KR101726648B1 - Novel pyrimidine derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating DRAK relating diseases containing the same as an active ingredient - Google Patents

Novel pyrimidine derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating DRAK relating diseases containing the same as an active ingredient Download PDF

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KR101726648B1
KR101726648B1 KR1020160024077A KR20160024077A KR101726648B1 KR 101726648 B1 KR101726648 B1 KR 101726648B1 KR 1020160024077 A KR1020160024077 A KR 1020160024077A KR 20160024077 A KR20160024077 A KR 20160024077A KR 101726648 B1 KR101726648 B1 KR 101726648B1
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amino
pyrazol
methoxy
phenyl
formula
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이광호
최길돈
박상준
이나리
정명은
김성진
양경민
이지희
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한국화학연구원
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • 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
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/308—Foods, ingredients or supplements having a functional effect on health having an effect on cancer prevention
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

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Abstract

The present invention relates to a novel pyrimidine derivative, a process for its preparation, and a pharmaceutical composition for the prevention or treatment of DRAK-related diseases containing the same as an active ingredient. The novel pyrimidine derivative, its optical isomer or its Pharmaceutically acceptable salts exhibit effective inhibitory activity against DRAK and are useful for the treatment of diseases caused therefrom, typically cancer and tumors.

Description

TECHNICAL FIELD The present invention relates to a novel pyrimidine derivative, a process for producing the same, and a pharmaceutical composition for preventing or treating DRAK-related diseases containing the same as an active ingredient. same as an active ingredient}

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

Apoptosis is a process in the cell cycle that is essential for organism expression, growth, and the maintenance of the stellar nature of living tissues. When the apoptosis process is inhibited as a part of diseases associated with apoptosis, when abnormal cells accumulate to cause diseases such as cancer, and apoptosis process is induced too much, excessive cell loss occurs, resulting in stroke, heart attack, And the like.

DRAK1 and DRAK2 have been identified as protein kinases which are directly related to apoptosis. Recently, DRAK1 and DRAK2 have been overexpressed, Induced apoptosis, and inhibited the tumor suppressor gene expression.

Recent studies have shown that DRK1 regulates the expression of p21Waf1 / Cip1, a tumor suppressor gene derived from TGF-β1, involved in human head and neck squamous cell carcinoma. Specifically, DRAK1, located in the cytoplasm, binds to Smad3 , Smad3 / Smad4 complex inducing the tumor suppressor gene of TGF-? 1 was inhibited, and it was confirmed that tumor and cancer cell growth was induced therefrom (Non-Patent Document 1).

In addition, DRAK2 (apoptosis-inducing protein kinase 2) induces cell growth of metastatic breast cancer, and has been shown to induce the growth of breast cancer cells by inhibiting the tumor suppressor activity of TGF-β1 (Non-Patent Document 2) In addition, DRAK1 and DRAK2 have been associated with autoimmune diseases and organ transplant rejection, and research has been conducted as a target to treat diseases by inhibiting or modulating DRAK1 and DRAK2 activity. However, No available targets are found.

Accordingly, the present inventors have found that the compound of the present invention has an excellent inhibitory activity against DRAK1 and DRAK2, and an excellent inhibitory activity against DRAK1 and DRAK2, The present invention can be used for prevention and treatment of cancer.

DRAK1 overexpression inhibits TGF-β signaling pathway. Y Park et al. Oncogene (2014), 1-9 (Oncogene advance online publication, 22 December 2014; doi: 10.1038 / onc.2014.423)

It is an object of the present invention to provide a compound useful as an active ingredient of a pharmaceutical composition for the prevention or treatment of DRAK-related diseases.

Another object of the present invention is to provide a process for producing the above compound.

It is still another object of the present invention to provide a pharmaceutical composition for preventing or treating DRAK-related diseases containing the above-mentioned compound as an active ingredient.

Another object of the present invention is to provide a health functional food for improving DRAK-related diseases containing the above-mentioned compound as an active ingredient.

In order to achieve the above object,

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

Figure 112016019587113-pat00001

(In the formula 1,

R 1 is hydrogen, halogen, C 1 -C 10 linear or branched alkyl, C 1 -C 10 straight or branched alkoxy, or unsubstituted or substituted C 3 -C 10 cycloalkyl,

Wherein said substituted C 3 -C 10 cycloalkyl is substituted with at least one substituent selected from the group consisting of halogen, C 1 -C 5 straight or branched chain alkyl and C 1 -C 5 straight or branched chain alkoxy Can be;

R 2 is - (CH 2 ) n -CN, - (CH 2 ) m -SO 2 CH 3 , or C 1 -C 10 linear or branched alkylcarbonyl, wherein n and m are integers from 0 to 5 ego; And

R 3 is hydrogen, halogen, -CN, C 1 -C 10 straight or branched chain alkyl substituted or unsubstituted with one or more halogens, or C 1 -C 10 straight or branched alkoxy.

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

Reacting a compound represented by the formula (2) with a compound represented by the formula (3) to prepare a compound represented by the formula (4) (step 1);

Reacting the compound represented by the formula (4) and the compound represented by the formula (5) prepared in the step 1 to prepare a compound represented by the formula (6) (step 2); And

Reacting the compound represented by the formula (6) and the compound represented by the formula (7) to prepare a compound represented by the formula (1) (step 3), and reacting the compound represented by the formula The method provides:

[Reaction Scheme 1]

Figure 112016019587113-pat00002

(In the above Reaction Scheme 1,

R 1 , R 2 , and R 3 are the same as defined in Formula 1).

Furthermore, the present invention relates to a pharmaceutical composition for preventing or treating DRAK (Death-Associated Protein Related Apoptosis Inducing Protein Kinase) -related diseases containing the compound represented by the above-mentioned formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient Gt;

The present invention also relates to a pharmaceutical composition for preventing or ameliorating a disease associated with DRAK (Death-Associated Protein Related Apoptosis Inducing Protein Kinase) containing the compound represented by Formula 1, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient Functional food composition.

The novel pyrimidine derivatives, their optical isomers, or pharmaceutically acceptable salts thereof according to the present invention exhibit an effective inhibitory activity against DRAK and have an effect useful for the treatment of diseases caused therefrom, typically cancer and tumors .

Hereinafter, the present invention will be described in detail.

The following description is intended to assist the understanding of the present invention, but the present invention is not limited thereto.

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

Figure 112016019587113-pat00003

(In the formula 1,

R 1 is hydrogen, halogen, C 1 -C 10 linear or branched alkyl, C 1 -C 10 straight or branched alkoxy, or unsubstituted or substituted C 3 -C 10 cycloalkyl,

Wherein said substituted C 3 -C 10 cycloalkyl is substituted with at least one substituent selected from the group consisting of halogen, C 1 -C 5 straight or branched chain alkyl and C 1 -C 5 straight or branched chain alkoxy Can be;

R 2 is - (CH 2 ) n -CN, - (CH 2 ) m -SO 2 CH 3 , or C 1 -C 10 linear or branched alkylcarbonyl, wherein n and m are integers from 0 to 5 ego; And

R 3 is hydrogen, halogen, -CN, C 1 -C 10 straight or branched chain alkyl substituted or unsubstituted with one or more halogens, or C 1 -C 10 straight or branched alkoxy.

Preferably.

R 1 is hydrogen, halogen, C 1 -C 5 linear or branched alkyl, C 1 -C 5 straight or branched alkoxy, or unsubstituted or substituted C 3 -C 5 cycloalkyl,

Wherein said substituted C 3 -C 5 cycloalkyl is substituted with at least one substituent selected from the group consisting of halogen, C 1 -C 3 straight or branched chain alkyl and C 1 -C 3 straight or branched chain alkoxy Can be;

R 2 is - (CH 2 ) n -CN, - (CH 2 ) m -SO 2 CH 3 , or C 1 -C 5 straight or branched chain alkylcarbonyl, and n and m are integers from 0 to 3 ego; And

R 3 is hydrogen, halogen, -CN, C 1 -C 5 straight or branched chain alkyl substituted with one or more halogens, or C 1 -C 5 straight or branched alkoxy.

More preferably,

R 1 is methyl, ethyl, propyl, isopropyl, cyclopropyl or tert-butyl;

R 2 is

Figure 112016019587113-pat00004
,
Figure 112016019587113-pat00005
,
Figure 112016019587113-pat00006
,
Figure 112016019587113-pat00007
or
Figure 112016019587113-pat00008
ego; And

R 3 is -H, -Cl, -F, -Br or -I.

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

(1) Synthesis of 2- (4 - ((4 - ((5-tert-butyl-1H-pyrazol- Nitrile;

(2) N4- (5- (tert-butyl) -1H-pyrazol-3-yl) -5-methoxy-N2- (4- (methylsulfonyl) phenyl) pyrimidine-2,4-diamine;

(3) Synthesis of N4- (5- (tert-butyl) -1H-pyrazol-3-yl) -5-methoxy-N2- (4- (methylsulfonyl) methyl) phenyl) pyrimidine- Diamine;

(4) 2- (4 - ((5-Methoxy-4 - ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) amino) phenyl) acetonitrile;

(5) 5-Methoxy-N4- (5-methyl-1H-pyrazol-3-yl) -N2- (4- (methylsulfonyl) phenyl) pyrimidine-2,4-diamine;

(6) 5-Methoxy-N4- (5-methyl-1H-pyrazol-3-yl) -N2- (4 - ((methylsulfonyl) methyl) phenyl) pyrimidine-2,4-diamine;

(7) 4 - (((5-Methoxy-4 - ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) amino) benzonitrile;

(8) Synthesis of 1- (4 - ((5-methoxy-4 - ((5-methyl-1H-pyrazol- ;

(9) 2-Chloro-4 - ((5-methoxy-4 - ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) amino) benzonitrile;

(10) 4 - ((4 - ((5-Cyclopropyl-1H-pyrazol-3-yl) amino) -5-methoxypyrimidin-2-yl) amino) benzonitrile;

(11) Preparation of 1- (4 - ((4 - ((5-cyclopropyl- 1 H- pyrazol-3-yl) amino) -5-methoxypyrimidin- 1-one;

(12) 2- (4 - ((4 - ((5-Cyclopropyl-1H-pyrazol-3-yl) amino) -5-methoxypyrimidin-2-yl) amino) phenyl) acetonitrile;

(13) N4- (5-Cyclopropyl-1H-pyrazol-3-yl) 5-methoxy-N2- (4- (methylsulfonyl) phenyl) pyrimidine-2,4-diamine;

(14) N4- (5-Cyclopropyl-1H-pyrazol-3-yl) 5-methoxy-N2- (4- (methylsulfonyl) methyl) phenyl) pyrimidine-2,4-diamine;

(15) 2- (4 - ((5-Methoxy-4 - ((5-propyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) amino) phenyl) acetonitrile;

(16) 5-Methoxy-N2- (4- (methylsulfonyl) phenyl) -N4- (5-propyl-1H-pyrazol-3-yl) pyrimidine-2,4-diamine;

(17) 5-Methoxy-N2- (4- (methylsulfonyl) phenyl) -N4- (5-propyl-1H-pyrazol-3-yl) pyrimidine-2,4-diamine;

(18) 4 - ((5-Methoxy-4 - ((5-propyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) amino) benzonitrile;

(19) Synthesis of 1- (4 - ((5-methoxy-4 - ((5-propyl-1H-pyrazol-3- yl) amino) pyrimidin- ;

(20) 2-Chloro-4 - ((5-methoxy-4 - ((5-propyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) amino) benzonitrile;

(21) 4 - ((4 - ((5-ethyl-1H-pyrazol-3-yl) amino) -5-methoxypyrimidin-2-yl) amino) benzonitrile;

(22) 2- (4 - ((4 - ((5-ethyl-1H-pyrazol-3-yl) amino) -5-methoxypyrimidin-2-yl) amino) phenyl) acetonitrile;

(23) N4- (5-Ethyl-1H-pyrazol-3-yl) -5-methoxy-N2- (4- (methylsulfonyl) phenyl) -pyrimidine-2,4-diamine;

(24) N4- (5-Ethyl-1H-pyrazol-3-yl) -5-methoxy-N2- (4- (methylsulfonyl) methyl) -phenyl) -pyrimidine-2,4-diamine;

(25) Synthesis of 1- (4 - ((4 - ((5-ethyl-1H-pyrazol-3-yl) amino) -5-methoxypyrimidin- ;

(26) 2-Chloro-4 - ((4 - ((5-ethyl-1H-pyrazol-3-yl) amino) -5-methoxypyrimidin-2-yl) amino) benzonitrile;

(27) 2- (4 - ((4 - ((5-isopropyl-1H-pyrazol-3-yl) amino) -5-methoxypyrimidin-2-yl) amino) phenyl) acetonitrile;

(28) N4- (5-isopropyl-1H-pyrazol-3-yl) -5-methoxy-N2- (4- (methylsulfonyl) -pyrimidine-

(29) N4- (5-Isopropyl-1H-pyrazol-3-yl) -5-methoxy-N2- (4- (methylsulfonyl) methyl) phenyl) pyrimidine-2,4-diamine.

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

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

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

Furthermore, the present invention encompasses the compounds represented by the formula (1) and pharmaceutically acceptable salts thereof as well as solvates, optical isomers and hydrates thereof which can be prepared therefrom.

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

Reacting a compound represented by the formula (2) with a compound represented by the formula (3) to prepare a compound represented by the formula (4) (step 1);

Reacting the compound represented by the formula (4) and the compound represented by the formula (5) prepared in the step 1 to prepare a compound represented by the formula (6) (step 2); And

Reacting the compound represented by the formula (6) and the compound represented by the formula (7) to prepare a compound represented by the formula (1) (step 3), and reacting the compound represented by the formula The method provides:

[Reaction Scheme 1]

Figure 112016019587113-pat00009

(In the above Reaction Scheme 1,

R 1 , R 2 , and R 3 are the same as defined in Formula 1).

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

In step (1), the compound represented by formula (2) is reacted with the compound represented by formula (3) to produce a compound represented by formula (4).

At this time, as the solvent which can be used in the above step, methanol, ethanol, tetrahydrofuran (THF), dichloromethane (DCM), toluene, acetonitrile and the like can be used, and ethanol can be preferably used.

In the above step, the reaction is preferably carried out at -10 ° C to 40 ° C, preferably at 0 ° C, and then at 40 ° C to 100 ° C. The reaction time is not particularly limited, , Preferably for 3 hours.

In the process for preparing a compound represented by the general formula (1) according to the present invention, the step (2) may be carried out by reacting the compound represented by the general formula (4) and the compound represented by the general formula (5) .

At this time, the base usable in the above step is not limited thereto, but is preferably N, N-diisopropylethylamine or KOAc.

Examples of the solvent which can be used in the above step include dimethylformamide (DMF), methanol, ethanol, isopropanol, tetrahydrofuran (THF), dichloromethane (DCM), toluene and acetonitrile Or may be used in admixture with H 2 O, preferably isopropanol or tetrahydrofuran (THF), alone or in combination, or it may be mixed with H 2 O and used.

Further, in the above step, the reaction is preferably performed at 0 to 30 ° C and heating to 30 to 70 ° C, and the reaction time is not particularly limited, but is preferably 0.5 to 20 hours.

In the method for preparing the compound represented by the formula (1) according to the present invention, the step (3) is a step of reacting the compound represented by the formula (6) prepared in the step 2 with the compound represented by the formula (7) .

At this time, as the solvent which can be used in the above step, dichloromethane (DCM), dimethylformamide (DMF), methanol, ethanol, propanol, isopropanol, ethoxyethanol, tetrahydrofuran (THF), toluene, acetonitrile Can be used, and ethoxyethanol can be preferably used.

Also, in the above step, the reaction is preferably carried out at a temperature of 80 ° C to 120 ° C. The reaction time is not particularly limited, but is preferably 0.5-20 hours.

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

Here, the DRAK-

Cancer, autoimmune diseases, inflammatory diseases, diabetes, diseases caused by rejection of organ transplants, and the like.

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

Here, the DRAK-

Cancer, autoimmune diseases, inflammatory diseases, diabetes, diseases caused by rejection of organ transplants, and the like.

The compound of formula (I) according to the present invention may be administered orally or parenterally in a variety of formulations at the time of clinical administration. In the case of formulation, the compound of the present invention may be used as a filler, an extender, a binder, a wetting agent, a disintegrant, Diluents or excipients.

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

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

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

The compound according to the present invention, an optical isomer thereof, or a pharmaceutically acceptable salt thereof can effectively inhibit DRAK, thereby preventing diseases caused by cancer, autoimmune diseases, inflammatory diseases, diabetes, or organ transplant rejection The results of this study were as follows.

First, as a result of conducting an experiment for evaluating the inhibitory activity against DRAK1 and DRAK2, the compound according to the present invention shows excellent inhibitory activity against DRAK1 and DRAK2, and is useful as a prophylactic and therapeutic agent for anti-inflammatory and anti-cancer Can be used.

In addition, as a result of the experiment for measuring the cancer cell killing effect of the compound of the present invention, it was found that the compound of the present invention can inhibit cancer cell death and growth with a unit concentration of 쨉 M or less, And thus it can be used effectively as a preventive and therapeutic agent.

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

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

< Example  1) 2- (4 - ((4 - ((5- ( Rat -Butyl) -lH- Pyrazole Yl) amino) -5- Methoxypyrimidine Yl) amino) phenyl) acetonitrile &lt; / RTI &gt;

step 1: 5 - ( tert -Butyl) -lH- Pyrazole -3- Amine  Produce

Figure 112016019587113-pat00010

4,4-Dimethyl-3-oxopentanenitrile (80 mmol, 10 g) was added to EtOH (200 mL) at room temperature and stirred. Hydrazine monohydrate (160 mmol, 7.74 ml) was slowly added at 0 ° C . Heated to 90 ° C, refluxed and reacted for 3 hours. After the reaction was completed, the reaction mixture was cooled at room temperature, and the solvent was removed under reduced pressure. Diluted with water, and extracted with EtOAc. Sodium sulfate was added to the extracted organic solvent to remove residual water, and the product was separated by MPLC to obtain the target compound in red color at a yield of 57%.

1 H NMR (CD 3 OD, 300 MHz) δ 5.43 (s, 1 H), δ 1.26 (s, 9 H).

Step 2: N- (5- ( tert -Butyl) -lH- Pyrazole Yl) -2- Chloro -5- Methoxypyrimidine -4- Amine  Produce

Figure 112016019587113-pat00011

(7.18 mmol, 1.29 g) and the compound prepared in Step 1 (7.18 mmol, 1 g) were added to THF / H2O (1: 1, 21 mL) After that, KOAc (9.36 mmol, 0.91 g) was added at room temperature, and the mixture was heated to 45 ° C and reacted for 16 hours. After the reaction was terminated, it was cooled to room temperature and the solvent was removed under reduced pressure. A saturated NaHCO 3 solution was added and extracted with EtOAc. Sodium sulfate was added to the extracted organic solvent to remove the remaining water, and the product was separated by MPLC to obtain the target compound as a white solid in a yield of 20%.

1 H NMR (CD 3 OD, 300 MHz)? 7.79 (s, 1H),? 6.57 (br s, 1H),? 3.98 (s, 3H),? 1.36 (s, 9H); Mass (M + H +) calcd for C 12 H 16 ClN 5 O 281.1, found 282.1.

step 3: 2 - (4 - ((4 - ((5- ( Rat -Butyl) -lH- Pyrazole Yl) amino) -5- Methoxypyrimidine Yl) amino) phenyl) acetonitrile &lt; / RTI &gt;

Figure 112016019587113-pat00012

(0.14 mmol, 40 mg) and 2- (4-aminophenyl) acetonitrile (0.14 mmol, 24.3 mg) were dissolved in ethoxyethanol (1.4 mL) containing 0.08 N HCl , And the mixture was heated to 100 DEG C and reacted for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and EtOAc was added thereto to confirm precipitation. The precipitate was cleanly filtered to obtain the target compound as a brown solid in a yield of 32.4%.

1 H NMR (DMSO-d 6 , 300 MHz)? 12.24 (br s, 1H),? 9.15 (br s, 1H),? 7.82 (s, 1H),? 7.72-7.69 7.8 Hz, 2H),? 7.21-7.18 (d, J = 7.8 Hz, 2H),? 6.25 (br s, 1H),? 3.91 (s, 2H) , [delta] 1.28 (s, 9 H); Mass (MH -) calcd for C 20 H 23 N 7 O 377.2, found 376.1.

< Example  2> N 4 - (5- ( tert -Butyl) -lH- Pyrazole Yl) -5- Methoxy -N 2 -(4-( Methyl sulfo Phenyl) pyrimidine-2,4-diamine

Figure 112016019587113-pat00013

The procedure of Example 1 was repeated except that 4- (methylsulfonyl) benzeneamine was used in place of 2- (4-aminophenyl) acetonitrile in Step 3 of Example 1 to obtain the desired compound as 13 % Yield.

1 H NMR (DMSO-d 6 , 300 MHz) δ 12.22 (br s, 1 H), δ 9.65 (br s, 1 H), δ 7.94-7.92 (d, J = 8.0 Hz, 2 H), δ 7.87 (s, 1H), 8 7.75-7.73 (d, J = 8.1 Hz, 2H),? 6.24 (br s, 1H) , [delta] 1.28 (s, 9 H); Mass (MH -) calcd for C 19 H 24 N 6 O 3 S 416.1, found 415.0.

< Example  3> N 4 - (5- ( tert -Butyl) -lH- Pyrazole Yl) -5- Methoxy -N 2 - (4- (methylsulfonyl) methyl) phenyl) pyrimidine-2,4-diamine

Figure 112016019587113-pat00014

The procedure of Example 1 was repeated except for using 4- (methylsulfonylmethyl) benzeneamine instead of 2- (4-aminophenyl) acetonitrile in Step 3 of Example 1 to obtain the title compound 28.6% yield.

1 H NMR (DMSO-d 6 , 300 MHz)? 12.28 (br s, 1H),? 9.22 (br s, 1H),? 7.83 (s, 1H),? 7.74-7.71 (D, J = 7.6 Hz, 2 H),? 6.25 (br s, 1 H),? 4.35 ,? 2.86 (s, 3 H),? 1.28 (s, 9 H); Mass (MH -) calcd for C 20 H 26 N 6 O 3 S 430.1, found 429.0.

< Example  4 > 2- (4 - ((5- Methoxy -4 - ((5- methyl -1H- Pyrazole Yl) amino) pyrimidin-2-yl) amino) phenyl) acetonitrile

step 1: 5 -Ethyl-1H- Pyrazole -3- Amine  Produce

The procedure of Step 1 of Example 1 was repeated except that 3-oxopentanonitrile was used in place of 4,4-dimethyl-3-oxopentanonitrile of Step 1 of Example 1 to obtain the desired compound .

step 2: 2 - Chloro -5- Methoxy -N- (5- ( tert -Butyl) -lH- Pyrazole Yl) pyrimidin-4- Amine  Produce

Figure 112016019587113-pat00015

(7.18 mmol, 1.29 g) and the compound prepared in Step 1 (7.18 mmol) were dissolved in THF / H2O (1: 1, 21 mL) KOAc (9.36 mmol, 0.91 g) was added thereto at room temperature, and the mixture was reacted at 45 ° C for 16 hours. After the reaction was terminated, it was cooled to room temperature and the solvent was removed under reduced pressure. A saturated NaHCO 3 solution was added and extracted with EtOAc. Sodium sulfate was added to the extracted organic solvent to remove the remaining water, followed by separation by MPLC to obtain the target compound as a white solid in 56% yield.

1 H NMR (CD 3 OD, 300 MHz) δ 7.78 (s, 1 H), δ 6.49 (s, 1 H), δ 3.97 (s, 3 H), δ 2.30 (s, 3 H); Mass (MH -) calcd for C 9 H 10 ClN 5 O 239.0, found 238.0.

step 3: 2 - (4 - ((5- Methoxy -4 - ((5- methyl -1H- Pyrazole Yl) amino) pyrimidin-2-yl) amino) phenyl) acetonitrile

Figure 112016019587113-pat00016

The compound (0.14 mmol) prepared in Step 2 and 2- (4-aminophenyl) acetonitrile (0.14 mmol, 24.3 mg) were dissolved in ethoxyethanol (1.4 mL) containing 0.08 N HCl, And reacted for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and EtOAc was added thereto to confirm precipitation. The precipitate was cleanly filtered to obtain the target compound as a brown solid in 46% yield.

1 H NMR (CD 3 OD, 300 MHz)? 7.52-7.42 (m, 5H),? 6.34 (s, 1H),? 3.96 (s, 5H),? 2.29 (s, 3H); Mass (M + H +) calcd for C 17 H 17 N 7 O 335.1, found 336.2.

< Example  5> 5- Methoxy -N 4 - (5- methyl -1H- Pyrazole Yl) -N- 2 -(4-( Methylsulfonyl ) Phenyl) pyrimidine-2,4-diamine

Figure 112016019587113-pat00017

The procedure of Example 4 was repeated except that 4- (methylsulfonyl) benzeneamine was used in place of 2- (4-aminophenyl) acetonitrile in Step 3 of Example 4 to obtain the target compound as 60 % Yield.

1 H NMR (DMSO-d 6 , 300 MHz)? 10.67 (br s, 1H),? 10.40 (br s, 1H),? 7.98-7.82 H), delta 3.90 (s, 3 H), delta 3.16 (s, 3 H), delta 2.28 (s, 3 H); Mass (MH -) calcd for C 16 H 18 N 6 O 3 S 374.12, found 373.1.

< Example  6> 5- Methoxy -N 4 - (5- methyl -1H- Pyrazole Yl) -N- 2 -(4-(( Methylsulfonyl ) methyl ) Phenyl) pyrimidine-2,4-diamine

Figure 112016019587113-pat00018

The procedure of Example 4 was repeated except for using 4- (methylsulfonylmethyl) benzeneamine instead of 2- (4-aminophenyl) acetonitrile in Step 3 of Example 4 to obtain the desired compound 12% yield.

1 H NMR (CD 3 OD, 300 MHz)? 7.53-7.49 (m, 5 H),? 6.40 (s, 1H),? 4.46 2.93 (s, 3 H),? 2.31 (s, 3 H); Mass (MH -) calcd for C 17 H 20 N 6 O 3 S 388.13, found 387.1.

< Example  7 > 4 - (((5- Methoxy -4 - ((5- methyl -1H- Pyrazole Yl) amino) pyrimidin-2-yl) amino) benzonitrile

Figure 112016019587113-pat00019

The procedure of Example 4 was repeated except that 4-aminobenzonitrile was used instead of 2- (4-aminophenyl) acetonitrile in Step 3 of Example 4 to obtain the title compound in 49% yield .

1 H NMR (CD 3 OD, 500 MHz)? 7.77-7.75 (d, J = 8.7 Hz, 2H),? 7.69-7.67 ),? 3.97 (s, 3 H),? 2.33 (s, 3 H); Mass (MH -) calcd for C 17 H 18 N 6 O 2 321.1, found 320.1.

< Example  8 >. 1- (4 - ((5- Methoxy -4 - ((5- methyl -1H- Pyrazole Yl) amino) pyrimidin-2-yl) amino) phenyl) ethan-

Figure 112016019587113-pat00020

The procedure of Example 4 was repeated except for using 1- (4-aminophenyl) ethanone instead of 2- (4-aminophenyl) acetonitrile in Step 3 of Example 4 to obtain the desired compound 47% yield.

1 H NMR (DMSO-d 6 , 300 MHz)? 10.78 (s, 1H),? 10.54 (s, 1H),? 7.94-7.91 (m, 3H),? 7.84-7.81 8.7 Hz, 2H),? 6.23 (s, 1H),? 3.89 (s, 3H),? 2.53 (s, 3H),? 2.28 (s, 3H); Mass (M + H +) calcd for C 16 H 15 N 7 O 338.1, found 339.2.

< Example  9> 2- Chloro -4 - ((5- Methoxy -4 - ((5- methyl -1H- Pyrazole Yl) amino) pyrimidin-2-yl) amino) benzonitrile

Figure 112016019587113-pat00021

The procedure of Example 4 was repeated except for using 4-amino-2-chlorobenzonitrile instead of 2- (4-aminophenyl) acetonitrile in Step 3 of Example 4 to obtain the desired compound 40% yield.

1 H NMR (DMSO-d 6 , 500 MHz)? 11.33 (br s, 1 H),? 10.67 (br s, 1 H),? (d, J = 8.5 Hz, 1H),? 7.75-7.73 (d, J = 8.2 Hz, 1H) [delta] 2.32 (s, 3 H); Mass (M + H +) calcd for C 16 H 14 ClN 7 O 355.1 found 356.1.

< Example  10> 4 - ((4 - ((5- Cyclopropyl -1H- Pyrazole Yl) amino) -5- Methoxy Yl) amino) benzonitrile &lt; / RTI &gt;

step 1: 5 - Cyclopropyl -1H- Pyrazole -3- Amine  Produce

Figure 112016019587113-pat00022

Was the same as Step 1 of Example 1 except that 3-cyclopropyl-3-oxopropanenitrile was used in place of 4,4-dimethyl-3-oxopentanenitrile of Step 1 of Example 1 To give the desired compound.

1 H NMR (CDCl, 500 MHz)? 5.32 (s, 1H),? 1.80-1.75 (m, 1H),? 0.94-0.91 (m, 2H),? 0.70-0.67 .

step 2: 2 - Chloro -5- Methoxy -N- (5- ( tert -Butyl) -lH- Pyrazole Yl) pyrimidin-4- Ah Manufacture of Min

Figure 112016019587113-pat00023

(7.18 mmol, 1.29 g) and the compound prepared in Step 1 (7.18 mmol) were dissolved in THF / H2O (1: 1, 21 mL) KOAc (9.36 mmol, 0.91 g) was added thereto at room temperature, and the mixture was reacted at 45 ° C for 16 hours. After the reaction was terminated, it was cooled to room temperature and the solvent was removed under reduced pressure. A saturated NaHCO 3 solution was added and extracted with EtOAc. Sodium sulfate was added to the extracted organic solvent to remove the remaining water, followed by separation by MPLC to obtain the target compound as a white solid in 56% yield.

1 H NMR (DMSO-d 6 , 300 MHz)? 12.18 (s, 1H), 9.13 (s, 1H), 7.88 H), 1.86-1.95 (m, 1H), 0.93 (d, J = 6.63 Hz, 2H), 0.66-0.71 (m, 2H); Mass (MH -) calcd for C 11 H 12 ClN 5 O 265.0, found 263.7.

step 3: 4 - ((4- ((5- Cyclopropyl -1H- Pyrazole Yl) amino) -5- Methoxypyrimidine Di-2-yl) amino) benzonitrile

Figure 112016019587113-pat00024

The compound (0.14 mmol) prepared in the above step 2 and 4-aminobenzonitrile (0.14 mmol) were dissolved in ethoxyethanol (1.4 mL) containing 0.08 N HCl and heated at 100 ° C. for 16 hours . After the reaction was completed, the reaction mixture was cooled to room temperature, and EtOAc was added thereto to confirm precipitation. The precipitate was cleanly filtered to obtain the target compound as a brown solid in 58% yield.

1 H NMR (CD 3 OD, 300 MHz)? 7.77-7.66 (m, 5 H),? 6.11 (s, 1H) , [delta] 1.07-1.02 (m, 2H), [delta] 0.72-0.67 (m, 2H); Mass (MH -) calcd for C 18 H 17 N 7 O 347.1, found 346.1.

< Example  11> 1- (4 - ((4 - ((5- Cyclopropyl -1-H- Pyrazole Yl) amino) -5- Meth Yl) amino) phenyl) ethan-1-one &lt; EMI ID =

Figure 112016019587113-pat00025

The procedure of Example 10 was repeated except that 1- (4-aminophenyl) ethanone was used instead of 4-aminobenzonitrile in Step 3 of Example 10 to obtain the desired compound in 48% yield Respectively.

1 H NMR (CD 3 OD, 500 MHz)? 7.95-7.94 (d, J = 8.8 Hz, 2H),? 7.79 (s, 1H),? 7.78-7.76 ), 6.19 (br s, 1 H),? 3.94 (s, 3 H),? 2.58 (s, 3 H),? 1.95-1.92 ) [delta] 0.77-0.75 (m, 2H); Mass (MH -) calcd for C 19 H 22 N 6 O 4 S 364.1, found 362.9.

< Example  12 is 2- (4 - ((4 - ((5- Cyclopropyl -1H- Pyrazole Yl) amino) -5- Methoxy Pyrimidin-2-yl) amino) phenyl) acetonitrile

Figure 112016019587113-pat00026

The procedure of Example 10 was repeated except for using 2- (4-aminophenyl) acetonitrile instead of 4-aminobenzonitrile in Step 3 of Example 10 to obtain the desired compound in 37% yield .

1 H NMR (CDCl 3 , 300 MHz)? 7.68 (s, 1H),? 7.56 (d J = 8.39 Hz, 2H),? 7.25 (d J = 8.39 Hz, 2H) (M, 1 H),? 3.8 (s, 3 H),? 3.72 (s, 2H),? 3.64 H), [delta] 0.69-0.75 (m, 2H); Mass (M + H +) calcd for C 19 H 19 N 7 O 361.1 found 362.7.

< Example  13> N 4 - (5- Cyclopropyl -1H- Pyrazole Yl) -5- Methoxy -N 2 -(4-( Methyl sulfide Phenyl) pyrimidine-2,4-diamine

Figure 112016019587113-pat00027

The procedure of Example 10 was repeated except for using 4- (methylsulfonyl) benzeneamine instead of 4-aminobenzonitrile in Step 3 of Example 10 to obtain the target compound in 44% yield .

1 H NMR (CD 3 OD, 300 MHz)? 7.93 (d, J = 8.77 Hz, 2H),? 7.49 (d J = 8.77 Hz, 2H),? 7.64 (m, 2H),? 0.68-0.73 (s, 3H),? (m, 2H); Mass (M + H +) calcd for C 18 H 20 N 6 O 3 S 400.1 found 401.7.

< Example  14> N 4 - (5- Cyclopropyl -1H- Pyrazole Yl) -5- Methoxy -N 2 -(4-( Methyl sulfide Phenyl) methyl) phenyl) pyrimidine-2,4-diamine

Figure 112016019587113-pat00028

The procedure of Example 10 was repeated except for using 4- (methylsulfonylmethyl) benzeneamine instead of 4-aminobenzonitrile in Step 3 of Example 10 to obtain the desired compound in 52% yield Respectively.

1 H NMR (CDCl 3 , 300 MHz)? 7.70 (s, 1H),? 7.62 (d, J = 8.09 Hz, 2H),? 7.34 (d, J = 8.09 Hz, 2H) (s, 3 H),? 1.84-1.93 (m, 1H),? 0.96 (d, J) = 6.86 Hz, 2 H),? 0.73 (d, J = 3.43 Hz, 2 H); Mass (M + H +) calcd for C 19 H 22 N 6 O 3 S 414.1 found 415.0.

< Example  15 2- (4 - ((5- Methoxy -4 - ((5-propyl-1H- Pyrazole Yl) amino) pyrimidin-2-yl) amino) phenyl) acetonitrile

step 1: 5 -Propyl-lH- Pyrazole -3- Amine  Produce

The procedure of Step 1 of Example 1 was repeated except that 3-oxoheptanenitrile was used in place of 4,4-dimethyl-3-oxopentanonitrile of Step 1 of Example 1 to obtain the target compound .

step 2: 2 - Chloro -5- Methoxy -N- (5- ( tert -Butyl) -lH- Pyrazole Yl) pyrimidin-4- Amine  Produce

Figure 112016019587113-pat00029

(3.07 mmol, 0.39 g) prepared in Step 1 and 2,4-dichloro-5-methoxypyrimidine (2.79 mmol, 0.50 g) were dissolved in isopropanol (30 ml) -Diisopropylethylamine), stirred, and heated to 60 DEG C for reaction for 5 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. MPLC with methanol / dichloromethane gave the desired compound in 61% yield.

1 H NMR (DMSO-d 6 , 300 MHz,) δ 12.16 (s, 1 H), δ 9.14 (s, 1 H), δ 7.88 (s, 1 H), δ 6.36 (s, 1 H), δ 3.89 (s, 3 H),? 2.56 (t, J = 7.46 Hz, 2H),? 1.55-1.67 (m, 2H),? 0.92 (t, J = 7.34 Hz, 3H); Mass (M + H +) calcd for C 11 H 14 ClN 5 O 267.1 found 269.4.

step 3: 2 - (4 - ((5- Methoxy -4 - ((5-propyl-1H- Pyrazole Yl) amino) pyrimidin-2-yl) amino) phenyl) acetonitrile

Figure 112016019587113-pat00030

The compound (0.14 mmol) prepared in Step 2 and 2- (4-aminophenyl) acetonitrile (0.14 mmol) were dissolved in ethoxyethanol (1.4 mL) containing 0.08 N HCl and heated to 100 ° C. And reacted for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and EtOAc was added thereto to confirm precipitation. The precipitate was cleanly filtered to give the desired compound in the form of a brown solid in 38% yield.

1 H NMR (CD 3 OD, 500 MHz)? 7.64 (s, 1H),? 7.63 (d, J = 8.12 Hz, 2H) (s, 1H), 8 3.92 (s, 3 H), 8 3.85 (s, 2 H),? 2.63 (br s, 2 H),? 1.68-1.75 J = 7.42 Hz, 3 H); Mass (M + H +) calcd for C 19 H 21 N 7 O 363.1 found 364.2.

< Example  16> 5- Methoxy -N 2 -(4-( Methylsulfonyl ) Phenyl) -N- 4 - (5-propyl-lH- Pyrazole -3-yl) pyrimidine-2,4-diamine

Figure 112016019587113-pat00031

The procedure of Example 15 was repeated, except that 4- (methylsulfonyl) benzeneamine was used instead of 2- (4-aminophenyl) acetonitrile (0.14 mmol) in Step 3 of Example 15 The target compound was prepared in 55% yield.

1 H NMR (CD 3 OD, 500 MHz)? 7.92 (d, J = 8.70 Hz, 2H),? 7.80 (d, J = 8.21 Hz, (s, 3 H),? 3.10 (s, 3 H),? 2.64 (s, 2H),? 1.70-1.77 (m, 2H),? 1.02 (t, J = 7.33 Hz, 3 H); Mass (M + H +) calcd for C 18 H 22 N 6 O 3 S 402.1 found 403.1.

< Example  17> 5- Methoxy -N 2 -(4-( Methylsulfonyl ) Phenyl) -N- 4 - (5-propyl-lH- Pyrazole -3-yl) pyrimidine-2,4-diamine

Figure 112016019587113-pat00032

The procedure of Example 15 was repeated, except that 4- (methylsulfonylmethyl) benzeneamine was used instead of 2- (4-aminophenyl) acetonitrile (0.14 mmol) in Step 3 of Example 15 To give the desired compound in 59% yield.

1 H NMR (CD 3 OD, 300 MHz) δ 2.06 (s, 1 H), δ 9.04 (s, 1 H), δ 7.82 (s, 1 H), δ 7.73 (d, J = 8.27 Hz, 2 H ), 6.73 (d, J = 8.27 Hz, 2H),? 6.54 (s, 1H),? 4.56 (s, 2H) ),? 2.53 (br s, 2 H),? 1.56-1.69 (m, 2H),? 0.93 (t, J = 7.33 Hz, 3 H); Mass (M + H +) calcd for C 19 H 24 N 6 O 3 S 416.1 found 417.2.

< Example  18 > 4 - ((5- Methoxy -4 - ((5-propyl-1H- Pyrazole Yl) amino) pyrimidin-2-yl) amino) benzonitrile

Figure 112016019587113-pat00033

The procedure of Example 15 was repeated except for using 4-aminobenzonitrile instead of 2- (4-aminophenyl) acetonitrile in Step 3 of Example 15 to obtain the desired compound in 66% yield .

1 H NMR (DMSO-d 6 , 300 MHz)? 10.77 (s, 1H),? 10.41 (s, 1H),? 7.93 (s, 1H),? 7.92-7.89 , 3 H),? 7.75-7.72 (d, J = 8.7 Hz, 2H),? 6.22 (s, 1H),? 3.90 , 2 H),? 1.65-1.58 (m, 2 H),? 0.94-0.89 (t, J = 7.3 Hz, 3 H); Mass (M + H +) calcd for C 18 H 19 N 7 O 349.1 found 349.9.

< Example  19> 1- (4 - ((5- Methoxy -4 - ((5-propyl-1H- Pyrazole Yl) amino) pyrimidin-2-yl) amino) phenyl) ethan-

Figure 112016019587113-pat00034

The procedure of Example 15 was repeated except for using 1- (4-aminophenyl) ethanone instead of 2- (4-aminophenyl) acetonitrile in Step 3 of Example 15 to obtain the desired compound 63% yield.

1H NMR (DMSO-d6, 300 MHz)? 10.64 (s, 1H),? 10.38 (s, 1H),? 7.94-7.90 (m, 3H),? 7.80-7.77 , 2.55 (s, 3 H),? 3.89 (s, 3 H),? 2.61-2.56 (t, J = 7.5 Hz, 2H) -1.57 (m, 2 H),? 0.93-0.88 (t, J = 7.3 Hz, 3 H); Mass (M + H @ +) calcd for C19H22N6O2 366.1 found 366.6.

< Example  20> 2- Chloro -4 - ((5- Methoxy -4 - ((5-propyl-1H- Pyrazole Yl) amino) pyrimidin-2-yl) amino) benzonitrile

Figure 112016019587113-pat00035

The procedure of Example 15 was repeated except for using 4-amino-2-chlorobenzonitrile instead of 2- (4-aminophenyl) acetonitrile in Step 3 of Example 15 to obtain the title compound 45% yield.

1 H NMR (DMSO-d 6 , 500 MHz)? 11.34 (br s, 1H),? 10.69 (br s, 1H),? 8.29 (d, J = 8.6 Hz, 1 H),? 6.26 (s, 1H),? 3.92 (s, 3 H), 7.76-7.74 ? 2.66-2.63 (t, J = 7.4 Hz, 2H),? 1.65-1.61 (m, 2H),? 0.93-0.90 (t, J = 7.3 Hz, 2H); Mass (M + H +) calcd for C 18 H 18 ClN 7 O 383.1 found 384.1.

< Example  21> 4 - ((4 - ((5-Ethyl-1H- Pyrazole Yl) amino) -5- Methoxypyrimidine Yl) amino) benzonitrile &lt; / RTI &gt;

step 1: 5 -Ethyl-1H- Pyrazole -3- Amine  Produce

The procedure of Step 1 of Example 1 was repeated except that 3-oxopentanonitrile was used in place of 4,4-dimethyl-3-oxopentanonitrile of Step 1 of Example 1 to obtain the desired compound .

step 2: 2 - Chloro -N- (5-ethyl-lH- Pyrazole Yl) -5- Methoxypyrimidine -4- Amine  Produce

Figure 112016019587113-pat00036

(2.79 mmol, 0.50 g) and the compound prepared in Step 1 (3.07 mmol) were dissolved in isopropanol (30 ml) at room temperature under nitrogen atmosphere using DIPEA (N, N-diisopropylethylamine Propylethylamine), stirred, and heated to 60 DEG C for reaction for 5 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. MPLC with methanol / dichloromethane afforded the title compound in 68% yield.

1 H NMR (DMSO-d 6 , 300 MHz)? 12.18 (s, 1H),? 9.15 (s, 1H),? 7.88 (s, 3 H),? 2.41 (q, J = 7.74 Hz, 2 H),? 1.20 (t, J = 7.74 Hz, 3 H); Mass (M + H +) calcd for C 19 H 24 N 6 O 3 S 253.1 found 254.1.

step 3: 4 - ((4 - ((5-ethyl-1H- Pyrazole Yl) amino) -5- Methoxypyrimidine Yl) amino) benzonitrile &lt; / RTI &gt;

Figure 112016019587113-pat00037

The compound (0.14 mmol) prepared in the above step 2 and 4-aminobenzonitrile (0.14 mmol) were dissolved in ethoxyethanol (1.4 mL) containing 0.08 N HCl and heated at 100 ° C. for 16 hours . After the reaction was completed, the reaction mixture was cooled to room temperature, and EtOAc was added thereto to confirm precipitation. The precipitate was cleanly filtered to give the desired compound in the form of a brown solid in 39% yield.

1 H (DMSO-d 6 , 300 MHz)? 11.05 (s, 1H),? 10.56 (s, 1H),? 7.98 H), 8 7.75 (d, J = 8.64 Hz, 2H), 6.23 (s, 1H) [delta] 1.20 (t, J = 7.78 Hz, 3 H); Mass (M + H +) calcd for C 17 H 17 N 7 O 335.1 found 336.0.

< Example  22 2- (4 - ((4 - ((5-Ethyl-1H- Pyrazole Yl) amino) -5-methoxypyrimidin-2-yl) amino) phenyl) acetonitrile

Figure 112016019587113-pat00038

The procedure of Example 21 was repeated except that 2- (4-aminophenyl) acetonitrile was used instead of 4-aminobenzonitrile in Step 3 of Example 21 to obtain the desired compound in 41% yield .

1 H NMR (CD 3 OD, 500 MHz) δ 8.64 (s, 1 H), δ 7.82 (s, 1 H), δ 7.72 (d, J = 8.76 Hz, 2 H), δ 7.20 (d, J = (D, J = 5.69 Hz, 2H),? 2.50 (s, 1H),? 1.21 (t, J = 7.48 Hz, 3 H); Mass (M + H +) calcd for C 18 H 19 N 7 O 349.1 found 350.1.

< Example  23> N 4 - (5-ethyl-lH- Pyrazole Yl) -5- Methoxy -N 2 -(4-( Methylsulfonyl ) Phenyl) -pyrimidine-2,4-diamine

Figure 112016019587113-pat00039

The target compound was prepared in a yield of 60% in the same manner as in Example 21, except that 4- (methylsulfonyl) benzeneamine was used instead of 4-aminobenzonitrile in Step 3 of Example 21, .

1 H NMR (CD 3 OD, 500 MHz) δ 8.06 (d, J = 4.63 Hz, 1 H), δ 7.99 (d, J = 8.83 Hz, 2 H), δ 7.84 (d, J = 8.65 Hz, 2 H),? 6.47 (s, 1H),? 3.11 (s, 3H),? 2.69 (q, J = 7.23 Hz, 2H),? 1.30 (t, J = 7.49 Hz, 3H); Mass (M + H +) calcd for C 17 H 20 N 6 O 3 S 388.1 found 389.1.

< Example  24> N 4 - (5-ethyl-lH- Pyrazole Yl) -5- Methoxy -N 2 -(4-( Methylsulfonyl ) Me Yl) -phenyl) -pyrimidine-2,4-diamine

Figure 112016019587113-pat00040

The procedure of Example 21 was repeated except for using 4- (methylsulfonylmethyl) benzeneamine instead of 4-aminobenzonitrile in Step 3 of Example 21 to obtain the desired compound in 39% yield Respectively.

1 H NMR (CD 3 OD, 500 MHz)? 7.84 (s, 1H),? 7.74 (d, J = 8.48 Hz, 2H),? 7.27 (d, J = 7.89 Hz, 2H) (d, J = 6.48 Hz, 2H),? 1.22 (s, 3H),? (t, J = 7.51 Hz, 3 H); Mass (M + H +) calcd for C 18 H 22 N 6 O 3 S 402.1 found 403.1.

< Example  25> 1- (4 - ((4 - ((5-Ethyl-1H- Pyrazole Yl) amino) -5- Methoxypyrimidine Yl) amino) phenyl) ethan-1-one

Figure 112016019587113-pat00041

The procedure of Example 21 was repeated except that 1- (4-aminophenyl) ethanone was used instead of 4-aminobenzonitrile in Step 3 of Example 21 to obtain the desired compound in 39% yield Respectively.

1 H NMR (CD 3 OD, 300 MHz)? 7.93 (d, J = 7.20 Hz, 2H),? 7.78 (d, J = 7.20 Hz, 3H) (s, 3 H),? 2.69 (d, J = 6.60 Hz, 2H),? 2.57 (s, 3 H),? 1.31 (t, J = 7.20 Hz,? Mass (M + H +) calcd for C 18 H 20 N 6 O 2 352.2 found 353.1.

< Example  26> 2- Chloro -4 - ((4 - ((5-ethyl-1H- Pyrazole Yl) amino) -5- Methoxypyridine Methyl-benzonitrile &lt; / RTI &gt;

Figure 112016019587113-pat00042

Amino-2-chlorobenzonitrile was used in place of 4-aminobenzonitrile in step 3 of Example 21 to obtain the title compound in 45% yield Respectively.

1 H NMR (DMSO-d 6 , 500 MHz)? 11.40 (br s, 1 H),? 10.73 (br s, 1 H),? 8.28 (d, J = 8.6 Hz, 1H),? 7.75-7.74 (d, J = 8.1 Hz, 1H),? 6.26 [delta] 2.71-2.66 (q, J = 7.5 Hz, 2H), 8 1.22-1.19 (t, J = 7.5 Hz, 3 H); Mass (M + H +) calcd for C 17 H 16 ClN 7 O 369.1 found 370.1.

< Example  27> 2- (4 - ((4 - ((5- Isopropyl -1H- Pyrazole Yl) amino) -5- Methoxy  Pyrimidin-2-yl) amino) phenyl) acetonitrile

step 1: 5 - Isopropyl -1H- Pyrazole -3- Amine  Produce

The procedure of Step 1 of Example 1 was repeated except that 4-methyl-3-oxopentanonitrile was used instead of 4,4-dimethyl-3-oxopentanenitrile of Step 1 of Example 1 To give the desired compound.

step 2: 2 - Chloro -N- (5- Isopropyl -1H- Pyrazole Yl) -5- Methoxypyrimidine -4-amine

Figure 112016019587113-pat00043

(2.79 mmol, 0.50 g) and the compound prepared in Step 1 (3.07 mmol) were dissolved in isopropanol (30 ml) at room temperature under nitrogen atmosphere using DIPEA (N, N-diisopropylethylamine Propylethylamine), stirred, and heated to 60 DEG C for reaction for 5 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. MPLC with methanol / dichloromethane gave the desired compound in 60% yield.

1 H NMR (DMSO-d 6 , 300 MHz)? 12.19 (s, 1H),? 9.13 (s, 1H),? 7.88 -3.01 (m, 1H),? 1.24 (s, 3H),? 1.22 (s, 3H); Mass (M + H +) calcd for C 11 H 14 ClN 5 O 267.1 found 268.4.

step 3: 2 - (4 - ((4 - ((5- Isopropyl -1H- Pyrazole Yl) amino) -5- Methoxypyrimidine Yl) amino) phenyl) acetonitrile &lt; / RTI &gt;

Figure 112016019587113-pat00044

The compound (0.14 mmol) prepared in Step 2 and 2- (4-aminophenyl) acetonitrile (0.14 mmol) were dissolved in ethoxyethanol (1.4 mL) containing 0.08 N HCl and heated to 100 ° C. And reacted for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and EtOAc was added thereto to confirm precipitation. The precipitate was cleanly filtered to obtain the desired compound in the form of brown solid in 43% yield.

1 H NMR (CD 3 OD, 300 MHz)? 7.50-7.23 (m, 3 H),? 7.42 (d J = 7.70 Hz, 2 H),? 6.34 H),? 3.93 (s, 2H),? 2.90-3.04 (m, 1H),? 1.26 (s, 3H),? 1.24 (s, 3H); Mass (M + H +) calcd for C 19 H 21 N 7 O 363.1 found 364.2.

< Example  28> N 4 - (5- Isopropyl -1H- Pyrazole Yl) -5- Methoxy -N 2 -(4-( Methyl sulfo Yl) -pyrimidine-2,4-diamine

Figure 112016019587113-pat00045

The procedure of Example 27 was repeated except for using 4- (methylsulfonyl) benzeneamine instead of 2- (4-aminophenyl) acetonitrile in Step 3 of Example 27 to obtain the target compound as 57 % Yield.

1 H NMR (CD 3 OD, 300 MHz)? 7.93 (d, J = 8.04 Hz, 2H),? 7.82 (d, J = 8.16 Hz, 2H) (s, 1 H),? 4.00 (s, 3 H),? 3.12 (s, 3 H),? 2.98-3.08 3 H); Mass (M + H +) calcd for C 18 H 22 N 6 O 3 S 402.1 found 403.1.

< Example  29> N 4 - (5- Isopropyl -1H- Pyrazole Yl) -5- Methoxy -N 2 -(4-( Methylsulfonyl ) Methyl) phenyl) pyrimidine-2,4-diamine

Figure 112016019587113-pat00046

The procedure of Example 27 was repeated except for using 4- (methylsulfonylmethyl) benzeneamine instead of 2- (4-aminophenyl) acetonitrile in Step 3 of Example 27 to obtain the title compound 39% yield.

1 H (CD 3 OD, 300 MHz)? 12.14 (s, 1H),? 9.08 (s, 1H),? 7.88 ),? 7.31 (d, J = 8.03 Hz, 2H),? 6.55 (s, 1H),? 4.40 , 1 H),? 2.91 (s, 3 H),? 1.29 (s, 3 H),? 1.27 (s, 3 H); Mass (M + H +) calcd for C 19 H 24 N 6 O 3 S 416.1 found 417.1.

The structures of the compounds prepared in Examples 1 to 29 are shown in Table 1 below.

Example rescue Example rescue One

Figure 112016019587113-pat00047
16
Figure 112016019587113-pat00048
 2
Figure 112016019587113-pat00049
 17
Figure 112016019587113-pat00050
 3
Figure 112016019587113-pat00051
 18
Figure 112016019587113-pat00052
 4
Figure 112016019587113-pat00053
 19
Figure 112016019587113-pat00054
 5
Figure 112016019587113-pat00055
 20
Figure 112016019587113-pat00056
 6
Figure 112016019587113-pat00057
 21
Figure 112016019587113-pat00058
 7
Figure 112016019587113-pat00059
 22
Figure 112016019587113-pat00060
 8
Figure 112016019587113-pat00061
 23
Figure 112016019587113-pat00062
 9
Figure 112016019587113-pat00063
 24
Figure 112016019587113-pat00064
 10
Figure 112016019587113-pat00065
 25
Figure 112016019587113-pat00066
 11
Figure 112016019587113-pat00067
 26
Figure 112016019587113-pat00068
 12
Figure 112016019587113-pat00069
 27
Figure 112016019587113-pat00070
 13
Figure 112016019587113-pat00071
 28
Figure 112016019587113-pat00072
 14
Figure 112016019587113-pat00073
 29
Figure 112016019587113-pat00074
 15
Figure 112016019587113-pat00075

< Experimental Example  1> DARK1  And DARK2  Evaluation of inhibitory activity

To evaluate the inhibitory activity of the compounds of the present invention on DRAK1 and DRAK2, the following experiment was conducted.

The recombinant DRAK1 and DRAK2 proteins provided by SignalChem were used as an enzyme source and protein kinase activity was measured using ADP-Glo (Promega). Basic activity measurements were performed according to the method provided by Promega and modified for DRAK1 and DRAK2.

The assay buffer used for the assay was 40 mM Tris-Cl (pH 7.5), 20 mM MgCl2, and 0.1 mg / ml BSA. The enzyme reaction was carried out using 1 μM ATP and 1 μM MRLC3 peptide as a protein substrate. Activity analysis of DRAK1 and DRAK2 phosphorylase proceeded according to the following reaction reaction recipe.

Component 1: 2.5 μl of the Example Compound Solution

Component 2: 2.5 μl of ATP and peptide mixture

Component 3: DRAK1 or DRAK2 enzyme

The enzymatic reaction begins by first mixing component 1 and component 2 and then adding component 3. After 2 hours incubation at room temperature, add 7.5 μl of ADP-Glo solution and incubate for 30 minutes at room temperature. Finally, add 15 μl of ADP-Glo detection solution and measure fluorescence using Envision equipment from Perkin-Elmer.

The IC 50 values were calculated by measuring the measured values of 7 different concentrations of the compound of the present invention using Prism (version 5.01, Graphpad Software, Inc.), and the results are shown in Table 2.

Example DRAK1 IC 50 ([mu] M) DRAK2 IC 50 (μM) One 3.5 9.2 2 > 10 3.5 3 > 10 > 10 4 0.017 0.02 5 0.017 0.009 6 0.11 0.17 7 0.14 0.087 8 0.1 0.011 9 0.59 0.35 10 0.049 0.31 11 0.046 0.005 12 0.001 0.023 13 0.03 0.009 14 0.01 0.08 15 0.11 0.018 16 0.16 0.008 17 0.4 0.047 18 0.34 0.53 19 0.29 0.064 20 2.7 5 21 0.074 0.014 22 0.025 0.006 23 0.027 0.002 24 0.07 0.013 25 0.04 0.056 26 0.96 0.5 27 0.17 0.064 28 0.42 0.018 29 0.15 0.11

Referring to Table 2, the compounds of the present invention was confirmed to have an inhibitory activity refers to, IC 50 values of 0.002 to about 10 of from 0.001 to 10 and the IC 50 for each DRAK2 DRAK1 against DRAK1 and DRAK2.

Accordingly, the compounds according to the present invention exhibit excellent inhibitory activity against DRAK1 and DRAK2, and can be effectively used as a preventive and therapeutic agent for antiinflammation and anti-cancer.

< Experimental Example  2> Pfeiffer cell line experiment

In order to measure the cancer cell killing effect of the compounds according to the present invention, cell line experiments were carried out as follows.

Pfeiffer cell lines purchased from ATCC are cultured in RPMI medium containing 10% FBS (Fetal bovine serum) and 1% penicillin / streptomycin under 5% carbon dioxide conditions. In order to measure the cancer cell killing effect by the compound of the present invention, the cultured Pfeiffer cell line was put into each well of a 96-well plate at 6000 cells / well. 1 ul of the 10 mM concentration of the Example compound is diluted with 99 ul of the cell culture medium and 10 ul of the solution of the Example compound is added to 90 ul of the cell line solution to start the experiment. The cell line to which the compound of the example is added is further cultured in a carbon dioxide incubator for 3 days. After 3 days, add 10 μl of Cyto X reagent from LPS solution to the cell line, incubate for 80 minutes in a CO2 incubator, and measure the absorbance at 450 nm.

For the measurement of half maximal growth inhibitory concentration (GI 50 ), experiments were carried out at different compound concentrations of 10 μM, 3.3 μM, 1.1 μM, 0.37 μM, 0.12 μM and 0.041 μM, quantitatively analyzed using the Prism program, Are shown in Table 3.

Example GI 50 ([mu] M) One 1.6 12 0.076 13 0.16 14 1.1 15 0.22 16 0.28 22 0.19 23 0.11 29 1.2

As shown in Table 3, the compound of the present invention exhibits a GI 50 value of 0.076 to 1.6 μM on a Pfeiffer cell line, so that the compound of the present invention has a cancer cell killing effect and can effectively inhibit cancer cell growth can confirm.

Therefore, the compounds according to the present invention exhibit excellent inhibitory activity against DRAK1 and DRAK2, and can prevent cancer cell death and growth with a unit concentration of less than or equal to μM, and thus are useful as prophylactic and therapeutic agents for anti-inflammatory and anti- Can be usefully used.

Claims (9)

Claims 1. A compound represented by the following formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof:
Figure 112016019587113-pat00076

(In the formula 1,
R 1 is hydrogen, halogen, C 1 -C 10 linear or branched alkyl, C 1 -C 10 straight or branched alkoxy, or unsubstituted or substituted C 3 -C 10 cycloalkyl,
Wherein said substituted C 3 -C 10 cycloalkyl is substituted with at least one substituent selected from the group consisting of halogen, C 1 -C 5 straight or branched chain alkyl and C 1 -C 5 straight or branched chain alkoxy Can be;

R 2 is - (CH 2 ) n -CN, - (CH 2 ) m -SO 2 CH 3 , or C 1 -C 10 linear or branched alkylcarbonyl, wherein n and m are integers from 0 to 5 ego; And

R 3 is hydrogen, halogen, -CN, C 1 -C 10 straight or branched chain alkyl substituted or unsubstituted with one or more halogens, or C 1 -C 10 straight or branched alkoxy.
The method according to claim 1,
R 1 is hydrogen, halogen, C 1 -C 5 linear or branched alkyl, C 1 -C 5 straight or branched alkoxy, or unsubstituted or substituted C 3 -C 5 cycloalkyl,
Wherein said substituted C 3 -C 5 cycloalkyl is substituted with at least one substituent selected from the group consisting of halogen, C 1 -C 3 straight or branched chain alkyl and C 1 -C 3 straight or branched chain alkoxy Can be;

R 2 is - (CH 2 ) n -CN, - (CH 2 ) m -SO 2 CH 3 , or C 1 -C 5 straight or branched chain alkylcarbonyl, and n and m are integers from 0 to 3 ego; And

R 3 is hydrogen, halogen, -CN, C 1 -C 5 straight or branched chain alkyl substituted with one or more halogens, or C 1 -C 5 straight or branched alkoxy, Or an optically active isomer thereof or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
R 1 is methyl, ethyl, propyl, isopropyl, cyclopropyl or tert-butyl;
R 2 is
Figure 112016019587113-pat00077
,
Figure 112016019587113-pat00078
,
Figure 112016019587113-pat00079
,
Figure 112016019587113-pat00080
or
Figure 112016019587113-pat00081
ego; And
R &lt; 3 &gt; is -H, -Cl, -F, -Br or -I, an optical isomer thereof or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
The compound represented by the formula (1) is any one selected from the group consisting of the following compounds, an optical isomer thereof or a pharmaceutically acceptable salt thereof:
(1) Synthesis of 2- (4 - ((4 - ((5-tert-butyl-1H-pyrazol- Nitrile;
(2) N4- (5- (tert-butyl) -1H-pyrazol-3-yl) -5-methoxy-N2- (4- (methylsulfonyl) phenyl) pyrimidine-2,4-diamine;
(3) Synthesis of N4- (5- (tert-butyl) -1H-pyrazol-3-yl) -5-methoxy-N2- (4- (methylsulfonyl) methyl) phenyl) pyrimidine- Diamine;
(4) 2- (4 - ((5-Methoxy-4 - ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) amino) phenyl) acetonitrile;
(5) 5-Methoxy-N4- (5-methyl-1H-pyrazol-3-yl) -N2- (4- (methylsulfonyl) phenyl) pyrimidine-2,4-diamine;
(6) 5-Methoxy-N4- (5-methyl-1H-pyrazol-3-yl) -N2- (4 - ((methylsulfonyl) methyl) phenyl) pyrimidine-2,4-diamine;
(7) 4 - (((5-Methoxy-4 - ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) amino) benzonitrile;
(8) Synthesis of 1- (4 - ((5-methoxy-4 - ((5-methyl-1H-pyrazol- ;
(9) 2-Chloro-4 - ((5-methoxy-4 - ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) amino) benzonitrile;
(10) 4 - ((4 - ((5-Cyclopropyl-1H-pyrazol-3-yl) amino) -5-methoxypyrimidin-2-yl) amino) benzonitrile;
(11) Preparation of 1- (4 - ((4 - ((5-cyclopropyl- 1 H- pyrazol-3-yl) amino) -5-methoxypyrimidin- 1-one;
(12) 2- (4 - ((4 - ((5-Cyclopropyl-1H-pyrazol-3-yl) amino) -5-methoxypyrimidin-2-yl) amino) phenyl) acetonitrile;
(13) N4- (5-Cyclopropyl-1H-pyrazol-3-yl) 5-methoxy-N2- (4- (methylsulfonyl) phenyl) pyrimidine-2,4-diamine;
(14) N4- (5-Cyclopropyl-1H-pyrazol-3-yl) 5-methoxy-N2- (4- (methylsulfonyl) methyl) phenyl) pyrimidine-2,4-diamine;
(15) 2- (4 - ((5-Methoxy-4 - ((5-propyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) amino) phenyl) acetonitrile;
(16) 5-Methoxy-N2- (4- (methylsulfonyl) phenyl) -N4- (5-propyl-1H-pyrazol-3-yl) pyrimidine-2,4-diamine;
(17) 5-Methoxy-N2- (4- (methylsulfonyl) phenyl) -N4- (5-propyl-1H-pyrazol-3-yl) pyrimidine-2,4-diamine;
(18) 4 - ((5-Methoxy-4 - ((5-propyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) amino) benzonitrile;
(19) Synthesis of 1- (4 - ((5-methoxy-4 - ((5-propyl-1H-pyrazol-3- yl) amino) pyrimidin- ;
(20) 2-Chloro-4 - ((5-methoxy-4 - ((5-propyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) amino) benzonitrile;
(21) 4 - ((4 - ((5-ethyl-1H-pyrazol-3-yl) amino) -5-methoxypyrimidin-2-yl) amino) benzonitrile;
(22) 2- (4 - ((4 - ((5-ethyl-1H-pyrazol-3-yl) amino) -5-methoxypyrimidin-2-yl) amino) phenyl) acetonitrile;
(23) N4- (5-Ethyl-1H-pyrazol-3-yl) -5-methoxy-N2- (4- (methylsulfonyl) phenyl) -pyrimidine-2,4-diamine;
(24) N4- (5-Ethyl-1H-pyrazol-3-yl) -5-methoxy-N2- (4- (methylsulfonyl) methyl) -phenyl) -pyrimidine-2,4-diamine;
(25) Synthesis of 1- (4 - ((4 - ((5-ethyl-1H-pyrazol-3-yl) amino) -5-methoxypyrimidin- ;
(26) 2-Chloro-4 - ((4 - ((5-ethyl-1H-pyrazol-3-yl) amino) -5-methoxypyrimidin-2-yl) amino) benzonitrile;
(27) 2- (4 - ((4 - ((5-isopropyl-1H-pyrazol-3-yl) amino) -5-methoxypyrimidin-2-yl) amino) phenyl) acetonitrile;
(28) N4- (5-isopropyl-1H-pyrazol-3-yl) -5-methoxy-N2- (4- (methylsulfonyl) -pyrimidine-
(29) N4- (5-Isopropyl-1H-pyrazol-3-yl) -5-methoxy-N2- (4- (methylsulfonyl) methyl) phenyl) pyrimidine-2,4-diamine.
As shown in Scheme 1 below,
Reacting a compound represented by the formula (2) with a compound represented by the formula (3) to prepare a compound represented by the formula (4) (step 1);
Reacting the compound represented by the formula (4) and the compound represented by the formula (5) prepared in the step 1 to prepare a compound represented by the formula (6) (step 2); And
(3), which comprises reacting a compound represented by the formula (6) and a compound represented by the formula (7) to prepare a compound represented by the formula (1) : &Lt;
[Reaction Scheme 1]
Figure 112016019587113-pat00082

(In the above Reaction Scheme 1,
R 1 , R 2 , and R 3 are the same as defined in Formula (1).
For the prophylaxis or treatment of diseases caused by cancer, autoimmune diseases, inflammatory diseases, diabetes mellitus or organ transplant rejection reaction containing the compound represented by the general formula (1) of claim 1 or an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient A pharmaceutical composition.
delete For the prevention or amelioration of diseases caused by cancer, an autoimmune disease, an inflammatory disease, a diabetes or an organ transplant rejection reaction containing the compound represented by the formula (1) of claim 1, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient Health functional food composition.
delete
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007059299A1 (en) * 2005-11-16 2007-05-24 Vertex Pharmaceuticals Incorporated Aminopyrimidines useful as kinase inhibitors
KR20100050557A (en) * 2007-08-28 2010-05-13 아이알엠 엘엘씨 2-biphenylamino-4-aminopyrimidine derivatives as kinase inhibitors
WO2013143466A1 (en) * 2012-03-27 2013-10-03 广东东阳光药业有限公司 Substituted pyrimidine derivative as aurora kinase inhibitor

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007059299A1 (en) * 2005-11-16 2007-05-24 Vertex Pharmaceuticals Incorporated Aminopyrimidines useful as kinase inhibitors
KR20100050557A (en) * 2007-08-28 2010-05-13 아이알엠 엘엘씨 2-biphenylamino-4-aminopyrimidine derivatives as kinase inhibitors
WO2013143466A1 (en) * 2012-03-27 2013-10-03 广东东阳光药业有限公司 Substituted pyrimidine derivative as aurora kinase inhibitor

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* Cited by examiner, † Cited by third party
Title
DRAK1 overexpression inhibits TGF-β signaling pathway. Y Park et al. Oncogene (2014), 1-9(Oncogene advance online publication, 22 December 2014; doi:10.1038/onc.2014.423)

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