WO2015130014A1 - Pyrimidine-2,4-diamine derivative and pharmaceutical anticancer composition containing same as active ingredient - Google Patents

Pyrimidine-2,4-diamine derivative and pharmaceutical anticancer composition containing same as active ingredient Download PDF

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Publication number
WO2015130014A1
WO2015130014A1 PCT/KR2015/000737 KR2015000737W WO2015130014A1 WO 2015130014 A1 WO2015130014 A1 WO 2015130014A1 KR 2015000737 W KR2015000737 W KR 2015000737W WO 2015130014 A1 WO2015130014 A1 WO 2015130014A1
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WO
WIPO (PCT)
Prior art keywords
phenyl
pyrimidine
diamine
isopropylsulfonyl
chloro
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PCT/KR2015/000737
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French (fr)
Korean (ko)
Inventor
정희정
김형래
김필호
박지훈
안선주
윤창수
이광호
이정옥
조성윤
채종학
하재두
황종연
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한국화학연구원
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Priority to CN201580010933.1A priority Critical patent/CN106029646B/en
Publication of WO2015130014A1 publication Critical patent/WO2015130014A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a pyrimidine-2, 4-diamine derivative or a pharmaceutically acceptable salt thereof and a pharmaceutical composition for preventing or treating cancer containing the same as an active ingredient.
  • Cancer is called a tumor, a cell mass composed of undifferentiated cells with unlimited proliferation, ignoring the necessary conditions in tissues, unlike normal cells that can proliferate and inhibit regular and resected proliferation according to individual needs.
  • This unlimited proliferation of cancer cells is an incurable disease that penetrates into surrounding tissues and, more seriously, metastasizes to other organs in the body, causing severe pain and eventually causing death.
  • the most representative drug that inhibits tyrosine kinase receptor which is one of the specific molecular biological factors, is Gleebag.
  • the gleeback inhibits the action of the Bcr-Abl fusion gene formed by chromosomal translocation in the Philadelphia chromosome observed in chronic myelogenous leukemia, and acts as an anticancer agent. Is reaping.
  • EGFR epidermal growth factor receptor
  • tyrosine key ⁇ 1 ⁇ inhibitors which makes repetition nip (gef itinib) and Ilo tinip ( er 1 ot i ni b) and sorafenib and sunitinib are used to treat renal cell carcinoma, but side effects such as bleeding, heart attack, heart failure, and liver failure have been known.
  • anaplastic lymphoma kinase (ALK) has been found in several tumors of the human body and has been studied as a target for targeted therapies.
  • ALK anaplastic lymphoma kinase
  • ALK-NPM Nucl eophosmin
  • ALK-NPM Nucl eophosmin
  • anaplastic lymphoma kinase is achieved by interaction with downstream molecules that are targets of anaplastic lymphoma kinase (ALK), which are mediators of intracellular signaling.
  • ALK anaplastic lymphoma kinase
  • ALK is linked to other tyrosine kinases that are normal or cancer-generated to interact or activate several different pathways.
  • anaplastic lymphoma kinase (ALK) genes in lung cancer cells fuse with EML4 genes to produce EML4-ALK, an active tyrosine kinase.
  • anaplastic lymphoma kinase (ALK) gene include large B-cell lymphoma, systemic breakfast syndrome, Fusion tax ⁇ salt
  • Inflammatory myofibroblastic sarcoma, esophageal squamous cell carcinoma, non-small cell lung cancer, rhabdomyomas, myofibroblastoma, breast cancer and myeloma cell lines have been shown to be expressed in a number of non-hematopoietic tumors.
  • a variety of anaplastic lymphoma kinase (ALK) proteins are commonly found and these fusion proteins are believed to be involved in tumor development. Accordingly, by blocking the activation pathway of anaplastic lymphoma kinase (ALK), a therapeutic agent for ALK-NPM for cancer treatment has been developed.
  • ALK anaplastic lymphoma kinase
  • Pfizer a drug developed as a selective suppressor for oncogenic mutations
  • Crizotinib PF-02341066
  • PF-02341066 a small molecule tyrosine kinase inhibitor
  • ALK anaplastic lymphoma kinase
  • CH5424802 (Chugai) is also known to reduce tumor size in neuroblastoma cell lines in addition to anaplastic large cell lymphoma cell lines.
  • Patent Literatures 1 to 3 conventional therapeutic candidates having various skeletons have been developed for the purpose of inhibiting the anaplastic lymphoma kinase (ALK) activity, and pyrimidine derivatives selectively inhibit the lymphoma kinase (ALK) to prevent cancer. It can be developed as. Accordingly, the present inventors have found that anaplastic anaplastic lymphoma kinase (ALK,
  • ALK anaplastic lymphoma kinase
  • Patent Document 2 W0 2008051547 A1
  • Patent Document 3 W0 2004080980 A1
  • Another object of the present invention is to provide a pharmaceutical composition for the prevention or measurement of cancer-containing pyrimidine -2,4-diamine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Another object of the present invention is a disease caused by hyperactivity of anaplastic Lymphoma Kinase (ALK) containing a pyrimidine-2,4-diamine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
  • ALK anaplastic Lymphoma Kinase
  • an inhibitor of anaplastic lymphoma kinase (ALK) containing pyrimidine ⁇ 2,4-diamine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a pyrimidine-2,4-pentaamine derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
  • R 1 , R 2 and R 3 are independently —H, halogen, or unsubstituted or straight chain alkyl substituted with one or more halogens;
  • R 5 unsubstituted or substituted with one or more -0H groups, wherein R 5 is -H, -0H, or d-alkyl; Is a double bond,
  • R 1 , R 2 and R 3 are independently halogen, or unsubstituted or one Again
  • a compound represented by Chemical Formula 4 by reacting the compound represented by Chemical Formula 2 with the compound represented by Chemical Formula 3 (step 1); And reacting the compound represented by Chemical Formula 4 and the compound represented by Chemical Formula 5 prepared in Step 1 to prepare a compound represented by Chemical Formula 1 (step 2); the pyrimidine-2,4-diamine comprising the Provided are methods for preparing the derivatives.
  • R 1 , R 2 , R 3 and R 4 are the same as defined in Chemical Formula 1). Furthermore, the present invention provides a pharmaceutical composition for preventing or treating cancer containing pyrimidine-2,4-diamine derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. In addition, the present invention contains a pyrimidine-2, 4-diamine derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient
  • the chain provides a pharmaceutical composition for the prevention or treatment of diseases caused by anaplastic lymphoma kinase (ALK) overactivity or due to Rl.
  • ALK anaplastic lymphoma kinase
  • the compound according to the present invention has a remarkably excellent effect of inhibiting anaplastic lymphoma kinase (ALK) activity, and thus has a therapeutic effect on cancer cells having EML4-ALK and NPM-ALK rounded anaplastic lymphoma kinase (ALfi) fusion proteins. It may be improved, and is expected to be effective in preventing cancer from recurring, and thus may be usefully used as a pharmaceutical composition for preventing or treating cancer.
  • ALK anaplastic lymphoma kinase
  • the present invention provides a pyrimidine-2,4-diamine body or a pharmaceutically acceptable salt of a child represented by the following Chemical Formula 1.
  • R 1 , 2 and R 3 are independently halogen or Ci- 10 straight alkyl substituted with unsubstituted or one or more halogens;
  • R ⁇ 1 is a chain
  • R 2 and R 3 are independently —H ′ halogen, or C o straight or branched alkyl substituted with unsubstituted or one or more halogens;
  • R 1 , R 2 and R 3 are independently d- 5 straight chain alkyl substituted with halogen, unsubstituted or halogen;
  • R 1 , R 2 and R 3 are independently halogen, unsubstituted or linear or branched alkyl substituted with one or more halogen;
  • R 1 is —C 1 , or —CF 3 ;
  • R 2 is. -CH 3 or -F
  • R 3 is -CH 3 , or -CHF 2 ;
  • R 1 is —C 1 or —CF 3 ;
  • R 2 is ⁇ H, — CH 3 , or —F;
  • R 3 is —CH 3 , —CH (CH 3 ) 2 , or —CHF 2 ;
  • the pyrimidine ⁇ 2,4-diamine derivative represented by Chemical Formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt, and the salt may be an acid formed by a pharmaceutically acceptable free acid. Addition salts are useful.
  • Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and Non-toxic organic acids such as alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids, organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-roluenesulfonic acid, tartaric acid and fumaric acid Obtained from Such toxic, nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate and pyrophosphate chlor
  • the acid addition salt according to the present invention is dissolved in a conventional method, for example, pyrimidine-2,4-diamine derivatives in an organic solvent, for example methane, ethane, acetone, methylene chloride, acetonitrile, and the like.
  • the precipitate produced by addition may be prepared by filtration and drying, or the solvent and excess acid may be distilled under reduced pressure, and then dried or crystallized under an organic solvent.
  • the present invention includes not only pyrimidine-2, 4-diamine derivatives represented by the general formula (1) and pharmaceutically acceptable salts thereof, but also possible solvates, hydrates, isomers, and the like that can be prepared therefrom. .
  • the present invention as shown in the following reaction formula 1, Preparing a compound represented by the formula (4) by reacting the compound represented by the formula (2) with the compound represented by the formula (3) (step 1); And the step of preparing the compound represented by Chemical Formula 1 by reacting the compound represented by Chemical Formula 4 and the compound represented by Chemical Formula 5 prepared in Step 1 (Step 2). Provides a process for the preparation of diamine derivatives.
  • step 1 is a step of preparing a compound represented by Chemical Formula 4 by reacting the compound represented by Chemical Formula 2 with the compound represented by Chemical Formula 3.
  • the compound represented by Formula 4 may be obtained by alkylating the compound represented by Formula 2 with the compound represented by Formula 3 under an organic solvent and a base.
  • usable solvents are tetrahydrofuran; Dioxane; Ether solvents including ethyl ether, 1,2-dimethoxyethane and the like; Lower alcohols including methanol, ethanol, propanol and butanol; Dimethylformamide (DMF), Dimethylsulphoxide (DMS0), Acetonasesulfonate, Toluenesulfonate, Chlorobenzenesulfonate, Xylenesulfonate, Phenyl Acetate, Pe Nylpropionate, Phenylbutyrate, Citrate, Lactate, ⁇ -Hydroxybutyrate, Glycolate, Maleate, Tartrate, Methanesulfonate, Propanesulfonate, Naphthalene-1-sulfonate, Naphthalene-2-sulfo Include nate or mandelate.
  • DMF Dimethylformamide
  • DMS0 Dimethylsulphoxide
  • the base is an organic base such as' pyridine, triethylamine, ⁇ , ⁇ -diisopropyl ethylamine (DIPEA), 1,8-diazabicyclo [5.4.0] -7-unthecene (DBU);
  • organic bases such as sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and sodium hydride can be used in equivalent or excess amounts.
  • the reaction temperature is 50-200 ⁇ :, stirring time is 0.5 ⁇ 20 hours.
  • step 2 is a step of preparing the compound represented by the formula (1) by reacting the compound represented by the formula (4) prepared in step 1 with the compound represented by the formula (5).
  • a compound represented by Chemical Formula 1 may be obtained by alkylating the compound represented by Chemical Formula 4 with a compound represented by Chemical Formula 5 under an organic solvent and a base.
  • usable solvents include tetrahydrofuran; Dioxane; Ether solvents including ethyl ether, 1,2-dimethoxyethane and the like; Lower alcohols including methane, ethanol, propane and butanol; Dimethylformamide (DMF), Dimethylsulphoxide (DMS0); Acetonazenesulfonate, Toluenesulfonate, Chlorobenzenesulfonate, Xylenesulfonate, Phenyl acetate, Phenylpropionate, Phenylbutyrate, Citrate, Rock Tate, ⁇ -hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1—sulfonate, naphthalene-2—sulfonate or mandelate.
  • the base may be an organic base such as pyridine, triethylamine, ⁇ , ⁇ -diisopropyl ethylamine (DIPEA), 1,8-diazabicyclo [5.4.0] -gundene (DBU);
  • organic base such as pyridine, triethylamine, ⁇ , ⁇ -diisopropyl ethylamine (DIPEA), 1,8-diazabicyclo [5.4.0] -gundene (DBU);
  • inorganic bases such as sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and sodium hydride may be used in equivalent or excess amounts, and the reaction temperature is 50-200 ° C. and the stirring time is 0.5-20 hours.
  • the present invention provides a pharmaceutical composition for preventing or treating cancer containing pyrimidine-2,4-diamine derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention is due to the overactivity of anaplastic lymphoma kinase (ALK) containing pyrimidine-2, 4-diamine derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient It provides a pharmaceutical composition for the prevention or treatment of the disease caused.
  • ALK anaplastic lymphoma kinase
  • the present invention provides an inhibitor of anaplastic lymphoma kinase (ALK) containing pyrimidine-2,4-diamine derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. to provide i.
  • ALK anaplastic lymphoma kinase
  • the ⁇ pharmaceutical composition and inhibitor according to the present invention are characterized by inhibiting the expression and growth of cancer cells by inhibiting the activity of anaplastic lymphoma kinase (ALK).
  • Aplastic lymphoma kinase is a gene that induces cell proliferation of cancers present in cancer cells, and the gene fusion process activates anaplastic lymphoma kinase (AUO), and at this time, tyrosine of anaplastic lymphoma kinase (ALK) Kinases behave abnormally to induce cell decay, prevent apoptosis, prevent cell death, rearrange bones and modify cell morphology, as well as anaplastic species kinase (ALK) It is linked to a tyrosine kinase and interacts with or activates several different pathways.Therefore, the anaplastic lymphoma kinase (ALK) of pyrimidine ⁇ 2, 4- sex senarim diamine derivative represented by Formula 1 according to the present invention.
  • the popping formulated compounds according to the present invention The (ALK) and the enzyme was treated in several cancer cells, a result of measuring the IC 50 and GI 50, pyrimidine-2,4-diamine derivatives of the compounds are increasing most control group represented by the formula (1) (greater separation tank tinip and LDK- 378) It was shown to be superior in activity to the compound (see Experimental Example 1-4.)
  • the pyrimidine-2, 4-diamine derivatives represented by the formula (1) according to the present invention showed the activity of anaplastic lymphoma kinase (ALK).
  • the composition of the present invention is used as a medicine, Pyrimidin-4-eu -2 derivative or a pharmaceutically acceptable thereof, represented by the learning 1
  • compositions containing possible salts as active ingredients may be formulated and administered in various oral or parenteral dosage forms as described below, but are not limited thereto.
  • Formulations for oral administration include, for example, tablets, pills, hard / soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, troches, and the like.
  • Toze dextrose, sucrose, manny, sorbitol, cellulose and / or glycine
  • lubricants e.g. silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols
  • Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellose, sodium carboxymethylcellose and / or polyvinylpyridine, optionally starch, agar, alginic acid or Disintegrants or boiling mixtures and / or such as its sodium salts. It may contain absorbents, colorants, flavors and sweeteners.
  • binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellose, sodium carboxymethylcellose and / or polyvinylpyridine, optionally starch, agar, alginic acid or Disintegrants or boiling mixtures and / or such as its sodium salts. It may contain absorbents, colorants, flavors and sweeteners.
  • the pharmaceutical composition comprising the pyrimidine- 2, 4-diamine derivative represented by the formula (1) as an active ingredient can be administered parenterally, parenteral administration is injected subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection By the way.
  • pyrimidine-2, 4-diamine derivatives or pharmaceutically acceptable salts thereof represented by the above formula (1) in order to formulate into a parenteral dosage form are mixed with water with a stabilizer or buffer to a solution or suspension. It can be prepared and prepared in ampule or vial unit dosage form.
  • the composition may be sterile and / or contain preservatives, stabilizers, hydrating or emulsifying accelerators, salts for controlling osmotic pressure and / or auxiliaries such as buffering agents and other therapeutically useful substances. It may be formulated according to the formulation or coating method.
  • the dosage of the pharmaceutical composition containing Gorimidine -2 and 4-diamine derivatives represented by Chemical Formula 1 as an active ingredient on the human body depends on the patient's age, weight, sex, dosage form, health condition and degree of disease. Can be varied, preferably 0.
  • the amount of 01 to 1000 mg / kg / day may be administered by oral or parenteral route by dividing a predetermined time interval several times a day, preferably once to three times a day, according to the judgment of a doctor or pharmacist. ⁇
  • Step 1 tert-Butyl 4- (4 '((5-chloro-4-((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) ⁇ 3-methoxyphenyl) ⁇ 5 ⁇ 6- dehydropy
  • Step 1 tert-Butyl 4- (4-((5-chloro-4-((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -5-isopropoxy-2 Preparation of -methylphenyl) ⁇ 5, 6-dropyridine-1 (2H) -carboxate
  • Step 2 5-chloro-N2- (2-isopropoxy-5-methyl-4- (l, 2,3,6-tetrahydropyridin-4-yl) phenyl) -N4- (2- (iso Preparation of Propylsulfonyl) phenyl) pyrimidine-2,4-diamine
  • Step 1 tert-Butyl 4- (4 — ((5-chloro-4-((2- (isopropylsulfonyl) phenyl) pyrimidin-2-yl) amino) -3- (dipoloromethoxy) phenyl ) -5,6-dihydropyri-2H) -carboxylate
  • Step 2 5-chloro-N2- (2- (difluoromethoxy) -4- (l, 2,3,6-tetrahydropyridin-4-yl) phenyl) -N4— (2 (isopropylsul Phenylphenyl) pyrimidine-2,4-
  • Step 2 5-Chloro-N2- (2- (difluoromethoxy) -4- (piperidin-4-yl) fe-N4- (2- (isopropylsulfonyl) phenyl) pyrimidine-2, Preparation of 4-diamine
  • Step 2 Preparation of 5-Chloro-N4- (2 (isopropylsulfonyl) phenyl) N2- (2-methoxyoxy-4- (—4-yl) phenyl) pyrimidine-2,4-diamine
  • Step 1 tert-Butyl 4- (4-((4-((2- (isopropylsulfonyl) phenyl) amino) -5 (trifluoromethyl) pyrimidin-2-yl) amino) -3 Preparation of Memethoxynyl) -5, 6--1 (2H) -carboxylate
  • Step 1 tert-Butyl 4- (5-isopropoxy-4-((4-((2- (isopropyl sulfonyl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl Preparation of Amino) -2-methyl-5,6-dihydropyridine-1 (2H) -carboxylate
  • Step 2 N2- (2-isopropoxy-5-methyl-4- (l'2,3,6'tetrahydro) Preparation of lopyridin-4-yl) phenyl) -N4- (2- (isopropylsulfonyl) phenyl) -5- (tripletomethyl) -2,4-diamine
  • Step 1 tert-Butyl 4- (3- (difluoromethoxy) -4-((4-((2- (isopropylsulfonyl) phenyl) amino) — 5- (trifluoromethyl) pyrimidine Preparation of 2-yl) amino) fe) -5, 6-dihydropyridine-1 (2H) -carboxylate
  • Step 2 N2- (2- (difluoromethoxy) -4- (1,2,3,6 ⁇ tetrahydro pyridin-4-yl) phenyl) -N4- (2- (isopropylsulfonyl) phenyl) Preparation of -5- (trifluoromethyl) pi-2,4-diamine
  • Step 1 tert-butyl 4- (3- (difluoromethoxy) -4 '((4-((2- (isopropylsulfonyl) phenyl) amino) -5- (trifluoromethyl) pyrimidine- 2-1) O ⁇ 'no) phenyl) Preparation of piperidine-1-carboxylic rate
  • Step 1 tert-butyl 4- (4-((5-chloro-4-((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -2-fluoro-5- Methoxyphenyl) — Preparation of 5,6-Dihi-1 (2H) -carboxylate
  • Step 2 5-chloro-N2- (5-fluoro-2-methoxy 4- (l, 2,3,6-tetra high-droppyri-don-4-yl) phenyl) - ⁇ 4- ⁇ 2- ⁇
  • Step 1 tert-Butyl 4- (4-((5-chloro-4-((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -5-methoxy-2- Preparation of Methylphenyl) -5, 6-Dihydro Dropi-1 (2H) -carboxylate
  • Step 1 tert-Butyl 4- (4-((5—chloro-4-((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -5-mesophy-2- Methylphenyl) piperidine-1-carboxy
  • 17 mg (0.026 ⁇ l) of 2-merylphenyl) paperidine-1′carboxylate was dissolved in MeOH, 3 ml of dioxane dissolved in 4M HC1 was added, and the mixture was stirred at room temperature for 0.5 hour. After the reaction was completed, HC1 was removed and decanted with ether to obtain 15 mg of the target compound in 99% yield.
  • ⁇ is 5 II No. 3 ⁇ 4 -N 4-(2- (isopropylsulfonyl) phenyl) —N 2-(2-methoxy-4- (1,2,3,6-tetrahydropyridine) 40 mg of 4-yl) phenyl) pyrimidine-2,4-diamine was dissolved in 1 mL of DMF and 0 (: 0 3 (651,0.2 01) was added with stirring. Bromoethanol (0.01 ml, 0.12 mmol) ) was added, and the mixture was stirred for 18 hours at silver, and after completion of reaction, the organic layer was extracted with MC / H 2 0, dried over MgSO 4 , and concentrated to give 12 mg of the target compound by column chromatography.
  • lymphoma kinase of the pyrimidine-2,4-diamine derivative represented by Formula 1 according to the present invention
  • ALK lymphoma kinase
  • a compound (2) prepared in Examples 1 to 18 was added to a Glenner 96 well round bottom plate, and anaplastic lymphoma kinase (ALK) enzyme (1).
  • biotinylated peptide substrate (2 were mixed and incubated for 15 minutes.
  • ⁇ solution (5 ⁇ ) was added thereto, followed by kinase reaction for 30 minutes at room temperature.
  • Anaplastic lymphoma kinase (ALK) Below is the enzymatic activity and the anaplastic lymphoma kinase (ALK) 50 of the compound for reducing the non-small cell lung cancer cells, L1196M cell bow of containing enzymatic to 50% Table 2 .
  • pyrimidine ⁇ 2,4-diamine derivatives according to the present invention have the effect of inhibiting the activity of anaplastic lymphoma kinase (ALK) at the enzyme stage even at low concentrations, especially the conventional anaplastic lymphoma kinase (ALK) activity. It can be seen that it has superior inhibitory activity than crizotinib (positive control group) used as a therapeutic agent for non-small cell lung cancer.
  • ALK anaplastic lymphoma kinase
  • the pyrimidine-2,4-diamine derivatives according to the present invention have excellent effects of inhibiting anaplastic lymphoma kinase (ALK) activity and thus, non-small cell lung cancer, neuroblastoma inflammatory myeloid fibroblastic tumor, rhabdomyosarcoma, myofibroblastoma
  • ALK anaplastic lymphoma kinase
  • Cell culture medium RPMI 1640 medium, FBSCfetal bovine serum and lysine were purchased from Gibco (Grand Island, NY). Cerium, amphotericin B and gentamicin used sig-chemical products.
  • reagents such as SRBCsulforhodamine B, trisma base, and trichloroacetic acid (TCA), which are reagents used in cytotoxicity measurement experiments, were purchased from Sigma Chemical.
  • MTS assay Cel ITi ter 96 R Aqueous Non-Radioact IV Cell Proliferation Assay was purchased from Promega.
  • T-25 culture vessels used for cell culture, 96-well folate and other disposable supernatants used for cell culture were manufactured by Lincoln Park (NJ). Go to use
  • the final dimethyl sulfoxide concentration was set at 0.5% or less.
  • the cancer cell lines used in the experiment were all human-derived cancer cell lines. Specifically, H2228 and H3122, which are cell-cell lung cancer cells, were used.
  • Cancer cell proliferation inhibition was measured using the MTS assay as follows. Specifically, after the incubation with the compound prepared in Examples 1 to 18, the PMS solution and MTS solution constituting the Promega CeMTiter 96 R AQueous Non- Radioactive Cell Proliferation Assay 20 L was added. After leaving for 4 hours in the incubator was taken out and left for 10 minutes at room temperature. After measuring the absorbance at 490 nM using Molecular Device's Spect r aMax250 model, GI 50 (Growth Inhibition 50%), a growth inhibitory effect, was calculated, and the results are shown in Table 3 below.
  • the example compounds according to the present invention were shown to reduce the proliferative activity by inhibiting anaplastic lymphoma kinase (ALK) of the non-small cell lung cancer cell lines H2228 and H3122.
  • ALK anaplastic lymphoma kinase
  • the results of the Bont manipulative experiment showed that most of the compound of the present invention had a proliferative inhibitory effect than the compounds of the controls 1 and 2, which are currently used as non-small cell lung cancer treatment agents. Therefore, the pyrimidine-2,4-diamine derivatives according to the present invention have excellent effects of inhibiting anaplastic lymphoma kinase (ALK) activity, so that non-small cell lung cancer, neuroblastoma, inflammatory myeloid fibroblast tumor, rhabdomyosarcoma, and myofiber It can be usefully used as an inhibitor of anaplastic lymphoma kinase (ALK) activity as well as a composition for preventing or treating cancers such as blastoma, breast cancer, gastric cancer, lung cancer and melanoma.
  • ALK anaplastic lymphoma kinase
  • BaF3 cells were infected with EML4-ALK L1196M gene with lentivirus to prepare BaF3 EML4-AL L1196M cell line stably expressing EML4-AL L1196M.
  • each well of a 96 well plate (4,000) in a volume of 90 / 4,000 each the concentration of the compound prepared in the Example lOuM, 2uM, 0.4 uM, 0.08 uM, 0.016 uM, 0.0032 uM, 0.00064 uM and OuM were added to each well and placed in a cell incubator at 37 ° C. for 3 days.
  • the example compounds according to the present invention are mostly in BaF3 EML4-ALK WT (wil d-type) cells and crizotinib (cr i zot i ni b) Resistant BaF3 EML4-AL L1196M cells showed low cytotoxic IC 50 values compared to controls 1 and 2. From the experimental results, it was found that most of the compound of the present invention had superior ALK inhibitory activity than the compounds of the control groups 1 and 2, which are currently used as non-small cell lung cancer treatment agents.
  • the parimidine-2,4-diamine derivative according to the present invention has an excellent effect of inhibiting anaplastic lymphoma kinase (ALK) activity, thus, non-small cell lung cancer, neuroblastoma, inflammatory myeloid fibroblastic tumor, rhabdomyosarcoma, and muscle islet. It can be useful as an inhibitor of anaplastic lymphoma kinase (ALK) as well as a composition for the prevention or treatment of cancers such as blastoma, breast cancer, gastric cancer, lung cancer and melanoma.
  • ALK anaplastic lymphoma kinase
  • Control oil group 2 0.001 0.009 0.025 0.023 0.041 0.019
  • the pyrimidine- 2,4-o amine derivative represented by Chemical Formula 1 according to the present invention can be formulated in various forms according to the purpose.
  • the following is an illustration of some formulation methods containing the pyrimidine-2,4-diamine derivative represented by Formula 1 according to the invention as an active ingredient, but the present invention is not limited thereto.
  • Formulation Example 1 Preparation of Pharmaceutical Formulations
  • Magnesium stearate 2 nig According to the conventional capsule preparation method, the above ingredients are mixed and filled into gelatin capsules to prepare a capsulant. 1-4. Preparation of Injectables
  • pH Adjuster Prepared at the above ingredient content per ample (2 ml) according to the conventional method of preparation.
  • the compound according to the present invention has a remarkably excellent effect of inhibiting anaplastic lymphoma kinase (ALK) activity, treatment of cancer cells with anaplastic lymphoma kinase (ALK) fusion proteins, such as EML4-ALK and NPM-ALK.
  • ALK anaplastic lymphoma kinase
  • the effect may be improved and may be useful as a pharmaceutical composition for preventing or treating cancer because it is expected to be effective in preventing cancer from recurring.

Abstract

The present invention relates to a pyrimidine-2,4-diamine derivative or pharmaceutically acceptable salts thereof, and a pharmaceutical composition for preventing or treating cancer, which contains a pyrimidine-2,4-diamine derivative as an active ingredient. A compound according to the present invention is very effective in suppressing anaplastic lymphoma kinase (ALK) activity, and as a result, can improve the effectiveness of treatment on cancer cells having anaplastic lymphoma kinase (ALK) fusion proteins, such as EML4-ALK and NPM-ALK, and is expected to effectively prevent recurrence of cancer, thus being useful as a composition for preventing or treating cancer.

Description

【명세서】  【Specification】
【발명의 명칭】  [Name of invention]
피리미딘 -2 , 4-디아민 유도체 및 이를 유효성분으로 함유하는 항암용 약학적 조성물  Pyrimidine-2, 4-diamine derivative and anticancer pharmaceutical composition containing the same as an active ingredient
【기술분야】 Technical Field
본 발명은 피리미딘 -2， 4-디아민 유도체 또는 이의 약학적으로 허용가능한 염 및 이를 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물에 관한 것이다.  The present invention relates to a pyrimidine-2, 4-diamine derivative or a pharmaceutically acceptable salt thereof and a pharmaceutical composition for preventing or treating cancer containing the same as an active ingredient.
【배경기술】 Background Art
암이란 개체의 필요에 따라 규칙적이고 절제 있는 증식과 억제 를 할 수 있는 정상세포와 달리 조직 내에서 필요한 상태를 무시하고 무제한의 증식올 하는 미분화 세포로 구성된 세포덩어리로서 종양이라 고도 한다. 이러한 무제한의 증식을 하는 암 세포는 주위의 조직으로 침투하고 더 심각한 경우는 신체의 다른 기관으로 전이가 되어 심각한 고통을 수반하고 결국 죽음을 초래하는 난치병이다.  Cancer is called a tumor, a cell mass composed of undifferentiated cells with unlimited proliferation, ignoring the necessary conditions in tissues, unlike normal cells that can proliferate and inhibit regular and resected proliferation according to individual needs. This unlimited proliferation of cancer cells is an incurable disease that penetrates into surrounding tissues and, more seriously, metastasizes to other organs in the body, causing severe pain and eventually causing death.
미국암협회 ( Amer i can Cancer Soc i ety ) 자료에 따르면 2007년 한 해 세계적으로 새로이 암 진단을 받은 환자는 1200만 명 이상이며 사 망자는 760만 명으로 매일 약 2만 명씩 암으로 사망하는 것으로 보고 되었다. 우리나라의 경우 2006년 통계청 보고에 따르면 암으로 인한 사망이 사망원인 1위를 차지하였다. 따라서， 암 발생 및 투병으로 인 한 정신적， 육체적 고통의 감소와 삶의 질 향상을 위해 치료 효과가 우수한 종양 치료제의 개발이 절실히 요구된다.  According to the American Cancer Society (Amer i can Cancer Soc i ety), more than 12 million new cases of cancer were diagnosed worldwide in 2007, with 7.6 million deaths, killing about 20,000 people every day. Was reported. In Korea, according to the 2006 statistics report, death from cancer was the number one cause of death. Therefore, there is an urgent need for the development of tumor therapeutics with excellent therapeutic effects in order to reduce mental and physical pain and improve quality of life due to cancer and disease.
그러나 많은 노력에도 아직까지 정상세포가 어떠한 기전을 거쳐 암 세포로 형질전환이 되는지에 대해서는 정확하게 규명되지는 않았으 나， 환경요인 , 화학물질， 방사선， 바이러스 등 외적 요인 및 유전 인 자， 면역학적 요인 등의 내적 요인 등이 복잡하게 얽혀 결과적으로 암 이 발생한다. 암의 발생에 관련되는 유전자에는 종양형성 유전자 ( oncogenes )와 종0。억게 유전 ^" ( t umor suppr es sor genes ) 7}- .있는데 , 이들 사이의 균형이 위에서 설명한 내적 혹은 외적 요인들에 의해 무 너질 때 암이 발생하게 된다. 암은 혈액암과 고형암으로 크게 분류획며， 폐암 위암， 유방암， 구강암, 간암， 자궁암， 식도암， 피부암 등 신체의 가의 모든 부위에서 발생하며， 이들의 치료방법으로 최근 글리백 또는 허셉틴과 같은 소수 의 표적치료제가 특정암의 치료에 이용되고 있으나 현재까지는 수술이 나 방사선 요법 및 세포증식올 억제하는 화학요법제를 이용한 항암제 치료가 주된 방법이다. 그러나 표적치료제가 아니기 때문에 기존 화학 요법제의 가장 큰 문제는 세포독성으로 인한 부작용과 약제 내성으로 써， 항암제에 의한 초기의 성공적인 반웅에도 불구하고 결국에는 치료 가 실패하게 되는 주요 요인이다. 따라서 , 이러한 화학요법제의 한계 를 극복하기 위해서는 항암작용 기전이 명확한 표적 치료제 개발이 지 속적으로 필요하다 이에， 표적 치료제를 개발하기 위한 종양 형성에 관여하는 특정 분자생물학적 인자들에 관한 많은 연구가 진행되고 있으며， 특히， 분 자생물학적 인자들은 암의 예후예측이나 화학요법 및 방사선치료 여부 를 결정하는데 다양하게 이용되고 있다 . However, many efforts have not yet precisely identified the mechanism by which normal cells are transformed into cancer cells. External factors such as environmental factors, chemicals, radiation, viruses, genetic factors, immunological factors, etc. The internal factors such as the back are complicated, resulting in cancer. The genes involved in the development of cancer include oncogenes and species 0 ”. (T umor suppr es sor genes) 7}- . The balance between them is due to internal or external factors described above. The cancer is classified into blood cancer and solid cancer, and it occurs in all parts of the body such as lung cancer, stomach cancer, breast cancer, oral cancer, liver cancer, uterine cancer, esophageal cancer, and skin cancer. Although a small number of targeted therapies, such as Gleebag or Herceptin, have been used to treat certain cancers, chemotherapy with surgery, radiation therapy, and chemotherapy that inhibits cell proliferation is currently the main method, but because it is not a targeted drug, The biggest problem with conventional chemotherapy is the side effects of cytotoxicity and drug resistance. Despite the grand and eventually treatment fails to be a major factor. Therefore, these anti-cancer chemotherapeutic agents have a clear mechanism of action targeted therapy development in order to overcome the limitations of paper There is a great deal of research on specific molecular biological factors involved in tumor formation for the development of targeted therapeutics. In particular, molecular biologic factors can be used to predict the prognosis of cancer, chemotherapy and radiotherapy. It is widely used to make decisions.
특정 분자생물학적 인자 중의 하나인 타이로신 키나아제 수용체 를 저해하는 가장 대표적인 약물로는 글리백을 들 수 있다. 상기 글리 백은 만성골수성백혈병에서 관찰되는 필라델피아 염색체에서 염색체 전좌에 의해 형성되는 Bcr-Abl 융합유전자의 작용을 억제하여 항암 작 용을 하며， 타이로신 키나아제 저해제로써， 만성골수성백혈병 환자에 투여 시 만족할 만한 성과를 거두고 있다 . 이 후， 타이로신 키나아제 저해제로 항암 효과를 나타내는 약물로는 비소세포성 폐암 치료제로 ]"용되는 EGFR(epidermal growth factor receptor) 타이로신 키나 ό1·제 억제제인 게피티닙 (gef itinib)와 엘로티닙 ( er 1 ot i ni b)가 있고， 신장 세포암종 치료제로 소라페닙 (sorafenib)과 수니티닙 (sunitinib)이 사 용되고 있으나， 출혈， 심장마비 , 심부전， 간부전 등의 부작용이 있는 것으로 알려진바 있다. 최근에는 역형성 림프종 키나아쩨 (ALK, Anaplastic lymphoma kinase)가 인체 여러 종양에서 발견되어 표적치료의 목표물로 연구되 고 있다. The most representative drug that inhibits tyrosine kinase receptor, which is one of the specific molecular biological factors, is Gleebag. The gleeback inhibits the action of the Bcr-Abl fusion gene formed by chromosomal translocation in the Philadelphia chromosome observed in chronic myelogenous leukemia, and acts as an anticancer agent. Is reaping. Thereafter, as tyrosine kinase inhibitors as drugs showing an anti-cancer effect is non-small cell property in cancer treatment] EGFR (epidermal growth factor receptor) that is used for "tyrosine key ό 1 · inhibitors which makes repetition nip (gef itinib) and Ilo tinip ( er 1 ot i ni b) and sorafenib and sunitinib are used to treat renal cell carcinoma, but side effects such as bleeding, heart attack, heart failure, and liver failure have been known. Recently, anaplastic lymphoma kinase (ALK) has been found in several tumors of the human body and has been studied as a target for targeted therapies.
역형성 림프종 키나아제 (ALK)의 발암과정은 주로 역형성 큰세포 림프종에서 관찰되는 ALK-NPM(Nucl eophosmin, 뉴클레오포스민)의 융합 유전자인 것으로 알려져 있다. 유전자 융합에 의해 역형성 림프종 키 나아제 (ALK)가 활성화되면 역형성 림프종 키나아제 (ALK)가 갖고 있는 타이로신 키나아제는 비정상적으로 행동하여 암올 유발하게 된다. 즉 , 비정상적으로 활성화된 역형성 림프종 키나아제 (ALK)는 세포의 증식을 유도하고 아포프토시스를 방해해 세포가 사멸되지 않게 하며 세포뻐대 를 재배열시키며 세포 형태를 변형시킨다. 역형성 림프종 키나아제 (ALK)의 암 유전자화는 역형성 림프종 키나아제 (ALK)의 표적 물질인 하위 분자 (downstream molecule)와의 상호작용에 의해 이루어지는데， 하위 분자는 세포내 신호전달을 매개하는 물질이다. 역형성 림프종 키 나아제 (ALK)는 정상이거나 암 유전자화한 다른 타이로신 키나아제와 연결되어 상호작용을 하거나 여러 종류의 다른 경로들을 활성화시킨다. 특히， 폐암 세포의 내부에서 역형성 림프종 키나아제 (ALK) 유전 자는 EML4(Echinoderm Micro tubule- Associated Protein-Like 4) 유전 자와 융합하여 활성형 티로신 인산화 효소 (tyrosine kinase)인 EML4- ALK를 생산하고， 이때， EML4-역형성 림프종 키나아제 (ALK)의 암화 능 력이 효소활성에 의존적이라는 것이 알려진 바 있고， 또한， Mosse 등 은 491개의 신경모세포종 검체에서 약 26 %의 역형성 림프종 키나아 제 (ALK) 유전자 증폭에 대하여 보고한 바 있다. 뿐만 아니라， 역형성 림프종 키나아제 (ALK) 유전자는 대형 B-세포 림프종， 전신성 조식구증， 융근세^염이 The carcinogenic process of anaplastic lymphoma kinase (ALK) is known to be a fusion gene of ALK-NPM (Nucl eophosmin), which is mainly observed in anaplastic large cell lymphoma. When anaplastic lymphoma kinase (ALK) is activated by gene fusion, tyrosine kinases possessed by anaplastic lymphoma kinase (ALK) behave abnormally and cause cancer. In other words, abnormally activated anaplastic lymphoma kinase (ALK) induces cell proliferation, disrupts apoptosis, prevents cell death, rearranges cell lines, and alters cell morphology. Cancer geneization of anaplastic lymphoma kinase (ALK) is achieved by interaction with downstream molecules that are targets of anaplastic lymphoma kinase (ALK), which are mediators of intracellular signaling. Anaplastic lymphoma kinase (ALK) is linked to other tyrosine kinases that are normal or cancer-generated to interact or activate several different pathways. In particular, anaplastic lymphoma kinase (ALK) genes in lung cancer cells fuse with EML4 genes to produce EML4-ALK, an active tyrosine kinase. At this time, it was known that the cancerous ability of EML4-anaplastic lymphoma kinase (ALK) was dependent on enzymatic activity, and Mosse et al. Reported that about 26% of anaplastic lymphoma kinase (ALK) in 491 neuroblastoma samples. Gene amplification has been reported. In addition, anaplastic lymphoma kinase (ALK) genes include large B-cell lymphoma, systemic breakfast syndrome, Fusion tax ^ salt
증육포합라성 근섬유아세포성 육종， 식도 편평 세포암， 비소세포폐암， 횡문 종， 근섬유모세포종, 유방암 및 혹색종 세포주 등 수많은 비조혈 종양에서 발현되는 것으로 밝혀졌고， 염증성 골수섬유모세포종양 는 희귀한 질환와 경우 여러 종류의 역형성 림프종 키나아제 (ALK) 단백질이 흔히 발견되어 이러한 융합 단백질들이 종양의 발생에 관련된 것으로 여겨지고 있다. 이에， 역형성 림프종 키나아제 (ALK)의 활성화 경로를 차단함으 로써， 암 치료를 목적으로 하는 ALK-NPM를 대상으로 한 치료제가 개발 되고 있다. 최근 화이자 (Pfizer)에서 종양원성 변이에 대한 선택적 억 제제로 개발한 약물로 소분자 타이로신 인산화효소 억제제의 하나인 크리조티닙 (PF-02341066)이 ATP 경쟁성 c-Met/HGFR와 역형성 림프종 키나아제 (ALK) 저해제로써 , 비소세포폐암의 치료에 효과가 있는 것으 로 알려져 있으며， 2011년 FDA에서 산약으로 허가를 받았다.  Inflammatory myofibroblastic sarcoma, esophageal squamous cell carcinoma, non-small cell lung cancer, rhabdomyomas, myofibroblastoma, breast cancer and myeloma cell lines have been shown to be expressed in a number of non-hematopoietic tumors. Cases A variety of anaplastic lymphoma kinase (ALK) proteins are commonly found and these fusion proteins are believed to be involved in tumor development. Accordingly, by blocking the activation pathway of anaplastic lymphoma kinase (ALK), a therapeutic agent for ALK-NPM for cancer treatment has been developed. Recently, Pfizer, a drug developed as a selective suppressor for oncogenic mutations, Crizotinib (PF-02341066), a small molecule tyrosine kinase inhibitor, is an ATP-competent c-Met / HGFR and anaplastic lymphoma kinase ( ALK) is known to be effective in the treatment of non-small cell lung cancer and was approved by the FDA in 2011 as a drug.
또한， 노바티스 (Novartis)사의 NVP-TAE684, LDK— 378과 쥬가이 In addition, Novartis's NVP-TAE684, LDK— 378 and Jugay
(Chugai)사의 CH5424802도 역형성 큰세포 림프종 세포주 이외에 신경 모세포종 세포주에서도 종양의 크기를 감소시키는 효과가 있는 것으로 알려져 있다. 특허문헌 1 내지 3에서는， 종래 역형성 림프종 키나아제 (ALK) 활성을 저해하기 위한 용도로 다양한 골격을 가진 치료후보 물질이 개 발되고 있고, 피리미딘 유도체가 림프종 키나아제 (ALK)를 선택적으로 저해하여 항암제로 개발될 수 있음을 개시하고 있다 . 이에， 본 발명자들은 역형성 역형성 림프종 키나아제 (ALK,CH5424802 (Chugai) is also known to reduce tumor size in neuroblastoma cell lines in addition to anaplastic large cell lymphoma cell lines. In Patent Literatures 1 to 3, conventional therapeutic candidates having various skeletons have been developed for the purpose of inhibiting the anaplastic lymphoma kinase (ALK) activity, and pyrimidine derivatives selectively inhibit the lymphoma kinase (ALK) to prevent cancer. It can be developed as. Accordingly, the present inventors have found that anaplastic anaplastic lymphoma kinase (ALK,
Anaplastic lymphoma kinase) 활성억제 효과를 나타내는 화합물을 개발하기 위해 노력하던 중， 특정 구조의 피리미딘— 2 ,4-디아민 유도체가 역형성 림프종 키나아제 (ALK)의 활성억제 효과가 현저히 우수한 것을 알아내어， 암의 예방 또는 치료제로 유용할 수 있음을 밝히고 본 발명을 완성하였다. In an effort to develop compounds exhibiting an inhibitory effect on Anaplastic lymphoma kinase activity, we found that pyrimidine- 2,4-diamine derivatives of certain structures have significantly superior activity inhibitory effects of anaplastic lymphoma kinase (ALK). The present invention was found to be useful as a prophylactic or therapeutic agent for the present invention.
【선행기술문헌】 Prior Art Documents
【특허문헌】  [Patent literature]
(특허문 ¾ 1) W0 2009143389 A1  (Patent document ¾ 1) W0 2009143389 A1
(특허문헌 2) W0 2008051547 A1  (Patent Document 2) W0 2008051547 A1
(특허문헌 3) W0 2004080980 A1  (Patent Document 3) W0 2004080980 A1
【발명의 상세한 설명】 [Detailed Description of the Invention]
【기술적 과제】  [Technical problem]
본 발명의 목적은 피라미딘 -2,4-디아민 유도체 또는 이의 약학 적으로 허용가능한 염을 제공하는 것이다. 본 발명의 다른 목적은 상기 피리미딘 -2， 4-디아민 유도체의 제 It is an object of the present invention to provide pyramidine-2,4-diamine derivatives or pharmaceutically acceptable salts thereof. Another object of the present invention is to prepare a pyrimidine-2,4-diamine derivative
또직 Again
제공하는 것이다  To provide
또즉 - R  That is-R
본 또 다른 목적은 피리미딘 -2,4-디아민 유도체 또는 이 의 약학적으로 허용가능한 염을 유효성분으로 함유하는 암의 예방 또 측알 - 는 치료용 약 조성물을 제공하는 것이다. 본 발명의 다른 목적은 피리미딘 -2,4-디아민 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 역형성 림프종 키 나아제 (ALK, Anaplastic Lymphoma Kinase) 과활성으로 인하여 유발되 는 질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다. 본 발명의 또 다른 목적은 피리미딘ᅳ2，4-디아민 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 역형성 림프종 키나아제 (ALK)의 저해제를 제공하는 것이다.  Another object of the present invention is to provide a pharmaceutical composition for the prevention or measurement of cancer-containing pyrimidine -2,4-diamine derivative or a pharmaceutically acceptable salt thereof as an active ingredient. Another object of the present invention is a disease caused by hyperactivity of anaplastic Lymphoma Kinase (ALK) containing a pyrimidine-2,4-diamine derivative or a pharmaceutically acceptable salt thereof as an active ingredient. It is to provide a pharmaceutical composition for the prophylaxis or treatment of. It is another object of the present invention to provide an inhibitor of anaplastic lymphoma kinase (ALK) containing pyrimidine ᅳ 2,4-diamine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
【기술적 해결방법】 Technical Solution
상기 목적올 달성하기 위하여，  In order to achieve the above object,
본 발명은 하기 화학식 1로 표시되는 피리미딘 -2，4ᅳ다아민 유도 체 또는 이의 약학적으로 허용가능한 염을 제공한다.  The present invention provides a pyrimidine-2,4-pentaamine derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
Figure imgf000005_0001
Figure imgf000005_0001
상기 화학식 1에서，  In Chemical Formula 1,
는 단일결합 또는 이중결합이고; 이 단일결합인 경우，  Is a single bond or a double bond; Is a single bond,
R1, R2 및 R3는 독립적으로 -H, 할로겐， 또는 비치환 또는 하나 이상의 할로겐이 치환된 직쇄 알킬이고; R 1 , R 2 and R 3 are independently —H, halogen, or unsubstituted or straight chain alkyl substituted with one or more halogens;
비치환 또는 하나 이상의 -0H기가 치환된 10 직쇄 또는 -C(=0)R5이고， 여기서 R5는 -H, -0H, 또는 d— 알킬이고; 이 이중결합인 경우, 10 straight chain or -C (= 0) R 5 unsubstituted or substituted with one or more -0H groups, wherein R 5 is -H, -0H, or d-alkyl; Is a double bond,
R1, R2 및 R3는 독립적으로 할로겐 , 또는 비치환 또는 하나 또직 R 1 , R 2 and R 3 are independently halogen, or unsubstituted or one Again
이상는쇄의 할로겐이 치환된 C^o 직쇄 또는 측쇄 알킬이고; The above is C ^ o straight or branched alkyl substituted with halogen of the chain;
또측 R 비치환 또는 하나 이상의 -0H기가 치환된 d-10 직쇄Another R unsubstituted or d- 10 straight chain substituted with one or more -0H groups
^는쇄 또는 -CO0)R5이고， 여기서 R5는 -H, -0H, 또는 d-io 즉알 ^ - 알킬이다. ^ Is a chain or -CO0) R 5 , where R 5 is -H, -0H, or d-io i.e. ^ -alkyl.
H쇄킬，  H chain kill ，
또한， 본 발명은 하기 반웅식 1에 나타낸 바와 같이，  In addition, the present invention, as shown in the following reaction formula 1,
화학식 2로 표시되는 화합물과 화학식 3으로 표시되는 화합물을 반웅시켜 화학식 4로 표시되는 화합물을 제조하는 단계 (단계 1); 및 상기 단계 1에서 제조한 화학식 4로 표시되는 화합물과 화학식 5로 표시되는 화합물올 반웅시켜 화학식 1로 표시되는 화합물올 제조 하는 단계 (단계 2);를 포함하는 상기 피리미딘 -2,4-디아민 유도체의 제조방법을 제공한다 . 1]  Preparing a compound represented by Chemical Formula 4 by reacting the compound represented by Chemical Formula 2 with the compound represented by Chemical Formula 3 (step 1); And reacting the compound represented by Chemical Formula 4 and the compound represented by Chemical Formula 5 prepared in Step 1 to prepare a compound represented by Chemical Formula 1 (step 2); the pyrimidine-2,4-diamine comprising the Provided are methods for preparing the derivatives. One]
Figure imgf000006_0001
Figure imgf000006_0002
Figure imgf000006_0001
Figure imgf000006_0002
(상기 반웅식 1에서，  (In the above reaction 1,
R1, R2, R3 및 R4는 상기 화학식 1에서 정의한 바와 같다). 나아가， 본 발명은 상기 화학식 1로 표시되는 피리미딘 -2，4-디 아민 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함 유하는 암의 예방 또는 치료용 약학적 조성물을 제공한다. 또한， 본 발명은 상기 화학식 1로 표시되는 피리미딘 -2， 4-디아 민 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유 R 1 , R 2 , R 3 and R 4 are the same as defined in Chemical Formula 1). Furthermore, the present invention provides a pharmaceutical composition for preventing or treating cancer containing pyrimidine-2,4-diamine derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. In addition, the present invention contains a pyrimidine-2, 4-diamine derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient
또직 Again
하는쇄는 역형성 림프종 키나아제 (ALK, Anaplastic Lymphoma Kinase) 과활 성으로또즉 R一 인하여 유발되는 질환의 예방 또는 치료용 약학적 조성물을 제 공한다. ^는쇄The chain provides a pharmaceutical composition for the prevention or treatment of diseases caused by anaplastic lymphoma kinase (ALK) overactivity or due to Rl. ^ Chain
측알 - 나아가， 본 H쇄킬발， 명은 상기 화학식 1로 표시되는 피리미딘 -2， 4-디아민 一0 -도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 역형성 키나아제 (ALK)의 저해제를 제공한다. Cheukal - In addition, the H chain kilbal, said pyrimidine-2, 4-diamine一0 of the formula (1) - inhibitors of Anaplastic kinase (ALK) containing a conductor or a pharmaceutically acceptable salt thereof as an active ingredient To provide.
【유리한 효과】 Advantageous Effects
본 발명에 의한 화합물은 역형성 림프종 키나아제 (ALK) 활성을 억제하는 효과가 현저히 우수하므로 이에 따른 EML4-ALK, NPM-ALK 둥의 역형성 림프종 키나아제 (ALfi) 융합 단백질을 가진 암세포에 대한 치료효과가 향상될 수 있으며， 암의 재발을 막는데 효과적일 것으로 예상되므로 암의 예방 또는 치료용 약학적 조성물로 유용하게 사용될 수 있다.  The compound according to the present invention has a remarkably excellent effect of inhibiting anaplastic lymphoma kinase (ALK) activity, and thus has a therapeutic effect on cancer cells having EML4-ALK and NPM-ALK rounded anaplastic lymphoma kinase (ALfi) fusion proteins. It may be improved, and is expected to be effective in preventing cancer from recurring, and thus may be usefully used as a pharmaceutical composition for preventing or treating cancer.
【발명의 실시를 위한 최선의 형태】 [Best form for implementation of the invention]
이하， 본 발명을 상세히 설명한다 본 발명은 하기 화학식 1로 표시되는 피리미딘 -2,4-디아민 체 또는 아의 약학적으로 허용가능한 염을 제공한다 .  Hereinafter, the present invention will be described in detail. The present invention provides a pyrimidine-2,4-diamine body or a pharmaceutically acceptable salt of a child represented by the following Chemical Formula 1.
[화학식 1]  [Formula 1]
상기 화학식 1에서， In Chemical Formula 1,
； 는 단일결합 또는 이중결합이고;  Is a single bond or a double bond;
이 단일결합인 경우， Is a single bond,
Rl, 2 및 R3는 독립적으로 할로겐， 또는 비치환 또는 하나 이상의 할로겐이 치환된 Ci-10 직쇄 알킬이고; R 1 , 2 and R 3 are independently halogen or Ci- 10 straight alkyl substituted with unsubstituted or one or more halogens;
비치환 또는 하나 이상의 -0H기가 치환된 10 직쇄 또는 -C(=0)R5이고， 여기서 R5는 -0H, 또는 d-uj 알킬이고; 또직 Unsubstituted or substituted with at least one -0H group is 10 straight chain or -C (= 0) R 5 , wherein R 5 is -0H, or d-uj alkyl; Again
는쇄 .  Silver chain.
^추ᅵ 이중결합인 경우,  ^ Chu In case of double bonds,
또츠 r  Tots r
R ^1는쇄, R2 및 R3는 독립적으로 -Hᅳ 할로겐， 또는 비치환 또는 하나 이상의 할로겐이 치환된 C o 직쇄 또는 측쇄 알킬이고; R ^ 1 is a chain, R 2 and R 3 are independently —H ′ halogen, or C o straight or branched alkyl substituted with unsubstituted or one or more halogens;
측알 - Side Egg-
H쇄킬， 비치환 또는 하나 이상의 ᅳ 0H기가 치환된 10 직쇄 또는 -C(=0)R5이고， 여기서 R5는 -H, ᅳ 0H, 또는 Ci-10 알킬이다 바람직하게는 H chainkill, unsubstituted or 10 straight chains substituted with one or more ᅳ 0H groups, or —C (= 0) R 5 , wherein R 5 is —H, ᅳ 0H, or Ci- 10 alkyl
이 단일결합인 경우  Is a single bond
상기 R1, R2 및 R3는 독립적으로 할로겐 , 비치환 또는 하나 상의 할로겐이 치환된 d-5 직쇄 알킬이고 ; R 1 , R 2 and R 3 are independently d- 5 straight chain alkyl substituted with halogen, unsubstituted or halogen;
R4는 -H, 비치환 또는 하나 이상의 -0H기가 치환된 d— 5 직쇄 또 측쇄 알킬， 또는 ᅳ C(=0)R5이고， 여기서 R5는 -0H, 또는 Ci-5 직쇄 는 측쇄 알킬이고; R 4 is d— 5 straight chain or branched alkyl substituted with —H, unsubstituted or one or more —0H groups, or ᅳ C (= 0) R 5 , wherein R 5 is —0H, or Ci-5 straight chain is branched alkyl ego;
=^이 이중결합인 경 우 ᅳ If = ^ is a double bond ᅳ
상기 R1, R2 및 R3는 독립적으로 할로겐， 비치환 또는 하나 이상의 할로겐이 치환된 직쇄 또는 측쇄 알킬이고 ; R 1 , R 2 and R 3 are independently halogen, unsubstituted or linear or branched alkyl substituted with one or more halogen;
R4는 -H, 비치환 또는 하나 이상의 -0H기가 치환된 Ci-5 직쇄 또 는 측쇄 알킬， 또는 -C(=0)R5이고, 여기서 R5는 -0H, 또는 d-5 직쇄 또는 측쇄 알킬이다. 더욱 바람직하게는， ^ ^이 단일결합인 경우， R 4 is Ci- 5 straight or branched alkyl substituted with -H, unsubstituted or one or more -0H groups, or -C (= 0) R 5 , wherein R 5 is -0H, or d- 5 straight or branched Alkyl. More preferably, when ^ ^ is a single bond,
상기 R1은 -C1, 또는 -CF3이고; R 1 is —C 1 , or —CF 3 ;
R2는 . -CH3, 또는 -F이고； R 2 is. -CH 3 or -F;
R3는 -CH3, 또는 -CHF2이고 ; R 3 is -CH 3 , or -CHF 2 ;
R4는 -CH3, -CH2CH3, -eH2CH20H, -C(=0)CH3, 또는 -C(=0)0H이 고 R 4 is -CH 3 , -CH2CH3, -eH 2 CH 2 0H, -C (= 0) CH 3 , or -C (= 0) 0H
'··^:.'',이 이중결합인 경우 상기 R1은 -C1, 또는 -CF3이고; When R is a double bond, the R 1 is —C 1 or —CF 3 ;
R2는 ᅳ H, — CH3, 또는 -F이고; R 2 is ᅳ H, — CH 3 , or —F;
R3는 -CH3, -CH(CH3)2, 또는 -CHF2이고;
Figure imgf000008_0001
상기 화학식 1로 표시되는 피리미딘 -2,4-디아민 유도체의 바람 직한 예로는 하기의 화합물들올 들 수 있다. R 3 is —CH 3 , —CH (CH 3 ) 2 , or —CHF 2 ;
Figure imgf000008_0001
Wind of the pyrimidine-2,4-diamine derivative represented by the formula (1) Examples thereof include the following compounds.
(1) 5ᅳ클로로ᅳ N4-(2- (이소프로필술포닐 )페닐) N2-(2-메록시 -4- (1,2,3,6-테트라하이드로피리딘 -4-일 )페닐)피리미딘ᅳ2，4-디아민 ;  (1) 5'chloro ᅳ N4- (2- (isopropylsulfonyl) phenyl) N2- (2-methoxy-4- (1,2,3,6-tetrahydropyridin-4-yl) phenyl) pyri Midine ᅳ 2,4-diamine;
(2) 5-클로로 -N2-(2-이소프로폭시 -5-메틸 -4-(1，2，3，6-테트라하 이드로피리딘 -4-일 )페닐 )-N4-(2- (이소프로필술포닐)페닐)피리미딘- (2) 5-chloro-N2- (2-isopropoxy-5-methyl-4- (1,2,3,6-tetrahydropyridin-4-yl) phenyl) -N4- (2- (iso Propylsulfonyl) phenyl) pyrimidine-
2，4-디아민 ; 2,4-diamine;
(3) 5-클로로ᅳ N2-(2— (디플루오로메톡시 )-4-(1,2，3，6-테트라하이 드로피리딘 -4-일)페닐 )-N4-(2(이소프로필술포닐 _페닐)피리미딘— 2， 4-디 아민；  (3) 5-chloro ᅳ N2- (2— (difluoromethoxy) -4- (1,2,3,6-tetrahydrodropyridin-4-yl) phenyl) -N4- (2 (isopropylsul Ponyl _phenyl) pyrimidine— 2, 4-diamine;
(4) 5-클로로 -N2-(2- (디플루오로메톡시 )-4- (피페리딘 -4-일 )페 닐 ) -N4 (2(이소프로필술포닐)페닐)피리미딘 -2, 4-디아민 ;  (4) 5-chloro-N2- (2- (difluoromethoxy) -4- (piperidin-4-yl) phenyl) -N4 (2 (isopropylsulfonyl) phenyl) pyrimidine-2, 4-diamine;
(5) 5-클로로 -N4-(2- (이소프로필술포닐)페닐 ) -N2-(2-메톡시 -4- (피페리딘 -4-일 )페닐)피리미딘 -2，4-디아민 ;  (5) 5-chloro-N4- (2- (isopropylsulfonyl) phenyl) -N2- (2-methoxy-4- (piperidin-4-yl) phenyl) pyrimidine-2,4-diamine ;
(6) N4-(2- (이소프로필술포닐 )페닐)ᅳ N2-(2-메톡시 -4-(1，2，3，6- 테트라하이드로피리딘 -4-일 )페닐) -5- (트리풀루오로메틸)피리미딘 -2， 4- 디아민 ;  (6) N4- (2- (isopropylsulfonyl) phenyl) ᅳ N2- (2-methoxy-4- (1,2,3,6-tetrahydropyridin-4-yl) phenyl) -5- ( Trifulomethyl) pyrimidine-2, 4-diamine;
(7) N2-(2-이소프로폭시 -5-메틸 -4-(1，2，3ᅳ 6-테트라하이드로피리 딘 -4—일 )페닐 )-N4-(2(이소프로필술포닐)페닐 )-5- (트리플루오로메틸 )피 리미딘ᅳ 2， 4-디아민；  (7) N2- (2-isopropoxy-5-methyl-4- (1,2,3 '6-tetrahydropyridin-4-yl) phenyl) -N4- (2 (isopropylsulfonyl) phenyl ) -5- (trifluoromethyl) pyrimidine 2,4-diamine;
(8) N2-(2- (디플루오로메록시 )-4-(1，2，3，6-테트라하이드로피리 딘 -4-일 )페닐) -N4-(2- (이소프로필술포닐 )페닐) -5- (트리플루오로메틸) 피리미딘 -2,4-디아민 ;  (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- (디플루오로메록시 )-4- (피페리딘 -4—일 )페닐) -N4-(2- (9) N2- (2- (difluoromethoxy) -4- (piperidin-4-yl) phenyl) -N4- (2-
(이소프로필술포닐)페닐 )-5- (트리플루오로메틸)피리미딘 -2 ,4-디아민； (10) 5-클로로 -N2-(5-플루오로 2ᅳ메톡시 -4-(1，2，3，6-테트라하이 드로피리딘 -4-일 )페닐 )-N4-(2- (이소프로필술포닐)페닐)피리미딘 -2,4- 디아민 ; (Isopropylsulfonyl) phenyl) -5- (trifluoromethyl) pyrimidine-2,4-diamine; (10) 5-chloro-N2- (5-fluoro 2'methoxy-4- (1,2 , 3,6-tetrahydropyridin-4-yl) phenyl) -N4- (2- (isopropylsulfonyl) phenyl) pyrimidine-2,4-diamine;
(11) 5-클로로 -N4-(2— (이소프로필술포닐 )페닐 )-N2— (2-메록시 -5- 메틸 -4-(1，2，3,6-테트라하이드로피리딘ᅳ4-일)페닐)피리미딘 -2, 4-디아 민；  (11) 5-Chloro-N4- (2— (isopropylsulfonyl) phenyl) -N2— (2-methoxy-5-methyl-4- (1,2,3,6-tetrahydropyridine ᅳ 4- Yl) phenyl) pyrimidine-2,4-diamine;
(12) 5-클로로 -N2-( 5-플루오로 -2—메특시 -4- (피페리딘 -4ᅳ일 )페 닐 )-N4-(2- (이소프로필술포닐)페닐 )피리미딘 -2 ,4-디아민；  (12) 5-Chloro-N2- (5-fluoro-2-methoxy-4- (piperidin-4xyl) phenyl) -N4- (2- (isopropylsulfonyl) phenyl) pyrimidine- 2,4-diamine;
(13) 5-클로로 -N4-( 2- (이소프로필술포닐)페닐 )-N2-(2-메톡시 -5- 메틸 -4- (피페리딘 -4-일 )페닐 )피리미딘 -2， 4-디아민 ;  (13) 5-chloro-N4- (2- (isopropylsulfonyl) phenyl) -N2- (2-methoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2 , 4-diamine;
(14) 5-클로로^2-(4-(1-에틸-1,2，3,6ᅳ테트라하이드로피리딘-4- 일 )-2-메록시페닐 )-N4-(2- (이소프로필술포닐)페닐)피리미딘 -2,4-디아 민 ;  (14) 5-chloro ^ 2- (4- (1-ethyl-1,2,3,6, tetrahydropyridin-4-yl) -2-methoxyphenyl) -N4- (2- (isopropylsul Ponyl) phenyl) pyrimidine-2,4-diamine;
(15) 5-클로로 -N2-(4-(l-에틸 -1， 2，3， 6-테트라하이드로피리딘 -4- 일 )-2-메록시페닐 )-N4-(2- (이소프로필술포닐 )페닐)피리미딘 -2,4-디아 민；  (15) 5-Chloro-N2- (4- (l-ethyl-1,2,3,6-tetrahydropyridin-4-yl) -2-methoxyphenyl) -N4- (2- (isopropylsul Ponyl) phenyl) pyrimidine-2,4-diamine;
(16) 1-(4-(4-((5-클로로 -4ᅳ((2- (이소프로필술포닐 )페닐 )아미 노 )피리미딘 -2—일 )아미노 )-3ᅳ메톡시페닐 )-5 ,6-디하이드로피리딘- K2H)-일 )에탄온 ; (17) 4-(4-((5ᅳ클로로ᅳ 4-((2- (이소프로필술포닐)페닐 )아미노)피 리미딘 -2-일)아미노) -3-메특시페닐) -5， 6-디하이드로피리딘 - 2H)-카르 복시산; (16) 1- (4- (4-((5-chloro-4 ′ ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -3'methoxyphenyl)- 5,6-dihydropyridin-K2H) -yl) ethanone; (17) 4- (4-((5 ᅳ chloro ᅳ 4-((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) -5, 6-dihydropyridine-2H) -carboxylic acid;
(18) 4-(4-((5-클로로 -4-((2- (이소프로필술포닐)페닐)아미노)피 리미딘 -2ᅳ일 )아미노 )-3-메특시페닐) -5,6-디하이드로피리딘 -1(2H)-메틸 . 본 발명의 상기 화학식 1로 표시되는 피리미딘ᅳ2，4-디아민 유도 체는 약학적으로 허용 가능한 염의 형태로 사용할 수 있으며， 염으로 는 약학적으로 허용 가능한 유리산 (free acid)에 의해 형성된 산 부가 염이 유용하다. 산 부가염은 염산， 질산， 인산， 황산， 브롬화수소산， 요드화수소산， 아질산 또는 아인산과 같은 무기산류와 지방족 모노 및 디카르복실레이트， 페닐-치환된 알카노에이트, 하이드록시 알카노에이 트 및 알칸디오에이트， 방향족 산류， 지방족 및 방향족 설폰산류와 같 은 무독성 유기산, 아세트산, 안식향산， 구연산， 젖산， 말레인산, 글 루콘산， 메탄설폰산， 4-롤루엔설폰산 , 주석산， 푸마르산과 같은 유기 산으로부터 얻었다. 아러한 약학적으로 무독한 염류로는 설페이트, 피 로설페이트， 바이설페이트， 설파이트， 바이설파이트， 니트레이트， 포 스페이트， 모노하이드로겐 포스페이트， 디하이드로겐 포스페이트， 메 타포스페이트， 피로포스페이트 클로라이드， 브로마이드， 아이오다이드， 플루오라이드， 아세테이트， 프로피오네이트， 데카노에이트， 카프릴레 이트, 아크랄레이트, 포메이트， 이소부티레이트， 카프레이트， 헵타노 에이트， 프로피올레이트， 옥살레이트， 말로네이트， 석시네이트, 수베 레이트 , 세바케이트, 푸마레이트， 말리에이트， 부틴 -1，4-디오에이트， 핵산 -1，6-디오에이트， 벤조에이트， 클로로벤조에이트， 메틸벤조에이트， 디니트로 벤조에이트， 하이드록시벤조에이트， 메톡시벤조에이트， 프탈 레이트， 테레프탈레이트, 벤젠설포네이트, 를루엔설포네이트， 클로로 벤젠설포네이트, 크실렌설포네이트， 페닐아세테이트， 페닐프로피오네 이트， 페닐부티레이트 시트레이트， 락테이트， βᅳ하이드톡시부티레이 트， 글리콜레이트， 말레이트， 타트레이트， 메탄설포네이트， 프로판설 포네이트， 나프탈렌 -1-설포네이트， 나프탈렌 -2-설포네이트 또는 만델 레이트를 포함한다.  (18) 4- (4-((5-chloro-4-((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2xyl) amino) -3-methoxyphenyl) -5,6 -Dihydropyridine-1 (2H) -methyl. The pyrimidine ᅳ 2,4-diamine derivative represented by Chemical Formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt, and the salt may be an acid formed by a pharmaceutically acceptable free acid. Addition salts are useful. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and Non-toxic organic acids such as alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids, organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-roluenesulfonic acid, tartaric acid and fumaric acid Obtained from Such toxic, nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate and pyrophosphate chloride. , Bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate , Succinate, subrate, sebacate, fumarate, maleate, butyne-1,4-dioate, nucleic acid-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate ， Hydroxybenzoate, Methoxybenzoate, Phthalate, Tereph Latex, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate citrate, lactate, β-hydroxybutyrate, glycolate, malate, Tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate or mandelate.
본 발명에 따른 산 부가염은 통상의 방법， 예를 들면 피리미딘- 2, 4-디아민 유도체를 유기용매， 예를 들면 메탄을, 에탄을， 아세톤， 메틸렌클로라이드 , 아세토니트릴 등에 녹이고 유기산 또는 무기산을 가하여 생성된 침전물을 여과, 건조하여 제조되거나， 용매와 과량의 산을 감압 증류한 후 건조하거나 유기용매 하에서 결정화시켜서 제조 할 수 있다. 또한, 본 발명은 상기 화학식 1로 표시되는 피리미딘 -2， 4-디아 민 유도체 및 이의 약학적으로 허용하는 염뿐만 아니라， 이로부터 제 조될 수 있는 가능한 용매화물， 수화물， 이성질체 등을 모두 포함한다. 또한， 본 발명은 하기 반웅식 1에 나타난 바와 같이， 화학식 2로 표시되는 화합물과 화학식 3으로 표시되는 화합물을 반웅시켜 화학식 4로 표시되는 화합물을 제조하는 단계 (단계 1 ) ; 및 상기 단계 1에서 제조한 화학식 4로 표시되는 화합물과 화학식 5로 표시되는 화합물을 반웅시켜 화학식 1로 표시되는 화합물을 제조 하는 단계 (단계 2 ) ;를 포함하는 제 1항의 피리미딘 -2，4-디아민 유도체 의 제조방법을 제공한다 . The acid addition salt according to the present invention is dissolved in a conventional method, for example, pyrimidine-2,4-diamine derivatives in an organic solvent, for example methane, ethane, acetone, methylene chloride, acetonitrile, and the like. The precipitate produced by addition may be prepared by filtration and drying, or the solvent and excess acid may be distilled under reduced pressure, and then dried or crystallized under an organic solvent. In addition, the present invention includes not only pyrimidine-2, 4-diamine derivatives represented by the general formula (1) and pharmaceutically acceptable salts thereof, but also possible solvates, hydrates, isomers, and the like that can be prepared therefrom. . In addition, the present invention, as shown in the following reaction formula 1, Preparing a compound represented by the formula (4) by reacting the compound represented by the formula (2) with the compound represented by the formula (3) (step 1); And the step of preparing the compound represented by Chemical Formula 1 by reacting the compound represented by Chemical Formula 4 and the compound represented by Chemical Formula 5 prepared in Step 1 (Step 2). Provides a process for the preparation of diamine derivatives.
Figure imgf000011_0001
Figure imgf000011_0001
4  4
Figure imgf000011_0002
Figure imgf000011_0002
상기 반웅식 1에서， 내지 R4는 본 명세서에서 정의한 바와 같 다. 이하， 본 발명에 따른 쎄조방법을 단계별로 상세히 설명한다. 본 발명에 따른 제조방법에 있어서， 상기 단계 1은 화학식 2로 표시되는 화합물과 화학식 3으로 표시되는 화합물을 반웅시켜 화학식 4로 표시되는 화합물을 제조하는 단계이다. In Reaction Formula 1, to R 4 is as defined herein. Hereinafter, the cleaning method according to the present invention will be described in detail step by step. In the preparation method according to the present invention, step 1 is a step of preparing a compound represented by Chemical Formula 4 by reacting the compound represented by Chemical Formula 2 with the compound represented by Chemical Formula 3.
구체적으로， 상기 화학식 2로 표시되는 화합물을 유기용매 및 염기 하에서 화학식 3으로 표시되는 화합물과 알킬화 반웅시켜 화학식 4로 표시되는 화합물을 얻을 수 있다.  Specifically, the compound represented by Formula 4 may be obtained by alkylating the compound represented by Formula 2 with the compound represented by Formula 3 under an organic solvent and a base.
이때， 사용가능한 용매는 테트라하이드로퓨란; 다이옥산; 에틸 에테르， 1，2-다이메록시에탄 등을 포함하는 에테르용매 ; 메탄올, 에탄 올， 프로판올 및 부탄올올 포함하는 저급 알코올 ; 디메틸포름아미드 ( DMF ) , 디메틸설폭사이드 ( DMS0)， 아세토나젠설포네이트， 를루엔설포네 이트， 클로로벤젠설포네이트 , 크실렌설포네이트， 페닐아세테이트， 페 닐프로피오네이트， 페닐부티레이트， 시크레이트， 락테이트， β -하이드 록시부티레이트， 글리콜레이트， 말레이트， 타트레이트， 메탄설포네이 트 , 프로판설포네이트 , 나프탈렌 -1-설포네이트， 나프탈렌 -2-설포네이 트 또는 만델레이트를 포함한다. In this case, usable solvents are tetrahydrofuran; Dioxane; Ether solvents including ethyl ether, 1,2-dimethoxyethane and the like; Lower alcohols including methanol, ethanol, propanol and butanol; Dimethylformamide (DMF), Dimethylsulphoxide (DMS0), Acetonasesulfonate, Toluenesulfonate, Chlorobenzenesulfonate, Xylenesulfonate, Phenyl Acetate, Pe Nylpropionate, Phenylbutyrate, Citrate, Lactate, β-Hydroxybutyrate, Glycolate, Maleate, Tartrate, Methanesulfonate, Propanesulfonate, Naphthalene-1-sulfonate, Naphthalene-2-sulfo Include nate or mandelate.
또한， 상기 염기는 '피리딘， 트리에틸아민， Ν,Ν-다이이소프로필 에틸아민 (DIPEA), 1，8—디아자비사이클로 [5.4.0]-7-운테센 (DBU) 등의 유기염기 ; 또는 소듬하이드록사이드， 소듐카보네이트， 포타슘카보네이 트， 세슘카보네이트， 소듐하이드라이드 등의 무기염기를 당량 또는 과 량으로 사용할 수 있으며， 반웅온도는 50-200 ΐ：， 교반시간은 0.5ᅳ 20 시간을 가진다.  In addition, the base is an organic base such as' pyridine, triethylamine, Ν, Ν-diisopropyl ethylamine (DIPEA), 1,8-diazabicyclo [5.4.0] -7-unthecene (DBU); Alternatively, inorganic bases such as sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and sodium hydride can be used in equivalent or excess amounts. The reaction temperature is 50-200 ΐ :, stirring time is 0.5 ᅳ 20 hours. Has
상기 반웅을 수행한 후， 유기용매로 추출， 건조, 여과 및 감압 증류하는 과정을 수행하고 추가적으로 칼럼크로마토그래피를 수행하여 상기 화학식 4로 표시되는 화합물을 얻을 수 있다. 본 발명에 따른 제조방법에 있어서， 상기 단계 2는 상기 단계 1 에서 제조한 화학식 4로 표시되는 화합물과 화학식 5로 표시되는 화합 물을 반응시켜 화학식 1로 표시되는 화합물올 제조하는 단계이다. 구체적으로， 상기 화학식 4로 표시되는 화합물을 유기용매 및 염기 하에서 화학식 5로 표시되는 화합물과 알킬화 반응시켜 화학식 1 로 표시되는 화합물을 얻을 수 있다.  After performing the reaction, extraction, drying, filtration and distillation under reduced pressure with an organic solvent may be performed, followed by column chromatography to obtain a compound represented by Chemical Formula 4. In the preparation method according to the present invention, step 2 is a step of preparing the compound represented by the formula (1) by reacting the compound represented by the formula (4) prepared in step 1 with the compound represented by the formula (5). Specifically, a compound represented by Chemical Formula 1 may be obtained by alkylating the compound represented by Chemical Formula 4 with a compound represented by Chemical Formula 5 under an organic solvent and a base.
이때 , 사용가능한 용매는 테트라하이드로퓨란; 다이옥산; 에틸 에테르， 1,2-다이메톡시에탄 등을 포함하는 에테르용매 ; 메탄을， 에탄 올, 프로판을 및 부탄올을 포함하는 저급 알코올; 디메틸포름아미드 (DMF), 디메틸설폭사이드 (DMS0)； 아세토나젠설포네이트， 를루엔설포네 이트， 클로로벤젠설포네이트， 크실렌설포네이트， 페닐아세테이트, 페 닐프로피오네이트， 페닐부티레이트, 시크레이트， 락테이트， β -하이드 록시부티레이트， 글리콜레이트， 말레이트， 타트레이트， 메탄설포네이 트， 프로판설포네이트, 나프탈렌 -1—설포네이트， 나프탈렌 -2—설포네이 트 또는 만델레이트를 포함한다 .  In this case, usable solvents include tetrahydrofuran; Dioxane; Ether solvents including ethyl ether, 1,2-dimethoxyethane and the like; Lower alcohols including methane, ethanol, propane and butanol; Dimethylformamide (DMF), Dimethylsulphoxide (DMS0); Acetonazenesulfonate, Toluenesulfonate, Chlorobenzenesulfonate, Xylenesulfonate, Phenyl acetate, Phenylpropionate, Phenylbutyrate, Citrate, Rock Tate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1—sulfonate, naphthalene-2—sulfonate or mandelate.
또한， 상기 염기는 피리딘 , 트리에틸아민， Ν,Ν-다이이소프로필 에틸아민 (DIPEA), 1,8-디아자비사이클로 [5.4.0]-그운테센 (DBU) 등의 유기염기 ; 또는 소듐하이드록사이드, 소듐카보네이트， 포타슘카보네이 트， 세슘카보네이트， 소듐하이드라이드 등의 무기염기를 당량 또는 과 량으로 사용할 수 있으며， 반응온도는 50-200 °C， 교반시간은 0.5-20 시간을 가진다. Further, the base may be an organic base such as pyridine, triethylamine, Ν, Ν-diisopropyl ethylamine (DIPEA), 1,8-diazabicyclo [5.4.0] -gundene (DBU); Alternatively, inorganic bases such as sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and sodium hydride may be used in equivalent or excess amounts, and the reaction temperature is 50-200 ° C. and the stirring time is 0.5-20 hours. Has
상기 반웅을 수행한 후， 유기용매로 추출， 건조， 여과 및 감압 증류하는 과정을 수행하고 추가적으로 칼럼크로마토그래피를 수행하여 상기 화학식 1로 표시되는 화합물을 얻을 수 있다. 나아가， 본 발명은 상기 화학식 1로 표시되는 피리미딘 -2，4-디 아민 유도체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함 유하는 암의 예방 또는 치료용 약학적 조성물을 제공한다. 또한， 본 발명은 상기 화학식 1로 표시되는 피리미딘 -2， 4-디아 민 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유 하는 역형성 림프종 키나아제 (ALK, Anaplastic Lymphoma Kinase) 과활 성으로 인하여 유발되는 질환의 예방 또는 치료용 약학적 조성물을 제 공한다. 나아가， 본 발명은 상기 화학식 1로 표시되는 피리미딘 -2，4-디 아민 유도체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함 유하는 역형성 림프종 키나아제 (ALK, Ana lastic Lymphoma Kinase) 저 해제를ᅵ 제공한다 . 본 발명에 따른 상기 ^학적 조성물 및 저해제는 역형성 림프종 키나아제 (ALK, Anaplastic Lymphoma Kinase)의 활성을 억제하여 암세 포의 발현 및 성장을 억제하는 것을 특징으로 한다 . 역형성 림프종 키나아제 (ALK)는 암세포에 존재하는 암의 세포증 식을 유도하는 유전자로써， 유전자 융합 과정에 의해 역형성 림프종 키나아제 (AUO가 활성화되고， 이때， 역형성 림프종 키나아제 (ALK)가 가지고 있는 타이로신 키나아제가 비정상적으로 행동하여 세포의 을 유도하고， 아포프토시스를 방해해 세포가 사멸되지 않게 하며 뼈대를 재배열시키며 세포 형태를 변형시킬 뿐만 아니라, 역형성 종 키나아제 (ALK)는 정상이거나 암 유전자화한 다른 타이로신 키 제와 연결되어 상호작용을 하거나 여러 종류의 다른 경로들을 활 시킨다. 이에， 본 발명에 따른 상기 화학식 1로 표시되는 피리미딘ᅳ 2， 4- 성증세나림 디아민 유도체의 역형성 림프종 키나아제 (ALK) 활성을 검증하기 위해， 포프화식아 본 발명에 따른 화합물들을 역형성 림프종 키나아제 (ALK) 효소 및 여 러 암세포에 처리한 후 IC50 및 GI50을 측정한 결과， 화학식 1로 표시 되는 피리미딘 -2，4-디아민 유도체 증 대부분의 화합물들이 대조군 (크 리조티닙 및 LDK-378) 화합물에 비하여 활성이 우수한 것으로 나타났 다 (실험예 1-4 참조). 본 발명에 따른 화학식 1로 표시되는 피리미딘 -2, 4-디아민 유도 체들은 역형성 림프종 키나아제 (ALK)의 활성을 억제하여 암을 예방 또 는 치료하는데 사용될 수 있다 . 예를 돌어， 비소세포폐암， 신경모세 포종， 염증성 골수섬유모세포종양， 종횡문근육종， 근섬유모세포종, 유 방암， 위암， 폐암， 흑색종， 대형 B-세포 림프종， 전신성 조식구증， 염 증성 근섬유아세포성 육종， 식도 편평 세포암， 자궁암， 전립선암 등에 유용할 수 있다. 본 발명의 조성물을 의약품으로 사용하는 경우, 상기 화학식 1 로 표시되는 피리미딘 -2ᅳ 4-디아민 유도체 또는 이의 약학적으로 허용 After performing the reaction, extraction, drying, filtration and distillation under reduced pressure with an organic solvent may be performed, and column chromatography may be further performed to obtain a compound represented by Chemical Formula 1. Furthermore, the present invention provides a pharmaceutical composition for preventing or treating cancer containing pyrimidine-2,4-diamine derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. In addition, the present invention is due to the overactivity of anaplastic lymphoma kinase (ALK) containing pyrimidine-2, 4-diamine derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient It provides a pharmaceutical composition for the prevention or treatment of the disease caused. Furthermore, the present invention provides an inhibitor of anaplastic lymphoma kinase (ALK) containing pyrimidine-2,4-diamine derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. to provide i. The ^ pharmaceutical composition and inhibitor according to the present invention are characterized by inhibiting the expression and growth of cancer cells by inhibiting the activity of anaplastic lymphoma kinase (ALK). Aplastic lymphoma kinase (ALK) is a gene that induces cell proliferation of cancers present in cancer cells, and the gene fusion process activates anaplastic lymphoma kinase (AUO), and at this time, tyrosine of anaplastic lymphoma kinase (ALK) Kinases behave abnormally to induce cell decay, prevent apoptosis, prevent cell death, rearrange bones and modify cell morphology, as well as anaplastic species kinase (ALK) It is linked to a tyrosine kinase and interacts with or activates several different pathways.Therefore, the anaplastic lymphoma kinase (ALK) of pyrimidine ᅳ 2, 4- sex senarim diamine derivative represented by Formula 1 according to the present invention. ) To validate the activity, the popping formulated compounds according to the present invention The (ALK) and the enzyme was treated in several cancer cells, a result of measuring the IC 50 and GI 50, pyrimidine-2,4-diamine derivatives of the compounds are increasing most control group represented by the formula (1) (greater separation tank tinip and LDK- 378) It was shown to be superior in activity to the compound (see Experimental Example 1-4.) The pyrimidine-2, 4-diamine derivatives represented by the formula (1) according to the present invention showed the activity of anaplastic lymphoma kinase (ALK). Can be used to prevent or treat cancer, eg, non-small cell lung cancer, neuroblastoma, inflammatory myeloid fibroblast tumor, rhabdomyosarcoma, myofibroblastoma, breast cancer, gastric cancer, lung cancer, melanoma, large It may be useful for B-cell lymphoma, systemic morning sickness, inflammatory myofibroblastic sarcoma, esophageal squamous cell carcinoma, uterine cancer, prostate cancer, etc. When the composition of the present invention is used as a medicine, Pyrimidin-4-eu -2 derivative or a pharmaceutically acceptable thereof, represented by the learning 1
기을민디명이 Gimin Mindi
가능한 염을 유효성분으로 함유하는 약학적 조성물은 임상투여 시에 다양한 하기의 경구 또는 비경구 투여 형태로 제제화되어 투여될 수 있으나， 이에 한정되는 것은 아니다. Pharmaceutical compositions containing possible salts as active ingredients may be formulated and administered in various oral or parenteral dosage forms as described below, but are not limited thereto.
경구 투여용 제형으로는 예를 들면 정제， 환제， 경 /연질 캅셀게， 액제， 현탁제 , 유화제， 시럽제， 과립제， 엘릭시르제 , 트로키제 등이 있는데， 이들 제형은 유효성분 이외에 희석제 (예 ： 락토즈， 덱스트로 즈, 수크로즈， 만니를， 솔비를， 셀를로오즈 및 /또는 글리신)， 활택제 (예 ： 실리카， 탈크， 스테아르산 및 그의 마그네슘 또는 칼슘염 및 /또 는 폴리에틸렌 글리콜)를 함유하고 있다. 정제는 또한 마그네슴 알루 미늄 실리케이트， 전분 페이스트， 젤라틴， 메틸셀를로즈， 나트륨 카복 시메틸셀를로즈 및 /또는 폴리비닐피를리딘과 같은 결합제를 함유할 수 있으며， 경우에 따라 전분， 한천， 알긴산 또는 그의 나트륨 염과 같은 붕해제 또는 비등 흔합물 및 /또는. 흡수제， 착색제， 향미제 및 감미제 를 함유할 수 있다.  Formulations for oral administration include, for example, tablets, pills, hard / soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, troches, and the like. Toze, dextrose, sucrose, manny, sorbitol, cellulose and / or glycine), lubricants (e.g. silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols) Doing. Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellose, sodium carboxymethylcellose and / or polyvinylpyridine, optionally starch, agar, alginic acid or Disintegrants or boiling mixtures and / or such as its sodium salts. It may contain absorbents, colorants, flavors and sweeteners.
상기 화학식 1로 표시되는 피리미딘— 2， 4-디아민 유도체를 유효 성분으로 하는 약학적 조성물은 비경구 투여할 수 있으며， 비경구 투 여는 피하주사， 정맥주사， 근육 내 주사 또는 흉부 내 주사를 주입하 는 방법에 의한다 .  The pharmaceutical composition comprising the pyrimidine- 2, 4-diamine derivative represented by the formula (1) as an active ingredient can be administered parenterally, parenteral administration is injected subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection By the way.
이때， 비경구 투여용 제형으로 제제화하기 위하여 상기 화학식 1로 표시되는 피리미딘 -2 , 4-디아민 유도체 또 ¾ 이의 약학적으로 허용 되는 염을 안정제 또는 완충제와 함께 물에 흔합하여 용액 또는 현탁 액으로 제조하고 , 이를 앰플 또는 바이알 단위 투여형으로 제조할 수 있다. 상기 조성물은 멸균되고 /되거나 방부제 , 안정화제， 수화제 또는 유화 촉진제， 삼투압 조절을 위한 염 및 /또는 완충쎄 등의 보조제 및 기타 치료적으로 유용한 물질올 함유할 수 있으며， 통상적인 방법인 흔합， 과립화 또는 코팅 방법에 따라 제제화할 수 있다.  At this time, pyrimidine-2, 4-diamine derivatives or pharmaceutically acceptable salts thereof represented by the above formula (1) in order to formulate into a parenteral dosage form are mixed with water with a stabilizer or buffer to a solution or suspension. It can be prepared and prepared in ampule or vial unit dosage form. The composition may be sterile and / or contain preservatives, stabilizers, hydrating or emulsifying accelerators, salts for controlling osmotic pressure and / or auxiliaries such as buffering agents and other therapeutically useful substances. It may be formulated according to the formulation or coating method.
상기 화학식ᅵ 1로 표시되는 괴리미딘 -2 , 4-디아민 유도체를 유효성분으로 함유하는 약학적 조성물의 인체에 대한 투아량은 환자의 나이， 몸무게， 성별 , 투여형태 , 건강상태 및 질환 정도에 따라 달리질 수 있으며 , 바람직하게는 0 . 01 내지 1000 mg/kg/일의 양으로 의사 또는 약사의 판단에 따라 일정 시간 간격을 1일 수회 , 바람직하게는 1일 1회 내지 3회로 분할하여 경구 또는 비경구적 경로를 통해 투여할 수 있다. ᅳ The dosage of the pharmaceutical composition containing Gorimidine -2 and 4-diamine derivatives represented by Chemical Formula 1 as an active ingredient on the human body depends on the patient's age, weight, sex, dosage form, health condition and degree of disease. Can be varied, preferably 0. The amount of 01 to 1000 mg / kg / day may be administered by oral or parenteral route by dividing a predetermined time interval several times a day, preferably once to three times a day, according to the judgment of a doctor or pharmacist. ᅳ
【발명의 실시를 위한 형태】 [Form for implementation of invention]
이하， 본 발명에 따른 상기 화학식 1로 표시되는 피리미딘 -2 , 4 아민 유도체의 제조방법을 제조예 또는 실시예를 통해 상세하게 설 한다. 하기 실시예는 상기 화학식 1로 표시되는 피리미딘 -2， 4—디아 유도체를 제조하는 방법의 일례로서， 본 발명을 예시하는 것일 뿐， 에 한정하지 않는다. 하기 실시예에 의해 설명되는 제조방법은 유 합성 분야에서 잘 알려진 합성조건， 적절한 시약 둥올 사용하여 얻 수 있다. <실시예 1> 5-클로로 -N4-(2- (이소프로필술포닐)페닐) -N2-(2-메 톡시 -4-(1，2，3，6-테트라하이드로피리딘 -4-일 )페닐)피리미딘 -2,4-디아 민의 제조 Hereinafter, a method for preparing pyrimidine-2,4 amine derivative represented by Chemical Formula 1 according to the present invention will be described in detail through Preparation Examples or Examples. The following examples are examples of a method for preparing pyrimidine-2,4-dia derivatives represented by Chemical Formula 1, which illustrate the present invention and are not limited thereto. The preparation method described by the examples below can be obtained using synthetic conditions well-known reagents well known in the field of oil synthesis. Example 1 5-Chloro-N 4-(2- (isopropylsulfonyl) phenyl) -N 2-(2-methoxy-4- (1,2,3,6-tetrahydropyridin-4-yl) Preparation of Phenyl) pyrimidine-2,4-diamine
단계 1 ： tert-부틸 4-(4ᅳ((5-클로로 -4-((2- (이소프로필술포닐 ) 페닐 )아미노)피리미딘 -2-일)아미노 )ᅳ3-메특시페닐 )ᅳ5ᅩ 6-디하이드로피 Step 1: tert-Butyl 4- (4 '((5-chloro-4-((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) ᅳ 3-methoxyphenyl) ᅳ 5 ᅩ 6- dehydropy
Figure imgf000015_0001
Figure imgf000015_0001
2， 5-디클로로 -N-(2- (이소프로필술포닐)페닐 )피리미딘 -4-아민 1.6g(4.6薩 ol)을 THF 25ml에 녹인 후 tert-부틸 4-(4-아미노 -3-메록시 페닐) -5,6-디하이드로피리딘 -K2H)-카복시레이트 1.4g(4.6麵 ol)을 첨 가하고, 잔트포스 266mg (0.46隱 ol), Cs2C03 4.5g( 13.8mmo 1 )을 순서대 로 첨가한 후， 질소를 층전하여 탈 가스 하였다. Pd(0Ac)2 (51.6mg, 0.23隱 ol)를 첨가하고， 질소 층전 후 130°C에서 18시간 교반하였다. 반웅 종료 후, EA/H20로 추출한 후 유기층은 MgS04로 건조하여 필터 후 농축하였다. 칼럼 크로마토그래피 (Hx:EA 4:1)를 이용하여 목적 화 합물 330mg을 20%의 수율로 얻었다 . 2, 1.6 g (4.6 薩 ol) of 5-dichloro-N- (2- (isopropylsulfonyl) phenyl) pyrimidin-4-amine was dissolved in 25 ml of THF, followed by tert-butyl 4- (4-amino-3- Methoxy phenyl) -5,6-dihydropyridine-K2H) -carboxylate was added 1.4 g (4.6 μl ol), and 266 mg (0.46 μl) xantose, 4.5 g (13.8 mmol 1) Cs 2 C0 3 After adding sequentially, nitrogen was layered and degassed. Pd (0Ac) 2 (51.6 mg, 0.23 μl) was added and stirred for 18 hours at 130 ° C. after nitrogen layer deposition. After the completion of reaction, the mixture was extracted with EA / H 2 0 and the organic layer was dried over MgS0 4 , concentrated after filtration. Column chromatography (Hx: EA 4: 1) gave 330 mg of the target compound in 20% yield.
:H NMR (CDCls, 300MHz) δ 9.55(s , 1Η) , 8.58(d， J=&.4Hz， 1Η)， 8.24(d, J=8.7Hz, 1H) ,8.16(s, 1H) , : H NMR (CDCls, 300MHz) δ 9.55 (s, 1Η), 8.58 (d, J = &. 4Hz, 1Η), 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,lH) , 6.92(s,2H) ,6.0-5.98(m, 1H) , 4.09(s,2H) , 3.92( s , 3H) , 3 , 65- 7.94 (d, J = 8.1Hz, 1H), 7.68 (t, J = 7.8Hz, 1H), 7.59 (s, lH), 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) . 단계 2 ： 5-클로로 -N4-(2- (이소프로필술포닐 )페닐) -N2-(2—메톡 시 -4— (1,2, 3,6-테트라하이드로피리딘 -4-일 )페닐)피리미딘 -2, 4-디아민 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 = 6.9 Hz, 6H). Step 2: 5-chloro-N4- (2- (isopropylsulfonyl) phenyl) -N2- (2—methoxy--4— (1,2,3,6-tetrahydropyridin-4-yl) phenyl) Pyrimidine-2,4-diamine
Figure imgf000015_0002
Figure imgf000015_0002
상기 단계 1에서 얻은 tert-부틸 4-(4-((5-클로로 -4-((2- (이소 프로필술포닐)페닐)아미노)피리미딘ᅳ 2-일)아미노 )-3-메특시페닐) -5，6- 디하이드로피리딘ᅳ 1(2H)-카복시레이트 화합물 1.13mg(1.84隱 ol)을 MeOH에 녹인 후， 4M HC1이 용해된 디옥산 6ml를 첨가한 후, 상온에서 0.5시간 교반하였다. 반웅이 종료된 후， HC1을 제거하고 에테르로 디 캔팅 (decanting)하여 목적 화합물 300mg을 99%의 수율로 얻었다. Tert-butyl 4- (4-((5-chloro-4-((2- (isopropylsulfonyl) phenyl) amino) pyrimidinyl 2-yl) amino) -3-methoxyphenyl ) -5,6-dihydropyridin ᅳ 1 (2H) -carboxylate compound 1.13 mg (1.84 隱 ol) was dissolved in MeOH, and then 6 ml of dioxane dissolved in 4M HC1 was added, and then at room temperature. It stirred for 0.5 hours. After the reaction was completed, HC1 was removed and decanted with ether to obtain 300 mg of the target compound in 99% yield.
l NMR (MeOH, 300ΜΗζ) δ 8.28(s, 1Η) , 8.22-8.21(m, 1H) , NMR (MeOH, 300ΜΗζ) δ 8.28 (s, 1Η), 8.22-8.21 (m, 1H),
04(d, J=4.8Hz, 1H) 7.75-7.56(m,lH),7.62-04 (d, J = 4.8 Hz, 1H) 7.75-7.56 (m, lH), 7.62-
7.58(m, 1H) ,7.51 (d,J=5.1Hz, 1H) ,7.20(3 , 1H) , 7.01-7.58 (m, 1H), 7.51 (d, J = 5.1Hz, 1H), 7.20 (3, 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) . 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 = 13.2,6 Hz).
<실시예 2> 5-클로로 -N2-(2-이소프로폭시 -5-메틸 -4-(1,2，3,6-테 트라하이드로피리딘 -4-일 )페닐) -N4-(2- (이소프로필술포닐)페닐)피리미 딘 -2, 4-디아민의 제조 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
단계 1 ： tert-부틸 4-(4-((5-클로로 -4-((2- (이소프로필술포닐 ) 페닐)아미노)피리미딘 -2-일 )아미노 )-5-이소프로폭시 -2-메틸페닐 )ᅳ5， 6- 드로피리딘 -1(2H)-카복사레이트의 제조  Step 1: tert-Butyl 4- (4-((5-chloro-4-((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -5-isopropoxy-2 Preparation of -methylphenyl) ᅳ 5, 6-dropyridine-1 (2H) -carboxate
Figure imgf000016_0001
Figure imgf000016_0001
2， 5-디클로로 -N-( 2- (이소프로필술포닐)페닐)피리미딘 -4-아민 lg(2.88 mmol)을 THF 20ml에 녹인 후 tert-부틸 4-(4-아마노 -5-이소프 로폭시 -2-메틸페닐 )-5，6-디하이드로피리딘— 1(2H)-카복시레이트  2,5-dichloro-N- (2- (isopropylsulfonyl) phenyl) pyrimidin-4-amine lg (2.88 mmol) was dissolved in 20 ml of THF, followed by tert-butyl 4- (4-anoma-5-isoprop. Foxy-2-methylphenyl) -5,6-dihydropyridine— 1 (2H) -carboxylate
955mg(2.88 麵 ol)을 첨가하고， 잔트포스 167mg(0.288 o 1 ) 및 Cs2C03 2.8g(8.64mmol)을 순서대로 넣어 준 후 질소 층전시켜 준 후 탈 가스 하였다. Pd(0Ac)2 (32mg,0.144讓 ol)를 첨가하고， 질소 충전 후 130°C 에서 18시간 교반하였다. 반웅 종료 후， EA/H20로 추출한 후 유기층은 MgS04로 건조하여 필터 후 농축하였다. 칼럼 크로마토그래피 (Hx:EA 4:1)를 이용하여 목적 화합물 642 mg을 34 의 수율로 얻었다. 955 mg (2.88 麵 ol) was added, 165 mg (0.288 o 1) of Zantforce and 2.8 g (8.64 mmol) of Cs 2 C0 3 were added in this order, followed by nitrogenous layer degassing. Pd (0Ac) 2 (32 mg, 0.144 Pa ol) was added and stirred for 18 hours at 130 ° C. after nitrogen filling. After completion of reaction, the mixture was extracted with EA / H 2 0 and the organic layer was dried over MgS0 4 , concentrated after filtration. Column chromatography (Hx: EA 4: 1) gave 642 mg of the target compound in a yield of 34.
JH NMR (CDCls, 300丽 ζ) δ 9.49(s, 1Η) , 8.57(d , J=8.4Hz , 1H) , JH NMR (CDCls, 300 ζ) δ 9.49 (s, 1Η), 8.57 (d, J = 8.4Hz, 1H),
8.16(s,lH), 8.04(s, 1H) , 7.94(dd , J=0.9Hz , 1.2Ηζ,1Η) , 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) . 단계 2 ： 5-클로로 -N2-(2-이소프로폭시 -5-메틸 -4-(l,2,3,6-테트 라하이드로피리딘 -4-일)페닐 )-N4-(2- (이소프로필술포닐)페닐)피리미딘 -2,4-디아민의 제조 8.16 (s, lH), 8.04 (s, 1H), 7.94 (dd, J = 0.9Hz, 1.2Ηζ, 1Η), 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 = 6.0 Hz, 6H), 1.33 (d, J = 6.9 Hz, 6H). Step 2: 5-chloro-N2- (2-isopropoxy-5-methyl-4- (l, 2,3,6-tetrahydropyridin-4-yl) phenyl) -N4- (2- (iso Preparation of Propylsulfonyl) phenyl) pyrimidine-2,4-diamine
Figure imgf000017_0001
Figure imgf000017_0001
상기 단계 1에서 얻은 tert-부틸 4-(4-((5-클로로 -4-((2- (이소 프로필술포닐)페닐)아미노)피리미딘 -2-일 )아미노 )-5-이소프로폭시 -2- 메틸페닐 )-5，6-디하이드로피리딘 -1(2H)-카복시레이트 화합물 600mg(0.91 ol)을 MeOH에 녹인 후， 4M HC1이 용해된 디옥산 5ml를 첨 가한 상온에서 0.5시간 교반하였다. 반웅이 종료된 후， HC1을 제 거하고 에테르로 디캔팅 (decanting)하여 목적 화합물 630 mg을 99%의 수율로 얻었다.  Tert-butyl 4- (4-((5-chloro-4-((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -5-isopropoxy obtained in step 1 above After dissolving 600 mg (0.91 ol) of 2-methylphenyl) -5,6-dihydropyridine-1 (2H) -carboxylate compound in MeOH, 5 ml of dioxane in which 4M HC1 was dissolved was added and stirred at room temperature for 0.5 hour. . After the reaction was completed, HC1 was removed and decanted with ether to obtain 630 mg of the target compound in 99% yield.
XH NMR (CDC13, 300MHz) δ 8.27(br s , 2Η) , 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,lH) , 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) . X H NMR (CDC1 3 , 300 MHz) δ 8.27 (br s, 2Η), 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, lH), 5.66 (s, 1H), 3.84 (s, 2H), 3.65 (s, 3H), 2.61 (s, 2H), 2.13 (s, 3H), 1.30 (d , J = 6 Hz, 6H), 1.26 (d, J = 6.9 Hz, 6H).
<실시예 3> 5-클로로 -N2-(2- (디플루오로메톡시 )-4-(1,2 3,6-테 트라하이드로피리딘 -4-일)페닐) -N4-(2- (이소프로필술포닐페닐)피리미 딘 -2, 4-디아민의 제조 Example 3 5-Chloro-N2- (2- (difluoromethoxy) -4- (1,2 3,6-tetrahydropyridin-4-yl) phenyl) -N4- (2- (iso Preparation of Propylsulfonylphenyl) pyrimidine-2,4-diamine
단계 1 ： tert—부틸 4-(4— ((5-클로로 -4-((2- (이소프로필술포닐 ) 페닐)피리미딘 -2-일)아미노 )-3- (디폴루오로메톡시 )페닐) -5,6-디하이드 로피리 - 2H)-카복시레이트의 제조  Step 1: tert-Butyl 4- (4 — ((5-chloro-4-((2- (isopropylsulfonyl) phenyl) pyrimidin-2-yl) amino) -3- (dipoloromethoxy) phenyl ) -5,6-dihydropyri-2H) -carboxylate
Figure imgf000017_0002
Figure imgf000017_0002
2，5-디클로로 -N-(2- (이소프로필술포닐 )페닐 )피리미딘 -4-아민 200 mg(0.58 ol)을 THF 5 ml에 녹인 후 tert-부틸 4-(4—아미노—3- (디플루오로메톡시 )페닐 )-5，6ᅳ디하이드로피리딘 -1(2H)-카복시레이트 195 mg(0.58 mmol)을 첨가해주고 잔트포스 33 mg (0.058 mmol) , CS2CO3 550 mg(1.74 ol)을 순서대로 넣어 준 후 질소 충전시켜 준 후 에 탈 가스 하였다. Pd(0Ac)2를 첨가하고， 질소 충전 후 130°C에서 18 시간 교반하였다. EA/H20로 추출한 후 유기층은 MgS04로 건조하여 필 터 후 농축하였다. 칼럼 크로마토그래피 (Hx:EA 6:1)를 이용하여 목적 화합물 120 mg을 32%의 수율로 얻었다.After dissolving 200 mg (0.58 ol) of 2,5-dichloro-N- (2- (isopropylsulfonyl) phenyl) pyrimidin-4-amine in 5 ml of THF, tert-butyl 4- (4-amino-3- 195 mg (0.58 mmol) of (difluoromethoxy) phenyl) -5,6 ᅳ dihydropyridine-1 (2H) -carboxylate was added, followed by 33 mg (0.058 mmol) of xantose and 550 mg (1.74 ol) of CS2CO3. After it was put in, it was filled with nitrogen and then degassed. Pd (0Ac) 2 was added and stirred for 18 hours at 130 ° C. after charging with nitrogen. After extraction with EA / H 2 O, the organic layer was dried over MgS0 4 , filtered and concentrated. By column chromatography (Hx: EA 6: 1) 120 mg of compound were obtained in 32% yield.
-匪 R (300 MHz, CDCls) δ 8.53(d, J=8.4Hz, 1H) , 8.31(d, J=9.애 z, 1H) , 8.18(s, 1H) , 7.94(d, J=8.1Hz, 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) . 단계 2 ： 5-클로로 -N2-(2- (디플루오로메톡시 )-4-(l,2,3,6-테트 라하이드로피리딘 -4-일 )페닐 )-N4— (2 (이소프로필술포닐페닐 )피리미딘- 2 ,4-  R (300 MHz, CDCls) δ 8.53 (d, J = 8.4 Hz, 1H), 8.31 (d, J = 9.z, 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 = 5.1 Hz, 2H), 6.01 (s, 1H), 4.08 (s, 2H) 3.66 ( t, J = 5.4 Hz, 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- (l, 2,3,6-tetrahydropyridin-4-yl) phenyl) -N4— (2 (isopropylsul Phenylphenyl) pyrimidine-2,4-
Figure imgf000018_0001
Figure imgf000018_0001
상기 단계 1에서 얻은 tert-부틸 4-(4-((5ᅳ클로로 4-((2- (이소 프로필술포닐)페닐)피리미딘 -2-일)아미노 )-3- (디플루오로메톡시 )페 닐 ) -5,6-디하이드로피리딘 -1(2H)_카복시레이트 화합물 100 mg(0.154 麵 ol)을 MeOH에 녹인 후， 4M HC1이 용해된 디옥산 7 ml를 첨가한 후 ， 상온에서 1시간 교반하였다. 반웅이 종료된 후， HC1을 제거하고 에테 르로 디캔팅 (decanting)하여 목적 화합물 (노란색 고체 90mg)을 95%의 수율로 얻었다.  Tert-butyl 4- (4-((5 ᅳ chloro 4-((2- (isopropylsulfonyl) phenyl) pyrimidin-2-yl) amino) -3- (difluoromethoxy) obtained in step 1 above. Phenyl) -5,6-dihydropyridine-1 (2H) _carboxylate Compound 100 mg (0.154 麵 ol) was dissolved in MeOH, and then 7 ml of dioxane dissolved in 4M HC1 was added, followed by 1 at room temperature. After the reaction was complete, HC1 was removed and decanted with ether to give the title compound (yellow solid 90 mg) in 95% yield.
ᅳ丽 R (300 丽 z, MeOD) δ 8.31(s , 1Η) , 8. ll-8.00(m, 1Η) , 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) . ᅳ 丽 R (300 丽 z, MeOD) δ 8.31 (s, 1Η), 8.ll-8.00 (m, 1Η), 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) .
<실시예 4> 5-클로로 -N2-(2- (디플루오로메특시 )-4- (피페리딘 -4- 일)페닐) -N4-(2- (이소프로필술포닐)페닐)피리미딘 -2，4-디아민의 제조 단계 1 ： tert-부틸 4-(4-((5-클로로 -4-((2- (이소프로필술포닐) 페닐)아미노 )피리미딘 -2-일 )아미노 ) -3- (디플루오로메톡시 )페닐)피페리 딘 -1-카복시레이트의 제조 Example 4 5-Chloro-N 2-(2- (difluoromepoxy) -4- (piperidin-4-yl) phenyl) -N 4-(2- (isopropylsulfonyl) phenyl) pyri Step 1: Preparation of midin-2,4-diamine: tert-butyl 4- (4-((5-chloro-4-((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino Preparation of) -3- (difluoromethoxy) phenyl) piperidine-1-carboxylate
Figure imgf000018_0002
2， 5-디클로로 -N-(2- (이소프로필술포닐)페닐 )파리미딘 -4-아민 87mg(0.25mtnol)을 THF 3ml에 녹인 후 tert-부틸 4- (아미노ᅳ 3ᅳ (디플루 오로메톡시 )페닐 )-5,6—디하이드로피리딘 -1(2H)-카복시레이트
Figure imgf000018_0002
2,5-dichloro-N- (2- (isopropylsulfonyl) phenyl) paramidin-4-amine 87 mg (0.25mtnol) was dissolved in 3 ml of THF and then tert-butyl 4- (amino ᅳ 3 ᅳ (difluoro) Methoxy) phenyl) -5,6—dihydropyridine-1 (2H) -carboxylate
85mg(0.25隱 ol)을 첨가하고， 잔트포스 15mg(0.025誦 ol )， Cs2C03 244g(0.75mmol)을 순서대로 첨가한 후， 질소를 층전하여 탈 가스 하였 다. Pd(0Ac)2 (2.81 ，0.013麵01)를 첨가하고， 질소 충전 후 130°C에서 18시간 교반하였다. 반웅 종료 후， EA/H20로 추출한 후 유기층은 MgS04로 건조하여 필터 후 농축하였다. 칼럼 크로마토그래피 (Hx:EA 4:1)를 이용하여 목적 화합물 25mg을 18%의 수율로 얻었다. 85 mg (0.25 μl ol) was added, Xantphos 15 mg (0.025 μl ol) and Cs 2 CO 3 244 g (0.75 mmol) were added in this order, followed by nitrogen degassing. Pd (0Ac) 2 (2.81, 0.013x01) was added and stirred at 130 ° C for 18 hours after nitrogen charging. After completion of reaction, the mixture was extracted with EA / H 2 0 and the organic layer was dried over MgS0 4 , concentrated after filtration. Column chromatography (Hx: EA 4: 1) gave 25 mg of the desired compound in 18% yield.
^-NMR (300 MHz,CDC13) δ 9.61(s, 1H)， 8.53(d; J=8.4Hz, 1H) ^ -NMR (300 MHz, CDC13) δ 9.61 (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) . 단계 2 ： 5-클로로 -N2-(2- (디풀루오로메톡시 )-4- (피페리딘 -4- 일 )페 -N4-(2- (이소프로필술포닐)페닐 )피리미딘 -2， 4-디아민의 제조 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 = 12.3 Hz, 2H), 1.49 (s, 9H), 1.32 (d, J = 6.6 Hz, 6H). Step 2: 5-Chloro-N2- (2- (difluoromethoxy) -4- (piperidin-4-yl) fe-N4- (2- (isopropylsulfonyl) phenyl) pyrimidine-2, Preparation of 4-diamine
Figure imgf000019_0001
상기 단계 1에서 얻은 tert-부틸 4-(4-((5-클로로 -4-((2- (이소 프로필술포닐)페닐)아미노)피리미딘 -2-일 )아미노 )-3- (디플루오로메톡 시 )페닐)피페리딘 -1-카복사레이트 화합물 23mg(0.042隱 ol)을 MeOH에 녹인 후, 4M HC1이 용해된 디옥산 3ml를 첨가한 후 상온에서 1시간 교반하였다. 반웅이 종료된 후， HC1을 제거하고 에테르로 디캔팅 (decanting)하여 목적 화합물 (노란색 고체， 21mg)을 93%의 수율로 얻 었다.
Figure imgf000019_0001
Tert-butyl 4- (4-((5-chloro-4-((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -3- (difluoro obtained in step 1 above 23 mg (0.042 톡 ol) of methoxy) phenyl) piperidine-1-carboxate compound was dissolved in MeOH, and 3 ml of dioxane in which 4M HC1 was dissolved was added, followed by stirring at room temperature for 1 hour. After the reaction was completed, HC1 was removed and decanted with ether to obtain the target compound (yellow solid, 21 mg) in a yield of 93%.
-匪 R (300 MHz,Me0D) δ 8.26-8.25(m , 1Η) , 8.16-8.14(m , 1Η) 7.95-7.94(m, 1Η) 7.68-7.48(m , 2H) , 7.24-7.07(m , 1H) , 3.64(s,lH), 3.57-3.51(m, 1H) , 1.28(d, J = 19.8Hz, 6H) .  -匪 R (300 MHz, Me0D) δ 8.26-8.25 (m, 1Η), 8.16-8.14 (m, 1Η) 7.95-7.94 (m, 1Η) 7.68-7.48 (m, 2H), 7.24-7.07 (m, 1H), 3.64 (s, lH), 3.57-3.51 (m, 1H), 1.28 (d, J = 19.8 Hz, 6H).
<실시예 5> 5-클로로 -N4-(2- (이소프로필술포닐 )페닐) -N2-(2-메 특시 -4- (피페리딘 -4-yl)페닐 )피리미딘 -2，4-디아민의 제조 Example 5 5-Chloro-N 4-(2- (isopropylsulfonyl) phenyl) -N 2-(2-methoxy-4- (piperidine-4-yl) phenyl) pyrimidine-2,4 Preparation of Diamine
단계 1 ： tert-부틸 4-(4-((5-클로로 -4ᅳ((2- (이소프로필술포닐 ) 페닐)아미노)피리미딘 -2-일)아미노 )-3-메록시페닐)피페리딘 -1-카복시 레이트의 제조 Step 1: tert-butyl 4- (4-((5-chloro-4 '((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) pi Preparation of Ferridine-1-carboxylate
Figure imgf000020_0001
Figure imgf000020_0001
2，5-디클로로 -N-(2- (이소프로필술포닐)페닐 )피리미딘ᅳ 4-아민 274g(0.79mmol )올 THF 20ml에 녹인 후 tert-부틸 4-(4-아미노 -3-메톡 시페닐)피페리딘 -1-카복시레이트 243g(0.79mmol)을 첨가하고， 잔트포 스 46mg (0.079讓 ol), Cs2C03 772g(2.37讓 ol)올 순서대로 첨가한 후, 질소를 충전하여 탈 가스 하였다. Pd(0Ac)2 (8.86 ，0.039誦01)를 첨 가하고， 질소 충전 후 13CTC에서 18시간 교반하였다. 반웅 종료 후， EA/H20로 추출한 후 유기층은 MgS04로 건조하여 필터 후 농축하였다. 칼럼 크로마토그래피 (Hx:EA 4:1)를 이용하여 목적 화합물 180mg올 37% 의 수율로 얻었다. 2,5-dichloro-N- (2- (isopropylsulfonyl) phenyl) pyrimidin ᅳ 4-amine 274 g (0.79 mmol) ol dissolved in 20 ml THF and tert-butyl 4- (4-amino-3-methoxy 243 g (0.79 mmol) of phenyl) piperidine-1-carboxylate were added, followed by 46 mg (0.079 μl) of xanthos and 772 g (2.37 μl) of Cs 2 C0 3 , followed by nitrogen. Degassing. Pd (0Ac) 2 (8.86, 0.039x01) was added and stirred for 18 hours at 13 CTC after nitrogen charge. After completion of reaction, the mixture was extracted with EA / H 2 0 and the organic layer was dried over MgS0 4 , concentrated after filtration. Column chromatography (Hx: EA 4: 1) was used to obtain 180 mg of the target compound in 37% yield.
丽 R (300 MHz, CDC13) δ 9.54(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 71H) , 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(sᅳ 9H) , 1.32(d J=6.6Hz, 6H) . 단계 2 ： 5-클로로 -N4-(2 (이소프로필술포닐 )페닐) N2-(2-메톡 시 -4- ( — 4-yl)페닐)피리미딘 -2 ,4-디아민의 제조 R (300 MHz, CDC13) δ 9.54 (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 7 1H), 7.30 (s, 1H), 7.30-7.28 (d, J = 7.8 Hz, 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 ᅳ 9H), 1.32 (d J = 6.6 Hz, 6H). Step 2: Preparation of 5-Chloro-N4- (2 (isopropylsulfonyl) phenyl) N2- (2-methoxyoxy-4- (—4-yl) phenyl) pyrimidine-2,4-diamine
Figure imgf000020_0002
Figure imgf000020_0002
상기 단계 1에서 얻은 tert-부틸 4-(4-((5-클로로 -4-((2- (이소 프로필술포닐)페닐)아미노)피리미딘 -2-일 )아미노 )-3ᅳ메록시페닐)피페 리딘 -1-카복시레이트 화합물 170mg(0.28麵 ol)을 MeOH에 녹인 후， 4M ΗΠ이 용해된 디옥산 3ml를 첨가한 후, 상온에서 0.5시간 교반하였다. 반웅이 종료된 후， HC1을 제거하고 에테르로 디캔팅 (decanting)하여 목적 화합물 150 mg을 99%의 수율로 얻었다.  Tert-butyl 4- (4-((5-chloro-4-((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -3 ᅳ methoxyphenyl) obtained in step 1 above) After dissolving the piperidine-1-carboxylate compound 170mg (0.28 Pa ol) in MeOH, 3 ml of dioxane dissolved in 4M ΗΠ was added, followed by stirring at room temperature for 0.5 hour. After the reaction was completed, HC1 was removed and decanted with ether to obtain 150 mg of the target compound in 99% yield.
^-NMR (300 MHz, MeOD) δ 8.22(br s， 1Η)， 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) . ^ -NMR (300 MHz, MeOD) δ 8.22 (br s, 1Η), 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 = 5.4 Hz, 6H).
<실시예 6> N4-(2- (이소프로필술포닐)페닐) -N2-(2-메톡시 -4- (1,2, 3,6-테트라하이드로피리딘 -4-일 )페닐) -5- (트리플루오로메틸)피리 미딘 -2，4-디아민의 제조 Example 6 N4- (2- (isopropylsulfonyl) phenyl) -N2- (2-methoxy-4- (1,2,3,6-tetrahydropyridin-4-yl) phenyl) -5 Preparation of (trifluoromethyl) pyrimidine-2,4-diamine
단계 1 ： tert-부틸 4-(4-((4-((2- (이소프로필술포닐)페닐)아미 노) -5- (트리플루오로메틸)피리미딘 -2-일 )아미노 )-3ᅳ메특시쩨닐 )-5， 6- -1(2H)-카복시레이트의 제조  Step 1: tert-Butyl 4- (4-((4-((2- (isopropylsulfonyl) phenyl) amino) -5 (trifluoromethyl) pyrimidin-2-yl) amino) -3 Preparation of Memethoxynyl) -5, 6--1 (2H) -carboxylate
Figure imgf000021_0001
Figure imgf000021_0001
2-클로로 -N-(2- (이소프로필술포닐)페닐 )-5- (트리플루오로메틸 ) . 피리미딘 -4-아민 100mg(0.26讓 ol)을 THF 2ml에 녹인 후 tert-부틸 4- (4-아미노 -3-메톡시페닐 )-5， 6—디하이드로피리딘— 1(2H)-카복시레이트 160mg(0.53薩 ol)을 첨가하고， 잔트포스 15mg (0.026隱 ol )， Cs2C03 275g(0.79mmol)을 순서대로 첨가한 후， 질소를 충전하여 탈 가스 하였 다. PcK0Ac)2 (3mg, 0.013Π Ο1)를 첨가하고， 질소 충전 후 150t>에서 2시간 교반하였다. 반웅 종료 후 , EA/H20로 추출한 후 유기층은 MgS04 로 건조하여 필터 후 농축하였다. 칼럼 크로마토그래피 (Hx:EA 4:1)를 이용하여 목적 화합물 15mg을 8.«의 수을로 얻었다 .2-Chloro-N- (2- (isopropylsulfonyl) phenyl) -5- (trifluoromethyl). Dissolve 100 mg (0.26 讓 ol) of pyrimidin-4-amine in 2 ml of THF and then tert-butyl 4- (4-amino-3-methoxyphenyl) -5, 6—dihydropyridine— 1 (2H) -carboxylate 160 mg (0.53 μl ol) was added, Xantphos 15 mg (0.026 μl ol) and Cs 2 C0 3 275 g (0.79 mmol) were added sequentially, followed by degassing with nitrogen. PcK0Ac) 2 (3 mg, 0.013π1) was added and stirred at 150t> for 2 hours after nitrogen filling. After completion of reaction, the mixture was extracted with EA / H 2 0 and the organic layer was dried over MgSO 4 , filtered and concentrated. Column chromatography (Hx: EA 4: 1) gave 15 mg of the target compound in a number of 8. «.
-簡簡 RR (300 MHz,CDC13) δ 9.63(s, 1H) , 8.60(s, 1Η) , -RR (300 MHz, CD13) δ 9.63 (s, 1H), 8.60 (s, 1Η),
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(br s , 1H)， 3.90(s, 1H) , 3.73(s, 1H) , 3.64(s,3H) , 3.17-3.13(m,lH). 2.62(s, 1H) , 2.51-7,92 (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 (br s, 1H), 3.90 (s, 1H), 3.73 (s, 1H), 3.64 (s, 3H), 3.17-3.13 (m, lH). 2.62 (s, 1 H), 2.51-
2.49(m, 1H) , 2.2(s, 1H) , 1.49(s,9H) , 1.27( d， J=5.7Hz， 6H) . 단계 2 ： N4-(2- (이소프로필술포닐 )페닐) -N2-(2-메톡시 -4- (1,2,3, 6-테트라하이드로피리딘 -4-일)페닐) -5- (트리플루오로메틸)피리 미디 -2.4-디아1？ᅵ의 체조 2.49 (m, 1H), 2.2 (s, 1H), 1.49 (s, 9H), 1.27 (d, J = 5.7 Hz, 6H). Step 2: N4- (2- (isopropylsulfonyl) phenyl) -N2- (2-methoxy-4- (1,2,3, 6-tetrahydropyridin-4-yl) phenyl) -5- ( Trifluoromethyl) pyrimidine -2.4-dia 1 ？ ᅵ Gymnastics
Figure imgf000021_0002
상기 단계 1에서 얻은 tert-부틸 4-(4— ((4-((2- (이소프로필술포 닐 )페닐)아미노) -5- (트리풀루오로메틸)피리미딘 -2-일 )아미노 )-3-메톡 시페닐 )-5，6-디하이드로피리딘 -1(2H)-카복시레이트 14mg(0.021薩 ol)을 MeOH에 녹인 후， 4M HC1이 용해된 디옥산 2ml를 첨가한 후， 상온에서 0.5시간 교반하였다. 반웅이 종료된 후， HC1을 제거하고 에테르로 디 캔팅 (decanting)하여 목적 화합물 14mg을 99¾»의 수율로 얻었다.
Figure imgf000021_0002
Tert-butyl 4- (4— ((4-((2- (isopropylsulfonyl) phenyl) amino) -5- (trifuluromethyl) pyrimidin-2-yl) amino) obtained in step 1 above) Dissolve 14 mg (0.021 μl) of -3-methoxyphenyl) -5,6-dihydropyridine-1 (2H) -carboxylate in MeOH, add 2 ml of dioxane dissolved in 4M HC1, and then store at room temperature. It stirred for 0.5 hours. After the reaction was completed, HC1 was removed and decanted with ether to obtain 14 mg of the target compound in a yield of 99¾ ».
-匪 R (300MHz, MeOD) δ 8.49-8.47 m, 1Η) , 8.00(d， J=l .5Hz， 2H) 7.77-7.76(m, 1H) ,7.61-7.58(m,3H) , 7.13—7. ll(m， 1H)， 6.86- -匪 R (300MHz, MeOD) δ 8.49-8.47 m, 1Η), 8.00 (d, J = l .5Hz, 2H) 7.77-7.76 (m, 1H), 7.61-7.58 (m, 3H), 7.13—7 . ll (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) . 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 = 3 Hz, 6H).
<실시예 7> N2-(2-이소프로폭시 -5-메틸 -4-(1，2，3，6-테트라하이 드로피리딘 -4-일 )페닐) -N4-(2- (이소프로필술포닐)페닐) -5- (트리플루오 로메틸)피리미딘 -2, 4-디아민의 제조 Example 7 N2- (2-isopropoxy-5-methyl-4- (1,2,3,6-tetrahydrodropyridin-4-yl) phenyl) -N4- (2- (isopropylsul Preparation of Ponyl) phenyl) -5- (trifluoromethyl) pyrimidine-2,4-diamine
단계 1 ： tert-부틸 4-(5-이소프로폭시 -4-((4-((2- (이소프로필 술포닐)페닐)아미노 )-5- (트리플루오로메틸)피리미딘 -2-일 )아미노 )-2- 메틸 _5，6-디하이드로피리딘 -1(2H)-카복시레이트의 제조  Step 1: tert-Butyl 4- (5-isopropoxy-4-((4-((2- (isopropyl sulfonyl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl Preparation of Amino) -2-methyl-5,6-dihydropyridine-1 (2H) -carboxylate
Figure imgf000022_0001
Figure imgf000022_0001
2-클로로 -N-(2- (이소프로필술포닐)페닐 )-5- (트라플루오로메틸) 피리미딘 -4ᅳ아민 5mg(0.58議 ol)을 THF 2ml에 녹인 후 tert-부틸 4— (4- 아미노ᅳ 5-이소프로폭시 -2-메틸페닐 )-5，6—디하이드로피리딘 -1(2H)-카복 시레이트 139mg(0.42隱 ol)을 첨가하고， 잔트포스 12mg (0.021薩01)， Cs2C03 205g(0.63隱 ol)을 순서대로 첨가한 후， 질소를 충전하여 탈 가 스 하였다. ?(1(0^)2(31 ，0.0105讓01)를 첨가하고, 질소 충전 후 150°C에서 2시간 동안 가열하였다. 반웅 종료 후， EA/H20로 추출한 후 유기층은 MgS04로 건조하여 필터 후 농축하였다. 칼럼 크로마토그래피 (Hx:EA 4:1)를 이용하여 목적 화합물 26mg을 17%의 수율로 얻었다. . 5 mg (0.58 議 ol) of 2-chloro-N- (2- (isopropylsulfonyl) phenyl) -5- (trifluoromethyl) pyrimidine-4 딘 amine was dissolved in 2 ml of THF, followed by tert-butyl 4— ( 4-amino-3-5-isopropoxy-2-methylphenyl) -5,6-dihydropyridine-l (2H) -carboxylate 139 mg (0.42 'ol) was added and xantose 12 mg (0.021'01); 205 g (0.63 0 ol) of Cs 2 CO 3 were added in this order, followed by degassing with nitrogen. (1 (0 ^) 2 (31,0.0105 讓 01) was added and heated for 2 hours at 150 ° C. after nitrogen filling, and after completion of reaction, the mixture was extracted with EA / H 2 0 and the organic layer was dried over MgS0 4 . The residue was filtered and concentrated to give 26 mg of the target compound in 17% yield by column chromatography (Hx: EA 4: 1).
ᅳ匪 R (300 MHz,CDC13) δ 9.12(s,lH) , 8.41(s,lH) , 8.31- 8.28(m, 1Η) , 7.97(d, J=7.8Hz,2H) , 7.82(s, 1H) , 7.64-7.58(m , 1H) , 7.34-7.26(m,lH),6.63(s,lH), 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) . 단계 2 ： N2-(2-이소프로폭시 -5-메틸 -4-(lᅳ 2,3，6ᅳ테트라하이드 로피리딘 -4-일 )페닐) -N4-(2- (이소프로필술포닐 )페닐) -5- (트리플투오로 메틸) -2, 4-디아민의 제조 ᅳ 匪 R (300 MHz, CDC13) δ 9.12 (s, lH), 8.41 (s, lH), 8.31- 8.28 (m, 1Η), 7.97 (d, J = 7.8Hz, 2H), 7.82 (s, 1H ), 7.64-7.58 (m, 1H), 7.34-7.26 (m, lH), 6.63 (s, lH), 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 = 6.3 Hz, 6H), 1.31 (d, J = 6.9 Hz, 6H). Step 2: N2- (2-isopropoxy-5-methyl-4- (l'2,3,6'tetrahydro) Preparation of lopyridin-4-yl) phenyl) -N4- (2- (isopropylsulfonyl) phenyl) -5- (tripletomethyl) -2,4-diamine
Figure imgf000023_0001
Figure imgf000023_0001
상기 단계 1에서 얻은 tert-부틸 4-(5-이소프로폭시 _4-((4-((2- (이소프로필술포닐)페닐 )아미노 )-5- (트리플루오로메틸 )피리미딘 -2-일 ) 아미노 )-2-메틸페닐 )-5，6-디하이드로피리딘 -1(2H)_카복시레이트  Tert-butyl 4- (5-isopropoxy _4-((4-((2- (isopropylsulfonyl) phenyl) amino) -5- (trifluoromethyl) pyrimidine-2- obtained in step 1 above Yl) amino) -2-methylphenyl) -5,6-dihydropyridine-1 (2H) _carboxylate
26mg(0.038薩 ol)을 MeOH에 녹인 후, 4M HCI이 용해된 디옥산 3ml를 첨 가한 후， 상은에서 1시간 교반하였다. 반웅이 종료된 후， HC1을 제거 하고 에테르로 디캔팅 (decanting)하여 목적 화합물 25mg을 99%의 수율 로 얻었다. After dissolving 26 mg (0.038 μl) in MeOH, 3 ml of dioxane dissolved in 4M HCI was added, followed by stirring for 1 hour at silver. After the reaction was completed, HC1 was removed and decanted with ether to obtain 25 mg of the target compound in 99% yield.
蘭 R (300 MHz,MeOD) δ 8.54-8.50(m , 1Η) 8.05(d, J=9Hz, 1H)， 7.80-7.75(m, 1Η) , 7.63-7.58(m , 1H) , 7.35( s , 1H) ( 6.82(s,lH),蘭 R (300 MHz, MeOD) δ 8.54-8.50 (m, 1Η) 8.05 (d, J = 9Hz, 1H), 7.80-7.75 (m, 1Η), 7.63-7.58 (m, 1H), 7.35 (s, 1H) ( 6.82 (s, lH),
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. OK s , 3H) , 1.32(d, J=6Hz,6H)， 1.24(d, J=6.9Hz, 6H) . 실시예 8> N2-(2- (디플루오로메특시 )-4-(1，2,3,6-테트라하이드 로피리 -4-일 )페닐) -N4-(2- (이소프로필술포닐)페닐) -5- (트리플루오로 메틸)피리미딘 -2，4—디아민의 제조 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. OK s, 3H), 1.32 (d, J = 6 Hz, 6H), 1.24 (d, J = 6.9 Hz, 6H). Example 8> N2- (2- (difluoromethoxy) -4- (1,2,3,6-tetrahydropyri-4-yl) phenyl) -N4- (2- (isopropylsulfonyl ) Phenyl) -5- (trifluoromethyl) pyrimidine-2,4-diamine
단계 1 ： tert-부틸 4-(3- (디폴루오로메톡시 )-4-((4-((2- (이소 프로필술포닐)페닐)아미노 )— 5- (트리플루오로메틸)피리미딘ᅳ2-일 )아미 노)페 )-5, 6-디하이드로피리딘 -1(2H)-카복시레이트의 제조  Step 1: tert-Butyl 4- (3- (difluoromethoxy) -4-((4-((2- (isopropylsulfonyl) phenyl) amino) — 5- (trifluoromethyl) pyrimidine Preparation of 2-yl) amino) fe) -5, 6-dihydropyridine-1 (2H) -carboxylate
Figure imgf000023_0002
Figure imgf000023_0002
2-클로로 -N-(2- (이소프로필술포닐)페닐 )-5- (트리플루오로메틸 ) 피리미딘 -4-아민 351 (0.08隱01)을 THF 2ml에 녹인 후 tert—부틸 4ᅳ (4-아미노 -3- (디플루오로메톡시 )페닐 )-5，6-디하이드로피리딘 -1(2H)-카 복시레이트 54mg(0.16隱 ol)을 첨가하고, 잔트포스 5mg(0.008麵 o 1 )， Cs2C03 77mg(0.24麵 ol)을 순서대로 첨가한 후， 질소를 충전하여 탈 가 스 하였다. Pd(0Ac)2 (lmg, 0.004讓 ol)를 첨가하고， 질소 층전 후 150°C에서 1시간 교반하였다. 반웅 종료 후， EA/H20로 추출한 후 유기 층은 MgS04로 건조하여 필터 후 농축하였다. 칼럼 크로마토그래피 (Ηχ:ΕΑ 4:1)를 이용하여 목적 화합물 3.5mg을 7%의 수을로 얻었다. Dissolve 2-chloro-N- (2- (isopropylsulfonyl) phenyl) -5- (trifluoromethyl) pyrimidin-4-amine 351 (0.08 隱 01) in 2 ml of THF and then add tert-butyl 4 ᅳ ( 4-amino-3- (difluoromethoxy) phenyl) -5,6-dihydropyridine-1 (2H) -carboxylate 54 mg (0.16 Pa ol) was added and 5 mg (0.008 Pa o 1) xanthos ， 77 mg (0.24 麵 ol) of Cs 2 CO 3 were added sequentially, followed by degassing with nitrogen. Pd (0Ac) 2 (lmg, 0.004 Pa ol) was added, and stirred at 150 ° C. for 1 hour after nitrogen layer deposition. After the completion of reaction, the mixture was extracted with EA / H 2 0 and the organic layer was dried over MgSO 4 , filtered and concentrated. Column chromatography (Ηχ: ΕΑ 4: 1) was used to obtain 3.5 mg of the target compound in 7% water.
XH-NMR (300 MHz, CDC13) δ 9.25(s, 1Η) , 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) , X H-NMR (300 MHz, CDC13) δ 9.25 (s, 1Η), 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) . 단계 2 ： N2-(2- (디플루오로메톡시 )-4-(1，2，3,6ᅳ테트라하이드로 피리딘 -4-일 )페닐 )-N4-(2- (이소프로필술포닐)페닐 )-5- (트리플루오로메 틸 )피 -2， 4-디아민의 제조 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 ᅳ tetrahydro pyridin-4-yl) phenyl) -N4- (2- (isopropylsulfonyl) phenyl) Preparation of -5- (trifluoromethyl) pi-2,4-diamine
Figure imgf000024_0001
상기 단계 1에서 얻은 tert-부틸 4ᅳ(3ᅳ (디플루오로메록시 )-4ᅳ ((4— ((2- (이소프로필술포닐)페닐 )아미노 )-5- (트리플루오로메틸)피리미 딘 -2ᅳ일 )아미노)페닐 )-5 ,6-디하이드로피리딘 - 2H)-카복시레이트의을릉 3.51 (3.53隱01)을 MeOH에 녹인 후, 4M HC1이 용해된 디옥산 1ml 수제첨 가한 후, 상은에서 0.5시간 교반하였다. 반웅이 종료된 후， HC1 거하고 에테르로 디캔팅 (decanting)하여 목적 화합물 7mg올 99% 율로 얻었다.
Figure imgf000024_0001
Tert-butyl 4 ′ (3 ′ (difluoromethoxy) -4 ′ ((4 — ((2- (isopropylsulfonyl) phenyl) amino) -5- (trifluoromethyl) pyrile obtained in step 1 above) After dissolving 3.51 (3.53 隱0 1) of midi-2 ylyl) amino) phenyl) -5,6-dihydropyridine-2H) -carboxylate in MeOH, 1 ml of dioxane dissolved in 4M HC1 was added manually. The phases were then stirred for 0.5 h at silver. After the reaction was completed, HC1 was removed and decanted with ether to obtain 7 mg of the target compound at 99% rate.
-匪 R (300 MHz, MeOD) δ 8.51(s,lH), 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,lH) , 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) . R (300 MHz, MeOD) δ 8.51 (s, lH), 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, lH), 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 = 3.9 Hz, 6H).
<실시예 9> N2-(2- (디플루오로메록시 )-4- (피페리딘 -4-일 )페닐) - N4-(2- (이소프로필술포닐)페닐) -5- (트리플루오로메틸)피리미딘 -2, 4-디 아민의 제조 Example 9 N2- (2- (difluoromethoxy) -4- (piperidin-4-yl) phenyl) -N4- (2- (isopropylsulfonyl) phenyl) -5- (trifluoro Preparation of rommethyl) pyrimidine-2,4-diamine
단계 1 ： tert-부틸 4-(3- (디플루오로메톡시 )-4ᅳ ( (4-( (2- (이소 프로필술포닐)페닐 )아미노 )-5- (트리플루오로메틸 )피리미딘 -2-일 )아口' 노)페닐)피페리딘 -1-카복시레이트의 제조 Step 1: tert-butyl 4- (3- (difluoromethoxy) -4 '((4-((2- (isopropylsulfonyl) phenyl) amino) -5- (trifluoromethyl) pyrimidine- 2-1) O口'no) phenyl) Preparation of piperidine-1-carboxylic rate
Figure imgf000025_0001
Figure imgf000025_0001
2-클로로 -N-(2- (이소프로필술포닐)페닐 )-5- (트리플루오로메틸) 피리미딘 -4-아민 60mg(0.16讓 ol)을 THF 3ml에 녹인 후 tert-부틸 4- (4-아미노— 3- (다플루오로메톡시 )페닐 )피페리딘 -1-카복시레이트  60 mg (0.16 讓 ol) of 2-chloro-N- (2- (isopropylsulfonyl) phenyl) -5- (trifluoromethyl) pyrimidin-4-amine was dissolved in 3 ml of THF, followed by tert-butyl 4- ( 4-amino— 3- (polyfluoromethoxy) phenyl) piperidine-1-carboxylate
110mg(0.32隱 ol)을 첨가하고， 잔트포스 9mg (0.32隱01)， Cs2C03 156g(0.48mmol)을 순서대로 첨가한 후， 질소를 충전하여 탈 가스 하였 다. Pd(0Ac)2 (2mg, 0.008瞧 ol)를 첨가하고， 질소 충전 후 130°C에서 18시간 교반하였다. 반응 종료 후， EA/H20로 추출한 후 유기층은 MgS04로 건조하여 필터 후 농축하였다. 칼럼 크로마토그래피 (Hx:EA 4:1)를 이용하여 목적 화합물 35mg을 32%의 수율로 얻었다.After addition of 110mg (0.32隱ol), and the addition of janteu force 9mg (0.32隱0 1), Cs 2 C0 3 156g (0.48mmol) sequentially, and degassing was filled with nitrogen. Pd (0Ac) 2 (2 mg, 0.008 μl) was added and stirred for 18 hours at 130 ° C. after nitrogen filling. After completion of the reaction, the mixture was extracted with EA / H 2 0 and the organic layer was dried over MgS0 4 , filtered and concentrated. Column chromatography (Hx: EA 4: 1) gave 35 mg of the target compound in 32% yield.
-匪 R (300 MHz,CDC13) , δ 9.43(s, 1Η) , 8.38(s, 1H) , 8.19(d,J=8.4Hz,lH), 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,lH), 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) . 단계 2 ： N2-(2- (디플루오로메톡시 )-4- (피페리딘— 4-일 )페닐) - -匪 R (300 MHz, CDC13), δ 9.43 (s, 1Η), 8.38 (s, 1H), 8.19 (d, J = 8.4Hz, lH), 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, lH), 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 = 6.9 Hz, 6H). Step 2: N2- (2- (difluoromethoxy) -4- (piperidin— 4-yl) phenyl)-
N4-(2- (이소프로필술포닐)페닐) -5- (트리플루오로메틸)피리미딘 -2, 4-디 아민 N4- (2- (isopropylsulfonyl) phenyl) -5- (trifluoromethyl) pyrimidine-2,4-diamine
Figure imgf000025_0002
Figure imgf000025_0002
상기 단계 1에서 얻은 tert-부틸 4-(3- (디플루오로메록시 )-4- ( (4-( (2- (이소프로필술포닐)페닐 )아미노 )-5- (트리플루오로메틸 )피리미 딘 -2-일 )아미노)페닐)피페리딘 -1-카복시레이트 3 (0.051讓01)을 MeOH에 녹인 후， 4M HC1이 용해된 디옥산 3ml를 첨가한 후， 상온에서 0.5시간 교반하였다. 반웅이 종료된 후， HC1을 제거하고 에테르로 디 캔팅 (decanting)하여 목적 화합물 29ing을 99%의 수율로 얻었다.  Tert-butyl 4- (3- (difluoromethoxy) -4-((4-((2- (isopropylsulfonyl) phenyl) amino) -5- (trifluoromethyl) pyrile obtained in step 1 above) Midin-2-yl) amino) phenyl) piperidine-1-carboxylate 3 (0.051 讓 01) was dissolved in MeOH, 3 ml of 4M HC1 dissolved dioxane was added, and the mixture was stirred at room temperature for 0.5 hour. . After the reaction was completed, HC1 was removed and decanted with ether to obtain the title compound 29ing in 99% yield.
^-NMR (300 MHz, MeOD)， δ 8.50(s,lH) , 7.9으 7.78(m， 2H)， 7.48-4.45(m,3H) , 7.23-7.19(m , 2Η) , 3.75-3.72(m , 1Η) , 3.59- 3.53(m,2H) , 2.14-1.88(m , 5H) , 1.19-1.15(m , 6H) ^ -NMR (300 MHz, MeOD), δ 8.50 (s, lH), 7.9 to 7.78 (m, 2H), 7.48-4.45 (m, 3H), 7.23-7.19 (m, 2Η), 3.75-3.72 (m , 1Η), 3.59- 3.53 (m, 2H), 2.14-1.88 (m, 5H), 1.19-1.15 (m, 6H)
<실시예 10> 5-클로로 -N2-(5-플루오로 -2-메록시 -4-(1，2，3，6-테 트라하이드로피리딘 -4-일 )페닐) -N4-(2- (이소프로필술포닐)페닐)피리미 딘 -2, 4-디아민의 제조 Example 10 5-Chloro-N 2-(5-fluoro-2-methoxy-4- (1,2,3,6-tetrahydropyridin-4-yl) phenyl) -N4- (2- Preparation of (isopropylsulfonyl) phenyl) pyrimidine-2,4-diamine
단계 1 ： tert-부틸 4-(4-((5-클로로 -4-((2- (이소프로필술포닐 ) 페닐 )아미노)피리미딘 -2-일 )아미노 )-2-플루오로 -5-메톡시페닐 )— 5,6-디 하이 -1(2H)-카복시레이트의 제조  Step 1: tert-butyl 4- (4-((5-chloro-4-((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -2-fluoro-5- Methoxyphenyl) — Preparation of 5,6-Dihi-1 (2H) -carboxylate
Figure imgf000026_0001
Figure imgf000026_0001
2， 5-디클로로 -N-(2- (이소프로필술포닐)페닐)피리미딘 -4-아민 123mg (0.35mmol)을 THF 4ml에 녹인 후 tert-부틸 4-(4—아미노 -2-플루 오로 -5-메록시페닐 )-5，6_디하이드로피리딘 - 2H)-카복시레이트  2,5-dichloro-N- (2- (isopropylsulfonyl) phenyl) pyrimidin-4-amine 123 mg (0.35 mmol) was dissolved in 4 ml of THF, followed by tert-butyl 4- (4-amino-2-fluoro -5-Methoxyphenyl) -5,6_dihydropyridine-2H) -carboxylate
115mg(0.35薩 ol)을 첨가하고， 잔트포스 20mg (0.033mmo 0， Cs2C03 322mg(lmmol)을 순서대로 첨가한 후， 질소를 충전하여 탈 가스 하였다 Pd(0Ac)2 (4mg, 0.033麵 ol)를 첨가하고， 질소 층전 후 130°C에서 8시 간 교반하였다. 반웅 종료 후, EA/H20로 추출한 후 유기층은 MgS04로 건조하여 필터 후 농축하였다. 칼럼 크로마토그래피 (Hx:EA 4:1)를 이 용하여 목적 화합물 82mg을 37%의 수율로 얻었다 . 115 mg (0.35 μl ol) was added, 20 mg (0.033 mmol 0, Cs 2 C0 3 322 mg (lmmol)) were added sequentially, followed by degassing with nitrogen. Pd (0Ac) 2 (4 mg, 0.033 μs) ol) was added and stirred for 8 hours at 130 ° C. after the nitrogen layer was extracted, extracted with EA / H 2 0 and the organic layer was dried over MgS0 4 , concentrated after filtration and column chromatography (Hx: EA). 4: 1) was used to give 82 mg of the target compound in 37% yield.
^-NMR (300 MHz, CDC13) δ 9.54(brs, 1H) , 8.52-8.49(m, 1H), 8.19-8.12(ni, 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(iii, 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=3.9Hz, 9H) ,, 1.31- 1.29(m, 6H) . 단계 2 ： 5-클로로 -N2-(5-플루오로 -2-메톡시 4-(l,2,3,6-테트라 하이-드로피리 -던 -4-일 )페닐 ) -Ν4-Τ2-Γ이 - ᅩ포—닐 ί페^)피리미딘- 2, 4-디아민의 제조 ^ -NMR (300 MHz, CDC13) δ 9.54 (brs, 1H), 8.52-8.49 (m, 1H), 8.19-8.12 (ni, 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 = 3.9 Hz, 3H), 3.64-3.62 (iii, 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- (l, 2,3,6-tetra high-droppyri-don-4-yl) phenyl) -Ν4-Τ2-Γ Preparation of bis - sulfonyl - nife -pyrimidine- 2,4-diamine
Figure imgf000026_0002
상기 단계 1에서 얻은 tert-부틸 4-(4-((5-클로로ᅳ4-((2- (이소 프로필술포닐 )페닐)아미노)피리미딘 -2ᅳ일 )아미노 )-2-플루오로 -5-메특 시페닐 )-5，6ᅳ디하이드로피리딘 -1(2H)-카복시레이트 70mg(0.11賺 ol)을 MeOH에 녹인 후， 4M HC1이 용해된 디옥산 3ml를 첨가한 후， 상온에서 0.5시간 교반하였다. 반웅이 종료된 후 , HC1을 제거하고 에테르로 디 캔팅 (decanting)하여 목적 화합물 77mg을 99%의 수율로 얻었다.
Figure imgf000026_0002
Tert-butyl 4- (4-((5-chloro5-4-((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2xyl) amino) -2-fluoro-5 obtained in step 1 above -Methocyphenyl) -5,6'dihydropyridine-1 (2H) -carboxylate 70mg (0.11 賺 ol) was dissolved in MeOH, 3ml of 4M HC1 dissolved dioxane was added, and stirred at room temperature for 0.5 hours. It was. After the reaction was completed, HC1 was removed and decanted with ether to obtain 77 mg of the target compound in 99% yield.
XH NMR (MeOD, 300ΜΗζ) δ 8.43(s, 1Η) , 8.17-8. ll(m, 2H) , 7.91-7.86(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). X H NMR (MeOD, 300ΜΗζ) δ 8.43 (s, 1Η), 8.17-8. ll (m, 2H), 7.91-7.86 (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 = 6.6 Hz, 6H).
<실시예 11> 5-클로로 -N4-(2- (이소프로필술포닐)페날) -N2-(2-메 톡시-5-메틸-4-(1，2,3，6-테트라하이드로피리딘 -4-일 )페닐)피리미딘- 2, 4-디아민의 제조 Example 11 5-Chloro-N 4-(2- (isopropylsulfonyl) phenal) -N 2-(2-methoxy-5-methyl-4- (1,2,3,6-tetrahydropyridine) Preparation of 4-yl) phenyl) pyrimidine-2,4-diamine
단계 1 ： tert-부틸 4-(4-((5-클로로 -4-((2- (이소프로필술포닐 ) 페닐)아미노 )피리미딘 -2-일 )아미노 ) -5-메톡시 -2-메틸페닐 )-5, 6-디하이 드로피 -1(2H)-카복시레이트의 제조  Step 1: tert-Butyl 4- (4-((5-chloro-4-((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -5-methoxy-2- Preparation of Methylphenyl) -5, 6-Dihydro Dropi-1 (2H) -carboxylate
Figure imgf000027_0001
Figure imgf000027_0001
2， 5-디클로로ᅳ N-( 2- (이소프로필술포닐)페닐 )피리미딘 -4-아민 2, 5-dichlorosulf N- (2- (isopropylsulfonyl) phenyl) pyrimidin-4-amine
107mg (0.31mmol)을 THF 4ml에 녹인 후 tert-부틸 4-( 4-아미노 -5-메록 시 -2-메틸페닐 )-5 ,6-디하이드로피리딘 -1(2H)-카복시레이트 107mg (0.31mmol) was dissolved in 4ml THF and then tert-butyl 4- (4-amino-5-methyl-2-methylphenyl) -5,6-dihydropyridine-1 (2H) -carboxylate
100mg(0.31mmol)을 첨가하고 잔트포스 18mg (0.31讓01)， Cs2C03 303mg(0.93mniol)올 순서대로 첨가한 후， 질소를 충전하여 탈 가스 하 였다 . Pd(0Ac)2 (4mg, 0.015匪 ol)를 첨가하고， 질소 충전 후 130°C에 서 18시간 교반하였다. 반웅 종료 후， EA/H20로 추출한 후 유기충은 MgS04로 건조하여 필터 후 농축하였다. 칼럼 크로마토그래피 (Hx:EA 4:1)를 이용하여 목적 화합물 32mg을 17%와 수율로 얻었다. 100 mg (0.31 mmol) was added, followed by Xantphos 18 mg (0.31 讓 01) and Cs 2 CO 3 303 mg (0.93 mmol) in order, followed by nitrogen degassing. Pd (0Ac) 2 (4 mg, 0.015 μl) was added and stirred for 18 hours at 130 ° C. after nitrogen filling. After the reaction was completed, the extract was extracted with EA / H 2 0 and the organic insects were dried with MgS0 4 and concentrated after filtration. Column chromatography (Hx: EA 4: 1) gave 32 mg of the target compound in 17% and yield.
XH NMR (CDCls, 300MHz ) δ 9.5(s, 1Η) , 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) . 단계 2 :5-클로로 -N4-(2- (이소프로필술포닐)페닐) -N2-(2-메톡 X H NMR (CDCls, 300MHz) δ 9.5 (s, 1Η), 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 = 5.4 Hz), 3.27-3.23 (m, 1H), 2.34 (d, J = 0.9 Hz), 2.12 (s, 3H), 1.50 (s, 9H), 1.32 (d, J = 6.9Hz). Step 2: 5-Chloro-N 4-(2- (isopropylsulfonyl) phenyl) -N 2-(2-methok
로피리딘 4ᅳ일 )페닐 )피리미딘 -2 ,4-디 아민의 Pyridine 4 euil) phenyl) pyrimidine-2, 4-di Amine
Figure imgf000028_0001
Figure imgf000028_0001
상기 단계 1에서 얻은 tert-부틸 4-(4-((5-클로로 -4-((2- (이소 프로필술포닐)페닐 )아미노)피리미딘 -2-일 )아미노 )-5-메톡시 -2ᅳ메틸페 닐) -5,6-디하이드로피리딘 -1(2H)_카복시레이트 27mg(0.04画 ol)올 MeOH 에 녹인 후， 4M HC1이 용해된 디옥산 3ml를 첨가한 후， 상온에서 1시 간 교반하였다. 반웅이 종료된 후， HC1을 제거하고 에테르로 디캔팅 (decanting)하여 목적 화합물 30mg을 99%의 수율로 얻었다.  Tert-butyl 4- (4-((5-chloro-4-((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -5-methoxy 2 ᅳ methylphenyl) -5,6-dihydropyridine-1 (2H) _carboxylate 27mg (0.04 画 ol) ol dissolved in MeOH, 3ml of 4M HC1 dissolved dioxane was added, and 1 at room temperature. Stir for time. After the reaction was completed, HC1 was removed and decanted with ether to obtain 30 mg of the target compound in 99% yield.
¾ 匪 R (MeOD, 300MHz ) δ 8.24(s, 1Η) , 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(sᅳ 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) .  ¾ 匪 R (MeOD, 300MHz) δ 8.24 (s, 1Η), 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 ᅳ 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).
<실시예 12> 5-클로로 -N2-(5-플루오로 -2-메록시 -4- (피페리딘 -4- 일 )페닐 )-N4-(2- (이소프로필술포닐 )페닐)피리미딘 -2, 4-디아민의 제조 단계 1 ： tert-부틸 4-(4-((5-클로로 -4-((2- (이소프로필술포닐 ) 페닐 )아미노 )피리미딘 -2-일 )아미노 )—2-플루오로 -5-메톡시페닐 )피페리 딘 -1- 제조 Example 12 5-Chloro-N2- (5-fluoro-2-methoxy-4- (piperidin-4-yl) phenyl) -N4- (2- (isopropylsulfonyl) phenyl) pyri Step 1: Preparation of midine-2, 4-diamine: tert-butyl 4- (4-((5-chloro-4-((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino ) —2-Fluoro-5-methoxyphenyl) piperidine-1- Preparation
Figure imgf000028_0002
Figure imgf000028_0002
2，5-디클로로 -N-(2ᅳ (이소프로필술포닐 )페닐)피리미딘 -4-아민 2,5-dichloro-N- (2 '(isopropylsulfonyl) phenyl) pyrimidin-4-amine
97mg(0.28mmol )올 THF 5ml에 녹인 후 tert-부틸 4— (4-아미노 -2-플루오 로ᅳ 5-메톡시페닐 )-5，6ᅳ디하이드로피리딘 -1(2H)-카복시레이트 97 mg (0.28 mmol) ol was dissolved in 5 ml of THF and then tert-butyl 4— (4-amino-2-fluoro 플루오 5-methoxyphenyl) -5, 6 ᅳ dihydropyridine-1 (2H) -carboxylate
90mg(0.28麵 ol )을 첨가하고， 잔트포스 17mg (0.03隱01)， Cs2C03 275mg(0.84隱 ol)을 순서대로 첨가한 후 질소를 충전하여 탈 가스 하 였다. Pd(0Ac)2 (4mg, 0.05mmol)를 첨가하고， 질소 충전 후 12C C에서 18시간 교반하였다. 반웅 종료 후， EA/H20로 추출한 후 유기층은 MgS04로 건조하여 필터 후 농축하였다. 칼럼 크로마토그래피 (Hx:EA 4:1)를 이용하여 목적 화합물 75.5mg을 42%의 수율로 얻었다. It was added to 90mg (0.28麵ol), and janteu force 17mg (0.03隱0 1), Cs 2 C0 3 275mg (0.84隱ol) to the filled with nitrogen and was degassed and then added in the order. Pd (0Ac) 2 (4 mg, 0.05 mmol) was added and stirred for 18 h at 12 C C after nitrogen charge. After completion of reaction, the mixture was extracted with EA / H 2 0 and the organic layer was dried over MgS0 4 , concentrated after filtration. Column chromatography (Hx: EA 4: 1) gave 75.5 mg of the target compound in 42% yield.
XH 匪 R (CDCls, 300MHz) δ 9.5(s,lH), 8.51(d, J=8.4Hz,lH) , 8.17(s,lH), 8.13(d, J=12.9Hz, 1H)， 7.94(dd, J=8.1Hz , 8.1Hz) , 7.74- X H 匪 R (CDCls, 300 MHz) δ 9.5 (s, lH), 8.51 (d, J = 8.4 Hz, lH), 8.17 (s, lH), 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) ; 7.69 (m, 1 H), 7.60 (s, 1 H), 6.65 (d, J = 6.6 Hz), 4.15-4.08 (m, 1H) ;
3.87(s,3H) , 3.24-3.19(m, 1H) , 2.86( t , J = 12.6Hz , 2H) : 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) . 단계 2 ： 5—클로로 -N2-(5-플루오로 -2-메톡시 -4- (피페리딘 -4-일 ) 페닐 )— -(2- (이소프로필술포닐)페닐 )피리미딘 -2 ,4-디아민의 제조 1.82 (d, J = 12.3 Hz, 2H), 1.49 (s, 9H), 1.32 (d, J = 6.9 Hz, 1H). Step 2: 5—Chloro-N 2-(5-fluoro-2-methoxy-4- (piperidin-4-yl) phenyl) —- (2- (isopropylsulfonyl) phenyl) pyrimidine-2 Preparation of 4-diamine
Figure imgf000029_0001
Figure imgf000029_0001
상기 단계 1에서 얻은 tert-부틸 4-(4ᅳ((5-클로로 -4-((2- (이소 프로필술포닐)페닐)아미노)피리미딘 -2-일 )아미노 )—2-플루오로 -5—메록 시페닐)피페리딘 -1-카복시레이트 75mg(0.048賺 ol)을 MeOH에 녹인 후， 4M HC1이 용해된 디옥산 3ml를 첨가한 후, 상온에서 1시간 교반하였다 반응이 종료된 후， HC1을 제거하고 에테르로 디캔팅 (decanting)하여 목적 화합물 65mg을 99%의 수율로 얻었다 .  Tert-butyl 4- (4 ′ ((5-chloro-4-((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino)-obtained in step 1- 2-fluoro- Dissolve 75 mg (0.048 賺 ol) of 5—Methoxyphenyl) piperidine-1-carboxylate in MeOH, add 3 ml of dioxane dissolved in 4M HC1, and stir at room temperature for 1 hour. , HC1 was removed and decanted with ether to give 65 mg of the target compound in 99% yield.
^ 匪 R (MeOD, 300丽 z) δ 8.34(s, 1Ή), 8.12-8.09(m , 1Η) ( ^ 匪 R (MeOD, 300 丽 z) δ 8.34 (s, 1Ή), 8.12-8.09 (m, 1Η) (
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) ,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 = 6.6 Hz, 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) . 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 = 6.6 Hz, 6H).
<실시예 13> 5-클로로 -N4-(2- (이소프로필술포닐 )페닐) -N2-(2-메 록시 -5-메틸 -4- (피페리딘 -4-일 )폐닐)피리미딘 -2,4-디아민의 제조 Example 13 5-Chloro-N 4-(2- (isopropylsulfonyl) phenyl) -N 2-(2-methoxy-5 -methyl-4- (piperidin-4-yl) phenyl) pyrimidine Preparation of -2,4-diamine
단계 1 ： tert-부틸 4-(4-((5—클로로 -4-((2- (이소프로필술포닐 ) 페닐)아미노)피리미딘 -2-일 )아미노 ) -5-메특시 -2-메틸페닐)피페리딘 -1- 카복시  Step 1: tert-Butyl 4- (4-((5—chloro-4-((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -5-mesophy-2- Methylphenyl) piperidine-1-carboxy
Figure imgf000029_0002
Figure imgf000029_0002
2,5-디클로로 -N-(2- (이소프로필술포닐 )페닐)피리미딘 -4ᅳ아민 86mg(0.25mmol)을 THF 3ml에 녹인 후 tert-부틸 4-(4-아미노 -5-메록시 -2-메틸페닐)피페리딘 -1-카복시레이트 80mg(0.25麵 ol )을 첨가하고， 잔 트포스 15mg (0.025隱 ol)ᅳ Cs2C03 244mg( 0.75圓 o 1 )을 순서대로 첨가한 후， 질소를 충전하여 탈 가스 하였다. Pd(0Ac)2 (3mg, 0.012mmol)를 첨가하고， 질소 층전 후 130°C에서 18시간 교반하였다. 반웅 종료 후 , EA/H20로 추출한 후 유기층은 MgS04로 건조하여 필터 후 농축하였다. 칼럼 크로마토그래피 (Hx:EA = 4:1)를 이용하여 목적 화합물 30mg을 20%의 수율로 얻었다. 86 mg (0.25 mmol) of 2,5-dichloro-N- (2- (isopropylsulfonyl) phenyl) pyrimidine-4 amine was dissolved in 3 ml of THF, followed by tert-butyl 4- (4-amino-5-methoxy -2-methylphenyl) piperidine-1-carboxylate 80 mg (0.25 Pa ol) was added to the mixture. Tphos 15mg (0.025 隱 ol) ᅳ Cs 2 C0 3 244mg (0.75 圓 o 1) was added sequentially, followed by nitrogen degassing. Pd (0Ac) 2 (3 mg, 0.012 mmol) was added, followed by stirring at 130 ° C. for 18 hours after nitrogen layer deposition. After completion of reaction, the mixture was extracted with EA / H 2 0 and the organic layer was dried over MgSO 4 , filtered and concentrated. Column chromatography (Hx: EA = 4: 1) gave 30 mg of the target compound in 20% yield.
¾ 丽 R (CDC13, 300MHz) δ 9.51(s, 1Η) , 8.59(d , J=8.4Hz , 1H) , 8.15(s, 1H) , 8.00(s,lH), 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) . 단계 2 ： 5-클로로 -N4— (2- (이소프로필술포닐 )페닐) -N2-(2-메특 시 -5- -4- (피페리딘 -4-일 )페닐 )피리미딘 -2， 4-디아민의 제조 ¾ δ R (CDC1 3 , 300MHz) δ 9.51 (s, 1Η), 8.59 (d, J = 8.4Hz, 1H), 8.15 (s, 1H), 8.00 (s, lH), 7.94 (dd, J = 12 , 8.1 Hz, 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 = 6.9 Hz, 6H) Step 2: 5-Chloro-N4— (2- (isopropylsulfonyl) phenyl) -N2- (2-methoxy-5--4- (piperidin-4-yl Preparation of Phenyl) Pyrimidine-2,4-Diamine
Figure imgf000030_0001
Figure imgf000030_0001
상기 단계 1에서 얻은 te -부틸 4-(4— ((5-클로로 -4-((2- (이소 프로필술포닐)페닐 )아미노)피리미딘 -2-일 )아미노 )-5-메톡시ᅳ2-메될페 닐)파페리딘 -1ᅳ카복시레이트 17mg(0.026隱 ol)을 MeOH에 녹인 후， 4M HC1이 용해된 디옥산 3ml를 첨가한 후， 상온에서 0.5시간 교반하였다. 반웅이 종료된 후， HC1을 제거하고 에테르로 디캔팅 (decanting)하여 목적 화합물 15mg을 99%의 수율로 얻었다 .  Te-butyl 4- (4— ((5-chloro-4-((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -5-methoxy ᅳ obtained in step 1 above. 17 mg (0.026 μl) of 2-merylphenyl) paperidine-1′carboxylate was dissolved in MeOH, 3 ml of dioxane dissolved in 4M HC1 was added, and the mixture was stirred at room temperature for 0.5 hour. After the reaction was completed, HC1 was removed and decanted with ether to obtain 15 mg of the target compound in 99% yield.
¾ 丽 R (MeOD, 300MHz) δ 8.27-8.23(m , 1Η) , S.OKd, 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) .  ¾ δ R (MeOD, 300MHz) δ 8.27-8.23 (m, 1Η), S.OKd, 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 = 5.4 Hz, 6H).
〈실시예ᅳ 14> 5^클—로로- 2-( —(1-에—틸-1,2,3，6-테트라하이드로피 리딘 -4-일 )-2-메록시페닐 )-N4-(2- (이소프로필술포닐)페닐 )피리미딘- 2,4-디아민의 제조 Example 14 14-Clot-Loro- 2-(-((1-E-Tyl-1,2,3,6-tetrahydropyridin-4-yl) -2-methoxyphenyl) -N4- Preparation of (2- (isopropylsulfonyl) phenyl) pyrimidine-2,4-diamine
Figure imgf000031_0001
Figure imgf000031_0001
상기 실시예 1에서 얻은 5-클로로ᅳ N4-(2- (이소프로필술포닐 )페 닐 )-N2-(2-메톡시 -4-( 1,2， 3， 6-테트라하이드로피리딘 -4-일 )페닐)피리미 딘 -2，4-디아민 50mg(0.097 mmol)을 EtOH 1ml에 넣어준 후 교반하면서 DIPEA(0.06ml，0.375誦 ol)을 첨가하였다. 아이오도에텐 5-chloro ᅳ N4- (2- (isopropylsulfonyl) phenyl) -N2- (2-methoxy-4- (1,2,3,6-tetrahydropyridine-4-) obtained in Example 1 above 50 mg (0.097 mmol) of 1) phenyl) pyrimidine-2,4-diamine was added to 1 ml of EtOH, followed by addition of DIPEA (0.06 ml, 0.375 μl) with stirring. Iodoethene
(0.016ml，0.15瞧 ol)를 첨가하여주고 상온에서 18시간 동안 교반하였다 반웅 종료 후， MC/H20로 추출 후 유기충은 MgS04로 건조한 뒤에 농축 하여 칼럼 크로마토그래피를 사용하여 목적 화합물 19.3mg을 얻었다. (0.016ml ， 0.15 瞧 ol) was added and stirred at room temperature for 18 hours. After completion of reaction, the extract was extracted with MC / H 2 0 and the organic worms were dried over MgS0 4 , concentrated and concentrated using column chromatography to give the desired compound 19.3. mg was obtained.
^-NMR. (300MHz, CDCls) , δ 9.55(s, 1Η) , 8.56(d , J=8.4Hz , 1H) , 8.25(d, J=9Hz, 1H) ,8.16(s, 1H) , 7.94(dd， J = l .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,lH), 5.29(s,lH), 3.92(s,3H) , 3.56(s,2H) , 3.26-3.21(m , 1H) , 3.15-3. ll(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) .  ^ -NMR. (300MHz, CDCls), δ 9.55 (s, 1Η), 8.56 (d, J = 8.4Hz, 1H), 8.25 (d, J = 9Hz, 1H), 8.16 (s, 1H), 7.94 (dd, J = l .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, lH) , 5.29 (s, lH), 3.92 (s, 3H), 3.56 (s, 2H), 3.26-3.21 (m, 1H), 3.15-3. ll (m, 2H), 2.99-2.92 (m, 2H), 2.83 (s, 2H), 1.42 (t, J = 7.2 Hz, 3H), 1.32 (d, J = 6.6 Hz, 6H).
<실시예 15> 5-클로로 -N2-(4— (1-에틸 -1,2,3,6—테트라하이드로피 리딘 -4-일 ) -2-메톡시페닐) -N4-(2- (이소프로필술포닐 )페닐)피리미딘- 2,4-디 Example 15 5-Chloro-N2- (4— (1-ethyl-1,2,3,6—tetrahydropyridin-4-yl) -2-methoxyphenyl) -N4- (2- ( Isopropylsulfonyl) phenyl) pyrimidine-2,4-di
Figure imgf000031_0002
Figure imgf000031_0002
상기 실시예 1에서 덛은 5二클호 ¾ -N4- ( 2- (이소프로필술포닐)페 닐 )— N2-(2-메특시 -4-(1，2， 3，6-테트라하이드로피리딘 -4-일 )페닐 )피리미 딘 -2 ,4-디아민 40mg을 DMF lmL에 녹여준 후 교반 하면서 0 (:03(651 ，0.2麵01)을 첨가하였다. 브로모에탄올 (0.01ml，0.12mmol) 을 첨가하여주고 상은에서 18시간 동안 교반하였다. 반웅 종료 후, MC/H20로 추출 후 유기층은 MgS04로 건조한 뒤 농축하여 칼럼 크로마 토그래피를 사용하여 목적 화합물 12mg을 얻었다. In Example 1, 덛 is 5 Ⅱ No. ¾ -N 4-(2- (isopropylsulfonyl) phenyl) —N 2-(2-methoxy-4- (1,2,3,6-tetrahydropyridine) 40 mg of 4-yl) phenyl) pyrimidine-2,4-diamine was dissolved in 1 mL of DMF and 0 (: 0 3 (651,0.2 01) was added with stirring. Bromoethanol (0.01 ml, 0.12 mmol) ) Was added, and the mixture was stirred for 18 hours at silver, and after completion of reaction, the organic layer was extracted with MC / H 2 0, dried over MgSO 4 , and concentrated to give 12 mg of the target compound by column chromatography.
^-NMR (300MHz, CDCI3) , δ 9.55( s , 1Η) , 8.58(d , J=7.8Hz , 1Η) , 8.25(d, J=9Hz, 1Η) , 8.17(s, 1Η) , 7.94-7.91(m, 1Η) , 7.68-7.63(m , 1Η) , 7.60(s, 1Η) , 6.93(s,2H) , 6.01(s, 1Η) , 3.92(s,3H) , 3.83-3.80(m , 2Η) , 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(dJ=6.9Hz , 6H) . ^ -NMR (300MHz, CDCI3), δ 9.55 (s, 1Η), 8.58 (d, J = 7.8Hz, 1Η), 8.25 (d, J = 9Hz, 1Η), 8.17 (s, 1Η), 7.94-7.91 (m, 1Η), 7.68-7.63 (m, 1Η), 7.60 (s, 1Η), 6.93 (s, 2H), 6.01 (s, 1Η), 3.92 (s, 3H), 3.83-3.80 (m, 2Η ), 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 (dJ = 6.9 Hz, 6H).
<실시예 16> l-(4-(4-((5-클로로 -4-((2- (이소프로필술포닐 )페 닐 )아미노)피리미딘 -2-일 )아미노 )-3-메톡시페닐) -5, 6-디하이드로피리 -1(2H)-일)에탄은의 제조 Example 16 l- (4- (4-((5-chloro-4-((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxy Preparation of Phenyl) -5, 6-dihydropyri-1 (2H) -yl) ethane silver
Figure imgf000032_0001
상기 실시예 1에서 얻은 5-클로로 -N4-(2- (이소프로필술포닐)페 닐 )-N2-(2-메톡시 -4-(1，2，3，6-테트라하이드로피리딘 -4-일 )페닐 )피리미 딘 -2，4-디아민 50mg(0.097 mmol)을 CH2C12 1ml에 넣어준 후 교반하며 Et3N(0.03ml ,0.23mmol)을 첨가하였다. 아세트산무수물
Figure imgf000032_0001
5-Chloro-N 4-(2- (isopropylsulfonyl) phenyl) -N 2-(2-methoxy-4- (1,2,3,6-tetrahydropyridine-4-) obtained in Example 1 above. 50 mg (0.097 mmol) of 1) phenyl) pyrimidine-2,4-diamine was added to 1 ml of CH 2 C1 2 , followed by stirring, and Et 3 N (0.03 ml, 0.23 mmol) was added thereto. Acetic anhydride
(0.02ml ,0.15mmol)을 첨가하여주고 상온에서 18시간 동안 교반하였다. 반웅 종료 후， MC/H20로 추출 후 유기층은 MgS04로 건조한 뒤 농축하 여 칼럼 크로마토그래피를 사용하여 목적 화합물 40mg을 얻었다. (0.02ml, 0.15mmol) was added thereto and stirred at room temperature for 18 hours. After completion of reaction, the mixture was extracted with MC / H 2 0, and the organic layer was dried over MgS0 4 and concentrated to obtain 40 mg of the target compound by column chromatography.
XH-NMR (300MHz, CDCls) , δ 9.57(s, 1Η) , 8.58(d , J=8.1Hz , 1H) , XH-NMR (300MHz, CDCls), δ 9.57 (s, 1Η), 8.58 (d, J = 8.1Hz, 1H),
8.23(dd, J-2.4,0.9Hz, 1H) ,8.16(s, 1H) , 7.94(dd , J=l .5 , 1.5Hz , 1H) , 7.67- 7.62(m,2H) ,6.92-6.87(m,2H) ,6.03(d, 16.5Hz, 1H)， 8.23 (dd, J-2.4,0.9Hz, 1H), 8.16 (s, 1H), 7.94 (dd, J = l .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) , 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) . 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 = 6.9 Hz, 6H).
<실시예 17> 4-(4-((5-클로로 -4-((2- (이소프로필술포닐)페닐)아 미노)피리미딘 -2-일 )아미노 )-3-메톡시페닐) -5,6-디하이드로피리딘- 1(2H)- Example 17 4- (4-((5-chloro-4-((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) 5,6-dihydropyridine-1 (2H)-
Figure imgf000032_0002
Figure imgf000032_0002
상기 실시예 1에서 얻은 5-클로로 -N4-(2- (이소프로필술포닐)페 닐 ) -N2-(2-메록시 -4-(1， 2， 3， 6-테트라하이드로피리딘 -4-일 )페닐)피리미 딘 -2，4-디아민 50mg(0.097 mmol)을 CH2C12 1ml에 녹여준 후 교반하며 Et3N 0.2ml를 첨가하였다. 글리콜산 (0.01ml ,0.15隱 ol), EDCI(24mg,0.15匪 ol), DMAP(20mg,0.15隱 ol )을 순서대로 첨가하여주고 상은에서 18시간 동안 교반하였다. 반웅 종료 후， MC/H20로 추출한 후 유기층은 MgS04로 건조한 뒤 농축하여 칼럼 크로마토그래피를 사용하 여 목적 화합물 28.4mg을 얻었다. 5-Chloro-N 4-(2- (isopropylsulfonyl) phenyl) -N 2-(2-methoxy-4- (1, 2, 3, 6-tetrahydropyridine-4-) obtained in Example 1 above. Il) phenyl) pyrimidine-2,4-diamine 50 mg (0.097 mmol) was dissolved in 1 ml of CH 2 C1 2 and stirred, and 0.2 ml of Et 3 N was added thereto. Glycolic acid (0.01ml, 0.15 隱 ol), EDCI (24 mg, 0.15 μl) and DMAP (20 mg, 0.15 μl) were added in this order and stirred for 18 hours at phase silver. After completion of reaction, the mixture was extracted with MC / H 2 0 and the organic layer was dried over MgS0 4 and concentrated to give 28.4 mg of the target compound by column chromatography.
^-NMR (300 MHz, CDC13) , δ 9.57(s,lH), 8.58(d， J=8.7Ηζ， 1Η) , 8.27(d,J=8.1Hz,lH),8.17(s,lH), 7.94(d , J = 7.2Hz , 1H) , 7.68-^ -NMR (300 MHz, CDC1 3 ), δ 9.57 (s, lH), 8.58 (d, J = 8.7Ηζ, 1Η), 8.27 (d, J = 8.1Hz, lH), 8.17 (s, lH), 7.94 (d, J = 7.2 Hz, 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,3H) , 3.68(s, 1H) , 3.52-3. 9(m , 1H) , 3.26- 3.19(m, 1H) , 2.60(s,2H) , 1.32(d , J=6.9Hz , 6H) . , 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, 3H), 3.68 (s, 1H) , 3.52-3. 9 (m, 1H), 3.26- 3.19 (m, 1H), 2.60 (s, 2H), 1.32 (d, J = 6.9Hz, 6H). ,
<실시예 18> 5-클로로-쀄4-(1-메틸-1,2，3,6-테트라하이드로피 리딘 -4-일 ) -2-메톡시페닐) -N4-(2- (이소프로필술포닐 )페닐)피리미딘- 2,4- Example 18 5-Chloro-X4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) -2-methoxyphenyl) -N4- (2- (isopropyl Sulfonyl) phenyl) pyrimidine-2,4-
Figure imgf000033_0001
Figure imgf000033_0001
상기 실시예 1에서 얻은 5ᅳ클로로 -N4-(2- (이소프로필술포닐 )페 닐 )-N2-(2-메록시 -4-(1， 2， 3ᅳ 6-테트라하이드로피리딘 -4-일 )페닐)피리미 딘 -2，4-디아민 50mg(0.097 mmol)을 EtOH 1ml에 녹여준 후 교반하면서 DIPEA(0.08ml，0.45隱 ol)을 첨가하여준다. 메틸아이오다이드 5 ′ Chloro-N 4-(2- (isopropylsulfonyl) phenyl) -N 2-(2-methoxy-4- (1, 2, 3 '6-tetrahydropyridine-4-) obtained in Example 1 50 g (0.097 mmol) of 1) phenyl) pyrimidine-2,4-diamine is dissolved in 1 ml of EtOH, and then DIPEA (0.08 ml, 0.45 μl ol) is added with stirring. Methyl iodide
(0.01ml ,0.15麵 ol) 첨가하여주고 상온에서 18시간 동안 교반하였다. 반웅 종료 후 MC/H20로 추출한 후 유기층은 MgS04로 건조한 뒤에 농 축하여 칼럼 크로마토그래피를 사용하여 목적 화합물 6.1mg을 얻었다. (0.01ml, 0.15 麵 ol) was added thereto, and the resultant was stirred at room temperature for 18 hours. After completion of reaction, the mixture was extracted with MC / H 2 0 and the organic layer was dried with MgS0 4 and concentrated to obtain 6.1 mg of the target compound by column chromatography.
^-NMR (300 MHz, CDC13) , δ 9.56(s, 1Η) , 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) . 하기 표 1에 실시예 1-18에서 제조한 화합물의 화학구조식을 정 리하여 나타내었다.  ^ -NMR (300 MHz, CDC13), δ 9.56 (s, 1Η), 8.55-8.53 (m, 1H), 8.29-8.26 (m, 1H), 8.17 (s, 1H), 7.94 (d, J-8.1 Hz, 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 = 6.9 Hz, 6H). Table 1 shows the chemical structures of the compounds prepared in Examples 1-18.
Figure imgf000033_0002
Figure imgf000033_0002
Figure imgf000034_0001
Figure imgf000034_0001
L£LOOO/ilOZW^IlDd ^IOOCI/SIOZ: O
Figure imgf000035_0001
L £ LOOO / ilOZW ^ IlDd ^ IOOCI / SIOZ: O
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000036_0001
<실험예 1> 역형성 림프종 키나아제 (ALK) 억제활성 실험 Experimental Example 1 Experiment of Anaplastic Lymphoma Kinase (ALK) Inhibitory Activity
본 발명에 따른 화학식 1로 표시되는 피리미딘 -2，4-디아민 유도 체의 림프종 키나아제 (ALK)의 증식 억제 활성을 효소단계에서 측정하 기 위하여 하기와 같은 실험을 수행하였다. 역형성 림프종 키나아제 (ALK)에 대한 저해활성을 측정하기 위하 여 그레이너 96 웰 라운드 형 바닥 플레이트에 실시예 1 내지 18에서 제조된 화합물 (2 )을 가하고, 역형성 림프종 키나아제 (ALK) 효소 (1 와 바이오틴이 붙은 펩타이드 기질 (2 을 15분 동안 흔합하여 배 양하였다. 여기에 ΑΤΡ 용액 (5 ^)을 가하여 상온에서 30분 동안 키나 아제 반웅을 수행하였다. 에틸렌다이아민테트라아세트산 용액에 녹은 스트랩트아비딘이 붙은 엑스엘 (XL 665)(5 와 유로피움 (Eu3+)이 붙 은 항-포스포타이로신 항체 (5 를 반웅액에 첨가하여 반웅을 중지시 키고 1시간 동안 배양한 후， 시간분해형광도 (Homogeneous Time- resolved fluorescence, HTRF Cisbio)를 이용하여 분석하였다. 왈락 인비전 2103(Wallac Envision 2103) 기기로 615/665 nm의 파장 범위에 서 판독하였다. 상기 실험을 수행한 시험화합물의 IC50은 프리즘 (버전 5.01, 그래프패드) 소프트웨어를 이용하여 구현하였다. In order to measure the proliferation inhibitory activity of the lymphoma kinase (ALK) of the pyrimidine-2,4-diamine derivative represented by Formula 1 according to the present invention, the following experiment was performed. To determine the inhibitory activity against anaplastic lymphoma kinase (ALK), a compound (2) prepared in Examples 1 to 18 was added to a Glenner 96 well round bottom plate, and anaplastic lymphoma kinase (ALK) enzyme (1). And biotinylated peptide substrate (2 were mixed and incubated for 15 minutes. ΑΤΡ solution (5 ^) was added thereto, followed by kinase reaction for 30 minutes at room temperature. Straps dissolved in ethylenediaminetetraacetic acid solution Anti-phosphotyrosine antibody with Xvide (XL 665) with avidin (5 and Europium (Eu 3+ ) (5) was added to the reaction solution to stop the reaction and incubated for 1 hour Fluorescence (Homogeneous Time-resolved fluorescence, HTRF Cisbio) was analyzed using a Wallac Envision 2103 instrument at a wavelength range of 615/665 nm. The IC 50 of water was implemented using Prism (version 5.01, GraphPad) software.
역형성 림프종 키나아제 (ALK) 효소활성 및 역형성 림프종 키나 아제 (ALK) 효소를 포함하고 있는 비소세포폐암세포인 L1196M의 세포활 성을 50%로 감소시키는 상기 화합물의 50을 하기 표 2에 나타내었다. Anaplastic lymphoma kinase (ALK) Below is the enzymatic activity and the anaplastic lymphoma kinase (ALK) 50 of the compound for reducing the non-small cell lung cancer cells, L1196M cell bow of containing enzymatic to 50% Table 2 .
【표 2】 Table 2
실시예 ALK wt . ALK L1196M  Example ALK wt. ALK L1196M
IC50 (uM) IC50 (uM)  IC50 (uM) IC50 (uM)
대조군 1 0.01 0.22  Control 1 0.01 0.22
( cr i zot i ni b)  (cr i zot i ni b)
대조군 2 0.001 一 0.009  Control 2 0.001 一 0.009
(LDK-378)_7l준  (LDK-378) _7l
1 <0.001 <0.001  1 <0.001 <0.001
2 〈0.001 <0.001  2 <0.001 <0.001
3 <0.001 <0.001  3 <0.001 <0.001
4 <0.001 <0.001  4 <0.001 <0.001
5 <0.001 <0.001  5 <0.001 <0.001
6 <0.001 <0.001  6 <0.001 <0.001
7 >0.001 >0.001 7>0.001> 0.001
체였 Sieve
의다 8 <0.001 <0.001  Of 8 <0.001 <0.001
9 >0.001 >0.001  9> 0.001> 0.001
10 <0.001 <0.001  10 <0.001 <0.001
11 <0.0.01 <0.001  11 <0.0.01 <0.001
12 <0.001 <0.001  12 <0.001 <0.001
13 <0.001 <0.001  13 <0.001 <0.001
14 <0.001 <0.001  14 <0.001 <0.001
15 <0.001 <0.001  15 <0.001 <0.001
16 O.001 <0.001  16 O.001 <0.001
17 <0.001 <0.001  17 <0.001 <0.001
18 〈0.001 <0.001 상기 표 2에 나타낸 바와 같이， 본 발명에 따른 실시예의 화합 물들은 대부분이 대조군 1 및 2의 화합물에 비하여 활성이 우수한 것 으로 나타났다.  18 <0.001 <0.001 As shown in Table 2, the compounds of the examples according to the present invention were found to be most active compared to the compounds of the control 1 and 2.
구체적으로， 상기 실시예 1-18의 화합물은 모두 대조군 1인 크 리조티닙 (crizotinib)보다 활성이 우수한 것으로 나타났으며， 또한 상 기 실시예 1-18중， 실시예 7 및 9를 제외한 나머지 화합물들은 대조군 2인 LDK-378보다 활성이 우수한 것으로 나타났다. 본 실험결과로부터 본 발명에 따른 피리미딘ᅳ2，4-디아민 유도체 들이 낮은 농도에서도 효소단계에서의 역형성 림프종 키나아제 (ALK)의 활성 억제 효과가 있으며 , 특히 종래 역형성 림프종 키나아제 (ALK) 활 성을 억제함으로써 , 비소세포폐암의 치료제로 이용되고 있는 크리조티 닙 (양성대조군)보다 우수한 저해 활성을 가진다는 것올 알 수 있다. 따라서， 본 발명에 따른 피리미딘 -2, 4-디아민 유도체는 역형성 림프종 키나아제 (ALK)활성을 억제하는 효과가 우수하므로 비소세포폐 암， 신경모세포종 염증성 골수섬유모세포종양， 종횡문근육종， 근섬유 모세포종， 유방암, 위암， 폐암 흑색종 등의 암의 예방 또는 치료용 조성물뿐만 아니라， 역형성 림프종 키나아제 (ALK) 활성 억제제로 유용 하게 사용될 수 있다.  Specifically, all of the compounds of Examples 1-18 were found to be more active than Crzotinib, which is a control group 1, and the other compounds except Examples 7 and 9 in Examples 1-18. Were better than the control 2 LDK-378. From these results, pyrimidine 미 2,4-diamine derivatives according to the present invention have the effect of inhibiting the activity of anaplastic lymphoma kinase (ALK) at the enzyme stage even at low concentrations, especially the conventional anaplastic lymphoma kinase (ALK) activity. It can be seen that it has superior inhibitory activity than crizotinib (positive control group) used as a therapeutic agent for non-small cell lung cancer. Thus, the pyrimidine-2,4-diamine derivatives according to the present invention have excellent effects of inhibiting anaplastic lymphoma kinase (ALK) activity and thus, non-small cell lung cancer, neuroblastoma inflammatory myeloid fibroblastic tumor, rhabdomyosarcoma, myofibroblastoma In addition to the composition for the prevention or treatment of cancer, such as breast cancer, stomach cancer, lung cancer melanoma, it can be usefully used as an inhibitor of anaplastic lymphoma kinase (ALK) activity.
<실험예 2> 암세포 증식억제 실험 Experimental Example 2 Cancer Cell Proliferation Inhibition Experiment
본 발명에 따른 화학식 1로 표시되는 피리미딘 -2，4-디아민 유도 암세포 증식 억제능을 알아보기 위해 하기와 같은 실험을 수행하  In order to determine the ability to inhibit the growth of pyrimidine-2,4-diamine-induced cancer cells represented by the formula (1) according to the present invention
<2-1> 실험 재료 <2-1> experimental material
시약  reagent
세포배양액인 RPMI 1640 배지， FBSCfetal bovine serum) 및 크 립신은 Gibco사 (Grand Island, NY)로부터 구입하였으며， 탄산수소나트 륨， 암포테리신 B 및 겐타마이신은 시그마케미컬 제품을 사용하였다. 또한， 세포독성 측정 실험에 사용한 시약인 SRBCsulforhod아민) B, 트리스마 염기 (trisma base) , 트리클로로아세트산 (TCA) 등의 시약 은 시그마케미컬사로부터 구입하였다. MTS assay를 위해서는 Cel ITi ter 96R Aqueous Non-Radioact i ve Cell Proliferation Assay 제 품을 프로메가 (Promega)사로부터 구입하였다. Cell culture medium RPMI 1640 medium, FBSCfetal bovine serum and lysine were purchased from Gibco (Grand Island, NY). Cerium, amphotericin B and gentamicin used sig-chemical products. In addition, reagents such as SRBCsulforhodamine B, trisma base, and trichloroacetic acid (TCA), which are reagents used in cytotoxicity measurement experiments, were purchased from Sigma Chemical. For the MTS assay, Cel ITi ter 96 R Aqueous Non-Radioact IV Cell Proliferation Assay was purchased from Promega.
또한, 세포배양을 위해 사용한 T-25 배양용기， 96-웰 (well) 폴 레이트 및 기타 세포배양에 사용한 일회용 초자류는 팔콘사 (Lincoln Park, NJ) 제품을 사용하였다. 사용가기  In addition, T-25 culture vessels used for cell culture, 96-well folate and other disposable supernatants used for cell culture were manufactured by Lincoln Park (NJ). Go to use
세포독성 측정을 위한 엘라아자 리더기 (microplate reader)는 Molecular Devi ces사 (Sunnyvale， CA)5 E—max나 Spectr aMax250 기종을 사용하였다.  As a microplate reader for measuring cytotoxicity, Molecular Devices (Sunnyvale, CA) 5 E—max or Spectr aMax250 was used.
<2-2> 실험방법 <2-2> Experimental method
단계 1 ： 세포 배양  Step 1: Cell Culture
최종 디메틸설폭사이드 농도는 0.5% 이하가 되도록 하였다 .  The final dimethyl sulfoxide concentration was set at 0.5% or less.
실험에 사용한 암세포주는 모두 인체기원 암세포주들로서， 구체 적으로는 바소세포폐암 세포주인 H2228, H3122를 사용하였다.  The cancer cell lines used in the experiment were all human-derived cancer cell lines. Specifically, H2228 and H3122, which are cell-cell lung cancer cells, were used.
배양액으로는 10% FBS(fetal bovine serum)가 첨가된 RPMI 1640 배지를 사용하여 37°C 및 5% 이산화탄소 인큐베이터에서 배양하였고, 3 내지 4일에 한 번씩 계대 유지하였다. 단계 2 ： 화합물 처리에 따른 증식억제 활성 평가 Cultures were incubated in 37 ° C and 5% carbon dioxide incubator using RPMI 1640 medium to which 10% FBS (fetal bovine serum) was added, and maintained once every 3 to 4 days. Step 2: Evaluation of Growth Inhibitory Activity Following Compound Treatment
96 웰 (well) 평평한 바닥 마이크로플레이트 (f l,at-bottom microplate)의 각 웰 (well)에 1 x 104 cel ls를 분주하고, 세포가 바닥 면에 부착하도록 24시간 동안 배양한 후 , 배양액을 제거하였다. 여기 에 실시예 1 내지 18의 화합물이 각각 희석된 배양액을 가하고 72시간 동안 배양하였다. 상기 화합물과의 배양이 종료된 후， 세포독성의 측 정은 단백질 염색 시약인 SRB를 이용하여 측정하거나 MT.S assay법올 이용하여 측정하였다. 실시예 1 내지 18의 화합물과의 배양이 종료된 후 , 배양액을 제거하고 각 웰 el 1 )에 차가운 TCA 용액을 처리하고 4°C에서 1시간 동안 방치하여 세포블을 고정시켰다. 상기 TCA 용액을 제거하고 실온에서 건조시킨 후， 1% 아세트산 용액에 0.4% SRB를 녹인 염색용액을 가하여 실온에서 30분 동안 방치하여 세포를 염색하였다. 세포와 결합하지 않은 여분의 SRB를 1% 아세트산 용액으로 세척하여 제거하고 염색된 세포들에 pH 10.3 내지 10.5의 10mM 트리스 완충용 액 (Trisma base; unbuffered)을 가하여 SRB를 용출시켰다. 각 웰 (well)의 흡광도는 엘라이자 리더기 (microplate reader)를 이용하여 520 mM의 파장 범위에서 측정하였다. Dispense 1 x 10 4 cel ls into each well of a 96 well flat bottom microplate (fl, at-bottom microplate), incubate for 24 hours to allow cells to adhere to the bottom surface, and then culture Removed. To this was added a culture solution in which the compounds of Examples 1 to 18 were diluted, and incubated for 72 hours. After incubation with the compound was terminated, cytotoxicity was measured using SRB, a protein staining reagent, or MT.S assay. After incubation with the compounds of Examples 1 to 18, the culture solution was removed and treated with cold TCA solution in each well el 1) and left at 4 ° C. for 1 hour to fix the cellble. After removing the TCA solution and drying at room temperature, a dye solution in which 0.4% SRB was dissolved in 1% acetic acid solution was added and left at room temperature for 30 minutes to stain cells. Extra SRB not bound to the cells was removed by washing with 1% acetic acid solution and SRB was eluted by adding 10 mM Tris buffer (unbuffered) at pH 10.3 to 10.5 to the stained cells. The absorbance of each well was measured in the wavelength range of 520 mM using a microplate reader.
약물을 가하지 않은 웰 (wellKC)과 약물을 가한 각 웰 (well)(T) 및 약물을 처음 가할 때의 웰 (wellMTz)의 0D값으로부터， Tz= j 경우에는 [(T-Tz)/(C-Tz)]100의 수식에 의해 ; 또는 From 0D values of wellKC without drug, well with each drug (T) with drug, and wellMTz when drug was first applied In the case of Tz = j, by the formula [(T-Tz) / (C-Tz)] 100; or
Tz>T^] 경우에는 [(Τ-Τζ)/(Τζ)]100 의 수식에 의해 약물의 세 포독성을 계산하였다.  In the case of Tz> T ^], the cell toxicity was calculated by the formula [(Τ-Τζ) / (Τζ)] 100.
MTS assay 법을 이용한 암세포 증식억제 측정은 다음과 같이 실 험하였다. 구체적으로 , 실시예 1 내지 실시예 18에서 제조된 화합물과 의 배양이 종료된 후， Promega사의 CeMTiter 96R AQueous Non- Radioactive Cell Proliferation Assay 제품을 구성하고 있는 PMS 용 액과 MTS 용액을 섞은 후 well당 20 L를 넣어주었다. 4시간 동안 배양 기에 놓아둔 후 꺼내어 상온에서 10분간 방치하였다. Molecular Device사의 Spect r aMax250 기종을 이용하여 490 nM에서꾀 흡광도를 측 정한 후 증식억제 효과인 GI50(Growth Inhibition 50%)값을 계산하였 고， 그 결과를 하기 표 3에 나타내었다. Cancer cell proliferation inhibition was measured using the MTS assay as follows. Specifically, after the incubation with the compound prepared in Examples 1 to 18, the PMS solution and MTS solution constituting the Promega CeMTiter 96 R AQueous Non- Radioactive Cell Proliferation Assay 20 L was added. After leaving for 4 hours in the incubator was taken out and left for 10 minutes at room temperature. After measuring the absorbance at 490 nM using Molecular Device's Spect r aMax250 model, GI 50 (Growth Inhibition 50%), a growth inhibitory effect, was calculated, and the results are shown in Table 3 below.
Figure imgf000039_0001
상기 표 3에 나타난 바와 같이， 본 발명에 따른 실시예 화합물 들은 비소세포폐암 세포주인 H2228 및 H3122의 역형성 림프종 키나아 제 (ALK)를 억제함으로써 그 증식활성을 감소시키는 것으로 나타났다 .
Figure imgf000039_0001
As shown in Table 3, the example compounds according to the present invention were shown to reduce the proliferative activity by inhibiting anaplastic lymphoma kinase (ALK) of the non-small cell lung cancer cell lines H2228 and H3122.
상이였 It was different
본트다기실험결과로부터 본 발명의 실시예 화합물들 대부분은 현재 비소세 포폐암 치료제로 사용되고 있는 대조군 1 및 2의 화합물보다 우수한 증식억제효과가 있음을 알 수 있었다. 따라서， 본 발명에 따른 피리미딘 -2,4-디아민 유도체는 역형성 림프종 키나아제 (ALK)활성을 억제하는 효과가 우수하므로 비소세포폐 암， 신경모세포종， 염증성 골수섬유모세포종양， 종횡문근육종， 근섬유 모세포종， 유방암， 위암， 폐암， 흑색종 등의 암의 예방 또는 치료용 조성물뿐만 아니라， 역형성 림프종 키나아제 (ALK) 활성 억제제로 유용 하게 사용될 수 있다. The results of the Bont manipulative experiment showed that most of the compound of the present invention had a proliferative inhibitory effect than the compounds of the controls 1 and 2, which are currently used as non-small cell lung cancer treatment agents. Therefore, the pyrimidine-2,4-diamine derivatives according to the present invention have excellent effects of inhibiting anaplastic lymphoma kinase (ALK) activity, so that non-small cell lung cancer, neuroblastoma, inflammatory myeloid fibroblast tumor, rhabdomyosarcoma, and myofiber It can be usefully used as an inhibitor of anaplastic lymphoma kinase (ALK) activity as well as a composition for preventing or treating cancers such as blastoma, breast cancer, gastric cancer, lung cancer and melanoma.
<실험예 3> EML4-ALK로 형질 감염된 BaF3 세포의 세포독성 평가 본 발명에 따른 화학식 1로 표시되는 피리미딘 -2,4-디아민 유도 체의 BaF3 EML4-ALK L1196M 및 BaF3 EML4-ALK WT 세포에 대한 세포독 성을 측정하기 위하여 하기와 같은 실험을 수행하였다ᅵ. 구체적으로， BaF3세포에 EML4-ALK wt( i ld-type) 유전자를 렌티 바이러스 (lent i virus)로 감염시켜 EML4-ALK wt가 안정적으로 발현하는 BaF3 EML4-ALK wt 세포주를 준비하였다. 또한， BaF3세포에 EML4-ALK L1196M 유전자를 렌티바이러스 (lentivirus)로 감염시켜 EML4-AL L1196M이 안정적으로 발현하는 BaF3 EML4-AL L1196M 세포주를 준비하 . 상기 두 개의 세포주의 세포 개수를 잘 측정한 다음 96 웰 플레 (well plate)의 각 웰 (well)에 4,000개씩 90/ 의 부피로 넣은 후， 실시예에서 제조한 화합물의 농도를 lOuM, 2uM, 0.4uM, 0.08uM, 0.016uM, 0.0032uM, 0.00064uM 및 OuM로 각 웰 (well)에 첨가하고， 3일 동안 37°C의 세포배양기 안에 넣었다. 3일 후, 각 웰 (well)에 WST-1 용액을 10 씩 첨가하고， 각 웰 (well)의 용액의 색깔이 변하면 ELISA (제조사 ： Molecular Devices, 모델명 ： EMax Endpoint EL ISA Microplate reader)를 이용하여 450nm에서 측정하였다. 측정된 값을 이용해서 세포의 양을 계산함으로써 각 화합물의 세포독성에서의 IC50 를 계산하였고， 그 결과를 하기 표 4에 나타내았다 . Experimental Example 3 Cytotoxicity Evaluation of BaF3 Cells Transfected with EML4-ALK BaF3 EML4-ALK L1196M and BaF3 EML4-ALK WT Cells of the Pyrimidine-2,4-Diamine Inducer of Formula 1 According to the Present Invention In order to measure cytotoxicity, the following experiment was carried out . Specifically, BaF3 EML4-ALK wt cell line stably expressing EML4-ALK wt was prepared by infecting BaF3 cells with EML4-ALK wt (i ld-type) gene with lent i virus. In addition, BaF3 cells were infected with EML4-ALK L1196M gene with lentivirus to prepare BaF3 EML4-AL L1196M cell line stably expressing EML4-AL L1196M. After measuring the number of cells of the two cell lines well, each well of a 96 well plate (4,000) in a volume of 90 / 4,000 each, the concentration of the compound prepared in the Example lOuM, 2uM, 0.4 uM, 0.08 uM, 0.016 uM, 0.0032 uM, 0.00064 uM and OuM were added to each well and placed in a cell incubator at 37 ° C. for 3 days. After 3 days, 10 wells of WST-1 solution were added to each well, and the color of the solution of each well was changed using ELISA (manufacturer: Molecular Devices, model name: EMax Endpoint EL ISA Microplate reader). Measured at 450 nm. IC 50 in the cytotoxicity of each compound was calculated by calculating the amount of cells using the measured values, and the results are shown in Table 4 below.
【표 4】 Table 4
실시예 BaF3 BaF3  Example BaF3 BaF3
EML4-ALK EML4-ALK  EML4-ALK EML4-ALK
L1196M (uM) WT (uM)  L1196M (uM) WT (uM)
대조군 1 1.1 0.06  Control 1 1.1 0.06
(cr i zot inib)  (cr i zot inib)
대조군 2 0.041 0.019  Control 2 0.041 0.019
(LDK-378)ᅳ기준  (LDK-378) ᅳ Standard
1 <0.01 <0.01  1 <0.01 <0.01
2 >0.01 <0.01 3 >0 01 <0 01 2> 0.01 <0.01 3> 0 01 <0 01
4 <0 01 <0 01  4 <0 01 <0 01
5 <0 01 <0 01  5 <0 01 <0 01
6 >0 01 <0 01  6> 0 01 <0 01
7 >0 01 >0 01  7> 0 01> 0 01
8 <0 01 <0 01  8 <0 01 <0 01
9 >0 01 >0 01  9> 0 01> 0 01
10 <0 01 <0 01  10 <0 01 <0 01
11 <0 01 <0 01  11 <0 01 <0 01
12 <0 01 <0 01  12 <0 01 <0 01
13 <0 01 <0 01  13 <0 01 <0 01
14 <0 01 <0 01  14 <0 01 <0 01
15 <0 01 <0 01  15 <0 01 <0 01
16 0 01 <0 01  16 0 01 <0 01
17 <0 01 <0 01  17 <0 01 <0 01
18 <0 01 <0 01 상기 표 4에 나타난 바와 같이， 본 발명에 따른 실시예 화합물 들은 대부분이 BaF3 EML4-ALK WT(w i l d-type ) 세포 및 크리조티닙 ( cr i zot i ni b )에 내성을 갖는 BaF3 EML4-AL L1196M 세포에서 세포독성 I C50값이 대조군 1 및 2에 비하여 낮은 것으로 나타났다. 본 실험결과 로부터 본 발명의 실시예 화합물들 대부분은 현재 비소세포폐암 치료 제로 사용되고 있는 대조군 1 및 2의 화합물보다 우수한 ALK 억제활성 이 있음을 알 수 있었다. 따라서， 본 발명에 따른 파리미딘 -2， 4-디아민 유도체는 역형성 림프종 키나아제 (ALK) 활성을 억제하는 효과가 뛰어나므로 , 비소세포 폐암， 신경모세포종， 염증성 골수섬유모세포종양， 종횡문근육종， 근섬 유모세포종, 유방암， 위암, 폐암， 흑색종 등의 암의 예방 또는 치료용 조성물뿐만 아니라， 역형성 림프종 키나아제 (ALK)의 저해제로 유용하 게 사용될 수 있다. 참조로 하기 표 5에 , 실험예 1-3(표 2-4)에서 얻은 실험결과를 종합하여 나타내었다. 【표 5】 18 <0 01 <0 01 As shown in Table 4, the example compounds according to the present invention are mostly in BaF3 EML4-ALK WT (wil d-type) cells and crizotinib (cr i zot i ni b) Resistant BaF3 EML4-AL L1196M cells showed low cytotoxic IC 50 values compared to controls 1 and 2. From the experimental results, it was found that most of the compound of the present invention had superior ALK inhibitory activity than the compounds of the control groups 1 and 2, which are currently used as non-small cell lung cancer treatment agents. Therefore, the parimidine-2,4-diamine derivative according to the present invention has an excellent effect of inhibiting anaplastic lymphoma kinase (ALK) activity, thus, non-small cell lung cancer, neuroblastoma, inflammatory myeloid fibroblastic tumor, rhabdomyosarcoma, and muscle islet. It can be useful as an inhibitor of anaplastic lymphoma kinase (ALK) as well as a composition for the prevention or treatment of cancers such as blastoma, breast cancer, gastric cancer, lung cancer and melanoma. In Table 5 below, the experimental results obtained in Experimental Examples 1-3 (Table 2-4) are collectively shown. Table 5
Figure imgf000041_0001
Figure imgf000041_0001
본디체명 Bondi body name
(cr i zot ini  (cr i zot ini
b)  b)
대조유탈군 2 0.001 0.009 0.025 0.023 0.041 0.019 크당  Control oil group 2 0.001 0.009 0.025 0.023 0.041 0.019
(LDK-378)_  (LDK-378) _
기준  standard
1 <0.001 <0.001 <0.01 <0.01 <0.01 <0.01 1 <0.001 <0.001 <0.01 <0.01 <0.01 <0.01
2 <0.001 <0.001 <0.01 <0.01 >0.01 <0.012 <0.001 <0.001 <0.01 <0.01> 0.01 <0.01
3 <0.001 <0.001 <0.01 <0.01 >0.01 <0.013 <0.001 <0.001 <0.01 <0.01> 0.01 <0.01
4 <0.001 <0.001 <0.01 >0.01 <0.01 <0.014 <0.001 <0.001 <0.01> 0.01 <0.01 <0.01
5 <0.001 <0.001 <0.01 <0.01 <0.015 <0.001 <0.001 <0.01 <0.01 <0.01
6 <0.001 <0.001 <0.01 <0.01 >0.01 <0.016 <0.001 <0.001 <0.01 <0.01> 0.01 <0.01
7 >0.001 >0.001 >0.01 >0.01 >0.01 >0.017> 0.001> 0.001> 0.01> 0.01> 0.01> 0.01
8 <0.001 <0.001 <0.01 <0.01 . <0.018 <0.001 <0.001 <0.01 <0.01. <0.01
9 >0.001 >0.001 >0.01 >0.01 >0.01 >0.019> 0.001> 0.001> 0.01> 0.01> 0.01> 0.01
10 <0.001 <0.001 <0.01 <0.01 <0.01 10 <0.001 <0.001 <0.01 <0.01 <0.01
11 〈0.001 <0.001 >0.01 <0.01 <0.01 11 <0.001 <0.001> 0.01 <0.01 <0.01
12 <0.001 <0.001 >0.01 < V0.01 <0.01 <0.01 v o 12 <0.001 <0.001> 0.01 <V0.01 <0.01 <0.01 v o
13 <0.001 <0.001 <0.01 o o  13 <0.001 <0.001 <0.01 o o
o <0.01 <0.01 o o  o <0.01 <0.01 o o
14 <0.001 <0.001 >0.01 <0.01 <0.01 <0.01 14 <0.001 <0.001> 0.01 <0.01 <0.01 <0.01
15 <0.001 <0.001 >0.01 <0.01 <0.01 <0.0115 <0.001 <0.001> 0.01 <0.01 <0.01 <0.01
16 <0.001 <0.001 <0.01 <0.01 <0.01 <0.01 o 16 <0.001 <0.001 <0.01 <0.01 <0.01 <0.01 o
17 <0.001 <0.001 <0.01 <0.01 <0.01 <0.01 o  17 <0.001 <0.001 <0.01 <0.01 <0.01 <0.01 o
18 <0.001 <0.001 <0.01 <0.01 <0.01 <0.01 한편， 본 발명에 따른 상기 화학식 1로 표시되는 피리미딘— 2,4- o 아민 유도체는 목적에 따라 여러 형태로 제제화가 가능하다. 하기는 o 발명에 따른 상기 화학식 1로 표시되는 피리미딘 -2，4-디아민 유도 를 활성성분으로 함유시킨 몇몇 제제화 방법올 예시한 것으로 본 발 이 이에 한정되는 것은 아니다. 제제예예 1> 약학적 제제의 제조  18 <0.001 <0.001 <0.01 <0.01 <0.01 <0.01 Meanwhile, the pyrimidine- 2,4-o amine derivative represented by Chemical Formula 1 according to the present invention can be formulated in various forms according to the purpose. The following is an illustration of some formulation methods containing the pyrimidine-2,4-diamine derivative represented by Formula 1 according to the invention as an active ingredient, but the present invention is not limited thereto. Formulation Example 1 Preparation of Pharmaceutical Formulations
산제의 제조  Manufacture of powder
화학식 1의 유도체 500 nig  500 nig derivative of Formula 1
100 nig  100 nig
10 nig 상기의 성분들을 흔합하고 기밀포에 충진하여 산제를 제조한다  10 nig The above ingredients are mixed and filled in an airtight cloth to prepare a powder.
1-2. 정제의 1-2. Tablet
화학식 1의 유도체 500 nig 옥수수전분 100 nig 유당 100 nig 스테아린산 마그네슘 2 nig 화 Λ만정이 Derivatives of Formula 1 500 nig Corn starch 100 nig Lactose 100 nig Magnesium stearate 2 nig ke Λ
상기의 성분들을 흔합한 후 통상의 정제의 제조방법에 따라서 성니제학  After mixing the above components according to the conventional method for producing tablets
타정하여 정제를 제조한다. Tableting to prepare tablets.
를수화  Sign language
당  Party
1-3 . 제조  1-3. Produce
화학식 1의 유도체 500 nig  500 nig derivative of Formula 1
옥수수전분 100 nig  Corn starch 100 nig
유당 100 nig  Lactose 100 nig
스테아린산 마그네슘 2 nig 통상의 캡슐제 제조방법에 따라 상기의 성분을 흔합하고 젤라틴 캡슐에 충전하여 캡술제를 제조한다. 1-4. 주사제의 제조  Magnesium stearate 2 nig According to the conventional capsule preparation method, the above ingredients are mixed and filled into gelatin capsules to prepare a capsulant. 1-4. Preparation of Injectables
화학식 1의 유도체  Derivative of formula 1
주사용 멸균 증류수  Sterile Distilled Water for Injection
pH 조절제 통상의 주사쎄의 제조방법에 따라 1 앰클당 ( 2 ml ) 상기의 성분 함량으로 제조한다 .  pH Adjuster Prepared at the above ingredient content per ample (2 ml) according to the conventional method of preparation.
^적적 ^ Enemy
Figure imgf000043_0001
^량량 유도체 100 nig
Figure imgf000043_0001
^ Amount of derivative 100 nig
10 g  10 g
5 g  5 g
적량 하다 후음여 통상의 액제의 제조방법에 따라 정제수에 각각의 성분을 가: 용해시키고 레몬 향을 적량 가한 다음 상기의 성분을 흔합한 정제수를 가하여 전체를 정제수를 가하여 전체 100 m 로 조절한 갈색 병에 층진하여 멸균시켜 액체를 제조한다.  Properly dissolve each component in purified water according to the usual method of preparing a liquid solution: add a suitable amount of lemon flavor, add the purified water mixed with the above ingredients, and add the purified water to the entire 100 m bottle. Layered and sterilized to prepare a liquid.
【산업상 이용가능성】 Industrial Applicability
본 발명에 의한 화합물은 역형성 림프종 키나아제 ( ALK ) 활성을 억제하는 효과가 현저히 우수하므로 이에 따른 EML4-ALK , NPM-ALK 등의 역형성 림프종 키나아쎄 ( ALK ) 융합 단백질을 가진 암세포에 대한 치료효과가 향상될 수 있으며， 암의 재발을 막는데 효과적일 것으로 예상되므로 암의 예방 또는 치료용 약학적 조성물로 유용할 수 있다.  Since the compound according to the present invention has a remarkably excellent effect of inhibiting anaplastic lymphoma kinase (ALK) activity, treatment of cancer cells with anaplastic lymphoma kinase (ALK) fusion proteins, such as EML4-ALK and NPM-ALK. The effect may be improved and may be useful as a pharmaceutical composition for preventing or treating cancer because it is expected to be effective in preventing cancer from recurring.

Claims

또직 는쇄 【청구의 범위】 【청구또측 R항 1】 하 ί는쇄ᅳ」기 화학식 1로 표시되는 피리미딘 -2,4-디아민 유도체 또는 이 의 약학적으로 허용가능한 염 : 측알 - [화학식 H쇄킬， 1] (상기 화학식 는 단일결합 또는 이중결합이고; ； ssla이 단일결합인 경우， R1, R2 및 R3는 독립적으로 할로겐， 또는 비치환 또는 하나 이상의 할로겐이 치환된 C o 직쇄 알킬이고; 비치환 또는 하나 이상의 -0H기가 치환된 직쇄 또는 -C(=0)R5이고， 여기서 R5는 -0H, 또는 알킬이고; 이 이중결합인 경우， R1, R2 및 R3는 독립적으로 할로겐， 또는 비치환 또는 하나 이상의 할로겐이 치환된 d-H) 직쇄 또는 측쇄 알킬이고; R4는 비치환 또는 하나 이상의 -0H기가 치환된 d-w 직쇄 또는 측쇄 알킬， 또는 -C(=0)R5이고 여기서 R5는 -H, -0H, 또는 직쇄 또는 측쇄 알킬이다) . 【청구항 2】 제 1항에 있어서， 단일결합인 경우， 상기 R R2 및 R3는 독립적 할로겐， 비치환 또는 하나 이상의 할로겐이 치환된 d-5 직쇄 알킬이고; R4는 -H, 비치환 또는 하나 이상의 -0H기가 치환된 d-5 직쇄 또 는 측쇄 알킬ᅳ 또는 -C(=0)R5이고， 여기서 R5는 -0H, 또는 d-5 직쇄 또는 측쇄 알킬이고 ; ^^이 이중결합인 경우' R 상 234기 R1, R2 및 R3는 독립적으로 -H, 할로겐， 비치환 또는 하나 는는는 7 이상와 할로겐이 치환된 d-5 직쇄 또는 측쇄 알킬이고; R4는 비치환 또는 하나 이상의 ᅳ애기가 치환된 d-5 직쇄 또는 측쇄 알킬， 또는 _C(=0)R5이고， 여기서 R5는 -0H, 또는 d-5 직쇄 또는 측쇄 알킬인 것을 특징으로 하는 피리미딘 -2 ,4-디아민 유도체 또는 이의 약학적으로 허용가능한 염 . 구항 3] 제 1항에 있아서 , 이 단일결합인 경우， R1은 -C1, 또는 -CF3이고; -H, -CH3, 또는 -F이고; -CH3, 또는 -CHF2이고; -H, -CH3, -CH2CH3, -CH2CH20H, -C(=0)CH3, 또는 -C(=0)0Ho 이 이중결합인 경우， 기 R1은 -C1ᅳ 또는 -CF3이고； 는 -H, -CH3, 또는 -F어고; 는 -CH3, -CH(CH3)2, 또는 -CHF2이고; 는 -H, -CH3> -CH2CH3) -CH2CH20H, -C(=0)CH3, 또는 C(=0)0H인 것을 특징으로 하는 피리미딘 -2， 4-디아민 유도체 또는 이의 약학적으로 허용가능한 염 . 【청구항 4】 제 1항에 있어서， 상기 화학식 1로 표시되는 피리미딘 -2， 4-디아민 유도체는 '하기 화합물 군으로부터 선택되는 어느 하나인 것을 특징으로 하는 피리미 딘 -2,4-디아민 유도체 또는 이의 약학적으로 허용 가능한 염 : Alternate chain 【Scope of Claims】 【Claim R Section 1】 Pyrimidine -2,4-diamine derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof: Side chain - [Formula H chain chain] , 1] (The above formula is a single bond or a double bond; When ssla is a single bond, R1, R2 and R3 are independently halogen, or unsubstituted or C o straight-chain alkyl in which one or more halogens are substituted; unsubstituted or a straight chain or -C(=0)R5 in which one or more -0H groups are substituted, where R5 is -0H or alkyl; in the case of this double bond, R1, R2 and R3 are independently halogen, or unsubstituted or one dH) straight or branched chain alkyl substituted by one or more of the halogens; R4 is unsubstituted or dw straight-chain or branched alkyl substituted with one or more -0H groups, or -C(=0)R5, where R5 is -H, -0H, or straight-chain or branched alkyl). 【Claim 2】 The method of claim 1, in the case of a single bond, R R2 and R3 are independent halogens, unsubstituted or d-5 straight chain alkyl substituted with one or more halogens; R4 is -H, unsubstituted or d-5 straight-chain or branched alkyl ᅳ or -C(=0)R5, unsubstituted or substituted with one or more -0H groups, where R5 is -0H, or d-5 straight-chain or branched alkyl; When ^^ is a double bond' R 234 groups R1, R2 and R3 are independently -H, halogen, unsubstituted or d-5 straight or branched alkyl in which halogen is substituted with 7 or more; R4 is unsubstituted or d-5 straight-chain or branched alkyl substituted with one or more eu groups, or _C(=0)R5, where R5 is -0H, or a pyrimidine characterized in that it is d-5 straight-chain or branched alkyl -2,4-diamine derivative or pharmaceutically acceptable salt thereof. Clause 3] In clause 1, when this is a single bond, R1 is -C1 or -CF3; -H, -CH3, or -F; -CH3, or -CHF2; When -H, -CH3, -CH2CH3, -CH2CH20H, -C(=0)CH3, or -C(=0)0Ho is a double bond, group R1 is -C1ᅳ or -CF3; is -H, - CH3, or -Fergo; is -CH3, -CH(CH3)2, or -CHF2; is -H, -CH3> -CH2CH3) -CH2CH20H, -C(=0)CH3, or C(=0)0H A pyrimidine -2, 4-diamine derivative or a pharmaceutically acceptable salt thereof . [Claim 4] The pyrimidine-2,4-diamine derivative of claim 1, wherein the pyrimidine-2,4-diamine derivative represented by Formula 1 is 'a pyrimidine-2,4-diamine derivative selected from the group of compounds below. or a pharmaceutically acceptable salt thereof:
(1) 5 클로로 -N4-(2- (이소프로필술포닐 )페닐) -N2ᅳ (2-메특시 -4- (1， 2， 3， 6-테트라하이드로피리딘— 4-일 )페닐)피리미딘 -2， 4ᅳ디아민； (1) 5 Chloro -N4- (2- (isopropylsulfonyl) phenyl) -N2ᅳ (2-methoxy -4- (1, 2, 3, 6-tetrahydropyridine— 4-yl) phenyl) pyridine Midine-2, 4-diamine;
(2) 5-클로로 -N2-(2-이소프로폭시ᅳ 5-메틸 -4-(1，2，3，6-테트라하 이드로피리딘 -4-일 )페닐 )-N4-(2- (이소프로필술포닐)페닐)피리미딘- (2) 5-chloro -N2- (2-isopropoxy ᅳ 5-methyl -4- (1, 2, 3, 6-tetrahydropyridin -4-yl ) phenyl ) -N4- (2- (iso Propylsulfonyl)phenyl)pyrimidine-
2 ,4-디아민 ; 2,4-diamine;
(3) 5-클로로 -N2- ( 2ᅳ (디플루오로메록시 ) -4- ( 1， 2 , 3， 6-테트라하이 드로피리딘 -4-일 )페닐 )-N4-(2(이소프로필술포닐ᅳ페닐 )피리미딘ᅳ2，4ᅳ디 아민 ; ' (3) 5-chloro -N2- ( 2ᅳ (difluoromeroxy) -4- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) -N4-(2 (isopropyl sulphenyl) phenyl-phenyl)pyrimidine-2,4-diamine; '
(4) 5ᅳ클로로 -N2-(2- (디플루오로메록시 )ᅳ4- (피페리딘 -4-일 )페 닐 ) -N4 (2(이소프로필술포닐 )페닐)피리미딘 -2，4-디아민 ; (4) 5ᅳChloro -N2-(2- (difluoromeroxy)ᅳ4- (piperidin-4-yl)phenyl)-N4 (2(isopropylsulfonyl)phenyl)pyrimidine-2， 4-diamine;
(5) 5ᅳ클로로 -N4-(2- (이소프로필술포닐)페닐 )-N2-(2-메록시 -4- (피페리딘 -4yl)페닐)피리미딘 -2, 4-디아민 ; (5) 5-chloro-N4-(2- (isopropylsulfonyl)phenyl)-N2-(2-meroxy-4- (piperidine-4yl)phenyl)pyrimidine-2, 4-diamine;
(6) N4-(2- (이소프로필술포닐)페닐 )-N2-(2-메특시 -4-(1，2，3, 6- 테트라하이드로피리딘 -4-일 )페닐 ) -5ᅳ (트리플루오로메틸)피리미딘 -2， 4- 디아민 ; (6) N4-(2- (isopropylsulfonyl)phenyl)-N2-(2-methoxy-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-5eu ( Trifluoromethyl) pyrimidine-2, 4-diamine;
(7) N2-(2-이소프로폭시 -5-메틸 -4— (1,2,3,6-테트라하이드로피리 딘 -4-일 )페닐) -N4-(2(이소프로필술포닐)페닐) -5- (트리플루오로메틸)피 리미딘 -2，4-디아민 ; (7) N2-(2-isopropoxy-5-methyl-4—(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N4-(2(isopropylsulfonyl)phenyl ) -5- (trifluoromethyl) pyrimidine -2,4-diamine;
(8) N2-(2- (디플루오로메톡시 )-4-(1，2, 3， 6-테트라하이드로피리 딘 -4-일 )페닐) -N4-(2- (이소프로필술포닐 )페닐)ᅳ 5- (트리플루오로메틸) 피리미딘 -2,4-디아민 ; (8) N2-(2- (difluoromethoxy)-4-(1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) -N4-(2- (isopropylsulfonyl) phenyl )ᅳ 5- (trifluoromethyl) pyrimidine -2,4-diamine;
(9) N2-(2- (디플루오로메톡시 )-4- (피페리딘 -4-일 )페닐 )-N4-(2- (이소프로필술포닐)페닐 )-5- (트리플루오로메틸)피리미딘 _2，4-디아민 ; (9) N2-(2- (difluoromethoxy)-4- (piperidin-4-yl)phenyl)-N4-(2- (isopropylsulfonyl)phenyl)-5- (trifluoromethyl ) Pyrimidine _2,4-diamine;
(10) 5ᅳ클로로 -N2-(5-플루오 ^-2ᅳ메톡시ᅳ 4-(1，2，3,6-테트라하이 드로피리딘— 4—일 )페닐 )-N4-(2- (이소프로필술포닐)페닐 )피리미딘 -2，4- 디아민 ; (10) 5-chloro -N2-(5-fluo ^-2-methoxy-4-(1,2,3,6-tetrahydropyridine— 4—yl)phenyl)-N4-(2- (isopropyl Sulfonyl)phenyl)pyrimidine-2,4-diamine;
(11) 5-클로로 -N4-(2- (이소프로필술포닐)페닐) -N2-(2-메톡시 -5- 메틸 -4-(1，2，3，6-테트라하이드로피리딘 -4-일)페닐)피리미딘 -2 ,4-디아 민 ; ᅳ (11) 5-Chloro -N4-(2- (isopropylsulfonyl)phenyl) -N2-(2-methoxy-5-methyl-4-(1,2,3,6-tetrahydropyridine-4- 1) phenyl) pyrimidine-2,4-diamine; ᅳ
(12) 5-클로로 -N2-(5-풀루오로 -2-메특시 -4- (피페리딘 -4-일 )페 닐 )-N4-(2- (이소프로필술포닐)페닐 )피리미딘 -2 ,4-디아민 ; (12) 5-chloro -N2- (5-fluoro -2-methoxy -4- (piperidin-4-yl) phenyl) -N4-(2- (isopropylsulfonyl) phenyl) pyri Mydine-2,4-diamine;
(13) 5-클로로 -N4-(2ᅳ (이소프로필술포닐 )페닐) -N2— (2-메톡시 -5- 메틸ᅳ 4- (피페리딘 -4-일 )페닐 )피리미딘 -2,4-디아민； (13) 5-chloro -N4- (2ᅳ (isopropylsulfonyl) phenyl) -N2— (2-methoxy -5- methylᅳ 4- (piperidin-4-yl) phenyl) pyrimidine -2 ,4-diamine;
(14) 5—클로로 -N2-(4-(l-에틸— 1,2，3，6_테트라하이드로피리딘 -4- 일 )-2-메톡시페닐 )-N4-(2- (이소프로필술포닐)페닐 )피리미딘 -2， 4ᅳ디아 민 ; (14) 5—Chloro -N2-(4-(l-ethyl— 1,2,3,6_tetrahydropyridin -4- yl)-2-methoxyphenyl)-N4-(2- (isopropyl sulphenyl) phenyl) phenyl) pyrimidine-2, 4-diamine;
(15) 5—클로로 -N2-(4-(l-에틸 -1， 2，3， 6_테트라하이드로피리딘 -4- 일 )-2-메톡시페닐 )-N4-(2- (이소프로필술포닐)페닐 )피리미딘 -2， 4ᅳ디아 민 ; (15) 5—Chloro -N2-(4-(l-ethyl-1，2，3，6_tetrahydropyridin-4- yl)-2-methoxyphenyl)-N4-(2- (isopropyl sulphenyl) phenyl) phenyl) pyrimidine-2, 4-diamine;
(16) 1-(4-(4-((5ᅳ클로로ᅳ4-((2— (이소프로필술포닐)페닐)아미 노 )피리미딘 -2-일 )아미노 )-3-메톡시페닐 )ᅳ5，6-디하이드로피리딘- 1(2H)-일 )에탄온 ; (16) 1-(4-(4-((5-chloro-4-((2— (isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl) ᅳ5,6-dihydropyridin-1(2H)-yl)ethanone;
(17) 4-(4-((5-클로로 -4-((2- (이소프로필술포닐 )페닐)아미노)피 리미딘 -2-일)아미노 )-3-메톡시페닐 )-5, 6-디하이드로피리딘 -1(2H)-카르 복시산; 및 (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-클로로 -4-((2ᅳ (이소프로필술포닐 )페닐 )아미노)피리미딘 -2-일 )아미노 ) -3- 메톡시페닐 )-5，6-디하이드로피리딘 -1(2H)-메틸ᅳ 【청구항 5】 (18) 4-(4-((5-chloro-4-((2ᅳ (isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)-5，6 -Dihydropyridine -1(2H)-methylᅳ [Claim 5]
하기 반웅식 1에 나타낸 바와 같이 As shown in reaction equation 1 below,
화학식 2로 표시되는 화합물과 화학식 3으로 표시되는 화합물을 반웅시켜 화학식 4로 표시되는 화합물을 제조하는 단계 (단계 1); 및 상기 단계 1에서 제조한 화학식 4로 표시되는 화합물과 화학식 5로 표시되는 화합물을 반웅시켜 화학식 1로 표시되는 화합물을 제조 하는 단계 (단계 2);를 포함하는 제 1항의 피리미딘ᅳ2，4-디아민 유도체 의 제조방법 : Preparing a compound represented by Formula 4 by reacting a compound represented by Formula 2 and a compound represented by Formula 3 (Step 1); and The pyrimidine ᅳ2,4- of claim 1, including a step (step 2) of producing a compound represented by Formula 1 by reacting the compound represented by Formula 4 prepared in Step 1 with the compound represented by Formula 5. Method for producing diamine derivatives:
[반웅식 1] [Banwoongsik 1]
Figure imgf000047_0001
Figure imgf000047_0001
(상기 반웅식 1에서， (In reaction 1 above,
R1, R2, R3 및 R4는 제 1항의 화학식 1에서 정의한 바와 같다). R 1 , R 2 , R 3 and R 4 are as defined in Formula 1 of Clause 1).
【청구항 6】 【Claim 6】
제 1항의 화학식 1로 표시되는 피리미딘 -2，4-디아민 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물. A pharmaceutical composition for the prevention or treatment of cancer containing a pyrimidine-2,4-diamine derivative represented by Formula 1 of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
【청구항 7】 【Claim 7】
제 6항에 있어서， In clause 6,
상기 약학적 조성물은 역형성 림프종 키나아제 (ALK, Anaplastic Lymphoma Kinase) 활성을 억제하여 암세포의 발현 및 성장을 억제하는 것을 특징으로 하는 약학적 조성물. The pharmaceutical composition is characterized in that it inhibits the expression and growth of cancer cells by inhibiting Anaplastic Lymphoma Kinase (ALK) activity.
【-청구항 8】 【-Claim 8】
제 6항에 있어서 , In clause 6,
상기 암은 비소세포폐암， 신경모세포종， 염증성 골수섬유모세포종양， 종횡문근육종， 근섬유모세포종， 유방암， 위암， 폐암, 흑색종， 대형 B-세포 림프종， 전신성 조식구증， 염증성 근섬유아세포성 육종 또는 식도 편평 세포암인 것을 특징으로 하는 약학적 조성물 . The cancers include non-small cell lung cancer, neuroblastoma, and inflammatory A pharmaceutical composition characterized in that it is myelofibroblastic tumor, longitudinal rhabdomyosarcoma, myofibroblastoma, breast cancer, gastric cancer, lung cancer, melanoma, large B-cell lymphoma, systemic hematophytosis, inflammatory myofibroblastic sarcoma, or esophageal squamous cell carcinoma.
【청구항 9】 【Claim 9】
제 1항의 피리미딘 -2， 4-디아민 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 역형성 림프종 키나아제 (ALK, Anaplastic Lymphoma Kinase) 과활성으로 인하여 유발되는 질환의 예방 또는 치료용 약학적 조성물. A pharmaceutical for the prevention or treatment of diseases caused by hyperactivity of Anaplastic Lymphoma Kinase (ALK) containing the pyrimidine-2, 4-diamine derivative of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. enemy composition.
【청구항 10】 【Claim 10】
제 1항의 피리미딘 -2， 4-디아민 유도체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 역형성 림프종 키나아제 (ALK, Anaplastic Lymphoma Kinase) 저해제 . Anaplastic Lymphoma Kinase (ALK) inhibitor containing the pyrimidine-2, 4-diamine derivative of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
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