Heteroaryl derivative and use thereof

Abstract

The present invention relates to: a heteroaryl derivative, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof; a method for preparing same; and a pharmaceutical composition containing same as an active ingredient for the prevention or treatment of cancer, wherein the heteroaryl derivative of the present invention can be usefully employed for the prevention or treatment of HER2-positive carcinoma.

Description

Heteroaryl derivatives and uses thereof

[0001] The present invention relates to a heteroaryl derivative, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, a method for preparing the same, and a pharmaceutical composition for preventing or treating cancer comprising the same as an active ingredient.

[0002] Cancer is often the result of mutations in numerous genes that play a role in a wide range of cellular processes. In many cases, cancer cells harbor mutations in genes that control processes such as cell growth, division, differentiation, or interaction with the extracellular environment. For example, mutations that increase the activity of the human epidermal growth factor receptor 2 (HER2), a cell surface receptor that promotes cell growth and division, are associated with many cancers.

[0003] Tumors are typically resistant to certain cancer drugs, or initially sensitive to a particular drug but later develop resistance. Resistance often results from mutations that alter cellular activity (e.g., mutations that constitutively activate signaling molecules) or alter gene expression (e.g., mutations that increase the expression of cell signaling receptors, such as HER2). Such drug resistance in tumors often coincides with, or results from, mutations that transform the cancer into a more aggressive (e.g., metastatic) form. Metastatic cancers are typically associated with a worse prognosis compared to non-metastatic cancers.

[0004] The MOUNTAINEER clinical trial (ClinicalTrials.gov Identifier #NCT03043313) reported that the combination of tucatinib and trastuzumab was effective in treating patients with HER2-positive metastatic colorectal cancer.

[0005] Furthermore, HER2 is an important prognostic and predictive factor in invasive breast cancer, with gene amplification observed in 20-25% of breast cancers, resulting in HER2 overexpression. Patients with breast cancer with HER2 gene amplification or overexpression have a poor prognosis, but are candidates for targeted therapy using trastuzumab (Herceptin, Genentech, South San Francisco, CA, USA), a monoclonal antibody against HER2. This amplification or overexpression of the HER2 gene has been reported in ovarian cancer, prostate cancer, colon cancer, pancreatic cancer, and gastric cancer in addition to breast cancer. Recently, a multi-center phase 3 clinical trial (ToGA trial) was published showing that when trastuzumab was administered in combination with existing chemotherapy (5-fluorouracil or capecitabine and cisplatin) to patients with HER2-positive advanced gastric cancer, the survival period of patients significantly increased compared to the group that received only the existing chemotherapy. As a result, HER2 status is becoming an important treatment predictor not only in breast cancer but also in gastric cancer.

[0006] In particular, cancers that overexpress HER2 (referred to as HER2-positive cancers) often have a poor prognosis or are resistant to many standard treatments. Therefore, new drugs are needed to effectively treat HER2-positive cancers or metastatic HER2-positive cancers.

[0007] One object of the present invention is to provide a compound, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof that can be used for preventing or treating cancer.

[0008] Another object of the present invention is to provide a method for producing the compound.

[0009] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer, which contains the compound, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0010] Another object of the present invention is to provide a method for preventing or treating cancer, comprising administering the compound, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0011] Another object of the present invention is to provide a use of the compound of formula 1, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof in the prevention or treatment of cancer.

[0012] To achieve the above purpose,

[0013] The present invention provides a compound of the following chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0014] [Chemical Formula 1]

[0015]

[0016] R 1 is a 5 to 12-membered heteroaryl containing one or more heteroatoms of N, S and O, wherein said heteroaryl is C 1-6 Alkyl, hydroxy (C 1-6 ) is unsubstituted or substituted with one or more substituents selected from alkyl, oxo (=O), and amine;

[0017] R 2 is pyridine, heterocycloalkyl containing one or more heteroatoms of N and O, or , wherein the pyridine is substituted or unsubstituted with an amine, and the heterocycloalkyl is hydroxy (C 1-6 ) is substituted or unsubstituted with alkyl, and the above R 4 and R5 are each independently hydrogen or hydroxy (C 1-6 ) is alkyl; and

[0018] R 3 Silver C 1-6 It's alkyl.

[0019] Another aspect of the present invention provides a method for producing a compound of the above chemical formula 1.

[0020] Another aspect of the present invention provides a pharmaceutical composition for preventing or treating cancer, comprising a compound of the present invention, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0021] The present invention also provides a method for preventing or treating cancer, comprising administering the compound, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0022] The present invention also provides the use of the compound of formula 1, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof in the prevention or treatment of cancer.

[0023] In one aspect of the present invention, the compound, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof exhibits high inhibitory activity against HER2, and therefore, a pharmaceutical composition containing the compound as an active ingredient can be usefully used for the prevention or treatment of diseases related to HER2, such as cancer, particularly HER2-positive cancer.

[0024] Figure 1 illustrates a synthetic scheme of compounds of Examples 1 to 5.

[0025] Figures 2 and 3 illustrate the synthetic schemes of compounds of Examples 6 to 25.

[0026] Figure 4 shows the results of Western blot after treating HCC1954 cells with each of the example compounds (9, 21, 25) for 2 hours. All of the compounds dose-dependently inhibited Pol II CTD (Ser2) phosphorylation at concentrations of 10 and 100 nM (4A), and it was confirmed that the example 25 compound showed superior Pol II CTD (Ser2) phosphorylation inhibition ability than dinaciclib (4B). When the proteasome inhibitor bortezomib (20 nM) was treated simultaneously, the degradation of cyclinK by the example 25 compound was inhibited and the inhibited CTD phosphorylation (Ser2) level was also restored, indicating that the degradation of cyclinK by the compound contributes to the cancer cell growth inhibitory activity of the compound (4C).

[0027] Figure 5 shows the genome-wide inhibitory activity of compound 25 (at a concentration of 10 μM) against 372 human-derived wild-type kinases. The percent residual activity for each kinase was visualized using TREEspotTM (https: / www.discoverx.com / services / drug-discovery-development-services / treespot-data-analysis), a web-based visualization tool.

[0028] Figure 6 shows the in vivo efficacy of Example 25 compound (10, 20 mg / kg, ip 2 / week) in the HCC1954 breast cancer orthotopic mouse model: (A) Tumor growth curves for each group. *p=0.006, **p<0.001. (B) Photographs of each resected tumor. (C) Body weights of mice for each group.

[0029] Figure 7 shows the hERG inhibition titration curve (IC) of Example 25 using Autopatch clamp. 50 = 37.9 μM).

[0030] Hereinafter, the present invention will be described in detail by way of an example.

[0031] The embodiments of the present invention may be modified in various ways, and the scope of the present invention is not limited to the embodiments described below. Furthermore, the embodiments of the present invention are provided to more fully explain the present invention to those of ordinary skill in the art.

[0032] Throughout the specification, reference to an element as "including" means that it may include other elements, but does not exclude other elements, unless otherwise specifically stated.

[0033] In the structural formulas of this specification, the symbol “-” that binds atoms and / or groups may indicate a single bond, and the symbol “=” may indicate a double bond. The above symbols may be omitted, and may also be indicated when necessary, such as when specifying a bonding atom or bonding position.

[0034] In this specification, “connected” between atoms may include not only cases where atoms are directly connected to each other, but also cases where atoms are indirectly connected to each other through other atoms and / or groups. In this case, the other atoms and / or groups are oxygen, sulfur, C 1-8 Alkylamino, or C 1-8 It may be, but is not limited to, an alkylene group, and the atoms and / or groups may be substituted or unsubstituted.

[0035] In this specification, “substituted or unsubstituted” may mean that one or more hydrogen atoms are substituted or unsubstituted with another atom or substituent unless otherwise stated. The substituents are halogen (chloro (Cl), iodo (I), bromo (Br), fluoro (F)), C 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, hydroxyl, C 1~10Alkoxy, amino, nitro, thiol, thioether, imine, cyano, phosphonato, phosphine, carboxy, carbamoyl, carbamic acid, acetal, urea, thiocarbonyl, sulfonyl, sulfonamide, ketone, aldehyde, ester, acetyl, isetoxy, amide, oxygen(=0), haloalkyl (e.g., trifluoromethyl), substituted aminoacyl and aminoalkyl, carbocyclic cycloalkyl which is monocyclic or fused or non-fused multiple rings (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or heterocycloalkyl which is monocyclic or fused or non-fused multiple rings (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiazinyl), carbocyclic or heterocyclic, It may be at least one selected from the group consisting of monocyclic or fused or non-fused multicyclic aryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothienyl or benzofuranyl), amino (primary, secondary or tertiary), aryl, aryloxy, and aryl-alkyl, but is not limited thereto. In addition, each of the above-mentioned exemplified substituents may be further substituted or unsubstituted with a substituent selected from these groups of substituents.

[0036] In this specification, “alkyl” may mean a straight or branched chain acyclic; cyclic; or a saturated hydrocarbon group combined therewith, unless otherwise stated. In addition, “C 1-6“Alkyl” may mean alkyl having 1 to 6 carbon atoms. Acyclic alkyl may include, but is not limited to, methyl, ethyl, N-propyl, N-butyl, N-pentyl, N-hexyl, N-heptyl, N-octyl, isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like, for example. Cyclic alkyl may include, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, and the like, for example. Alkyl in which acyclic and cyclic alkyl are combined may include, but is not limited to, methylcyclopropyl, cyclopropylmethyl, ethylcyclopropyl, cyclopropylethyl, methylcyclobutyl, It may include, but is not limited to, cyclobutylmethyl, ethylcyclopentyl, or cyclopentylmethyl.

[0037] In this specification, “hydroxyalkyl” may mean an alkyl group in which one or more hydrogen atoms are independently substituted with one or more -OH groups. Specifically, “hydroxy(C 1-6 )alkyl" may mean a straight or branched chain alkyl containing 1 to 6 carbon atoms, each of which is independently substituted with one or more hydrogen atoms by one or more -OH groups. For example, hydroxy (C 1-6 )alkyl can be hydroxymethyl, hydroxyethyl, hydroxypropyl, dihydroxypropyl, or dihydroxybutyl.

[0038] In this specification, when “cycloalkyl” is described, it may mean cyclic alkyl among alkyls, and alkyl here is as defined above.

[0039] As used herein, “heterocycloalkyl” may mean a hydrocarbon ring containing one or more heteroatoms selected from N, O, and S as ring-forming atoms, and may be saturated or partially unsaturated. Unless otherwise stated, a heterocycloalkyl may be monocyclic or polycyclic, such as a spiro ring, a bridged ring, or a fused ring. Also, “heterocycloalkyl having 3 to 12 atoms” may mean a heterocycloalkyl having 3 to 12 ring-forming atoms, and as an example, the heterocycloalkyl may be pyrrolidine, piperidine, N-methylpiperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine-2,4(1H,3H)-dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, It may include, but is not limited to, tropane, 2-azaspiro[3.3]heptane, (1R,5S)-3-azabicyclo[3.2.1]octane, (1s,4s)-2-azabicyclo[2.2.2]octane, or (1R,4R)-2-oxa-5-azabicyclo[2.2.2]octane.

[0040] In this specification, “alkylamino” may mean -(NR′R″), where R′ and R″ are each independently hydrogen and C 1-6 It can be selected from the group consisting of alkyl, and the selected R′ and R″ can be independently substituted or unsubstituted. In addition, “C 1-6 “Alkylamino” is C 1-6 Amino containing alkyl, i.e., -NH(C 1-6 alkyl) or -N-(C 1-6alkyl)2, and may include, but is not limited to, dimethylamino, diethylamino, methylethylamino, methylpropylamino, or ethylpropylamino.

[0041] As used herein, “aryl” may refer to an aromatic ring in which one hydrogen is removed from an aromatic hydrocarbon ring, and may be monocyclic or polycyclic. “Aryl having 6 to 12 atoms” may refer to an aryl having 6 to 12 ring-forming atoms, including, but not limited to, phenyl, naphthalenyl, or anthracenyl.

[0042] As used herein, “heteroaryl” may mean an aromatic ring containing one or more heteroatoms selected from N, O, and S as ring forming atoms, and may be monocyclic or polycyclic. In addition, “heteroaryl of 5 to 12 atoms” may mean a heteroaryl containing 5 to 12 ring forming atoms, and as an example, thienyl, thiophenyl, purinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isothiazolyl, oxadiazolyl, triazolyl, pyridinyl, bipyridinyl, triazinyl, triazolyl, acridyl, pyridazinyl, pyrazinyl, quinolinyl, quinazoline, quinoxalinyl, phenoxazyl, phthalazinyl, pyrimidinyl, pyrido pyrimidinyl, pyrido pyrazinyl, pyrazino pyrazinyl, isoquinoline, indolyl, carbazolyl, imidazopyridazinyl, imidazopyridinyl, It may include, but is not limited to, imidazopyrimidinyl, pyrazolopyrimidinyl, imidazopyrazinyl, or pyrazolopyridinyl, N-arylcarbazolyl, N-heteroarylcarbazolyl, N-alkylcarbazolyl, benzoxazolyl, benzoimidazolyl, benzothiazolyl, benzocarbazolyl, benzothiophenyl, dibenzothiophenyl, thienothiophenyl, benzofuranyl, phenanthrolinyl, isoxazolyl, oxadiazolyl, thiadiazolyl, benzothiazolyl, tetrazolyl, phenothiazinyl, dibenzosilole, or dibenzofuranyl.

[0043] As used herein, "isomer" may refer to a compound of the present invention or a salt thereof that has the same chemical formula or molecular formula but is structurally or sterically different. Such isomers include structural isomers such as tautomers, stereoisomers such as R or S isomers having an asymmetric carbon center, geometric isomers (trans, cis), and optical isomers (enantiomers). All of these isomers and mixtures thereof are also included within the scope of the present invention.

[0044] According to a specific embodiment of the present invention, a compound of the following chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is provided.

[0045] [Chemical Formula 1]

[0046]

[0047] R 1 is a 5 to 12-membered heteroaryl containing one or more heteroatoms of N, S and O, wherein said heteroaryl is C 1-6 Alkyl, hydroxy (C 1-6 ) is unsubstituted or substituted with one or more substituents selected from alkyl, oxo (=O), and amine;

[0048] R 2 is pyridine, heterocycloalkyl containing one or more heteroatoms of N and O, or , wherein the pyridine is substituted or unsubstituted with an amine, and the heterocycloalkyl is hydroxy (C 1-6 ) is substituted or unsubstituted with alkyl, and the above R 4 and R 5 are each independently hydrogen or hydroxy (C 1-6 ) is alkyl; and

[0049] R 3 Silver C 1-6 It could be an alkyl.

[0050] According to a specific embodiment of the present invention,

[0051] R 1 is a heteroaryl selected from pyrazole, oxazole, thiazole, furan, indazole, dihydrobenzimidazole, and triazole, wherein said heteroaryl is unsubstituted or substituted with one or more substituents selected from C1-3 alkyl, hydroxy(C1-3)alkyl, oxo(=O), and amine,

[0052] The above R 1 When this is pyrazole, oxazole, and furan, R2 is pyridine, piperidine, morpholine, or , wherein the pyridine is substituted or unsubstituted with an amine, the piperidine or morpholine is substituted or unsubstituted with a hydroxy(C1-3)alkyl, and the R 4 and R 5 are each independently hydrogen or hydroxy(C1-3)alkyl,

[0053] The above R 1 When this thiazole, indazole, dihydrobenzimidazole, and triazole, R 2 is pyridine; and

[0054] R 3 Silver C 1-3 It could be an alkyl.

[0055] According to a specific embodiment of the present invention,

[0056]

[0057]

[0058] R 3 It can be ethyl.

[0059] Examples of the compound of the above chemical formula 1 according to the present invention include compounds of Examples 1 to 25 listed in the Examples below, stereoisomers thereof, or pharmaceutically acceptable salts thereof.

[0060] The compound represented by the above chemical formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt thereof. In particular, the pharmaceutically acceptable salt may be an acid addition salt formed by a free acid. Here, the acid addition salt can be obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc.; non-toxic organic acids such as aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates, and alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids, etc.; organic acids such as trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc. The types of these pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, It may include phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and the like.The above acid addition salt can be prepared by a conventional method, for example, dissolving the derivative of chemical formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc., adding an organic acid or an inorganic acid, filtering and drying the resulting precipitate, or it can be prepared by distilling the solvent and an excess acid under reduced pressure, drying, and crystallizing in the organic solvent. In addition, the pharmaceutically acceptable salt may be a salt obtained using a base or a metal salt. As an example of a metal salt, an alkali metal or alkaline earth metal salt can be obtained by dissolving a compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. As the alkali metal salt, sodium, potassium, or calcium salts may be pharmaceutically suitable. In addition, the corresponding salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

[0061] Furthermore, the present invention may be a compound represented by the above chemical formula 1 and a pharmaceutically acceptable salt thereof, as well as a stereoisomer thereof, particularly an enantiomer.

[0062] Another aspect of the present invention provides a method for preparing a compound of formula 1.

[0063] Specifically, the above method

[0064] A step of preparing a compound of chemical formula 3 from a compound of chemical formula 2;

[0065] A step of preparing a compound of chemical formula 4 from a compound of chemical formula 3; and

[0066] A step of preparing a compound of formula 1 from a compound of formula 4 may be included.:

[0067] [Chemical Formula 2]

[0068]

[0069] [Chemical Formula 3]

[0070]

[0071] [Chemical Formula 4]

[0072]

[0073] [Chemical Formula 1]

[0074]

[0075] In the above formula, Hal is a leaving group, halogen, and R1 to R3 are the same as defined above.

[0076] The manufacturing method according to the present invention is described in detail in the following synthetic method of the compound and examples.

[0077] Another aspect of the present invention provides a pharmaceutical composition for preventing or treating cancer, comprising a compound of the above chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0078] It was experimentally confirmed that the compound represented by chemical formula 1 of the present invention can exhibit CDK12 inhibitory activity, and specifically, exhibits inhibitory activity against CDK12 / cyclinK.

[0079] In addition, the compound represented by chemical formula 1 of the present invention can exhibit inhibitory activity against HER2.

[0080] Accordingly, another aspect of the present invention can provide a pharmaceutical composition for preventing or treating a HER2-related disease, comprising a compound of the above chemical formula 1, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0081] The type of cancer is not limited, but may include any number of cancers known to be associated with HER2, including solid tumors, particularly HER2-positive cancers. For example, the cancer may be selected from the group consisting of colorectal cancer, gastric cancer, lung cancer (e.g., non-small cell lung cancer (NSCLC)), biliary tract cancer (e.g., cholangiocarcinoma, gallbladder cancer), bladder cancer, esophageal cancer, melanoma, ovarian cancer, liver cancer, prostate cancer, pancreatic cancer, colon cancer, head and neck cancer, uterine cancer, breast cancer, and cervical cancer. Specifically, the cancer prevented or treated by the pharmaceutical composition of the present invention may be selected from the group consisting of colorectal cancer, esophageal cancer, gastric cancer, cholangiocarcinoma, non-small cell lung cancer, bladder cancer, breast cancer, and biliary tract cancer, and more specifically, the cancer may be breast cancer, particularly HER2-positive breast cancer.

[0082] Additionally, the present invention can also be used to treat patients with HER2-positive breast cancer and HER2-positive breast cancer or triple-negative breast cancer that is resistant to HER2-antibody treatment (e.g., Herceptin (trastuzumab)).

[0083] The pharmaceutical composition for preventing or treating cancer of the present invention can be used for clinical administration and can be prepared so that it can be administered in various oral and parenteral dosage forms.

[0084] A pharmaceutical composition for preventing or treating cancer, comprising the compound of the above chemical formula 1, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient, may be administered as an individual therapeutic agent or may be used in combination with other therapeutic agents currently in use.

[0085] Another aspect of the present invention provides a method for preventing or treating cancer, comprising administering to a subject in need thereof a compound of the above-described chemical formula 1, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

[0086] Another aspect of the present invention provides a use of the compound of formula 1 or a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof in the prevention or treatment of cancer.

[0087] Meanwhile, the novel compound represented by Chemical Formula 1 according to the present invention can be formulated into various forms depending on the purpose. The following are examples of several formulation methods containing the compound represented by Chemical Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.

[0088]

[0089] Hereinafter, the present invention will be described in detail through examples and experimental examples.

[0090] However, the following examples, manufacturing examples, and experimental examples are only illustrative of the present invention, and the content of the present invention is not limited thereto.

[0091]

[0092] [Method of compound synthesis]

[0093] [Manufacturing Example 1] Synthesis of compounds of Examples 1 to 5

[0094] According to the scheme illustrated in Figure 1, compounds of Examples 1 to 5 were synthesized.

[0095] [Intermediate I:N-((6-chloropyridin-3-yl)methyl)-9-ethyl-2-iodo-9H-purin-6-amine]

[0096] (6-Chloropyridin-3-yl)methanamine (1.2 equiv) and Et3N (9 mL, 3.0 equiv) were added to a solution of 6-chloro-9-ethyl-2-iodo-9H-purine (14 g, 1.0 equiv) in methanol (30 mL) at room temperature. The reaction mixture was heated to 50°C and stirred for 12 h. After the reaction, the methanol solvent was evaporated. The residue was dissolved in EtOAc, washed with water, and the aqueous layer was extracted with EtOAc (3 x 100 mL). The organic extract was dried over MgSO4 and purified by column chromatography using 2% MeOH in dichloromethane as the eluent to give intermediate I (15 g, 78% yield).

[0097] 1 H NMR (400 MHz, CDCl3) δ 8.46 (d,J= 2.4 Hz, 1H), 7.75 (dd,J= 8.2, 2.3 Hz, 1H), 7.68 (s, 1H), 7.33 (d,J= 8.2 Hz, 1H), 6.13 (s, 1H), 4.84 (s, 2H), 4.24 (q,J= 7.3 Hz, 2H), 1.54 (t,J= 7.3 Hz, 3H).

[0098]

[0099] [Intermediate II:N-((6-chloropyridin-3-yl)methyl)-9-ethyl-2-(pyridin-3-yl)-9H-purin-6-amine]

[0100] A 2 M aqueous solution of 1,4-dioxane (60 mL), intermediate I (23 g, 1.0 equiv), pyridineboronic acid (1.1 equiv), Pd(PPh3)4 (0.1 equiv), and K2CO3 (2 equiv) was added to a dried 250 mL flask under nitrogen, and the reaction mixture was stirred at 100°C for 6 h. After the reaction, the mixture was cooled to room temperature, filtered on a Celite-545 bed, and the filtrate was collected. The organic layer was extracted with EtOAc and dried over MgSO4. After the solvent was evaporated in vacuo, the residue was purified by column chromatography using MeOH:dichloromethane (4:96) to obtain intermediate II (11 g, 54% yield).

[0101] 1 H NMR (400 MHz, CDCl3) δ 9.71 - 9.65 (m, 2H), 8.72 - 8.65 (m, 4H), 8.52 (d,J= 2.1 Hz, 2H), 7.84 (s, 2H), 7.78 (dd,J= 8.2, 2.5 Hz, 2H), 7.44 - 7.37 (m, 2H), 7.31 (d,J= 7.1 Hz, 1H), 6.21 (s, 2H), 5.01 (d,J= 5.2 Hz, 4H), 4.36 (q,J= 7.3 Hz, 4H), 1.63 (t,J= 7.3 Hz, 6H).

[0102]

[0103] [Intermediate III: 9-ethyl-N-((6-hydrazineylpyridin-3-yl)methyl)-2-(pyridin-3-yl)-9H-purin-6-amine]

[0104] Intermediate II (5 g), NH2NH2·H2O (8 mL) were mixed in ethanol solvent (6 mL) while stirring at room temperature, and the reaction mixture was stirred at 150°C overnight. After the reaction, the mixture was cooled to room temperature, water (10 mL) was added, and the solid was filtered to obtain 4.25 g (yield 85%) of Intermediate III.

[0105]

[0106] [Intermediate IV:N-((6-azidopyridin-3-yl)methyl)-9-ethyl-2-(pyridin-3-yl)-9H-purin-6-amine]

[0107] Intermediate III was added to water (5 mL) at 0°C, and HCl (10.8 mmol) and NaNO2 (2.58 mmol) were slowly added sequentially, and the reaction mixture was stirred at 0°C for 30 min. Then, 10 mL of an aqueous solution of NaN3 (3.6 mmol) was added dropwise to the mixture at 0°C, and the mixture was stirred at 0°C for 30 min, and then the reaction mixture was stirred at room temperature for 12 h. After the reaction, dichloromethane (50 mL) was added to the mixture, the organic phase was extracted, and the aqueous layer was extracted again with dichloromethane (30 mL × 2). The organic layers were combined, concentrated, and dried to obtain 0.3 g (yield 72%) of solid intermediate IV.

[0108]

[0109] Example 1 Synthesis method:

[0110] Intermediate III (70 mg, 1 eq), sulfuric acid (0.1 mL) or acetic acid (0.2 mL), and 3-oxobutanenitrile (1.5 eq) were added to ethanol (2 mL) at room temperature, and the mixture was refluxed with stirring. After the reaction, the ethanol solvent was evaporated, and the product was purified by column chromatography using 4% MeOH in dichloromethane (40-56% yield).

[0111]

[0112] [Example 1: N-((6-(5-amino-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-9-ethyl-2-(pyridin-3-yl)-9H-purin-6-amine]

[0113] 1H NMR (400 MHz, DMSO-d6) δ 9.52 (d, J = 1.6 Hz, 1H), 8.65 (t, J = 7.3 Hz, 2H), 8.57 (s, 1H), 8.45 (s, 1H), 8.26 (s, 1H), 7.96 (d, J = 8.6) Hz, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.51 (dd, J = 8.0, 4.8 Hz, 1H), 6.67 (s, 2H), 5.21 (s, 1H), 4.84 (s, 2H), 4.28 (q, J = 7.2 Hz, 2H), 2.06 (s, 3H), 1.49 (t, J = 7.3 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 156.00, 153.57, 150.76, 150.15, 150.08, 149.46, 146.24, 141.80, 138.94, 135.31, 131.64, 123.96, 112.91, 88.79, 38.69, 15.78, 14.36. HRMS (ESI) calcd for C 22 H 22 N 10 [M+H] + : 427.2029, found: 427.2105.

[0114]

[0115] Example 2-4 Synthesis method:

[0116] Intermediate II (0.1 g, 0.236 mmol), aryl boronic acid / ester (0.250 mmol), tetrakis(triphenylphosphine)palladium (0.006 mmol), 1,4-dioxane (3 mL), and 1 mL of 2 M K2CO3 aqueous solution were mixed under nitrogen, and the stirred mixture was warmed to 100 °C for 12 h. After cooling, the solution was filtered on a Celite-545 bed, and the organic layer was extracted with EtOAc. The solvent was evaporated in vacuo, and the residue was purified by column chromatography using 4% MeOH in dichloromethane as the eluent (26-61% yield).

[0117] [실시예2: 9-ethyl-N-((6-(oxazol-2-yl)pyridin-3-yl)methyl)-2-(pyridin-3-yl)-9H-purin-6-amine]

[0118] 1 H NMR (400 MHz, CDCl3) δ 9.65 (d, J = 1.5 Hz, 1H), 8.79 (d, J = 1.6 Hz, 1H), 8.73 - 8.57 (m, 2H), 8.05 (d, J = 8.1 Hz, 1H), 7.87 (dd, J = 8.1, 2.2 Hz, 1H), 7.83 - 7.71 (m, 2H), 7.43 - 7.33 (m, 1H), 7.00 (d, J = 33.6 Hz, 1H), 5.04 (s, 2H), 4.31 (q, J = 7.3 Hz, 2H), 1.58 (t, J = 7.3 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 160.59, 156.90, 154.22, 150.26, 149.81, 149.37, 145.17, 140.13, 139.72, 136.28, 136.15, 135.44, 134.11, 128.80, 123.16, 121.86, 119.19, 38.91, 15.52. HRMS (ESI) calcd for C 21 H 18 N8O [M+H] + : 399.1604, found: 399.1690.

[0119]

[0120] [실시예3: 9-ethyl-2-(pyridin-3-yl)-N-((6-(thiazol-2-yl)pyridin-3-yl)methyl)-9H-purin-6-amine]

[0121] 1H NMR (400 MHz, CDCl3) δ 9.70 (s, 1H), 8.84 (s, 1H), 8.76 (d, J = 8.0 Hz, 1H), 8.73 - 8.67 (m, 2H), 8.33 (s, 1H), 7.86 (dd, J = 8.9, 2.8 Hz, 2H), 7.69 (d, J = 8.1 Hz, 1H), 7.44 (dd, J = 7.6, 4.7 Hz, 1H), 6.39 (s, 1H), 5.05 (s, 2H), 4.36 (q, J = 7.3 Hz, 2H), 1.63 (t, J = 7.3 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 154.41, 150.37, 149.97, 149.36, 140.51, 140.29, 140.12, 136.37, 135.34, 133.98, 123.13, 119.66, 38.91, 15.53, 15.49. HRMS (ESI) calcd for C 21 H 18 N8S [M+H] + : 415.1375, found: 415.1449.

[0122]

[0123] [실시예4: 5-(5-(((9-ethyl-2-(pyridin-3-yl)-9H-purin-6-yl)amino)methyl)pyridin-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one]

[0124] 1H NMR (400 MHz, Acetone-d6) δ 9.68 (s, 2H), 8.81 (d, J = 22.4 Hz, 2H), 8.64 (dd, J = 4.7, 1.7 Hz, 1H), 8.11 (s, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.84 (d, J = 5.9 Hz, 2H), 7.76 (d, J = 8.3 Hz, 1H), 7.71 - 7.62 (m, 1H), 7.47 (dd, J = 7.8, 4.8 Hz, 1H), 7.08 (d, J = 8.2 Hz, 1H), 5.09 (s, 2H), 4.39 (dd, J = 14.6, 7.3 Hz, 2H), 1.58 (t, J = 7.3 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 155.98, 155.55, 150.78, 149.48, 149.27, 141.80, 136.77, 135.31, 134.08, 131.84, 131.08, 130.72, 123.97, 119.74, 119.59, 108.93, 106.96, 38.69, 15.79. HRMS (ESI) calcd for C 25 H 21 N9O [M+H] + : 464.1869, found: 464.1959.

[0125]

[0126] Example 5 Synthesis method:

[0127] Intermediate IV (0.04 mol), prop-2-yn-1-ol (1 eq), CuI (0.4 g, 0.05 eq), and DIEA (1 eq) were sequentially added to DMF (5 mL) and stirred at 100°C for 12 h. Water (20 mL) was added to the reaction mixture, extracted with EtOAc, and the organic layer was washed with water, dried over Na2SO4, and the solvent was evaporated to secure the compound.

[0128]

[0129] [Example 5: (1-(5-(((9-ethyl-2-(pyridin-3-yl)-9H-purin-6-yl)amino)methyl)pyridin-2-yl)-1H-1,2,3-triazol-4-yl)methanol]

[0130] Yield 40%; 1 H NMR (400 MHz, DMSO-d6) δ 9.52 (d, J = 1.5 Hz, 1H), 8.76 - 8.57 (m, 5H), 8.28 (s, 1H), 8.20 - 8.02 (m, 2H), 7.51 (dd, J = 7.8, 5.0 Hz, 1H), 5.31 (t, J = 5.6 Hz, 1H), 4.92 (s, 2H), 4.61 (d, J = 5.1 Hz, 2H), 4.29 (q, J = 7.3 Hz, 2H), 1.49 (t, J = 7.3 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 150.79, 149.48, 148.50, 141.93, 139.55, 135.31, 120.10, 113.86, 55.28, 38.71, 15.77. HRMS (ESI) calcd for C 21 H 20 N 10 O [M+H] + : 429.1822, found: 429.1904.

[0131]

[0132] [Manufacturing Example 2]

[0133] According to the schemes shown in Figures 2 and 3, compounds from Examples 6 to 25 were synthesized.

[0134]

[0135] Synthesis method of intermediate VI:

[0136] Intermediate V (1 g) and NH2NH2·H2O (2 mL) were added to ethanol (1 mL) with stirring at room temperature, and the mixture was heated to 150°C with stirring overnight. After the reaction was cooled to room temperature, water (10 mL) was added, and the solid was filtered to obtain 808 mg (yield 81%) of intermediate VI.

[0137] 1 H NMR (400 MHz, CDCl3) δ 8.46 (d,J= 2.4 Hz, 1H), 7.75 (dd,J= 8.2, 2.3 Hz, 1H), 7.68 (s, 1H), 7.33 (d,J= 8.2 Hz, 1H), 6.13 (s, 1H), 4.84 (s, 2H), 4.24 (q,J= 7.3 Hz, 2H), 1.54 (t,J= 7.3 Hz, 3H).

[0138]

[0139] Synthesis method of intermediate VIIa-c:

[0140] Compound VI (800 mg, 1 eq.), 1.5 equivalents of each carbonyl reagent (1,1,3,3-tetramethoxypropan-2-ylium, 2,4-dioxopentan-3-ylium, or 3-oxobutanenitrile), H2SO4, or HCl (1 equivalent) were added to ethanol (2 mL) at room temperature, and the mixture was refluxed with stirring. After the reaction was completed, the ethanol solvent was evaporated, and the product was purified by column chromatography using 2% MeOH in dichloromethane (yield 71%). This Boc-protected intermediate was dissolved in dichloromethane, and 2 mL of 4 M HCl (in 1,4-dioxane) was slowly added, and the mixture was stirred at room temperature for 4 h. The resulting solid was filtered to obtain each intermediate VIIa-c (yield 98%).

[0141]

[0142] Synthesis of intermediate VIIIa-b:

[0143] Under nitrogen, (6-chloropyridin-3-yl)methanamine (0.1 g, 0.236 mmol), 3-furanylboronic acid (0.250 mmol), and Pd(PPh3)4 (0.006 mmol) were added to 1,4-dioxane (3 mL), and 1 mL of 2 M K2CO3 aqueous solution was added. The reaction mixture was heated at 110°C with stirring for 12 h. After the reaction, it was cooled to room temperature, and the solution was filtered on a Celite-545 bed, and the organic layer was extracted with EtOAc, and water was removed with anhydrous Na2SO4. The solvent was evaporated in vacuo, and the residue was purified by column chromatography using 4% MeOH in dichloromethane to obtain intermediate VIII.

[0144]

[0145] Synthesis method of intermediate IX:

[0146] 2,6-dichloro-9-isopropyl-9H-purine (4.33 g, 18.66 mmol) was added to methanol (15.0 mL), (6-(heteroaryl)pyridin-3-yl)methanamine (VIIa-c or VIIIa-b) (22.5 mmol) and Et3N (6 g, 68.7 mmol) were added at room temperature, and the mixture was heated at 50°C for 12 h. After the methanol was evaporated, the residue was dissolved in EtOAc, washed with water, and extracted with EtOAc (3x100 mL). The combined organic extracts were dried over MgSO4 and purified by column chromatography (2-3% MeOH in dichloromethane) to give each intermediate IX (up to 65% yield).

[0147]

[0148] Synthetic method for examples 10, 13, 17, and 21:

[0149] Under nitrogen, each intermediate IX (0.5 g, 2.7 mmol), (6-aminopyridin-3-yl)boronic acid (0.4 g, 3.2 mmol), and Pd(PPh3)4 (0.09 g, 0.082 mmol) were stirred in 1,4-dioxane (5 mL), 1 mL of 2 M aqueous Na2CO3 solution was added, and the mixture was heated to 100°C for 12 h. After cooling to room temperature, the solution was filtered on a Celite-545 bed, and the organic layer was extracted with EtOAc. The organic layer was concentrated and purified by column chromatography (10% MeOH in dichloromethane) to obtain the pure product.

[0150]

[0151] [Example 10: 2-(6-aminopyridin-3-yl)-N-((6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-9-ethyl-9H-purin-6-amine]

[0152] 1 H NMR (400 MHz, MeOD) δ 8.91 (d, J = 1.6 Hz, 1H), 8.54 (d, J = 1.3 Hz, 1H), 8.41 (dd, J = 8.8, 2.1 Hz, 1H), 8.02 (s, 1H), 7.98 (dd, J = 8.4, 2.1 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 6.62 (d, J = 8.8 Hz, 1H), 6.02 (s, 1H), 4.93 (s, 2H), 4.28 (q, J = 7.3 Hz, 2H), 2.47 (s, 3H), 2.21 (s, 3H), 1.52 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, MeOD) δ 161.33, 158.80, 155.32, 153.08, 151.23, 148.30, 148.24, 143.02, 141.62, 139.37, 139.14, 135.30, 125.29, 119.04, 117.65, 109.51, 109.47, 39.77, 15.77, 13.79, 13.30. HRMS (ESI) 441.2282.

[0153]

[0154] [실시예13:N-((6-(5-amino-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-2-(6-aminopyridin-3-yl)-9-ethyl-9H-purin-6-amine]

[0155] Yield 34%; 1 H NMR (400 MHz, DMSO-d6) δ 8.92 (d, J = 1.9 Hz, 1H), 8.43 (s, 1H), 8.29 (dd, J = 8.7, 2.3 Hz, 2H), 8.14 (s, 1H), 7.94 (dd, J = 8.6, 2.2 Hz, 1H), 7.74 (d, J = 8.5 Hz, 1H), 6.67 (s, 2H), 6.50 (d, J = 8.6 Hz, 1H), 6.29 (s, 2H), 5.22 (s, 1H), 4.79 (s, 2H), 4.22 (q, J = 7.3 Hz, 2H), 2.06 (s, 3H), 1.46 (t, J = 7.3 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 161.05, 157.41, 153.53, 150.15, 150.06, 148.95, 146.20, 140.74, 138.92, 136.81, 131.89, 123.08, 112.87, 107.58, 88.80, 38.44, 15.80, 14.37. HRMS (ESI) calcd for C22H23N11 [M+H] + : 442.2138, found: 442.2217.

[0156]

[0157] [실시예17: 2-(6-aminopyridin-3-yl)-9-ethyl-N-((6-(oxazol-2-yl)pyridin-3-yl)methyl)-9H-purin-6-amine]

[0158] Yield 46%; 1 H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 1H), 8.78 (s, 1H), 8.39 (s, 1H), 8.26 (dd, J = 7.8, 2.8 Hz, 2H), 8.14 (s, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.97 (dd, J = 8.1, 1.7 Hz, 1H), 7.42 (s, 1H), 6.48 (d, J = 8.7 Hz, 1H), 6.27 (s, 2H), 4.85 (s, 2H), 4.22 (q, J = 7.2 Hz, 2H), 1.45 (t, J = 7.2 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 161.06, 160.65, 157.39, 149.69, 148.96, 144.55, 141.35, 140.85, 138.12, 136.79, 129.17, 123.01, 122.19, 107.56, 38.46, 15.80. HRMS (ESI) calcd for C 21 H 19 N9O [M+H] + : 414.1713, found: 414.1793.

[0159]

[0160] [실시예21: 2-(6-aminopyridin-3-yl)-9-ethyl-N-((6-(furan-3-yl)pyridin-3-yl)methyl)-9H-purin-6-amine]

[0161] Yield 53%; 1H NMR (400 MHz, DMSO-d6) δ 8.98 (d, J = 1.2 Hz, 1H), 8.93 (d, J = 2.1 Hz, 1H), 8.41 (s, 1H), 8.36 (s, 1H), 8.29 (dd, J = 8.7, 2.3 Hz, 1H), 8.16 (s, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.82 (t, J = 1.7 Hz, 1H), 7.49 (d, J = 8.2 Hz, 1H), 7.20 (d, J = 1.8 Hz, 1H), 6.50 (d, J = 8.7 Hz, 1H), 6.29 (s, 2H), 4.76 (s, 2H), 4.23 (q, J = 7.2 Hz, 2H), 1.46 (t, J = 7.2 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 161.08, 157.38, 148.98, 145.24, 143.78, 140.97, 140.14, 139.16, 137.06, 136.83, 125.20, 124.32, 122.97, 117.83, 109.26, 107.61, 49.10, 38.48, 15.78. HRMS (ESI) calcd for C 22 H 20 N8O2[M+H] + : 429.1709, found: 429.1794.

[0162]

[0163] Synthesis method for examples 6-7, 11-12, 14-15, 18-19, 22-23:

[0164] At room temperature, the corresponding IX, the corresponding amine (2 equivalents), and Et3N (4 equivalents) were added to n-butanol (2.0 mL), and the reaction mixture was heated at 120°C for 12 h. After the reaction, the mixture was cooled to room temperature, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (2-5% MeOH in dichloromethane).

[0165]

[0166] [실시예6: 2,2'-((6-(((6-(1H-pyrazol-1-yl)pyridin-3-yl)methyl)amino)-9-ethyl-9H-purin-2-yl)azanediyl)bis(ethan-1-ol)]

[0167] Yield 41%; 1 H NMR (400 MHz, CDCl3) δ 8.56 (d, J = 2.3 Hz, 1H), 8.45 (s, 1H), 7.96 (d, J = 8.5 Hz, 1H), 7.84 (d, J = 8.6 Hz, 1H), 7.75 (s, 1H), 7.53 (d, J = 12.9 Hz, 1H), 6.48 (s, 2H), 4.78 (s, 2H), 4.08 (dd, J = 14.6, 7.3 Hz, 2H), 4.00 (t, J = 8.6 Hz, 2H), 3.92 - 3.85 (m, 4H), 3.83 - 3.76 (m, 4H), 1.48 (t, J = 7.3 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 153.96, 150.81, 147.24, 142.02, 138.10, 131.98, 127.04, 112.24, 107.78, 86.12, 65.37, 62.83, 57.93, 56.57, 52.48, 43.24, 38.55, 15.27. HRMS (ESI) calcd for C 20 H 25 N9O2[M+H] + : 424.2131, found: 424.2208.

[0168]

[0169] [실시예7: 2-((6-(((6-(1H-pyrazol-1-yl)pyridin-3-yl)methyl)amino)-9-ethyl-9H-purin-2-yl)amino)propane-1,3-diol]

[0170] 1H NMR (400 MHz, MeOD) δ 8.53 (s, 1H), 8.44 (s, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.73 (s, 2H), 6.50 (s, 1H), 4.78 (s, J = 14.7 Hz, 2H), 4.11 (s, J = 2.9 Hz, 1H), 4.10 - 4.03 (m, 2H), 3.78 - 3.65 (m, 4H), 1.42 (t, J = 7.2 Hz, 3H). 13 C NMR (101 MHz, MeOD) δ 160.68, 155.88, 151.73, 148.59, 143.11, 139.83, 138.81, 135.12, 128.37, 114.59, 113.17, 108.82, 62.64, 55.94, 49.00, 39.41, 15.68. HRMS 410.206.

[0171]

[0172] [실시예11: 2-((6-(((6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)amino)-9-ethyl-9H-purin-2-yl)amino)ethan-1-ol]

[0173] 1 H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 7.71 (s, 2H), 7.40 (s, 1H), 6.59 (s, 1H), 5.95 (s, 1H), 5.40 (t, J = 5.6 Hz, 1H), 4.71 (s, 2H), 4.01 (q, J = 7.3 Hz, 2H), 3.80 - 3.74 (m, 2H), 3.52 (dd, J = 9.7, 5.4 Hz, 2H), 2.57 (s, 3H), 2.26 (s, 3H), 1.42 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 160.22, 154.75, 152.85, 149.87, 146.88, 141.56, 137.80, 136.83, 131.61, 115.62, 114.47, 109.02, 64.34, 45.27, 38.53, 15.42, 14.50, 13.71. HRMS 408.2255.

[0174]

[0175] [실시예12: 2,2'-((6-(((6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)amino)-9-ethyl-9H-purin-2-yl)azanediyl)bis(ethan-1-ol)]

[0176] 1 H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 7.77 - 7.69 (s, 2H), 7.42 (s, 1H), 6.73 (s, 1H), 5.96 (s, 1H), 4.69 (s, 2H), 4.01 (q, J = 7.3 Hz, 2H), 3.86 - 3.78 (m, 4H), 3.76 - 3.69 (m, 4H), 2.57 (s, 3H), 2.26 (s, 3H), 1.42 (t, J = 7.3 Hz, 3H). 13 C NMR (101 MHz, MeOD) δ 160.48, 155.41, 152.98, 151.23, 147.92, 143.03, 139.08, 138.71, 135.56, 117.75, 114.11, 109.48, 62.21, 53.52, 42.26, 39.36, 15.65, 13.75, 13.31. HRMS 452.2515.

[0177]

[0178] [실시예14: 2-((6-(((6-(5-amino-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)amino)-9-ethyl-9H-purin-2-yl)amino)ethan-1-ol]

[0179] Yield 38%; 1 H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 1.9 Hz, 1H), 7.88 (d, J = 8.6 Hz, 1H), 7.77 (dd, J = 8.6, 2.3 Hz, 1H), 7.49 (s, 1H), 6.26 (s, 1H), 5.85 (d, J = 22.9 Hz, 2H), 5.41 (s, 1H), 5.35 (s, 1H), 4.77 (s, 2H), 4.09 (q, J = 7.3 Hz, 2H), 3.87 - 3.80 (m, 2H), 3.60 (dd, J = 9.6, 5.6 Hz, 2H), 2.23 (s, 3H), 1.54 - 1.45 (m, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 159.73, 153.47, 150.15, 150.02, 146.32, 139.03, 137.49, 112.78, 88.79, 60.88, 44.50, 37.93, 15.72, 14.39. HRMS (ESI) calcd for C 19 H 24 N 10 O [M+H] + : 409.2135, found: 409.2214.

[0180]

[0181] [실시예15: 2,2'-((6-(((6-(5-amino-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)amino)-9-ethyl-9H-purin-2-yl)azanediyl)bis(ethan-1-ol)]

[0182] Yield 36%; 1H NMR (400 MHz, CDCl3) δ 8.20 (t, J = 11.0 Hz, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.66 (dd, J = 8.6, 2.1 Hz, 1H), 7.47 - 7.34 (m, 1H), 6.35 (s, 1H), 5.77 (d, J = 22.4 Hz, 2H), 5.26 (s, 1H), 5.23 (s, 1H), 4.63 (s, 2H), 3.98 (q, J = 7.3 Hz, 2H), 3.83 - 3.75 (m, 4H), 3.73 - 3.64 (m, 4H), 2.14 (s, 3H), 1.43 - 1.35 (m, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 158.62, 153.46, 150.14, 149.99, 146.08, 138.82, 137.67, 132.13, 112.78, 88.77, 60.01, 52.15, 37.99, 15.66, 14.38. HRMS (ESI) calcd for C 21 H 28 N 10 O2[M+H] + : 453.2397, found: 453.2476.

[0183]

[0184] [실시예18: 2,2'-((9-ethyl-6-(((6-(oxazol-2-yl)pyridin-3-yl)methyl)amino)-9H-purin-2-yl)azanediyl)bis(ethan-1-ol)]

[0185] 1 H NMR (400 MHz, MeOD) δ 8.68 (s, 1H), 8.08 (d, J = 8.1 Hz, 1H), 8.05 (s, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.74 (s, 1H), 7.36 (s, 1H), 4.83 - 4.80 (m, 2H), 4.10 (q, J = 7.2 Hz, 2H), 3.72 (s, 8H), 1.43 (t, J = 7.2 Hz, 3H).13 C NMR (101 MHz, MeOD) δ 161.92, 160.41, 155.35, 152.49, 149.89; 114.03, 62.13, 53.50, 42.58, 39.39, HRMS 425.2049.

[0186]

[0187] [Figure 19: 2-((9-ethyl-6-(((6-(oxazol-2-yl)pyridin-3-yl)methyl)amino)-9H-purin-2-yl)amino)propane-1,3-diol]

[0188] 1 H NMR (400 MHz, CDCl3) δ 8.67(s,1H), 7.97(d,J = 7.9Hz,1H), 7.76(s,1H), 7.73(d,J=7.4Hz,1H), 7.44(s,1H), 7.26(s,1H), 6.72(s,1). 1H), 5.60(s,1H), 4.71(s,2H), 4.02(s,1H), 3.99(d,J=7.1Hz,2H), 3.81(m,4H), 1.40(t,J=6.7Hz,3H). 13 C NMR (101 MHz, MeOD) δ 161.92; 95.27, 62.60, 55.92, 42.37, 39.41, HRMS 411.1903.

[0189]

[0190] [Figure 22: 2,2'-((9-ethyl-6-(((6-(furan-3-yl)pyridin-3-yl)methyl)amino)-9H-purin-2-yl)azanediyl)bis(ethan-1-ol)]

[0191] 1 H NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 7.97 (s, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.44 (t, J = 1.6 Hz, 1H), 7.37 (s, 1H), 7.32 (d, J = 8.1 Hz, 1H), 6.84 (d, J = 1.1 Hz, 1H), 6.61 (s, 1H), 4.71 (d, J = 4.4 Hz, 2H), 4.03 (q, J = 7.3 Hz, 2H), 3.68 - 3.58 (m, 4H), 1.74 - 1.61 (m, 2H), 1.56 - 1.46 (m, 2H), 1.41 (t, J = 7.3 Hz, 3H). 13 C NMR (101 MHz, MeOD) δ 160.74, 155.27, 152.86, 151.49, 149.20, 145.33, 142.69, 138.34, 137.84, 135.86, 127.61, 121.65, 113.47, 109.55, 62.91, 50.32, 42.41, 39.28, 35.81, 31.03, 25.01, 15.54. HRMS 424.2314.

[0192]

[0193] [실시예23: 2-((9-ethyl-6-(((6-(furan-3-yl)pyridin-3-yl)methyl)amino)-9H-purin-2-yl)amino)propane-1,3-diol]

[0194] 1H NMR (400 MHz, MeOD) δ 8.54 (s, 1H), 8.09 (s, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.74 (s, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.57 (s, 1H), 6.93 (s, 1H), 4.77 (s, 2H), 4.09 (dd, J = 14.4, 6.9 Hz, 3H), 3.71 (qd, J = 10.9, 5.4 Hz, 4H), 1.42 (t, J = 7.2 Hz, 3H). 13 C NMR (101 MHz, MeOD) δ 155.88, 151.66, 149.42, 145.39, 142.78, 138.84, 138.24, 135.35, 127.57, 121.73, 114.56, 109.55, 62.61, 55.94, 39.43, 15.68. HRMS 410.1949.

[0195]

[0196] Synthesis method for examples 8-9, 16, 20, 24-25:

[0197] At room temperature, the corresponding IX, the corresponding chiral cycloamine (2.0 equiv.), and K2CO3 (4 equiv.) were added to DMF (2.0 mL), and the mixture was heated at 150°C for 12 h. After the reaction, the mixture was cooled to room temperature, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (2-5% MeOH in dichloromethane).

[0198]

[0199] [Example 8: (S)-2-(1-(6-(((6-(1H-pyrazol-1-yl)pyridin-3-yl)methyl)amino)-9-ethyl-9H-purin-2-yl)piperidin-2-yl)ethan-1-ol]

[0200] 1H NMR (400 MHz, MeOD) δ 8.54 (d, J = 2.2 Hz, 1H), 8.46 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.74 (s, 1H), 7.72 (s, 1H), 6.50 (s, 1H), 5.01 - 4.93 (m, 1H), 4.77 (s, 2H), 4.75 (s, 1H), 4.08 (dd, J = 14.4, 7.2 Hz, 2H), 3.58 - 3.49 (m, 1H), 3.48 - 3.39 (m, 1H), 2.85 (t, J = 12.9 Hz, 1H), 2.09 (ddd, J = 18.9, 9.8, 4.6 Hz, 1H), 1.64 (dd, J = 26.8, 8.5 Hz, 7H), 1.44 (t, J = 7.2 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 154.42, 151.00, 147.52, 142.10, 138.49, 136.66, 132.66, 127.13, 112.31, 107.85, 58.57, 47.00, 39.20, 38.44, 32.39, 29.85, 25.86, 19.95, 15.44. HRMS 448.2577.

[0201]

[0202] [실시예9: (R)-2-(4-(6-(((6-(1H-pyrazol-1-yl)pyridin-3-yl)methyl)amino)-9-ethyl-9H-purin-2-yl)morpholin-3-yl)ethan-1-ol]

[0203] 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 8.38 (s, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.71 (s, 1H), 7.43 (s, 1H), 6.53 (s, 1H), 6.44 (s, 1H), 4.77 (s, 2H), 4.66 (d, J = 12.2 Hz, 1H), 4.62 (d, J = 14.8 Hz, 1H), 4.02 (q, J = 7.1 Hz, 2H), 3.91 (d, J = 10.8 Hz, 1H), 3.74 (q, J = 11.5 Hz, 2H), 3.62 (d, J = 11.5 Hz, 1H), 3.51 (t, J = 10.7 Hz, 1H), 3.37 (t, J = 11.4 Hz, 1H), 3.12 (t, J = 11.4 Hz, 1H), 2.31 (t, J = 12.8 Hz, 1H), 1.78 (t, J = 12.8 Hz, 1H), 1.45 (t, J = 7.2 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 158.69, 154.57, 151.01, 149.07, 147.39, 142.13, 138.28, 136.93, 132.40, 127.09, 124.22, 113.68, 112.30, 107.90, 70.62, 67.42, 58.38, 47.96, 39.38, 38.48, 31.77, 15.41. HRMS 450.2369.

[0204]

[0205] [실시예16: (S)-2-(1-(6-(((6-(5-amino-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)amino)-9-ethyl-9H-purin-2-yl)piperidin-2-yl)ethan-1-ol]

[0206] Yield 28%; 1H NMR (400 MHz, CDCl3) δ 8.23 (t, J = 11.1 Hz, 1H), 7.75 (dt, J = 8.6, 5.5 Hz, 2H), 7.40 (s, 1H), 5.76 (d, J = 19.8 Hz, 2H), 5.25 (d, J = 12.3 Hz, 1H), 4.90 (d, J = 11.9 Hz, 1H), 4.83 - 4.57 (m, 3H), 3.98 (q, J = 7.3 Hz, 2H), 3.53 (d, J = 11.9 Hz, 1H), 3.31 (dd, J = 11.7, 9.4 Hz, 1H), 2.72 (t, J = 12.5 Hz, 1H), 2.15 (d, J = 4.6 Hz, 3H), 2.10 - 2.01 (m, 1H), 1.77 - 1.50 (m, 8H), 1.41 (t, J = 7.3 Hz, 3H), 1.18 (m, 1H). 13 C NMR (101 MHz, CDCl3) δ 154.38, 153.84, 150.85, 149.12, 145.74, 138.25, 136.48, 130.08, 113.24, 113.04, 89.92, 58.44, 46.83, 39.03, 38.27, 32.27, 31.58, 29.73, 25.74, 22.64, 19.84, 15.31, 14.11, 14.09. HRMS (ESI) calcd for C 24 H 32 N 10 O [M+H] + : 477.2761, found: 477.2836.

[0207]

[0208] [실시예20: (R)-2-(4-(9-ethyl-6-(((6-(oxazol-2-yl)pyridin-3-yl)methyl)amino)-9H-purin-2-yl)morpholin-3-yl)ethan-1-ol]

[0209] 1H NMR (400 MHz, CDCl3) δ 8.74 (s, 1H), 8.09 (d, J = 8.2 Hz, 1H), 7.83 (d, J = 9.0 Hz, 1H), 7.79 (s, 1H), 7.48 (s, 1H), 7.30 (s, 1H), 6.35 (s, 1H), 4.83 (d, J = 12.3 Hz, 2H), 4.62 (dd, J = 27.3, 12.4 Hz, 2H), 4.05 (q, J = 7.2 Hz, 2H), 3.90 (d, J = 8.7 Hz, 1H), 3.76 (d, J = 11.4 Hz, 1H), 3.73 - 3.67 (m, 1H), 3.62 (d, J = 12.5 Hz, 1H), 3.49 (t, J = 10.5 Hz, 1H), 3.36 (t, J = 10.8 Hz, 1H), 3.15 - 3.08 (m, 1H), 2.31 (t, J = 12.9 Hz, 1H), 1.78 (m, 2H), 1.47 (t, J = 7.3 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 160.80, 158.73, 154.62, 149.54, 145.34, 139.90, 137.11, 136.30, 128.96, 122.03, 70.66, 67.44, 62.53, 58.42, 48.00, 39.43, 38.53, 31.83, 29.84, 15.45, 14.25. HRMS 451.2215.

[0210]

[0211] [실시예24: (S)-2-(1-(9-ethyl-6-(((6-(furan-3-yl)pyridin-3-yl)methyl)amino)-9H-purin-2-yl)piperidin-2-yl)ethan-1-ol]

[0212] 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 7.99 (s, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.47 (s, 1H), 7.39 (d, J = 8.9 Hz, 2H), 6.87 (s, 1H), 6.28 (s, 1H), 4.96 (d, J = 11.6 Hz, 1H), 4.84 (d, J = 13.9 Hz, 1H), 4.77 (s, 2H), 4.02 (q, J = 7.2 Hz, 2H), 3.58 (d, J = 11.0 Hz, 1H), 3.37 (t, J = 11.5 Hz, 1H), 2.77 (t, J = 13.0 Hz, 1H), 2.11 (t, J = 13.0 Hz, 1H), 1.76 (d, J = 5.8 Hz, 1H), 1.72 - 1.47 (m, 6H), 1.45 (t, J = 7.2 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 159.16, 154.51, 150.96, 149.31, 143.95, 141.26, 136.61, 136.23, 132.86, 126.97, 119.97, 113.36, 108.75, 58.58, 46.96, 39.16, 38.40, 32.39, 29.84, 25.86, 19.95, 15.44. HRMS 448.2456.

[0213]

[0214] [실시예25: (R)-2-(4-(9-ethyl-6-(((6-(furan-3-yl)pyridin-3-yl)methyl)amino)-9H-purin-2-yl)morpholin-3-yl)ethan-1-ol]

[0215] 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 8.00 (s, 1H), 7.68 (d, J = 8.1 Hz, 1H), 7.47 (d, J = 4.2 Hz, 2H), 7.40 (d, J = 8.1 Hz, 1H), 6.87 (s, 1H), 6.41 (s, 1H), 4.77 (s, 2H), 4.66 (d, J = 12.9 Hz, 1H), 4.61 (s, 1H), 4.04 (q, J = 7.3 Hz, 2H), 3.91 (d, J = 11.2 Hz, 1H), 3.76 (t, J = 9.8 Hz, 1H), 3.71 (d, J = 11.5 Hz, 1H), 3.63 (d, J = 11.6 Hz, 1H), 3.51 (t, J = 10.6 Hz, 1H), 3.38 (t, J = 11.6 Hz, 1H), 3.18 - 3.08 (m, 1H), 2.31 (t, J = 12.8 Hz, 1H), 1.79 (t, J = 12.8 Hz, 1H), 1.46 (t, J = 7.3 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 154.51, 151.04, 149.20, 144.03, 141.35, 136.83, 136.21, 132.58, 126.84, 120.03, 108.72, 70.61, 67.45, 58.42, 48.02, 39.41, 38.55, 31.77, 15.43. HRMS 450.2254.

[0216]

[0217] [Experimental Example]

[0218] Experimental Example 1. Measurement of the breast cancer growth inhibitory activity of compounds.

[0219] HER2-positive breast cancer cell lines (100 μL volume / well, 5,000 SK-Br3 cells, 5,000 BT474 cells, 5,000 JIMT1 cells, 3,000 HCC-1954 cells per well) were seeded in tissue culture-treated 96-well plates and cultured in a cell incubator for 24 h. Serially diluted compounds (10 point 1 / 3 dilutions from 10 mM, duplicated) were prepared in compound plates, and 500 nL of compound solutions were pin-transferred to the cells in the assay plate using a pintool system (JANUS liquid handler, PerkinElmer, USA) and cultured in a cell incubator for 72 h. In experiments with SKBr3, HCC1954, and JIMT1 cell lines, Cell-titer GloTM reagent (50 μL of a 5-fold diluted solution, Promega) was added to each well, and in experiments with the BT474 cell line, WST reagent was used. Envision TM The luminescence signal was measured using a plate reader (PerkinElmer, USA), and the titration curve was fitted and IC 50 / GI 50 The values ​​were generated using Prism 7.0 s / w (GraphPad, San Diego, USA). The breast cancer cell line growth inhibition activity evaluation was performed at least twice for each example, and the GI 50 The mean and standard deviation of the values ​​are expressed as average±stdev in Table 1-2.

[0220]

[0221] The compound of the present invention was treated with SK-Br3, HCC-1954, and JIMT-1 breast cancer cell lines at various concentrations for 72 hours, and then the proliferation inhibition ability was measured. 50 The values ​​were calculated. In vitro IC for CDK12 / cyclinK 50 GI value and growth inhibition of breast cancer cell lines50 The values ​​are shown in Tables 1 and 2 respectively.

[0222]

[0223]

[0224]

[0225]

[0226]

[0227] For Example 25, which showed the best growth inhibition ability against two HER2-positive breast cancer cell lines, the growth inhibition ability (GI) against four HER2-positive breast cancer cell lines, including BT474 (trastuzumab-sensitive) and JIMT1 (trastuzumab-resistant) cell lines, was additionally evaluated. 50 ) are summarized in Table 2.

[0228]

[0229] Growth inhibition ability of HER2-positive breast cancer cell line of Example 25 (GI 50 , μM)HER2-positive breast cancer cell lineTrastuzumab-sensitivityCompoundExample 25DinaciclibTHZ531SK-Br3Sensitive0.015±0.0020.015±0.0010.049±0.002BT474Sensitive0.010±0.0000.010±0.0010.044±0.011HCC-1954Resistant0.009±0.0010.014±0.0010.067±0.001JIMT1Resistant0.021±0.0010.023±0.0021.840±0.048

[0230] Experimental Example 2. Measurement of CyclinK degradation, inhibition of PolII CTD Ser2 phosphorylation, and suppression of downstream gene expression.

[0231] In order to confirm the intracellular CDK12 inhibition and cyclinK degradation of the compounds of the present invention compared to the control drug dinaciclib, three compounds (Examples 9, 21, and 25) showing high cancer cell growth inhibitory activity were treated with HCC-1954 cells at concentrations of 10 and 100 nM, respectively, for 2 hours, and then Western blot experiments were performed using Pol II CTD p-Ser2 antibodies and cyclinK antibodies. As shown in Fig. 4, all compounds showed strong cyclinK degradation ability in a dose-dependent manner. Example 25 showed superior inhibition of Pol II phosphorylation (p-CTD Ser2) and very strong cyclinK degradation ability compared to dinaciclib. In addition, co-treatment with the proteasome inhibitor bortezomib (20 nM) restored the decrease in cyclinK and p-CTD (Ser2) caused by Example 25, indicating that Example 25 promotes proteasome-mediated degradation of cyclinK in breast cancer cells and that cyclinK degradation contributes to the anticancer effect.

[0232]

[0233] Experimental Example 3. Kinome-wide inhibitory activity profiling

[0234] The activity of a panel of human kinases was measured at a concentration of 1 μM in Example 25 (Table 3, Fig. 5). Among 372 human wild-type kinases, the following kinases were inhibited by more than 90% by 1 μM in Example 25 - CDK1 / cyclinA, CDK1 / cyclinB, CDK1 / cyclinE, CDK2 / cyclinA, CDK2 / cyclinA1, CDK2 / cyclinO, CDK2 / cyclinE, CDK2 / cyclinE2, CDK3 / cyclinE, CDK3 / cyclinE2, CDK5 / p25, CDK5 / p35, CDK6 / cyclinD1, CDK9 / cyclinT1, CDK9 / cyclinT2, CDK12 / cyclinK, CDK14 / cyclinY, CDK15 / cyclinA2, CDK18 / cyclinY, LKB1, GSK3a / b, MAK. These results demonstrate that Example 25 is a pan-CDK inhibitor that can potently inhibit not only CDK12 / cyclinK but also several other CDKs, and that it is a highly selective inhibitor for CDKs, as the only kinases outside the CDK family that are potently inhibited are GSK3a / b and MAK. In particular, while THZ531, a selective inhibitor for CDK12, showed very low growth inhibition ability in the trastuzumab-resistant JIMT1 cell line, Example 25 showed very strong inhibition ability similar to dinaciclib (Table 2), indicating that compounds that inhibit pan-CDKs are advantageous in overcoming resistance to trastuzumab.

[0235]

[0236] Genome-wide inhibition (% inhibition) profiling of Example 25 (1 μM concentration). Mean and standard deviation for duplicate measurements.NoHuman kinase% 저해능표준편차1ABL18.700.162ABL2 / ARG5.821.103ACK116.421.224AKT10.171.045AKT26.410.746AKT34.371.827ALK0.210.158ALK1 / ACVRL1-2.180.879ALK2 / ACVR1-2.170.4010ALK3 / BMPR1A-1.290.9311ALK4 / ACVR1B2.770.0812ALK5 / TGFBR12.270.5813ALK6 / BMPR1B-4.340.8114ARAF4.181.8515ARK5 / NUAK125.360.4316ASK1 / MAP3K510.051.1217AURORA A2.540.5818AURORA B20.397.9419AURORA C40.651.3720AXL9.490.4421BLK3.150.2222BMPR213.673.6823BMX / ETK1.490.8524BRAF4.810.4125BRK7.310.2526BRSK16.651.8527BRSK23.920.1028BTK5.850.0129C-KIT-0.310.3030C-MER4.320.1431C-MET5.680.6332c-Src8.340.1133CAMK1A-4.111.7034CAMK1B-6.733.3735CAMK1D0.101.6436CAMK1g4.330.4537CAMK2A-2.922.9438CAMK2B0.150.8539CAMK2d4.230.7740CAMK2G-4.661.1541CAMK42.410.8742CAMKK122.620.4843CAMKK254.240.0644CDC7 / DBF4-0.880.4345CDK1 / CYCLIN A99.330.0346CDK1 / CYCLIN B99.220.1647CDK1 / CYCLIN E100.020.1248CDK14 / CYCLIN Y (PFTK1)91.660.0649CDK15 / CYCLIN A298.370.2450CDK15 / CYCLIN B184.550.5151CDK16 / CYCLIN Y (PCTAIRE)84.660.0952CDK17 / CYCLIN Y (PCTK2)86.870.0753CDK18 / CYCLIN Y (PCTK3)94.070.0654CDK2 / CYCLIN A99.740.0855CDK2 / CYCLIN A1101.060.1656CDK2 / CYCLIN E100.120.0257CDK2 / CYCLIN E299.750.1158CDK2 / CYCLIN O100.580.4459CDK3 / CYCLIN C16.360.3560CDK3 / CYCLIN E99.900.0061CDK3 / CYCLIN E299.990.0062CDK4 / CYCLIN D183.680.1563CDK4 / CYCLIN D288.290.0264CDK4 / CYCLIN D387.340.1165CDK5 / P25100.960.0966CDK5 / P35100.230.0167CDK6 / CYCLIN D199.050.1368CDK6 / CYCLIN D256.840.6969CDK6 / CYCLIN D376.610.4770CDK7 / CYCLIN H79.170.1471CDK9 / CYCLIN K100.440.0272CDK9 / CYCLIN T199.340.0273CDK9 / CYCLIN T298.790.0474CHK110.562.8475CHK261.740.0876CK1A117.421.3977CK1A1L11.502.6578CK1D39.870.8679CK1EPSILON32.501.7080CK1G1-1.220.2081CK1G28.412.0182CK1G314.830.4783CK2A-0.840.1184CK2A27.001.6185CLK123.141.0386CLK222.001.1887CLK35.810.2688CLK412.261.1489COT1 / MAP3K86.810.7790CSK0.320.1791CTK / MATK0.761.3492DAPK1-2.391.4493DAPK22.720.7794DCAMKL110.910.3495DCAMKL28.611.4696DDR1-5.630.6897DDR2-0.500.4598DMPK-0.920.1699DMPK27.603.91100DRAK1 / STK17A2.051.37101DYRK1 / DYRK1A23.461.10102DYRK1B27.782.03103DYRK24.210.33104DYRK315.891.99105DYRK40.991.46106EGFR-2.661.39107EPHA13.440.23108EPHA26.830.18109EPHA38.440.59110EPHA416.450.42111EPHA56.621.65112EPHA614.770.30113EPHA729.950.30114EPHA8-1.910.16115EPHB130.132.74116EPHB222.520.28117EPHB32.810.52118EPHB411.780.72119ERBB2 / HER22.221.51120ERBB4 / HER43.330.23121ERK137.440.75122ERK2 / MAPK122.651.48123ERK5 / MAPK74.611.36124ERK7 / MAPK1556.750.92125ERN1 / IRE17.560.45126ERN2 / IRE2-0.871.54127FAK / PTK217.760.01128FER-2.081.42129FES / FPS33.730.11130FGFR133.850.86131FGFR221.803.13132FGFR314.410.06133FGFR49.430.13134FGR8.460.23135FLT1 / VEGFR110.580.50136FLT319.310.05137FLT4 / VEGFR30.200.66138FMS-7.510.75139FRK / PTK55.030.65140FYN3.750.44141GCK / MAP4K222.781.29142GLK / MAP4K339.321.05143GRK1-2.663.13144GRK20.430.87145GRK3-9.050.33146GRK4-3.702.16147GRK52.050.82148GRK6-0.100.78149GRK72.380.86150GSK3A90.600.06151GSK3B93.660.09152HASPIN11.880.69153HCK14.730.52154HGK / MAP4K45.702.64155HIPK1-9.440.41156HIPK22.530.58157HIPK38.732.02158HIPK417.710.53159HPK1 / MAP4K17.<h2 style=";text-align:left;direction:ltr">900.61160IGF1R6.121.80161IKKA / CHUK7.200.54162IKKB / IKBKB6.350.16163IKKE / IKBKE8.960.24164IR-1.640.42165IRAK12.701.93166IRAK40.804.00167IRR / INSRR15.582.62168ITK-0.230.22169JAK12.020.86170JAK2-0.742.87171JAK31.160.96172JNK116.652.81173JNK28.972.21174JNK36.83 0.98175KDR / VEGFR2-0.083.01176KHS / MAP4K51.260.06177KSR1-5.500.08178KSR23.910.39179LATS126.612.17180LATS216.010.88181LCK-1.510.25 182LCK2 / ICK62.320.45183LIMK120.000.93184LIMK24.330.64185LKB194.7 40.36186LOK / STK1021.510.74187LRRK233.840.19188LYN-4.900.91189LYN B-0.073.61190MAK93.220.17191MAPKAPK21.902.74192MAPKAPK37.780.48193MAPKAPK5 / PRAK-1.740.20194MARK123.360.81195MARK2 / PAR-1BA24.291.82196MARK326.870.56197MARK420.022.84198MAST34.231.00199MASTL0.482.47200MEK14.320.66201MEK27.930.58202MEK31.360.65203M EK5-4.870.13204MEKK14.131.91205MEKK26.060.28206MEKK317.521.83207MEKK60.592.00208MELK62.711.22209MINK / MINK11.611.81210MKK417 .680.28211MKK630.771.31212MKK7-0.544.91213MLCK / MYLK12.030.66214MLCK2 / MYLK2-0.240.50215MLK1 / MAP3K94.460.28216MLK2 / MAP3K1013.<h2 style=";text-align:left;direction:ltr">890.51217MLK3 / MAP3K1113.231.47218MLK4-5.760.08219MNK15.263.10220MNK2-1.971.44221MRCKA / CDC42BPA-0.880.62222MRCKB / CDC42BPB-0.9 10.35223MSK1 / RPS6KA57.441.18224MSK2 / RPS6KA45.280.03225MSSK1 / STK236.312.34226MST1 / STK43.261.05227MST2 / STK310.510.88228MST3 / ST K2457.745.69229MST410.110.75230MUSK21.261.99231MYLK3-2.400.59232MYLK45.690.55233MYO3A0.550.92234MYO3B14.721.36235NEK12.570.76236NEK117.331.85237NEK22.701.65238NEK32.701.19239NEK4-7.516.00240NEK50.512.04241NEK6-0.600.03242NEK7-2.530.84243NEK97.500.48 244NIM1-2.150.14245NLK34.221.96246OSR1 / OXSR15.860.70247P38A / MAPK1410.560.28248P38B / MAPK118.761.39249P38d / MAPK130.480.09250P3 8g-2.261.97251P70S6K / RPS6KB12.960.02252P70S6KB / RPS6KB2-2.240.3 4253PAK127.451.41254PAK218.700.35255PAK310.912.45256PAK463.730. 34257PAK551.870.63258PAK614.121.43259PASK1.515.58260PBK / TOPK-1.830.52261PDGFRA8.460.32262PDGFRB-1.781.33263PDK1 / PDPK12.750.8 1264PHKG137.640.09265PHKG20.750.59266PIM1-1.273.21267PIM22.074.95268PIM32.7511.74269PKA0.633.42270PKACB4.780.40271PKACG5.370.55272PKCA2.191.17273PKCB14.821.32274PKCb215.880.19275PKCD8.720.01276PKCepsilon4.820.95277PKCETA13.200.43278PKCG13.320.83279PKCIOTA-1.791.41280PKCMU / PRKD11.800.45281PKCNU / PRKD31.330.39282PKCTHETA13.441.95283PKCZETA1.090.76284PKD2 / PRKD23.710.82285PKG1A10.360.38286PKG1B-0.063.08287PKG2 / PRKG28.335.12288PKN1 / PRK17.242.55289PKN2 / PRK2-2.291.92290PKN3 / PRK313.291.44291PLK1-1.561.26292PLK23.441.03293PLK35.780.28294PLK4 / SAK10.050.60295PRKX9.175.76296PYK217.362.76297RAF16.360.05298RET-0.200.57299RIPK29.392.28300RIPK4-3.763.22301RIPK5-4.683.06302ROCK114.800.58303ROCK211.490.01304RON / MST1R-5.310.58305ROS / ROS112.491.51306RSK17.450.99307RSK216.520.32308RSK312.570.67309RSK431.860.83310SBK1-0.680.34311SGK18.380.68312SGK22.011.20313SGK3 / SGKL4.151.89314SIK120.860.74315SIK229.610.18316SIK351.140.17317SLK / STK25.392.76318SNARK / NUAK28.781.49319SNRK-2.831.00320SRMS-2.740.05321SRPK112.751.24322SRPK2-1.970.33323SSTK / TSSK6-1.461.58324STK1615.031.97325STK21 / CIT5.440.65326STK22D / TSSK1-6.500.45327STK25 / YSK144.600.<h2 style=";text-align:left;direction:ltr">53328STK32B / YANK218.562.39329STK32C / YANK315.581.92330STK336.672.36331STK38 / NDR133.150.15332STK38L / NDR231.410.38333STK39 / STLK310.970.25334SYK-2.540.43335TAK1-7.513.61336TAOK160.250.61337TAOK2 / TAO181.11 0.24338TAOK3 / JIK50.030.50339TBK16.140.42340TEC-0.120.55341TESK1-11.941.32342TESK24.320.37343TGFBR25.630.36344TIE2 / TEK9.571.06345TLK115.381.91346TLK226.932.43347TNIK7.880.28348TNK11.281.33349TRKA0.280.1 1350TRKB8.990.48351TRKC13.341.67352TSSK2-4.800.92353TSSK3 / STK22C-8.292.33354TTBK13.400.02355TTBK24.6 40.64356TXK13.291.46357TYK1 / LTK-2.730.81358TYK28.280.99359TYRO3 / SKY1.960.84360ULK126.600.52361ULK23. 290.19362ULK35.781.23363VRK1-3.300.52364VRK23.041.46365WNK12.340.79366WNK20.091.68367WNK3-0.330.14368YES / YES115.382.40369YSK4 / MAP3K19-7.262.60370ZAK / MLTK1.750.60371ZAP70-2.222.61372ZIPK / DAPK3-3.850.42.<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0237] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0238] <h2 style=";text-align:left;direction:ltr"> 실험예 4. 실시예 25의 HCC1954 유방암 마우스 xenograft 모델 효능 평가<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0239] The in vivo efficacy of Example 25 was evaluated using a mouse orthotopic breast cancer model of HCC1954 cells (Fig. 6). Each drug (n = 6) was administered intraperitoneally twice a week, starting on day 18. As expected, trastuzumab (20 mg / kg) had no anticancer effect in the HCC1954 tumor mouse model, whereas Example 25 (10 mg / kg, 20 mg / kg) exhibited antitumor activity immediately after the first injection, inhibited tumor growth in a dose-dependent manner, and exhibited antitumor efficacy that was particularly higher than that of dinaciclib. However, mice administered 20 mg / kg began to lose body weight from day 11 after administration, which appears to be due to cumulative drug toxicity caused by long-term, high-dose administration.

[0240]

[0241] Experimental Example 5. Evaluation of hERG inhibition ability of Example 25

[0242] In the hERG autopatch clamp experiment, the inhibitory effect of Example 25 on the hERG channel was almost not observed (IC 50 = 37.9 μM). This indicates that the toxicity observed at high doses of Example 25 is not related to hERG (Fig. 7), and the toxicity observed at 20 mg / kg administration could be expected to be due to Example 25's strong simultaneous inhibition of multiple CDKs.

[0243]

[0244] While the present invention has been described in detail through preferred manufacturing examples, exemplary compounds, and experimental examples, the scope of the present invention is not limited to the specific exemplary compounds and should be interpreted in accordance with the appended claims. Furthermore, those skilled in the art will appreciate that numerous modifications and variations are possible without departing from the scope of the present invention.

Claims

1. A compound of the following chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] R 1 is a 5 to 12-membered heteroaryl containing one or more heteroatoms of N, S and O, wherein said heteroaryl is C 1-6 Alkyl, hydroxy (C 1-6 ) is unsubstituted or substituted with one or more non-hydrogen substituents selected from alkyl, oxo (=O), and amine; R 2 is pyridine, heterocycloalkyl containing one or more heteroatoms of N and O, or , wherein the pyridine is substituted or unsubstituted with an amine, and the heterocycloalkyl is hydroxy (C 1-6 ) is substituted or unsubstituted with alkyl, and the above R 4 and R 5 are each independently hydrogen or hydroxy (C 1-6 ) is alkyl; and R 3 Silver C 1-6 It's alkyl.

2. In paragraph 1, R 1 is a heteroaryl selected from pyrazole, oxazole, thiazole, furan, indazole, dihydrobenzoimidazole, and triazole, wherein said heteroaryl is C 1-3 Alkyl, hydroxy (C 1-3 ) is unsubstituted or substituted with one or more non-hydrogen substituents selected from alkyl, oxo (=O) and amine, The above R 1 When this pyrazole, oxazole, and furan are R 2 is pyridine, piperidine, morpholine or , wherein the pyridine is substituted or unsubstituted with an amine, and the piperidine or morpholine is hydroxy (C 1-3 ) is substituted or unsubstituted with alkyl, and the above R 4 and R 5 are each independently hydrogen or hydroxy (C 1-3 ) is alkyl, The above R 1 When this thiazole, indazole, dihydrobenzimidazole, and triazole, R 2 is pyridine; and R 3 Silver C 1-3 alkyl, A compound of formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

3. In paragraph 1, R 3 A compound of formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

4. In the first paragraph, the compound of the chemical formula 1 is a compound that is any one of the compounds (1) to (25) below, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. (1) N-((6-(5-amino-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-9-ethyl-2-(pyridin-3-yl)-9H-purin-6-amine, (2) 9-ethyl-N-((6-(oxazol-2-yl)pyridin-3-yl)methyl)-2-(pyridin-3-yl)-9H-purin-6-amine, (3) 9-ethyl-2-(pyridin-3-yl)-N-((6-(thiazol-2-yl)pyridin-3-yl)methyl)-9H-purin-6-amine, (4) 5-(5-(((9-ethyl-2-(pyridin-3-yl)-9H-purin-6-yl)amino)methyl)pyridin-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one, (5) (1-(5-(((9-ethyl-2-(pyridin-3-yl)-9H-purin-6-yl)amino)methyl)pyridin-2-yl)-1H-1,2,3-triazol-4-yl)methanol, (6) 2,2'-((6-(((6-(1H-pyrazol-1-yl)pyridin-3-yl)methyl)amino)-9-ethyl-9H-purin-2-yl)azanediyl)bis(ethan-1-ol), (7) 2-((6-(((6-(1H-pyrazol-1-yl)pyridin-3-yl)methyl)amino)-9-ethyl-9H-purin-2-yl)amino)propane-1,3-diol, (8) (S)-2-(1-(6-(((6-(1H-pyrazol-1-yl)pyridin-3-yl)methyl)amino)-9-ethyl-9H-purin-2-yl)piperidin-2-yl)ethan-1-ol, (9) (R)-2-(4-(6-(((6-(1H-pyrazol-1-yl)pyridin-3-yl)methyl)amino)-9-ethyl-9H-purin-2-yl)morpholin-3-yl)ethan-1-ol, (10) 2-(6-aminopyridin-3-yl)-N-((6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-9-ethyl-9H-purin-6-amine, (11) 2-((6-(((6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)amino)-9-ethyl-9H-purin-2-yl)amino)ethan-1-ol, (12) 2,2'-((6-(((6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)amino)-9-ethyl-9H-purin-2-yl)azanediyl)bis(ethan-1-ol), (13) N-((6-(5-amino-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-2-(6-aminopyridin-3-yl)-9-ethyl-9H-purin-6-amine, (14) 2-((6-(((6-(5-amino-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)amino)-9-ethyl-9H-purin-2-yl)amino)ethan-1-ol, (15) 2,2'-((6-(((6-(5-amino-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)amino)-9-ethyl-9H-purin-2-yl)azanediyl)bis(ethan-1-ol), (16) (S)-2-(1-(6-(((6-(5-amino-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)amino)-9-ethyl-9H-purin-2-yl)piperidin-2-yl)ethan-1-ol, (17) 2-(6-aminopyridin-3-yl)-9-ethyl-N-((6-(oxazol-2-yl)pyridin-3-yl)methyl)-9H-purin-6-amine, (18) 2,2'-((9-ethyl-6-(((6-(oxazol-2-yl)pyridin-3-yl)methyl)amino)-9H-purin-2-yl)azanediyl)bis(ethan-1-ol), (19) 2-((9-ethyl-6-(((6-(oxazol-2-yl)pyridin-3-yl)methyl)amino)-9H-purin-2-yl)amino)propane-1,3-diol, (20) (R)-2-(4-(9-ethyl-6-(((6-(oxazol-2-yl)pyridin-3-yl)methyl)amino)-9H-purin-2-yl)morpholin-3-yl)ethan-1-ol, (21) 2-(6-aminopyridin-3-yl)-9-ethyl-N-((6-(furan-3-yl)pyridin-3-yl)methyl)-9H-purin-6-amine, (22) 2,2'-((9-ethyl-6-(((6-(furan-3-yl)pyridin-3-yl)methyl)amino)-9H-purin-2-yl)azanediyl)bis(ethan-1-ol), (23) 2-((9-ethyl-6-(((6-(furan-3-yl)pyridin-3-yl)methyl)amino)-9H-purin-2-yl)amino)propane-1,3-diol, (24) (S)-2-(1-(9-ethyl-6-(((6-(furan-3-yl)pyridin-3-yl)methyl)amino)-9H-purin-2-yl)piperidin-2-yl)ethan-1-ol, 및 (25) (R)-2-(4-(9-ethyl-6-(((6-(furan-3-yl)pyridin-3-yl)methyl)amino)-9H-purin-2-yl)morpholin-3-yl)ethan-1-ol., 5. A step of preparing a compound of chemical formula 3 from a compound of chemical formula 2; A step of preparing a compound of chemical formula 4 from a compound of chemical formula 3; and A method for producing a compound of formula 1, comprising: a step of producing a compound of formula 1 from a compound of formula 4; [Chemical Formula 2] [Chemical Formula 3] [Chemical Formula 4] [Chemical Formula 1] In the above formula, Hal is a leaving group halogen, and R 1 Inland R 3 are each the same as defined in Article 1.

6. A pharmaceutical composition for preventing or treating cancer, comprising a compound of chemical formula 1 of any one of claims 1 to 4, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient; and a pharmaceutically acceptable carrier.

7. In paragraph 6, A pharmaceutical composition for preventing or treating cancer, wherein the compound of the above chemical formula 1 inhibits HER2 (Human epidermal growth factor receptor 2).

8. In paragraph 6, A pharmaceutical composition for preventing or treating cancer, wherein the cancer is at least one selected from the group consisting of colorectal cancer, stomach cancer, lung cancer, biliary tract cancer, bladder cancer, esophageal cancer, melanoma, ovarian cancer, liver cancer, prostate cancer, pancreatic cancer, colon cancer, head and neck cancer, uterine cancer, breast cancer, and cervical cancer.

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