KR101235100B1 - Tertiary amine compound comprising triazole as tripodal linkers, preparation method and application thereof - Google Patents

Abstract

The present invention relates to a tertiary amine compound having an amine or a carboxylic acid functional group at the terminal of two different alkyne functional groups and one triazole linkage represented by the following Chemical Formula 1, a method for preparing the same, and an application thereof. According to the present invention, stepwise amine or carboxylic acid and selective click chemistry and deprotection in tertiary amines enable high yield and easy synthesis of multifunctional compounds having three respective functions. In the present invention, medicinal chemistry, drug delivery system, new drug development, and molecular imaging, multi-functional or multi-image, dimer or trimer compounds may be universally applied to synthesis of new substances.
[Formula 1]

Description

Triple-linked tertiary amine compound containing triazole, preparation method and application thereof {TERTIARY AMINE COMPOUND COMPRISING TRIAZOLE AS TRIPODAL LINKERS, PREPARATION METHOD AND APPLICATION THEREOF}

The present invention relates to a method for preparing a tricyclic compound that is easy to prepare a multifunctional compound applied to the life science field, and an application thereof, and more particularly, to a tricyclic tertiary amine compound including triazole, and a method and a use thereof. will be.

In order to effectively treat the disease, it is being developed to enable the diagnosis and treatment at the early stage of the disease by understanding the biological functions in the human body, searching for specific biomarkers related to the disease, and developing a substance that selectively labels the disease. To this end, it is necessary to design and synthesize a compound in the form of a combination of molecules capable of various functions. Therefore, multifunctional compounds that can function in a single molecule can be used to contribute to the research of more advanced disease treatment and diagnostic drugs.

Compounds that can be used for this purpose are classified by function: 1) disease-target compounds having strong binding and selectivity with specific proteins 2) compounds that are non-toxic and stable to prevent immune reactions or degradation by enzymes in the human body 3 ) Reporter compounds capable of locating molecules such as optical / fluorescent dyes, radioactive isotopes, quantum dots and magnetic compounds 4) Compounds that facilitate absorption, distribution, metabolism and release in the human body by controlling polarity 5) Diseases occur Carrier compounds that can effectively carry the drug to the place can be classified. There is a demand for the development and application of a linking compound capable of designing and manufacturing the compounds listed above for the purpose of research.

Examples of multifunctional compounds that have been studied so far are listed as follows.

PEGylation (PEGylation), which is used as a method to sustain the effect of drugs by effectively slowing down the rapid decomposition of bioactive substances due to in vivo immune system or enzyme activity, is the result of research on functional molecules. PEG-INTRON and PEGASYS PEGylated in inferon are sold as blockbusters. PEGylation is also used to enhance the in vivo stability of liposomes and viral capsids used in drug delivery systems.

Another functional compound is a molecular probe that labels compounds with high binding and selectivity to disease-specific proteins with radioisotopes or fluorescent dyes to obtain an image of the tissue in progress of the disease. In particular, radiopharmaceuticals that are labeled with radioisotopes are attracting attention as cutting-edge molecular imaging technology applicable to the human body. Molecular designs should be designed so that the distribution and accumulation of drugs in the human body is quick due to the characteristics of isotopes with relatively short half-lives. Recently, a new field of research called theragnostics, which is a combination of therapeutics and diagnostics, has been developed, which is used to label early compounds with radioisotopes for selective compounds for newly obtained disease-specific biomarkers. In addition to use in diagnosis, the concept of treating a disease with the same compound.

Arginine-glycine-aspartic acid (RGD) has a strong binding ability with integrin protein, which is widely distributed on the surface of tumor cells, and many studies are being conducted as radiopharmaceuticals for tumor diagnosis. Was recently for radiopharmaceuticals as "cRGDyK" combines the monosaccharides of galactose (galactose) and positron emitting radioisotopes of ¹⁸ F in the "galacto- ^[18 F] cRDGyK" compound reported PET, additional galactose residue of the drug compound Dynamics It is known to play a role in improving pharmacokinetics activity to provide better diagnostic images. However, it has a complex synthetic route of several stages, and has a disadvantage in that the synthesis in each stage is difficult and the yield is low.

Nanoparticles are being studied as new carriers in drug delivery systems, and efforts have been made to impart various functions to the surface. In contrast to drug delivery due to passive EPR (Enhanced Permeability and Retention) effects, active drug delivery systems effectively introduce drugs into diseased areas by introducing disease-targeting ligand compounds onto the nanoparticle surface. . In addition, the PEGylation of the surface of the nanoparticles can increase the stability, inhibit nonspecific binding and reduce the toxicity.

Dimer and trimer compounds in which several drugs are combined are used as the most common method for maximizing drug effects by increasing the binding capacity of bioactive molecules to the target protein. This can be made relatively easily using spacer molecules having the same substituents.

One of the researches currently attracting the most attention in the field of molecular imaging is the multimodality technology. This aims to obtain a better image by supplementing the shortcomings of each imaging technology. By labeling two or more reporter compounds on a disease-target ligand compound, an optical / fluorescent dye and a radioisotope can be labeled at the same time to obtain optical and nuclear medical images using a single molecule, and positron emission tomography ( Molecular probe studies have been reported to simultaneously obtain Positron Emission Tomography (PET) and nuclear magnetic resonance (MRI) images. Liposomes have also been studied to realize various optical and MRI images and PET images and optical images at the same time.

The above-mentioned multifunctional compounds have been prepared by various conjugation methods, and common amide bonds, oxime bonds, 1,4-addition reactions with -SH of peptide cysteine residues (thio-ene), Staudinger amide bonds and the like are used. In addition, copper (I) -catalyzed alkyne / azide [3 + 2] cycloaddition (CuAAC), a representative click chemistry reported in 2003, has been reported to date. It is the most widely used bioconjugation method. Click chemistry is attracting attention as an alternative to the conventional bioconjugation method because it has a relatively fast reaction at room temperature, has a high reaction selectivity that reacts only with alkyne and azide functional groups, and the reaction proceeds well in aqueous solution. .

Conjugation methods between various compounds using click chemistry have been reported, and dimer, tetramer synthesis for the same compound has been studied as the easiest method. In addition, a method of synthesizing a compound in which two different alkane groups are selectively introduced by introducing two different alkyne groups at the end of the peptide compound to impart responsive selectivity of step click chemistry has been disclosed. A single silyl protecting group was able to perform two consecutive click chemistry with high reactivity selectivity, but there is a disadvantage that it is limited to a specific peptide in the method utilization. In 2008, a study was reported on synthesizing nucleotide monomers having different alkyn groups and introducing three different azide compounds step by step to synthesize oligonucleotides having various functions. Three different click chemistries could be performed with high selectivity through two different silyl protecting groups, but were limited to oligonucleotide applications, and were not generally available.

Recently, studies of effective alkyne / azide [3 + 2] ring reactions without the use of copper catalysts have been reported. A study has been reported in which two different compounds are introduced onto a protein surface by applying alkyne / azide [3 + 2] ring reaction under a catalyst. However, to date, no linking compound and a method for preparing a multifunctional compound using the same have been reported.

Accordingly, the present inventors have constructed a tri-linked tertiary amine compound capable of easily and variously preparing a multifunctional compound useful in various life science fields, and a method for preparing various multifunctional compounds using the same, and completed the present invention.

It is an object of the present invention to provide a tri-linked tertiary amine compound comprising triazoles which can readily substitute compounds of various functions.

Another object of the present invention is to provide a method for preparing the triple-linked tertiary amine compound.

Still another object of the present invention is to provide a method for preparing a multifunctional compound using the triple-linked tertiary amine compound.

In order to achieve the above object, the present invention provides a tertiary amine compound having an amine or carboxylic acid functional group at the terminal of two different alkyne functional groups and one triazole linker represented by the following formula (1).

(In Formula 1, l, m, n, o, p and R, P, X are as defined in the specification.)

As the present invention is represented by the following Scheme 1,

Provided is a method for preparing a tertiary amine compound represented by Chemical Formula 1-1 including alkyne / azide [3 + 2] ring reaction of azido compounds represented by Chemical Formula 3 and Chemical Formula 4 as starting materials under a copper catalyst. .

[Reaction Scheme 1]

(In Scheme 1, l, m, n, o, p and P, X, Y are as defined in the specification)

Furthermore, the present invention is represented by the following scheme 2,

Tertiary amine of Formula 1-2 comprising the step of alkyne / azide [3 + 2] ring reaction of a tertiary amine compound represented by Formula 3 as a starting material and an azido compound represented by Formula 5 under a copper catalyst Provided are methods for preparing the compounds.

[Reaction Scheme 2]

(In Scheme 2, l, m, n, o, p and P, Z are as defined in the specification.)

Furthermore, the present invention provides a method for preparing a trifunctional compound of Formula 2 in which three compounds A, B, and C are combined from a tertiary amine compound represented by Formula 1.

As represented by Scheme 3 below,

Subjecting the compound of Formula 1, which is a starting material, to the alkyne / azide [3 + 2] ring reaction with the azido compound of Formula 6-1 under a reaction solvent and a copper catalyst (step 1);

Deprotecting the P protecting group of the compound (step 2);

Subjecting the compound of Formula 8 to the alkyne / azide [3 + 2] ring reaction with the azido compound of Formula 6-2 under a reaction solvent and a copper catalyst (step 3); And

It provides a method of preparing a compound of Formula 2 comprising the step (step 4) of reacting a compound of Formula 9 and a compound of Formula 10 in an organic solvent.

Scheme 3

(In Scheme 3, l, m, n, o, p and R ₁ , R ₂ , X, W, A, B, C are as defined in the specification)

Furthermore, the present invention is represented by the following Scheme 4,

Preparing a compound of Chemical Formula 11 by reacting a starting compound of Chemical Formula 1 with a compound of Chemical Formula 10 in an organic solvent (Step 1);

Subjecting the compound of Formula 11 to the alkyne / azide [3 + 2] ring reaction with the azido compound of Formula 6-1 under a reaction solvent and a copper catalyst (step 2);

Deprotecting the P protecting group of the compound (step 3) and

It provides a compound of formula 2 comprising the step (step 4) of the compound of formula 13 and the azido compound of formula 6-2 in combination with the azido compound of formula 6-2 under a copper catalyst.

[Reaction Scheme 4]

(In Scheme 4, l, m, n, o, p and R ₁ , R ₂ , X, W, A, B, C are as defined in the specification)

In addition, in preparing the compounds of Formula 2 of Scheme 3 and Scheme 4, the synthetic sequence for introducing A, B, C compounds is not limited to the order of Scheme 3 and Scheme 4, and may be changed in some cases.

In addition, when R ₁ is —NH ₂ in Schemes 3 and 4, carbamate (-NH (CO ₂ -t Bu) or -NH (CO ₂ -CH ₂ Ph)) may be used to improve the polarity and physical properties of the compound. Compounds can also be used.

In addition, when R ₁ is —CO ₂ H in Schemes 3 and 4, ester (—CO ₂ -t Bu or —CO ₂ —CH ₂ Ph) compounds may be used to improve the polarity and physical properties of the compound.

According to the present invention, the tertiary amine compound of Formula 1 has three functional groups having different reaction selectivity, and can introduce two terminal alkyne groups and additional functional compounds capable of introducing functional compounds through click chemistry. Have amine or carboxylic acid functionality. In addition, the two terminal alkyne groups are characterized by being capable of silyl protecting one of them to have reaction selectivity for click chemistry. The tertiary amine compound of formula (1) according to the present invention makes it easy to synthesize multifunctional compounds having three independent functions in high yield. Therefore, the present invention can be universally applied to the synthesis of new materials such as multifunctional or multi-image, dimer or trimer compounds in the fields of medicinal chemistry, drug delivery system, new drug development and molecular imaging.

1 is a schematic diagram of a method for preparing a multifunctional compound having three independent functions through step click chemistry and amide condensation reaction of the tertiary amine compound of Chemical Formula 1 of the present invention.

Hereinafter, the present invention will be described in detail.

The present invention provides a tertiary amine compound having an amine or carboxylic acid functional group at the terminal of two different alkyne functional groups and one triazole linker represented by the following formula (1).

[Formula 1]

In Formula 1,

P is hydrogen, triC ₁ -C ₄ alkyl silyl group, diC ₁ -C ₄ alkylC ₃ -C ₈ aryl silyl group, or diC ₃ -C ₈ arylC ₁ -C ₄ alkyl silyl group,

l, m, n, o and p are each independently an integer from 1 to 5,

X is independently a single bond, carbonyl (C═O), —NHCO— or —CONH—,

R is —NH—Y, or —CO ₂ —Z,

Y is hydrogen, —CO ₂ -t Bu, —CO ₂ -CH ₂ Ph, or —CO ₂ -tC (Ph) ₃ ),

Z is hydrogen, —t Bu, —CH ₂ Ph or —CO ₂ —tC (Ph) ₃ .

Preferably,

P is hydrogen trimethylsilyl (TMS); Triethylsilyl (TES); Triisopropylsilyl (TIPS); t - butyl-dimethyl-silyl (t -butyldimethylsilyl, TBDMS); t - butyl and diphenyl silyl (t -butyldiphenylsilyl, TBDPS) or triphenyl silyl (triphenylsilyl, TPS),

l, m, n, o and p are each independently an integer of 1 to 3,

X is a single bond, carbonyl (C═O), —NHCO— or —CONH—,

R is —NH ₂ , —NH (CO ₂ —t Bu), —NH (CO ₂ —CH ₂ Ph), —CO ₂ H, —CO ₂ -t Bu, or —CO ₂ —CH ₂ Ph.

Preferred examples of the tertiary amine of the novel structure represented by Chemical Formula 1 according to the present invention are shown in Table 1 below.

division compound One

2

3

4

5

6

7

8

9

10

The compound name of the tertiary amine of the novel structure represented by Formula 1 of Table 1 is as follows:

(1a) t-butyl-3- (4-(((N-3- (t-butyldimethylsilyl) prop-2-ynyl) -N-propazyl) amino) methyl) -1H-1,2 , 3-triazol-1-yl) propylcarbamate,

(1b) N-((1- (3-aminopropyl) -1H-1,2,3-triazol-4-yl) methyl) -N- (3- ( t -butyldimethylsilyl) prop- 2-ynyl) -N-propazylamine,

(1c) t-butyl-3- (4-((((N-3- (triisopropylsilyl) prop-2-ynyl) -N-propazyl) amino) methyl) -1H-1,2,3 -Triazol-1-yl) propylcarbamate,

(1d) N-((1- (3-aminopropyl) -1H-1,2,3-triazol-4-yl) methyl) -N- (3- (triisopropylsilyl) prop-2- Phosphorus) -N-propazylamine,

(1e) 4- (3- (4-(((N-3- ( t -butyldimethylsilyl) propyn-2-yl) -N-propazyl) amino) methyl) -1H-1,2, 3-triazol-1-yl) propylamino) -oxobutanoic acid,

(1f) 4- (3- (4-(((N-3- (triisopropylsilyl) propyn-2-yl) -N-propazyl) amino) methyl) -1H-1,2,3- Triazol-1-yl) propylamino) -oxobutanoic acid,

(1 g) t-butyl-2- (4-(((N-3- ( t -butyldimethylsilyl) propyn-2-yl) -N-propazyl) amino) methyl) -1H-1,2 , 3-triazol-1-yl) acetate,

(1h) 2- (4-(((N-3- ( t -butyldimethylsilyl) propyn-2-yl) -N-propazyl) amino) methyl) -1H-1,2,3-tria Zol-1-yl) acetic acid,

(1i) t-butyl-2- (4-(((N-3- (triisopropylsilyl) propyn-2-yl) -N-propazyl) amino) methyl) -1H-1,2,3 -Triazol-1-yl) acetate, and

(1j) 2- (4-(((N-3- (triisopropylsilyl) propyn-2-yl) -N-propazyl) amino) methyl) -1H-1,2,3-triazole- 1-yl) acetic acid.

In addition, the present invention provides a method for preparing a tertiary amine compound of Formula 1 (compound of Formula 1-1 and compound of Formula 1-2).

Method 1:

As represented by Scheme 1 below,

A method for preparing a tertiary amine compound of Chemical Formula 1-1, comprising alkyne / azide [3 + 2] ring reaction of azido compounds represented by Chemical Formula 3 and Chemical Formula 4 as starting materials under a copper catalyst.

[Reaction Scheme 1]

In Scheme 1, l, m, n, o, p and P, X are as defined in Formula 1,

Y is hydrogen, —CO ₂ —tBu, —CO ₂ —CH ₂ Ph, or —CO ₂ —tC (Ph) ₃ .

When Y is —CO ₂ —t Bu, —CO ₂ —CH ₂ Ph or —CO ₂ —tC (Ph) ₃ in the compound of Formula 1-1 obtained in Preparation Method ₁ , Y may be obtained through a conventional deprotection reaction. It can be used by substituting with hydrogen.

Recipe 2:

As represented by Scheme 2 below,

Tertiary amine of Formula 1-2 comprising the step of alkyne / azide [3 + 2] ring reaction of a tertiary amine compound represented by Formula 3 as a starting material and an azido compound represented by Formula 5 under a copper catalyst Method for preparing the compound.

[Reaction Scheme 2]

In Scheme 2, l, m, n, o, p and P, X are as defined in Formula 1,

Z is hydrogen, -t Bu, -CH ₂ Ph or tC (Ph) ₃ .

In the above Preparation 1 and 2 according to the present invention, the reaction solvent used in Schemes 1 and 2 is tetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane (1, 2-dichloroethane), benzene, toluene, acetonitrile, dimethylformamide (N, N-dimethylformamide), dimethyl sulfoxide, methanol, ethanol, isopropanol, t -butanol, water and mixed solvents thereof may be used. .

In addition, in the above production methods 1 and 2 according to the present invention, the copper catalyst used in the reaction schemes 1 and 2 is a copper catalyst having a number of oxidation 1 such as CuI, CuBr, CuCl or CuSO ₄ , Cu (OAc) ₂ , Cu ( A copper catalyst having an oxidation number of 2, such as NO ₃ ) ₂ , Cu (OTf) ₂ , or CuO, can be used.

In the production methods 1 and 2 according to the present invention, when the oxidation number of the copper catalyst used in the reaction schemes 1 and 2 is 1, the alkali metal salt of bicarbonate ions, the alkali metal salt of carbonate ions, or triethylamine, diisopropylethylamine Bases such as, pyridine, lutidine, collidine and the like can be further used.

In the above Preparation 1 and 2 according to the present invention, when the oxidation number of the copper catalyst used in Schemes 1 and 2 is 2, Na-ascorbate, sodium sulfite (Na ₂ SO ₃ ), dithiothreitol Reducing agents such as (dithiothreitol) can be further used.

In addition, when Z is tBu, —CH ₂ Ph, or tC (Ph) ₃ in the compound of Formula 1-2 obtained in Preparation Method ₂ , Z may be substituted with hydrogen through a conventional deprotection reaction.

The present invention also provides a method for preparing a triple multifunctional compound of formula (2) in which three compounds of A, B, and C are combined, as in Scheme 3 or 4, from the tertiary amine compound represented by formula (1).

Recipe 3:

As represented by Scheme 3 below,

Subjecting the compound of Formula 1, which is a starting material, to the alkyne / azide [3 + 2] ring reaction with the azido compound of Formula 6-1 under a reaction solvent and a copper catalyst (step 1);

Deprotecting the P protecting group of the compound (step 2);

Subjecting the compound of Formula 8 to the alkyne / azide [3 + 2] ring reaction with the azido compound of Formula 6-2 under a reaction solvent and a copper catalyst (step 3); And

A process for preparing a compound of formula 2 comprising reacting a compound of formula 9 with a compound of formula 10 in an organic solvent (step 4).

Scheme 3

In Scheme 3,

l, m, n, o, p and P, X are as defined in Formula 1,

R ₁ is the same as R defined in Chemical Formula 1,

-OCOCl; ―NCO; ―NCS; -SO₂Cl; 또는 ―NH₂이고, R ₂ is —CO ₂ H; -COF -COCl; -COBr;

-OCOCl; -NCO; -NCS; -SO ₂ Cl; Or —NH ₂ ,

W is —NHCO—; -NHCOO-; -NHCONH-; -NHCSNH-; -NHSO _2- ; Or —CONH-,

A, B, and C are each independently

Certain proteins and biopolymer compounds in vivo, any one selected from the group of organic compounds having selective binding to biological tissues (Group 1);

Any one selected from the group of specific proteins and biopolymer compounds in vivo, peptides having a selective binding ability to biological tissues, sugars, lipids, nucleotides or derivatives thereof (group 2);

Any one selected from the group of fluorescent dye near infrared fluorescent dye optical dye quantum dots derivatives for in vivo molecular imaging diagnosis (group 3);

Any one selected from the group consisting of a complex containing a radioactive isotope comprising a radioisotope for diagnosis of molecular imaging in vivo (group 4);

Any one selected from the group of derivatives of gadolinium, iron oxide, and manganese metal having magnetic and supermagnetism for in vivo molecular imaging diagnosis (group 5);

Any one selected from the group of biotin derivatives for in vivo molecular imaging (group 6);

Any one selected from the group of oligo ethylene glycol derivatives for in vivo stability (group 7);

Any one selected from the group of monosaccharides or polysaccharides (oligo-saccharides) for in vivo pharmacokinetics (group 8); And

Organic polymer dendrimers for drug delivery in vivo; Viral capsid chitosan nanoparticle group (group 9).

Preparation 4:

Furthermore, the present invention is represented by the following Scheme 4,

Preparing a compound of Chemical Formula 11 by reacting a starting compound of Chemical Formula 1 with a compound of Chemical Formula 10 in an organic solvent (Step 1);

Subjecting the compound of Formula 11 to the alkyne / azide [3 + 2] ring reaction with the azido compound of Formula 6-1 under a reaction solvent and a copper catalyst (step 2);

Deprotecting the P protecting group of the compound (step 3); And

A process for preparing a compound of formula (2) comprising the step of subjecting a compound of formula (13) to an alkyne / azide [3 + 2] ring reaction with azido compound of formula (6-2) under a copper catalyst.

[Reaction Scheme 4]

In Scheme 4,

l, m, n, o, p and P, X are as defined in Formula 1,

R ₁ , R ₂ , X, W and A, B, C are as defined in Scheme 3 above.

와의 통상적인 아미드화 반응; 아민과 클로로포메이트 (-OCOCl) 와의 통상적인 카바메이트화 반응; 아민과 아이소시아네이트 (―NCO)와의 통상적인 유레아화 반응; 아민과 아이소싸이오시아네이트 (―NCS)와의 통상적인 싸이오유레아화 반응; 아민과 술포닐 할라이드 (-SO₂Cl) 또는 무수 술포닐 산((-SO₂)O)과의 통상적인 술폰아미드화 반응중에서 선택하여 사용할 수 있다.In the above Preparation 3 and 4 according to the present invention, the reaction required in Step 4 of Scheme 3 and Step 1 of Scheme 4 is -CO ₂ H which is an amine and a carboxylic acid derivative; —COF; —COCl; —COBr;

Conventional amidation reactions with; Conventional carbamatelation of amines with chloroformate (-OCOCl); Conventional urealation of amines with isocyanates (-NCO); Conventional thiourealation reactions of amines with isothiocyanates (-NCS); It can be selected and used in the conventional sulfonation reaction of amine with sulfonyl halide (-SO ₂ Cl) or sulfonyl anhydride ((-SO ₂ ) O).

In addition, in the preparation methods 3 and 4 according to the present invention, the reaction solvent used in steps 1 and 3 of Scheme 3 and steps 2 and 4 of Scheme 4 is tetrahydrofuran, 1,4-dioxane, dichloromethane , Chloroform, carbon tetrachloride, 1,2-dichloroethane, benzene, toluene, acetonitrile, dimethylformamide (N, N-dimethylformamide), dimethylsulfoxide, methanol, ethanol, isopropanol, t -butanol, water and mixed solvents thereof may be used.

In addition, in the preparation methods 3 and 4 according to the present invention, the copper catalyst used in steps 1 and 3 of Scheme 3 and steps 2 and 4 of Scheme 4 is a copper catalyst having an oxidation number of 1, such as CuI, CuBr, CuCl, etc. Alternatively, a copper catalyst having an oxidation number of 2, such as CuSO ₄ , Cu (OAc) ₂ , Cu (NO ₃ ) ₂ , Cu (OTf) ₂ , CuO, or the like can be used.

When using a copper catalyst having 1 oxidation number, an alkali metal salt of bicarbonate ions, an alkali metal salt of carbonate ions, or a base such as triethylamine, diisopropylethylamine, pyridine, lutidine, collidine, or the like may be additionally used.

When using a copper catalyst having 2 oxidation number, a reducing agent such as Na-ascorbate, sodium sulfite (Na ₂ SO ₃ ), dithiothreitol, etc. may be additionally used.

In addition, in the above-mentioned preparation methods 3 and 4 according to the present invention, the deprotection gasification reaction required in step 2 of scheme 3 and step 3 of scheme 4 may use a conventionally known desilylation method.

Hereinafter, the present invention will be described in more detail with reference to Production Examples and Examples. However, the following examples are merely to illustrate the present invention, but the content of the present invention is not limited thereto.

< Manufacturing example  1> N, N- Dipropazol -N- (3- (t- Butyldimethylsilyl ) Prof Preparation of 2-ynyl) amine (3a)

Tripropazyl amine 14a (10.75 mL, 76 mmol) was dissolved in anhydrous tetrahydrofuran (200 mL) and 2.5 M butyllithium / hexane solution (18 mL, 91.2 mmol) was added dropwise at −78 ° C. under nitrogen. The reaction was stirred for 30 minutes at −78 ° C. and a solution of tert -butyldimethylsilyl chloride (TBDMS-Cl, 15a , 5.7 g, 37.5 mmol) in anhydrous tetrahydrofuran (100 mL) was added dropwise. The reaction was stirred at room temperature for 2 hours, saturated aqueous ammonium chloride solution was added, extracted with ethyl acetate, the organic layers were combined, dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was subjected to column chromatography (5% ethyl acetate / hexane) to give the title compound 3a (5.5 g, 60%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.10 (s, 6H), 0.93 (s, 9H), 2.25 (t, J = 2.4 Hz, 1H), 3.48 (d, J = 2.4 Hz, 4H), 3.50 (s, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ −4.6, 16.5, 26.1, 41.7, 43.0, 73.3 78.5, 88.6, 100.8.

< Manufacturing example  2> N, N- Dipropazol -N- (3- ( Triisopropylsilyl ) Prof Preparation of 2-ynyl) amine (3b)

Except for using triisopropylsilyl chloride ( 15b ) instead of tert -butyldimethylsilyl chloride ( 15a ) to give the target compound 3b (oil, 65%) in the same manner as in Preparation Example 1.

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.10 (s, 6H), 1.06 (S, 18H), 1.07 (S, 3H), 2.50 (t, J = 2.4 Hz, 1H), 3.48 (d, J = 2.4 Hz, 4H), 3.55 (s, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 11.1, 18.6, 41.7, 43.0, 73.2, 78.6, 86.5, 101.7.

< Manufacturing example  3> N, N- Dipropazol -N- (3- ( Triethylsilyl ) Prof Preparation of 2-ynyl) amine (3c)

The target compound 3c (54%) was obtained by the same method as Preparation Example 1, except that triethylsilyl chloride ( 15c ) was used instead of tert -butyldimethylsilyl chloride ( 15a ).

¹ H NMR (400 MHz, CDCl ₃ ) δ 2.25 (t, J = 2.4 Hz, 1H), 3.48 (d, J = 2.4 Hz, 4H), 3.51 (s, 2H), 0.98 (t, J = 8.0 Hz , 8H), 0.59 (q, J = 8.0 Hz, 6H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 4.3, 7.4, 42.1, 43.4, 73.2, 78.6, 87.7, 101.2.

< Manufacturing example  4> N, N- Dipropazol -N- (3- ( Triphenyl ) Prof Preparation of 2-ynyl) amine (3d)

The target compound 3d (30%) was obtained by the same method as Preparation Example 1, except that triphenylsilyl chloride ( 15d ) was used instead of tert -butyldimethylsilyl chloride ( 15a ).

¹ H NMR (400 MHz, CDCl ₃ ) δ 2.26 (t, J = 2.4 Hz, 1H), 3.54 (d, J = 2.4 Hz, 4H), 3.69 (s, 2H), 7.32-7.46 (m, 9H) , 7.63-7.68 (m, 6 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 42.0, 43.3, 73.5, 78.5, 85.7, 105.3, 128.0, 130.0, 133.3, 135.5.

< Example  1> Preparation of Compounds 1a and 1b

Step 1: Preparation of Compound 1a

Compound 3a (4.42 g, 18.0 mmol) obtained in Preparation Example 1 was dissolved in acetonitrile (110 mL), and dissolved in acetonitrile in 0.1 M copper iodide solution (12.0 mL, 1.2 mmol) and acetonitrile. 0.2 M triethylamine solution (6.0 mL, 1.2 mmol) was added. Azido compound 4a (1.2 g, 6.0 mmol) dissolved in acetonitrile (73.0 mL) was added to the reaction mixture, which was stirred for 3 hours at room temperature. The solvent was concentrated under reduced pressure and then column chromatography (3% methanol / dichloromethane) was performed to give the title compound 1a (1.37 g, 51%) as a solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.10 (S, 6H), 0.94 (S, 9H), 1.43 (S, 9H), 2.06 (p, J = 6.4 Hz, 2H), 2.25 (t, J = 2.0 Hz, 1H), 3.12 (q, J = 6.4 Hz, 2H), 3.44 (d, J = 2.0 Hz, 2H), 3.49 (s, 2H), 3.84 (s, 2H), 4.40 (t, J = 6.8 Hz, 2H), 4.74 (brs, 1 H) 7.57 (s, 1 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ −4.6, 16.5, 26.1, 28.3, 30.7, 37.3, 41.9, 43.2, 47.5, 47.9, 73.2, 78.7, 79.5, 88.5, 101.0, 123.2, 144.7, 156.0.

Step 2: Preparation of Compound 1b

20% tetrafluoroacetic acid / dichloromethane solution (175 ml) was added to 1a (1.1 g, 2.47 mmol) obtained in step 1, followed by stirring at room temperature for 1 hour. The reaction was concentrated under reduced pressure to give the title compound 1b (845 mg, 99%) as a liquid without purification.

¹ H NMR (400 MHz, acetone- d ₆ ) δ 0.10 (S, 6H), 0.94 (S, 9H), 2.29 (p, J = 6.4 Hz, 2H), 2.74 (t, J = 2.0 Hz, 1H) , 3.40-3.48 (m, 4H), 3.50 (s, 2H), 3.80 (s, 2H), 4.54 (t, J = 6.8 Hz, 2H), 7.89 (s, 1H); MS (ESI) m / z 346.4 (M + H) ⁺ .

< Example  2> Preparation of Compounds 1c and 1d

Step 1: Preparation of Compound 1c

A target compound 1c (oil, 1.4 g, 48%) was obtained by the same method as Step 1 of Example 1, except that compound 3b, which was obtained in Preparation Example 2, was used instead of compound 3a .

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.07 (s, 18H), 1.08 (s, 3H), 1.43 (s, 9H), 2.08 (p, J = 6.8 Hz, 2H), 2.28 (t, J = 2.0 Hz, 1H), 3.13 (q, J = 6.8 Hz, 2H), 3.46 (d, J = 2.0 Hz, 2H), 3.53 (s, 2H), 3.87 (s, 2H), 4.40 (t, J = 6.8 Hz, 2H), 4.76 (brs, 1 H) 7.57 (s, 1 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 11.2, 18.6, 28.4, 30.7, 37.3, 42.0, 43.3, 47.6, 47.9, 73.2, 79.0, 79.5, 86.5, 102.0, 123.2, 145.0, 156.2.

Step 2: Preparation of Compound 1d

A target compound 1d (oil, 1.19 g, 99%) was obtained by the same method as step 2 of Example 1, except that compound 1c, which was obtained in step 1, was used instead of compound 1a .

¹ H NMR (400 MHz, acetone) δ 0.10 (S, 6H), 0.94 (S, 9H), 2.20-2.40 (m, 2H), 2.74 (t, J = 2.0 Hz, 1H), 3.24-3.50 (m , 4H), 3.55 (s, 2H), 3.83 (s, 2H), 4.53 (t, J = 5.2 Hz, 2H), 7.86 (s, 1H); MS (ESI) m / z 388.5 (M + H) ⁺ .

< Example  3> Preparation of Compound 1e

Except for using compound 5a (1.1 g, 4.5 mmol) instead of compound 4a in the same manner as in Step 1 of Example 1 to obtain the target compound 1e (77.5 mg, 12%) as a solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.09 (s, 6H), 0.92 (s, 9H), 2.10 (p, J = 6.4 Hz, 2H), 2.29 (t, J = 2.4 Hz, 1H), 2.45 (t, J = 6.4 Hz, 2H), 2.61 (t, J = 6.4 Hz, 2H), 3.25 (q, J = 6.0 Hz, 2H), 3.47 (d, J = 2.4 Hz, 2H), 3.51 (s , 2H), 3.84 (s, 2H), 4.40 (t, J = 6.4 Hz, 2H), 7.02 (t, J = 5.6 Hz, 1H), 7.67 (s, 1H), 9.27 (brs, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ −4.3, 16.4, 26.0, 29.8, 30.0, 30.9, 36.5, 41.4, 42.8, 47.5, 47.8, 74.0, 77.8, 89.3, 100.0, 123.9, 143.6, 173.0, 176.1.

< Example  4> Preparation of Compound 1f

Except for using the compound 5a instead of compound 4a in the same manner as in Step 1 of Example 2 to obtain the target compound 1f (130 mg, 18%) as a solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.07 (s, 18H), 1.08 (s, 3H), 2.15 (p, J = 6.8 Hz, 2H), 2.31 (t, J = 2.0 Hz, 1H), 2.45 (t, J = 6.0 Hz, 2H), 2.63 (t, J = 5.6 Hz, 2H), 3.33 (q, J = 6.0 Hz, 2H), 3.58 (d, J = 2.0 Hz, 2H), 3.63 (s , 2H), 3.90 (s, 2H), 4.44 (t, J = 6.0 Hz, 2H), 6.35 (brs, 1H), 7.62 (s, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 11.1, 18.6, 30.0 (2C), 30.9, 36.5, 41.4, 42.9, 47.6, 47.9, 74.1, 77.9, 87.4, 101.0, 124.0, 143.5, 173.1, 175.9.

< Example  5> Preparation of Compound 1g and 1h

Step 1: Preparation of 1 g of Compound

Except for using the compound 5b instead of compound 4a in the same manner as in Step 1 of Example 1 to obtain the target compound 1g (560 mg, 55%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.11 (s, 6H), 0.94 (s, 9H), 2.28 (t, J = 2.4 Hz, 1H), 3.45 (d, J = 2.4 Hz, 2H), 3.49 (s, 2H), 3.89 (s, 2H), 5.05 (s, 2H), 7.65 (s, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ −4.6, 16.5, 26.1, 27.9, 41.9, 43.2, 47.9, 51.6, 73.3, 78.8, 83.8, 88.6, 101.1, 124.2, 144.9, 165.2.

Step 2: Preparation of Compound 1h

1 g (400 mg, 1 mmol) of the compound obtained in step 1 was dissolved in 20% tetrafluoroacetic acid / dichloromethane solution (70 ml) at room temperature, and then stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure and then dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted again with dichloromethane and the organic layer was dehydrated with anhydrous sodium sulfate, filtered and concentrated. The desired compound 1h (263 mg, 76%) was obtained as a solid without purification.

¹ H NMR (400 MHz, CDCl ₃ ) δ0.13 (s, 6H), 0.93 (s, 9H), 2.69 (s, 1H), 4.06 (s, 2H), 4.10 (s, 2H), 4.50 (s , 2H), 5.14 (s, 2H), 8.15 (s, 1H) ¹³ C NMR (100 MHz, CDCl ₃ ) δ-5.1, 16.4, 25.9, 41.3, 42.8, 47.2, 51.3, 71.5, 79.4, 92.7, 96.2 , 128.4, 136.9, 169.2.

< Example  6> Preparation of Compounds 1i and 1j

Step 1: Preparation of Compound 1i

A target compound 1i (580 mg, 51%) was obtained in the same manner as in Example 1, except that compound 5b was used instead of compound 4a .

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.07 (S, 18H), 1.08 (s, 3H), 1,47 (s, 9H), 2.30 (t, J = 2.4 Hz, 1H), 3.47 (d, J = 2.4 Hz, 2H), 3.53 (s, 2H), 3.90 (s, 2H), 5.04 (s, 2H), 7.64 (s, 1H) ¹³ C NMR (100 MHz, CDCl ₃ ) δ 11.2, 18.6, 27.9, 42.0, 43.2, 47.9, 51.5, 73.3, 79.1, 83.8, 86.5, 102.0, 124.2, 145.0, 165.1.

Step 2: Preparation of Compound 1j

A target compound 1j (294 mg, 76%) was obtained in the same manner as step 2 of Example 5, except that compound 1i obtained in step 1 was used instead of compound 1g .

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.07 (m, 21H), 2.45 (s, 1H), 3.78 (s, 2H), 3.82 (s, 2H), 4.13 (s, 2H), 5.07 (s, 2H), 7.88 (s, 1 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 11.1, 18.5, 40.9, 42.3, 47.0, 51.9, 75.0, 76.3, 90.3 97.8, 126.3, 140.4, 169.7.

The present invention provides a method for introducing three compounds using the new triple-linked compound 1a - 1j obtained in Example 1-6. For this purpose, the azido compounds, carboxylic acid derivative compounds, and amine derivative compounds listed below were used.

Azido  compound

Carboxylic acid  Derivative compounds

Amine derivative compounds

< Example  7> Preparation of Compound 2a

Step 1: Preparation of Compound 7a

Compound 1b (124.4 mg, 0.360 mmol) obtained in step 2 of Example 1 was dissolved in tetrahydrofuran (4.5 mL), and copper sulfate (7.50 mg, 0.030 mmol) and sodium ascorbate (Na-Asc., 11.9 mg) , 0.060 mmol) was added. Benzyl azide 6c (0.037 mL, 0.300 mmol) and water (4.5 mL) were added to the reaction mixture, which was stirred for 12 hours at room temperature. After adding water, the organic compound was extracted with dichloromethane and the organic layer was dried with anhydrous sodium sulfate. After dehydration and concentration under reduced pressure, column chromatography (4% methanol / dichloromethane) was performed to obtain the target compound 7a (70 mg, 49%) as a liquid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.11 (s, 6H), 0.95 (s, 9H), 2.01 (p, J = 6.8 Hz, 2H), 2.72 (t, J = 6.8 Hz, 2H), 3.38 (s, 2H), 3.83 (s, 2H), 3.84 (s, 2H), 4.45 (t, J = 6.8 Hz, 2H), 5.52 (s, 2H), 7.22-7.40 (m, 5H), 7.49 ( s, 1 H), 7.58 (s, 1 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ -4.6, 16.7, 26.3, 33.6, 38.7, 43.5, 47.8, 48.0, 48.1, 54.3, 89.0, 101.3, 123.1, 123.3, 128.2, 128.9, 129.3, 134.8, 144.8, 145.3.

Step 2: Preparation of Compound 8a

7a (60.5 mg, 0.126 mmol) obtained in step 1 was dissolved in tetrahydrofuran (1.5 mL), and then 1M solution of tetrabutylammonium fluoride / tetrahydrofuran (0.32 mL, 0.320 mmol) was added at 0 ° C. Then stirred at room temperature for 1 hour. The solution of the reaction was concentrated under reduced pressure and then subjected to column chromatography (3% methanol / dichloromethane) to give the title compound 8a (38.0 mg, 83%) as a liquid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 2.01 (p, J = 6.8 Hz, 2H), 2.27 (t, J = 2.0 Hz, 1H), 2.71 (t, J = 6.8 Hz, 2H), 3.35 (d , J = 2.0 Hz, 2H), 3.84 (s, 2H), 3.85 (s, 2H), 4.45 (t, J = 6.8 Hz, 2H), 5.52 (s, 2H), 7.22-7.40 (m, 5H) , 7.52 (s, 1 H), 7.61 (s, 1 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 33.5, 38.6, 42.0, 47.0, 47.6, 47.7, 54.1, 73.7, 78.4, 123.1, 123.2, 128.0, 128.7, 129.1,134.6, 144.2, 144.8.

Step 3: Preparation of Compound 9a

Compound 8a (29.2 mg, 0.08 mmol) obtained in step 2 was dissolved in tetrahydrofuran (1.2 mL), copper sulfate (2.0 mg, 0.008 mmol) and sodium ascorbate (Na-Asc., 3.17 mg, 0.016 mmol) Added. 4-methoxybenzyl azide 6d (10.88 mg, 0.067 mmol) and water (1.2 mL) were added to the reaction mixture. The mixture was stirred at room temperature for 12 hours. After adding water, the organic compound was extracted with dichloromethane. After dehydration with anhydrous sodium sulfate and concentration, column chromatography (5% methanol / dichloromethane) was performed to obtain the target compound 9a (12.0 mg, 34%) as a liquid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 2.02 (p, J = 6.8 Hz, 2H), 2.27 (t, J = 2.0 Hz, 1H), 2.71 (t, J = 6.8 Hz, 2H), 3.35 (d , J = 2.0 Hz, 2H), 3.84 (s, 2H), 3.85 (s, 2H), 4.45 (t, J = 6.8 Hz, 2H), 5.52 (s, 2H), 7.22-7.40 (m, 5H) , 7.52 (s, 1 H), 7.61 (s, 1 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 33.5, 38.6, 42.0, 47.0, 47.6, 47.7, 54.1, 73.7, 78.4, 123.1, 123.2, 128.0, 128.7, 129.1, 134.6, 144.2, 144.8

Step 4: Preparation of Compound 2a

Compound 9a (25.0 mg, 0.052 mmol) obtained in step 3 was dissolved in tetrahydrofuran (4.0 mL), and a solution of phenyl isocyanate 10a (7.46 mg, 0.063 mmol) dissolved in tetrahydrofuran (0.2 mL) was added dropwise. After stirring for 1 hour at room temperature, the solvent was concentrated under reduced pressure. Column chromatography of the concentrate (5% methanol / dichloromethane) was carried out to afford the desired compound 2a (70 mg, 49%) as a liquid.

¹ H NMR (400 MHz, CDCl 3) δ (s, 6H), 0.95 (s, 9H), 2.01 (p, J = 6.8 Hz, 2H), 2.72 (t, J = 6.8 Hz, 2H), 2.72 (t , J = 6.8 Hz, 2H), 3.69 (s, 2H), 3.70 (s, 2H), 3.82 (s, 2H), 4.45 (t, J = 6.8 Hz, 2H), 5.45 (s, 2H), 5.52 (s, 2H), 6.86-6.92 (m, 2H), 7.20-7.40 (m, 7H), 7.63 (s, 1H), 7.68 (s, 1H), 7.77 (s, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 33.5, 38.6, 46.9, 47.0, 47.1, 47.6, 47.8, 53.7, 54.1, 55.3, 114.4, 123.5, 123.8, 124.0, 126.7, 128.0, 128.7, 129.1, 129.6, 134.7 , 143.7, 144.2, 144.3, 159.8.

< Example  8> Preparation of Compound 2b

Step 1: Preparation of Compound 7b

Compound 1a (500 mg, 1.12 mmol) obtained in Preparation Example 1 was dissolved in acetonitrile (7 mL), and 0.1 M copper iodide solution (2.2 mL, 0.22 mmol) dissolved in acetonitrile and 0.2 dissolved in acetonitrile M triethylamine solution (1.1 mL, 0.22 mmol) was added. Benzyl azide 5c (179 mg, 1.34 mmol) dissolved in acetonitrile (4.7 mL) was added to the reaction mixture, which was stirred for 1 hour at room temperature. The solvent was concentrated under reduced pressure and then column chromatography (5% methanol / dichloromethane) was performed to give the title compound 7b (384 mg, 59%) as a liquid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.12 (s, 6H), 0.95 (s, 9H), 1.44 (s, 9H), 2.10 (p, J = 6.0 Hz, 2H), 3.11 (q, J = 6.0 Hz, 2H), 3.70-4.00 (m, 4H), 4.40 (t, J = 6.0 Hz, 2H), 4.90 (brs, 1H), 5.52 (s, 2H), 7.20-7.40 (m, 5H), 7.53 (s, 1 H), 7.65 (s, 1 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ -4.5, 16.4, 26.1, 28.3, 30.6, 37.3, 43.3, 47.6 (3C), 54.1, 79.4, 88.9, 101.0, 123.0, 123.3, 128.0, 128.7, 129.0, 134.5 , 144.7, 144.9, 156.0.

Step 2: Preparation of Compound 8b

7b (348.3 mg, 0.6 mmol) obtained in step 1 was dissolved in tetrahydrofuran (8.0 mL), and then 1M solution of tetrabutylammonium fluoride / tetrahydrofuran (1.5 mL, 1.5 mmol) was added at 0 ° C. Stir for the next 1 hour. The reaction mixture was concentrated under reduced pressure and then subjected to column chromatography (5% methanol / dichloromethane) to obtain the title compound 8b (260 mg, 93%) as a liquid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.44 (s, 9H), 2.08 (p, J = 6.4 Hz, 2H), 2.30 (t, J = 2.0 Hz, 1H), 3.12 (q, J = 6.4 Hz , 2H), 3.53 (d, J = 2.0 Hz, 2H), 3.85 (s, 2H), 3.86 (s, 2H), 4.40 (t, J = 6.8 Hz, 2H), 4.90 (brs, 1H), 5.52 (s, 2H), 7.20-7.40 (m, 5H), 7.54 (s, 1H), 7.68 (s, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 28.2, 30.6, 37.2, 42.0, 47.4, 47.6 (2C), 54.0, 73.7, 78.3, 79.3, 122.9, 123.3, 127.9, 128.6, 129.0, 134.6, 144.3, 144.7, 156.0.

Step 3: Preparation of Compound 9b

Compound 8b (97 mg, 0.209 mmol) obtained in step 2 was dissolved in acetonitrile (1.3 mL), and 0.1 M copper iodide solution (0.58 mL, 0.058 mmol) dissolved in acetonitrile and 0.2 M dissolved in acetonitrile. Triethylamine solution (0.29 mL, 0.058 mmol) was added. Azido compound 6a (93.5 mg, 0.251 mmol) dissolved in acetonitrile (0.88 mL) was added to the reaction mixture, which was stirred for 1 hour at room temperature. The solvent was concentrated under reduced pressure and then column chromatography (5% methanol / dichloromethane) was carried out to give target compound 9b (142 mg, 81%) as a solid.

¹ H NMR (400 MHz, CDCl ₃ ) δδ 1.44 (s, 9H), 1.82 (s, 3H), 2.03 (s, 3H), 2.08 (s, 3H), 2.10 (s, 3H), 2.04-2.12 ( m, 2H), 3.13 (q, J = 6.0 Hz, 2H), 3.63-3.74 (m, 4H), 3.77 (s, 2H), 4.03-4.06 (m, 1H), 4.17 (dd, J = 12.6, 1.6 Hz, 1H), 4,32 (dd, J = 12.6, 4.8 Hz, 1H), 4.42 (t, J = 6.0 Hz, 2H), 4.94 (brs, 1H), 5.26 (t, J = 9.6 Hz, 1H), 5.43 (t, J = 9.6 Hz, 1H), 5.47 (t, J = 9.6 Hz, 1H), 5.54 (s, 2H), 5.89 (d, J = 8.4 Hz, 1H), 7.20-7.40 ( m, 5H), 7.73 (s, 1 H), 7.85 (s, 1 H), 8.04 (s, 1 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δδ 20.1, 20.4, 20.5, 20.7, 28.3, 30.5, 37.3, 47.0, 47.1, 47.6, 52.4, 54.1, 61.4, 67.6, 70.4, 72.5, 75.0, 79.4, 85.7, 122.4 , 123.8, 124.1, 128.0, 128.7, 129.0, 134.6, 143.7, 144.2, 144.6, 156.0, 168.8, 169.3, 169.9, 170.5.

Step 4: Preparation of Compound 9c

Compound 9b (111.4 mg, 0.133 mmol) obtained in step 3 was dissolved in dichloromethane (9.3 mL) and 20% trifluoroacetic acid / dichloromethane (9.3 mL) was added. The reaction mixture was stirred for 1 hour, concentrated under reduced pressure, dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The water layer was extracted again with dichloromethane, the organic layers were combined, dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound 9c (98.2 mg, 99%) as a solid.

MS (ESI): m / z = 738 [M + l] ⁺ .

Step 5: Preparation of Compound 2b

To a reaction vessel obtained by dissolving compound 9c (17.50 mg, 0.024 mmol) obtained in step 4 in tetrahydrofuran (1.1 mL), a solution of fluorescein isothiocyanate ( 10b , 9.24 mg, 0.024 mmol) was added dropwise. It was. After stirring for 2 hours at room temperature, the solvent was concentrated under reduced pressure. The desired compound 2b (26 mg, 99%) was obtained as a solid without purification.

MS (ESI): m / z = 1127 [M + l] ⁺ .

< Example  9> Preparation of Compound 2c

Step 1: Preparation of Compound 7c

Compound 1a (200 mg, 0.449 mmol) obtained in step 1 of Example 1 was dissolved in acetonitrile (2.8 mL), and 0.1 M copper iodide solution (0.9 mL, 0.09 mmol) and acetonitrile dissolved in acetonitrile. To 0.2 M triethylamine solution (0.45 mL, 0.09 mmol) was added. The azide compound 6a (201.0 mg, 0.539 mmol) dissolved in acetonitrile (1.9 mL) was added to the reaction mixture, which was stirred for 1 hour at room temperature. The solvent was concentrated under reduced pressure and then column chromatography (5% methanol / dichloromethane) was performed to give the title compound 7c (304 mg, 83%) as a solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.11 (s, 6H), 0.94 (s, 9H), 1.41 (s, 9H), 1.83 (s, 3H), 2.00 (s, 3H), 2.04 (s, 3H), 2.06 (s, 3H), 2.00-2.12 (m, 2H), 3.10 (q, J = 6.0 Hz, 2H), 3.37 (s, 2H), 3.81 (s, 2H), 3.83 (s, 2H ), 3.96-4.20 (m, 1H), 4.12 (d, J = 12.4 Hz, 1H), 4.28 (dd, J = 12.8, 4.8 Hz, 1H), 4.38 (t, J = 6.8 Hz, 2H), 4.86 (brs, 1 H), 5.18-5.24 (m, 1 H), 5.30-5.42 (m, 2 H), 5.80-5.88 (m, 1 H), 7.62 (s, 1 H), 7.80 (s, 1 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ -4.5, 16.4, 20.1, 20.4, 20.5, 20.6, 26.1, 28.3, 30.6, 37.2, 43.2, 47.5, 47.6, 47.8, 61.4, 67.6, 70.3, 72.4, 75.0, 79.4, 85.7, 88.9, 100.9, 121.3, 123.1, 144.7, 145.5, 156.0, 168.8, 169.3, 169.8, 170.4.

Step 2: Preparation of Compound 8c

7c (243.3 mg, 0.297 mmol) obtained in step 1 was dissolved in tetrahydrofuran (4.0 mL), and then 1M solution of tetrabutylammonium fluoride / tetrahydrofuran (0.74 mL, 0.743 mmol) was added at 0 ° C. Stir for the next 1 hour. The solution of the reaction was concentrated under reduced pressure and then subjected to column chromatography (5% methanol / dichloromethane) to give target compound 8c (145.0 mg, 69%) as a solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.43 (s, 9H), 1.85 (s, 3H), 2.02 (s, 3H), 2.06 (s, 3H), 2.08 (s, 3H), 2.02-2.12 ( m, 2H), 2.32 (d, J = 2.0 Hz, 1H), 3.12 (q, J = 6.4 Hz, 2H), 3.34 (d, J = 2.0 Hz, 2H), 3.85 (s, 2H), 3.87 ( s, 2H), 3.96-4.20 (m, 1H), 4.14 (dd, J = 12.8, 2.0 Hz, 1H), 4.30 (dd, J = 12.8, 4.8 Hz, 1H), 4.41 (t, J = 6.8 Hz , 2H), 4.82 (brs, 1H), 5.18-5.26 (m, 1H), 5.38-5.44 (m, 2H), 5.82-5.90 (m, 1H), 7.66 (s, 1H), 7.84 (s, 1H ); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 20.2, 20.49, 20.52, 20.7, 28.3, 30.7, 37.3, 42.0, 47.5, 47.6, 47.8, 61.5, 67.6, 70.4, 72.5, 73.9, 75.1, 78.3, 79.5, 85.7 , 121.5, 123.3, 144.5, 145.3, 156.1, 168.9, 169.3, 169.9, 170.5.

Step 3: Preparation of Compound 9d

Compound 8c (100 mg, 0.142 mmol) obtained in step 2 was dissolved in acetonitrile (0.88 mL), and 0.1 M copper iodide solution (0.28 mL, 0.028 mmol) dissolved in acetonitrile and 0.2 M dissolved in acetonitrile. Triethylamine solution (0.14 mL, 0.028 mmol) was added. The azide compound 6e (86.4 mg, 0.17 mmol) dissolved in acetonitrile (0.6 mL) was added to the reaction mixture, which was stirred for 1 hour at room temperature. The solvent was concentrated under reduced pressure and then column chromatography (5% methanol / dichloromethane) was performed to give the desired compound 9d (112.1 mg, 65%) as a solid.

¹ H NMR (400 MHz, CDCl ₃ ) δδ 1.43 (s, 9H), 1.47 (s, 9H), 1.83 (s, 3H), 2.02 (s, 3H), 2.07 (s, 3H), 2.08 (s, 3H), 1.92-2.22 (m, 6H), 2.31-2.38 (m, 2H), 3.11-3.16 (m, 2H), 3.17-3.24 (m, 2H), 3.62-3.76 (m, 4H), 3.77 ( s, 2H), 3.39-4.10 (m, 1H), 4.14-4.17 (m, 1H), 4,21 (t, J = 6.0 Hz, 2H), 4.28-4.40 (m, 7H), 4.98 (brs, 1H), 5.26 (t, J = 9.6 Hz, 1H), 5.43 (t, J = 9.6 Hz, 1H), 5.48 (t, J = 9.6 Hz, 1H), 5.88 (d, J = 8.4 Hz, 1H) , 5.90 (brs, 1H), 6.81 (brs, 1H), 7.28-7.32 (m, 2H), 7.37-7.41 (m, 2H), 7.59-7.62 (m, 2H), 7.75 (d, J = 7.6 Hz , 2H), 7.84 (s, 1 H), 7.90 (s, 1 H), 8.05 (s, 1 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δδ 20.0, 20.40, 20.41, 20.6, 27.9, 28.2, 28.5, 29.5, 29.8, 30.5, 32.4, 36.2, 37.2, 46.8, 47.0, 47.6, 54.0, 61.4, 66.8, 67.5 , 70.3, 72.4, 74.9, 79.3, 82.2, 85.6, 119.8, 122.5, 124.1, 124.4, 125.0, 125.1, 126.9, 127.6, 141.1, 143.6, 143.8, 144.6, 156.0, 156.3, 168.7, 169.2, 169.8, 170.4, 171.1 , 172.6.

Step 4: Preparation of Compound 9e

9d (91.3 mg, 0.075 mmol) obtained in step 3 was added to 20% trifluoroacetic acid / dichloromethane (5.3 mL), followed by stirring at room temperature for 1 hour. The solution of the reaction was concentrated under reduced pressure and then dissolved in dichloromethane. The organic solution was washed with saturated aqueous sodium bicarbonate solution, the aqueous layer was extracted again with dichloromethane, dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound 9e (91 mg, 100%) as a solid without purification.

MS (ESI): m / z = 1078 [M + Na] ⁺ .

Step 5: Preparation of Compound 2c

Compound 9e (25.50 mg, 0.0242 mmol) and compound 10c (13.53 mg, 0.0242 mmol) obtained in step 4 were dissolved in 0.1 M aqueous sodium carbonate solution and stirred at room temperature for 20 hours. After removing water under reduced pressure, the title compound 9d (36.1 mg, 99%) was obtained as a solid without separation purification.

MS (ESI): m / z = 1507 [M + H] ⁺ .

< Example  10> Preparation of Compound 2d

Step 1: Preparation of Compound 11a

N- ( t -butoxycarbonyl) -L-phenylalanine ( 10d , 69.85 mg, 0.263 mmol) was dissolved in dichloromethane (5 mL) and then 1-hydroxybenzotriazole (HOBt, 53.4 mg, 0.395 mmol ) And N, N, N ', N'-tetramethyl-O- (benzotriazol-1-yl) uronium tetrafluoroborate (TBTU, 126.8 mg, 0.395 mmol) were added. Compound 1b (91 mg, 0.263 mmol) and diisopropylethylamine (0.13 mL, 0.79 mmol) dissolved in dichloromethane (1.6 mL) were added dropwise to the reaction, followed by stirring at room temperature for 1 hour. The reaction was washed with saturated sodium bicarbonate, washed again with 0.1 M aqueous hydrochloric acid solution, dehydrated with anhydrous sodium sulfate, concentrated and subjected to column chromatography (5% methanol / dichloromethane) to give the target compound 11a as a liquid (129 mg, 83%).

¹ H NMR (400 MHz, CDCl ₃ ) δδ 0.12 (s, 6H), 0.95 (s, 9H), 1.41 (s, 9H), 1.98 (p, J = 6.8 Hz, 2H), 2.26 (t, J = 2.4 Hz, 1H), 3.00-3.16 (m, 3H), 3.20-3.28 (m, 1H), 3.45 (d, J = 2.4 Hz, 2H), 3.50 (s, 2H), 3.84 (s, 2H), 4.14-4.24 (m, 2H), 4.26-4.38 (m, 1H), 5.09 (d, J = 6.8 Hz, 1H), 6.28 (t, J = 6.0 Hz, 1H), 7.20-7.32 (m, 5H) , 7.54 (s, 1 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δδ -4.4, 16.6, 26.4, 28.4, 30.1, 36.2, 38.6, 42.0, 43.4, 47.3, 48.1, 56.3, 73.4, 78.9, 80.3, 88.7, 101.2, 123.3, 127.2, 128.9, 129.4, 136.8, 144.9, 155.4, 171.8.

Step 2: Preparation of Compound 12a

Compound 11a (99.6 mg, 0.168 mmol) obtained in step 1 was dissolved in acetonitrile (1.0 mL), and 0.1 M copper iodide solution (0.34 mL, 0.034 mmol) dissolved in acetonitrile and 0.2 M in acetonitrile. Triethylamine solution (0.17 mL, 0.034 mmol) was added. Benzyl azide 6c (24.6 mg, 0.185 mmol) dissolved in acetonitrile (0.6 mL) was added to the reaction mixture, which was stirred for 1 hour at room temperature. The solvent was concentrated under reduced pressure and then subjected to column chromatography (4% methanol / dichloromethane) to give the title compound 12a (75 mg, 61%) as a liquid.

¹ H NMR (400 MHz, CDCl ₃ ) δδ 0.12 (s, 6H), 0.95 (s, 9H), 1.40 (s, 9H), 1.98 (p, J = 6.4 Hz, 2H), 3.00-3.10 (m, 3H), 3.14-3.24 (m, 1H), 3.38 (s, 2H), 3.81 (s, 2H), 3.84 (s, 2H), 4.12-4.23 (m, 2H), 4.32-4.36 (m, 1H) , 5.09 (d, J = 7.6 Hz, 1H), 5.51 (s, 2H), 6.36 (t, J = 6.0 Hz, 1H), 7.18-7.40 (m, 10H), 7.50 (s, 1H), 7.59 ( s, 1 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δδ -4.5, 16.5, 26.1, 28.2, 29.7, 36.3, 38.4, 43.5, 47.0, 47.5, 48.1, 54.2, 56.1, 80.2, 88.9, 101.1, 122.9, 123.5, 127.0, 128.1, 128.7 (2C), 129.1, 129.3, 134.6, 136.7, 144.5, 145.1, 155.4, 171.7.

Step 3: Preparation of Compound 13a

12a (70 mg, 0.096 mmol) obtained in step 2 was dissolved in tetrahydrofuran (1.2 mL), and then 1.0M solution of tetrabutylammonium fluoride / tetrahydrofuran (0.24 mL, 0.24 mmol) was added at 0 ° C. Stir for the next 1 hour. The solution of the reaction was concentrated under reduced pressure and then subjected to column chromatography (5% methanol / dichloromethane) to give the title compound 13a (53.8 mg, 91%) as a liquid.

¹ H NMR (400 MHz, CDCl ₃ ) δδ 1.40 (s, 9H), 2.00 (p, J = 6.4 Hz, 2H), 2.27 (t, J = 2.4 Hz, 1H), 3.00-3.10 (m, 3H) , 3.18-3.24 (m, 1H), 3.35 (d, J = 2.4 Hz, 2H), 3.81 (s, 2H), 3.84 (s, 2H), 4.10-4.23 (m, 2H), 4.30-4.38 (m , 1H), 5.07 (brs, 1H), 5.52 (s, 2H), 6.27 (t, J = 6.0 Hz, 1H), 7.20-7.40 (m, 10H), 7.52 (s, 1H), 7.59 (s, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ) δδ 28.2, 29.8, 36.1, 38.4, 42.2, 47.0, 47.6, 47.8, 54.1, 56.1, 80.3, 73.7, 78.4, 123.0, 123.6, 127.0, 128.0, 128.7 (2C), 129.1, 129.3, 134.6, 136.6, 144.4, 144.9, 155.4, 171.7.

Step 4: Preparation of Compound 2c

Compound 13a (46 mg, 0.075 mmol) obtained in step 3 was dissolved in acetonitrile (0.5 mL), and 0.1 M copper iodide solution (0.15 mL, 0.015 mmol) dissolved in acetonitrile and 0.2 M dissolved in acetonitrile. Triethylamine solution (0.075 mL, 0.015 mmol) was added. Azido compound 6b (19.96 mg, 0.09 mmol) dissolved in acetonitrile (0.32 mL) was added to the reaction mixture, which was stirred for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure and then subjected to column chromatography (6% methanol / dichloromethane) to obtain the target compound 2c (51.8 mg, 83%) as a liquid.

¹ H NMR (400 MHz, CDCl ₃ ) δδ 1.39 (s, 9H), 2.01 (p, J = 6.4 Hz, 2H), 2.98-3.10 (m, 3H), 3.12-3.24 (m, 1H), 3.61- 3.76 (m, 16H), 3.88 (t, J = 4.8 Hz, 2H), 4.08-4.30 (m, 2H), 4.30-4.42 (m, 1H), 4.53 (t, J = 5.2 Hz, 2H), 4.54 (dt, J = 48.0, 4.0 Hz, 2H), 5.21 (brs, 1H), 5.53 (s, 2H), 6.57 (t, J = 6.0 Hz, 1H), 7.18-7.40 (m, 10H), 7.71 ( s, 1 H), 7.74 (s, 1 H), 7.87 (s, 1 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δδ 28.2, 29.5, 36.0, 38.5, 46.9, 47.0, 47.1, 47.2, 50.2, 54.1, 56.0, 69.4, 70.3 (d, J = 19.8 Hz, 1C), 70.48, 70.50 , 70.54, 70.7, 80.1, 83.1 (d, J = 168 Hz, 1C) 123.7, 124.5, 124.7, 126.9, 127.9, 128.6 (2C), 129.1, 129.3, 134.7, 136.7, 143.7, 143.8, 144.3, 155.3, 171.8 .

< Example  11> Preparation of Compound 2e

Step 1: Preparation of Compound 11b

Tetrahydrofuran solution in which 1b (100 mg, 0.289 mmol) obtained in step 2 of Example 1 was dissolved in tetrahydrofuran (2 mL), and phenyl isocyanate 10a (37.7 mg, 0.317 mmol) was dissolved (1 mL) was added dropwise. After stirring for 1 hour at room temperature, the solvent was concentrated under reduced pressure. Column chromatography (80% ethyl acetate / n -hexane) of the concentrate was carried out to obtain the title compound 11b (73.7 mg, 55%) as a liquid.

¹ H NMR (400 MHz, CDCl ₃ ) δδ 0.10 (s, 6H), 0.94 (s, 9H), 2.14 (p, J = 6.8 Hz, 2H), 2.24 (t, J = 2.0 Hz, 1H), 3.30 (q, J = 6.0 Hz, 2H), 3.43 (d, J = 2.0 Hz, 2H), 3.46 (s, 2H), 3.83 (s, 2H), 4.46 (t, J = 6.8 Hz, 2H), 5.77 (t, J = 6.0 Hz, 1H), 7.01 (t, J = 7.2 Hz, 1H), 7.22-7.30 (m, 2H), 7.38-7.42 (m, 2H), 7.46 (s, 1H), 7.59 ( s, 1 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δδ -4.4, 16.7, 26.3, 30.9, 37.2, 42.1, 43.4, 47.9, 48.3, 73.7, 78.6, 89.0, 101.0, 120.1, 123.1, 123.6, 129.2, 139.4, 144.9, 156.4.

Step 2: Preparation of Compound 12b

Compound 11b (64 mg, 0.138 mmol) obtained in step 1 was dissolved in acetonitrile (0.8 mL), and copper iodide solution (0.1 M, 0.27 mL, 0.027 mmol) dissolved in acetonitrile was dissolved in acetonitrile. Ethylamine solution (0.2 M, 0.13 mL, 0.027 mmol) was added. Benzyl azide 6c (0.019 mL, 0.152 mmol) dissolved in acetonitrile (0.6 mL) was added to the reaction mixture, which was stirred for 1 hour at room temperature. The solvent was concentrated under reduced pressure and then column chromatography (5% methanol / dichloromethane) was carried out to give target compound 12b (67 mg, 81%) as a liquid.

¹ H NMR (400 MHz, CDCl ₃ ) δδ 0.12 (s, 6H), 0.94 (s, 9H), 2.19 (p, J = 6.4 Hz, 2H), 3.14 (q, J = 6.0 Hz, 2H), 3.41 (s, 2H), 3.75 (s, 2H), 3.86 (s, 2H), 4.45 (t, J = 6.4 Hz, 2H), 5.51 (s, 2H), 6.08 (t, J = 6.0 Hz, 1H) , 7.0 (t, J = 7.2 Hz, 1H), 7.24-7.27 (m, 4H), 7.37-7.42 (m, 5H), 7.47 (s, 1H), 7.60 (s, 1H), 7.68 (s, 1H ); ¹³ C NMR (100 MHz, CDCl ₃ ) δδ -4.3, 16.7, 26.3, 30.0, 36.9, 44.0, 46.9, 47.8, 49.1, 54.5, 89.4, 100.8, 119.6, 128.3, 129.1, 129.3, 129.4, 134.4, 139.7, 145.2, 145.3, 156.4

Step 3: Preparation of Compound 13b

12b (67 mg, 0.11 mmol) obtained in step 2 was dissolved in tetrahydrofuran (2 mL), and then 1.0 M solution of tetrabutylammonium fluoride / tetrahydrofuran (0.28 mL, 0.28 mmol) was added at 0 ° C. Stir for the next 1 hour. The reaction mixture was concentrated under reduced pressure and then subjected to column chromatography (5% methanol / dichloromethane) to obtain the target compound 13b (50.5 mg, 95%) as a liquid.

¹ H NMR (400 MHz, CDCl ₃ ) δδ 2.14 (p, J = 6.4 Hz, 2H), 2.26 (t, J = 2.0 Hz, 1H), 3.17 (q, J = 6.0 Hz, 2H), 3.35 (d , J = 2.0 Hz, 2H), 3.77 (s, 2H), 3.84 (s, 2H), 4.42 (t, J = 6.4 Hz, 2H), 5.49 (s, 2H), 6.11 (t, J = 5.6 Hz , 1H), 6.98 (t, J = 7.2 Hz, 1H), 7.22-7.27 (m, 4H), 7.35-7.41 (m, 5H), 7.49 (s, 1H), 7.66 (s, 1H), 7.81 ( s, 1 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δδ 30.2, 36.8, 42.4, 47.2, 47.7, 48.3, 54.3, 74.0, 78.0, 119.4, 122.6, 123.2, 124.1, 128.1, 128.9, 129.0, 129.2, 134.4, 139.5, 144.6 , 144.9, 156.3

Step 4: Preparation of Compound 2e

Compound 13b (30 mg, 0.06 mmol) obtained in step 3 was dissolved in acetonitrile (0.3 mL), and 0.1 M copper iodide solution (0.12 mL, 0.012 mmol) dissolved in acetonitrile and 0.2 M dissolved in acetonitrile. Triethylamine solution (0.06 mL, 0.012 mmol) was added. 4-methoxybenzyl azide 6d (10.8 mg, 0.006 mmol) dissolved in acetonitrile (0.26 mL) was added to the reaction mixture, which was stirred for 1 hour at room temperature. The solvent was concentrated under reduced pressure and then column chromatography (5% methanol / dichloromethane) was performed to give the desired compound 2e (31.8 mg, 82%) as a liquid.

¹ H NMR (400 MHz, CDCl ₃ ) δδ 0.12 (s, 6H), 0.94 (s, 9H), 2.19 (p, J = 6.4 Hz, 2H), 3.14 (q, J = 6.0 Hz, 2H), 3.41 (s, 2H), 3.75 (s, 2H), 3.86 (s, 2H), 4.45 (t, J = 6.4 Hz, 2H), 5.51 (s, 2H), 6.08 (t, J = 6.0 Hz, 1H) , 7.0 (t, J = 7.2 Hz, 1H), 7.24-7.27 (m, 4H), 7.37-7.42 (m, 5H), 7.47 (s, 1H), 7.60 (s, 1H), 7.68 (s, 1H ); ¹³ C NMR (100 MHz, CDCl ₃ ) δδ -4.3, 16.7, 26.3, 30.0, 36.9, 44.0, 46.9, 47.8, 49.1, 54.5, 89.4, 100.8, 119.6, 128.3, 129.1, 129.3, 129.4, 134.4, 139.7, 145.2, 145.3, 156.4

< Example  12> Preparation of Compound 2f

Step 1: Preparation of Compound 11c

Compound 1h (100 mg, 0.289 mmol) obtained in step 2 of Example 5 was dissolved in dichloromethane (1.5 mL), and then 1-hydroxybenzotriazole (HOBt, 58.5 mg, 0.433 mmol) and N, N , N ', N'-tetramethyl-O- (benzotriazol-1-yl) uronium tetrafluoroborate (TBTU, 139 mg, 0.433 mmol) was added. 10 g (81.3 mg, 0.289 mmol) and diisopropylethylamine (0.15 mL, 0.866 mmol) dissolved in dichloromethane (1.8 mL) were added dropwise to the reaction, followed by stirring at room temperature for 1 hour. The reaction was washed with saturated sodium bicarbonate, washed again with 0.1 M aqueous hydrochloric acid solution, dehydrated with anhydrous sodium sulfate, concentrated and subjected to column chromatography (5% methanol / dichloromethane) to give the target compound 11c as a solid (106.3 mg, 64%).

¹ H NMR (400 MHz, CDCl ₃ ) δδ 0.09 (s, 6H), 0.93 (s, 9H), 1.40 (s, 9H), 1.42 (s, 9H), 2.24 (t, J = 2.4 Hz, 1H) , 2.66 (dd, J = 17.2, 4.4 Hz, 1H), 2.87 (dd, J = 17.2, 4.4 Hz, 1H), 3.44 (d, J = 2.8 Hz, 2H), 3.48 (s, 2H), 3.88 ( s, 2H), 4.65 (p, J = 4.4 Hz, 1H), 5.08 (s, 2H), 6.85 (d, J = 8.4 Hz, 1H), 7.67 (s, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ -4.5, 16.4, 26.4, 27.9, 37.0, 41.8, 43.2, 47.8, 49.2, 52.6, 73.2, 78.7, 81.9, 82.7, 88.4, 101.1, 124.3, 145.2, 164.8, 168.9, 169.9.

Step 2: Preparation of Compound 12c

Compound 11c (101 mg, 0.176 mmol) obtained in step 1 was dissolved in acetonitrile (1.1 mL), and 0.1 M copper iodide solution (0.35 mL, 0.035 mmol) dissolved in acetonitrile and 0.2 M dissolved in acetonitrile. Triethylamine solution (0.17 mL, 0.035 mmol) was added. Benzyl azide 6c (28.1 mg, 0.211 mmol) dissolved in acetonitrile (0.74 mL) was added to the reaction mixture, which was stirred for 1 hour at room temperature. The solvent was concentrated under reduced pressure and then column chromatography (5% methanol / dichloromethane) was carried out to give target compound 12c (84 mg, 68%) as a solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.11 (s, 6H), 0.95 (s, 9H), 1.40 (s, 9H), 1.42 (s, 9H), 2.66 (dd, J = 17.2, 4.4 Hz, 1H), 2.87 (dd, J = 17.2, 4.4 Hz, 1H), 3.40 (s, 2H), 3.85 (s, 2H), 3.87 (s, 2H), 4.65 (p, J = 4.4 Hz, 1H), 5.07 (s, 2H), 5.52 (s, 2H), 6.91 (d, J = 8.4 Hz, 1H), 7.20-7.40 (m, 5H), 7.50 (s, 1H), 7.71 (s, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ -4.5, 16.5, 26.1, 27.8, 28.0, 37.0, 43.4, 47.8, 47.9, 49.3, 52.7, 54.1, 82.0, 82.8, 88.9, 101.1, 122.9, 124.6, 128.1, 128.7, 129.1, 134.6, 145.2, 145.1, 164.8, 168.9, 169.9.

Step 3: Preparation of Compound 13c

Compound 12c (71.7 mg, 0.1 mmol) obtained in step 2 was dissolved in tetrahydrofuran (1.3 mL), and then 1.0M solution of tetrabutylammonium fluoride / tetrahydrofuran (0.25 mL, 0.25 mmol) was added at 0 ° C. It was then stirred at room temperature for 1 hour. The solution of the reaction was concentrated under reduced pressure and then subjected to column chromatography (5% methanol / dichloromethane) to give target compound 13c (40 mg, 69%) as a solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.31 (s, 9H), 1.33 (s, 9H), 2.18 (t, J = 2.4 Hz, 1H), 2.59 (dd, J = 17.2, 4.4 Hz, 1H) , 2.79 (dd, J = 17.2, 4.4 Hz, 1H), 3.27 (s, 2H), 3.76 (s, 2H), 3.78 (s, 2H), 4.57 (p, J = 4.4 Hz, 1H), 5.0 ( s, 2H), 5.43 (s, 2H), 6.84 (d, J = 8.0 Hz, 1H), 7.17-7.30 (m, 5H), 7.44 (s, 1H), 7.65 (s, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 27.8, 28.0, 37.0, 42.1, 47.6, 47.9, 49.3, 52.6, 54.1, 73.7, 78.4, 82.0, 82.8, 123.0, 124.6, 128.0, 128.7, 129.1, 134.7, 144.9 , 145.0, 164.8, 168.9, 170.0.

Step 4: Preparation of Compound 2f

Compound 13c (30 mg, 0.05 mmol) obtained in step 3 was dissolved in acetonitrile (0.4 mL), and 0.1 M copper iodide solution (0.1 mL, 0.01 mmol) dissolved in acetonitrile and 0.2 M dissolved in acetonitrile. Triethylamine solution (0.05 mL, 0.01 mmol) was added. The azide compound 6b (13.4 mg, 0.06 mmol) dissolved in acetonitrile (0.3 mL) was added to the reaction mixture, which was stirred for 1 hour at room temperature. The solvent was concentrated under reduced pressure and then subjected to column chromatography (5% methanol / dichloromethane) to give the title compound 2f (23 mg, 57%) as a solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.39 (s, 9H), 1.42 (s, 9H), 2.70 (dd, J = 17.2, 4.4 Hz, 1H), 2.87 (dd, J = 17.2, 4.4 Hz, 1H), 3.60-3.70 (m, 10H), 3.72-3.82 (m, 6H), 3.88 (t, J = 4.8 Hz, 2H), 4.53 (t, J = 4.8 Hz, 2H), 4.54 (dt, J = 48.0, 4.0 Hz, 2H), 4.67 (p, J = 4.4 Hz, 1H), 5.13 (s, 2H), 5.53 (s, 2H), 7.05 (d, J = 6.0 Hz, 1H), 7.27-7.38 (m, 5H), 7.74 (s, 1 H), 7.89 (s, 1 H), 7.93 (s, 1 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 37.0, 47.0 (2C), 47.2, 49.2, 50.1, 52.5, 54.0, 69.3, 70.2 (d, J = 19.4 Hz, 1C), 70.39, 70.41, 70.45, 70.6, 81.7, 82.5, 83.0 (d, J = 167.6 Hz, 1C), 123.8, 124.7, 125.4, 127.9, 128.5, 128.9, 134.7, 143.6, 144.3 (2C), 164.8, 168.9, 169.8.

< Example  13> Preparation of Compound 2g

Step 1: Preparation of Compound 11d

Compound 1h (100 mg, 0.289 mmol) obtained in step 2 of Example 5 was dissolved in dichloromethane (1.5 mL), and then 1-hydroxybenzotriazole (HOBt, 58.5 mg, 0.433 mmol) and N, N , N ', N'-tetramethyl-O- (benzotriazol-1-yl) uronium tetrafluoroborate (TBTU, 139 mg, 0.433 mmol) was added. Benzyl amine 10e (31 mg, 0.289 mmol) and diisopropylethylamine (0.15 mL, 0.866 mmol) dissolved in dichloromethane (1.8 mL) were added to the reaction, followed by stirring at room temperature for 1 hour. The reaction was washed with saturated sodium bicarbonate, washed again with 0.1 M aqueous hydrochloric acid solution, dehydrated with anhydrous sodium sulfate and concentrated, followed by column chromatography (5% methanol / dichloromethane) to give the target compound 11d as a solid (82 mg, 65%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.12 (s, 6H), 0.95 (s, 9H), 2.25 (t, J = 2.4 Hz, 1H), 3.42 (d, J = 2.4 Hz, 2H), 3.47 (s, 2H), 3.86 (s, 2H), 4.43 (d, J = 5.6 Hz, 2H), 5.06 (s, 2H), 6.60-6.64 (m, 1H), 7.19-7.37 (m, 5H), 7.68 (s, 1 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ −4.6, 16.5, 26.1, 41.9, 43.3, 43.7, 47.7, 53.1, 73.4, 78.6, 88.7, 100.8, 124.5, 127.7, 127.8, 128.8, 137.0, 145.4, 164.9.

Step 2: Preparation of Compound 12d

Compound 11d (61.9 mg, 0.142 mmol) obtained in step 1 was dissolved in acetonitrile (0.88 mL), and 0.1 M copper iodide solution (0.28 mL, 0.028 mmol) dissolved in acetonitrile and 0.2 M dissolved in acetonitrile. Triethylamine solution (0.14 mL, 0.028 mmol) was added. Compound 6c (22.7 mg, 0.171 mmol) dissolved in acetonitrile (0.6 mL) was added to the reaction mixture, which was stirred for 1 hour at room temperature. The solvent was concentrated under reduced pressure and then subjected to column chromatography (5% methanol / dichloromethane) to give the title compound 12d (60 mg, 74%) as a solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.11 (s, 6H), 0.94 (s, 9H), 3.37 (s, 2H), 3.81 (s, 2H), 3.85 (s, 2H), 4.42 (d J = 5.6 Hz, 2H), 5.07 (s, 2H), 5.47 (s, 2H), 6.82 (brs, 1H), 7.19-7.40 (m, 10H), 7.45 (s, 1H), 7.71 (s, 1H) ; ¹³ C NMR (100 MHz, CDCl ₃ ) δ -4.5, 16.4, 26.1, 38.5, 43.6, 47.7, 47.8, 52.9, 54.1, 89.0, 100.8, 122.9, 124.7, 127.5, 127.7, 128.0, 128.6, 128.7, 129.1, 134.5, 137.4, 144.9, 145.1, 165.1.

Step 3: Preparation of Compound 13d

12d (42.8 mg, 0.075 mmol) obtained in step 2 was dissolved in tetrahydrofuran (1.0 mL), and then 1.0M solution of tetrabutylammonium fluoride / tetrahydrofuran (0.19 mL, 0.19 mmol) was added at 0 ° C. Then stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and then subjected to column chromatography (5% methanol / dichloromethane) to give target compound 13d (28.6 mg, 84%) as a solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 2.45 (t, J = 2.4 Hz, 1H), 3.31 (d, J = 1.6 Hz, 2H), 3.79 (s, 2H), 3.83 (s, 2H), 4.42 (d, J = 6.0 Hz, 2H), 5.06 (s, 2H), 5.48 (s, 2H), 6.94 (t, J = 5.6 Hz, 1H), 7.18-7.40 (m, 10H), 7.48 (s, 1H), 7.73 (s, 1 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 42.2, 43.6, 47.7, 47.8, 52.9, 54.1, 73.9, 78.2, 123.0, 124.9, 127.6, 127.7, 128.0, 128.6, 128.7, 129.1, 134.5, 137.3, 144.8, 144.9 , 165.1.

Step 4: Preparation of 2g

Compound 13d (28.5 mg, 0.063 mmol) obtained in step 3 was dissolved in acetonitrile (0.4 mL), and 0.1 M copper iodide solution (0.12 mL, 0.013 mmol) dissolved in acetonitrile and 0.2 M dissolved in acetonitrile. Triethylamine solution (0.06 mL, 0.013 mmol) was added. Compound 6a (22.7 mg, 0.171 mmol) dissolved in acetonitrile (0.3 mL) was added to the reaction mixture, which was stirred for 1 hour at room temperature. The solvent was concentrated under reduced pressure and then column chromatography (5% methanol / dichloromethane) was carried out to give 2 g (44 mg, 85%) of the title compound as a solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.80 (s, 3H), 2.03 (s, 3H), 2.07 (s, 6H), 3.68-3.80 (m, 4H), 3.98-4.04 (m, 1H), 4.14-4.18 (m, 1H), 4.31 (dd, J = 12.8, 4.8 Hz, 1H), 4.42 (d, J = 4.4 Hz, 2H), 5.13 (s, 2H), 5.26 (t, J = 9.6 Hz , 1H), 5.38-5.48 (m, 2H), 5.50 (s, 2H), 5.80-5.88 (m, 1H), 7.18-7.37 (m, 10H), 7.67 (s, 1H), 7.93 (s, 1H ), 7.99 (s, 1 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 20.1, 20.4, 20.5, 20.7, 43.5, 47.0 (3C), 53.0, 54.2, 61.4, 67.6, 70.4, 72.5, 75.1, 85.7, 122.4, 123.7, 125.6, 127.5, 127.7, 128.1, 128.4, 128.6, 128.7, 129.0, 134.5, 137.4, 144.2 (2C), 144.6, 165.1, 168.9, 169.3, 169.9, 170.5.

< Example  14> Preparation of Compound 2h

Step 1: Preparation of Compound 11e

Compound 1h (100 mg, 0.289 mmol) obtained in step 2 of Example 5 was dissolved in dichloromethane (1.5 mL), and then 1-hydroxybenzotriazole (HOBt, 58.5 mg, 0.433 mmol) and N, N , N ', N'-tetramethyl-O- (benzotriazol-1-yl) uronium tetrafluoroborate (TBTU, 139 mg, 0.433 mmol) was added. Trypamine 10f (46.2 mg, 0.289 mmol) and diisopropylethylamine (0.15 mL, 0.866 mmol) dissolved in dichloromethane (1.8 mL) were added to the reaction, followed by stirring at room temperature for 1 hour. The reaction was washed with saturated sodium bicarbonate, washed again with 0.1 M aqueous hydrochloric acid solution, dehydrated with anhydrous sodium sulfate, concentrated and subjected to column chromatography (5% methanol / dichloromethane) to give the target compound 11e as solid (109 mg, 77%).

¹ H NMR 400 MHz, CDCl ₃ ) δ 0.12 (s, 6H), 0.95 (s, 9H), 2.30 (t, J = 2.4 Hz, 1H), 2.94 (t, J = 6.4 Hz, 2H), 3.46 ( d, J = 6.4 Hz, 2H), 3.49 (s, 2H), 3.55 (q, J = 6.4 Hz, 2H), 3.81 (s, 2H), 4.93 (s, 2H), 5.92-5.97 (m, 1H ), 6.84 (d, J = 2.0 Hz, 1H), 7.11 (td, J = 8.0, 1.2 Hz, 1H), 7.19 (td, J = 8.0, 1.2, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.40 (s, 1 H), 7.53 (d, J = 8.0 Hz, 1 H), 8.41 (s, 1 H); ¹³ C NMR (400 MHz, CDCl ₃ ) δ -4.6, 16.5, 24.6, 26.1, 39.5, 42.1, 43.3, 47.7, 53.1, 73.6, 78.6, 89.0, 100.9, 111.4, 111.8, 118.5, 119.4, 122.2, 122.4, 124.3, 126.9, 136.4, 145.2, 164.9.

Step 2: Preparation of Compound 12e

Compound 11e (103 mg, 0.211 mmol) obtained in step 1 was dissolved in acetonitrile (1.25 mL), and 0.1 M copper iodide solution (0.42 mL, 0.042 mmol) dissolved in acetonitrile and 0.2 M dissolved in acetonitrile. Triethylamine solution (0.21 mL, 0.042 mmol) was added. The azide compound 6a (94.5 mg, 0.253 mmol) dissolved in acetonitrile (0.88 mL) was added to the reaction mixture, which was stirred for 1 hour at room temperature. The solvent was concentrated under reduced pressure and then column chromatography (5% methanol / dichloromethane) was carried out to give target compound 12e (88.3 mg, 49%) as a solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.15 (s, 6H), 0.98 (s, 9H), 1.83 (s, 3H), 2.03 (s, 3H), 2.08 (s, 6H), 2.94 (t, J = 6.4 Hz, 2H), 3.39 (s, 2H), 3.48-3.60 (m, 2H), 3.79 (s, 2H), 3.87 (s, 2H), 4.01 (ddd, J = 10.2, 4.8, 2.0 Hz , 1H), 4.17 (dd, J = 12.8, 2.0 Hz, 1H), 4.32 (dd, J = 12.6, 4.8 Hz, 1H), 4.94 (s, 2H), 5.25 (t, J = 9.6 Hz, 1H) , 5.39 (t, J = 9.2 Hz, 1H), 5.44 (t, J = 9.6 Hz, 1H), 5.86 (d, J = 8.8 Hz, 1H), 5.92-5.98 (m, 1H), 6.81 (d, J = 2.0 Hz, 1H), 7.08 (t, J = 7.2 Hz, 1H), 7.16 (t, J = 7.2 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.41 (s, 1H) , 7.52 (d, J = 8.0 Hz, 1 H), 7.81 (s, 1 H), 8.99 (s, 1 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ-4.5, 16.5, 20.1, 20.50, 20.53, 20.7, 24.5, 26.1, 39.4, 43.3, 47.5, 47.9, 53.1, 61.4, 67.6, 70.5, 72.4, 75.2, 85.8, 89.4, 100.7, 111.47, 111.49, 118.4, 119.2, 121.4, 122.0, 122.6, 124.4, 126.9, 136.5, 145.3, 145.5, 165.0, 169.2, 169.4, 169.9, 170.5.

Step 3: Preparation of Compound 13e

Compound 12e (64.4 mg, 0.075 mmol) obtained in step 2 was dissolved in tetrahydrofuran (1.0 mL), and then 1.0M solution of tetrabutylammonium fluoride / tetrahydrofuran (0.19 mL, 0.19 mmol) was added at 0 ° C. It was then stirred at room temperature for 1 hour. The solution of the reaction was concentrated under reduced pressure and then subjected to column chromatography (5% methanol / dichloromethane) to give target compound 13e (15 mg, 27%) as a solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.84 (s, 3H), 2.03 (s, 3H), 2.08 (s, 6H), 2.34 (t, J = 2.4 Hz, 1H), 2.94 (t, J = 6.4 Hz, 2H), 3.35 (s, 2H), 3.55 (q, J = 6.4 Hz, 2H), 3.80 (s, 2H), 3.87 (s, 2H), 3.98-4.04 (m, 2H), 4.17 ( dd, J = 12.8, 2.0 Hz, 1H), 4.32 (dd, J = 12.6, 4.4 Hz, 1H), 4.96 (s, 2H), 5.25 (t, J = 9.2, 1H), 5.40 (t, J = 9.2, 1H), 5.44 (t, J = 9.2, 1H), 5.82 (t, J = 5.2 Hz, 1H), 5.86 (d, J = 8.0 Hz, 1H), 6.82 (d, J = 2.0 Hz, 1H ), 7.09 (t, J = 8.0 Hz, 1H), 7.17 (t, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.40 (s, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.84 (s, 1H), 8.94 (s, 1H); MS (ESI): m / z = 770 [M + Na] ⁺ .

Step 4: Preparation of Compound 2h

Compound 13e (9.7 mg, 0.013 mmol) obtained in step 3 was dissolved in acetonitrile (0.2 mL), and 0.1 M copper iodide solution (0.026 mL, 0.026 mmol) dissolved in acetonitrile and 0.2 M dissolved in acetonitrile. Triethylamine solution (0.013 mL, 0.003 mmol) was added. The azide compound 6e (7.9 mg, 0.016 mmol) dissolved in acetonitrile (0.1 mL) was added to the reaction mixture, which was stirred for 1 hour at room temperature. The solvent was concentrated under reduced pressure and then column chromatography (5% methanol / dichloromethane) was performed to give the title compound 2h (5 mg, 31%) as a solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.49 (s, 9H), 1.83 (s, 3H), 1.85-1.94 (m, 1H), 2.03 (s, 3H), 2.07 (s, 6H), 2.10- 2.16 (m, 2H), 2.20-2.30 (m, 3H), 2.94 (t, J = 6.4 Hz, 2H), 3.12-3.28 (m, 2H), 3.55 (q, J = 6.0 Hz, 2H), 3.66 (s, 2H), 3.72 (s, 2H), 3.74 (s, 2H), 3.96-4.02 (m, 1H), 4.12-4.24 (m, 3H), 4.30 (dd, J = 12.8, 5.2, Hz, 1H), 4.34-4.42 (m, 4H), 4.95 (s, 2H), 5.24-5.28 (m, 1H), 5.41-5.47 (m, 2H), 5.71 (d, J = 7.6 Hz, 1H), 5.83 -5.90 (m, 2H), 6.45-6.50 (m, 1H), 6.80-6.83 (m, 1H), 7.05 (t, J = 7.6 Hz, 1H), 7.12 (t, J = 7.6 Hz, 1H), 7.27-7.34 (m, 3H), 7.40 (t, J = 7.6 Hz, 2H), 7.45-7.54 (m, 2H), 7.56-7.61 (m, 2H), 7.71-7.79 (m, 2H), 7.76 ( s, 1 H), 7.96 (s, 1 H), 9.46 (s, 1 H); MS (ESI): m / z 1255.7 (M + H) ⁺ , 1278.0 (M + Na) ⁺ .

Claims (20)

Tertiary amine compound represented by the following formula (1):
[Formula 1]

(In Formula 1,
P is hydrogen, triC ₁ -C ₄ alkyl silyl group, diC ₁ -C ₄ alkylC ₃ -C ₈ aryl silyl group, or diC ₃ -C ₈ arylC ₁ -C ₄ alkyl silyl group,
l, m, n, o and p are each independently an integer from 1 to 5,
X is independently a single bond, carbonyl (C═O), —NHCO— or —CONH—,
R is —NH—Y, or —CO ₂ —Z,
Y is hydrogen, —CO ₂ -t Bu, —CO ₂ -CH ₂ Ph, or —CO ₂ -tC (Ph) ₃ ),
Z is hydrogen, —t Bu, —CH ₂ Ph or —CO ₂ —tC (Ph) ₃ . The method of claim 1,
P is hydrogen, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), t -butyldimethylsilyl (TBS), triisopropylsilyl (TIPS), t -butyldiphenylsilyl (TBDPS), or triphenylsilyl (TPS),
l, m, n, o and p are each independently an integer of 1 to 3,
X is a single bond, carbonyl (C═O), —NHCO— or —CONH—,
R is —NH ₂ , —NH (CO ₂ —t Bu), —NH (CO ₂ —CH ₂ Ph), —CO ₂ H, —CO ₂ —t Bu, or —CO ₂ —CH ₂ Ph Tertiary amine compound made into. The method of claim 1,
The tertiary amine compound is
(1a) t-butyl-3- (4-(((N-3- (t-butyldimethylsilyl) prop-2-ynyl) -N-propazyl) amino) methyl) -1H-1,2 , 3-triazol-1-yl) propylcarbamate;
(1b) N-((1- (3-aminopropyl) -1H-1,2,3-triazol-4-yl) methyl) -N- (3- ( t -butyldimethylsilyl) prop- 2-ynyl) -N-propazylamine;
(1c) t-butyl-3- (4-((((N-3- (triisopropylsilyl) prop-2-ynyl) -N-propazyl) amino) methyl) -1H-1,2,3 -Triazol-1-yl) propylcarbamate;
(1d) N-((1- (3-aminopropyl) -1H-1,2,3-triazol-4-yl) methyl) -N- (3- (triisopropylsilyl) prop-2- Phosphoryl) -N-propazylamine;
(1e) 4- (3- (4-(((N-3- ( t -butyldimethylsilyl) propyn-2-yl) -N-propazyl) amino) methyl) -1H-1,2, 3-triazol-1-yl) propylamino) -oxobutanoic acid;
(1f) 4- (3- (4-(((N-3- (triisopropylsilyl) propyn-2-yl) -N-propazyl) amino) methyl) -1H-1,2,3- Triazol-1-yl) propylamino) -oxobutanoic acid;
(1 g) t-butyl-2- (4-(((N-3- ( t -butyldimethylsilyl) propyn-2-yl) -N-propazyl) amino) methyl) -1H-1,2 , 3-triazol-1-yl) acetate;
(1h) 2- (4-(((N-3- ( t -butyldimethylsilyl) propyn-2-yl) -N-propazyl) amino) methyl) -1H-1,2,3-tria Zol-1-yl) acetic acid;
(1i) t-butyl-2- (4-(((N-3- (triisopropylsilyl) propyn-2-yl) -N-propazyl) amino) methyl) -1H-1,2,3 -Triazol-1-yl) acetate; And
(1j) 2- (4-(((N-3- (triisopropylsilyl) propyn-2-yl) -N-propazyl) amino) methyl) -1H-1,2,3-triazole- Tertiary amine compound, characterized in that one selected from the group consisting of 1-yl) acetic acid. As represented by Scheme 1 below,
And alkyne / azide [3 + 2] ring reaction of the azido compound represented by Formula 3 and Formula 4, which are starting materials, under a copper catalyst,

Reaction solvents used in Scheme 1 are tetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, benzene, toluene, acetonitrile, dimethylformamide, dimethyl sulfoxide (DMSO ), Methanol, ethanol, isopropanol, t -butanol, water and combinations thereof,

The copper catalyst used in Scheme 1 may be a copper catalyst having an oxidation number of 1 selected from the group consisting of CuI, CuBr, and CuCl or CuSO ₄ , Cu (OAc) ₂ , Cu (NO ₃ ) ₂ , Cu (OTf) ₂ , And a copper catalyst having an oxidation number of 2 selected from the group consisting of CuO.
[Reaction Scheme 1]

(In Scheme 1,
l, m, n, o, p and P, X are as defined in Formula 1 of claim 1,
Y is hydrogen, —CO ₂ -tBu, —CO ₂ —CH ₂ Ph, or —CO ₂ -tC (Ph) ₃ ) delete delete 5. The method of claim 4,
In the case of the copper catalyst of oxidation number 1 in Scheme 1,
Tertiary amine compound of formula 1-1 characterized by using an alkali metal salt of bicarbonate ion, an alkali metal salt of carbonate ion, or a base selected from triethylamine, diisopropylethylamine, pyridine, lutidine and collidine Manufacturing method. 5. The method of claim 4,
In the case of the copper catalyst of oxidation number 2 in Scheme 1,
A method for preparing a tertiary amine compound of formula 1-1, wherein a reducing agent is Na-ascorbate, sodium sulfite (Na ₂ SO ₃ ), or dithiothreitol. As represented by Scheme 2 below,
And alkyne / azide [3 + 2] ring reaction of the tertiary amine compound represented by Chemical Formula 3, which is a starting material, and the azido compound represented by Chemical Formula 5, under a copper catalyst,

Reaction solvents used in Scheme 1 are tetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, benzene, toluene, acetonitrile, dimethylformamide, dimethyl sulfoxide (DMSO ), Methanol, ethanol, isopropanol, t -butanol, water and combinations thereof,

The copper catalyst used in Scheme 1 may be a copper catalyst having an oxidation number of 1 selected from the group consisting of CuI, CuBr, and CuCl or CuSO ₄ , Cu (OAc) ₂ , Cu (NO ₃ ) ₂ , Cu (OTf) ₂ , And a copper catalyst having an oxidation number of 2 selected from the group consisting of CuO.
[Reaction Scheme 2]

(In Scheme 2,
l, m, n, o, p and P, X are as defined in Formula 1 of claim 1,
Z is hydrogen, -t Bu, -CH ₂ Ph or tC (Ph) ₃ ) delete delete 10. The method of claim 9,
In the case of the copper catalyst of oxidation number 1 in Scheme 2,
Tertiary amine compounds of formula 1-2 characterized by using an alkali metal salt of bicarbonate ions, an alkali metal salt of carbonate ions, or a base selected from triethylamine, diisopropylethylamine, pyridine, lutidine and collidine Manufacturing method. 10. The method of claim 9,
In the case of the copper catalyst of oxidation number 2 in Scheme 1,
A method for preparing a tertiary amine compound of Chemical Formula 1-2, using a reducing agent that is Na-ascorbate, sodium sulfite (Na ₂ SO ₃ ), or dithiothreitol. As represented by Scheme 3 below,
Subjecting the compound of Formula 1, which is a starting material, to the alkyne / azide [3 + 2] ring reaction with the azido compound of Formula 6-1 under a reaction solvent and a copper catalyst (step 1);
Deprotecting the P protecting group of the compound (step 2);
Subjecting the compound of Formula 8 to the alkyne / azide [3 + 2] ring reaction with the azido compound of Formula 6-2 under a reaction solvent and a copper catalyst (step 3); And
Reacting the compound of formula 9 and the compound of formula 10 in an organic solvent (step 4),

The reaction solvent used in the click chemistry step of Scheme 3 is tetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, benzene, toluene, aceto Nitrile, dimethylformamide (N, N-dimethylformamide), dimethyl sulfoxide, methanol, ethanol, isopropanol, t -butanol, water or a mixed solvent thereof,

The copper catalyst used in the click chemistry step of Scheme 3 may be a copper catalyst having an oxidation number of 1 selected from the group consisting of CuI, CuBr, and CuCl, or C uSO ₄ , Cu (OAc) ₂ , Cu (NO ₃ ) ₂ , Cu ( OTf) ₂ and CuO, a copper catalyst having an oxidation number of 2 selected from the group consisting of

The deprotecting step is a method for preparing a compound of formula (2), characterized in that carried out by a disylation (desilyation) method.
[Reaction Scheme 3]

In Scheme 3,
l, m, n, o, p are as defined in formula 1 of claim 1,
R ₁ is the same as R defined in Formula 1 of claim 1,
R ₂ is —CO ₂ H; —COF; —COCl; —COBr;

-OCOCl; -NCO; -NCS; —SO ₂ Cl; Or —NH ₂ ,
W is —NHCO—; -NHCOO-; -NHCONH-; -NHCSNH-; -NHSO _2- ; Or —CONH-,
A, B, and C are each independently
Certain proteins and biopolymer compounds in vivo, any one selected from the group of organic compounds having selective binding to biological tissues (Group 1);
Any one selected from the group of specific proteins and biopolymer compounds in vivo, peptides having a selective binding ability to biological tissues, sugars, lipids, nucleotides or derivatives thereof (group 2);
Any one selected from the group of fluorescent dye near infrared fluorescent dye optical dye quantum dots derivatives for in vivo molecular imaging diagnosis (group 3);
Any one selected from the group consisting of a complex containing a radioactive isotope comprising a radioisotope for diagnosis of molecular imaging in vivo (group 4);
Any one selected from the group of derivatives of gadolinium, iron oxide, and manganese metal having magnetic and supermagnetism for in vivo molecular imaging diagnosis (group 5);
Any one selected from the group of biotin derivatives for in vivo molecular imaging (group 6);
Any one selected from the group of oligo ethylene glycol derivatives for in vivo stability (group 7);
Any one selected from the group of monosaccharides or polysaccharides (oligo-saccharides) for in vivo pharmacokinetics (group 8); And
Organic polymer dendrimers for drug delivery in vivo; Viral capsid chitosan nanoparticles are selected from the group consisting of any one selected from the group (group 9). As represented by Scheme 4 below,
Preparing a compound of Chemical Formula 11 by reacting a starting compound of Chemical Formula 1 with a compound of Chemical Formula 10 in an organic solvent (Step 1);
Subjecting the compound of Formula 11 to the alkyne / azide [3 + 2] ring reaction with the azido compound of Formula 6-1 under a reaction solvent and a copper catalyst (step 2);
Deprotecting the P protecting group of the compound (step 3) and
A compound of Formula 13 is subjected to an alkyne / azide [3 + 2] ring reaction with azido compound of Formula 6-2 under a copper catalyst (Step 4),

The reaction solvent used in the click chemistry step of Scheme 4 is tetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, benzene, toluene, aceto Nitrile, dimethylformamide (N, N-dimethylformamide), dimethyl sulfoxide, methanol, ethanol, isopropanol, t -butanol, water or a mixed solvent thereof,

The copper catalyst used in the click chemistry step of Scheme 4 may be a copper catalyst having an oxidation number of 1 selected from the group consisting of CuI, CuBr, and CuCl, or CuSO ₄ , Cu (OAc) ₂ , Cu (NO ₃ ) ₂ , Cu (OTf). ) Is a copper catalyst having an oxidation number of 2 selected from the group consisting of ₂ and CuO,

The deprotecting step is a method for preparing a compound of formula (2), characterized in that carried out by a disylation (desilyation) method.
[Reaction Scheme 4]

(In Scheme 4,
l, m, n, o, and p are as defined in Formula 1 of claim 1,
R ₁ , R ₂ , X, W and A, B, C are as defined in Scheme 3 of claim 14) delete delete 16. The method according to claim 14 or 15,
When using a copper catalyst having 1 oxidation number in the click chemistry step, the base used may be an alkali metal salt of bicarbonate ions, an alkali metal salt of carbonate ions, or triethylamine, diisopropylethylamine, pyridine, rutidine, or collidine. Method for producing a tertiary amine compound of formula 2, characterized in that. 16. The method according to claim 14 or 15,
In the case of using a copper catalyst having an oxidation number of 2 in the click chemistry step, the reducing agent may be Na-ascorbate, sodium sulfite (Na ₂ SO ₃ ), or dithiothreitol. Method for producing an amine compound. 16. The method according to claim 14 or 15,
In the deprotection step, a method of preparing a tertiary amine compound of formula (2), characterized in that it uses a disylation method.

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