KR102030886B1 - 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 imidazolyl pyrimidine derivative, a method for preparing the same, and a pharmaceutical composition for preventing or treating cancer containing the same as an active ingredient, the imidazolyl pyrimidine derivative according to the present invention, an optical isomer thereof, or The pharmaceutically acceptable salts thereof are excellent in the activity of Wee1 kinase, as well as in inhibiting cell proliferation of liver cancer cell lines, such as Wee1 kinase related diseases such as liver cancer, lung cancer, colon cancer, gastric cancer, breast cancer, colon cancer, Bone cancer, pancreatic cancer, head or neck cancer, uterine cancer, ovarian cancer, rectal cancer, esophageal cancer, small intestine cancer, anal muscle cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, prostate cancer, bladder cancer, kidney cancer, ureter Useful as a pharmaceutical composition for the prevention or treatment of solid cancer, preferably liver cancer such as cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system tumor liver cancer Can.

Description

Novel imidazolyl pyrimidine derivatives, preparation method, and pharmaceutical composition for use in preventing or treating cancer containing the novel imidazolyl pyrimidine derivative, preparation method thereof and 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 preparation method thereof 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 improves patient survival, new methods for obtaining effective treatment for advanced human hepatocellular carcinoma (HCC) are needed. Treatment alternatives are needed. Thus, the induction of apoptosis by chemotherapy and low molecular weight transport is an emerging alternative.

Transforming growth factor beta-1 (TGF-β1) strongly inhibits human hepatocellular carcinoma (HCC) cell growth. In particular, it promotes cell growth in non-epithelial cells, such as fibroblasts and stellate cells, while in rodents and by cell death or cell cycle arrest. It inhibits cell growth in both human hepatocellular carcinoma (HCC) cells.

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

In surgically excised samples, Wee1 kinase is overexpressed in human hepatocellular carcinoma (HCC), but kinase expression is not 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, Wee1 kinase expression is upregulated only in tumor cells, and elevated kinases play an important role in cancer cell survival.

Wee1 kinase is a negative regulator of cdc2. Since TGF-β1 is a multifunctional cytokine, it is not a practical therapeutic alternative. Wee1 kinase negatively regulates the G2 / M phase by inhibiting the early stages of mitosis before DNA damage is repaired, thereby preventing premature mitotic entry and subsequent cell death. It is considered. Certain inhibitors or siRNAs may be used to inhibit Wee1 kinase to induce apoptosis in human hepatocellular carcinoma (HCC) cells. Thus, Wee1 kinase inhibitors may be new therapeutic strategies and alternatives emerging in Wee1 kinase-overexpressing carcinomas such as human hepatocellular carcinoma (HCC), and these types of inhibitors may present a realistic therapeutic alternative to advanced solid cancers. Can be.

Therefore, the present inventors while studying a compound that inhibits Wee1 kinase, the imidazolyl pyrimidine derivative, optical isomer or pharmaceutically acceptable salt thereof according to the present invention is remarkably excellent in the inhibitory effect of Wee1 kinase, The present invention has been completed and found to be useful as a prophylactic or therapeutic agent for Wee1 kinase related diseases such as liver cancer.

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 imidazolyl pyrimidine derivatives, optical isomers thereof or pharmaceutically acceptable salts thereof.

Another object of the present invention is to provide a method for preparing the imidazolyl pyrimidine derivative.

Another object of the present invention to provide a pharmaceutical composition for the prevention or treatment of Wee1 kinase-related diseases containing the imidazolyl pyrimidine derivative, optical isomer thereof or pharmaceutically acceptable salt thereof as an active ingredient.

Another object of the present invention is to provide a nutraceutical composition for preventing or ameliorating Wee1 kinase-related diseases containing the imidazolyl pyrimidine derivative, its optical isomer, 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 Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

[Formula 1]

(In the above formula 1,

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

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

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

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

R ³ is unsubstituted or substituted 5 to 10 atoms, including -NR ⁴ R ⁵ , unsubstituted or substituted C _6-10 cycloalkyl, or at least one hetero atom selected from the group consisting of N, O, S Heterocycloalkyl,

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

The substituted cycloalkyl or substituted heterocycloalkyl is selected from the group consisting of C _1-10 straight or C _3-10 branched alkyl, halogen, amino, C _1-3 alkylcarbonyl or N, O, S Optionally substituted with 5 to 10 atoms of unsubstituted or substituted hetero cycloalkyl containing one or more hetero atoms selected,

Wherein the substituted hetero cycloalkyl may be substituted with C _1-5 straight chain or C _3-5 branched alkyl).

In addition, the present invention as shown in Scheme 1,

Preparing a compound represented by Chemical Formula 3 from the compound represented by Chemical Formula 2 (step 1); And

Preparing a compound represented by Chemical Formula 1 by reacting the compound represented by Chemical Formula 3 prepared in Step 1 with the compound represented by Chemical Formula 4 (step 2); Provide the manufacturing method:

Scheme 1

(In the above Reaction Scheme 1,

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

Furthermore, the present invention provides a pharmaceutical composition for preventing or treating a Wee1 kinase related disease containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

In another aspect, the present invention provides a health functional food composition for preventing or ameliorating Wee1 kinase-related diseases containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

Imidazolyl pyrimidine derivatives, optical isomers thereof or pharmaceutically acceptable salts thereof according to the present invention are excellent in inhibiting the cell proliferation of hepatic cancer cell lines as well as the activity of Wee1 kinase. For example, liver cancer, lung cancer, colon cancer, stomach cancer, breast cancer, colon cancer, bone cancer, pancreatic cancer, head or neck cancer, uterine cancer, ovarian cancer, rectal cancer, esophageal cancer, small intestine cancer, anal muscle cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, Solid cancers, such as vaginal carcinoma, vulvar carcinoma, prostate cancer, bladder cancer, kidney cancer, ureter cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system tumor liver cancer, etc., preferably can be used as a pharmaceutical composition for the prevention or treatment of liver cancer .

Hereinafter, the present invention will be described in detail.

The following description is presented to aid in understanding the invention, and the present invention is not limited to the contents of the following description.

The present invention provides a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

[Formula 1]

(In the above formula 1,

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

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

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

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

R ³ is unsubstituted or substituted 5 to 10 atoms, including -NR ⁴ R ⁵ , unsubstituted or substituted C _6-10 cycloalkyl, or at least one hetero atom selected from the group consisting of N, O, S Heterocycloalkyl,

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

The substituted cycloalkyl or substituted heterocycloalkyl is selected from the group consisting of C _1-10 straight or C _3-10 branched alkyl, halogen, amino, C _1-3 alkylcarbonyl or N, O, S Optionally substituted with 5 to 10 atoms of unsubstituted or substituted hetero cycloalkyl containing one or more hetero atoms selected,

Wherein the substituted hetero cycloalkyl may be substituted with C _1-5 straight chain or C _3-5 branched alkyl).

Preferably,

X is iodo (I),

Preferably,

,

,

,

,

,

또는

이고,R ³ is

,

,

,

,

,

or

ego,

Most preferably,

Preferred examples of the compound represented by 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) 4- (1H-imidazol-1-yl) -5-iodo-N- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-2-amine ;

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

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

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

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

(8) N1- (4- (1H-imidazol-1-yl) -5-iodopyridin-2-yl) -N4- (2- (dimethylamino) ethyl) -N4-methylbenzene-1,4 -Diamine;

(9) 1- (4- (4-((4- (1H-imidazol-1-yl) -5-iodopyrimidin-2-yl) amino) phenyl) piperazin-1-yl) ethane- 1-one;

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

(11) 4- (1H-imidazol-1-yl) -5iodo-N- (2-methoxy-4- (4-morpholinopiperidin-1-yl) phenyl) pyrimidine-2- Amines;

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

(13) 4- (1H-imidazol-1-yl) -5-iodo-N- (2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidine-1 -Yl) phenyl) pyrimidin-2-amine;

(14) N- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -4- (1H-imidazol-1-yl) -5-iodopyrimidine 2-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- (1H-imidazol-1-yl))-N- (4- (4-methylpiperazin-1-yl) phenyl) -5- (trifluoromethyl) pyrimidin-2-amine ; And

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

On the other hand, the compound represented by the formula (1) of the present invention can be used in the form of a pharmaceutically acceptable salt, the acid addition salt formed by the pharmaceutically acceptable free acid is useful as the salt. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Non-toxic organic acids such as dioate, aromatic acids, aliphatic and aromatic sulfonic acids and the like, and 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. Such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, eye Odide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suve Latex, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chloro Zensulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, 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, a precipitate produced by dissolving a derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile and adding an organic or inorganic acid. The solvent may be prepared by filtration and drying, or the solvent and excess acid may be distilled under reduced pressure, dried, and then crystallized under an organic solvent.

Bases can also be used to make pharmaceutically acceptable metal salts. Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt. Corresponding salts are also obtained by reacting alkali or alkaline earth metal salts with a suitable negative salt (eg silver nitrate).

Furthermore, the present invention includes not only the compound represented by Formula 1 and pharmaceutically acceptable salts thereof, but also solvates, stereoisomers, hydrates, and the like that can be prepared therefrom.

In addition, the present invention as shown in Scheme 1,

Preparing a compound represented by Chemical Formula 3 from the compound represented by Chemical Formula 2 (step 1); And

Preparing a compound represented by Chemical Formula 1 by reacting the compound represented by Chemical Formula 3 prepared in Step 1 with the compound represented by Chemical Formula 4 (step 2); Provide the manufacturing method:

Scheme 1

(In the above Reaction Scheme 1,

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

Hereinafter, a method for preparing a compound represented by Chemical Formula 1 according to the present invention will be described in detail step by step.

In the method for preparing a compound represented by Formula 1 according to the present invention, Step 1 of Scheme 1 is a step of preparing a compound represented by Formula 3 from the compound represented by Formula 2.

At this time, the step 1 may be understood as a reaction to introduce the imidazole substituent, there is no particular limitation, the reaction temperature may be preferably carried out at 40-90 ℃, the reaction time is carried out for 5 to 20 hours Can be.

In addition, 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; Dimethylformamide (DMF), Dimethylsulfoxide (DMSO), Dichloromethane (DCM), Dichloroethane, Water, Acetonazenesulfonate, Toluenesulfonate, Chlorobenzenesulfonate, Xylenesulfonate, Phenyl acetate, Phenylpropionate , Phenylbutyrate, cyclate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and Mixtures thereof can be used, preferably dimethylformamide (DMF).

In the method for preparing a compound represented by Formula 1 according to the present invention, Step 2 of Scheme 1 is a step of preparing a compound represented by Formula 1 by reacting the compound represented by Formula 4 from the compound represented by Formula 3 .

In this case, step 2 may be understood as a reaction for introducing an aniline derivative, and there is no particular limitation, but after addition of imidazolyl pyrimidine derivative, aniline derivative and K ₂ CO ₃ , Pd ₂ (dab ₃ ) and The compound of the present invention may be prepared by adding Xphos to react, the reaction temperature may be preferably performed at 60-100 ° C., and the reaction time may be performed for 5 to 20 hours.

In addition, as the solvent usable in step 2, H ₂ O, ethanol, sec-BuOH, tetrahydrofuran (THF), dichloromethane, toluene, acetonitrile, dimethylformamide and the like and mixtures thereof may be used. Preference is given to using -BuOH.

The present invention also provides a pharmaceutical composition for preventing or treating a disease related to Wee1 kinase containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

In this case, the Wee1 kinase-related disease is solid cancer, and the solid cancer is liver cancer, lung cancer, colon cancer, gastric cancer, breast cancer, colon cancer, bone cancer, pancreatic cancer, head or neck cancer, uterine cancer, ovarian cancer, rectal cancer, esophageal cancer, small intestine cancer, anal muscle cancer. , Fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, prostate cancer, bladder cancer, kidney cancer, ureter cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system tumor, etc., preferably liver cancer.

Furthermore, the present invention provides a health functional food composition for preventing or ameliorating a disease caused by Wee1 kinase overactivity containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. do.

In general, Wee1 kinase negatively regulates the G2 / M phase by inhibiting the early stages of mitosis before DNA damage is repaired, thus premature mitotic entry and subsequent cell death. It is believed to prevent.

Thus, as a result of experiments to evaluate the inhibitory activity of Wee1 kinase of the compound represented by the formula (1) according to the present invention, Example compound 1-21 according to the present invention was found to have excellent inhibitory activity of Wee1 kinase In particular, it was shown to effectively inhibit the activity of Wee1 kinase at very low concentrations of 1 μM or less (see Table 2 of Experimental Example 1).

In addition, as a result of experiments to evaluate the cell proliferation inhibitory activity of the liver cancer cell line of the compound represented by the formula (1) according to the present invention, Example compound 1-21 according to the present invention of Hep3B and Huh7 cells It has been shown to inhibit cell proliferation at low concentrations and to effectively inhibit cell proliferation at very low concentrations of μM units (see Table 3 of Experimental Example 2).

Accordingly, the imidazolyl pyrimidine derivatives, optical isomers thereof or pharmaceutically acceptable salts thereof according to the present invention are excellent in the activity of Wee1 kinase, as well as in inhibiting the cell proliferation of cancer cell lines, preferably liver cancer cell lines, Wee1. It can be usefully used as a pharmaceutical composition for the prophylaxis or treatment of kinase related diseases, for example, the aforementioned solid cancer, preferably liver cancer.

On the other hand, the compound represented by the formula (1) according to the present invention can be administered in various oral and parenteral dosage forms at the time of clinical administration, when formulated, commonly used fillers, extenders, binders, wetting agents, disintegrants, surfactants It is prepared using diluents or excipients.

Solid form preparations for oral administration include tablets, patients, powders, granules, capsules, troches, and the like, which form at least one excipient such as starch, calcium carbonate, water, or the like. It is prepared by mixing cross, lactose or gelatin. In addition to simple excipients, lubricants such as magnesium styrate talc are also used. Liquid preparations for oral administration include suspensions, solvents, emulsions or syrups, and include various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. Can be.

Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, and the like.

As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerol, gelatin and the like can be used.

In addition, the effective dosage of the compound of the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and is generally about 0.001-100 mg / kg / day, preferably Preferably 0.01-35 mg / kg / day. Based on an adult patient weighing 70 kg, it is generally 0.07-7000 mg / day, preferably 0.7-2500 mg / day, once a day at regular intervals according to the judgment of the doctor or pharmacist. Multiple doses may be administered.

Hereinafter, the present invention will be described in detail by Examples and Experimental Examples.

However, the following Examples and Experimental Examples are merely illustrative of the present invention, but the content of the present invention is not limited thereto.

In the following example compound,

Each analysis condition is as follows.

HPLC analysis conditions

Device Name: Shimadzu

Column: YMC-pack pro C18, 150 × 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 TM} 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 × 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 preparation method of the compound of the present invention will be described in detail.

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

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

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

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

Compound (1.2 equiv), 4- (4-methylpiperazin-1-yl) aniline (1.0 equiv) and K ₂ CO ₃ (5.0 equiv) prepared in step 1 were added to sec-BuOH (0.1 M) After melting, sonication was performed for 1 minute to remove the gas. Pd ₂ (dab ₃ ) (0.1 equiv) and Xphos (0.1 equiv) were added to the reaction mixture at 80 ° C., followed by reaction for 14 hours. After the reaction, the reaction mixture was filtered through celite and washed with EtOAc and MeOH. The filtrate obtained was concentrated and then purified by SFC to give the title 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 Preparation of Pyrimidin-2-amine

Except for 4- (4-methylpiperazin-1-yl) aniline used in Step 2 of Example 1, except that 4-morpholinoaniline was used, the same procedure as in Example 1 was performed. Was prepared.

HPLC t _R min: 4.20; ¹ H NMR (400 MHz, CDCl 3) 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, 1 H), 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 Preparation of -1-yl) phenyl) pyrimidin-2-amine

Except for using 4- (3-methoxy-4-methylpiperazin-1-yl) aniline instead of 4- (4-methylpiperazin-1-yl) aniline used in Step 2 of Example 1 And, the same as in Example 1 to perform 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- (1H-imidazol-1-yl) -5-iodopyrimidin-2-amine

Instead of 4- (4-methylpiperazin-1-yl) aniline used in step 2 of Example 1, using 1- (4-aminophenyl) -N, N-dimitelpiperidin-4-amine Except that, in the same manner as in Example 1 to prepare a 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), 2.28 (s, 6H), 1.93 (m, 3H), 1.22 ( m, 2H); 489 [M + H].

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

4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl instead of 4- (4-methylpiperazin-1-yl) aniline used in step 2 of Example 1 above A target compound was prepared in the same manner as in Example 1, except that aniline was used.

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 (m, 5H), 2.66 (s, 7H), 2.09 -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- Methylpipera Preparation of Jin-1-yl) piperidin-1-yl) phenyl) pyrimidin-2-amine

3-methoxy-4- (4- (4-methylpiperazin-1-yl) piperi instead of 4- (4-methylpiperazin-1-yl) aniline used in step 2 of Example 1 above A target compound was prepared in the same manner as in Example 1, except that din-1-yl) aniline was used.

HPLC t _R min: 3.56; ¹ H NMR (400 MHz, MeOH-d ₄ ) δ 8.71 (s, 1H), 8.32 (s, 1H), 7.81 (s, 1H), 7.72 (s, 1H), 7.34 (s, 1H), 7.06 ( s, 1H), 7.05 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 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) Preparation of Phenyl) pyrimidin-2-amine

In place of 4- (4-methylpiperazin-1-yl) aniline used in Step 2 of Example 1, except that 4- (4-morpholinopiperidin-1-yl) aniline was used, In the same manner as in Example 1, the target compound was prepared.

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, 3H), 3.59 (m, 2H), 3.36 (m, 4H), 2.90 (t, J = 11.2 Hz, 2H), 2.05 (m, 2H), 1.91 (m, 2H); 531 [M + H].

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

In place of 4- (4-methylpiperazin-1-yl) aniline used in Step 2 of Example 1, except that 4- (4-morpholinopiperidin-1-yl) aniline was used, In the same manner as in Example 1, the target compound was prepared.

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), 3.16-3.15 (m, 2H), 3.24 (s, 6H), 2.18 (s, 3H); 464 [M + H].

< Example  9> 1- (4- (4-((4- (1H-imidazol-1-yl) -5- Iodopyrimidine Preparation of 2-yl) amino) phenyl) piperazin-1-yl) ethan-1-one

In place of 4- (4-methylpiperazin-1-yl) aniline used in Step 2 of Example 1, 1- (4- (4-aminophenyl) piperazin-1-yl) ethanone was used. Except that, in the same manner as in Example 1 to prepare a target compound.

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 Preparation of Phenyl) -4- (1H-imidazol-1-yl) -5-iodopyrimidin-2-amine

Example 1, 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 In the same manner as in the title 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 (brs, 1H), 4.09 (t, J = 5.2 Hz, 2H), 3.91 (m, 2H), 2.62 (s, 6H); 451 [M + H]

< Example  11> 4- (1H-imidazol-1-yl)- 5 Iodo -N- (2- Methoxy -4- (4- Morpholino pipepe Preparation of Ridin-1-yl) phenyl) pyrimidin-2-amine

Instead of 4- (4-methylpiperazin-1-yl) aniline used in step 2 of Example 1, using 2-methoxy-4- (4-morpholinopiperidin-1-yl) aniline Except that, in the same manner as in Example 1 to prepare a 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), 6.68 (d, J = 2.5 Hz, 1H), 6.58 (d, J = 11.3 Hz, 1H), 3.87 (s, 3H), 3.87 (br, 4H), 3.81 (br, 1H), 2.96 ( 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- Morpholino Preparation of Phenyl) pyrimidin-2-amine

Same as Example 1, 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 target 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 Preparation of -1-yl) piperidin-1-yl) phenyl) pyrimidin-2-amine

2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperi instead of 4- (4-methylpiperazin-1-yl) aniline used in step 2 of Example 1 above A target compound was prepared in the same manner as in Example 1, except that din-1-yl) aniline was used.

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

1- (4-amino-2-methoxyphenyl) -N, N-dimethylpiperidine- in place of 4- (4-methylpiperazin-1-yl) aniline used in step 2 of Example 1 above A target compound was prepared in the same manner as in Example 1, except that 4-amine was used.

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 , J = 8.6 Hz, 1H), 6.92 (d, J = 8.6 Hz, 1H), 3.85 (s, 3H), 3.44 (d, J = 11.8 Hz, 2H), 2.60-2.51 (m, 3H) 2.45 ( 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 Preparation of -1-yl) phenyl) pyrimidin-2-amine

Except for 2,4-dichloro-5-iodopyrimidine used in Step 1 of Example 1, except that 2,4-dichloropyrimidine was used, the same procedure as in Example 1 was carried out Prepared.

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

In the same manner as in Example 1, except that 2,4-dichloro-5-methylpyrimidine was used in place of the 2,4-dichloro-5-iodopyrimidine used in Step 1 of Example 1 To prepare the target compound.

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

In the same manner as in Example 1, except that 2,4-dichloro-5-fluoropyrimidine was used in place of the 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 Preparation of -1-yl) phenyl) pyrimidin-2-amine

In the same manner as in Example 1 except that 2,4,5-trichloropyrimidine was used in place of the 2,4-dichloro-5-iodopyrimidine used in Step 1 of Example 1 The desired compound was prepared.

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

In the same manner as in Example 1, except that 2,4-dichloro-5-bromopyrimidine was used in place of the 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 -1-yl) phenyl) -5- ( Trifluoromethyl Preparation of Pyrimidin-2-amine

Example 1 except that 2,4-dichloro-5-trifluoromethylpyrimidine was used in place of 2,4-dichloro-5-iodopyrimidine used in Step 1 of Example 1 In the same manner to prepare the target compound.

< Example  21> 4- (1H-imidazol-1-yl) -5- methyl -N- (4- (4- Morpholinopiperidine -1-yl) Preparation of Phenyl) pyrimidin-2-amine

In the same manner as in Example 7, except that 2,4-dichloro-5-methylpyrimidine was used in place of the 2,4-dichloro-5-iodopyrimidine used in Step 1 of Example 7. To prepare the target compound.

The chemical structure of the compound prepared in Example 1-21 is shown in Table 1 below.

Example Chemical formula 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  Kinase Inhibitory Activity Assessment

In order to evaluate the inhibitory activity of Wee1 kinase of the compound represented by Formula 1 according to the present invention, the following experiment was performed.

Recombinant Wee1 kinase (Invitrogen, Carlsbad, CA), 3.4umol / l poly G: T (4: 1) (Signal Chem, Richmond, BC, Canada), 20 μmol / L ATP (Invitrogen, Carlsbad, CA) in 384-well plates ) Was added to the kinase reaction buffer (40 mmol / L TrisHCl, 10 mmol / L MgCl 2 and 0.1 μg / μL bovine serum albumin (BSA)) and mixed. Example 1-21 compounds according to the present invention were added at concentrations of 1 μM or less, more than 1 μM to 10 μM, more than 10 μM to 100 μM and more than 100 μM, respectively, and then reacted in a 30 ° C. incubator for 1 hour. After the reaction was completed, the same amount of Kinase-Glo (Promega, Madison, WI) solution was added for 1 hour and the detection solution was added for 10 minutes at room temperature. microplate reader enzyme linked immunosorbent assay (ELISA microplate reader;, Bio-Tek) by measuring the amount of luciferase (luciferase) was calculated by using the IC ₅₀ values for kinase. The results are shown in Table 2 below.

Example Wee1 (IC ₅₀ , μM) 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 confirmed in Table 2, it was shown that Example Compound 1-21 according to the present invention can excellently inhibit Wee1 kinase at an nM unit concentration of 1 μM or less.

In particular, when comparing Example 1 and Example 15-20 compounds, Example 1 compound has an iodo (I) substituent at the pyrimidine 5 position, and Example 15-20 compounds at the pyrimidine 5 position And hydrogen, methyl, fluoro, chloro, bromo, or trifluoromethyl have substituents. From the structural differences of the above compounds, Wee1 kinase inhibitory activity is remarkably changed. That is, when the iodo (I) substituent is located at the pyrimidine 5 position as in the compound of Example 1 of the present invention, it has a Wee1 kinase inhibitory activity of up to about 20 times that of the compound of Example 15-20 described above.

Also, when the Example 7 compound is compared with the Example 21 compound, the Example 7 compound according to the present invention has an iodo (I) substituent at the pyrimidine 5 position, which is about 4 times higher than the Example 21 compound It can be confirmed that it has Wee1 kinase inhibitory activity.

Accordingly, the imidazolyl pyrimidine derivatives, optical isomers thereof or pharmaceutically acceptable salts thereof according to the present invention exhibit excellent inhibitory activity of Wee1 kinase and therefore are used for the prevention or treatment of diseases related to Wee1 kinase, for example, liver cancer. It can be usefully used as a pharmaceutical composition.

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

In order to evaluate the cell proliferation inhibitory activity of the liver cancer cell line of the compound represented by the formula (1) according to the present invention was carried out the following experiment.

Hep3B cells (manufacturer: ATCC) and Huh7 cells (Rinken cell bank), which are liver cancer cell lines, were placed in 96-well plates at a concentration of 3000 cells / well, and cultured for 24 hours to attach the cells to the culture vessel. In the above medium, 1-14 compounds were dissolved in concentrations of 1 μM or less, 1 μM or more and 10 μM or less, 10 μM or more and 100 μM or less and 100 μM or more, and then replaced with a well plate containing cells and incubated for 72 hours. Then MTS (3,-(4, 5-dimethylthiazol-2-yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfophenyl) -2H-tetrazolium salt, Promega) solution One hour after 20 μl was added to each well, GI ₅₀ was calculated by measuring 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 above,

A is 1 μM or less,

B is greater than 1 μM and less than or equal to 10 μM, and

C is greater than 10 µM and less than or equal to 100 µM.

As confirmed in Table 3, Example Compounds 1-14 according to the present invention were shown to inhibit cell proliferation of Hep3B and Huh7 cells, which are liver cancer cell lines, at micromolar concentrations. In particular, Examples 1, 3 and 6 have been shown to effectively inhibit Hep3B and Huh7 cell proliferation which are liver cancer cell lines at very low concentrations of 10 μM or less.

Therefore, imidazolyl pyrimidine derivatives, optical isomers thereof, or pharmaceutically acceptable salts thereof according to the present invention can effectively inhibit the activity of Wee1 kinase and can also inhibit the cell proliferation of liver cancer cell lines. It may be usefully used as a pharmaceutical composition for preventing or treating liver cancer.

On the other hand, the derivative according to the present invention can be formulated in various forms according to the purpose. Examples of preparations for the compositions of the present invention are illustrated below.

However, this invention is not limited to the following formulation example, It demonstrates only as an illustration.

Preparation Example 1 Preparation of Pharmaceutical Formulation

1. Preparation of powder

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

1 g lactose

The above ingredients were mixed and filled in airtight cloth to prepare a powder.

2. Preparation of Tablets

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

Corn starch 100 mg

Lactose 100 mg

2 mg magnesium stearate

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

3. Preparation of Capsule

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

Corn starch 100 mg

Lactose 100 mg

2 mg magnesium stearate

After mixing the above components, the capsule was prepared by filling in gelatin capsules according to the conventional method for producing a capsule.

4. Preparation of Granules

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

Soy extract 50 mg

Glucose 200 mg

Starch 600 mg

After mixing the above components, 100 μl of 30% ethanol was added, dried at 60 ° C. to form granules, and then filled into fabric.

Claims (10)

A compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
[Formula 1]

(In the above formula 1,
X is iodo (I);

R ¹ is H, or methoxy;
R ² is H, unsubstituted or substituted C _1-2 alkoxy,
The substituted alkoxy is substituted with dimethylamino; And

R ³ is

,

,

,

,

,

or

to be).
delete delete The method of claim 1,
Compound represented by the formula (1) is characterized in that any one selected from the following compound group,
Compounds, stereoisomers thereof, or pharmaceutically acceptable salts 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) 4- (1H-imidazol-1-yl) -5-iodo-N- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-2-amine ;
(4) N- (4- (4- (dimethylamino) piperidin-1-yl) phenyl) -4- (1H-imidazol-1-yl) -5-iodopyrimidin-2-amine;
(5) 4- (1H-imidazol-1-yl) -5-iodo-N- (4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) Pyrimidin-2-amine;
(6) 4- (1H-imidazol-1-yl) -5-iodo-N- (3-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidine-1 -Yl) phenyl) pyrimidin-2-amine;
(7) 4- (1H-imidazol-1-yl) -5-iodo-N- (4- (4-morpholinopiperidin-1-yl) phenyl) pyrimidin-2-amine;
(8) N1- (4- (1H-imidazol-1-yl) -5-iodopyridin-2-yl) -N4- (2- (dimethylamino) ethyl) -N4-methylbenzene-1,4 -Diamine;
(9) 1- (4- (4-((4- (1H-imidazol-1-yl) -5-iodopyrimidin-2-yl) amino) phenyl) piperazin-1-yl) ethane- 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-4- (4-morpholinopiperidin-1-yl) phenyl) pyrimidine-2- Amines;
(12) 4- (1H-imidazol-1-yl) -5-iodo-N- (2-methoxy-4-morpholino) phenyl) pyrimidin-2-amine;
(13) 4- (1H-imidazol-1-yl) -5-iodo-N- (2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidine-1 -Yl) phenyl) pyrimidin-2-amine; And
(14) N- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -4- (1H-imidazol-1-yl) -5-iodopyrimidine 2-amine.
As shown in Scheme 1 below,
Preparing a compound represented by Chemical Formula 3 from the compound represented by Chemical Formula 2 (step 1); And
Reacting the compound represented by Chemical Formula 3 prepared in Step 1 with the compound represented by Chemical Formula 4 to prepare a compound represented by Chemical Formula 1 (step 2); Manufacturing Method:
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 solid cancer, comprising the compound represented by Formula 1 of claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
delete The method of claim 6,
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, rectal cancer, esophageal cancer, small intestine cancer, anal muscle cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma Pharmaceutical composition, characterized in that selected from the group consisting of vaginal carcinoma, vulvar carcinoma, prostate cancer, bladder cancer, kidney cancer, ureter cancer, renal cell carcinoma, renal pelvic carcinoma and central nervous system tumor.
The method of claim 6,
The solid cancer is a pharmaceutical composition, characterized in that liver cancer.
A health functional food composition for preventing or improving solid cancer containing the compound represented by the formula (1) of claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.