4-morpholinopiperidin-1-yl) aniline was used in place of 4- (4-methylpiperazin-1-yl) aniline used in step 2 of Example 1, The procedure of Example 1 was repeated to produce the desired compound.

HPLC t _R min: 3.98; ^{1 H NMR (400 MHz, Methanol} -d 4) δ 8.76 (s, 1H), 8.41 (s, 1H), 7.82 (s, 1H), 7.45 (d, J = 9.1 Hz, 2H), 7.17 (s, 1H), 6.78 (d, J = 9.1 Hz, 2H), 3.52-3.49 (m, 2H), 3.16-3. 464 [M + H].

< Example  9> 1- (4- (4 - ((4- (1H-Imidazol-1-yl) -5- Iodopyrimidine Yl) amino) phenyl) piperazin-1-yl) ethan-1-one

(4- (4-aminophenyl) piperazin-1-yl) ethanone was used in place of 4- (4-methylpiperazin-1-yl) , The target compound was prepared in the same manner as in Example 1,

HPLC t _R min: 4.18; ^{1 H NMR (400 MHz, Methanol} -d 4) δ 8.76 (s, 1H), 8.38 (s, 1H), 7.79 (s, 1H), 7.50 (d, J = 9.0 Hz, 2H), 7.13 (s, 1H), 6.97 (d, J = 10.8 Hz, 2H), 3.72-3.66 (m, 4H), 36.15-3.07 (m, 4H), 2.13 (s, 3H); 490 [M + H].

< Example  10> N- (3- (2- (dimethylamino) Ethoxy ) Phenyl) -4- (1H-imidazol-1-yl) -5-iodopyrimidin-

The procedure of Example 1 was repeated except that 3- (3- (dimethylamino) propoxy) aniline was used in place of 4- (4-methylpiperazin-1-yl) aniline used in Step 2 of Example 1, The target compound was prepared.

HPLC t _R min: 4.75; ^{1 H NMR (400 MHz, MeOH} -d4) δ 8.63 (s, 1H), 8.33 (brs, 1H), 7.66 (brs, 1H), 7.07 (s, 1H), 6.91 (d, J = 8.2 Hz, 1H ), 6.15 (d, J = 8.2 Hz, 2H), 6.06 (br s, 1H), 4.09 (t, J = 5.2 Hz, 2H), 3.91 (m, 2H), 2.62 451 [M + H] &lt;

< Example  11> 4- (1H-Imidazol-1-yl) - 5 Iodo -N- (2- Methoxy -4- (4- Molopolypope 1-yl) phenyl) pyrimidin-2-amine

(4-morpholinopiperidin-1-yl) aniline was used in place of 4- (4-methylpiperazin-1-yl) aniline used in step 2 of Example 1 The procedure of Example 1 was repeated to produce the target compound.

HPLC t _R min: 4.04; ^{1 H NMR (400 MHz, Methanol} -d 4) δ 8.75 (s, 1H), 8.38 (s, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.79 (s, 1H), 7.14 (s, 1H), 6.87 (d, J = 2.5 Hz, 1H), 6.58 br, 4H), 2.81-2.71 (m, 2H), 2.14-2.11 (m, 2H), 1.77-1.68 (m, 2H); 562 [M + H].

< Example  12> 4- (1H-Imidazol-1-yl) -5- Iodo -N- (2- Methoxy -4- Molpolino ) Phenyl) pyrimidin-2-amine

The procedure of Example 1 was repeated except that 2-methoxy-4-morpholinoaniline was used in place of 4- (4-methylpiperazin-1-yl) aniline used in Step 2 of Example 1 To give the desired compound.

HPLC t _R min: 4.49; ^{1 H NMR (400 MHz, Methanol} -d 4) δ 8.76 (s, 1H), 8.43 (s, 1H), 7.81 (d, J = 8.7 Hz), 7.17 (s, 1H), 6.66 (s, 1H) , 6.55 (d, J = 11.2 Hz, 1H), 3.87 (s, 3H), 3.84-3.82 (m, 4H), 63.14-3.10 (m, 4H); 479 [M + H].

< Example  13> 4- (1H-Imidazol-1-yl) -5- Iodo -N- (2- Methoxy  -4- (4- (4- Methylpiperazine Yl) piperidin-1-yl) phenyl) pyrimidin-2-amine

(4-methylpiperazin-1-yl) piperidine was used in place of 4- (4-methylpiperazin-1-yl) aniline used in step 2 of Example 1, Pyridin-1-yl) aniline was used in place of the compound obtained in Example 1, the target compound was prepared.

HPLC t _R min: 3.77; 575 [M + H].

< Example  14> N- (4- (4- (Dimethylamino) piperidin-1-yl) -2- Methoxyphenyl ) -4- (1H-imidazol-1-yl) -5-iodopyrimidin-2-amine

(4-amino-2-methoxyphenyl) -N, N-dimethylpiperidine-1-carboxylic acid was used in the place of 4- (4-methylpiperazin- 4-amine was used in place of 4-amino-4-methylpyridine, the target compound was prepared.

HPLC t _R min: 3.65; ^{1 H NMR (400 MHz, Methanol} -d4) δ 8.79 (s, 1H), 8.41 (s, 1H), 7.81 (s, 1H), 7.42 (s, 1H), 7.15 (s, 1H), 7.11 (d (D, J = 8.6 Hz, 1H), 6.92 (d, J = 8.6 Hz, 1H), 3.85 s, 6H), 1.99-1.96 (m, 2H), 1.79-1.69 (m, 2H); 520 [M + H].

< Example  15> 4- (1H-Imidazol-1-yl)) - N- (4- (4- Methylpiperazine -1-yl) phenyl) pyrimidin-2-amine

The procedure of Example 1 was repeated except that 2,4-dichloropyrimidine was used instead of 2,4-dichloro-5-iodopyrimidine used in Step 1 of Example 1 to obtain the title compound .

< Example  16> 4- (1H-imidazol-1-yl)) - 5- methyl -N- (4- (4- Methylpiperazine -1-yl) phenyl) pyrimidin-2-amine

The procedure of Example 1 was repeated, except that 2,4-dichloro-5-methylpyrimidine was used instead of 2,4-dichloro-5-iodopyrimidine used in Step 1 of Example 1 To give the desired compound.

< Example  17> 4- (1H-imidazol-1-yl)) - 5- Fluoro -N- (4- (4- Methylpiperazine -1-yl) phenyl) pyrimidin-2-amine

The procedure of Example 1 was repeated, except that 2,4-dichloro-5-fluoropyrimidine was used instead of 2,4-dichloro-5-iodopyrimidine used in Step 1 of Example 1 To give the desired compound.

< Example  18> 4- (1H-Imidazol-1-yl)) - 5- Chloro -N- (4- (4- Methylpiperazine -1-yl) phenyl) pyrimidin-2-amine

The procedure of Example 1 was repeated, except that 2,4,5-trichloropyrimidine was used instead of 2,4-dichloro-5-iodopyrimidine used in Step 1 of Example 1 The target compound was prepared.

< Example  19> 4- (1H-Imidazol-1-yl)) - 5- Bromo -N- (4- (4- Methylpiperazine -1-yl) phenyl) pyrimidin-2-amine

The procedure of Example 1 was repeated, except that 2,4-dichloro-5-bromopyrimidine was used instead of 2,4-dichloro-5-iodopyrimidine used in Step 1 of Example 1 To give the desired compound.

< Example  20> 4- (1H-Imidazol-1-yl)) - N- (4- (4- Methylpiperazine Yl) phenyl) -5- ( Trifluoromethyl ) Pyrimidin-2-amine

Example 1 was repeated except that 2,4-dichloro-5-trifluoromethylpyrimidine was used in place of 2,4-dichloro-5-iodopyrimidine used in Step 1 of Example 1 above. The target compound was prepared.

< Example  21> 4- (1H-Imidazol-1-yl) -5- methyl -N- (4- (4- Morpholinopiperidine -1-yl) phenyl) pyrimidin-2-amine

The procedure of Example 7 was repeated except that 2,4-dichloro-5-methylpyrimidine was used instead of 2,4-dichloro-5-iodopyrimidine used in Step 1 of Example 7 To give the desired compound.

The chemical structures of the compounds prepared in Examples 1-21 are shown in Table 1 below.

Example Compound structure One

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

< Experimental Example  1> Wee1  Evaluation of kinase inhibitory activity

In order to evaluate the inhibitory activity of the compound represented by formula (1) according to the present invention on Wee1 kinase, the following experiment was conducted.

(Invitrogen, Carlsbad, CA), 3.4 umol / l polyG: T (4: 1) (Signal Chem, Richmond, BC, Canada), 20 umol / L ATP ) Were added to and mixed with kinase reaction buffer (40 mmol / L TrisHCl, 10 mmol / L MgCl2 and 0.1 μg / μL BSA (bovine serum albumin)). Each of the compounds of Examples 1-21 according to the present invention was added at a concentration of 1 μM or less, 1 μM or more to 10 μM or less, 10 μM or more to 100 μM or less, and 100 μM or more, followed by reaction at 30 ° C. in an incubator for 1 hour. After the reaction was completed, the same amount of a Kinase-Glo (Promega, Madison, WI) solution was added and reacted for 1 hour. Further, a detection solution was added and further reacted at room temperature for 10 minutes, IC ₅₀ values of kinase were calculated by measuring the amount of luciferase using a microplate ELISA reader (Bio-Tek). The results are shown in Table 2 below.

Example Wee 1 (IC ₅₀ , uM) One 0.068 2 0.343 3 0.213 4 0.426 5 0.256 6 0.0078 7 0.345 8 0.289 9 0.458 10 37.45 11 17.19 12 > 50 13 4.51 14 0.035 15 1.32 16 0.656 17 0.515 18 1.32 19 0.346 20 0.339 21 1.207

As can be seen in Table 2, Example Compound 1-21 according to the present invention was found to be able to exert an excellent inhibition of Wee1 kinase at an nM unit concentration of 1 μM or less.

In particular, in the comparison of the compounds of Example 1 and Examples 15-20, the compound of Example 1 had an iodo (I) substituent at the position of pyrimidine 5 and the compounds of Examples 15-20 had the substitution , Hydrogen, methyl, fluoro, chloro, bromo, or trifluoromethyl as substituents. From the structural differences of the above compounds, it can be seen that the Wee1 kinase inhibitory activity is significantly different. That is, when the compound of Example 1 of the present invention has an iodo (I) substituent at the 5-position of pyrimidine, it has Wee1 kinase inhibitory activity up to about 20 times higher than that of the compound of Example 15-20 described above.

In addition, when the compound of Example 7 and the compound of Example 21 were compared, the compound of Example 7 according to the present invention had an iodo (I) substituent at the position of pyrimidine 5, Lt; RTI ID = 0.0 &gt; Wee1 &lt; / RTI &gt; kinase inhibitory activity.

Therefore, the imidazolium pyrimidine derivative, its optical isomer or pharmaceutically acceptable salt thereof according to the present invention exhibits an excellent inhibitory activity of Wee1 kinase, so that the disease associated with Wee1 kinase, for example, for prevention or treatment of liver cancer May be useful as pharmaceutical compositions.

< Experimental Example  2> Evaluation of cell proliferation inhibitory activity of liver cancer cell line

The following experiment was conducted to evaluate the inhibitory activity of the compound represented by the formula (1) according to the present invention on the cell growth of liver cancer cells.

Hep3B cells (manufacturer: ATCC) and Huh7 cells (manufacturer: Rinken cell bank) were put into a 96-well plate at a concentration of 3000 cells / well and cultured for 24 hours to attach the cells to the culture container. To the medium, the compounds 1-14 were dissolved at a concentration of 1 μM or less, 1 μM or more and 10 μM or less, 10 μM or more and 100 μM or more and 100 μM or more, respectively, and the wells were incubated for 72 hours. Thereafter, a solution of MTS (3, - (4,5-dimethylthiazol-2-yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfophenyl) -2H-tetrazolium salt, Promega) Was added to each well. After 1 hour, a GI ₅₀ was calculated by measuring the absorbance at a wavelength of 490 nm using a microplate ELISA reader (Bio-Tek). The results are shown in Table 3 below.

Example Hep3B (GI ₅₀ ) Huh7 (GI ₅₀ ) One A C 2 C C 3 B C 4 C C 5 C C 6 C B 7 C C 8 - - 9 C C 10 C C 11 C C 12 C C 13 C C 14 C -

In Table 3,

A is 1 [mu] M or less,

B is greater than 1 [mu] M to 10 [mu] M, and

C is more than 10 [mu] M to 100 [mu] M or less.

As shown in Table 3, Example Compound 1-14 according to the present invention was found to inhibit cell proliferation of hepatoma cell lines Hep3B and Huh7 cells at micromolar concentrations. In particular, Examples 1, 3, and 6 effectively inhibited hepatoma cell lines Hep3B and Huh7 cell proliferation at very low concentrations of 10 μM or less.

Accordingly, the imidazolium pyrimidine derivative, its optical isomer or pharmaceutically acceptable salt thereof according to the present invention not only can effectively inhibit the activity of the Wee1 kinase but also can suppress the cell proliferation of the liver cancer cell line , And a pharmaceutical composition for preventing or treating liver cancer.

Meanwhile, the derivatives according to the present invention can be formulated into various forms according to the purpose. Examples of formulations for the composition of the present invention are illustrated below.

It should be noted, however, that the present invention is not limited to the following formulation examples, and an explanation will be given merely as an example.

&Lt; Formulation Example 1 > Preparation of pharmaceutical preparation

1. Manufacturing of powder

2 g of the compound of formula 1 according to the invention

Lactose 1 g

The above components were mixed and packed in airtight bags to prepare powders.

2. Preparation of tablets

100 mg of the compound of formula 1 according to the present invention

Corn starch 100 mg

Lactose 100 mg

Magnesium stearate 2 mg

After mixing the above components, tablets were prepared by tableting according to a conventional method for producing tablets.

3. Preparation of capsules

100 mg of the compound of formula 1 according to the present invention

Corn starch 100 mg

Lactose 100 mg

Magnesium stearate 2 mg

After mixing the above components, the capsules were filled in gelatin capsules according to the conventional preparation method of capsules.

4. Manufacture of granules

The compound of formula 1 according to the invention in an amount of 150 mg

Soybean extract 50 mg

Glucose 200 mg

Starch 600 mg

After mixing the above components, 100 μl of 30% ethanol was added and the mixture was dried at 60 ° C. to form granules, which were then filled in a capsule.

Claims (10)

Claims 1. A compound represented by the following formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]

(In the formula 1,
X is hydrogen, halogen, unsubstituted or substituted C _1-3 straight chain or branched C ₃ alkyl,
The substituted straight chain or branched chain alkyl may be substituted with halogen;

R ¹ and R ² are each independently an unsubstituted or substituted C _1-5 straight chain or C _3-5 branched chain alkoxy,
The substituted straight chain or branched alkoxy may be substituted with dimethylamino; And

R ³ is -NR ⁴ R ⁵ , unsubstituted or substituted C _6-10 cycloalkyl, or an unsubstituted or substituted 5 to 10 membered heteroaromatic ring containing one or more heteroatoms selected from the group consisting of N, O, and S Lt; RTI ID = 0.0 &gt;
Wherein R ⁴ and R ⁵ are each independently an unsubstituted or substituted C _1-5 straight chain or C _3-5 branched chain alkyl and the substituted straight chain or branched chain alkyl may be substituted with dimethylamino However,
Said substituted cycloalkyl or substituted heterocycloalkyl is selected from the group consisting of C _1-10 straight chain or C _3-10 branched chain alkyl, halogen, amino, C _1-3 alkylcarbonyl or N, O, S Which may be unsubstituted or substituted with 5 to 10 atoms of unsubstituted or substituted heterocycloalkyl containing one or more heteroatoms selected,
Wherein said substituted heterocycloalkyl may be substituted with a C _1-5 straight chain or C _3-5 branched chain alkyl.
The method according to claim 1,
And X is iodo (I).
A compound, an optical isomer thereof or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
R ³ is

,

,

,

,

,

or

&Lt; / RTI &gt;
A compound, an optical isomer thereof or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
Wherein the compound represented by the formula (1) is any one selected from the group consisting of the following compounds:
A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
(1) 4- (1H-imidazol-1-yl)) - 5-iodo-N- (4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-2-amine;
(2) 4- (1H-Imidazol-1-yl) -5-iodo-N- (4-morpholinophenyl) pyrimidin-2-amine;
(3) Synthesis of 4- (1H-imidazol-1-yl) -5-iodo-N- (3-methoxy- ;
(4) N- (4- (4- (Dimethylamino) piperidin-1-yl) phenyl) -4- (1H-imidazol-1-yl) -5-iodopyrimidin-2-amine;
(5) 4- (lH-imidazol-l-yl) -5-iodo-N- (4- Pyrimidin-2-amine;
(6) 4- (1H-imidazol-1-yl) -5-iodo-N- (3-methoxy- Yl) phenyl) pyrimidin-2-amine;
(7) 4- (1H-Imidazol-1-yl) -5-iodo-N- (4- (4 -morpholinopiperidin-1-yl) phenyl) pyrimidin-2-amine;
(8) Synthesis of N1- (4- (1H-imidazol-1-yl) -5-iodopyridin-2-yl) -N4- (2- (dimethylamino) ethyl) - diamines;
(9) Synthesis of 1- (4- (4 - ((4- (1H-imidazol-1-yl) -5-iodopyrimidin- 1-one;
(10) N- (3- (2- (Dimethylamino) ethoxy) phenyl) -4- (1H-imidazol-1-yl) -5-iodopyrimidin-2-amine;
(11) 4- (1H-imidazol-1-yl) -5-iodo-N- (2-methoxy- Amine;
(12) 4- (1H-Imidazol-1-yl) -5-iodo-N- (2-methoxy-4-morpholino) phenyl) pyrimidin-2-amine;
(13) 4- (lH-imidazol-l-yl) -5-iodo-N- (2-methoxy- Yl) phenyl) pyrimidin-2-amine;
(14) Synthesis of N- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -4- (lH-imidazol- Amine;
(15) 4- (1H-Imidazol-1-yl)) - N- (4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-2-amine;
(16) 4- (1H-Imidazol-1-yl)) - 5-methyl-N- (4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-2-amine;
(17) 4- (1H-Imidazol-1-yl)) - 5-fluoro-N- (4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-2-amine;
(18) 4- (1H-Imidazol-1-yl)) - 5-chloro-N- (4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-2-amine;
(19) 4- (1H-imidazol-1-yl)) - 5-bromo-N- (4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-2-amine;
(20) 4- (1 H-imidazol-1-yl) - N- (4- (4-methylpiperazin- 1 -yl) phenyl) -5- (trifluoromethyl) pyrimidin- ; And
(21) 4- (1H-Imidazol-1-yl) -5-methyl-N- (4- (4 -morpholinopiperidin-1-yl) phenyl) pyrimidin-2-amine.
As shown in Scheme 1 below,
A step of preparing a compound represented by the formula (3) from the compound represented by the formula (2) (step 1); And
Reacting the compound represented by the formula (3) and the compound represented by the formula (4) to prepare the compound represented by the formula (1) (step 2), and reacting the compound represented by the formula Manufacturing method:
[Reaction Scheme 1]

(In the above Reaction Scheme 1,
X, R ¹ , R ² and R ³ are as defined in claim 1.
A pharmaceutical composition for preventing or treating Wee1 kinase-related diseases, which comprises the compound represented by the general formula (1) of claim 1, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
The method according to claim 6,
Wherein the Wee1 kinase-related disease is solid tumor.
8. The method of claim 7,
The present invention relates to a solid tumor which is useful for the treatment of liver cancer, lung cancer, colon cancer, stomach cancer, breast cancer, colon cancer, pancreatic cancer, head or neck cancer, uterine cancer, ovarian cancer, rectum cancer, Wherein the composition is selected from the group consisting of vaginal cancer, vulvar carcinoma, prostate cancer, bladder cancer, kidney cancer, ureter cancer, renal cell carcinoma, renal pelvic carcinoma and central nervous system tumor.
8. The method of claim 7,
Wherein the solid cancer is liver cancer.
A health functional food composition for preventing or ameliorating a Wee1 kinase-related disease comprising the compound represented by the general formula (1) of claim 1, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.