CN106029646B - The diamine derivative of pyrimidine 2,4 and contain anticancer pharmaceutical composition of the derivative as active component - Google Patents

Abstract

The present invention relates to a pyrimidine-2,4-diamine derivative or a pharmaceutically acceptable salt thereof and a pharmaceutical composition containing the pyrimidine-2,4-diamine derivative as an active ingredient for preventing or treating cancer. The compounds of the present invention are very effective in inhibiting the activity of anaplastic lymphoma kinase (ALK), therefore, the compounds of the present invention can improve the ability of fusion proteins with anaplastic lymphoma kinase (ALK) (such as EML4-ALK and NPM-ALK ) of cancer cells, and is expected to effectively prevent the recurrence of cancer, therefore, the compound of the present invention is useful as a composition for preventing or treating cancer.

Description

Pyrimidine-2,4-diamine derivatives and anticancer drugs containing the derivatives as active ingredients pharmaceutical composition

technical field

The present invention relates to a pyrimidine-2,4-diamine derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the pyrimidine-2,4-diamine derivative as an active ingredient for preventing or treating cancer.

Background technique

Unlike normal cells that proliferate or inhibit according to certain rules and necessary methods, cancer cells proliferate infinitely in tissues regardless of these necessary rules and methods. Cancer is a cell mass composed of such infinitely proliferating undifferentiated cells, which also called a tumor. Unrestricted proliferation of cancer cells invades surrounding tissues and even other organs, causing severe pain and problems, and even death. Therefore, cancer is considered an incurable disease.

According to the report of the American Cancer Society, there were at least 12 million new patients diagnosed with cancer worldwide in 2007, of which 7.6 million died, indicating that about 20,000 patients died of cancer every day. In Korea, cancer death was the number one cause of death in 2006, according to Statistics Korea. Therefore, there is an urgent need to develop an anticancer agent excellent in cancer therapeutic effects in order to reduce emotional pain and physical pain caused by the onset of cancer and experienced during the treatment of cancer while improving the quality of life of patients.

Despite all previous efforts, the mechanisms by which normal cells become cancerous are not yet clearly understood. Cancer develops through a combination of external factors (such as environmental factors, chemicals, radiation, and viruses) and internal factors (such as genetic and immune factors). The genes involved in the development of cancer are oncogenes and tumor suppressor genes. Cancer develops when the balance between two cancer-related genes is disrupted by any of the above internal or external factors.

Cancers are mainly divided into blood cancers and solid cancers. Cancer develops in nearly every part of the body, leading to cancers of the lung, stomach, breast, mouth, liver, uterus, esophagus, and skin, among others. Several targeted agents (such as Gleevec and Herceptin) are used to treat some cancers, but surgery, radiation therapy, chemotherapy to inhibit cell proliferation are the main anti-cancer treatments. However, these methods are not targeted therapy, and the biggest problem of conventional chemotherapy is side effects caused by cytotoxicity and drug resistance, which is the reason why treatment with anticancer agents fails even after successful early treatment with anticancer agents. In order to overcome the limitations of chemotherapy, there is a continuous need for the development of targeted agents based on a clear understanding of their anticancer mechanisms.

In order to develop targeting agents, studies of specific molecular biological factors involved in tumor formation have been conducted. In particular, molecular biological factors are used in the prediction of cancer prognosis or in decision making for chemotherapy or radiation therapy.

The most representative drug capable of inhibiting tyrosine kinase receptors, one of the molecular biological factors involved in cancer, is Gleevec. Gleevec shows anticancer effects by inhibiting the Bcr-Abl fusion gene formed by the translocation in the Philadelphia chromosome observed in chronic myeloid leukemia. Gleevec is one of the tyrosine kinase inhibitors and is used in the treatment of chronic myelogenous leukemia. Effective in myeloid leukemia. Other anticancer agents that are tyrosine kinase inhibitors are: gefitinib and erlotinib, the EGFR (epidermal growth factor receptor) tyrosine used in the treatment of non-small cell lung cancer kinase inhibitors; and sorafenib and sunitinib used in the treatment of renal cell carcinoma. However, these drugs show side effects such as bleeding, heart attack, heart failure, and liver failure.

Recently, anaplastic lymphoma kinase (ALK) was identified in a variety of tumors and, therefore, anaplastic lymphoma kinase has been the target of investigation.

The ALK-NPM (nucleolin phosphoprotein) fusion gene found in anaplastic large cell lymphoma is thought to be a key factor in ALK-mediated cancer development. Once ALK is activated by gene fusion, the tyrosine kinase contained in ALK starts to act abnormally to cause cancer. That is, abnormally activated anaplastic lymphoma kinase (ALK) induces cell proliferation, interrupts apoptosis to prevent cell death, rearranges the cytoskeleton, and thus changes cell shape. Oncogenic transformation of anaplastic lymphoma kinase (ALK) is accomplished through interactions between ALK and its downstream molecules. Downstream molecules are substances that mediate intracellular signal transduction. ALK interacts with normal genes or other oncogenically transformed tyrosine kinase genes to activate a variety of other pathways.

Specifically, the ALK gene in lung cancer cells was fused to the EML4 (echinoderm microtubule-associated-like 4) gene to generate the active tyrosine kinase EML4-ALK. At this time, the cancer-inducing activity of EML4-ALK depends on the enzyme activity. Mosse et al. also reported that approximately 26% of ALK gene amplification had been demonstrated in 491 neuroblastoma samples. In addition, the ALK gene is found in many non-hematopoietic tumors including: large B-cell lymphoma, systemic histiocytosis, inflammatory myofibroblastic tumor, squamous cell carcinoma of the esophagus, non-small cell lung cancer, rhabdomyosarcoma , myofibroblastoma, breast cancer and melanoma cell lines. In inflammatory myeloblastoma, a rare disease, different classes of anaplastic lymphoma kinase (ALK) fusion proteins are frequently observed, suggesting that such fusion proteins are deeply involved in tumor development.

By using a method of blocking the ALK activation pathway, an anticancer agent targeting ALK-NPM is being developed. Crizotinib (PF- 02341066) is effective in the treatment of non-small cell lung cancer, therefore, crizotinib was approved as a new drug by FDA in 2011.

NVP-TAE684 and LDK-378 developed by Novartis and CH5424802 developed by Chugai were also demonstrated to reduce tumor size not only in anaplastic large cell lymphoma cell line but also in neuroblastoma cell line .

Patent Document 1 to Patent Document 3 describe that in order to inhibit ALK activity, candidate therapeutic agents having various frameworks are being developed, and pyrimidine derivatives can selectively inhibit ALK, so they can be developed as anticancer agents.

Therefore, the present inventors attempted to develop compounds that effectively inhibit the activity of anaplastic lymphoma kinase (ALK, Anaplastic lymphomakinase). As a result, the present inventors found that a pyrimidine-2,4-diamine derivative having a specific structure is extremely excellent in inhibiting ALK activity, and thus can be used as a cancer preventive or cancer therapeutic agent, thereby completing the present invention.

prior art literature

patent documents

Patent Document 1: WO 2009143389 A1

Patent Document 2: WO 2008051547 A1

Patent Document 3: WO 2004080980 A1

Contents of the invention

The object of the present invention is to provide pyrimidine-2,4-diamine derivatives or pharmaceutically acceptable salts thereof.

Another object of the present invention is to provide a process for preparing said pyrimidine-2,4-diamine derivatives.

Another object of the present invention is to provide a pharmaceutical composition containing the pyrimidine-2,4-diamine derivative or a pharmaceutically acceptable salt thereof as an active ingredient for preventing or treating cancer.

A further object of the present invention is to provide a drug containing the pyrimidine-2,4-diamine derivative or a pharmaceutically acceptable salt thereof as an active ingredient for the prevention or treatment of anaplastic lymphoma kinase (ALK) caused by overactivation. Pharmaceutical composition for causing disease.

Still another object of the present invention is to provide an anaplastic lymphoma kinase (ALK) inhibitor comprising the pyrimidine-2,4-diamine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

In order to achieve the above objects, the present invention provides pyrimidine-2,4-diamine derivatives represented by formula 1 or pharmaceutically acceptable salts thereof.

[Formula 1]

In formula 1,

Indicates a single or double bond;

when is a single key,

R ¹ , R ² and R ³ are independently -H, halogen, or C _1-10 linear alkyl unsubstituted or substituted with one or more halogens;

R ⁴ is -H; C _1-10 straight or branched chain alkyl unsubstituted or substituted with one or more -OH groups; or -C(=O)R ⁵ , at this time R ⁵ is -H, -OH or C _1-10 straight chain or branched chain alkyl;

when is a double bond,

R ¹ , R ² and R ³ are independently -H, halogen, or C _1-10 straight chain or branched alkyl unsubstituted or substituted with one or more halogens;

R ⁴ is -H; C _1-10 straight or branched chain alkyl unsubstituted or substituted with one or more -OH groups; or -C(=O)R ⁵ , at this time R ⁵ is -H, -OH or C _1-10 straight chain or branched chain alkyl.

The present invention also provides a method for preparing the above-mentioned pyrimidine-2,4-diamine derivatives, the method comprising the following steps shown in the following reaction formula 1:

Prepare the compound represented by Formula 4 by reacting the compound represented by Formula 2 with the compound represented by Formula 3 (step 1); and

The compound represented by Formula 1 is prepared by reacting the compound represented by Formula 4 prepared in Step 1 with the compound represented by Formula 5 (Step 2).

[Reaction 1]

(In Reaction Formula 1, R ¹ , R ² , R ³ and R ⁴ are as defined in Formula 1).

The present invention also provides a pharmaceutical composition containing the pyrimidine-2,4-diamine derivative represented by formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient for preventing or treating cancer.

The present invention also provides a pyrimidine-2,4-diamine derivative represented by formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient for the prevention or treatment of anaplastic lymphoma kinase (ALK) caused by overactivation. Pharmaceutical composition for causing disease.

In addition, the present invention provides an anaplastic lymphoma kinase (ALK) inhibitor comprising a pyrimidine-2,4-diamine derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

Beneficial effect

The compounds of the present invention are excellent in inhibiting anaplastic lymphoma kinase (ALK), therefore, they can be advantageously used to improve the therapeutic effect on cancer cells containing ALK fusion proteins such as EML4-ALK and NPM-ALK , and the compound of the present invention is effective in preventing recurrence of cancer, therefore, it can be effectively used as a pharmaceutical composition for preventing or treating cancer.

Detailed ways

Hereinafter, the present invention is described in detail.

The present invention provides a pyrimidine-2,4-diamine derivative represented by formula 1 or a pharmaceutically acceptable salt thereof.

[Formula 1]

In formula 1,

Indicates a single or double bond;

when is a single key,

R ¹ , R ² and R ³ are independently -H, halogen, or C _1-10 linear alkyl unsubstituted or substituted with one or more halogens;

R ⁴ is -H; C _1-10 straight or branched chain alkyl unsubstituted or substituted with one or more -OH groups; or -C(=O)R ⁵ , at this time R ⁵ is -H, -OH or C _1-10 straight chain or branched chain alkyl;

when is a double bond,

R ¹ , R ² and R ³ are independently -H, halogen, or C _1-10 straight chain or branched alkyl unsubstituted or substituted with one or more halogens;

R ⁴ is -H; C _1-10 straight or branched chain alkyl unsubstituted or substituted with one or more -OH groups; or -C(=O)R ⁵ , at this time R ⁵ is -H, -OH or C _1-10 straight chain or branched chain alkyl.

Preferably,

when is a single key,

R ¹ , R ² and R ³ are independently -H, halogen, or C _1-5 linear alkyl unsubstituted or substituted with one or more halogens;

R ⁴ is -H; C _1-5 straight or branched chain alkyl unsubstituted or substituted with one or more -OH groups; or -C(=O)R ⁵ , where R ⁵ is -OH or C _1-5 straight chain or branched chain alkyl;

when is a double bond,

R ¹ , R ² and R ³ are independently -H, halogen, or C _1-5 linear or branched alkyl unsubstituted or substituted with one or more halogens;

R ⁴ is -H; C _1-5 straight or branched chain alkyl unsubstituted or substituted with one or more -OH groups; or -C(=O)R ⁵ , where R ⁵ is -OH or C _1-5 straight chain or branched chain alkyl.

More preferably,

when is a single key,

R ¹ is -Cl or -CF ₃ ;

R ² is -H, -CH ₃ or -F;

R ³ is -CH ₃ or -CHF ₂ ;

^R4 is -H, _{-CH3 , -CH2CH3} , _-CH2CH2OH , -C(=O)CH3 or _-C (=O ₎ OH;

when is a double bond,

R ¹ is -Cl or -CF ₃ ;

R ² is -H, -CH ₃ or -F;

R ³ is -CH ₃ , -CH(CH ₃ ) ₂ or -CHF ₂ ;

^R4 _is -H, _{-CH3 , -CH2CH3} , _-CH2CH2OH , -C(=O)CH3 or _-C (=O)OH.

The pyrimidine-2,4-diamine derivative represented by formula 1 of the present invention can be enumerated by the following compounds:

(1) 5-Chloro-N4-(2-(isopropylsulfonyl)phenyl)-N2-(2-methoxy-4-(1,2,3,6-tetrahydropyridin-4-yl) ) phenyl) pyrimidine-2,4-diamine;

(2) 5-chloro-N2-(2-isopropoxy-5-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N4-(2- (isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;

(3) 5-chloro-N2-(2-(difluoromethoxy)-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N4-(2-(iso Propylsulfonylphenyl)pyrimidine-2,4-diamine;

(4) 5-chloro-N2-(2-(difluoromethoxy)-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine -2,4-diamine;

(5) 5-chloro-N4-(2-(isopropylsulfonyl)phenyl)-N2-(2-methoxy-4-(piperidin-4-yl)phenyl)pyrimidine-2,4 - diamines;

(6) N4-(2-(isopropylsulfonyl)phenyl)-N2-(2-methoxy-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl) -5-(trifluoromethyl)pyrimidine-2,4-diamine;

(7) N2-(2-isopropoxy-5-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N4-(2-(isopropyl Sulfonyl)phenyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine;

(8) N2-(2-(difluoromethoxy)-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl) )phenyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine;

(9) N2-(2-(difluoromethoxy)-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)-5-(tri Fluoromethyl)pyrimidine-2,4-diamine;

(10) 5-chloro-N2-(5-fluoro-2-methoxy-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N4-(2-(iso Propylsulfonyl)phenyl)pyrimidine-2,4-diamine;

(11) 5-chloro-N4-(2-(isopropylsulfonyl)phenyl)-N2-(2-methoxy-5-methyl-4-(1,2,3,6-tetrahydro Pyridin-4-yl)phenyl)pyrimidine-2,4-diamine;

(12) 5-chloro-N2-(5-fluoro-2-methoxy-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine -2,4-diamine;

(13) 5-chloro-N4-(2-(isopropylsulfonyl)phenyl)-N2-(2-methoxy-5-methyl-4-(piperidin-4-yl)phenyl) Pyrimidine-2,4-diamine;

(14) 5-chloro-N2-(4-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-methoxyphenyl)-N4-(2-( (isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;

(15) 5-chloro-N2-(4-(1-hydroxyethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-methoxyphenyl)-N4-(2- (isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;

(16) 1-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxybenzene Base)-5,6-dihydropyridine 1(2H)-yl)ethanone;

(17) 4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)- 5,6-dihydropyridine-1(2H)-carboxylic acid; and

(18) 4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)- 1(2H)-Methyl-5,6-dihydropyridine.

The pyrimidine-2,4-diamine derivative represented by Formula 1 of the present invention can be used as a pharmaceutically acceptable salt, wherein the salt is preferably an acid addition salt formed of a pharmaceutically acceptable free acid . The acid addition salts described herein can be obtained from inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, nitrous, and phosphorous; nontoxic organic acids such as aliphatic monocarboxylic acids; Esters/dicarboxylates, phenyl substituted alkanoates, hydroxyalkanoates, alkanedioates, aromatic acids and aliphatic/aromatic sulfonic acids; or organic acids such as acetic acid, benzoic acid , citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid and fumaric acid. Pharmaceutically non-toxic salts are enumerated by: sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate , pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, caprate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate Acid, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioic acid salt, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate salt, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate , phenylbutyrate, citrate, lactate, hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene -2-sulfonate and mandelate.

The acid addition salts of the present invention can be prepared by conventional methods known to those skilled in the art. For example, the pyrimidine-2,4-diamine derivative represented by Formula 1 is dissolved in an organic solvent such as methanol, ethanol, acetone, methylene chloride or acetonitrile, and an organic acid or an inorganic acid is added thereto to induce precipitation. Then, the precipitate was filtered and dried to obtain the salt. Alternatively, the solvent and excess acid are distilled under reduced pressure and dried to obtain the salt. Alternatively, the precipitate is crystallized in an organic solvent to give the salt.

The present invention includes not only pyrimidine-2,4-diamine derivatives represented by formula 1, but also pharmaceutically acceptable salts, solvates, hydrates or derivatives derived from said pyrimidine-2,4-diamine Optical isomers of substances.

The present invention also provides a method for preparing the above-mentioned pyrimidine-2,4-diamine derivatives, the method comprising the following steps shown in the following reaction formula 1:

Prepare the compound represented by Formula 4 by reacting the compound represented by Formula 2 with the compound represented by Formula 3 (step 1); and

The compound represented by Formula 1 is prepared by reacting the compound represented by Formula 4 prepared in Step 1 with the compound represented by Formula 5 (Step 2).

[Reaction 1]

(In Reaction Formula 1, R ¹ to R ⁴ are as defined in this specification.)

Hereinafter, the preparation method of the present invention is described step by step in more detail.

In the preparation method of the present invention, step 1 is to obtain the compound represented by formula 4 by reacting the compound represented by formula 2 with the compound represented by formula 3.

Specifically, the compound represented by Formula 4 is prepared by reacting the compound represented by Formula 2 with the compound represented by Formula 3 via alkylation in the presence of an organic solvent and a base.

At this time, the organic solvent used herein is selected from the group consisting of tetrahydrofuran; dioxane; ether solvents including diethyl ether and 1,2-dimethoxyethane; lower alcohols including methanol, ethanol , propanol and butanol; dimethylformamide (DMF), dimethylsulfoxide (DMSO), Tosylate, Chlorobenzenesulfonate, Xylenesulfonate, Phenylacetate, Phenylpropionate, Phenylbutyrate, Citrate, Lactate, Beta-Hydroxybutyrate, Glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and mandelate.

The base used herein is selected from the group consisting of organic bases such as pyridine, triethylamine, N,N-diisopropylethylamine (DIPEA) and 1,8-diazabicyclo[5.4. 0]-7-undecene (DBU); and inorganic bases such as sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and sodium hydride, which may be used in equivalent or excess amounts. The reaction temperature is 50° C. to 200° C., and the stirring time is 0.5 hours to 20 hours.

After the above reaction was completed, extraction was performed using an organic solvent, followed by drying, filtration, and distillation under reduced pressure. Column chromatography was additionally performed to obtain the compound represented by Formula 4.

In the preparation method of the present invention, step 2 is to obtain the compound represented by formula 1 by reacting the compound represented by formula 4 prepared in step 1 with the compound represented by formula 5.

Specifically, the compound represented by Formula 1 is prepared by reacting the compound represented by Formula 4 with the compound represented by Formula 5 via alkylation in the presence of an organic solvent and a base.

At this time, the organic solvent used herein is selected from the group consisting of tetrahydrofuran; dioxane; ether solvents including diethyl ether and 1,2-dimethoxyethane; lower alcohols including methanol, ethanol , propanol and butanol; dimethylformamide (DMF), dimethylsulfoxide (DMSO), Tosylate, Chlorobenzenesulfonate, Xylenesulfonate, Phenylacetate, Phenylpropionate, Phenylbutyrate, Citrate, Lactate, Beta-Hydroxybutyrate, Glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and mandelate.

The base used herein is selected from the group consisting of organic bases such as pyridine, triethylamine, N,N-diisopropylethylamine (DIPEA) and 1,8-diazabicyclo[5.4. 0]-7-undecene (DBU); and inorganic bases such as sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and sodium hydride, which may be used in equivalent or excess amounts. The reaction temperature is 50° C. to 200° C., and the stirring time is 0.5 hours to 20 hours.

After the above reaction was completed, extraction was performed using an organic solvent, followed by drying, filtration, and distillation under reduced pressure. Column chromatography was additionally performed to obtain the compound represented by Formula 1.

The present invention also provides a pharmaceutical composition containing the pyrimidine-2,4-diamine derivative represented by formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient for preventing or treating cancer.

The present invention also provides a pyrimidine-2,4-diamine derivative represented by formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient for the prevention or treatment of anaplastic lymphoma kinase (ALK) caused by overactivation. Pharmaceutical composition for causing disease.

In addition, the present invention provides an anaplastic lymphoma kinase (ALK) inhibitor comprising a pyrimidine-2,4-diamine derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

The pharmaceutical composition and inhibitor of the present invention are characterized in inhibiting the expression and growth of cancer cells by inhibiting the activation of anaplastic lymphoma kinase (ALK).

ALK is a gene that induces the proliferation of cancer cells activated by gene fusion. At this point, tyrosine kinases contained in ALK begin to act abnormally to induce cell proliferation, interrupt apoptosis, rearrange the cytoskeleton, change cell shape and activate other pathways, or interact with other tyrosine kinases, normal or oncogenic effect.

In order to examine the ALK inhibitory activity of the pyrimidine-2,4-diamine derivative represented by formula 1 of the present invention, the compound of the present invention was treated with ALK enzyme and various cancer cells, and _IC50 and _GI50 were measured. As a result, most of the compounds of the pyrimidine-2,4-diamine derivatives represented by Formula 1 showed excellent inhibitory activity compared to the control compounds (crizotinib and LDK-378) (see Experimental Example 1 to Experimental Implementation Example 3).

The pyrimidine-2,4-diamine derivative represented by formula 1 of the present invention can be used for preventing or treating cancer by inhibiting the activity of anaplastic lymphoma kinase (ALK). For example, the derivatives can be used in the treatment of non-small cell lung cancer, neuroblastoma, inflammatory myeloblastic tumor, rhabdomyosarcoma, myofibroblastoma, breast cancer, gastric cancer, lung cancer, melanoma, large B-cell lymphoid tumor, systemic histiocytosis, inflammatory myofibroblastic tumor, squamous cell carcinoma of the esophagus, uterus, and prostate.

A pharmaceutical composition containing the pyrimidine-2,4-diamine derivative represented by Formula 1 of the present invention or a pharmaceutically acceptable salt thereof can be prepared for oral administration or parenteral administration.

Formulations for oral administration are exemplified by tablets, pills, hard/soft capsules, solutions, suspensions, emulsions, syrups, granules, elixirs, lozenges and the like. Such formulations may include, in addition to the active ingredient, diluents (such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and/or glycine) and lubricants (such as silicon dioxide, talc, stearic acid, and its magnesium or calcium salts, and/or polyethylene glycol). Tablets may contain binders (such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone) and, if desired, disintegrants (such as starch, agarose, , alginic acid or its sodium salt or azeotropic mixture), and/or absorbents, coloring agents, flavoring agents and sweeteners may additionally be contained herein.

The pharmaceutical composition containing the pyrimidine-2,4-diamine derivative represented by Formula 1 as an active ingredient can be administered parenterally, including subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection.

In order to prepare the composition as a preparation for parenteral administration, the pyrimidine-2,4-diamine derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof is mixed with a stabilizer or a buffer in water to generate a solution or suspension, which is then formulated into ampoules or vials. Compositions described herein may be sterilized and additionally contain preservatives, stabilizers, wettable powders or emulsifiers, salts and/or buffers for adjusting osmotic pressure and other therapeutically useful substances, and the The composition can be formulated by conventional mixing, granulating or coating methods.

The effective dosage of the pharmaceutical composition containing the pyrimidine-2,4-diamine derivative represented by Formula 1 as an active ingredient of the present invention can be determined according to age, body weight, sex, administration method, health condition and severity of disease. The dose is preferably 0.01 mg/kg/day to 1000 mg/kg/day, and can be administered orally or parenterally several times a day, or preferably 1 to 3 times a day.

Hereinafter, the method for preparing the pyrimidine-2,4-diamine derivative represented by Formula 1 of the present invention will be described in more detail using Production Examples and Examples. The following examples are merely examples for explaining the method for preparing the pyrimidine-2,4-diamine derivative represented by Formula 1, and the present invention is not limited thereto. The preparation methods described by the following examples can be accomplished by using synthetic conditions and appropriate reagents well known in the field of organic synthesis.

Example 1: 5-chloro-N4-(2-(isopropylsulfonyl)phenyl)-N2-(2-methoxy-4-(1,2,3,6-tetrahydropyridine-4- Preparation of yl)phenyl)pyrimidine-2,4-diamine

Step 1: 4-(4-((5-Chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)- Preparation of tert-butyl 5,6-dihydropyridine-1(2H)-carboxylate

2,5-dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine (1.6g, 4.6mmol) was dissolved in 25ml of THF, and 4-(4- Amino-3-methoxyphenyl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.4 g, 4.6 mmol). Add 4,5-bisdiphenylphosphine-9,9-dimethylxanthene to it in sequence (266mg, 0.46mmol) and _Cs2CO3 (4.5g, 13.8mmol), then degassed _by filling with nitrogen. To this was added Pd(OAc) ₂ (51.6mg, 0.23mmol). After filling with nitrogen, the reaction mixture was stirred at 130 °C for 18 hours. After completion of the reaction, the mixture was then extracted with EA/ _H2O . The organic layer was dried over MgSO ₄ , filtered, and concentrated. Column chromatography (Hx:EA4:1) was performed to obtain the target compound (330 mg, yield: 20%).

¹ H NMR (CDCl ₃ , 300MHz) δ9.55(s, 1H), 8.58(d, J=8.4Hz, 1H), 8.24(d, J=8.7Hz, 1H), 8.16(s, 1H), 7.94 (d, J=8.1Hz, 1H), 7.68(t, J=7.8Hz, 1H), 7.59(s, 1H), 6.92(s, 2H), 6.0-5.98(m, 1H), 4.09(s, 2H), 3.92(s, 3H), 3, 65-3.63(m, 2H), 3.29-3.19(m, 1H), 2.53(s, 2H), 1.66(s, 3H), 1.49(s, 9H) , 1.32 (d, J=6.9Hz, 6H).

Step 2: 5-Chloro-N4-(2-(isopropylsulfonyl)phenyl)-N2-(2-methoxy-4-(1,2,3,6-tetrahydropyridin-4-yl ) phenyl) pyrimidine-2, the preparation of 4-diamine

4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxy obtained in step 1 Phenyl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester compound (1.13 g, 1.84 mmol) was dissolved in MeOH, to which was added 6 ml of dioxane dissolved in 4M HCl, It was then stirred at room temperature for 0.5 hours. After the reaction was complete, HCl was then removed followed by decantation with ether. As a result, 300 mg of the target compound was obtained (yield: 99%).

¹ H NMR (MeOH, 300MHz) δ8.28(s, 1H), 8.22-8.21(m, 1H), 8.04(d, J=4.8Hz, 1H), 7.75-7.56(m, 1H), 7.62-7.58 (m, 1H), 7.51(d, J=5.1Hz, 1H), 7.20(s, 1H), 7.01-7.00(m, 1H), 6.24(s, 1H), 3.94(s, 3H), 3.91( s, 2H), 3.43-3.40(m, 1H), 2.85(s, 2H), 1.26(d, J=13.2, 6Hz).

Example 2: 5-chloro-N2-(2-isopropoxy-5-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N4-(2 Preparation of -(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine

Step 1: 4-(4-((5-Chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2- Preparation of tert-butyl methylphenyl)-5,6-dihydropyridine-1(2H)-carboxylate

2,5-dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine (1 g, 2.88 mmol) was dissolved in 20 ml of THF, and 4-(4-amino - tert-butyl 5-isopropoxy-2-methylphenyl)-5,6-dihydropyridine-1(2H)-carboxylate (955 mg, 2.88 mmol). 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (167mg, 0.288mmol) and Cs ₂ CO ₃ (2.8g, 8.64mmol) were sequentially added thereto, followed by degassing by filling nitrogen gas. To this was added Pd(OAc) ₂ (32mg, 0.144mmol). After filling with nitrogen, the reaction mixture was stirred at 130 °C for 18 hours. After completion of the reaction, the mixture was then extracted with EA/ _H2O . The organic layer was dried over MgSO ₄ , filtered, and concentrated. Column chromatography (Hx:EA 4:1) was performed to obtain the target compound (642 mg, yield: 34%).

¹ H NMR (CDCl ₃ , 300MHz) δ9.49(s, 1H), 8.57(d, J=8.4Hz, 1H), 8.16(s, 1H), 8.04(s, 1H), 7.94(dd, J= 0.9Hz, 1.2Hz, 1H), 7.66-7.59(m, 2H), 6.63(s, 1H), 5.54(brs, 1H), 4.58-4.54(m, 1H), 4.04(s, 2H)3.63(t , J=5.4Hz, 2H), 3.30-3.21(m, 1H), 2.35-2.33(m, 2H), 2.09(s, 3H), 1.50(s, 9H), 1.38(d, J=6.0Hz, 6H), 1.33(d, J=6.9Hz, 6H).

Step 2: 5-Chloro-N2-(2-isopropoxy-5-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N4-(2- Preparation of (isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine

4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy obtained in step 1 tert-butyl-2-methylphenyl)-5,6-dihydropyridine-1(2H)-carboxylate compound (600mg, 0.91mmol) was dissolved in MeOH, to which was added 5ml of dioxane, followed by stirring at room temperature for 0.5 h. After the reaction was complete, HCl was then removed followed by decantation with ether. As a result, 630 mg of the target compound was obtained (yield: 99%).

¹ H NMR (CDCl ₃ , 300MHz) δ8.27(brs, 2H), 8.04(d, J=7.5Hz, 1H), 7.78-7.73(m, 1H), 7.60-7.55(m, 1H), 7.34( s, 1H), 6.87(s, 1H), 5.66(s, 1H), 3.84(s, 2H), 3.65(s, 3H), 2.61(s, 2H), 2.13(s, 3H), 1.30(d , J=6Hz, 6H), 1.26(d, J=6.9Hz, 6H).

Example 3: 5-chloro-N2-(2-(difluoromethoxy)-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N4-(2-( Preparation of isopropylsulfonylphenyl)pyrimidine-2,4-diamine

Step 1: 4-(4-((5-Chloro-4-((2-(isopropylsulfonyl)phenyl)pyrimidin-2-yl)amino)-3-(difluoromethoxy)phenyl )-5,6-dihydropyridine-1 (2H)- formic acid tert-butyl ester

2,5-dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine (200mg, 0.58mmol) was dissolved in 5ml of THF, and 4-(4-amino - tert-butyl 3-(difluoromethoxy)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (195 mg, 0.58 mmol). 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (33 mg, 0.058 mmol) and Cs ₂ CO ₃ (550 mg, 1.74 mmol) were sequentially added thereto, followed by degassing by filling with nitrogen . Pd(OAc) ₂ was added thereto. After filling with nitrogen, the reaction mixture was stirred at 130 °C for 18 hours. After completion of the reaction, the mixture was then extracted with EA/ _H2O . The organic layer was dried over MgSO ₄ , filtered, and concentrated. Column chromatography (Hx:EA 6:1) was performed to obtain the title compound (120 mg, yield: 32%).

¹ H-NMR (300MHz, CDCl ₃ ) δ8.53(d, J=8.4Hz, 1H), 8.31(d, J=9.0Hz, 1H), 8.18(s, 1H), 7.94(d, J=8.1 Hz, 1H) 7.66(t, J=7.2, 1H) 7.33-7.29(m, 2H), 7.17(d, J=5.1Hz, 2H), 6.01(s, 1H), 4.08(s, 2H) 3.66( t, J=5.4Hz, 2H), 3.26-3.21(m, 1H), 2.50(s, 2H), 1.49(s, 9H), 1.33(d, J=6.6, 6H).

Step 2: 5-Chloro-N2-(2-(difluoromethoxy)-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N4-(2-(iso Preparation of Propylsulfonylphenyl)pyrimidine-2,4-diamine

4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)pyrimidin-2-yl)amino)-3-(difluoromethoxy yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (100 mg, 0.154 mmol) was dissolved in MeOH, to which was added 7 ml of dioxane dissolved in 4M HCl, It was then stirred at room temperature for 1 hour. Immediately after the completion of the reaction, HCl was removed, followed by decantation with ether. As a result, 90 mg of the target compound was obtained as a yellow solid (yield: 95%).

¹ H-NMR (300MHz, MeOD) δ8.31(s, 1H), 8.11-8.00(m, 1H), 8.00(d, J=10.8Hz, 1H), 7.62-7.55(m, 4H), 7.38( s, 1H), 6.24(d, J=0.9Hz, 1H), 3.9(s, 2H), 3.50(s, 2H), 2.82(s, 2H), 1.23(d, J=4.2Hz, 6H).

Example 4: 5-Chloro-N2-(2-(difluoromethoxy)-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl) Preparation of pyrimidine-2,4-diamine

Step 1: 4-(4-((5-Chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-(difluoromethoxy) Preparation of tert-butyl phenyl)piperidine-1-carboxylate

2,5-Dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine (87mg, 0.25mmol) was dissolved in 3ml of THF, and 4-(4-amino - tert-butyl 3-(difluoromethoxy)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (85 mg, 0.25 mmol). 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (15 mg, 0.025 mmol) and Cs ₂ CO ₃ (244 mg, 0.75 mmol) were sequentially added thereto, followed by degassing by filling with nitrogen . To this was added Pd(OAc) ₂ (2.8mg, 0.013mmol). After filling with nitrogen, the reaction mixture was stirred at 130 °C for 18 hours. After completion of the reaction, the mixture was then extracted with EA/ _H2O . The organic layer was dried over MgSO ₄ , filtered, and concentrated. Column chromatography (Hx:EA4:1) was performed to obtain the title compound (25 mg, yield: 18%).

¹ H-NMR (300MHz, CDCl3) δ9.61(s, 1H), 8.53(d; J=8.4Hz, 1H) 8.22(t, J=8.1Hz, 2H), 7.93(d, J=7.8, 1H ), 7.64(t, J=8.1, 1H), 7.28(d, J=7.5Hz, 2H), 7.01(d, J=8.7Hz, 2H), 4.28-4.24(m, 2H), 3.25-3.21( m, 1H), 2.84(t, J=12.9Hz, 2H), 2.67(t, J=12.3Hz, 1H), 2.17(s, 1H), 1.85(d, J=12.3Hz, 2H), 1.49(s , 9H), 1.32 (d, J=6.6Hz, 6H).

Step 2: 5-Chloro-N2-(2-(difluoromethoxy)-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine - Preparation of 2,4-diamine

The 4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-(difluoro Methoxy)phenyl)piperidine-1-carboxylic acid tert-butyl ester compound (23 mg, 0.042 mmol) was dissolved in MeOH, 3 ml of dioxane dissolved in 4M HCl was added thereto, followed by stirring at room temperature for 1 Hour. After the reaction was complete, HCl was then removed followed by decantation with ether. As a result, 21 mg of the target compound was obtained as a yellow solid (yield: 93%).

¹ H-NMR (300MHz, MeOD) δ8.26-8.25(m, 1H), 8.16-8.14(m, 1H), 7.95-7.94(m, 1H), 7.68-7.48(m, 2H), 7.24-7.07(m , 1H), 3.64(s, 1H), 3.57-3.51(m, 1H), 1.28(d, J=19.8Hz, 6H).

Example 5: 5-chloro-N4-(2-(isopropylsulfonyl)phenyl)-N2-(2-methoxy-4-(piperidin-4-yl)phenyl)pyrimidine-2, Preparation of 4-diamine

Step 1: 4-(4-((5-Chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piper Preparation of tert-butyl pyridine-1-carboxylate

2,5-dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine (274 mg, 0.79 mmol) was dissolved in 20 ml of THF, and 4-(4-amino -tert-butyl 3-methoxyphenyl)piperidine-1-carboxylate (243 mg, 0.79 mmol). 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (46 mg, 0.079 mmol) and Cs ₂ CO ₃ (772 mg, 2.37 mmol) were sequentially added thereto, followed by degassing by filling with nitrogen . To this was added Pd(OAc) ₂ (8.86mg, 0.039mmol). After filling with nitrogen, the reaction mixture was stirred at 130 °C for 18 hours. After completion of the reaction, the mixture was then extracted with EA/ _H2O . The organic layer was dried over MgSO ₄ , filtered, and concentrated. Column chromatography (Hx:EA 4:1) was performed to obtain the title compound (180 mg, yield: 37%).

¹ H-NMR (300MHz, CDCl3) δ9.54(s, 1H), 8.59(d, J=8.4Hz, 1H), 8.17(d, J=7.5Hz, 2H), 7.93-7.90(m, 1H) , 7.67-7.50(m, 1H), 7.30(s, 1H), 7.30-7.28(d, J=7.8Hz, 1H), 6.75-6.73(m, 2H), 4.23(brs, 2H), 4.15-4.08 (m, 1H), 3.8(s, 3H), 3.26-3.22(m, 1H), 2.85-2.76(m, 2H), 2.66-2.58(m, 1H), 1.86-1.81(m, 2H), 1.49 (s, 9H), 1.32 (d, J=6.6Hz, 6H).

Step 2: 5-Chloro-N4-(2-(isopropylsulfonyl)phenyl)-N2-(2-methoxy-4-(piperidin-4-yl)phenyl)pyrimidine-2,4 - Preparation of diamines

4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxy obtained in step 1 Phenyl)piperidine-1-carboxylic acid tert-butyl ester (170 mg, 0.28 mmol) was dissolved in MeOH, to which was added 3 ml of dioxane dissolved in 4M HCl, followed by stirring at room temperature for 0.5 hr. After the reaction was complete, HCl was then removed followed by decantation with ether. As a result, 150 mg of the target compound was obtained (yield: 99%).

¹ H-NMR (300MHz, MeOD) δ8.22 (brs, 1H), 8.01 (d, J=5.7Hz, 1H), 7.75-7.73 (m, 1H), 7.59-7.57 (m, 1H), 7.38-7.36 (m, 1H), 7.05(s, 1H), 6.86-6.83(m, 1H), 3.89(s, 3H), 3.55-3.49(m, 2H), 3.20-3.16(m, 2H), 3.01-2.94( m, 1H), 2.11-1.95(m, 4H), 1.25(d, J=5.4Hz, 6H).

Example 6: N4-(2-(isopropylsulfonyl)phenyl)-N2-(2-methoxy-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl )-5-(trifluoromethyl)pyrimidine-2,4-diamine preparation

Step 1: 4-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxy Preparation of tert-butyl phenyl)-5,6-dihydropyridine-1(2H)-carboxylate

Dissolve 2-chloro-N-(2-(isopropylsulfonyl)phenyl)-5-(trifluoromethyl)pyrimidin-4-amine (100mg, 0.26mmol) in 2ml of THF, add tert-butyl 4-(4-amino-3-methoxyphenyl)-5,6-dihydropyridine-1(2H)-carboxylate (160 mg, 0.53 mmol). 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (15 mg, 0.026 mmol) and Cs ₂ CO ₃ (275 mg, 0.79 mmol) were sequentially added thereto, followed by degassing by filling with nitrogen . To this was added Pd(OAc) ₂ (3mg, 0.013mmol). After filling with nitrogen, the reaction mixture was stirred at 150 °C for 2 hours. After completion of the reaction, the mixture was then extracted with EA/ _H2O . The organic layer was dried over MgSO ₄ , filtered, and concentrated. Column chromatography (Hx:EA 4:1) was performed to obtain the title compound (15 mg, yield: 8.4%).

¹ H-NMR (300MHz, CDCl3) δ9.63(s, 1H), 8.60(s, 1H), 7.92(d, J=6Hz, 1H), 7.82(D, J=9Hz, 1H), 7.14-7.06 (m, 3H), 6.98-6.88(m, 1H), 6.19(s, 1H), 4.17(s, 1H), 4.07(brs, 1H), 3.90(s, 1H), 3.73(s, 1H), 3.64(s, 3H), 3.17-3.13(m, 1H), 2.62(s, 1H), 2.51-2.49(m, 1H), 2.2(s, 1H), 1.49(s, 9H), 1.27(d, J=5.7Hz, 6H).

Step 2: N4-(2-(isopropylsulfonyl)phenyl)-N2-(2-methoxy-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl) - Preparation of 5-(trifluoromethyl)pyrimidine-2,4-diamine

4-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)- tert-butyl 3-methoxyphenyl)-5,6-dihydropyridine-1(2H)-carboxylate (14 mg, 0.021 mmol) was dissolved in MeOH, to which was added 2 ml of dioxygen dissolved in 4M HCl Hexacyclic followed by stirring at room temperature for 0.5 h. After the reaction was complete, HCl was then removed followed by decantation with ether. As a result, 14 mg of the target compound was obtained (yield: 99%).

¹ H-NMR (300MHz, MeOD) δ8.49-8.47m, 1H), 8.00(d, J=1.5Hz, 2H), 7.77-7.76(m, 1H), 7.61-7.58(m, 3H), 7.13 -7.11(m, 1H), 6.86-6.84(m, 1H), 6.18(s, 1H), 3.9(s, 3H), 3.88-3.86(m, 2H), 3.50-3.47(m, 2H), 2.82 -2.79(m, 2H), 1.22(d, J=3Hz, 6H).

Example 7: N2-(2-isopropoxy-5-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N4-(2-(isopropyl Preparation of (sulfonyl)phenyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine

Step 1: 4-(5-Isopropoxy-4-((4-((2-(isopropylsulfonyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl) Preparation of tert-butyl amino)-2-methylphenyl)-5,6-dihydropyridine-1(2H)-carboxylate

Dissolve 2-chloro-N-(2-(isopropylsulfonyl)phenyl)-5-(trifluoromethyl)pyrimidin-4-amine (5mg, 0.58mmol) in 2ml of THF and add tert-butyl 4-(4-amino-5-isopropoxy-2-methylphenyl)-5,6-dihydropyridine-1(2H)-carboxylate (139 mg, 0.42 mmol). 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (12 mg, 0.021 mmol) and Cs ₂ CO ₃ (205 mg, 0.63 mmol) were sequentially added thereto, followed by degassing by filling with nitrogen . To this was added Pd(OAc) ₂ (3mg, 0.0105mmol). After filling with nitrogen, the reaction mixture was stirred at 150 °C for 2 hours. After completion of the reaction, the mixture was then extracted with EA/ _H2O . The organic layer was dried over MgSO ₄ , filtered, and concentrated. Column chromatography (Hx:EA 4:1) was performed to obtain the target compound (26 mg, yield: 17%).

¹ H-NMR (300MHz, CDCl3) δ9.12(s, 1H), 8.41(s, 1H), 8.31-8.28(m, 1H), 7.97(d, J=7.8Hz, 2H), 7.82(s, 1H), 7.64-7.58(m, 1H), 7.34-7.26(m, 1H), 6.63(s, 1H), 5.54-5.53(m, 1H), 4.59(t, J=6Hz, 1H), 4.03( s, 2H), 3.63-3.59(m, 2H), 3.26-3.21(m, 1H), 2.32(s, 2H), 1.97(s, 3H), 1.50(s, 9H), 1.38(d, J= 6.3Hz, 6H), 1.31(d, J=6.9Hz, 6H).

Step 2: N2-(2-isopropoxy-5-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N4-(2-(isopropyl Preparation of sulfonyl)phenyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine

4-(5-isopropoxy-4-((4-((2-(isopropylsulfonyl)phenyl)amino)-5-(trifluoromethyl)pyrimidine- 2-yl)amino)-2-methylphenyl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (26 mg, 0.038 mmol) was dissolved in MeOH, to which was added 3 ml of Dioxane in 4M HCl, followed by stirring at room temperature for 1 hour. After the reaction was complete, HCl was then removed followed by decantation with ether. As a result, 25 mg of the target compound was obtained (yield: 99%).

¹ H-NMR (300MHz, MeOD) δ8.54-8.50(m, 1H), 8.05(d, J=9Hz, 1H), 7.80-7.75(m, 1H), 7.637.58(m, 1H), 7.35 (s, 1H), 6.82(s, 1H), 5.63(d, J=1.2Hz, 1H), 4.66-4.62(m, 1H), 3.83(s, 2H), 3.74-3.72(m, 1H), 3.59-3.57(m, 1H), 2.58(s, 2H), 2.03-2.01(s, 3H), 1.32(d, J=6Hz, 6H), 1.24(d, J=6.9Hz, 6H).

Example 8: N2-(2-(difluoromethoxy)-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N4-(2-(isopropylsulfonate Preparation of acyl)phenyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine

Step 1: 4-(3-(Difluoromethoxy)-4-((4-((2-(isopropylsulfonyl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-2 Preparation of -yl)amino)phenyl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

Dissolve 2-chloro-N-(2-(isopropylsulfonyl)phenyl)-5-(trifluoromethyl)pyrimidin-4-amine (35mg, 0.08mmol) in 2ml of THF, add tert-butyl 4-(4-amino-3-(difluoromethoxy)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (54 mg, 0.16 mmol). 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (5 mg, 0.008 mmol) and Cs ₂ CO ₃ (77 mg, 0.24 mmol) were sequentially added thereto, followed by degassing by filling with nitrogen . To this was added Pd(OAc) ₂ (1 mg, 0.004 mmol). After filling with nitrogen, the reaction mixture was stirred at 150 °C for 1 hour. After completion of the reaction, the mixture was then extracted with EA/ _H2O . The organic layer was dried over MgSO ₄ , filtered, and concentrated. Column chromatography (Hx:EA 4:1) was performed to obtain the title compound (3.5 mg, yield: 7%).

¹ H-NMR (300MHz, CDCl3) δ9.25(s, 1H), 8.43(s, 1H), 8.30-8.27(m, 1H), 8.23-8.20(m, 1H), 7.97-7.94(m, 1H ), 7.65-7.59(m, 1H), 7.54(s, 1H), 7.37-7.32(m, 1H), 7.16(s, 1H), 7.11-7.08(m, 1H), 6.03-6.00(m, 1H ), 4.10(s, 2H), 3.66-3.63(m, 2H), 3.25-3.16(m, 1H), 2.49-2.48(m, 2H), 2.04(s, 3H), 1.49(s, 9H), 1.31(d, J=6, 9Hz, 6H).

Step 2: N2-(2-(Difluoromethoxy)-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl) ) phenyl)-5-(trifluoromethyl)pyrimidine-2, the preparation of 4-diamine

4-(3-(difluoromethoxy)-4-((4-((2-(isopropylsulfonyl)phenyl)amino)-5-(trifluoromethyl) obtained in step 1 )pyrimidin-2-yl)amino)phenyl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (3.5mg, 3.53mmol) was dissolved in MeOH, to which was added 1ml dissolved in 4M Dioxane in HCl, followed by stirring at room temperature for 0.5 h. After the reaction was complete, HCl was then removed followed by decantation with ether. As a result, 7 mg of the target compound was obtained (yield: 99%).

¹ H-NMR (300MHz, MeOD) δ8.51(s, 1H), 7.99(d, J=4.5Hz, 1H), 7.71(s, 1H), 7.63(d, J=4.2Hz, 1H), 7.58 -7.55(m, 1H), 7.33(s, 1H), 7.20-7.18(m, 1H), 6.21(s, 1H), 3.90(s, 2H), 3.51-3.50(m, 3H), 2.81(s , 2H), 1.22 (d, J=3.9Hz, 6H).

Example 9: N2-(2-(difluoromethoxy)-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)-5-( Preparation of trifluoromethyl)pyrimidine-2,4-diamine

Step 1: 4-(3-(Difluoromethoxy)-4-((4-((2-(isopropylsulfonyl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-2 Preparation of -yl)amino)phenyl)piperidine-1-carboxylic acid tert-butyl ester

Dissolve 2-chloro-N-(2-(isopropylsulfonyl)phenyl)-5-(trifluoromethyl)pyrimidin-4-amine (60mg, 0.16mmol) in 3ml of THF and add tert-butyl 4-(4-amino-3-(difluoromethoxy)phenyl)piperidine-1-carboxylate (110 mg, 0.32 mmol). 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (9 mg, 0.32 mmol) and Cs ₂ CO ₃ (156 mg, 0.48 mmol) were sequentially added thereto, followed by degassing by filling with nitrogen . To this was added Pd(OAc) ₂ (2mg, 0.008mmol). After filling with nitrogen, the reaction mixture was stirred at 130 °C for 18 hours. After completion of the reaction, the mixture was then extracted with EA/ _H2O . The organic layer was dried over MgSO ₄ , filtered, and concentrated. Column chromatography (Hx:EA 4:1) was performed to obtain the title compound (35 mg, yield: 32%).

¹ H-NMR (300MHz, CDCl3), δ9.43(s, 1H), 8.38(s, 1H), 8.19(d, J=8.4Hz, 1H), 7.89(dd, J=7.8Hz, 8.1Hz, 1H), 7.53-7.48(m, 1H), 7.39(s, 1H), 7.22(t, J=7.5Hz, 1H), 7.11-7.08(m, 1H), 7.04(s, 1H), 4.29-4.23 (m, 2H), 3.29-3.20(m, 1H), 2.86-2.77(m, 1H), 2.72-2.63(m, 1H), 2.17(s, 1H), 2.04(s, 1H), 1.87-1.83 (m, 4H), 1.49(s, 9H), 1.31(d, J=6.9Hz, 6H).

Step 2: N2-(2-(Difluoromethoxy)-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)-5-(tri Preparation of fluoromethyl)pyrimidine-2,4-diamine

4-(3-(difluoromethoxy)-4-((4-((2-(isopropylsulfonyl)phenyl)amino)-5-(trifluoromethyl) obtained in step 1 )pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylic acid tert-butyl ester (35 mg, 0.051 mmol) was dissolved in MeOH, to which was added 3 ml of dioxane dissolved in 4M HCl, followed by Stir at room temperature for 0.5 hours. After the reaction was complete, HCl was then removed followed by decantation with ether. As a result, 29 mg of the target compound was obtained (yield: 99%).

1H-NMR (300MHz, MeOD), δ8.50(s, 1H), 7.90-7.78(m, 2H), 7.48-4.45(m, 3H), 7.23-7.19(m, 2H), 3.75-3.72(m , 1H), 3.59-3.53(m, 2H), 2.14-1.88(m, 5H), 1.19-1.15(m, 6H).

Example 10: 5-chloro-N2-(5-fluoro-2-methoxy-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N4-(2-( Preparation of isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine

Step 1: 4-(4-((5-Chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-5-methoxy Preparation of tert-butyl phenyl)-5,6-dihydropyridine-1(2H)-carboxylate

2,5-dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine (123 mg, 0.35 mmol) was dissolved in 4 ml of THF, and 4-(4-amino - tert-butyl 2-fluoro-5-methoxyphenyl)-5,6-dihydropyridine-1(2H)-carboxylate (115 mg, 0.35 mmol). 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (20 mg, 0.033 mmol) and Cs ₂ CO ₃ (322 mg, 1 mmol) were sequentially added thereto, followed by degassing by filling nitrogen. To this was added Pd(OAc) ₂ (4mg, 0.033mmol). After filling with nitrogen, the reaction mixture was stirred at 130° C. for 8 hours. After completion of the reaction, the mixture was then extracted with EA/ _H2O . The organic layer was dried over MgSO ₄ , filtered, and concentrated. Column chromatography (Hx:EA 4:1) was performed to obtain the target compound (82 mg, yield: 37%).

¹ H-NMR (300MHz, CDCl3) δ9.54(brs, 1H), 8.52-8.49(m, 1H), 8.19-8.12(m, 2H), 7.95-7.92(m, 1H), 7.74-7.66(m , 2H), 7.33-7.26(m, 2H), 6.72-6.69(m, 1H), 5.92-5.90(m, 1H), 4.08(s, 2H), 3.90(d, J=3.9Hz, 3H), 3.64 -3.62(m, 2H), 3.24-3.22(m, 1H), 2.52(brs, 2H), 2.05(d, J=3.9Hz, 1H), 1.61(d, 4H), 1.51(d, J=3.9 Hz, 9H), 1.31-1.29 (m, 6H).

Step 2: 5-chloro-N2-(5-fluoro-2-methoxy-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N4-(2-(iso Preparation of propylsulfonyl)phenyl)pyrimidine-2,4-diamine

The 4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-5 -methoxyphenyl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (70 mg, 0.11 mmol) was dissolved in MeOH, to which was added 3 ml of dioxane dissolved in 4M HCl ring, followed by stirring at room temperature for 0.5 h. After the reaction was complete, HCl was then removed followed by decantation with ether. As a result, 77 mg of the target compound was obtained (yield: 99%).

¹ H NMR (MeOD, 300MHz) δ8.43(s, 1H), 8.17-8.11(m, 2H), 7.917.86(m, 1H), 7.72-7.67(m, 1H), 7.53(d, J= 12.3Hz, 1H), 7.08(d, J=6.6Hz, 1H), 6.12(s, 1H), 4.0(s, 3H), 3.81(d, J=5.1Hz, 1H), 3.67(d, J= 3.4Hz, 1H), 3.53(m, 3H), 2.85(s, 2H), 1.32(d, J=6.6Hz, 6H).

Example 11: 5-chloro-N4-(2-(isopropylsulfonyl)phenyl)-N2-(2-methoxy-5-methyl-4-(1,2,3,6-tetra Preparation of hydropyridin-4-yl)phenyl)pyrimidine-2,4-diamine

Step 1: 4-(4-((5-Chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methanol Preparation of tert-butyl phenyl)-5,6-dihydropyridine-1(2H)-carboxylate

2,5-Dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine (107mg, 0.31mmol) was dissolved in 4ml of THF, and 4-(4-amino - tert-butyl 5-methoxy-2-methylphenyl)-5,6-dihydropyridine-1(2H)-carboxylate (100 mg, 0.31 mmol). 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (18 mg, 0.31 mmol) and Cs ₂ CO ₃ (303 mg, 0.93 mmol) were sequentially added thereto, followed by degassing by filling with nitrogen . To this was added Pd(OAc) ₂ (4mg, 0.015mmol). After filling with nitrogen, the reaction mixture was stirred at 130 °C for 18 hours. After completion of the reaction, the mixture was then extracted with EA/ _H2O . The organic layer was dried over MgSO ₄ , filtered, and concentrated. Column chromatography (Hx:EA 4:1) was performed to obtain the target compound (32 mg, yield: 17%).

¹ H NMR (CDCl ₃ , 300MHz) δ9.5(s, 1H), 8.57(d, J=8.4Hz, 1H), 8.16(s, 1H), 7.94(dd, J=7.8, 8.1Hz, 1H) , 7.66-7.60(m, 1H), 7.51(s, 1H), 6.61(s, 1H), 5.55(s, 1H), 4.04(d, 2.4Hz, 2H), 3.87(s, 3H), 3.64( t, J=5.4Hz), 3.27-3.23(m, 1H), 2.34(d, J=0.9Hz), 2.12(s, 3H), 1.50(s, 9H), 1.32(d, J=6.9Hz) .

Step 2: 5-Chloro-N4-(2-(isopropylsulfonyl)phenyl)-N2-(2-methoxy-5-methyl-4-(1,2,3,6-tetrahydro Preparation of pyridin-4-yl)phenyl)pyrimidine-2,4-diamine

4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy obtained in step 1 -2-Methylphenyl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (27 mg, 0.04 mmol) was dissolved in MeOH, to which was added 3 ml of dioxygen dissolved in 4M HCl Hexacyclone, followed by stirring at room temperature for 1 hour. After the reaction was complete, HCl was then removed followed by decantation with ether. As a result, 30 mg of the target compound was obtained (yield: 99%).

¹ H NMR (MeOD.300MHz) δ8.24(s, 1H), 8.03(d, J=7.56Hz, 1H), 6.52-6.46(m, 1H), 6.34(t, J=7.5Hz, 1H), 7.31(s, 1H), 6.88(s, 1H), 5.67(s, 1H), 3.85(s, 3H), 3.75-3.71(m, 1H), 3.59-3.57(m, 1H), 2.62(s, 2H), 2.14(s, 3H), 1.26(d, J=6.3Hz, 6H).

Example 12: 5-Chloro-N2-(5-fluoro-2-methoxy-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl) Preparation of pyrimidine-2,4-diamine

Step 1: 4-(4-((5-Chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-5-methoxy Preparation of tert-butyl phenyl)piperidine-1-carboxylate

2,5-dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine (97mg, 0.28mmol) was dissolved in 5ml of THF, and 4-(4-amino - tert-butyl 2-fluoro-5-methoxyphenyl)-5,6-dihydropyridine-1(2H)-carboxylate (90 mg, 0.28 mmol). 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (17 mg, 0.03 mmol) and Cs ₂ CO ₃ (275 mg, 0.84 mmol) were sequentially added thereto, followed by degassing by filling with nitrogen . To this was added Pd(OAc) ₂ (4mg, 0.05mmol). After filling with nitrogen, the reaction mixture was stirred at 120 °C for 18 hours. After completion of the reaction, the mixture was then extracted with EA/ _H2O . The organic layer was dried over MgSO ₄ , filtered, and concentrated. Column chromatography (Hx:EA4:1) was performed to obtain the title compound (75.5 mg, yield: 42%).

¹ H NMR (CDCl ₃ , 300MHz) δ9.5(s, 1H), 8.51(d, J=8.4Hz, 1H), 8.17(s, 1H), 8.13(d, J=12.9Hz, 1H), 7.94 (dd, J=8.1Hz, 8.1Hz), 7.74-7.69(m, 1H), 7.60(s, 1H), 6.65(d, J=6.6Hz), 4.15-4.08(m, 1H), 3.87(s , 3H), 3.24-3.19(m, 1H), 2.86(t, J=12.6Hz, 2H), 1.82(d, J=12.3Hz, 2H), 1.49(s, 9H), 1.32(d, J= 6.9Hz, 1H).

Step 2: 5-Chloro-N2-(5-fluoro-2-methoxy-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine - Preparation of 2,4-diamine

The 4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-5 -Methoxyphenyl)piperidine-1-carboxylic acid tert-butyl ester (75mg, 0.048mmol) was dissolved in MeOH, to which was added 3ml of dioxane dissolved in 4M HCl, followed by stirring at room temperature for 1 hour . After the reaction was complete, HCl was then removed followed by decantation with ether. As a result, 65 mg of the target compound was obtained (yield: 99%).

¹ H NMR (MeOD, 300MHz) δ8.34(s, 1H), 8.12-8.09(m, 1H), 8.04-8.02(d, J=7.8Hz, 1H), 7.82-7.77(m, 1H), 7.63 -7.58(m, 1H), 7.40(d, J=11.7Hz, 1H), 6.96(d, J=6.6Hz, 1H), 3.91(s, 3H), 3.73(d, J=5.1Hz, 1H) , 3.59(d, J=4.5Hz, 2H), 3.40-3.36(m, 1H), 3.18-3.16(m, 3H), 1.24(d, J=6.6Hz, 6H).

Example 13: 5-Chloro-N4-(2-(isopropylsulfonyl)phenyl)-N2-(2-methoxy-5-methyl-4-(piperidin-4-yl)phenyl ) pyrimidine-2, the preparation of 4-diamine

Step 1: 4-(4-((5-Chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methanol Preparation of tert-butyl phenyl)piperidine-1-carboxylate

2,5-Dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine (86 mg, 0.25 mmol) was dissolved in 3 ml of THF, and 4-(4-amino - tert-butyl 5-methoxy-2-methylphenyl)piperidine-1-carboxylate (80 mg, 0.25 mmol). 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (15 mg, 0.025 mmol) and Cs ₂ CO ₃ (244 mg, 0.75 mmol) were sequentially added thereto, followed by degassing by filling with nitrogen . To this was added Pd(OAc) ₂ (3mg, 0.012mmol). After filling with nitrogen, the reaction mixture was stirred at 130 °C for 18 hours. After completion of the reaction, the mixture was then extracted with EA/ _H2O . The organic layer was dried over MgSO ₄ , filtered, and concentrated. Column chromatography (Hx:EA 4:1) was performed to obtain the target compound (30 mg, yield: 20%).

¹ H NMR (CDCl ₃ , 300MHz) δ9.51(s, 1H), 8.59(d, J=8.4Hz, 1H), 8.15(s, 1H), 8.00(s, 1H), 7.94(dd, J= 12, 8.1Hz, 1H), 7.65-7.59(m, 1H), 7.47((s, 1H), 6.69(s, 1H), 4.29(d, J=20.1Hz, 2H), 3.86(s, 3H) , 3.28-3.23(m, 1H), 2.86-2.78(m, 3H), 2.19(s, 3H), 1.77-1.73(d, J=12.6Hz, 2H), 1.49(s, 9H), 1.32(d , J=6.9Hz, 6H).

Step 2: 5-Chloro-N4-(2-(isopropylsulfonyl)phenyl)-N2-(2-methoxy-5-methyl-4-(piperidin-4-yl)phenyl) Preparation of pyrimidine-2,4-diamine

4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy obtained in step 1 -2-methylphenyl)piperidine-1-carboxylic acid tert-butyl ester (17 mg, 0.026 mmol) was dissolved in MeOH, 3 ml of dioxane dissolved in 4M HCl was added thereto, followed by stirring at room temperature for 0.5 Hour. After the reaction was complete, HCl was then removed followed by decantation with ether. As a result, 15 mg of the target compound was obtained (yield: 99%).

¹ H NMR (MeOD, 300MHz) δ8.27-8.23(m, 1H), 8.01(d, J=7.5Hz, 1H), 7.75-7.71(m, 1H), 7.57-7.52(m, 1H), 7.31 (s, 1H), 6.9 (s, 1H), 3.88 (s, 3H), 3.73 (d, J = 5.1Hz, 1H), 3.65 (s, 2H), 3.57-3.47 (m, 3H), 3.21- 3.18(m, 2H), 2.22(s, 3H), 1.25(d, J=5.4Hz, 6H).

Example 14: 5-chloro-N2-(4-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-methoxyphenyl)-N4-(2- Preparation of (isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine

The 5-chloro-N4-(2-(isopropylsulfonyl)phenyl)-N2-(2-methoxy-4-(1,2,3,6-tetrahydro Pyridin-4-yl)phenyl)pyrimidine-2,4-diamine (50mg, 0.097mmol) was dissolved in 1ml of EtOH, to which DIPEA (0.06ml, 0.375mmol) was added under stirring. Iodoethane (0.016ml, 0.15mmol) was added thereto, followed by stirring at room temperature for 18 hours. After completion of the reaction, the mixture was then extracted with MC/ _H2O . The organic layer was dried over MgSO ₄ and concentrated. Column chromatography was performed to obtain the title compound (19.3 mg).

¹ H-NMR (300MHz, CDCl ₃ ), δ9.55(s, 1H), 8.56(d, J=8.4Hz, 1H), 8.25(d, J=9Hz, 1H), 8.16(s, 1H), 7.94(dd, J=1.5, 1.5Hz, 1H), 7.68-7.63(m, 1H), 7.59(s, 1H), 7.31-7.28(m, 1H), 6.91-6.88(m, 2H), 5.98( s, 1H), 5.29(s, 1H), 3.92(s, 3H), 3.56(s, 2H), 3.26-3.21(m, 1H), 3.15-3.11(m, 2H), 2.99-2.92(m, 2H), 2.83(s, 2H), 1.42(t, J=7.2Hz, 3H), 1.32(d, J=6.6Hz, 6H).

Example 15: 5-chloro-N2-(4-(1-hydroxyethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-methoxyphenyl)-N4-(2 Preparation of -(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine

The 5-chloro-N4-(2-(isopropylsulfonyl)phenyl)-N2-(2-methoxy-4-(1,2,3,6-tetrahydro Pyridin-4-yl)phenyl)pyrimidine-2,4-diamine (40 mg) was dissolved in 1 ml of DMF, to which CS ₂ CO ₃ (65 mg, 0.2 mmol) was added under stirring. Bromoethanol (0.01 ml, 0.12 mmol) was added thereto, followed by stirring at room temperature for 18 hours. After completion of the reaction, the mixture was then extracted with MC/ _H2O . The organic layer was dried over MgSO ₄ and concentrated. Column chromatography was performed to obtain the title compound (12 mg).

¹ H-NMR (300MHz, CDCl ₃ ), δ9.55(s, 1H), 8.58(d, J=7.8Hz, 1H), 8.25(d, J=9Hz, 1H), 8.17(s, 1H), 7.94-7.91(m, 1H), 7.68-7.63(m, 1H), 7.60(s, 1H), 6.93(s, 2H), 6.01(s, 1H), 3.92(s, 3H), 3.83-3.80( m, 2H), 3.64(s, 1H), 3.45(s, 2H), 3.28-3.19(m, 1H), 3.02-2.99(m, 2H), 2.88-2.85(m, 2H), 2.71-2.70( m, 2H), 1.32 (d, J=6.9Hz, 6H).

Example 16: 1-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxy Preparation of phenyl)-5,6-dihydropyridin-1(2H)-yl)ethanone

The 5-chloro-N4-(2-(isopropylsulfonyl)phenyl)-N2-(2-methoxy-4-(1,2,3,6-tetrahydro Pyridin-4-yl)phenyl)pyrimidine-2,4-diamine (50mg, 0.097mmol) was dissolved in _1ml of _CH2Cl2 , to which _Et3N (0.03ml, 0.23mmol) was added under stirring. Acetic anhydride (0.02ml, 0.15mmol) was added thereto, followed by stirring at room temperature for 18 hours. After completion of the reaction, the mixture was then extracted with MC/ _H2O . The organic layer was dried over MgSO ₄ and concentrated. Column chromatography was performed to obtain the title compound (40 mg).

¹ H-NMR (300MHz, CDCl ₃ ), δ9.57(s, 1H), 8.58(d, J=8.1Hz, 1H), 8.23(dd, J=2.4.0.9Hz, 1H), 8.16(s, 1H), 7.94(dd, J=1.5.1.5Hz, 1H), 7.67-7.62(m, 2H), 6.92-6.87(m, 2H), 6.03(d, 16.5Hz, 1H), 4.26(d, J =2.7Hz, 1H), 4.15(d, J=2.7Hz, 1H), 3.93(s, 3H), 3.85(t, J=5.7Hz, 1H), 3.70-3.66(m, 1H), 3.28-3.19 (m, 1H), 2.60-2.55(m, 2H), 2.18(d, J=8.7Hz, 3H), 1.32(d, J=6.9Hz, 6H).

Example 17: 4-(4-((5-Chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl) -5,6-Dihydropyridine-1(2H)-carboxylic acid

The 5-chloro-N4-(2-(isopropylsulfonyl)phenyl)-N2-(2-methoxy-4-(1,2,3,6-tetrahydro Pyridin-4-yl)phenyl)pyrimidine-2,4-diamine (50mg, 0.097mmol) was dissolved in _1ml of _CH2Cl2 , to which _Et3N (0.2ml) was added under stirring. Glycolic acid (0.01 ml, 0.15 mmol), EDCI (24 mg, 0.15 mmol) and DMAP (20 mg, 0.15 mmol) were added thereto, followed by stirring at room temperature for 18 hours. After completion of the reaction, the mixture was then extracted with MC/ _H2O . The organic layer was dried over MgSO ₄ and concentrated. Column chromatography was performed to obtain the title compound (28.4 mg).

¹ H-NMR (300MHz, CDC l ₃ ), δ9.57(s, 1H), 8.58(d, J=8.7Hz, 1H), 8.27(d, J=8.1Hz, 1H), 8.17(s, 1H ), 7.94(d, J=7.2Hz, 1H), 7.68-7.60(m, 1H), 7.31(d, J=8.1Hz, 1H), 6.92-6.87(m, 2H), 4.31-4.20(m, 3H), 3.96(s, 2H), 3.68(s, 1H), 3.52-3.49(m, 1H), 3.26-3.19(m, 1H), 2.60(s, 2H), 1.32(d, J=6.9Hz , 6H).

Example 18: 5-chloro-N2-(4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-methoxyphenyl)-N4-(2- Preparation of (isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine

The 5-chloro-N4-(2-(isopropylsulfonyl)phenyl)-N2-(2-methoxy-4-(1,2,3,6-tetrahydro Pyridin-4-yl)phenyl)pyrimidine-2,4-diamine (50 mg, 0.097 mmol) was dissolved in 1 ml of EtOH, to which DIPEA (0.08 ml, 0.45 mmol) was added with stirring. Iodomethane (0.01 ml, 0.15 mmol) was added thereto, followed by stirring at room temperature for 18 hours. After completion of the reaction, the mixture was then extracted with MC/ _H2O . The organic layer was dried over MgSO ₄ and concentrated. Column chromatography was performed to obtain the title compound (6.1 mg).

¹ H-NMR (300MHz, CDCl3), δ9.56(s, 1H), 8.55-8.53(m, 1H), 8.29-8.26(m, 1H), 8.17(s, 1H), 7.94(d, J= 8.1Hz, 1H), 7.70-7.63(m, 2H), 6.90(s, 2H), 5.97(s, 1H), 3.93(s, 3H), 3.74(s, 2H), 3.64(s, 1H), 3.24-3.21(m, 1H), 2.97-2.94(m, 2H), 2.85(s, 3H), 1.32(d, J=6.9Hz, 6H).

Table 1 shows the chemical formulas of the compounds prepared in Example 1 to Example 18.

Table 1

Experimental Example 1: Inhibition of Anaplastic Lymphoma Kinase (ALK) Activity

In order to measure the activity of the pyrimidine-2,4-diamine derivative represented by Formula 1 to inhibit anaplastic lymphoma kinase (ALK) at the enzyme level, the following experiments were performed.

In order to measure the activity of inhibiting ALK, each compound (2 μl) prepared in Examples 1 to 18 was loaded in a 96-well round bottom plate. Then, each compound was mixed with ALK enzyme (1 μl) and biotin-conjugated peptide substrate (2 μl), followed by incubation for 15 minutes. ATP solution (5 µl) was added thereto, followed by kinase reaction at room temperature for 30 minutes. Streptavidin-conjugated XL 665 (5 μl) and europium (Eu ³⁺ )-conjugated anti-phosphotyrosine antibody (5 μl) dissolved in ethylenediaminetetraacetic acid solution were added to the reaction solution, to terminate the reaction. Following completion of the reaction, a one-hour incubation followed by analysis using homogeneous time-resolved fluorescence (HTRF, Cisbio). _{OD615nm/665nm} was measured with Wallac Envision 2103. The _IC50 of each compound was determined using prism software (version 5.01, Graphpad).

Table 2 below shows the IC ₅₀ of each compound, which is the concentration that inhibits 50% of ALK enzyme activity and L1196M (ALK-containing non-small cell lung cancer cell line) activity.

Table 2

As shown in Table 2, the compounds of the present invention showed superior ALK inhibitory activity compared to the compounds of Control 1 and Control 2.

Specifically, all the compounds of Examples 1 to 18 showed stronger inhibitory activity than Control 1 (crizotinib). Except for the compounds of Example 7 and Example 9, most of these compounds of Examples 1 to 18 showed stronger activity than Control 2 (LDK-378).

From the experimental results of the present invention, it is confirmed that even at low concentrations, the pyrimidine-2,4-diamine derivatives of the present invention are effective in inhibiting ALK activity, in particular, compared with the conventional Compared with crizotinib (positive control), the pyrimidine-2,4-diamine derivatives of the present invention are more effective.

Therefore, the pyrimidine-2,4-diamine derivative of the present invention is excellent in inhibiting ALK activity, and therefore, it can be effectively used not only as an ALK inhibitor but also as a prophylaxis or treatment of cancers such as Composition of: non-small cell lung cancer, neuroblastoma, inflammatory myeloblastic tumor, rhabdomyosarcoma, myofibroblastic tumor, breast cancer, gastric cancer, lung cancer, and melanoma. Experimental Example 2: Inhibition of Cancer Cell Proliferation

The following experiments were conducted to investigate the activity of the pyrimidine-2,4-diamine derivatives represented by formula 1 of the present invention in inhibiting the proliferation of cancer cells.

<2-1>Experimental materials

Reagent

RPMI 1640, cell culture medium, FBS (fetal bovine serum) and trypsin were purchased from Gibco (Grand Island, NY), and sodium bicarbonate, amphotericin B and gentamicin were purchased from Sigma Chemical.

Reagents SRB (sulforhodamine) B, trisma base, trichloroacetic acid (TCA) used for cytotoxicity tests were purchased from Sigma Chemical. For ^MTS analysis, the CellTiter 96 ^R Aqueous Non-Radioactive Cell Proliferation Assay kit was purchased from Promega.

For cell culture, T-25 culture vessels, 96-well plates and other disposable glassware were purchased from Falcon (Lincoln Park, NJ).

device

E-max or SpectraMax 250 from Molecular Devices (Sunnyvale, CA) was used as ELISA reader for cytotoxicity testing.

<2-2> Experimental method

Step 1: Cell Culture

The final dimethylsulfoxide concentration was at most 0.5%.

The cancer cell lines used herein are all human-derived cancer cell lines, more specifically, non-small cell lung cancer cell line H2228 and non-small cell lung cancer cell line H3122.

For the medium, RPMI 1640 supplemented with 10% FBS (fetal bovine serum) was used. The cells were cultured in an incubator at 37°C and 5% CO ₂ , and subcultured every 3 to 4 days.

Step 2: Evaluation of Proliferation Inhibitory Activity Depending on Compound Treatment

Cells were distributed in 96-well flat-bottomed microplates at a density of 1 × ¹⁰⁴ cells per well, followed by incubation for 24 hours until cells were adhered to the bottom. Then, discard the culture medium. Each of the compounds of Example 1 to Example 18 diluted in the medium was added thereto, followed by further culturing for 72 hours. Following completion of incubation with these compounds, cytotoxicity was measured using SRB, protein staining reagents or using the MTS assay. After incubation with the compounds of Examples 1-18 is complete, the medium is removed and the wells will be treated with cold TCA solution. Place the plate at 4°C for 1 hour to fix the cells. The TCA solution was removed and the cells were dried at room temperature. A staining solution containing 0.4% SRB (dissolved in 1% acetic acid solution) was added to the cells and left at room temperature for 30 minutes to stain the cells. Excess SRB not yet conjugated to cells was removed by washing the plate with 1% acetic acid solution. 10 mM tris buffer (Trisma base; unbuffered) at pH 10.3-10.5 was added to the stained cells, followed by elution of SRB. The _OD520nm of each well was measured using a microplate reader.

The cytotoxicity of each compound was calculated using the OD value (C) of the compound-untreated wells, the OD value (T) of the compound-treated wells (T) and the OD value (Tz) of the first treated wells by the following formula,

When Tz=T, [(T-Tz)/(C-Tz)] 100; or

When Tz>T, [(T-Tz)/(Tz)]100.

The activity of compounds to inhibit proliferation of cancer cells was measured by using the MTS assay as follows. Specifically, when the cultivation with the compounds of Examples 1 to 18 is completed, the PMS solution and the MTS solution contained in the CellTiter96 ^R water-based non-radioactive cell proliferation assay kit (Promega) are mixed, and 20 μl of the described solution. After 4 hours, the plates were left at room temperature for 10 minutes. OD _490nm was measured using a SpectraMax250 (Molecular Device). _GI50 (growth inhibition 50%) was calculated to evaluate proliferation inhibitory activity, and the results are shown in Table 3 below.

table 3

As shown in Table 3, the compounds of the examples of the present invention inhibited ALK activity in non-small cell lung cancer cell line H2228 and non-small cell lung cancer cell line H3122, resulting in the inhibition of cell proliferation. The experimental results confirmed that, compared with the reference compound 1 and reference compound 2, which have been used to treat non-small cell lung cancer, most of the compounds of the present invention have excellent growth inhibitory effects on cancer cells.

Therefore, the pyrimidine-2,4-diamine derivative of the present invention is excellent in inhibiting ALK activity, and therefore, it can be effectively used not only as an ALK inhibitor but also as a prophylaxis or treatment of cancers such as Composition of: non-small cell lung cancer, neuroblastoma, inflammatory myeloblastic tumor, rhabdomyosarcoma, myofibroblastic tumor, breast cancer, gastric cancer, lung cancer, and melanoma. Experimental Example 3: Evaluation of Cytotoxicity in BaF3 Cells Transfected with EML4-ALK

The following experiment was performed to evaluate the cytotoxicity of the pyrimidine-2,4-diamine derivative represented by Formula 1 of the present invention in BaF3EML4-ALKL1196M cells and BaF3EML4-ALK WT cells.

Specifically, BaF3 cells were transfected with EML4-ALK wt (wild type) by using lentivirus to construct a BaF3 EML4-ALK wt cell line stably expressing EML4-ALK wt. In addition, BaF3 cells were transfected with EML4-ALK L1196M by using lentivirus to construct a BaF3EML4-ALK L1196M cell line stably expressing EML4-ALK L1196M. The number of cells of the above two cell lines was counted. Cells were distributed in 96-well plates at a density of 4,000 cells (90 μl) per well. Compounds of the Examples were added to individual wells of the plate at concentrations of 10 μM, 2 μM, 0.4 μM, 0.08 μM, 0.016 μM, 0.0032 μM, 0.00064 μM, and 0 μM. Cells were cultured in a 37°C incubator for 3 days. The WST-1 solution was added to each well of the culture plate (10 µl/well). When the color of the solution in the well changed, the OD _450nm was measured using an ELISA reader (EMax Endpoint ELISA microplate reader, Molecular Devices). _IC50 was calculated by calculating the cell volume using the obtained OD to show the cytotoxicity of each compound. The results are shown in Table 4.

Table 4

As shown in Table 4, in BaF3EML4-ALK WT (wild type) cells and BaF3EML4-ALK L1196M cells with crizotinib resistance, most of the compounds of the embodiments of the present invention are more effective than the control compound 1 and the control compound 2. out lower IC ₅₀ . The above results show that compared with the reference compound 1 and reference compound 2 which have been used in the treatment of non-small cell lung cancer, most of the compounds in the examples of the present invention have excellent ALK inhibitory activity.

Therefore, the pyrimidine-2,4-diamine derivative of the present invention is excellent in inhibiting ALK activity, and therefore, it can be effectively used not only as an ALK inhibitor but also as a prophylaxis or treatment of cancers such as Composition of: non-small cell lung cancer, neuroblastoma, inflammatory myeloblastic tumor, rhabdomyosarcoma, myofibroblastic tumor, breast cancer, gastric cancer, lung cancer, and melanoma.

Table 5 shows the results of Experimental Example 1 to Experimental Example 3 (Tables 2 to 4).

table 5

Meanwhile, the pyrimidine-2,4-diamine derivative represented by Formula 1 of the present invention can be prepared in various forms according to the purpose of use. The following are examples of formulations of pyrimidine-2,4-diamine derivatives represented by Formula 1 of the present invention, however, the examples do not limit the present invention thereto.

Production Example 1: Preparation of Pharmaceutical Preparations

1-1 Preparation of powder

Derivatives represented by formula 1 500mg

Lactose 100mg

Talc 10mg

The powder is prepared by mixing all the above-mentioned components and filling the components in an airtight package according to a conventional method for preparing a powder.

Preparation of 1-2 tablets

Tablets are prepared by mixing all the above ingredients by a conventional method for making tablets. 1-3 Preparation of Capsules

Capsules are prepared by mixing all the above-mentioned ingredients and filling said ingredients in gelatin capsules according to the conventional method for the preparation of capsules.

1-4 Preparation of Injectable Solutions

Derivatives represented by formula 1 500mg

Appropriate amount of sterilized distilled water

Appropriate amount of pH adjuster

Injectable solutions are prepared by mixing all the above-mentioned components and putting the mixture into 2 ml ampoules by a conventional method for preparing injectable solutions.

1-5 Preparation of Liquid Preparations

All the above components were dissolved in purified water. After adding the lemon flavor, the total volume was adjusted to 100 ml by adding purified water. The liquid preparation was prepared by putting the mixture into a brown bottle and sterilizing it by a conventional method for preparing a liquid preparation.

Industrial applicability

The compound of the present invention is excellent in inhibiting anaplastic lymphoma kinase (ALK), so the compound of the present invention can improve the therapeutic effect on cancer cells containing ALK fusion proteins (such as EML4-ALK and NPM-ALK), because the present invention The inventive compound is expected to be effective in preventing recurrence of cancer, and it can be effectively used as a pharmaceutical composition for preventing or treating cancer.

Those skilled in the art will appreciate that the conception and specific embodiment disclosed in the foregoing specification may be readily utilized as a basis for modifying or designing other embodiments for carrying out the same purposes of the present invention. Those skilled in the art will also realize that such equivalent embodiments do not depart from the spirit and scope of the invention as set forth in the appended claims.

Claims (7)

1. a kind of compound or its pharmaceutically acceptable salt, the compound is selected from the group being made up of following compound：

(1) the chloro- N4- of 5- (2- (isopropelsulfonyl) phenyl)-N2- (2- methoxyl groups -4- (1,2,3,6- tetrahydropyridine -4- bases) Phenyl) pyrimidine -2,4- diamines；

(2) the chloro- N2- of 5- (2- isopropoxy -5- methyl -4- (1,2,3,6- tetrahydropyridine -4- bases) phenyl)-N4- (2- (isopropyls Base sulfonyl) phenyl) pyrimidine -2,4- diamines；

(3) the chloro- N2- of 5- (2- (difluoro-methoxy) -4- (1,2,3,6- tetrahydropyridine -4- bases) phenyl)-N4- (2- (isopropyl sulphurs Aminosulfonylphenyl) pyrimidine -2,4- diamines；

(4) the chloro- N2- of 5- (2- (difluoro-methoxy) -4- (piperidin-4-yl) phenyl)-N4- (2- (isopropelsulfonyl) phenyl) are phonetic Pyridine -2,4- diamines；

(5) the chloro- N4- of 5- (2- (isopropelsulfonyl) phenyl)-N2- (2- methoxyl groups -4- (piperidin-4-yl) phenyl) pyrimidine -2, 4- diamines；

(6) N4- (2- (isopropelsulfonyl) phenyl)-N2- (2- methoxyl groups -4- (1,2,3,6- tetrahydropyridine -4- bases) phenyl) - 5- (trifluoromethyl) pyrimidine -2,4- diamines；

(10) the chloro- N2- of 5- (the fluoro- 2- methoxyl groups -4- of 5- (1,2,3,6- tetrahydropyridine -4- bases) phenyl)-N4- (2- (isopropyl sulphurs Acyl group) phenyl) pyrimidine -2,4- diamines；

(11) the chloro- N4- of 5- (2- (isopropelsulfonyl) phenyl)-N2- (2- methoxyl group -5- methyl -4- (1,2,3,6- tetrahydrochysene pyrroles Pyridine -4- bases) phenyl) pyrimidine -2,4- diamines；

(12) the chloro- N2- of 5- (fluoro- 2- methoxyl groups -4- (piperidin-4-yl) phenyl of 5-)-N4- (2- (isopropelsulfonyl) phenyl) are phonetic Pyridine -2,4- diamines；

(13) the chloro- N4- of 5- (2- (isopropelsulfonyl) phenyl)-N2- (2- methoxyl group -5- methyl -4- (piperidin-4-yl) phenyl) Pyrimidine -2,4- diamines；

(14) the chloro- N2- of 5- (4- (1- ethyl -1,2,3,6- tetrahydropyridine -4- bases) -2- methoxyphenyls)-N4- (2- (isopropyls Sulfonyl) phenyl) pyrimidine -2,4- diamines；

(15) (2- is (different by-N4- by the chloro- N2- of 5- (4- (1- hydroxyethyl -1,2,3,6- tetrahydropyridine -4- bases) -2- methoxyphenyls) Sulfonyl propyl base) phenyl) pyrimidine -2,4- diamines；

(16) 1- (4- (4- ((the chloro- 4- of 5- ((2- (isopropelsulfonyl) phenyl) amino) pyrimidine -2-base) amino) -3- methoxyl groups Phenyl) -5,6- dihydropyridines -1 (2H)-yl) ethyl ketone；

(17) 4- (4- ((the chloro- 4- of 5- ((2- (isopropelsulfonyl) phenyl) amino) pyrimidine -2-base) amino) -3- methoxybenzenes Base) -5,6- dihydropyridines -1 (2H)-formic acid；And

(18) 4- (4- ((the chloro- 4- of 5- ((2- (isopropelsulfonyl) phenyl) amino) pyrimidine -2-base) amino) -3- methoxybenzenes Base) -1 (2H)-methyl -5,6- dihydropyridines.

2. a kind of method for being used to prepare the compound of claim 1, methods described are included shown in following reaction equation 1 Following steps：

Step 1：Reacted by the compound for representing the compound that formula 2 represents and formula 3, the compound that formula 4 represents；And

Step 2：The compound represented by the compound that the formula 4 for making to prepare in step 1 represents with formula 5 is reacted, and formula 1 represents The compound.

[reaction equation 1]

In the reaction equation 1, R¹、R²、R³And R⁴Defined by the compound described in claim 1.

3. a kind of pharmaceutical composition for being used for prevention or treating cancer, described pharmaceutical composition contain describedization of claim 1 Compound or its pharmaceutically acceptable salt are as active component.

4. the pharmaceutical composition as claimed in claim 3 for being used for prevention or treating cancer, wherein, described pharmaceutical composition passes through Suppress anaplastic lymphoma kinase (ALK) activity to suppress cancer cell expression and growth.

Be used to prevent or the pharmaceutical composition for the treatment of cancer 5. as claimed in claim 3, wherein, the cancer be selected from by with Lower formed group：Non-small cell lung cancer, neuroblastoma, inflammatory haematogonium knurl, rhabdomyosarcoma, muscle fibre are female thin Born of the same parents' knurl, breast cancer, stomach cancer, lung cancer, melanoma, large B cell lymphoid tumor, generalized tissue cellular proliferative disorder, inflammatory muscle fibre Blastoma and esophageal squamous cell carcinoma.

6. a kind of pharmaceutical composition, described pharmaceutical composition contains the compound of claim 1 or its is pharmaceutically acceptable Salt as active component, for preventing or treating as the disease caused by anaplastic lymphoma kinase (ALK) overactivity.

7. a kind of anaplastic lymphoma kinase (ALK) inhibitor, the inhibitor contain claim 1 the compound or its Pharmaceutically acceptable salt is as active component.