KR101723881B1 - Novel triazole derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating Aurora Kinase relating diseases containing the same as an active ingredient - Google Patents

Abstract

The present invention relates to a novel triazole derivative, a production method thereof, and an aurora kinase-associated pharmaceutical composition containing the same as an active ingredient. According to the present invention, the novel triazole derivative, an optical isomer thereof, or a pharmaceutically acceptable salt thereof exhibits excellent inhibitory activities as aurora kinase at nanomolar scale, thereby showing effectiveness in the treatment of various types of cancer or tumor as the pharmaceutical composition containing the same.

Description

TECHNICAL FIELD [0001] The present invention relates to a novel triazole derivative, a process for producing the same, and a pharmaceutical composition containing the same as an active ingredient. ingredient}

The present invention relates to a novel triazole derivative, a process for preparing the same, and a pharmaceutical composition containing the same as an active ingredient.

Aurora kinase is one of the serine / threonine kinases and one of the targets that has received great attention to date for therapeutic purposes of cancer. The aurora kinase A is aurora kinase A, aurora kinase B, and aurora kinase C, and Aurora kinase A and B are commonly overexpressed in human tumor cells or cancers and occur in breast, pancreas, stomach, intestines and kidney organs , Which is known to play an important role in various organ tumors including cancer. Specifically, over-expressed Aurora kinase A causes abnormal phosphorylation of the normal cell cycle target and the cytoplasmic target leading to chromosome instability, tumor transformation, tumor progression and compound resistance enhancement, and similarly overexpressed Aurora kinase B is transformed Increases phosphorylation of histone H3 in mice and produces more aggressive tumors.

In addition, Aurora kinases (A, B and C) are regulatory proteins and play a key role in the mitotic division of cell differentiation. Aurora kinase A is involved in the dorsal pole and regulates central repopulation, growth, and mitotic spindle assembly. Aurora kinase B is involved in chromatin remodeling, phosphorylation of histone H3 at serine-10, cleavage of the centrosome, cleavage of the salt boundaries and cytoplasmic cleavage. Aurora kinase C, the third isoenzyme, has not yet been clearly elucidated, but is analogous to the function and location of Aurora A and B above.

Over the past decade, extensive research has been conducted to develop small molecule inhibitors that selectively target Aurora kinase. As a result of these efforts, several Aurora kinase inhibitors have been identified, one of which is a more selective inhibitor of Aurora kinase A as an inhibitor produced as part of an attempt to treat humans (Non-Patent Document 1). In addition, inhibitors targeting Aurora kinase B have recently been developed. However, compounds exhibiting an inhibitory activity against Aurora kinase have been developed. However, no compounds showing inhibitory activity suitable for therapeutic purposes have been developed yet.

Accordingly, the present inventors have made efforts to develop a compound that can excellently inhibit Aurora kinase and can be used therefor for the treatment of diseases such as cancer and tumor. The novel triazole derivative according to the present invention is a novel Aurora kinase A and B, and can be effectively used as an anticancer agent and antitumor agent for cancer and tumor from a pharmaceutical composition containing the same. Thus, the present invention has been completed.

EA Harrington et al., Nature Medicine. 262-7 (2004).

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 Aurora Kinase-related diseases.

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

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

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer containing the above-mentioned compound as an active ingredient.

Another object of the present invention is to provide a health functional food for preventing or ameliorating Aurora Kinase-related diseases containing the above 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.

[Chemical Formula 1]

In Formula 1,

R ¹ is unsubstituted, substituted or fused phenyl, or - (CH ₂ ) _n -NR ² R ³ ;

And wherein said substituted phenyl is a phenyl substituted one to three -NO _2,

Wherein the fused phenyl is heteroaryl of unsubstituted hexa ring containing one or more N or heterocycloalkyl of unsubstituted 5-6 heterocyclic ring containing at least one O;

Wherein R ² may be a straight or branched chain alkyl of -H, or C _1-5, unsubstituted 5-8 each containing a hetero atom, at least one member selected from the group consisting of N, O and S together with the R ³ Form heterocycloalkyl of the ring;

R ³ is C _1-5 linear or branched alkyl, C _1-5 straight or branched alkylcarbonyl, unsubstituted or substituted aryl of 6-10 ring, - (CH ₂ ) _m -NR ⁴ R ⁵ , Or heteroaryl of an unsubstituted or substituted 5-10 heterocyclic ring containing at least one heteroatom selected from the group consisting of N, O and S,

Wherein R < ⁴ > and R < ⁵ > together form a 5- to 8-membered heterocycloalkyl comprising at least one heteroatom selected from the group consisting of N, O and S, wherein m is an integer from 1 to 3,

The aryl of the substituted 6-10-arylene ring and the heteroaryl of the 5-10-arylene are independently selected from the group consisting of halogen, C _1-5 linear or branched alkyl and C _1-5 straight or branched alkoxy The substituent may be substituted; And

And n is an integer of 1 to 5.

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); And

(Step 2), which comprises reacting the compound represented by Formula 4 and the compound represented by Formula 5, prepared in Step 1, to prepare a compound represented by Formula 1 ≪ / RTI >

[Reaction Scheme 1]

In the above Reaction Scheme 1,

R ¹ is the same as defined in the above formula (1).

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

The present invention also provides a pharmaceutical composition for preventing or treating cancer comprising the compound represented by the formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

Further, the present invention provides a health functional food for preventing or ameliorating Aurora Kinase-related diseases containing the compound represented by the formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

The novel triazole derivative, its optical isomer, or pharmaceutically acceptable salt thereof according to the present invention exhibits an excellent inhibitory activity of a nano-mol unit as an aurora kinase inhibitor, and is a pharmaceutical composition containing the same as an inhibitor of various cancers or tumors There is a useful effect in treatment.

Hereinafter, the present invention will be described in detail.

The following description is provided to assist the understanding of the invention, and the present invention is not limited to the following description.

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

[Chemical Formula 1]

In Formula 1,

R ¹ is unsubstituted, substituted or fused phenyl, or - (CH ₂ ) _n -NR ² R ³ ;

And wherein said substituted phenyl is a phenyl substituted one to three -NO _2,

Wherein the fused phenyl is heteroaryl of unsubstituted hexa ring containing one or more N or heterocycloalkyl of unsubstituted 5-6 heterocyclic ring containing at least one O;

Wherein R ² may be a straight or branched chain alkyl of -H, or C _1-5, unsubstituted 5-8 each containing a hetero atom, at least one member selected from the group consisting of N, O and S together with the R ³ Form heterocycloalkyl of the ring;

R ³ is C _1-5 linear or branched alkyl, C _1-5 straight or branched alkylcarbonyl, unsubstituted or substituted aryl of 6-10 ring, - (CH ₂ ) _m -NR ⁴ R ⁵ , Or heteroaryl of an unsubstituted or substituted 5-10 heterocyclic ring containing at least one heteroatom selected from the group consisting of N, O and S,

Wherein R < ⁴ > and R < ⁵ > together form a 5- to 8-membered heterocycloalkyl comprising at least one heteroatom selected from the group consisting of N, O and S, wherein m is an integer from 1 to 3,

The aryl of the substituted 6-10-arylene ring and the heteroaryl of the 5-10-arylene are independently selected from the group consisting of halogen, C _1-5 linear or branched alkyl and C _1-5 straight or branched alkoxy The substituent may be substituted; And

N is an integer of 1 to 5,

Preferably,

Wherein R ² is -H or C _1-3 straight chain or branched chain alkyl, or R ³ is taken together to form a heterocyclic ring of unsubstituted six-membered rings containing at least one heteroatom selected from the group consisting of N and O, Alkyl;

R ³ is C _1-3 linear or branched alkyl, C _1-3 linear or branched alkylcarbonyl, unsubstituted 6-10-membered ring aryl, - (CH ₂ ) _m -NR ⁴ R ⁵ , or N , Heteroaryl of an unsubstituted or substituted 5-10 heterocyclic ring containing at least one heteroatom selected from the group consisting of O and S,

Wherein R < ⁴ > and R < ⁵ > together form a heterocycloalkyl of a hexa ring containing at least one heteroatom selected from the group consisting of N, O and S, wherein m is an integer from 1 to 2,

Wherein said heteroaryl of said substituted 5-10 heterocyclic ring may be substituted independently with one or more substituents selected from the group consisting of halogen, C _1-5 straight or branched chain alkyl and C _1-5 straight or branched alkoxy; And

Wherein n is an integer of 1 to 3,

More preferably, @@

를 형성하고;Wherein R ² is either -H or methyl, and is connected with the R ³

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ego; And

And n is an integer of 1 to 2.

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

(1) Methyl 3- (2-hydroxy-5- (4- (3-nitrophenyl) -1H-1,2,3-triazol-1-yl) benzamido) benzoate;

(2) Methyl 3- (2-hydroxy-5- (4- (quinoxalin-6-yl) -1H-1,2,3-triazol-1-yl) benzamido) benzoate;

(3) Synthesis of methyl 3- (5- (4- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -1H-1,2,3- triazol- -2-hydroxybenzamido) benzoate;

(4) Synthesis of methyl 3- (5- (4- (benzo [d] [1,3] dioxol-5-yl) -1H-1,2,3- triazol- Amido) benzoate;

(5) Methyl 3- (2-hydroxy-5- (4- (phenylamino) methyl-1H-1,2,3-triazol-1-yl) benzamido) benzoate;

(6) Synthesis of methyl 3- (2-hydroxy-5- (4 - ((5-methylisoxazol-3- yl) amino) methyl-1H-1,2,3-triazol- Amido) benzoate;

(7) Synthesis of methyl 3- (2-hydroxy-5- (4 - ((6-methylpyridin-2-yl) amino) methyl-1H-1,2,3-triazol- ) Benzoate;

(8) Methyl 3- (2-hydroxy-5- (4- (pyrimidin-2-ylamino) methyl-1H-1,2,3-triazol-1-yl) benzamido) benzoate;

(9) Synthesis of methyl 3- (2-hydroxy-5- (4- (2- (pyrimidin-2-ylamino) ethyl) -1H-1,2,3- triazol- ) Benzoate;

(10) Methyl 3- (2-hydroxy-5- (4- (oxazol-2-ylamino) methyl-1H-1,2,3-triazol-1-yl) benzamido) benzoate;

(11) Synthesis of methyl 3- (5- (4- (benzo [d] [1,3] dioxol-2-ylamino) methyl-1H-1,2,3-triazol- Lt; / RTI > benzoamido) benzoate;

(12) Synthesis of methyl 3- (2-hydroxy-5- (4- (thieno [3,2-d] pyrimidin-4-ylamino) methyl-1H-1,2,3- Yl) benzamido) benzoate;

(13) methyl 3- (2-hydroxy-5- (4- (2- (thieno [3,2-d] pyrimidin- Triazol-1-yl) benzamido) benzoate;

(14) Methyl 3- (2-hydroxy-5- (4- (N-morpholino) methyl-1H-1,2,3-triazol-1-yl) benzamido) benzoate;

(15) Synthesis of methyl 3- (2-hydroxy-5- (4 - ((2- (N-morpholino) ethyl) amino) methyl-1H-1,2,3-triazol- Amido) benzoate;

(16) Synthesis of methyl 3- (5- (4- (2 - ((N, N-dimethylamino) ethyl) -1H-1,2,3- triazol- 1 -yl) -2- Benzoate;

(17) Methyl 3- (2-hydroxy-5- (4- (2-acetamidoethyl) -1H-1,2,3-triazol-1-yl) benzamido) benzoate;

(18) Synthesis of methyl 3- (2-hydroxy-5- (4 - ((5-methyl-1H-pyrazol- ) ≪ / RTI > benzamido) benzoate;

(19) Synthesis of methyl 3- (2-hydroxy-5- (4- (thiazol-2-yl) amino) methyl-1H-1,2,3- triazol- 1- yl) benzamido) benzoate ;

(20) Synthesis of methyl 3- (5- (4- (1H-imidazol-2-ylamino) methyl-1H-1,2,3-triazol- 1 -yl) -2- Eight;

(21) Methyl 3- (2-hydroxy-5- (4- (pyridin-2-ylamino) methyl-1H-1,2,3-triazol-1-yl) benzamido) benzoate;

(22) Synthesis of methyl 3- (2-hydroxy-5- (4 - ((4-methylpyridin-2-yl) amino) methyl-1H-1,2,3-triazol- ) Benzoate;

(23) Methyl 3- (2-hydroxy-5- (4- (pyridin-4-ylamino) methyl-1H-1,2,3-triazol-1-yl) benzamido) benzoate; And

(24) Methyl 3- (2-hydroxy-5- (4- (pyrimidin-4-ylamino) methyl-1H-1,2,3-triazol-1-yl) benzamido) benzoate.

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 innocuous salts include, but are not limited to, 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, chloro Such as benzenesulfonate, benzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate,? -Hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1-sulfonate, naphthalene-2-sulfonate, mandelate and the like.

The acid addition salt according to the present invention can be prepared by a conventional method, for example, 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); And

(Step 2), which comprises reacting the compound represented by Formula 4 and the compound represented by Formula 5, prepared in Step 1, to prepare a compound represented by Formula 1 ≪ / RTI >

[Reaction Scheme 1]

In the above Reaction Scheme 1,

R ¹ is the same as defined in the above 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, H ₂ O, ethanol, tetrahydrofuran (THF), methylene chloride, toluene, acetonitrile and the like can be used as the solvent which can be used in the above step, and H ₂ O or tetrahydrofuran (THF) Can be used.

In the above step, the reaction is preferably carried out at a temperature ranging from 0 ° C to the boiling point of the solvent. The reaction time is not particularly limited, but it is preferably 0.5-20 hours.

In the method for preparing the compound represented by the formula (1) according to the present invention, the step (2) is a step of reacting the compound represented by the formula (4) and the compound represented by the formula (5) .

The solvent used in this step may be dimethylformamide (DMF), H ₂ O, methanol, ethanol, tetrahydrofuran (THF), methylene chloride, toluene, acetonitrile, Amide (DMF), H ₂ O, t-butanol (t-BuOH) can be used.

In the above step, the reaction is preferably carried out at a temperature ranging from 0 ° C to the boiling point of the solvent. The reaction time is not particularly limited, but is preferably 0.5 to 45 hours.

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

Herein, Aurora Kinase-related diseases include, but are not limited to, all diseases that can be expressed from a non-normal activity such as abnormality, transformation, overexpression, etc. of the Aurora kinase enzyme. In particular, examples of diseases related to aurora kinase include cancers, and when the compound is derived from the abnormal activity of aurora kinase in association with cell proliferation of cancer cells, the compound of the present invention, its optical isomer and its acceptable salts, The activity can be effectively inhibited by the unit of nano moles and can be usefully used for the prevention or treatment of diseases referred to as the aurora kinase-related diseases.

The present invention also provides a pharmaceutical composition for preventing or treating cancer comprising the compound represented by the formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

Herein, the compound may be characterized by inhibiting Aurora kinase to prevent or treat cancer, wherein the cancer is selected from the group consisting of colon cancer, liver cancer, stomach cancer, breast cancer, colon cancer, pancreatic cancer, head or neck cancer, Ovarian cancer, rectal cancer, esophageal cancer, small intestine cancer, anorectal cancer, colon cancer, fallopian tube carcinoma, endometrial carcinoma, uterine cancer, vaginal carcinoma, vulvar carcinoma, hodgkin's disease, prostate cancer, bladder cancer, kidney cancer, Cell carcinoma, kidney pelvic carcinoma, central nervous system tumor, and leukemia.

Further, the present invention provides a health functional food for preventing or ameliorating Aurora Kinase-related diseases containing the compound represented by the formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

Herein, the Aurora Kinase-related diseases include, but are not limited to, colon cancer, liver cancer, gastric cancer, breast cancer, colon cancer, bone cancer, pancreatic cancer, head or neck cancer, uterine cancer, ovarian cancer, rectum cancer, esophageal cancer, small intestine cancer, A cancer selected from the group consisting of carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, prostate cancer, bladder cancer, renal cancer, ureter cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system tumor and leukemia Or two or more.

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 compounds according to the present invention, their optical isomers, or their pharmaceutically acceptable salts have been found experimentally to be effective in the treatment of Aurora kinase-related diseases by acting on Aurora kinase A or Aurora kinase B.

First, experiments were conducted to evaluate the inhibitory activity of the enzyme units of the compound of Example of the present invention with respect to Aurora kinase A or Aurora kinase B. As a result, it was found that the compound of the present invention was effective against Aurora kinase A or Aurora kinase B 2, 3, 4, 5, 6, 9, 11, 12, 13, 18, 21 and 21 of the 24 example compounds of the present invention, and in particular, 22 compound exhibits a high inhibitory activity, and in the case of Aurora kinase B, the compound of Example 13 exhibits a high inhibitory activity. Thus, the compounds according to the present invention can be used not only for Aurora kinase-related diseases, but also for cancer derived therefrom Cancer of the stomach, cancer of the colon, cancer of the liver, stomach cancer, breast cancer, colon cancer, bone cancer, pancreatic cancer, head or neck cancer, uterine cancer, ovarian cancer, rectal cancer, esophageal cancer, small intestine cancer, Prevention and treatment of cancer of the distal potential of cancer of the cervical carcinoma, vagina carcinoma, vulvar carcinoma, Hodgkin's disease, prostate cancer, bladder cancer, kidney cancer, ureter cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system tumor and leukemia or solid tumor (See Experimental Example 1).

Further, as a result of conducting an experiment for evaluating the IC ₅₀ for Aurora kinase A and Aurora kinase B of the compound represented by the formula 1 according to the present invention, it was found that the compound of the example of the present invention, and showed a low IC ₅₀ values, in the case of Aurora kinase B, it can be confirmed to exhibit a lower IC ₅₀ value than the prior art, the compounds according to the present invention can exhibit excellent inhibitory activity against both Aurora kinases a and B Or alternatively can exhibit an excellent inhibitory activity against aurora kinase of either Aurora kinase A or Aurora kinase B, and thus can be used for the treatment of a disease caused by Aurora kinase such as colon cancer, liver cancer, stomach cancer, breast cancer , Colon cancer, bone cancer, pancreatic cancer, head or neck cancer, uterine cancer, ovarian cancer, rectal cancer, esophageal cancer, small intestine cancer, Neoplasms, renal cell carcinomas, renal pelvic carcinomas, central nervous system tumors and leukemias, or solid tumors, including, but not limited to, prostate cancer, prostate cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, prostate cancer, And may be useful for prevention and treatment of cancer which is a distal potential.

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.

All reactions were carried out in a flame-dried glass vessel fitted with a glass stopper under argon static pressure, using a magnetic stirrer, unless otherwise stated. Air- and moisture-sensitive liquids and solutions were transferred through injections or stainless steel-steel cannulas. TLC was performed on a 0.25 mm E. Merck silica gel 60 F ₂₅₄ plate and visualized under ultraviolet light (254 nm) or stained using potassium ammonium molybdate (CAM), potassium permanganate (KMnO4), p-anisaldehyde . Flash chromatography was performed on E. Merck 230-400 mesh silica gel 60. All reagents were purchased from commercial suppliers and were not further purified unless otherwise noted. The solvent was distilled under argon gas at 760 mm Hg using a suitable drying agent (CaH ₂ or Na wire). All water- and / or oxygen-sensitive solids were handled and stored in a glovebox under nitrogen gas (N2). NMR spectra were recorded on Varian Unity 400 instruments at 24 < 0 > C. The chemical shifts were: TMS ( ¹ H, 0 ppm), CDCl ₃ ( ¹ H, 7.26 ppm; ¹³ C, 77.2 ppm), DMSO-d ₆ ( ¹ H, 2.50 ppm; ¹³ C, 39.5 ppm ), acetone-d ₆ ( ¹ H, 2.05 ppm; ¹³ C, 206.3, 29.9 ppm), benzene-d ₆ ( ¹ H, 7.15 ppm; ¹³ C, 128.5 ppm), CD ₃ OD ( ¹ H, 3.31 ppm; ¹³ C, 49.1 ppm); And the coupling constant is expressed in Hz. High resolution mass spectra electrospray ionization (HRMS-ESI) was obtained on an Agilent technologies 6220 TOF LC / MS spectrometer.

The compound of Example of the present invention was synthesized by performing a click chemistry. First, a hinge binder of the compound of Example was synthesized as follows.

Specifically, it is possible to form hinge bonds through Cu (I) -catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) from various alkynes and azaisosalicylamides having hydrogen-bond donor / , 3-triazolyl salicylamide derivatives can be synthesized. 9a to 9x compounds effective in the hinge bonding portion and three synthesis methods for synthesizing the compounds are shown in Reaction Scheme 2 below.

[Reaction Scheme 2]

The first synthesis method is aryl acetylene 9a to 9d was obtained through the TMS acetylene and aryl halide 10 of Sonogashira cross-coupling reaction and then, alkynyl 11a to 11d of the de-TMS protecting group in reaction K ₂ CO _3. The obtained 9a to 9d have 1 to 2 hydrogen-bond acceptors at the meta or para position. A second synthesis method was obtained through nucleophilic aromatic substitution reactions with alkyne 9i and aryl chlorides 12i and 12k to 12m using 9/9 to 9m propyl / homoprotein. As a final method, the majority of the alkyne was obtained through the propanation reaction of various amines, with the alkynes 9e to 9h, 9j, 9n, and 9o being the propanilization reactions of the amine without additional protecting groups, while the alkynes 9r to 9x were Boc Lt; RTI ID = 0.0 > protected-protected < / RTI > amine.

Next, azidesaryl amide was synthesized from commercially available 5-aminosalicylic acid as shown in Reaction Scheme 3 below.

[Reaction Scheme 3]

NaNO ₂ was added to a sulfuric acid solution of 5-aminosalicylic acid to make an amino group as a diazonium salt, which was then reacted with NaN ₃ to give 5-azidic salicylic acid (2) in a yield of 99%. Subsequently, a CDI coupling reaction of the compound represented by the formula (2) and the substituted aniline containing an electron-withdrawing ester group was carried out to obtain the amide represented by the formula (4) in a yield of 21%, but 3- (diethoxyphosphoryloxy) -1,2,3-benzotriazin-4 (3H) -one (DEPBT) in an improved yield of 64% in the manner of the azithosalicylamide of formula (4).

The CuAAC reaction was performed using the prepared alkyne moieties 9a to 9x and the azide compound represented by the above formula 4 under standard conditions of click (click conditions: i) using CuI and DMF as a solvent, or ii) using CuSO4, Sodium and t-BuOH / H2O as solvent).

Under the above-mentioned click conditions, all the reactions were carried out as shown in the following examples.

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> methyl  3- (2- Hydroxy -5- (4- (3- Nitrophenyl ) -1H-1,2,3- Triazole -1-yl) benzamido) benzoate (1a)

step 1: 5 - Azido -2- Hydroxybenzoic acid  Produce

5-Aminosalicylic acid (1.05 g, 6.53 mmol) was dissolved in a mixture of H ₂ SO ₄ (5 mL) and H ₂ O (26.1 mL). The mixture was cooled to 0 ℃ was added, one drop of a solution of _{NaNO 2 (557 mg, 7.84 mmol} ) is H ₂ O (5 ml) dissolved. After stirring at 0 ° C for 1.5 hours, a solution of H ₂ O (4 mL) in which NaN ₃ (722 mg, 11.1 mmol) was dissolved was added dropwise at 0 ° C. The suspension obtained from above was stirred at 0 &lt; 0 &gt; C for 1.5 hours and at room temperature for 13 hours. The reaction mixture was extracted with EtOAc (3 x 300 mL). The combined organic extract from the washed with brine (brine), dried over anhydrous MgSO _4, and filtered. And evaporated to dryness under reduced pressure to give the title compound as a red solid (1.16 g, 99%).

TLC: _Rf 0.31 (5: 1 EtOAc / MeOH). ^{1 H NMR (400 MHz, DMSO} -d 6): δ 13.75 (brs, 1H), 11.30 (brs, 1H), 7.42 (d, J = 2.8 Hz, 1H), 7.15 (dd, J = 8.8, 2.8 Hz , &Lt; / RTI &gt; 1H), 7.02 (d, J = 8.8 Hz, 1H). ^{13 C NMR (100 MHz, DMSO} -d 6): δ 170.9, 158.3, 130.2, 126.6, 119.7, 118.9, 113.9.

Step 2: methyl  3- (5-azido-2- Hydroxybenzamide ) Benzoate  Produce

0 ℃ under an argon gas-methyl-3-aminobenzoate (751 mg, 4.87 mmol), Et 3 N (1.54 mL, 11.0 mmol) and DEPBT (3- (ethoxy phosphoryl the die oxy) -l, 2,3-benzo (3.00 g, 6.68 mmol) was added to THF (5.4 mL) in which 5-azido-2-hydroxybenzoic acid (1.00 g, 5.58 mmol) Respectively. After stirring at 70 ° C for 5 hours, the reaction mixture was quenched with distilled water (28 mL) and the combined organic layers were dried over anhydrous MgSO ₄ , filtered and concentrated by rotary evaporation. The residue was purified by column chromatography (4: 1 hexane / ethyl acetate) to give the title compound as a brown solid (968 mg, 64%).

TLC: _Rf 0.33 (4: 1 hexanes / EtOAc). ^{1 H NMR (400 MHz, DMSO} -d 6): δ 11.60 (brs, 1H), 10.61 (brs, 1H), 8.40 (t, J = 1.2 Hz, 1H), 7.94 (dm, J = 8.0 Hz, 1H ), 7.74 (dt, J = 8.0, 1.2 Hz, 1H), 7.65 (d, J = 2.8 Hz, 1H), 7.53 , &Lt; / RTI &gt; 1H), 7.05 (d, J = 8.4 Hz, 1H), 3.88 (s, 3H). ^{13 C NMR (100 MHz, DMSO} -d 6): δ 166.0, 165.5, 155.4, 138.5, 130.4, 130.2, 129.3, 125.3, 124.8, 124.5, 121.2, 119.3, 119.0, 118.8, 52.3.

Step 3: methyl  3- (2- Hydroxy -5- (4- (3- Nitrophenyl ) -1H-1,2,3- Triazole -1-yl) benzamido) benzoate (1a)

At room temperature, a screw cap vial was charged with methyl 3- (5-azido-2-hydroxybenzamido) benzoate (62.5 mg, 200 μmol), alkyne 9a (40.0 mg, 272 μmol) (19.5 mg, 100 [mu] mol) and anhydrous DMF (0.4 mL). The reaction mixture was stirred at 80 &lt; 0 &gt; C for 16 hours. The reaction was terminated and the reaction mixture was cooled to room temperature. Purification by column chromatography (40: 1 CH ₂ Cl ₂ / MeOH) afforded the title compound as an ivory solid (65.3 mg, 71%).

TLC: _Rf 0.34 (40: 1 CH ₂ Cl ₂ / MeOH 2). Mp: 278.0-280.0 占 폚. ^{1 H NMR (400 MHz, DMSO} -d 6): δ 11.87 (s, 1H), 10.71 (brs, 1H), 9.55 (s, 1H), 8.77 (t, J = 2.0 Hz, 1H), 8.45-8.44 (dd, J = 8.0, 1.2 Hz, 1H), 8.25 (ddd, J = 8.0, 2.0, 1.2 Hz, 1H), 8.01 J = 8.0 Hz, 1H), 7.75 (dd, J = 8.0 Hz, 1H) 7.25 (d, J = 8.8 Hz, 1H), 3.89 (s, 3H). ^{13 C NMR (100 MHz, DMSO} -d 6): δ 166.0, 165.1, 157.7, 148.4, 145.2, 138.6, 132.0, 131.3, 130.7, 130.2, 129.3, 128.5, 125.3, 125.1, 124.8, 122.7, 121.3, 121.0 ( 2C), 119.6, 119.6, 118.4, 52.2. HRMS (ESI) m / z calcd for C ₂₃ H ₁₈ N ₅ O ₆ ⁺ ([M + H] ⁺ ) 460.1252, found 460.1246.

< Example  2> methyl  3- (2- Hydroxy -5- (4- ( Quinoxaline -6-yl) -1H-1,2,3- Triazole -1-yl) benzamido) benzoate (1b)

The procedure of Example 1 was repeated except that alkyne 9b was used in place of alkyne 9a used in step 3 of Example 1 to obtain the desired compound as a pale yellowish white solid (51.8 mg, 74%).

_{TLC: R f 0.21 (20:} 1 CH 2 Cl 2 / MeOH). Mp: 270.1-272.1 [deg.] C. ^{1 H NMR (400 MHz, DMSO} -d 6): δ 11.87 (s, 1H), 10.71 (s, 1H), 9.59 (s, 1H), 9.00 (d, J = 1.6 Hz, 1H), 8.97 (d (M, 2H), 8.25 (d, J = 7.6 Hz, 1H), 8.65 J = 8.8 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.56 (t, J = 8.0 Hz, 1 H), 7.26 (d, J = 8.8 Hz, 1 H), 3.89 (s, 3H). ^{13 C NMR (100 MHz, DMSO} -d 6): δ 166.0, 165.2, 158.1, 146.4, 146.0, 145.6, 142.6, 142.1, 138.6, 131.9, 130.2, 130.0, 129.3, 128.4, 127.6, 125.4, 125.1, 124.7, 124.5, 121.4, 121.2, 121.0, 119.5, 118.5, 52.2. HRMS (ESI) m / z calcd for C 25 H 19 N 6 O 4 + ([M + H] +) 467.1462, found 467.1464.

< Example  3> methyl  3- (5- (4- (2,3- Dihydrobenzo [b] [1,4] dioxin Yl) -1H-1,2,3-triazol-1-yl) -2-hydroxybenzamido) benzoate (1c)

The target compound was obtained as an ivory solid (92.5 mg, 98%) in the same manner as in Example 1, except that the alkyne 9c was used instead of the alkyne 9a used in the step 3 of Example 1 above.

_{TLC: R f 0.18 (40:} 1 CH 2 Cl 2 / MeOH). Mp: 246.1-247.8 [deg.] C. ^{1 H NMR (400 MHz, DMSO} -d 6): δ 11.84 (s, 1H), 10.69 (brs, 1H), 9.14 (s, 1H), 8.44 (t, J = 2.0 Hz, 1H), 8.41 (d (Dd, J = 8.8 Hz, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.97 J = 8.0 Hz, 1H), 7.43 (s, 1H), 7.42 (dd, J = 8.8, 2.0 Hz, 1H), 7.23 (d, J = 8.8, 1.2 Hz, 1 H), 4.29 (s, 4 H), 3.88 (s, 3 H). ^{13 C NMR (100 MHz, DMSO} -d 6): δ 166.0, 165.4, 158.1, 146.9, 143.7, 143.5, 138.6, 130.2, 129.2, 128.5, 125.2, 125.2, 124.8, 123.7, 121.1 (2C), 119.1, 119.0 , 118.5, 118.4, 117.6, 113.9, 64.1, 52.2. HRMS (ESI) m / z calcd for C 25 H 21 N 4 O 6 + ([M + H] +) 473.1456, found 473.1455.

< Example  4> methyl  3- (5- (4- ( Benzo [d] [l, 3] dioxole -5-yl) -1H-1,2,3- Triazole -1-yl) -2-hydroxybenzamido) benzoate (1d)

The target compound was obtained as an ivory solid (54.0 mg, 54%) in the same manner as in Example 1 except that alkyne 9d was used instead of alkyne 9a used in Step 3 of Example 1 above.

_{TLC: R f 0.28 (20:} 1 CH 2 Cl 2 / MeOH). Mp: 271.3-273.3 [deg.] C. ^{1 H NMR (400 MHz, DMSO} -d 6): δ 11.83 (s, 1H), 10.68 (s, 1H), 9.14 (s, 1H), 8.44 (t, J = 2.0 Hz, 1H), 8.40 (d J = 8.8 Hz, 1H), 7.99 (dm, J = 8.0 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.08 (s, 2H), 7.23 (d, J = , 3.88 (s, 3 H). ^{13 C NMR (100 MHz, DMSO} -d 6): δ 166.0, 165.3, 158.3, 147.8, 147.2, 147.1, 138.7, 130.2, 129.3, 128.3, 125.3, 125.1, 124.7, 124.4, 121.2, 121.0, 119.3, 119.0, 119.0, 118.6, 108.8, 105.7, 101.2, 52.2. HRMS (ESI) m / z calcd for C ₂₄ H ₁₉ N ₄ O ₆ ⁺ ([M + H] ⁺ ) 459.1299, found 459.1295.

< Example  5> methyl  3- (2- Hydroxy -5- (4- ( Phenylamino ) methyl -1H-1,2,3- Triazole -1-yl) benzamido) benzoate (1e)

(50.0 mg, 160 μmol), alkyne 9e (21.0 mg, 160 μmol) and TBTA (4.3 mmol) prepared in Step 2 of Example 1, mg, 5 mol%) was dissolved in 1: 1 t-BuOH / H ₂ O (380 μL). CuSO ₄ (1 M solution, 3.2 μL, 2 mol%) and sodium ascorbate (1 M solution, 16.0 μL, 10 mol%) were added and the reaction mixture was stirred at 80 ° C. for 2 hours. After termination of the reaction, the mixture was concentrated and basified with saturated aqueous NaHCO ₃ (3 mL) and extracted with CH ₂ Cl ₂ (3 × 5 mL). The combined organic extracts were dried over anhydrous MgSO ₄ , filtered and concentrated by rotary evaporation to give the crude product as a brown solid. Purification by column chromatography (60: 1 CH ₂ Cl ₂ / MeOH) afforded the title compound as a light brown solid (45.3 mg, 64%).

_{TLC: R f 0.27 (20:} 1 CH 2 Cl 2 / MeOH). Mp: 166.0-168.0 占 폚. ¹ H NMR (400 MHz, DMSO-d ₆ ):? 11.85 (brs, 1H), 10.66 (br s, 1H), 8.62 (s, 1H), 8.41 (t, J = 1.6 Hz, 1H), 8.35 J = 8.8 Hz, 1H), 7.98 (dm, J = 8.0 Hz, 1H), 7.92 (dd, J = (d, J = 8.0 Hz, 1H), 7.18 (d, J = 8.8 Hz, 1H), 7.08 (t, J = 7.6 Hz, IH), 6.13 (m, IH), 4.37 (d, J = 4.8 Hz, 2H), 3.88 (s, 3H). ^{13 C NMR (100 MHz, CDCl} 3 + CD 3 OD): δ 167.2, 166.7, 160.1, 147.5, 147.4, 137.8, 130.9, 129.4, 129.3, 129.1, 126.3, 126.1, 126.0, 122.3, 120.6, 120.4, 119.2, 118.4, 116.8, 113.4, 52.4, 39.8. HRMS (ESI) m / z calcd for C ₂₄ H ₂₂ N ₅ O ₄ ⁺ ([M + H] ⁺ ) 444.1666, found 444.1669.

< Example  6> methyl  3- (2- Hydroxy -5- (4 - ((5- Methyl isoxazole -3- Yl) amino ) Me Yl) benzamido) benzoate (1f) &lt; RTI ID = 0.0 &gt;

Example A methyl prepared in Step 2 of one 3- (5-azido-2-hydroxy-benz amido) benzoate (68.80 mg, 220 μmol), alkynyl 9f (30.0 mg, 220 μmol) and CuSO ₄ ( 7.0 mg, 44.1 μmol) was dissolved in 1: 1 t-BuOH / H ₂ O (2.2 mL). The reaction mixture was stirred at room temperature for 24 hours. After termination of the reaction, the present tan solution was filtered, washed with H ₂ O (20 mL) and dried in vacuo (solid A). The filtrate was extracted with CH ₂ Cl ₂ (3 x 20 mL). The combined organic extracts were dried over anhydrous MgSO ₄ , filtered and concentrated by rotary evaporation (residue B). The solid A and the residual B were added together. Purification by column chromatography (100: 1 to 80: 1 CH ₂ Cl ₂ / MeOH) gave the target compound as a purple solid (82.2 mg, 83%).

_{TLC: R f 0.16 (40:} 1 CH 2 Cl 2 / MeOH). Mp: 161.2-163.2 占 폚. ^{1 H NMR (400 MHz, DMSO} -d 6): δ 11.87 (s, 1H), 10.67 (s, 1H), 8.58 (s, 1H), 8.41 (t, J = 2.0 Hz, 1H), 8.35 (d J = 8.8 Hz, 1H), 7.98 (dm, J = 8.0 Hz, 1H), 7.93 (dd, J = 8.8, 2.8 Hz, 1H) (t, J = 8.0 Hz, 1H), 7.18 (d, J = 8.8 Hz, 1H), 6.55 , J = 5.2 Hz, 2H), 3.88 (s, 3H), 2.22 (d, J = 0.8 Hz, 3H). ^13.1 C NMR (100 MHz, CDCl ₃ + CD ₃ OD): δ 170.1, 169.9, 166.1, 166.1, 159.6, 136.9, 136.8, 130.1, 129.8, 128.2, 127.8, 125.4, 125.1, 125.0, 121.5, 118.4, 115.4, 51.4, 38.6, 28.7. HRMS (ESI) m / z calcd for C 22 H 21 N 6 O 5 + ([M + H] +) 449.1568, found 449.1573.

< Example  7> methyl  3- (2- Hydroxy -5- (4 - ((6- Methyl pyridine -2- Amino ) methyl -1H-1,2,3-triazol-1-yl) benzamido) benzoate (1 g)

(119 mg, 380 [mu] mol), 9 g (140 mg, 960 [mu] mol) of Alkyne and CuSO ₄ ( ₂ mL) were added to a solution of methyl 3- (5-azido-2-hydroxybenzamido) benzoate 12.3 mg, 77.3 μmol) was dissolved in 1: 1 t-BuOH / H ₂ O (8 mL). The reaction mixture was stirred at room temperature for 20 hours. After termination of the reaction, the present tan solution was filtered, washed with H ₂ O (30 mL) and dried in vacuo (solid A). The filtrate was extracted with CH ₂ Cl ₂ (3 × 30 mL). The combined organic extracts were dried over anhydrous MgSO ₄ , filtered and concentrated by rotary evaporation (residue B). The solid A and the residual B were added together. Purification by column chromatography (40: 1 CH ₂ Cl ₂ / MeOH) gave the title compound as a white solid (82.2 mg, 83%).

TLC: _Rf 0.17 (20: 1 CH ₂ Cl ₂ / MeOH). Mp: 183.7-185.7 [deg.] C. ^{1 H NMR (400 MHz, DMSO} -d 6): δ 11.86 (s, 1H), 10.76 (brs, 1H), 8.54 (s, 1H), 8.40 (t, J = 2.0 Hz, 1H), 8.34 (d J = 8.8 Hz, 1H), 7.97 (dm, J = 8.0 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.16 (d, J = 8.8 Hz, 1H), 6.85 (brt, J = 5.6 Hz, 1H), 6.38 (d, J = 7.2 Hz, 1H), 6.35 (d, J = 8.0 Hz, 1H), 4.57 (d, J = 5.6 Hz, 2H), 3.88 (s, 3H), 2.28 ^{13 C NMR (100 MHz, CDCl} 3 + CD 3 OD): δ 167.3, 166.7, 160.2, 157.2, 155.1, 146.6, 139.9, 137.9, 130.9, 129.3, 129.2, 126.4, 126.1, 126.0, 122.4, 120.9, 120.7, 119.2, 116.9, 113.1, 104.8, 52.4, 37.9, 23.0. HRMS (ESI) m / z calcd for C ₂₄ H ₂₃ N ₆ O ₄ ⁺ ([M + H] ⁺ ) 459.1775, found 459.1780.

< Example  8> methyl  3- (2- Hydroxy -5- (4- (pyrimidin-2- Amino ) methyl -1H-1,2,3-triazol-1-yl) benzamido) benzoate (1h)

Example A methyl prepared in Step 2 of one 3- (5-azido-2-hydroxy-benz amido) benzoate (93.8 mg, 300 μmol), alkynyl 9h (40.0 mg, 300 μmol) , CuSO 4 ( 9.4 mg, 60.1 μmol) and sodium ascorbate (59.5 mg, 300 μmol) were dissolved in 1: 1 t-BuOH / H ₂ O (3.2 mL). The reaction mixture was stirred at room temperature for 20 hours. After 20 hours additional alkyne 9h (16.0 mg, 12 μmol) was added and the mixture was stirred at room temperature for a further 24 hours. After the above procedure, the present tan solution was filtered, washed with H ₂ O (20 mL) and dried in vacuo (solid A). The filtrate was extracted with CH ₂ Cl ₂ (3 x 20 mL). The combined organic extracts were dried over anhydrous MgSO ₄ , filtered and concentrated by rotary evaporation (residue B). The solid A and the residual B were added together. Purification by column chromatography (40: 1 CH ₂ Cl ₂ / MeOH) afforded the title compound as a light brown solid (57.9 mg, 43%).

_{TLC: R f 0.21 (20:} 1 CH 2 Cl 2 / MeOH). Mp: 162.0-164.0 占 폚. ^{1 H NMR (400 MHz, DMSO} -d 6): δ 11.85 (brs, 1H), 10.66 (brs, 1H), 8.52 (s, 1H), 8.40 (t, J = 1.6 Hz, 1H), 8.34 (d J = 8.8 Hz, 1H), 8.31 (d, J = 4.8 Hz, 2H), 7.98 (dm, J = 8.0 Hz, 1H), 7.92 J = 8.0 Hz, 1H), 7.63 (t, J = 6.0 Hz, 1H), 7.54 J = 4.8 Hz, 1H), 4.62 (d, J = 6.0 Hz, 2H), 3.88 (s, 3H). ^{13 C NMR (100 MHz, CDCl} 3 + CD 3 OD): δ 167.2, 166.6, 161.7, 160.0, 158.2, 146.6, 137.8, 130.8, 129.2, 129.1, 126.3, 126.0, 125.9, 122.3, 120.7, 120.6, 119.1, 116.8, 111.2, 52.4, 36.7. HRMS (ESI) m / z calcd for C 22 H 20 N 7 O 4 + ([M + H] +) 446.1571, found 446.1572.

< Example  9> methyl  3- (2- Hydroxy -5- (4- (2- (pyrimidin-2- Amino ) Ethyl) -1H-1,2,3-triazol-1-yl) benzamido) benzoate (1i)

At room temperature, a screw cap vial was charged with methyl 3- (5-azido-2-hydroxybenzamido) benzoate (62.5 mg, 200 μmol), alkyne 9i (44.2 mg, 300 mu mol), CuI (19.5 mg, 100 [mu] mol) and anhydrous DMF (0.4 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the residue was purified by column chromatography (40: 1 CH ₂ Cl ₂ / MeOH) to obtain the target compound as an ivory solid (39.2 mg, 43%).

TLC: _Rf 0.38 (10: 1 CH ₂ Cl ₂ / MeOH). Mp: 226.9-228.9 占 폚. ^{1 H NMR (400 MHz, DMSO} -d 6): δ 11.83 (s, 1H), 10.67 (s, 1H), 8.56 (s, 1H), 8.42 (t, J = 1.6 Hz, 1H), 8.35 (d J = 8.8 Hz, 1H), 8.28 (d, J = 4.4 Hz, 2H), 7.99 (dm, J = 8.0 Hz, 1H), 7.91 J = 8.0 Hz, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.29 (brt, J = 6.4 Hz, 1H) J = 4.8 Hz, 1H), 3.88 (s, 3H), 3.61 (q, J = 7.2 Hz, 2H), 2.98 (t, J = 7.2 Hz, 2H). ^{13 C NMR (100 MHz, DMSO} -d 6): δ 166.0, 165.5, 162.2, 157.9, 157.7, 145.7, 138.5, 130.2, 129.3, 128.9, 125.4, 125.2, 124.8, 121.2, 120.9, 120.7, 119.0, 118.3, 110.1, 52.2, 40.4, 25.3. HRMS (ESI) m / z calcd for C ₂₃ H ₂₂ N ₇ O ₄ ⁺ ([M + H] ⁺ ) 460.1728, found 460.1733.

< Example  10> methyl  3- (2- Hydroxy -5- (4- ( Oxazole -2- Amino ) methyl -1H-1,2,3-triazol-1-yl) benzamido) benzoate (1j)

At room temperature, 2-aminooxazole (78.9 mg, 901 μmol), dry DMF (0.9 mL), and propargyl bromide (120 m, 991 μmol) were added to the screw cap vial. The reaction mixture was heated to 80 &lt; 0 &gt; C and stirred for 24 hours. The reaction was terminated and the reaction mixture was allowed to cool to room temperature. (62.5 mg, 200 μmol), CuI (19.5 mg, 100 μmol) and DIPEA (106 μmol) prepared in Step 2 of Example 1, mg, 901 [mu] mol) was added to the reaction mixture and stirred for 2 hours. After completion of the reaction, the residue was purified by column chromatography (20: 1 CH ₂ Cl ₂ / MeOH) to obtain the target compound as a beige solid (30.7 mg, 35%).

TLC: _Rf 0.24 (5: 1 CH ₂ Cl ₂ / MeOH (x 2)). Mp: 189.1-191.1 [deg.] C. ^{1 H NMR (400 MHz, CD} 3 OD): δ 8.48 (s, 1H), 8.43 (t, J = 1.6 Hz, 1H), 8.30 (s, 1H), 7.94 (dm, J = 8.0 Hz, 1H) , 7.78 (dt, J = 8.0, 1.6 Hz, 1H), 7.71 (dm, J = 8.8 Hz, 1H) 1H), 6.99 (d, J = 8.8 Hz, 1H), 5.25 (s, 2H), 3.93 (s, 3H). ^{13 C NMR (100 MHz, DMSO} -d 6): δ 166.5, 166.2, 165.7, 157.2, 140.8, 140.0, 138.9, 132.6, 130.2, 129.3, 125.1, 124.2, 123.4, 122.0, 121.7, 121.0, 120.2, 118.9, 118.4, 52.2, 40.1. HRMS (ESI) m / z calcd for C 21 H 19 N 6 O 5 + ([M + H] +) 435.1411, found 435.1411.

< Example  11> methyl  3- (5- (4- ( Benzo [d] [l, 3] dioxole - 2-amino ) methyl -1H-1,2,3-triazol-1-yl) -2-hydroxybenzamido) benzoate (1k)

To the screw cap vial at room temperature was added methyl 3- (5-azido-2-hydroxybenzamido) benzoate (62.5 mg, 200 μmol), alkyne 9k (51.7 mg, 300 mu mol), CuI (19.5 mg, 100 [mu] mol) and anhydrous DMF (0.4 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the residue was purified by column chromatography (40: 1 CH ₂ Cl ₂ / MeOH) to give the target compound as an ivory solid (61.4 mg, 63%).

_{TLC: R f 0.21 (40:} 1 CH 2 Cl 2 / MeOH). Mp: 246.0-246.8 [deg.] C. ^{1 H NMR (400 MHz, DMSO} -d 6): δ 11.85 (brs, 1H), 10.65 (brs, 1H), 8.68 (s, 1H), 8.51 (t, J = 2.4 Hz, 1H), 8.40 (t J = 8.0Hz, 1H), 7.93 (dd, J = 8.8,3.2Hz, 1H), 7.74 (d, J = J = 8.0 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.36 (d, J = 7.2 Hz, 1H), 7.27 J = 8.8 Hz, 1H), 7.12 (td, J = 8.0, 1.2 Hz, 1H), 7.00 (s, 3 H). ^{13 C NMR (100 MHz, DMSO} -d 6): δ 166.0, 165.6, 162.3, 158.0, 148.3, 145.7, 143.1, 138.5, 130.2, 129.3, 128.7, 125.5, 125.2, 124.8, 123.6, 121.4, 121.2, 121.1, 120.3, 118.9, 118.4, 115.7, 108.7, 52.2, 37.8. HRMS (ESI) m / z calcd for C 25 H 21 N 6 O 5 + ([M + H] +) 485.1568, found 485.1569.

< Example  12> methyl  3- (2- Hydroxy -5- (4- ( Thieno [3,2-d] pyrimidine -4- Sun Ami Methyl-1H-1,2,3-triazol-1-yl) benzamido) benzoate (11)

To the screw cap vial at room temperature was added methyl 3- (5-azido-2-hydroxybenzamido) benzoate (62.5 mg, 200 μmol), alkyne (56.8 mg, 300 μmol) prepared in step 2 of Example 1 above mu mol), CuI (19.5 mg, 100 [mu] mol) and anhydrous DMF (0.4 mL). The reaction mixture was stirred at room temperature for 5 hours. After the reaction was completed, the residue was purified by column chromatography (40: 1 CH ₂ Cl ₂ / MeOH) to give the target compound as an ivory solid (62.2 mg, 62%).

TLC: _Rf 0.33 (15: 1 CH ₂ Cl ₂ / MeOH (x 2)). Mp: 240.3-242.0 占 폚. ^{1 H NMR (400 MHz, DMSO} -d 6): δ 11.83 (brs, 1H), 10.65 (brs, 1H), 8.61 (s, 1H), 8.50 (s, 1H), 8.47 (t, J = 5.6 Hz J = 8.0 Hz, 1H), 8.40 (d, J = 7.9 Hz, 1H) ), 7.92 (dd, J = 8.8,3.2 Hz, 1H), 7.74 (dt, J = 8.0, 1.6 Hz, 1H), 7.54 1H), 7.15 (d, J = 8.8 Hz, 1H), 4.85 (d, J = 5.6 Hz, 2H), 3.87 (s, 3H). ^{13 C NMR (100 MHz, DMSO} -d 6): δ 166.0, 165.6, 159.3, 157.9, 156.6, 154.5, 146.0, 138.5, 133.2, 130.0, 129.3, 128.7, 125.5, 125.2, 124.8, 124.3, 121.4, 121.2, 121.1, 118.9, 118.3, 114.9, 52.2, 35.7. HRMS (ESI) m / z calcd for C ₂₄ H ₂₀ N ₇ O ₄ S ⁺ ([M + H] ⁺ ) 502.1292, found 502.1287.

< Example  13> methyl  3- (2- Hydroxy -5- (4- (2- ( Thieno [3,2-d] pyrimidine -4- Work Amino) ethyl) -1H-1,2,3-triazol-1-yl) benzamido) benzoate (1m)

To the screw cap vial at room temperature was added methyl 3- (5-azido-2-hydroxybenzamido) benzoate (62.5 mg, 200 μmol), alkyne (61.0 mg, 300 μmol) prepared in step 2 of Example 1 above mu mol), CuI (19.5 mg, 100 [mu] mol) and anhydrous DMF (0.4 mL). The reaction mixture was stirred at 40 &lt; 0 &gt; C for 24 hours. After the reaction was terminated, the reaction mixture was diluted with CH ₂ Cl ₂ (30 mL) and washed with saturated aqueous NaHCO ₃ (30 mL). From the above, the organic extract was dried over anhydrous MgSO ₄ , filtered and concentrated by rotary evaporation. Purification by column chromatography (40: 1 CH ₂ Cl ₂ / MeOH) afforded the title compound as a pale green solid (44.7 mg, 43%).

TLC: _Rf 0.14 (20: 1 CH ₂ Cl ₂ / MeOH (x 2)). Mp: 194.7-196.7 [deg.] C. ^{1 H NMR (400 MHz, DMSO} -d 6): δ 11.84 (brs, 1H), 10.69 (brs, 1H), 8.59 (s, 1H), 8.48 (s, 1H), 8.42 (t, J = 2.0 Hz J = 8.0 Hz, 1H), 8.35 (d, J = 2.8 Hz, 1H), 8.09 (d, J = 5.6 Hz, 1H) ), 7.91 (dd, J = 8.8,2.8 Hz, 1H), 7.75 (dt, J = 8.0, 1.2 Hz, 1H), 7.55 , 7.18 (d, J = 8.8 Hz, 1H), 3.88 (s, 3H), 3.84 (m, 2H), 3.09 (t, J = 7.2 Hz, 2H). ^{13 C NMR (100 MHz, DMSO} -d 6): δ 166.0, 165.5, 159.3, 158.6, 156.8, 154.5, 145.4, 138.7, 132.9, 130.2, 129.3, 128.3, 125.3, 125.1, 124.7, 124.4, 121.1, 121.0, 120.8, 118.9, 118.6, 114.8, 52.2, 40.0, 25.2. HRMS (ESI) m / z calcd for C 25 H 22 N 7 O 4 S + ([M + H] +) 516.1448, found 516.1445.

< Example  14> methyl  3- (2- Hydroxy -5- (4- (N- Morpolino ) methyl -1H-1,2,3- tree Azol-1-yl) benzamido) benzoate (1n)

At room temperature, a screw cap vial was charged with methyl 3- (5-azido-2-hydroxybenzamido) benzoate (62.5 mg, 200 μmol), alkyne 9n (37.6 mg, 300 mu mol), CuI (19.5 mg, 100 [mu] mol) and anhydrous DMF (0.4 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the residue was purified by column chromatography (40: 1 CH ₂ Cl ₂ / MeOH) to give the target compound as an ivory solid (62.2 mg, 62%).

_{TLC: R f 0.28 (20:} 1 CH 2 Cl 2 / MeOH). ^{Mp: 204.0-206.0 ℃ 1 H NMR (} 400 MHz, DMSO-d 6): δ 11.84 (brs, 1H), 10.72 (s, 1H), 8.64 (s, 1H), 8.42 (s, 1H), 8.38 ( J = 8.0 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H) 1H), 7.17 (d, J = 8.8 Hz, 1H), 3.88 (s, 3H), 3.67 (s, 2H), 3.59 (s, 4H), 2.52 (s, ^{13 C NMR (100 MHz, DMSO} -d 6): δ 166.0, 165.7, 158.3, 144.0, 138.5, 130.2, 129.3, 128.7, 125.5, 125.2, 124.8, 122.3, 121.2, 121.0, 118.6, 66.0 (2C), 52.7 , 52.2. HRMS (ESI) m / z calcd for C 22 H 24 N 5 O 5 + ([M + H] +) 438.1772, found 438.1772.

< Example  15> methyl  3- (2- Hydroxy -5- (4 - ((2- (N- Morpolino ) Ethyl) amino) Me Yl) benzamido) benzoate (1 o) &lt; RTI ID = 0.0 &gt;

At room temperature, a screw cap vial was charged with methyl 3- (5-azido-2-hydroxybenzamido) benzoate (62.5 mg, 200 μmol), alkyne 9o (53.0 mg, 300 mu mol), CuI (19.5 mg, 100 [mu] mol) and anhydrous DMF (0.4 mL). The reaction mixture was heated to 80 &lt; 0 &gt; C and stirred for 14 hours. The reaction mixture was cooled to room temperature and purified by column chromatography (40: 1 CH ₂ Cl ₂ / MeOH) to give the target compound as an ivory solid (86.8 mg, 86%).

_{TLC: R f 0.09 (10:} 1 CH 2 Cl 2 / MeOH). Mp: 174.5-176.5 [deg.] C. ^{1 H NMR (400 MHz, DMSO} -d 6): δ 8.35 (s, 1H), 8.28 (s, 1H), 8.03 (d, J = 3.2 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H J = 8.0 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 6.0 Hz, 2H) 2.33 (s, 3H), 3.84 (s, 2H), 3.56 (t, J = 4.8 Hz, 4H) (m, 4H). ^{13 C NMR (100 MHz, CD} 3 OD + CDCl 3): δ 170.0, 168.2, 167.8, 146.0, 140.1 (2C), 131.2, 129.5, 126.6, 125.8, 125.1, 123.3, 122.9, 122.1, 121.9, 119.2, 67.4 , 58.0, 54.2, 52.5, 45.2, 44.3. HRMS (ESI) m / z calcd for C ₂₄ H ₂₉ N ₆ O ₅ ⁺ ([M + H] ⁺ ) 481.2194, found 481.2195.

< Example  16> methyl  3- (5- (4- (2 - (( N, N - Dimethylamino ) Ethyl) -1H-1,2,3- Tria 1-yl) -2-hydroxybenzamido) benzoate (1p)

Under an argon gas present in the screw cap vial _{K 2 CO 3 (429 mg,} 3.10 mmol), dimethylamine solution (in methanol, 2M, 1ml, 2.07 mmol), and 4-bromo-1-mobu tin (429 mg, 2.07 mmol ). The reaction mixture was heated to 60 &lt; 0 &gt; C and stirred for 24 hours. The reaction was terminated and the reaction mixture was allowed to cool to room temperature. (62.5 mg, 200 袖 mol), CuI (19.5 mg, 100 袖 mol) and anhydrous DMF (0.4 袖 mol) prepared in Step 2 of Example 1, mL) was added and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated by rotary evaporation at room temperature. Diluted with CH ₂ Cl ₂ (10 mL) and washed with water (3 x 7 mL). The aqueous layer was extracted with CH ₂ Cl ₂ / MeOH (10: 1, 10 × 10 mL) and the combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated by rotary evaporation. Purification by column chromatography (20: 1 CH ₂ Cl ₂ / MeOH) afforded the title compound as an ivory solid (55.2 mg, 68%).

_{TLC: R f 0.17 (10:} 1 CH 2 Cl 2 / MeOH). Mp: 195.0-197.0 占 폚. ^{1 H NMR (400 MHz, acetone} -d 6): δ 8.50 (d, J = 2.4 Hz, 1H), 8.49 (t, J = 2.0 Hz, 1H), 8.32 (s, 1H), 8.11 (ddd, J J = 8.0 Hz, 1H), 7.91 (dd, J = 8.8, 2.4 Hz, 1H), 7.82 , 7.27 (s, 3H), 2.91 (t, J = 7.2 Hz, 2H), 2.65 (t, J = 7.2 Hz, 2H) . ^{13 C NMR (100 MHz, DMSO} -d 6): δ 166.1, 165.7, 163.5, 144.4, 139.5, 130.2, 129.3, 125.5, 125.1, 124.6, 123.9, 121.3, 120.7, 120.5, 120.0, 118.4, 57.0, 52.2, 43.6, 22.1. HRMS (ESI) m / z calcd for C 21 H 24 N 5 O 4 + ([M + H] b) 410.1823, found 410.1829.

< Example  17> methyl  3- (2- Hydroxy -5- (4- (2- Acetamidoethyl ) -1H-1,2,3- The 1-yl) benzamido) benzoate (1q) &lt; RTI ID = 0.0 &gt;

To the screw cap vial at room temperature was added methyl 3- (5-azido-2-hydroxybenzamido) benzoate (44.4 mg, 142 μmol), alkyne 9q (33.4 mg, 300 (13.8 mg, 71.1 μmol), anhydrous DMF (0.3 mL) and DIPEA (16.6 mg, 142 μmol). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the product was purified by column chromatography (10: 1 CH ₂ Cl ₂ / MeOH) to obtain the target compound as a white solid (23.2 mg, 44%).

TLC: _Rf 0.35 (10: 1 CH ₂ Cl ₂ / MeOH). Mp: 226.2-228.2 [deg.] C. ^{1 H NMR (400 MHz, DMSO} -d 6): δ 11.83 (s, 1H), 10.70 (brs, 1H), 8.53 (s, 1H), 8.42 (t, J = 2.0 Hz, 1H), 8.34 (d J = 8.8 Hz, 1H), 7.99-7.97 (m, 2H), 7.90 (dd, J = 8.8, 2.8 Hz, 1H) J = 8.0 Hz, 1H), 7.17 (d, J = 8.8 Hz, 1H), 3.88 (s, 3H), 3.37 (td, J = 7.2, 6.0 Hz, 2H) 1H), 1.81 (s, 3H). ^{13 C NMR (100 MHz, DMSO} -d 6): δ 169.2, 166.0, 165.5, 157.6, 145.5, 138.5, 130.2, 129.3, 128.9, 125.3, 125.2, 124.8, 121.1, 121.0, 120.8, 119.1, 118.3, 52.2, 38.3, 25.6, 22.6. HRMS (ESI) m / z calcd for C 21 H 25 N 5 O 5 + ([M + H] +) 424.1615, found 424.1623.

< Example  18> methyl  3- (2- Hydroxy -5- (4 - ((5- methyl -1H- Pyrazole -3- Yl) amino ) Me Yl-benzamido) benzoate (1r ') [0142] &lt; EMI ID =

Step 1: methyl  3- (2- Hydroxy -5- (4- (N- ( tert - Butoxycarbonyl ) -N- (5- methyl Yl) amino) methyl) -1H-1,2,3-triazol-1-yl) benzamido) benzoate (1 r)

To the screw cap vial at room temperature was added methyl 3- (5-azido-2-hydroxybenzamido) benzoate (31.3 mg, 100 μmol), alkyne 9r (50.4 mg, 150 μmol) prepared in step 2 of Example 1 above , CuI (9.7 mg, 50 [mu] mol) and anhydrous DMF (0.2 mL). The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, purification was carried out by column chromatography (40: 1 CH ₂ Cl ₂ / MeOH) to obtain the target compound as an ivory solid (38.8 mg, 71%).

TLC: _Rf 0.32 (20: 1 CH ₂ Cl ₂ / MeOH). Mp: 145.6-147.6 &lt; 0 &gt; C. ^{1 H NMR (400 MHz, acetone} -d 6): δ 12.25 (brs, 1H), 11.23 (brs, 1H), 10.27 (s, 1H), 8.43-8.42 (m, 2H), 8.24 (s, 1H) , 8.07 (dm, J = 8.0 Hz, 1H), 7.93 (dd, J = 8.8, 2.8 Hz, 1H), 7.83 1H), 7.17 (s, 3H), 2.26 (s, 3H), 1.51 (s, 9H). ^{13 C NMR (100 MHz, DMSO} -d 6): δ 166.0 (2C), 165.6, 157.9, 152.6, 145.9, 138.5 (2C), 130.2, 129.3, 128.7, 125.7, 125.3, 124.9, 121.2 (2C), 121.1 , 118.8, 118.3, 97.6, 80.4, 52.2, 42.2, 27.9, 10.7. HRMS (ESI) m / z calcd for C ₂₇ H ₃₀ N ₇ O ₆ ⁺ ([M + H] ⁺ ) 548.2252, found 548.2246.

Step 2: methyl  3- (2- Hydroxy -5- (4 - ((5- methyl -1H- Pyrazole -3- Amino ) methyl -1H-1,2,3-triazol-1-yl) benzamido) benzoate (1 r ')

To a screw cap vial at room temperature was added methyl 3- (2-hydroxy-5- (4- (N- (tert-butoxycarbonyl) -N- Yl) benzamido) benzoate (19.6 mg, 35.8 μmol) and CH ₂ Cl ₂ (0.36 mL) were added. The TFA solution (20% v / v in CH ₂ Cl ₂ , 1.2 mL total) was tested by TLC with dropwise addition at room temperature. After the reaction was terminated, the reaction mixture was diluted with CH ₂ Cl ₂ (3 mL), basified to pH 8 with saturated aqueous NaHCO ₃ (3 mL) and stirred for 30 min. The resulting supernatant was filtered, and the filtrate obtained from the above was extracted with CH ₂ Cl ₂ (3 × 10 mL). The combined organic extracts were dried over anhydrous MgSO ₄ , filtered, and concentrated by rotary evaporation. The filtered solid and crude residue were purified by column chromatography (20: 1 CH ₂ Cl ₂ / MeOH) to give the title compound as an ivory solid (14.6 mg, 91%).

_{TLC: R f 0.24 (10:} 1 CH 2 Cl 2 / MeOH). Mp: 198.2-200.2 占 폚. ^{1 H NMR (400 MHz, DMSO} -d 6): δ 11.85 (brs, 1H), 11.21 (brs, 1H), 8.44 (s, 1H), 8.40 (t, J = 1.6 Hz, 1H), 8.27 (s J = 8.0 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H) ), 7.04 (br s, 1H), 5.42 (s, IH), 5.30 (s, IH), 4.30 (d, J = 5.6 Hz, 2H), 3.88 (s, 3H), 2.08 ^{13 C NMR (100 MHz, DMSO} -d 6): δ 166.1, 165.8, 162.1, 161.2, 147.4, 139.3 (2C), 130.1, 129.2, 126.3, 125.2, 124.8, 124.1, 121.1, 120.7 (2C), 119.7, 118.3, 90.0, 52.2, 38.5, 10.7. HRMS (ESI) m / z calcd for C 22 H 22 N 7 O 4 + ([M + H] +) 448.1728, found 448.1729.

< Example  19> methyl  3- (2- Hydroxy -5- (4- ( Thiazole -2- Amino ) methyl -1H-1,2,3-triazol-1-yl) benzamido) benzoate (1s')

Step 1: methyl  3- (5- (4- (N- ( tert - Butoxycarbonyl ) Thiazol-2- Amino ) methyl -1H-1,2,3-triazol-1-yl) -2-hydroxybenzamido) benzoate (1s)

At room temperature, a screw cap vial was charged with methyl 3- (5-azido-2-hydroxybenzamido) benzoate (62.5 mg, 200 μmol), alkyne 9s (71.5 mg, 300 , CuI (19.5 mg, 100 [mu] mol), and anhydrous DMF (0.4 mL). The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the residue was purified by column chromatography (80: 1 CH ₂ Cl ₂ / MeOH) to obtain the target compound as a pale brown solid (98.2 mg, 89%).

_{TLC: R f 0.20 (40:} 1 CH 2 Cl 2 / MeOH). Mp: 114.1-116.1 [deg.] C. ¹ H NMR (400 MHz, DMSO-d ₆ ):? 11.82 (s, IH), 10.65 (brs, IH), 8.56 (s, IH), 8.41 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.75 2H), 3.88 (s, 3H), 1.51 (s, 2H), 7.28 (d, J = , 9H). ^{13 C NMR (100 MHz, CDCl} 3 + CD 3 OD): δ 166.1, 165.9, 160.7, 159.3, 151.5, 143.5, 136.8, 135.3, 129.8, 128.2, 128.0, 125.4, 125.1, 125.0, 121.4, 120.4, 119.5, 118.2, 115.5, 113.9, 84.0, 51.4, 41.5, 27.1. HRMS (ESI) m / z calcd for C ₂₆ H ₂₇ N ₆ O ₆ S ⁺ ([M + H] ⁺ ) 551.1707, found 551.1702.

Step 2: methyl  3- (2- Hydroxy -5- (4- ( Thiazole -2- Amino ) methyl -1H-1,2,3- The 1-yl) benzamido) benzoate (1s') &lt; EMI ID =

To a screw cap vial at room temperature was added methyl 3- (5- (4- (N- (tert-butoxycarbonyl) thiazol-2-ylamino) methyl-1H- a-yl) -2-hydroxy-benz amido) benzo this agent (52.5 mg, 95.4 μmol) and CH ₂ Cl ₂ (0.96 mL) was added. TFA solution (20% v / v in CH ₂ Cl ₂ , 2.4 mL total) was added dropwise at room temperature while confirming by TLC. After the reaction was terminated, the reaction mixture was diluted with CH ₂ Cl ₂ (3 mL), basified to pH 8 with saturated aqueous NaHCO ₃ (5 mL) and stirred for 30 min. The resultant sorbate was filtered, and the filtrate obtained from the above was extracted with CHCl ₃ / IPA (4: 1, 3 x 10 mL). The combined organic extracts were dried over anhydrous MgSO ₄ , filtered, and concentrated by rotary evaporation. The filtered solid and crude residue were purified by column chromatography (30: 1 CH ₂ Cl ₂ / MeOH) to give the title compound as a pale yellow solid (31.1 mg, 72%).

_{TLC: R f 0.41 (10:} 1 CH 2 Cl 2 / MeOH). Mp: 137.0-139.0 [deg.] C. ^{1 H NMR (400 MHz, DMSO} -d 6): δ 11.86 (s, 1H), 10.68 (s, 1H), 8.61 (s, 1H), 8.41 (s, 1H), 8.35 (d, J = 2.8 Hz (D, J = 8.0 Hz, 1H), 8.04 (t, J = 5.6 Hz, 1H), 7.98 J = 4.0 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.18 ), 4.58 (d, J = 5.6 Hz, 2H), 3.88 (s, 3H). ^{13 C NMR (100 MHz, CDCl} 3 + CD 3 OD): δ 167.2, 164.3, 163.2, 156.6, 142.8, 135.0, 134.9, 127.8, 126.2, 126.1, 123.4, 123.0, 119.4, 119.3, 118.2, 118.1, 116.0, 114.3, 104.1, 49.3, 37.1. HRMS (ESI) m / z calcd for C 21 H 19 N 6 O 4 S + ([M + H] +) 451.1183, found 451.1183.

< Example  20> methyl  3- (5- (4- (1H-Imidazol-2- Amino ) methyl -1H-1,2,3- Triazole -1-yl) -2-hydroxybenzamido) benzoate (1 t ')

Step 1: methyl  Amino) methyl-1H-1,2-benzoimidazol-2-yl) -1H-pyrazolo [3,4-d] pyrimidin- 3-triazol-1-yl) -2-hydroxybenzamido) benzoate (1 t)

To the screw cap vial at room temperature was added methyl 3- (5-azido-2-hydroxybenzamido) benzoate (15.5 mg, 49.6 μmol), alkyne 9t (23.9 mg, 74.4 , CuI (4.8 mg, 24.8 [mu] mol) and anhydrous DMF (0.1 mL). The reaction mixture was stirred at room temperature for 45 hours. After completion of the reaction, the residue was purified by column chromatography (40: 1 CH ₂ Cl ₂ / MeOH) to obtain the target compound as a yellow solid (26.0 mg, 83%).

TLC: _Rf 0.52 (20: 1 CH ₂ Cl ₂ / MeOH (x 2)). Mp: 144.7-146.7 占 폚. ^{1 H NMR (400 MHz, DMSO} -d 6): δ 11.87 (s, 1H), 8.55 (s, 1H), 8.41 (s, 1H), 8.29 (s, 1H), 7.97 (d, J = 7.2 Hz 1H, J = 8.0 Hz, 1H), 7.84 (s, 1H), 7.73 (d, J = 7.2 Hz, 1H), 7.54 (s, 1H), 4.85 (s, 2H), 3.88 (s, 3H), 1.47 (s, 9H), 1.30 (s, 9H). ^{13 C NMR (100 MHz, DMSO} -d 6): δ 166.0, 165.4, 162.3, 157.8, 153.1, 152.7, 146.1, 138.5, 130.2, 129.3, 128.6, 126.3, 125.3, 124.8, 122.0, 121.2, 121.0, 118.7, 118.4, 85.2, 80.7, 52.2, 43.2, 35.7, 30.7, 27.7, 27.2. HRMS (ESI) m / z calcd for C 31 H 36 N 7 O 8 + ([M + H] +) 634.2620, found 634.2626.

Step 2: methyl  3- (5- (4- (1H-Imidazol-2- Amino ) methyl -1H-1,2,3- Triazole -1-yl) -2-hydroxybenzamido) benzoate (1 t ')

To a screw cap vial at room temperature was added methyl 3- (5- (4- (N- (tert-butoxycarbonyl) -N- (1- (tert-butoxycarbonyl) imidazol- Yl) -2-hydroxybenzamido) benzoate (20.6 mg, 32.5 μmol) and CH ₂ Cl ₂ (0.33 mL) were added to a solution of . TFA solution (20% v / v in CH ₂ Cl ₂ , 1.6 mL total) was added dropwise at room temperature while confirming by TLC. After the reaction was terminated, the reaction mixture was diluted with CH ₂ Cl ₂ (3 mL), basified to pH 8 with saturated aqueous NaHCO ₃ (5 mL) and stirred for 30 min. The resultant sorbate was filtered, and the filtrate obtained from the above was extracted with CHCl ₃ / IPA (4: 1, 3 x 10 mL). The combined organic extracts were dried over anhydrous MgSO ₄ , filtered, and concentrated by rotary evaporation. The filtered solid and crude residue were purified by column chromatography (10: 1 CH ₂ Cl ₂ / MeOH) to give the title compound as an ivory solid (14.7 mg, yield in the proper order).

TLC: _Rf 0.14 (5: 1 CH ₂ Cl ₂ / MeOH (x 2)). Mp: 153.0-155.0 占 폚. ^{1 H NMR (400 MHz, DMSO} -d 6): δ 11.88 (s, 2H), 8.56 (s, 1H), 8.40 (t, J = 1.2 Hz, 1H), 8.23 (d, J = 2.8 Hz, 1H J = 8.0 Hz, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 6.98 (s, 2H), 4.56 (d, J = 6.0 Hz, 1H), 3.88 (s, 3H). ^{13 C NMR (100 MHz, DMSO} -d 6): δ 166.1, 165.5, 147.4, 144.6, 139.0, 130.2, 129.2, 125.3, 124.7, 124.1, 121.6, 121.4, 121.2, 120.7, 119.7, 118.8, 115.8, 114.3, 52.2, 38.0. HRMS (ESI) m / z calcd for C 21 H 20 N 7 O 4 + ([M + H] +) 434.1571, found 434.1569.

< Example  21> methyl  3- (2- Hydroxy -5- (4- (pyridin-2- Amino ) methyl -1H-1,2,3-triazol-1-yl) benzamido) benzoate (1 u ')

Step 1: methyl  3- (5- (4- (N- ( tert - Butoxycarbonyl ) Pyridin-2- Amino ) methyl -1H-1,2,3-triazol-1-yl) -2-hydroxybenzamido) benzoate (1 u)

(50.0 mg, 160 μmol), alkyne 9u (37.2 mg, 160 μmol) and TBTA (4.3 μmol) prepared in Step 2 of Example 1, mg, 5 mol%) was dissolved in 1: 1 t-BuOH / H ₂ O (0.38 mL). CuSO ₄ (0.25 M solution, 12.8 μL, 2 mol%) and sodium ascorbate (0.25 M solution, 64.0 μL, 10%) were added and the reaction mixture was stirred at 80 ° C. for 30 minutes. After termination of the reaction, the reaction mixture was concentrated, basified with saturated aqueous NaHCO ₃ (3 mL) and extracted with CH ₂ Cl ₂ (3 × 5 mL). The combined organic extracts were dried over anhydrous MgSO ₄ , filtered, and concentrated by rotary evaporation to give a brown solid as the crude product. Purification by column chromatography (100: 1 → 80: 1 → 70: 1 CH ₂ Cl ₂ / MeOH) gave the title compound as a brown solid (41.3 mg, 47%).

_{TLC: R f 0.20 (40:} 1 CH 2 Cl 2 / MeOH). ^{1 H NMR (400 MHz, DMSO} -d 6): δ 11.82 (brs, 1H), 10.65 (brs, 1H), 8.50 (s, 1H), 8.41 (d, J = 2.8 Hz, 1H), 8.39 (m (Dd, J = 8.0 Hz, 1H), 7.90 (dd, J = 8.8, 2.8 Hz, 1H), 7.77 J = 8.0 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.75 8.8 Hz, 1 H), 7.14 (dd, J = 7.6, 1.2 Hz, 1H), 5.22 (s, 2H), 3.88 (s, 3H), 1.43 (s, 9H). ^{13 C NMR (100 MHz, CDCl} 3 + CD 3 OD): δ 167.2, 160.6, 154.0, 153.6, 147.1, 146.4, 138.5, 137.8, 130.9, 129.2, 129.1, 126.3, 126.2, 126.1, 122.6, 122.5, 121.3, 120.5, 120.3, 120.2, 119.3, 116.4, 82.8, 52.4, 42.9, 28.2. HRMS (ESI) m / z calcd for C 28 H 29 N 6 O 6 + ([M + H] +) 545.2143, found 545.2142.

Step 2: methyl  3- (2- Hydroxy -5- (4- (pyridin-2- Amino ) methyl -1H-1,2,3- tree Azol-1-yl) benzamido) benzoate (1 u ')

2-ylamino) methyl-1H-1,2,3-triazole-1 (1 H) -quinolinone prepared in Step 1 above at 0 ° C. Was added dropwise TFA (251 mg, 2.20 mmol) in CH ₂ Cl ₂ (0.7 mL) containing potassium carbonate (40.0 mg, 73.5 μmol) dissolved in tetrahydrofuran Stir for 1.5 hours. After the reaction was terminated, water (10 mL) was added and the mixture was extracted with CH ₂ Cl ₂ (3 × 10 mL). The combined organic extracts were dried over anhydrous MgSO ₄ , filtered, and concentrated by rotary evaporation. Purification by column chromatography (15: 1 CH ₂ Cl ₂ / MeOH) afforded the title compound as an ivory solid (35.1 mg, yield of the desired product).

TLC: _Rf 0.45 (10: 1 CH ₂ Cl ₂ / MeOH). Mp: 140.0-142.0 占 폚. ^{1 H NMR (400 MHz, DMSO} -d 6): δ 11.86 (s, 1H), 10.75 (brs, 1H), 8.54 (s, 1H), 8.40 (t, J = 2.0 Hz, 1H), 8.34 (d J = 8.8 Hz, 1H), 8.01 (dm, J = 4.8 Hz, 1H), 7.97 (dm, J = 8.0 Hz, 1H), 7.91 J = 8.0 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.39 (ddd, J = 8.4, 6.8, 1.6 Hz, (Dd, J = 6.8, 5.2, 1.2 Hz, 1H), 4.59 (d, J = 5.2 Hz, 1H), 6.99 (brt, J = 5.6 Hz, 2H), 3.88 (s, 3H). ^{13 C NMR (100 MHz, CDCl} 3 + CD 3 OD): δ 167.1, 166.9, 160.5, 158.0, 147.2, 146.9, 138.1, 137.8, 130.8, 129.2, 129.0, 126.3, 126.1, 126.0, 122.3, 120.7, 120.3, 119.3, 116.4, 113.5, 108.5, 52.4, 37.2. HRMS (ESI) m / z calcd for C ₂₃ H ₂₁ N ₆ O ₄ ⁺ ([M + H] ⁺ ) 445.1619, found 445.1617.

< Example  22> methyl  3- (2- Hydroxy -5- (4 - ((4- Methyl pyridine Yl) amino) methyl -1H-1,2,3-triazol-1-yl) benzamido) benzoate (1v ')

Step 1: methyl  3- (5- (4- (N- ( tert - Butoxycarbonyl ) -N- (4- Methyl pyridine Yl) amino) methyl-1H-1,2,3-triazol-1-yl) -2-hydroxybenzamido) benzoate (1v)

(50.0 mg, 160 탆 ol), alkyne 9v (78.9 mg, 320 탆 ol), CuI (30.5 .5), prepared in Step 2 of Example 1, mg, 160 μmol) and DIPEA (27.7 μL, 160 μmol) were dissolved in DMF (0.57 mL). The reaction mixture was stirred at room temperature for 0.8 hours. After completion of the reaction, 10% aqueous ammonia was added, and the mixture was stirred at room temperature for 20 minutes. The mixture was extracted with CH ₂ Cl ₂ (5 × 5 mL). The combined organic extracts were dried over anhydrous MgSO ₄ , filtered, and concentrated by rotary evaporation to give a brown solid as the crude product. Purification by column chromatography (40: 1 CH ₂ Cl ₂ / MeOH) afforded the title compound as an orange solid (63.2 mg, 71%).

_{TLC: R f 0.24 (30:} 1 CH 2 Cl 2 / MeOH). Mp: 81.3-83.3 [deg.] C. ¹ H NMR (400 MHz, Acetone-d ₆ ): 隆 10.32 (br s, 1H), 8.44 (s, 1H), 8.43 (s, 1H), 8.32 (Dd, J = 8.0, 1.6, 0.8 Hz, 1H), 7.61 (s, 1H) 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.16 (d, J = 8.8 Hz, 1H), 6.95 , 3.91 (s, 3H), 2.35 (s, 3H), 1.49 (s, 9H). ^{13 C NMR (100 MHz, CDCl} 3 + CD 3 OD): δ 167.1, 166.3, 159.6, 154.0, 153.5, 150.2, 146.6, 146.2, 137.8, 130.7, 129.2, 129.1, 126.2, 126.0, 125.9, 122.3, 122.2, 121.9, 121.2, 120.9, 118.9, 117.0, 82.4, 52.2, 42.9, 28.0, 21.0. HRMS (ESI) m / z calcd for C ₂₉ H ₃₁ N ₆ O ₆ ⁺ ([M + H] ⁺ ) 559.2300, found 559.2294.

Step 2: methyl  3- (2- Hydroxy -5- (4 - ((4- Methyl pyridine Yl) amino) methyl -1H-1,2,3-triazol-1-yl) benzamido) benzoate (1v ')

(4-methylpyridin-2-yl) amino) methyl-1H-1, 2- TFA (367 mg, 3.22 mmol) was added to a CH ₂ Cl ₂ (1 mL) solution containing 60 mg (107 μmol) of 2-hydroxybenzamido) Was added dropwise and stirred at room temperature for 1.5 hours. After the reaction was completed, saturated aqueous NaHCO ₃ (5 mL) was added to pH 7 at 0 ° C., basified to pH 10 with 1 N NaOH (0.4 mL), CH ₂ Cl ₂ 10 mL). The combined organic extracts were dried over anhydrous MgSO ₄ , filtered, and concentrated by rotary evaporation. Purification by column chromatography (20: 1 CH ₂ Cl ₂ / MeOH) afforded the title compound as a light yellow solid (15.7 mg, 32%).

_{TLC: R f 0.19 (20:} 1 CH 2 Cl 2 / MeOH). Mp: 132.0-134.0 占 폚. ^{1 H NMR (400 MHz, DMSO} -d 6): δ 11.89 (s, 1H), 10.73 (brs, 1H), 8.52 (s, 1H), 8.40 (t, J = 1.6 Hz, 1H), 8.34 (d (Dd, J = 8.8 Hz, 1H), 7.97 (dm, J = 8.0 Hz, 1H), 7.91 J = 8.0 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.16 (d, J = (m, 2H), 4.58 (d, J = 6.0 Hz, 2H), 3.88 (s, 3H), 2.15 (s, 3H). ^{13 C NMR (100 MHz, CDCl} 3 + CD 3 OD): δ 167.3, 167.2, 160.9, 158.2, 149.6, 147.1, 146.8, 137.8, 130.9, 129.3, 129.0, 126.4, 126.2, 126.1, 122.4, 120.6, 119.9, 119.5, 116.2, 115.3, 108.6, 52.4, 37.4, 21.2. HRMS (ESI) m / z calcd for C ₂₄ H ₂₃ N ₆ O ₄ ⁺ ([M + H] ⁺ ) 459.1775, found 459.1779.

< Example  23> methyl  3- (2- Hydroxy -5- (4- (pyridin-4- Amino ) methyl -1H-1,2,3-triazol-1-yl) benzamido) benzoate (1w ')

Step 1: methyl  3- (5- (4- (N- ( tert - Butoxycarbonyl ) Pyridin-4- Amino ) methyl -1H-1,2,3-triazol-1-yl) -2-hydroxybenzamido) benzoate (1w)

(75.0 mg, 240 μmol), alkyne 9 w (83.7 mg, 360 μmol) and TBTA (6.4 g, 360 μmol) prepared in Step 2 of Example 1, mg, 5 mol%) was dissolved in 1: 1 t-BuOH / H ₂ O (0.6 mL). CuSO ₄ (0.25 M solution, 19.2 μL, 2 mol%) and sodium ascorbate (0.25 M solution, 96.0 μL, 10%) were added and the reaction mixture was stirred at 80 ° C. for 2 hours. After termination of the reaction, the reaction mixture was concentrated, basified with saturated aqueous NaHCO ₃ (6 mL) and extracted with CH ₂ Cl ₂ (4 × 10 mL). The combined organic extracts were dried over anhydrous MgSO ₄ , filtered, and concentrated by rotary evaporation to give a brown solid as the crude product. Purification by column chromatography (30: 1 CH ₂ Cl ₂ / MeOH) afforded the title compound as an ivory solid (54.8 mg, 42%).

_{TLC: R f 0.16 (30:} 1 CH 2 Cl 2 / MeOH). Mp: 198.5-200.5 캜. ^{1 H NMR (400 MHz, CDCl} 3 + CD 3 OD): δ 8.58 (d, J = 6.0 Hz, 2H), 8.42-8.41 (m, 2H), 8.34 (t, J = 1.6 Hz, 1H), 8.17 (dd, J = 6.0 Hz, 1H), 7.95 (ddd, J = 8.0, 2.4, 1.2 Hz, 1H), 7.87 , 1.28 (s, 2H), 3.93 (s, 3H), 1.57 (s, 9H, ). ^{13 C NMR (100 MHz, CDCl} 3 + CD 3 OD): δ 166.2, 165.3, 159.0, 152.3, 149.3, 148.7, 144.1, 136.9, 129.8, 128.3, 128.0, 125.3, 125.0, 124.9, 121.2, 120.4, 120.0, 118.2, 118.0, 116.2, 82.2, 51.4, 43.7, 27.2. HRMS (ESI) m / z calcd for C 28 H 29 N 6 O 6 + ([M + H] +) 545.2143, found 545.2141.

Step 2: methyl  3- (2- Hydroxy -5- (4- (pyridin-4- Amino ) methyl -1H-1,2,3- tree Azol-1-yl) benzamido) benzoate (1w ')

Methyl-1H-1,2,3-triazole-1 (1 H) -quinolinone prepared in Step 1 at 0 ° C was added dropwise to a solution of methyl 3- (5- (4- (N- (tert-butoxycarbonyl) pyridin- (314 mg, 2.75 mmol) was added dropwise at room temperature to a solution of the compound obtained in Step (1) in CH ₂ Cl ₂ (0.9 mL) containing 50 mg (91.8 μmol) of 2- Stir for 1.5 hours. After the reaction was completed, a saturated aqueous solution of NaHCO ₃ (5 mL) was added at 0 ° C to a pH of 7, and the resulting supernatant was filtered and washed with water. The solid was dried in vacuo to give a light pink solid (23.6 mg, 58%).

TLC: _Rf 0.15 (10: 1 CH ₂ Cl ₂ / MeOH). Mp: 143.0-145.0 [deg.] C. ^{1 H NMR (400 MHz, CDCl} 3 + CD 3 OD): δ 8.31 (d, J = 2.8 Hz, 1H), 8.28 (s, 1H), 8.24 (t, J = 1.6 Hz, 1H), 7.91 (m , 7.90 (d, J = 7.2 Hz, 2H), 7.81 (dd, J = 8.8,2.8 Hz, 1H) J = 8.0 Hz, 1H), 7.05 (d, J = 8.8 Hz, 1H), 6.77 (d, J = 7.2 Hz, 2H), 4.57 (s, 2H), 3.86 (s, ^{No 13 C NMR (100 MHz,} DMSO-d 6): δ 166.1, 165.4, 161.6, 156.8, 143.8, 142.0, 139.2, 130.2, 129.3, 126.3, 125.3, 124.7, 124.2, 121.5, 121.4, 120.7, 119.5, 118.9 , 107.6, 52.2, 37.4. HRMS (ESI) m / z calcd for C ₂₃ H ₂₁ N ₆ O ₄ ⁺ ([M + H] ⁺ ) 445.1619, found 445.1623.

< Example  24> methyl  3- (2- Hydroxy -5- (4- (pyrimidin-4- Amino ) methyl -1H-1,2,3-triazol-1-yl) benzamido) benzoate (1x ')

Step 1: methyl  3- (5- (4- (N- ( tert - Butoxycarbonyl ) Pyridin-4- Amino ) methyl -1H-1,2,3-triazol-1-yl) -2-hydroxybenzamido) benzoate (1x)

To the screw cap vial at room temperature was added methyl 3- (5-azido-2-hydroxybenzamido) benzoate (63.0 mg, 202 μmol), alkyne 9x (94.0 mg, 404 , CuI (38.5 mg, 202 [mu] mol), and anhydrous DMF (0.72 mL). The reaction mixture was then stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was diluted with EtOAc (15 mL) and washed with water (3 x 5 mL). The organic extract was dried over anhydrous MgSO ₄ , filtered, and concentrated by rotary evaporation. Purification by column chromatography (80: 1 CH ₂ Cl ₂ / MeOH) afforded the title compound as a dark brown solid (61.2 mg, 55%).

TLC: _Rf 0.37 (20: 1 CH ₂ Cl ₂ / MeOH). Mp: 107.2-109.2 [deg.] C. ^{1 H NMR (400 MHz, acetone} -d 6): δ 10.52 (brs, 1H), 8.90 (s, 1H), 8.59 (d, J = 8.0 Hz, 1H), 8.45 (s, 2H), 8.41 (s , 8.05 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.15 (d, J = 6.0 Hz, 1H), 5.45 (s, 2H), 3.91 (s, 3H), 1.55 (s, 9H). ^{13 C NMR (100 MHz, acetone} -d 6): δ 168.6, 167.0, 162.1, 160.6, 158.7, 157.9, 153.9, 146.8, 139.1, 131.9, 130.1, 127.6, 126.6, 126.5, 123.0, 123.0, 122.0, 121.0, 120.0, 116.7, 114.1, 83.7, 52.6, 41.6, 28.3. HRMS (ESI) m / z calcd for C ₂₇ H ₂₈ N ₇ O ₆ ⁺ ([M + H] ⁺ ) 546.2096, found 546.2103.

Step 2: methyl  3- (2- Hydroxy -5- (4- (pyrimidin-4- Amino ) methyl -1H-1,2,3- The 1-yl) benzamido) benzoate (1x ') &lt; EMI ID =

To a screw cap vial at room temperature was added methyl 3- (5- (4- (N- (tert-butoxycarbonyl) pyridin-4-ylamino) methyl-1H- a-1-yl) -2-hydroxy-benz amido) benzo this agent (30.4 mg, 55.7 μmol) and CH ₂ Cl ₂ (0.56 mL) was added. TFA solution (20% v / v in CH ₂ Cl ₂ , 1.8 mL total) was added dropwise at room temperature while confirming by TLC. After the reaction was terminated, the reaction mixture was diluted with CH ₂ Cl ₂ (3 mL), basified to pH 8 with saturated aqueous NaHCO ₃ (5 mL) and stirred for 30 min. The resultant crude liquid was filtered, and the filtrate obtained from the above was extracted with CH ₂ Cl ₂ (5 × 15 mL). The combined organic extracts were dried over anhydrous MgSO ₄ , filtered, and concentrated by rotary evaporation. The filtered solid and crude residue were purified by column chromatography (20: 1 CH ₂ Cl ₂ / MeOH) to give the title compound as a white solid (22.6 mg, 91%).

_{TLC: R f 0.15 (20:} 1 CH 2 Cl 2 / MeOH). Mp: 231.2-233.2 [deg.] C. ^{1 H NMR (400 MHz, DMSO} -d 6): δ 11.86 (s, 1H), 8.59 (s, 1H), 8.46 (s, 1H), 8.40 (t, J = 2.0 Hz, 1H), 8.32 (s J = 8.0 Hz, 1H), 7.74-7.84 (m, 2H), 7.74 (d, J = 8.0 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.14 (brs, 1H), 6.56 (d, J = 6.0 Hz, 1H), 4.63 (s, 2H), 3.88 (s, 3H). ^{13 C NMR (100 MHz, DMSO} -d 6): δ 166.0, 165.5, 161.5, 158.1, 154.0, 145.7, 138.6, 130.2, 129.3, 128.3, 125.5, 125.2 (2C), 124.7, 121.2, 121.1 (2C), 118.9, 118.5, 52.2, 35.2. HRMS (ESI) m / z calcd for C 22 H 20 N 7 O 4 + ([M + H] +) 446.1571, found 446.1576.

< Comparative Example  1> methyl  3- (5- (4- (3,5- Dimethoxyphenyl ) -1H-1,2,3- Triazole Yl) -2- Hydroxybenzamide ) Benzoate

The objective compound was prepared in the same manner as in the preparation method disclosed in Korean Patent Laid-Open No. 10-2015-0134731.

The chemical structures of the compounds prepared in Examples 1-24 are shown in Table 1 below.

Example constitutional formula Example constitutional formula One

13

2

14

3

15

4

16

5

17

6

18

7

19

8

20

9

21

10

22

11

23

12

24

< Experimental Example  1> Aurora Kinase (Aurora Kinase ) Evaluation of inhibitory activity against A and B

In order to evaluate the inhibitory activity of the compounds of formula (1) according to the present invention against Aurora kinase A and Aurora kinase B, the following experiment was conducted.

Specifically, a single-dose kinase assay (in vitro) for orrA kinase A and aurora kinase B at a concentration of 10 μM of the example compound in the presence of 1 μM ATP was performed to evaluate the compounds of the present invention as Aurora kinase inhibitors And the mean value was used. A known non-selective kinase inhibitor, staurosporine, was used as a control. The analyzed Aurora kinase inhibitory activity was expressed as a percentage (%), and the results are shown in Table 2 below.

Example
Inhibitory activity (%) Aurora kinase A Aurora kinase B One 77.0 32.3 2 62.3 29.4 3 61.7 24.6 4 67.9 26.0 5 64.7 20.4 6 71.8 19.3 7 55.9 16.7 8 29.2 20.2 9 70.2 23.9 10 0.00 3.54 11 75.4 37.3 12 62.5 -3.61 13 69.1 73.7 14 11.7 12.6 15 15.3 6.04 16 6.44 6.51 17 13.2 10.3 18 66.9 15.5 19 54.1 13.8 20 30.0 10.9 21 79.6 22.6 22 75.3 19.8 23 9.25 6.16 24 29.5 11.7 The control (staurosporine) <0.001 0.001

In the case of Aurora kinase A, the compounds of Examples 1, 2, 3, 4, 5, 6, and 7 of the 24 example compounds of the present invention exhibited significantly higher inhibitory activity than those of the control group, 9, 11, 12, 13, 18, 21 and 22 showed a high inhibitory activity, while the Aurora kinase B showed a high inhibitory activity.

Accordingly, the compound represented by the formula (1) according to the present invention exhibits excellent inhibitory activity against Aurora kinase A and B, and as a pharmaceutical composition containing the same, not only a disease related to Aurora kinase but also cancer derived therefrom Ovarian cancer, rectal cancer, esophageal cancer, small intestine cancer, anorectal cancer, colon cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, carcinoma of the uterine cervix, Can be useful for the prevention and treatment of cancers which are distantly displaced from the central nervous system tumor and leukemia or solid tumor, such as malignant carcinoma, Hodgkin's disease, prostate cancer, bladder cancer, kidney cancer, ureter cancer, renal cell carcinoma, have.

< Experimental Example  2> Aurora Kinase ) IC for A and B ₅₀  evaluation

In order to evaluate the IC ₅₀ for Aurora kinase A and Aurora kinase B of the compound represented by formula (1) according to the present invention, the following experiment was conducted.

Specifically, in Examples 1, 2, 4, 5, 6, 8, 9, 11, 12, 13, 18, and 18 of the Example compounds of the present invention showing high inhibitory activity in Experimental Example 1 in the presence of 10 μM ATP, 21 and 22 were analyzed in a 3-fold serial dilution and a 10-dose IC ₅₀ mode at a starting concentration of 30 μM and staurosporine, a known non-selective kinase inhibitor, and Comparative Example 1 were used as controls Respectively. The IC ₅₀ values analyzed are shown in Table 3 below.

Example IC ₅₀ ([mu] M) Aurora kinase A Aurora kinase B One 0.284 1.33 2 0.607 7.30 4 0.638 2.19 5 5.15 36.5 6 12.4 54.8 8 15.4 40.7 9 7.67 15.2 11 3.52 10.2 12 0.801 20.1 13 2.97 0.364 18 13.7 49.5 21 6.43 32.1 22 6.07 16.3 Comparative Example 1 0.768 5.94 The control (staurosporine) 0.002 0.007

Referring to Table 3, the IC ₅₀ values of the compound of the present invention of the present invention indicate that, in the case of Aurora kinase A, the compounds of Examples 1, 2 and 4 among the 24 example compounds of the present invention exhibited lower IC ₅₀ values than those of Comparative Example 1 , And in the case of Aurora kinase B, the compounds of Examples 1, 4 and 13 exhibit lower IC ₅₀ values than those of Comparative Example 1. [ In particular, the compound of Example 1 and the compound of Example 13 exhibited low IC50 values in both of Aura kinase A and B. However, the compound of Example 1 selectively showed a low IC ₅₀ value with respect to Aura kinase A, 13 &lt; / RTI &gt; compounds exhibit lower IC ₅₀ values than Aurora kinase B. &lt; RTI ID = 0.0 &gt;

Therefore, the compound represented by the formula (1) according to the present invention can exhibit an excellent inhibitory activity against both of Aurora kinase A and B, or alternatively has excellent inhibitory activity against aurora kinase of either Aurora kinase A or Aurora kinase B The present invention also provides a pharmaceutical composition containing the same and a pharmaceutical composition containing the same as a pharmaceutical composition for preventing or treating a disease associated with atherosclerosis such as colon cancer, liver cancer, stomach cancer, breast cancer, colon cancer, bone cancer, pancreatic cancer, head or neck cancer, uterine cancer, Renal cell carcinoma, renal pelvic carcinoma, renal pelvic carcinoma, renal pelvis carcinoma, renal pelvic carcinoma, renal pelvic carcinoma, renal pelvic carcinoma, pancreatic cancer, pancreatic cancer, Neurogenic tumors and leukemia diseases or cancer which is a distal potential of solid tumors.

Claims (11)

Claims 1. A compound represented by the following formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]

(In the formula 1,
R ¹ is unsubstituted, substituted or fused phenyl, or - (CH ₂ ) _n -NR ² R ³ ;

And wherein said substituted phenyl is a phenyl substituted one to three -NO _2,
Wherein the fused phenyl is heteroaryl of unsubstituted hexa ring containing one or more N or heterocycloalkyl of unsubstituted 5-6 heterocyclic ring containing at least one O;

Wherein R ² may be a straight or branched chain alkyl of -H, or C _1-5, unsubstituted 5-8 each containing a hetero atom, at least one member selected from the group consisting of N, O and S together with the R ³ Form heterocycloalkyl of the ring;

R ³ is C _1-5 linear or branched alkyl, C _1-5 straight or branched alkylcarbonyl, unsubstituted or substituted aryl of 6-10 ring, - (CH ₂ ) _m -NR ⁴ R ⁵ , Or heteroaryl of an unsubstituted or substituted 5-10 heterocyclic ring containing at least one heteroatom selected from the group consisting of N, O and S,

Wherein R &lt; ⁴ &gt; and R &lt; ⁵ &gt; together form a 5- to 8-membered heterocycloalkyl comprising at least one heteroatom selected from the group consisting of N, O and S, wherein m is an integer from 1 to 3,

The aryl of the substituted 6-10-arylene ring and the heteroaryl of the 5-10-arylene are independently selected from the group consisting of halogen, C _1-5 linear or branched alkyl and C _1-5 straight or branched alkoxy The substituent may be substituted; And

And n is an integer of 1 to 5).
The method according to claim 1,
Wherein R ² is -H or C _1-3 straight chain or branched chain alkyl, or R ³ is taken together to form a heterocyclic ring of unsubstituted six-membered rings containing at least one heteroatom selected from the group consisting of N and O, Alkyl;

R ³ is C _1-3 linear or branched alkyl, C _1-3 linear or branched alkylcarbonyl, unsubstituted 6-10-membered ring aryl, - (CH ₂ ) _m -NR ⁴ R ⁵ , or N , Heteroaryl of an unsubstituted or substituted 5-10 heterocyclic ring containing at least one heteroatom selected from the group consisting of O and S,

Wherein R &lt; ⁴ &gt; and R &lt; ⁵ &gt; together form a heterocycloalkyl of a hexa ring containing at least one heteroatom selected from the group consisting of N, O and S, wherein m is an integer from 1 to 2,

Wherein said heteroaryl of said substituted 5-10 heterocyclic ring may be substituted independently with one or more substituents selected from the group consisting of halogen, C _1-5 straight or branched chain alkyl and C _1-5 straight or branched alkoxy; And

Wherein n is an integer from 1 to 3, an optical isomer thereof or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
Wherein R ² is either -H or methyl, and is connected with the R ³

&Lt; / RTI &gt;
R &lt; ³ &gt;

,

,

,

,

,

,

, Methyl, methylcarbonyl,

,

,

,

,

,

,

or

ego; And
Wherein n is an integer of 1 to 2. 10. An optically active compound of the formula:
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) Methyl 3- (2-hydroxy-5- (4- (3-nitrophenyl) -1H-1,2,3-triazol-1-yl) benzamido) benzoate;
(2) Methyl 3- (2-hydroxy-5- (4- (quinoxalin-6-yl) -1H-1,2,3-triazol-1-yl) benzamido) benzoate;
(3) Synthesis of methyl 3- (5- (4- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -1H-1,2,3- triazol- -2-hydroxybenzamido) benzoate;
(4) Synthesis of methyl 3- (5- (4- (benzo [d] [1,3] dioxol-5-yl) -1H-1,2,3- triazol- Amido) benzoate;
(5) Methyl 3- (2-hydroxy-5- (4- (phenylamino) methyl-1H-1,2,3-triazol-1-yl) benzamido) benzoate;
(6) Synthesis of methyl 3- (2-hydroxy-5- (4 - ((5-methylisoxazol-3- yl) amino) methyl-1H-1,2,3-triazol- Amido) benzoate;
(7) Synthesis of methyl 3- (2-hydroxy-5- (4 - ((6-methylpyridin-2-yl) amino) methyl-1H-1,2,3-triazol- ) Benzoate;
(8) Methyl 3- (2-hydroxy-5- (4- (pyrimidin-2-ylamino) methyl-1H-1,2,3-triazol-1-yl) benzamido) benzoate;
(9) Synthesis of methyl 3- (2-hydroxy-5- (4- (2- (pyrimidin-2-ylamino) ethyl) -1H-1,2,3- triazol- ) Benzoate;
(10) Methyl 3- (2-hydroxy-5- (4- (oxazol-2-ylamino) methyl-1H-1,2,3-triazol-1-yl) benzamido) benzoate;
(11) Synthesis of methyl 3- (5- (4- (benzo [d] [1,3] dioxol-2-ylamino) methyl-1H-1,2,3-triazol- Lt; / RTI &gt; benzoamido) benzoate;
(12) Synthesis of methyl 3- (2-hydroxy-5- (4- (thieno [3,2-d] pyrimidin-4-ylamino) methyl-1H-1,2,3- Yl) benzamido) benzoate;
(13) methyl 3- (2-hydroxy-5- (4- (2- (thieno [3,2-d] pyrimidin- Triazol-1-yl) benzamido) benzoate;
(14) Methyl 3- (2-hydroxy-5- (4- (N-morpholino) methyl-1H-1,2,3-triazol-1-yl) benzamido) benzoate;
(15) Synthesis of methyl 3- (2-hydroxy-5- (4 - ((2- (N-morpholino) ethyl) amino) methyl-1H-1,2,3-triazol- Amido) benzoate;
(16) Synthesis of methyl 3- (5- (4- (2 - ((N, N-dimethylamino) ethyl) -1H-1,2,3- triazol- 1 -yl) -2- Benzoate;
(17) Methyl 3- (2-hydroxy-5- (4- (2-acetamidoethyl) -1H-1,2,3-triazol-1-yl) benzamido) benzoate;
(18) Synthesis of methyl 3- (2-hydroxy-5- (4 - ((5-methyl-1H-pyrazol- ) &Lt; / RTI &gt; benzamido) benzoate;
(19) Methyl 3- (2-hydroxy-5- (4- (thiazol-2-ylamino) methyl-1H-1,2,3-triazol-1-yl) benzamido) benzoate;
(20) Synthesis of methyl 3- (5- (4- (1H-imidazol-2-ylamino) methyl-1H-1,2,3-triazol- 1 -yl) -2- Eight;
(21) Methyl 3- (2-hydroxy-5- (4- (pyridin-2-ylamino) methyl-1H-1,2,3-triazol-1-yl) benzamido) benzoate;
(22) Synthesis of methyl 3- (2-hydroxy-5- (4 - ((4-methylpyridin-2-yl) amino) methyl-1H-1,2,3-triazol- ) Benzoate;
(23) Methyl 3- (2-hydroxy-5- (4- (pyridin-4-ylamino) methyl-1H-1,2,3-triazol-1-yl) benzamido) benzoate; And
(24) Methyl 3- (2-hydroxy-5- (4- (pyrimidin-4-ylamino) methyl-1H-1,2,3-triazol-1-yl) benzamido) benzoate.
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); And
Reacting the compound represented by the formula (4) and the compound represented by the formula (5) to prepare a compound represented by the formula (1) (step 2); and reacting the compound represented by the formula : &Lt;
[Reaction Scheme 1]

(In the above Reaction Scheme 1,
R ¹ is as defined in formula (I) of claim 1).
delete A pharmaceutical composition for preventing or treating cancer comprising the compound represented by the general formula (1) of claim 1, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
8. The method of claim 7,
Wherein said compound inhibits Aurora kinase to prevent or treat cancer.
8. The method of claim 7,
Wherein the cancer is selected from the group consisting of colon cancer, liver cancer, stomach cancer, breast cancer, colon cancer, bone cancer, pancreatic cancer, head or neck cancer, uterine cancer, ovarian cancer, rectal cancer, esophageal cancer, small intestine cancer, Wherein the composition is selected from the group consisting of vaginal cancer, vulvar carcinoma, Hodgkin's disease, prostate cancer, bladder cancer, kidney cancer, ureter cancer, renal cell carcinoma, renal pelvic carcinoma central nervous system tumor and leukemia.
Cancer, colon cancer, bone cancer, pancreatic cancer, head or neck cancer, uterine cancer, ovarian cancer, ovarian cancer, ovarian cancer, ovarian cancer, ovarian cancer, Cancer of the prostate, cancer of the bladder, cancer of the kidney, cancer of the ureter, cancer of the kidney, cancer of the endometrium, cancer of the endometrium, cancer of the cervix, vaginal cancer, vulvar carcinoma, Hodgkin's disease, prostate cancer, small intestine cancer, , Renal pelvic carcinoma, central nervous system tumor, and leukemia.
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