KR20170031307A

KR20170031307A - Diphenyl sulfate derivatives or pharmaceutically acceptable salts thereof, preparation method thereof and pharmaceutical composition for use in preventing or treating hepatitis C virus related diseases

Info

Publication number: KR20170031307A
Application number: KR1020150128517A
Authority: KR
Inventors: 김병문; 유영수; 배일학; 장승기; 이승기; 김희선
Original assignee: 서울대학교산학협력단; 포항공과대학교 산학협력단
Priority date: 2015-09-10
Filing date: 2015-09-10
Publication date: 2017-03-21
Also published as: KR101766822B1

Abstract

The present invention relates to a diphenyl sulfate derivative or a pharmaceutically acceptable salt thereof, a production method thereof, and a pharmaceutical composition for preventing or treating hepatitis C virus-associated diseases containing the same as an active ingredient. According to the present invention, the diphenyl sulfate derivative excellently inhibits infection by hepatitis C virus and replication of hepatitis C virus, and thus can be useful as pharmaceutical compositions for preventing or treating liver diseases such as hepatocellular cancer, cirrhosis, chronic hepatitis C, and acute hepatitis C caused by hepatitis C virus.

Description

TECHNICAL FIELD The present invention relates to a diphenyl sulfate derivative or a pharmaceutically acceptable salt thereof, a process for preparing the same, and a pharmaceutical composition for preventing or treating hepatitis C virus-related diseases containing the same as an active ingredient and pharmaceutical composition for use in preventing or treating hepatitis C virus related diseases}

The present invention relates to a diphenylsulfate derivative or a pharmaceutically acceptable salt thereof, a process for preparing the same, and a pharmaceutical composition for preventing or treating a hepatitis C virus-related disease containing the same as an active ingredient.

Hepatitis C virus (HCV) is a membrane-associated virus that belongs to the Flavivirus family. The hepatitis C virus genome is (+) - RNA (plus-strand RNA), which is 9.6 kb in size and expresses a poly-protein consisting of 3,010 amino acids. The multiprotein is separated into three structural proteins and six nonstructural proteins by the enzymes of the host cell and the virus.

At the 5 'and 3' ends of the hepatitis C virus genome, almost all the genotypes have the same nucleotide sequence but the poisons. At the 5 'end, 330 to 341 nucleotides have been found, and at the 3' end, 98 nucleotides have been found behind poly A (poly A), which is presumed to play an important role in RNA replication and detoxification of the virus. The amino terminus of the viral genome produces the core antigen genes Core (E1, E2), which is a viral structural protein, and the rest of the viral genome, to construct nonstructural proteins. The central antigen gene is the capsid protein of the virus, E1 and E2 are the envelope proteins of the virus, and these proteins are separated by the signal peptidase in the endoplasmic reticulum. Nonstructural proteins are separated by the serine protease, NS3, and the cofactor, NS4A. NS5B has RNA-dependent RNA polymerase function and is the most important enzyme for viral replication.

Hepatitis C virus is a major human pathogen that is estimated to infect 170 million people worldwide - approximately five times the number infected with human immunodeficiency virus type 1. Severe progressive liver disease, including cirrhosis and hepatocellular carcinoma, occurs at a high rate among individuals infected with these hepatitis C viruses.

Infection by hepatitis C virus is reported to be caused by transfusion and community-acquired, and about 70% of infections are caused by kidney dialysis. Once infected with the hepatitis C virus, about 20% are known to cause acute hepatitis accompanied by cirrhosis within five years and metastasis to liver cancer (see Non-Patent Document 1-2). This high rate of chronic infection is an uncommon event in RNA viruses and is evidence that hepatitis C virus is a mediator of high rates of liver cancer. In recent years, hepatitis C virus (HBV) tests have been successfully performed on all blood samples. Although transfusion-induced infections have been significantly reduced, localized infection has not been effectively managed and infection rates are high. .

Unlike hepatitis B virus (HBV), hepatitis C virus is distributed throughout the world, and 1.5% to 2% of the world's population is reported to be infected. Hepatitis C virus infection is characterized by progression to chronic hepatitis. The probability of liver metastasis and liver metastasis is significantly higher than that of hepatitis B virus. Because hepatitis C virus is taxonomically different from the hepatitis B virus, it can not be prevented by the hepatitis B virus vaccine.

Meanwhile, the combination therapy of interferon and ribavirin, which is an antiviral agent, has been used as a therapeutic agent for hepatitis C virus infection (see Non-Patent Document 3), but the response is remarkably different depending on the genotype, The side effects of the two drugs used are not only large but also expensive. Therefore, development of a more effective new anti-C hepatitis virus agent is required.

In order to overcome the above problem, the anti-C hepatitis virus agent that has been studied so far has a characteristic that the pharmacological activity of the anti-C hepatitis virus agent is expressed by blocking the specific phase of the life cycle of the hepatitis C virus.

The life cycle of hepatitis C virus is as follows. Hepatitis C virus attached to the surface of the host cell invades into the host cell by endocytosis. Thereafter, a precursor protein consisting of about 3,000 amino acid residues is generated from the hepatitis C virus genome RNA that has invaded into the host cell. The hepatitis C virus genome or the NS3 and NS4 protease encoded by the signal peptidase of the host cell to produce capsid protein, envelope protein, NS3 and NS4 protease, NS5B About 10 virus proteins such as RNA polymerase are produced. The genomic RNA replicated by the NS 2B polymerase binds to the capsid protein and envelope protein mediated by α-glucosidase and becomes a viral particle. Then, the hepatitis C virus particles are released from host cells (see Non-Patent Document 4).

Until recently, HCV could not be infected or propagated in cultured cells. However, a limited development in 1999 led to the development of a system in which transfection of HCV RNA was performed by transfection of the HCV RNA portion encoding non-structural proteins into the liver cancer cell line, It is called replicon. The use of replicon has enabled in vitro screening of drugs that inhibit HCV proliferation (see Non-Patent Document 5).

In addition, Dr. Wakita's team in Japan in 2001, cloned HCV from a Japanese patient who rarely had fulminant hepatitis as HCV (designated as JFH-1 in Japanese fulminant hepatitis) I made flicons, which showed very strong replicon activity. In the end, in 2005, HCV RNA was transfected with HCV RNA, which is a non-structural part of JFH-1 as a backbone after selective selection of hepatocellular carcinoma cell lines in which HCV replication is well- An HCV infection model was established. HCV obtained from the cultured cells was called HCVcc (cc is derived from cell culture). HCVcc has also been reported to cause HCV infection in chimpanzees, confirming the success of the cell culture HCV infection model. In vitro transfection of JFH-1 RNA into liver cancer cell lines has shown that HCVcc can be obtained and HCVcc obtained can again infect liver cancer cells. The success of these cell culture HCV infection models further facilitates recent HCV studies and accelerates new discoveries (see non-patent reference 5).

Agents that exhibit anti-hepatitis C virus activity by blocking certain stages of the hepatitis C virus life cycle as described above may be selected from the group consisting of an RNA polymerase inhibitor-type, a protease inhibitor-type, a-glucosidase Inhibitor-type and other types. For example, RNA polymerase inhibitor types such as MK-7009 (Merck) and R7128 (Pharmasset / Roche) are on Phase 1 of clinical trials and include VCH-759 (Virochem), R1626 (Roche), valopicitabine Idenix) is on clinical trial 2. In addition, among the protease inhibitor types, ITMN-191 (R-7227, InterMune / Roche) is on clinical trial 1, TMC435350 (Medivir / Tibotec) is on clinical trial 2, Boceprevir (SCH 503034), Schering ) And Telaprevir (Vertex) are on Phase 3 of the trial. In addition, the cyclophilin inhibitor type DEBIO-025 (DEBIO) and the glucosidase I inhibitor type celgosivir (MIGEBIX) are on clinical trial 2 (see non-patent reference 6).

However, since the appearance of a virus having resistance to the hepatitis C hepatitis virus drug which has undergone clinical trials has already been reported, a hepatitis C virus effect as a mechanism different from the known hepatitis C virus hepatitis virus The development of new anti-hepatitis C virus drugs is urgently required.

Accordingly, the present inventors have made efforts to develop a compound exhibiting an inhibitory activity against interleukin-C hepatitis virus, and have found that the diphenylsulfate derivative according to the present invention inhibits infection by hepatitis C virus and replication of hepatitis C virus It can be used as a pharmaceutical composition for preventing or treating liver diseases such as acute hepatitis C, chronic hepatitis C, cirrhosis and hepatocellular carcinoma, which are caused by hepatitis C virus. Completed.

Davis et al, New. Engl. J. Med., [0010] 321 (1989) 1501; Alter et al., Leonard et al., Current Pespective in Hepatology, (1989) p. 83; Hayashi N., et al., J. Gastroenterol., 41, (2006), 17; Manns MP., Et al., Nat. Rev. Drug. Discov., 6, (2007), 991; Trends of Hepatitis C virus research, Korean Society of Biochemistry and Molecular Biology, 2013, 12; Kronenberger B., et al., Clin Liver Dis., 12, (2008), 529.

It is an object of the present invention to provide a diphenylsulfate derivative, an optical isomer thereof or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a process for preparing the diphenylsulfate derivative.

It is still another object of the present invention to provide a pharmaceutical composition for preventing or treating hepatitis C virus-related liver diseases, which comprises the diphenylsulfate derivative, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

Another object of the present invention is to provide a health functional food composition for preventing or ameliorating hepatitis C virus-related liver disease, which comprises the above diphenylsulfate derivative, an optical isomer thereof or a pharmaceutically acceptable salt thereof 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,

A is a single bond, -O-, -NH- or C _1-2 alkylene;

X is selected from the group consisting of 5 to 8 heteroaryl, carbonylamino (- (C = O) NH-) or aminocarbonyl (-NH (C = O) -;

R ¹ is hydrogen, halogen or C _1-5 alkyl or C _1-5 alkoxy of straight or branched chain; And

R ² and R ³ are each independently hydrogen; Unsubstituted straight-chain or branched C _1- ₅ alkyl, C _1- ₅ alkoxy or C _1- ₅ alkoxy-carbonyl-amino; Or unsubstituted or substituted and unsubstituted _6- C ₈ aryl, wherein the substituted _6- C ₈ aryl substituted one or more selected from the group consisting of C _1- ₅ alkyl, C _1- ₅ alkoxy halogen and straight-chain or branched . &Lt; / RTI >

Also, as shown in the following Reaction Scheme 1,

There is provided a process for preparing a compound represented by the above formula (1), comprising the step of reacting a compound represented by the formula (2) with a compound represented by the formula (3) in the presence of a base to prepare a compound represented by the formula (1).

[Reaction Scheme 1]

In the above Reaction Scheme 1,

R ¹ , R ² , R ³ , X and A are as defined in Formula 1; And

PG is an amine protection group.

Further, the present invention provides a pharmaceutical composition for the prevention or treatment of hepatitis C virus-related liver disease, which comprises the compound represented by the above-mentioned formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention also provides a health functional food composition for preventing or ameliorating hepatitis C virus-related liver diseases, which comprises the compound represented by Chemical Formula 1, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

The diphenylsulfate derivatives according to the present invention are useful for the treatment of infections caused by hepatitis C virus; And the replication of hepatitis C virus. Therefore, the pharmaceutical composition for preventing or treating liver diseases such as acute hepatitis C, chronic hepatitis C, cirrhosis and hepatocellular carcinoma caused by hepatitis C virus Can be usefully used.

Hereinafter, the present invention will be described in detail.

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,

A is a single bond, -O-, -NH- or C _1-2 alkylene;

Preferably,

A is a single bond, -O- or -NH-;

X is a 5- to 8-membered heteroaryl, carbonylamino (- (C = O) NH-) or aminocarbonyl (-NH (C = O )-)ego;

R ¹ is hydrogen, C _1-5 straight or branched chain alkyl, fluoro, bromo or chloro; And

R ² and R ³ are each independently linear or branched C _1- ₅ alkyl,

Or unsubstituted or substituted phenyl, wherein said R ⁴ is a linear or branched C _1- ₃ alkyl, phenyl substituted by one or more substituents selected from the group consisting of C _1- ₃ alkyl, halogen and straight-chain or branched . &Lt; / RTI >

More preferably,

A is a single bond or -O-;

X is

,

or

ego;

R < ¹ > is hydrogen, methyl or fluoro;

R ² and R ³ are each independently methyl, isopropyl, t-butyl,

,

or

to be.

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

(1) Synthesis of dimethyl ((1R, 1'R) - ((2S, 2'S) - (((sulfonylpiperidine (4,1- phenylene)) bis (azanediyl) bis (Pyrrolidine-2,1-diyl)) bis (2-oxo-1-phenylethane-2,1-diyl)) dicarbamate

(2) Synthesis of bis (4 - ((S) -1 - ((R) -2 - ((methoxycarbonyl) amino) -2-phenylacetyl) pyrrolidine-2-carboxamido) ;

(3) bis (4 - ((S) -1 - ((methoxycarbonyl) -D-valyl) pyrrolidine-2-carboxamido) phenyl) sulfate;

(4) Synthesis of bis (3 - ((S) -1 - ((R) -2 - ((methoxycarbonyl) amino) -2-phenylacetyl) pyrrolidine-2-carboxamido) ;

(5) Synthesis of bis (4- (2 - ((S) -1 - ((R) -2- (methoxycarbonylamino) -3-methylbutanoyl) pyrrolidin- 5-yl) phenyl) sulphate;

(6) Synthesis of bis (4- (2 - ((S) -1 - ((R) -2- (methoxycarbonylamino) -2- phenylacetyl) pyrrolidin- Yl) phenyl) sulphate;

(7) bis (3 - ((S) -1 - ((methoxycarbonyl) -D-valyl) pyrrolidine-2-carboxamido) phenyl) sulfate;

(8) Synthesis of bis (3- (2 - ((S) -1 - ((R) -2- (methoxycarbonylamino) -3-methylbutanoyl) pyrrolidin- 5-yl) phenyl) sulphate;

(9) Synthesis of bis (3- (2 - ((S) -1 - ((R) -2- (methoxycarbonylamino) -2- phenylacetyl) pyrrolidin- Yl) phenyl) sulphate;

(10) Synthesis of bis (5 - ((S) -1 - ((R) -2- (methoxycarbonyl) amino) -2-phenylacetyl) pyrrolidine- Methylphenyl) sulfate;

(11) bis (5 - ((S) -1 - ((methoxycarbonyl) -D-valyl) pyrrolidine-2-carboxamido) -2-methylphenyl) sulfate;

(12) Synthesis of 3 - ((S) -1 - ((R) -2 - ((methoxycarbonyl) amino) -2-phenylacetyl) pyrrolidine- (S) -1 - ((R) -2 - ((methoxycarbonyl) amino) -2-phenylacetyl) pyrrolidine-2-carboxamido) phenyl) sulfate;

(13) Synthesis of 3 - ((S) -1 - ((methoxycarbonyl) -D-valyl) pyrrolidine-2-carboxamido) Carbonyl) -D-valyl) pyrrolidine-2-carboxamido) phenyl) sulfate;

(14) Synthesis of bis (2-fluoro-5 - ((S) -1 - ((R) -2 - ((methoxycarbonyl) amino) -2-phenylacetyl) pyrrolidine- Di) phenyl) sulphate;

(15) Synthesis of bis (3- (2 - ((S) -1 - ((S) -2- (methoxycarbonylamino) -3-methylbutanoyl) pyrrolidin- 5-yl) phenyl) sulphate;

(16) bis (2-fluoro-5 - ((S) -1 - ((methoxycarbonyl) -D-valyl) pyrrolidine-2-carboxamido) phenyl) sulfate;

(17) Synthesis of bis (3 - ((S) -1 - ((R) -2 - ((methoxycarbonyl) amino) -2-phenylacetyl) pyrrolidine- Methylphenyl) sulfate;

(18) Synthesis of bis (3- (2 - ((S) -1 - ((R) -2- (methoxycarbonylamino) -3,3-dimethylbutanoyl) pyrrolidin- -Imidazol-5-yl) phenyl) sulphate;

(19) Synthesis of bis (4- (2 - ((S) -1 - ((S) -2- (methoxycarbonylamino) -3-methylbutanoyl) pyrrolidin- 5-yl) phenyl) sulphate;

(20) 3- (2 - ((S) -1 - ((S) -2- (Methoxycarbonylamino) -3-methylbutanoyl) pyrrolidin- Yl) -1H-imidazol-2-yl) phenyl) -4- (2 - ((S) -1 - ((S) -2- (methoxycarbonylamino) -3-methylbutanoyl) pyrrolidin- 5-yl) phenyl sulfate;

(21) 3- (2 - ((S) -1 - ((S) -2- (Methoxycarbonylamino) -2-phenylacetyl) pyrrolidin- Yl) -1H-imidazol-2-yl) -pyrrolidine The title compound was prepared from 4- (2 - ((S) -1 - ((S) -2- (methoxycarbonylamino) 5-yl) phenyl sulfate;

(22) 3- (2 - ((S) -1 - ((R) -2- (Methoxycarbonylamino) -3-methylbutanoyl) pyrrolidin- Yl) -1H-imidazol-2-yl) phenyl) -4- (2 - ((S) -1 - ((R) -2- (methoxycarbonylamino) -3-methylbutanoyl) pyrrolidin- 5-yl) phenyl sulfate;

(23) 2-Fluoro-3 - ((R) -1 - ((R) -2- (methoxycarbonylamino) -2-phenylacetyl) pyrrolidine- -Fluoro-3 - ((S) -1 - ((R) -2- (methoxycarbonylamino) -2-phenylacetyl) pyrrolidine-2-carboxamido) phenyl sulfate;

(24) 2-Fluoro-3 - ((R) -1 - ((R) -2- (methoxycarbonylamino) -3-methylbutanoyl) pyrrolidine- 2-fluoro-3 - ((S) -1 - ((R) -2- (methoxycarbonylamino) -3-methylbutanoyl) pyrrolidine-2-carboxamido) phenylsulfate;

(25) Synthesis of bis (2-fluoro-5- (2 - ((S) -1 - ((R) -2- (methoxycarbonylamino) -3-methylbutanoyl) pyrrolidin- ) -1H-imidazol-5-yl) phenyl) sulphate;

(26) bis (2-fluoro-5- (2 - ((S) -1 - ((R) -2- (methoxycarbonylamino) -2- phenylacetyl) pyrrolidin- -1H-imidazol-5-yl) phenyl) sulfate;

(27) Synthesis of bis (2-fluoro-5- (2 - ((S) -1 - ((S) -2- (methoxycarbonylamino) -3- methylbutanoyl) pyrrolidin- ) -1H-imidazol-5-yl) phenyl) sulphate;

(28) Synthesis of bis (3 - ((S) -1 - ((R) -2- (methoxycarbonylamino) -3-methylbutanoyl) pyrrolidine-2-carboxamido) ) Sulphate;

(29) Synthesis of Dimethyl (2R, 2'R) -1,1 '- ((2S, 2'S) -2,2'- (4,4'-sulfonylbis Bis (pyrrolidine-2,1-diyl)) bis (3-methyl-1-oxobutane-2,1-diyl) dicarbamate;

(30) Synthesis of bis (3- (2 - ((S) -1 - ((S) -2- (methoxycarbonylamino) -4- methylpentanoyl) pyrrolidin- 5-yl) phenyl) sulphate;

(31) Synthesis of bis (3- (2 - ((S) -1 - ((S) -2- (methoxycarbonylamino) propanoyl) pyrrolidin- Yl) phenyl) sulphate;

(32) Synthesis of bis (3- (2 - ((S) -1 - ((S) -2- (methoxycarbonylamino) -2- phenylacetyl) pyrrolidin- Yl) phenyl) sulphate;

(33) Synthesis of bis (3 - ((S) -1 - ((S) -2- (methoxycarbonylamino) -3,3-dimethylbutanoyl) pyrrolidine- ) Sulphate;

(34) 2-Fluoro-3 - ((S) -1 - ((R) -2- (methoxycarbonylamino) -2- phenylacetyl) pyrrolidine- Fluoro-5 - ((S) -1 - ((R) -2- (methoxycarbonylamino) -2-phenylacetyl) pyrrolidine-2-carboxamido) phenyl sulfate;

(35) 2-Fluoro-3 - ((S) -1 - ((R) -2- (methoxycarbonylamino) -3-methylbutanoyl) pyrrolidine- 2-fluoro-5 - ((S) -1 - ((R) -2- (methoxycarbonylamino) -3-methylbutanoyl) pyrrolidine-2-carboxamido) phenyl sulfate.

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

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

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.

Also, as shown in the following Reaction Scheme 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 (1).

[Reaction Scheme 1]

In the above Reaction Scheme 1,

R ¹ , R ² , R ³ , X and A are as defined in Formula 1; And

PG is an amine protection group.

Hereinafter, a method for preparing the compound represented by Formula 1 according to the present invention will be described in detail.

The method for preparing the compound represented by Formula 1 according to the present invention can be carried out by reacting the compound represented by Formula 2 and the compound represented by Formula 3 as shown in Reaction Scheme 1, .

Specifically, after the amine protecting group of the compound represented by the general formula (2) is removed, the compound represented by the general formula (1) may be prepared by reacting the compound represented by the general formula (3) in the presence of an amide reagent.

Examples of the amine protecting group include t-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz) ), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), 2,2,2-trichloroethoxycarbonyl Troc), 2-trimethylsilylethoxycarbonyl (Teoc), or aryloxycarbonyl (Alloc), and preferably t-butyloxycarbonyl (Boc).

The amine protecting group may be removed by a conventional method. For example, the acid can be removed under the condition of using an acid or a base, and the acid includes hydrochloric acid, sulfuric acid, trifluoroacetic acid, bromic acid, etc. The base includes piperidine and ammonia gas, It can be used in excess.

Further, the amide reagent may be selected from the group consisting of benzotriazol-1-yl-oxy-tris (dimethylamino) -phosphonium hexafluorophosphate (Py-BOP), O- N, N-tetramethyl-europium-hexafluoro-phosphate (HBTU), 2- (7-aza-lH-benzotriazol- 1-yl) -1,1,3,3-tetramethyluronium hexa (EDCI) or carbonyldi (dicyclohexylcarbodiimide) (DCC), such as, for example, fluorophosphate (HATU), hydroxybenzotriazole (HOBt), dicyclohexylcarbodiimide (EDCI) is reacted with diisopropylethylamine (DIPEA), triethylamine (TEA) or triethylamine (TEA). It can be used with dimethylaminopyridine (DMAP).

As the reaction organic solvent, a reaction can be carried out using methanol, dimethylformamide, tetrahydrofuran, dichloromethane, toluene or the like, preferably dichloromethane.

Preparation of starting material (compound of formula 2)

When A is -O-, the compound of Formula 2, which is the starting material of Reaction Scheme 1, can be prepared as shown in Reaction Scheme 2 or Reaction Scheme 3.

The derivative 2a of the compound represented by the formula (2) wherein A is -O- in the above formula (2)

Reacting a compound represented by the formula (5) with a compound represented by the formula (6) to prepare a compound represented by the formula (2a)

As shown in Scheme 2 below,

And reacting the compound represented by the formula (4) with 1,1'-sulfonyldiimidazole to prepare a compound represented by the formula (2a).

[Reaction Scheme 2]

In the above Reaction Scheme 2

X and R < ¹ > are as defined in Formula 1 above;

PG is an amine protection group; And

(2a) is a derivative of the above formula (2).

Hereinafter, a method of preparing the compound represented by the above formula (2a) will be described in detail.

In the process for producing the compound represented by formula (2) according to the present invention, a process for producing a compound represented by the formula (2a) by reacting a compound represented by the formula (4) with 1,1'-sulfonyldiimidazole &Lt; / RTI >

The base used in the reaction may be sodium hydroxide, sodium carbonate, potassium carbonate or cesium carbonate. Cesium carbonate may be used, and equivalents or excess thereof may be used.

Further, as the solvent which can be used in the above reaction, there are acetonitrile, dichloromethane, tetrahydrofuran, dimethylformamide (DMF) and the like, preferably tetrahydrofuran, which can be used singly or in combination .

Further, as shown in the following Reaction Scheme 3,

And reacting the compound represented by the formula (5) with the compound represented by the formula (6) to prepare a compound represented by the formula (2a).

[Reaction Scheme 3]

In Scheme 3,

X and R < ¹ > are as defined in Formula 1 above;

PG is an amine protection group; And

(2a) is a derivative of the above formula (2)

A process for producing a compound represented by the formula (2a) according to the present invention includes a step of reacting a compound represented by the formula (5) and a compound represented by the formula (6) in the presence of a base to prepare a compound represented by the formula &Lt; / RTI >

In addition, the base which can be used in the above reaction is exemplified by trimethylamine, triethylamine, N, N-diisopropylethylamine (DIPEA), N-methylpiperidine, pyridine, lutidine, N, (DMAP), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) and the like, preferably 1,8-diazabicyclo [5.4.0] -7-undecene DBU) can be used, and they can be used singly or in combination.

Further, as the solvent usable in the above reaction, ether solvents such as tetrahydrofuran, dioxane, dichloromethane and 1,2-dimethoxyethane, aromatic hydrocarbon solvents such as benzene, toluene and xylene, dimethylformamide Dimethylformamide (DMF), dimethylsulfoxide (DMSO), acetonitrile and the like, preferably dimethylformamide (DMF), which may be used alone or in combination.

The present invention also provides a pharmaceutical composition for preventing or treating hepatitis C virus-related liver diseases, which comprises the compound represented by the formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

Herein, the hepatitis C virus-related hepatitis may include hepatitis C virus-related liver diseases, which is characterized by liver diseases such as acute hepatitis C, chronic hepatitis C, liver cirrhosis, hepatocellular carcinoma and the like.

As a result of measuring the inhibitory activity of the compound represented by the formula (1) according to the present invention for inhibiting infection by the hepatitis C virus, the compounds according to the present invention inhibited infection by hepatitis C virus Respectively. In particular, Examples 2, 4, 6, 12, 14, 21, 26, 33, and 34 showed excellent inhibition of infection by hepatitis C virus even at a very low EC ₅₀ value of 1 nM or less (See Experimental Example 1).

In addition, as a result of measuring the inhibitory activity against the hepatitis C virus replication of the compound of formula (1) according to the present invention, the compounds according to the present invention exhibited excellent inhibition of replication of hepatitis C virus at low concentrations . In particular, Examples 2, 4, 6, 10, 12, 14, 15, 19, 21, 26, 29, 31, and 34 compounds in the EC ₅₀ value at very low concentrations to less than 1 nM the replication of the hepatitis virus type C (See Experimental Example 2).

Therefore, the compounds according to the present invention exhibit excellent inhibition of infection by hepatitis C virus and excellent suppression of hepatitis C virus replication. Therefore, the compounds according to the present invention are effective against acute hepatitis C, chronic hepatitis C Hepatitis, liver cirrhosis, hepatocellular carcinoma, and the like.

When the composition of the present invention is used as a medicine, the pharmaceutical composition containing the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient can be administered orally or parenterally May be formulated and administered, but the present invention is not limited thereto.

Examples of formulations for oral administration include tablets, pills, light / soft capsules, liquids, suspensions, emulsions, syrups, granules, elixirs and troches, (E.g., silica, talc, stearic acid or a magnesium salt or a calcium salt and / or polyethylene glycol), and the like. The tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, optionally mixed with starch, agar, alginic acid or its sodium salt The same disintegrating or boiling mixture and / or absorbing agent, coloring agent, flavoring agent and sweetening agent.

The pharmaceutical composition containing the compound represented by the formula (1) as an active ingredient may be administered parenterally, and the parenteral administration may be by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.

In order to formulate the composition for parenteral administration, the biphenyl diamide derivative of the above formula (1) or a pharmaceutically acceptable salt thereof is mixed with water or a stabilizer or a buffer to prepare a solution or suspension, which is then mixed with an ampule or vial unit May be prepared in dosage forms. The compositions may contain sterilized and / or preservatives, stabilizers, wettable or emulsifying accelerators, adjuvants such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, Or may be formulated according to the coating method.

The dosage of the pharmaceutical composition containing the compound represented by the formula (1) as an active ingredient may vary depending on the patient's age, body weight, sex, dosage form, health condition and disease severity, 200 mg / kg / day, depending on the judgment of the physician or pharmacist. The dose may be administered orally or parenterally by dividing the time interval by several times a day, preferably once or three times a day.

Furthermore, the present invention provides a health functional food composition for preventing or ameliorating hepatitis C virus-related liver disease comprising the compound represented by the formula (1) of the present invention, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

The health functional food according to the present invention is characterized in that the compound represented by Formula 1, its pharmaceutically acceptable salt or its optical isomer thereof is used as a food, drink or the like for the purpose of prevention or improvement of liver disease caused by hepatitis C virus It can be added to health functional foods.

There is no particular limitation on the kind of the food. Examples of foods to which the above substances can be added include dairy products including dairy products, meat, sausage, bread, biscuits, rice cakes, chocolate, candies, snacks, confectionery, pizza, ramen, other noodles, gums, ice cream, Beverages, alcoholic beverages and vitamin complexes, dairy products, and dairy products, all of which include health functional foods in a conventional sense.

The compound represented by the formula (1) according to the present invention, a pharmaceutically acceptable salt thereof or an optical isomer thereof can be directly added to the food or can be used together with other food or food ingredients, and can be suitably used according to a conventional method. The amount of the active ingredient to be mixed can be suitably determined according to the intended use (for prevention or improvement). Generally, the amount of the compound in the health functional food may be 0.1 to 90 parts by weight based on the total weight of the food. However, in the case of long-term ingestion intended for health and hygiene purposes or health control purposes, the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount in the above range.

The health functional beverage of the present invention is not particularly limited to the other ingredients other than the above-mentioned compounds as essential ingredients in the indicated ratios and may contain various flavors or natural carbohydrates as additional ingredients such as ordinary beverages. Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; Daisakaride, for example Maltose, sucrose etc; And polysaccharides such as dextrin, cyclodextrin and the like, and sugar alcohols such as xylitol, sorbitol, and erythritol. Natural flavors (e.g., tau martin, stevia extract, etc.) and synthetic flavorings (e.g., saccharin, aspartame, etc.) can be advantageously used as flavorings other than those described above. The ratio of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 healthy function foods of the present invention.

In addition to the above, the health functional food containing the compound represented by the formula (I) according to the present invention, the pharmaceutically acceptable salt thereof or the optical isomer thereof as an active ingredient is useful as various nutrients, vitamins, minerals (electrolytes) (For example, cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, Alcohols, carbonating agents used in carbonated drinks, and the like. In addition, the health functional food of the present invention may contain natural fruit juice and pulp for the production of fruit juice drinks and vegetable drinks.

These components may be used independently or in combination. The proportion of such additives is not so important, but is generally selected in the range of 0.1 to about 20 parts by weight per 100 parts by weight of the health functional food according to the present invention.

Hereinafter, examples and experimental examples of the present invention will be described in detail.

However, the following Examples and Experimental Examples are merely illustrative of the present invention, and the present invention is not limited to the following Examples and Experimental Examples.

< Manufacturing example 1 > (R) -2- ( Methoxycarbonylamino ) -3- Methylbutanic Acid's Produce

Sodium carbonate (276 mg, 2.6 mmol) was dissolved in a solution of D-vailine (586 mg, 5.00 mmol) in sodium hydroxide (5 mL of 1M H ₂ O, 5 mmol) Cooled in an ice water bath. Methylene chloroformate (0.420 mL, 5.40 mmol) was added in small portions, the ice bath was removed, and the reaction mixture was stirred at room temperature for 3.25 hours. The reaction mixture was washed with ether (3 X 9 mL), the water layer was cooled in an ice bath and acidified to pH 1-2 by addition of con.HCl and extracted with dichloromethane (3 X 9 mL) . The organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo to give the desired compound (760 mg, 87% yield) Obtained as a white solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 300MHz): 12.54 (s, 1H), 7.32 (d, 1H), 3.84 (t, 1H), 3.54 (s, 3H), 2.03 (m, 1H ), 0.87 (d, 6H).

< Manufacturing example 2 > (S) -2- ( Methoxycarbonylamino ) -3- Methylbutanic Acid's Produce

Sodium carbonate (1.83 g, 12.7 mmol) was dissolved in an aqueous sodium hydroxide solution (33 mL of 1 M / H ₂ O, 33 mmol) of L-vailine (3.900 g, 33.29 mmol) Cooled in an ice water bath. Methylene chloroformate (2.8 mL, 36.1 mmol) was added in small portions, the ice bath was removed, and the reaction mixture was stirred at room temperature for 3.25 hours. The reaction mixture was washed with ether (3 x 17 mL) and the water layer was cooled in an ice bath and acidified to pH 1-2 by addition of con.HCl and extracted with dichloromethane (3 X 17 mL) . The organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo to give the desired compound (5.00 g, 86% yield) Obtained as a white solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 12.51 (br s, 1H), 7.32 (d, 1H), 3.84 (t, 1H), 3.54 (s, 3H), 2.03 (m, 1H), 0.88 (d, J = 12,6H).

< Manufacturing example 3 > (R) -2- ( Methoxycarbonylamino )-2- Phenylacetic Acid's Produce

Sodium carbonate (0.55 g, 5.2 mmol) was dissolved in an aqueous sodium hydroxide solution (10 mL of 1 M / H ₂ O, 10 mmol) of D-phenylglycine (1.500 g, 10.0 mmol) Was cooled in an ice bath. Methylene chloride formate (0.85 mL, 11.0 mmol) was added in small portions, the ice bath was removed, and the reaction mixture was stirred at room temperature for 3.25 hours. The reaction mixture was washed with ether (3 X 18 mL) and the water layer was cooled in an ice bath and then acidified to pH 1-2 with conc.HCl and extracted with dichloromethane (3 X 18 mL) . The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated in vacuo and the resulting oil residue was treated with diethyl ether / hexane (5/4, 10 mL) to give a precipitate. The resulting precipitate was filtered, washed with diethyl ether / hexane (1/3) and then dried under vacuum to obtain 1.4 g of the target compound (R) -2- (methoxycarbonylamino) -2- phenylacetic acid , 67% yield) Obtained as a white solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 500MHz): 12.79 (br s, 1H), 7.96 (d, J = 12, 1H), 7.40-7.29 (m, 5H), 5.13 (d, J = 12, 1H), 3.55 (s, 3H).

< Manufacturing example 4> (S) -2- ( Methoxycarbonylamino )-2- Phenylacetic Acid's Produce

Sodium carbonate (0.631 g, 5.95 mmol) was dissolved in an aqueous sodium hydroxide solution (10 mL of 1M / H ₂ O, 10 mmol) of L-phenyl glycine (1.8 g, 11.9 mmol) The mixture was cooled in an ice bath. Methylene chloroformate (1.01 mL, 13.1 mmol) was added in small portions, the ice bath was removed, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with ether (3 X 18 mL) and the water layer was cooled in an ice bath and then acidified to pH 1-2 with conc.HCl and extracted with dichloromethane (3 X 18 mL) . The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated in vacuo and the resulting oil residue was treated with diethyl ether / hexane (5/4, 10 mL) to give a precipitate. The resulting precipitate was filtered, washed with diethyl ether / hexane (1/3), and dried under vacuum to obtain the target compound (S) -2- (methoxycarbonylamino) -2- phenylacetic acid , 52% yield) Obtained as a white solid.

< Manufacturing example 5> die - tert - butyl 2,2 '- ( ((Sulfonylbis (4,1-phenylene)) bis (azaendiyl)) bis (carbonyl) ) Preparation of (2S, 2'S) -bis (pyrrolidine-1-carboxylate)

(481 mg, 1.94 mmol), N-Boc-L-proline (1.00 g, 4.65 mmol) and 1-ethyl-3- (3- dimethylaminopropyl) carbodiimide (EDCI) (945 mg, 5.03 mmol) was dissolved in dichloromethane (10 mL), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with 1 N aqueous hydrochloric acid solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give the desired compound tert-butyl (S) -2 - ((4 - {(4- {(R) -1- (tert- Phenyl) carbamoyl) pyrrolidine-1-carboxylate (544 mg, 44% yield) was converted to the title compound Obtained as a white solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 10.43 (s, 2H), 7.89-7.79 (m, 8H), 4.27-4.18 (m, 2H), 3.44-3.39 (m, 4H) , 2.19-2.16 (m, 2H), 1.99-1.78 (m, 6H), 1.38-1.23 (app br s, 18H);

^{_{13 C NMR (DMSO-d 6}} , δ = 39.52 ppm, 100 MHz): 172.31, 153.01, 143.44, 135.30, 128.49, 119.22, 112.95, 78.58, 62.80, 60.42, 46.54, 45.14, 33.13, 30.93, 30.09, 27.93, 26.68, 26.60, 23.95, 23.35, 13.13.

< Manufacturing example 6> 3-Amino-2- Methylphenol Produce

After dissolving 2-methyl-3-nitrophenol (2.0 g, 13.1 mmol) in methanol (50 mL) at room temperature, 10 wt% palladium on charcoal (100 mg) . The reaction mixture was stirred under a hydrogen gas for 24 hours, and 10% by weight of palladium / charcoal was filtered with Celite. The filtrate was concentrated in vacuo to give the desired compound (1.62 g, 99% yield) as a solid.

^{_{1 H NMR (CD 3 OD,}} δ = 3.31 ppm, 400MHz): 6.77-6.73, (t, 1H), 6.29-6.27 (d, 1H), 6.22-6.20 (d, 1H), 2.02 (s, 3H) ;

¹³ C NMR (CD ₃ OD,? = 49.00 ppm, 100 MHz): 156.69, 147.48, 127.22, 110.86, 108.78, 106.65, 9.18.

< Manufacturing example 7 > (S) - tert - Butyl 2 - ((3- Hydroxy -2- Methylphenyl ) Carbamoyl ) Pyrrolidine -1-car Decylate Manufacturing

Amino-2-methylphenol (1.19 g, 5.52 mmol), N-Boc-L-proline (1.43 g, 6.63 mmol) and 1-ethyl- 3- ) Carbodiimide (EDCI) (928 mg, 7.18 mmol) was dissolved in dichloromethane (20 mL), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with 1 N aqueous hydrochloric acid solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo to give the desired compound (1.76 g, 99% yield) as a white solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 9.36-9.24 (t, 2H), 6.94 (s, 1H), 6.82-6.78 (d, 1H), 6.65 (s, 1H), 4.29 (s, 1H), 3.42-3.32 (m, 2H), 2.23-2.14 (d, IH), 1.99 (s, 3H), 1.89-1.81 (m, 3H), 1.42-1.37 ;

¹³ C NMR (DMSO-d ₆ ,? = 39.52 ppm, 100 MHz): 171.26, 155.74, 153.34, 137.14, 125.51, 119.25, 116.24, 111.80, 78.49, 59.95, 46.61, 31.37, 28.10, 23.28,

< Manufacturing example 8> (2S, 2'S) -di- tert - butyl 2,2 '- (3,3'- Sulfonylbis (oxy) bis (2- methyl -3,1-phenylene)) Bis ( Azaneddir ) Bis ( Oxomethylene ) Dipyrrolidine -One- Carboxylate Produce

Pyrrolidine-1-carboxylate (485 mg, 1.51 mmol), cesium carbonate (217 mg, 0.35 mmol) obtained in Preparation Example 7, , 0.666 mmol) and 1,1'-sulfonyldiimidazole (120 mg, 0.605 mmol) were dissolved in dimethylformamide (10 mL) and the reaction mixture was refluxed at 60 ° C for 12 hours. The reaction mixture was filtered through a short silica column and then concentrated in vacuo. The residue was purified by silica gel flash column chromatography using hexane: ethyl acetate as a mobile phase to give the desired compound (321 mg, 75% yield) as a yellow solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 9.66-9.61 (d, 2H), 7.41 (s, 2H), 7.37-7.33 (t, 2H), 7.26-7.24 (d, 2H) 2H), 3.42 (s, 2H), 3.34 (s, 2H), 2.25-2.23 (br d, 2H), 2.11 (s, 6H), 1.97-1.82 1.41-1.35 (app br s, 18H);

^{_{13 C NMR (DMSO-d 6}} , δ = 39.52 ppm, 100 MHz): 171.67, 153.81, 153.22, 148.62, 138.29, 126.84, 125.85, 125.05, 118.07, 78.59, 59.92, 46.58, 31.26, 29.99, 28.07, 24.05, 23.24, 11.35.

< Manufacturing example 9> 5-Amino-2- Of fluorophenol Produce

2-fluoro-5-nitrophenol (1.0 g, 6.37 mmol) was dissolved in methanol (25 mL) at room temperature, and then 10 wt% palladium on charcoal (50 mg) Was added. The reaction mixture was stirred under a hydrogen gas for 24 hours, and 10% by weight of palladium / charcoal was filtered with Celite. The filtrate was concentrated in vacuo to give the desired compound (809 mg, 99% yield) as a solid.

^{_{1 H NMR (CD 3 OD,}} δ = 3.31 ppm, 400MHz): 6.78-6.73, (t, 1H), 6.34-6.31 (q, 1H), 6.17-6.13 (m, 1H);

¹³ C NMR (CD ₃ OD,? = 49.00 ppm, 100 MHz): 147.94, 145.65, 145.15, 116.60, 107.67, 106.22;

¹⁹ F NMR (376 MHz, CD ₃ OD): -152.91.

PREPARATION EXAMPLE 10 Synthesis of (S) - tert - Butyl 2 -((4- Fluoro -3- Hydroxyphenyl ) Carbamoyl ) Pyrrolidine -1-carboxylate

Amino-2-fluorophenol (510 mg, 3.93 mmol), N-Boc-L-proline (1.02 g, 4.72 mmol) and 1-ethyl- Propyl) carbodiimide (EDCI) (661 mg, 5.11 mmol) was dissolved in dichloromethane (20 mL) and stirred at room temperature for 16 hours. The reaction mixture was diluted with 1 N aqueous hydrochloric acid solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel flash column chromatography using hexane: ethyl acetate as mobile phase to give the desired compound (748 mg, 59% yield) as a white solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 10.19-9.87 (d, 2H), 7.39-7.37 (d, 1H), 7.06-7.01 (t, 1H), 6.94-6.92 (d, 1H), 4.22-4.13 (m, 1H), 3.42-3.29 (m, 2H), 2.20-2.14 (m, 1H), 1.89-1.76 (m, 3H), 1.39-1.27 (app br s, 9H);

¹³ C NMR (DMSO-d ₆ ,? = 39.52 ppm, 100 MHz): 171.29, 153.17, 148.29, 145.93, 144.67, 135.57, 115.83, 109.96, 108.99, 78.49, 60.37, 46.59, 31.02, 27.97, 23.43;

^{19 F NMR (376 MHz, DMSO} -d 6): -142.31.

< Manufacturing example 11> (S) - tert - Butyl 2 - ((3 - (( tert - Butyl dimethylsilyl ) Oxy )-4- Fluorophenyl ) &Lt; / RTI > carbamoyl) pyrrolidine-1-carboxylate

Pyrrolidine-1-carboxylate (321 mg, 0.988 mmol), tert-butyl (3-fluoro- Dimethylsilyl chloride (223 mg, 1.48 mmol) and imidazole (108 mg, 1.58 mmol) were dissolved in dichloromethane (10 mL) and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel flash column chromatography using hexane: ethyl acetate as mobile phase to give the desired compound (318 mg, 73% yield) as a white oil.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 9.95 (s, 1H), 7.51-7.38 (q, 1H), 7.09 (s, 2H), 4.22-4.12 (m, 1H), 3.42 (M, 3H), 1.39-1.25 (app br s, 9H), 0.95 (s, 1H) 9H), 0.17 (s, 6H);

^{_{13 C NMR (DMSO-d 6}} , δ = 39.52 ppm, 100 MHz): 171.38, 153.08, 150.51, 148.14, 142.08, 135.72, 115.92, 113.02, 78.41, 60.40, 46.55, 30.94, 27.85, 25.34, 23.42, 17.95, -4.89;

^{19 F NMR (376 MHz, DMSO} -d 6): -138.76.

< Manufacturing example 12> (S) - tert - Butyl 2 -((4- Fluoro -3 - (( Fluorosulfonyl ) Oxy ) Phenyl ) Carbamoyl ) Pyrrolidine -One- Carboxylate Produce

Pyrrolidine-1-carboxylate (229 mg, 0.707 mmol) obtained in Preparation Example 10 and N, N (4-fluoro- -Diisopropylethylamine (228 mL, 0.919 mmol) was dissolved in dichloromethane (5 mL), and the mixture was stirred at room temperature for 5 hours under sulfuryl fluoride (SO ₂ F ₂ ). The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give the desired compound (260 mg, 90% yield) as a white oil.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 10.42 (s, 1H), 8.14-8.12 (d, 1H), 7.64-7.56 (m, 2H), 4.24-4.15 (m, 1H) , 3.41 (s, 1H), 3.31 (s, 1H), 2.22-2.17 (m, 1H), 1.93-1.78 (m, 3H), 1.39-1.25 (app s, 9H);

^{_{13 C NMR (DMSO-d 6}} , δ = 39.52 ppm, 100 MHz): 172.14, 153.63, 153.05, 149.36, 146.90, 136.55, 135.74, 135.60, 120.93, 118.14, 113.36, 78.65, 60.46, 46.59, 30.92, 30.11, 27.90, 24.00, 23.40;

^{_{19 F NMR (DMSO-d 6}} , 376 MHz): -136.06.

< Manufacturing example 13> die - tert Bis (2,2 '- (((sulfonylbis (oxy)) bis (4-fluoro-3,1-phenylene) 2'S) -bis (pyrrolidine-1-carboxylate)

(S) -tert-butyl 2 - ((3 - ((tert-butyldimethylsilyl) oxy) -4-fluorophenyl) carbamoyl) pyrrolidine- 1-carboxylate mg, 0.472 mmol), (S) -tert-butyl 2 - ((4-fluoro-3 - ((fluorosulfonyl) oxy) phenylcarbamoyl) pyrrolidine- Carboxylate (130 mg, 0.394 mmol) and DBU (11.8 mL, 0.08 mmol) were dissolved in dichloromethane (10 mL) and stirred at 50 ° C for 24 hours. The reaction mixture was diluted with 1N aqueous hydrochloric acid solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel flash column chromatography using hexane: ethyl acetate as mobile phase to give di-tert-butyl 2,2 '- ((((sulfonylbis (oxy)) bis (4- (2S, 2'S) -bis (pyrrolidine-1-carboxylate) (217 mg, 78% yield) was obtained as a white solid .

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 10.33 (s, 2H), 8.11-8.08 (t, 2H), 7.60-7.58 (d, 2H), 7.53-7.48 (t, 2H) (M, 2H), 3.42-3.40 (m, 2H), 3.35-3.32 (m, 2H), 2.21-2.18 (m, 2H), 1.91-1.78 app br s, 18H);

^{_{13 C NMR (DMSO-d 6}} , δ = 39.52 ppm, 100 MHz): 171.92, 153.60, 153.04, 149.87, 147.41, 136.27, 119.94, 117.90, 113.55, 78.60, 60.45, 46.57, 30.92, 30.11, 27.86, 23.99, 23.40;

^{19 F NMR (376 MHz, DMSO} -d 6): -135.44.

< Manufacturing example 14> (S) - tert -Butyl 2 - ((3- Hydroxyphenyl ) Carbamoyl ) Pyrrolidine -One- Carboxylate Produce

(3.00 g, 27.5 mmol), N-Boc-L-proline (7.11 g, 33.0 mmol) and 1-ethyl-3- (3- dimethylaminopropyl) carbodiimide (EDCI) , 35.7 mmol) were dissolved in dichloromethane (50 mL), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with 1 N aqueous hydrochloric acid solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel flash column chromatography using hexane: ethyl acetate as mobile phase to give the desired compound (2.33 g, 28% yield) as a white solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 9.83 (s, 1H), 9.36 (s, 1H), 7.18 (s, 1H), 7.08-7.04 (t, 1H), 6.96-6.94 (d, IH), 6.45-6.43 (d, IH), 4.24-4.15 (m, IH), 3.37 (m, IH), 3.33-3.32 -1.75 (m, 3H), 1.39-1.27 (app br s, 9H);

¹³ C NMR (DMSO-d ₆ ,? = 39.52 ppm, 100 MHz): 171.40, 157.63, 153.23, 140.15, 129.28, 110.38, 110.11, 106.55, 78.49, 60.40, 46.60, 31.06, 27.98, 23.44.

< Manufacturing example 15> (S) - tert - Butyl 2 - ((3 - (( tert - Butyl dimethylsilyl ) Oxy ) Phenyl ) Carbamoyl ) Pyrrolidine -One- Carboxylate Produce

(S) -tert-butyl 2 - ((3-hydroxyphenyl) carbamoyl) pyrrolidine-1-carboxylate (702 mg, 2.29 mmol) obtained in Preparation Example 14, tert-butyldimethylsilyl chloride 518 mg, 3.44 mmol) and imidazole (249 mg, 3.66 mmol) were dissolved in tetrahydrofuran (10 mL), and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel flash column chromatography using hexane: ethyl acetate as mobile phase to give the desired compound (1.47 g, 91% yield) as a white oil.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 9.93 (s, 1H), 7.35-7.24 (d, 1H), 7.16-7.09 (m, 2H), 6.52-6.51 (d, 1H) , 4.23-4.13 (m, IH), 3.44-3.38 (m, IH), 3.32-3.30 (m, IH), 2.21-2.12 app s, 9H), 0.93 (s, 9H), 0.17 (s, 6H);

^{_{13 C NMR (DMSO-d 6}} , δ = 39.52 ppm, 100 MHz): 171.50, 155.27, 153.11, 140.22, 129.48, 114.63, 112.27, 110.84, 78.44, 60.40, 46.56, 30.95, 27.89, 25.55, 23.43, 17.95, -4.53.

< Manufacturing example 16> tert - butyl (S) -2 - ((3 - (((4 - ((S) tert - Butoxycarbonyl ) Pyrrolidine -2-carboxamido) phenoxy) sulfonyl) oxy) phenyl) carbamoyl) pyrrolidine-1-carboxylate

((S) -tert-butyl 2 - ((3 - ((tert-butyldimethylsilyl) oxy) phenyl) carbamoyl) pyrrolidine- 1-carboxylate (172 mg, 0.408 mmol) Pyrrolidine-1-carboxylate (106 mg, 0.272 mmol), DBU (8.14 mL, 0.05 mmol) was added to a solution of (S) -tert-butyl 2 - [(4- ((fluorosulfonyl) oxy) phenyl) carbamoyl) mmol) and dichloromethane (10 mL), and the mixture was stirred at 50 DEG C for 24 hours. The reaction mixture was diluted with 1N aqueous hydrochloric acid solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel flash column chromatography using hexane: ethyl acetate as a mobile phase to give the desired compound (170 mg, 93% yield) as a white solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 500MHz): 10.34-10.23 (d, 2H), 7.96-7.88 (m, 1H), 7.75-7.73 (d, 2H), 7.58-7.55 (t, 2H), 3.36-3.31 (m, 2H), 2.23-7.17 (m, 2H) 2.15 (m, 2H), 1.93-1.77 (m, 6H), 1.39-1.24 (app br s, 18H);

¹³ C NMR (DMSO-d ₆ ,? = 39.52 ppm, 125 MHz): 171.80, 153.08, 149.91, 144.95, 144.91, 140.75, 138.75, 130.59, 121.56, 120.58, 118.31, 115.45, 111.39, 78.54, 60.41, 46.58, , 30.14, 27.90, 23.99, 23.40.

< Manufacturing example 17> die - tert - butyl 2,2 '- ( (((Sulfonylbis (oxy)) bis (3,1-phenylene)) bis (azaenediyl) ) Bis (carbonyl)) (2S, 2'S) -bis (pyrrolidine-1-carboxylate)

(773 mg, 2.52 mmol), cesium carbonate (1.11 g, 2.52 mmol) obtained in the above Production Example 15 and (S) -tert-butyl 2 - ((3- hydroxyphenyl) carbamoyl) pyrrolidine- ) And 1,1'-sulfonyldiimidazole (200 mg, 1.01 mmol) were dissolved in tetrahydrofuran (20 mL), and the reaction mixture was refluxed at 66 ° C for 12 hours. The reaction mixture was filtered through a short silica column and then concentrated in vacuo. The residue was purified by silica gel flash column chromatography using hexane: ethyl acetate as mobile phase to give the desired compound (378 mg, 56% yield) as a white solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 10.32 (s, 1H), 8.21-7.77 (m, 3H), 7.59-7.57 (d, 2H), 7.47 (s, 1H), 7.40 (S, 2H), 1.88-1.80 (m, 6H), 7.21-7.22 (m, 1H), 7.12-7.08 1.39-1.24 (app br s, 18H);

¹³ C NMR (DMSO-d ₆ ,? = 39.52 ppm, 100 MHz): 172.03,153.06,149.87,140.75,130.57,118.38,115.33,111.43,78.58,60.46,46.56,30.93,27.88,23.39

< Manufacturing example 18> (S) - tert - Butyl 2 - ((3- Hydroxy -4- Methylphenyl ) Carbamoyl ) Pyrrolidine -One- Carbop Manufacture of silicate

(EDCI) and N-Boc-L-proline (2.10 g, 9.74 mmol) and 1-ethyl-3- (3- dimethylaminopropyl) carbodiimide (1.36 g, 10.6 mmol) was dissolved in dichloromethane (25 mL), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with 1 N aqueous hydrochloric acid solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give the desired compound (1.92 g, 74% yield) as a white solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 9.73 (s, 1H), 9.27 (s, 1H), 7.21 (s, 1H), 6.94-6.92 (d, 1H), 6.86-6.84 (d, IH), 4.23-4.13 (m, IH), 3.39 (s, 2H), 2.20-2.17 (app br s, 9H);

¹³ C NMR (DMSO-d ₆ ,? = 39.52 ppm, 100 MHz): 171.05, 155.19, 153.17, 137.64, 130.18, 118.63, 109.93, 106.16, 78.40, 60.30, 46.54, 30.99, 27.95, 23.39, 15.50.

< Manufacturing example 19> Synthesis of (2S, 2'S) -di- tert - butyl 2,2 '- (3,3'- Sulfonylbis (oxy) bis (4- methyl -3,1-phenylene)) Bis ( Azaneddir ) Bis ( Oxomethylene ) Dipyrrolidine -One- Carboxylate Produce

Pyrrolidine-1-carboxylate (349 mg, 1.09 mmol) obtained in Preparation 18, cesium carbonate (163 mg, , 0.499 mmol) and 1,1'-sulfonyldiimidazole (90.0 mg, 0.454 mmol) were dissolved in dimethylformamide (10 mL) and the reaction mixture was refluxed at 60 ° C for 12 hours. The reaction mixture was filtered through a short silica column and then concentrated in vacuo. The residue was purified by silica gel flash column chromatography using hexane: ethyl acetate as mobile phase to give the desired compound (229 mg, 72% yield) as a white solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 10.22 (s, 2H), 7.95 (s, 2H), 7.54-7.48 (q, 2H), 7.34-7.32 (d, 2H), 4.24 -4.13 (m, 2H), 3.42-3.31 (m, 4H), 2.20-2.17 (d, 8H), 1.91-1.77 (m, 6H), 1.38-1.23 (app br s, 18H);

¹³ C NMR (DMSO-d ₆ ,? = 39.52 ppm, 100 MHz): 171.76, 153.07, 148.19, 138.42, 131.91, 124.47, 118.45, 111.63, 78.53, 60.42, 46.55, 30.93, 27.87, 23.40,

< Manufacturing example 20> die - tert - butyl 2,2 '- ( (((Sulfonylbis (oxy)) bis (4,1-phenylene)) bis (azaendiyl) ) Bis (carbonyl)) (2S, 2'S) -bis (pyrrolidine-1-carboxylate)

(464 mg, 1.51 mmol), cesium carbonate (164 mg, 0.505 mmol) and 1,1'- (tert-butyldimethylsilyloxy) -Sulfonyldiimidazole (100 mg, 0.505 mmol) was dissolved in tetrahydrofuran (25 mL) and the reaction mixture was refluxed at 66 DEG C for 12 hours. The reaction mixture was filtered through a short silica column and then concentrated in vacuo. The residue was purified by silica gel flash column chromatography using hexane: ethyl acetate as mobile phase to give the desired compound (102 mg, 30% yield) as a yellow solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 10.28 (s, 1H), 7.72-7.70 (d, 4H), 7.39-7.37 (d, 4H), 4.23-4.16 (m, 2H) , 3.39-3.32 (m, 4H), 2.21-2.16 (t, 2H), 1.86-1.78 (m, 6H), 1.38-1.25 (app br s, 18H);

¹³ C NMR (DMSO-d ₆ ,? = 39.52 ppm, 100 MHz): 172.16, 153.45, 145.24, 138.81, 121.89, 120.92, 78.98, 62.96, 60.65, 46.82, 31.20, 28.17, 23.65.

< Manufacturing example 21> (S) -1- tert - Butyl 2 - (2- (4- Hydroxyphenyl )-2- Oxoethyl ) Pyrrolidine -1,2- Ica Radix Manufacture

After dissolving 2-bromo-4-hydroxyacetophenone (1.00 g, 4.65 mmol) and N-Boc-L-proline (1.10 g, 5.12 mmol) in acetonitrile (50 mL), diisopropylethylamine (1.44 mL, 5.58 mmol) portionwise, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with 1 N aqueous hydrochloric acid solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel flash column chromatography using hexane: ethyl acetate as mobile phase to give the desired compound (1.20 g, 74% yield) as a white solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 10.49 (s, 1H), 7.86-7.85 (d, 2H), 6.88-6.86 (t, 2H), 5.53-5.32 (m, 2H) , 4.32-4.29 (m, 1H), 3.11 (m, 2H), 2.29-2.14 (m, 2H), 1.90-1.85 (m, 2H), 1.36 (app br s, 9H);

¹³ C NMR (DMSO-d ₆ ,? = 39.52 ppm, 100 MHz): 190.47, 172.31, 162.68, 152.95, 130.41, 125.35, 115.44, 78.94, 66.11, 58.55, 46.17, 30.43, 27.93, 23.05.

< Manufacturing example 22> (S) - tert Butyl 2- (5- (4- Hydroxyphenyl ) -1H- Imidazole -2 days) Pyrrolidine -One- Carboxylate Produce

(S) -1-tert-butyl 2- (2- (4-hydroxyphenyl) -2-oxoethyl) pyrrolidine-1,2-dicarboxylate (2.00 g, 5.72 mmol ) And ammonium acetate (6.62 g, 85.9 mmol) were dissolved in toluene (20 mL), and then the reaction mixture was heated to 90 DEG C and stirred for 20 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel flash column chromatography using hexane: ethyl acetate as mobile phase to give the desired compound (887 mg, 47% yield) as a yellow solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 11.76 (br s, 1H), 9.48 (br s, 1H), 7.53 (s, 2H), 7.20 (s, 1H), 6.77-6.75 (d, 2H), 4.83-4.76 (d, 1H), 3.54-3.35 (d, 2H), 2.20-1.81 (m, 4H), 1.39-1.17 (app br s, 9H);

¹³ C NMR (DMSO-d ₆ ,? = 39.52 ppm, 100 MHz): 155.93, 153.82, 153.47, 150.09, 125.54, 115.30, 78.23, 55.26, 46.34, 33.41, 31.88, 27.93, 23.85, 23.16.

< Manufacturing example 23> (S) -1- tert - Butyl 2 - (2- (3- Hydroxyphenyl )-2- Oxoethyl ) Pyrrolidine -1,2- Ica Radix Manufacture

After dissolving 2-bromo-3-hydroxyacetophenone (1.00 g, 4.65 mmol) and N-Boc-L-proline (1.10 g, 5.12 mmol) in acetonitrile (50 mL), diisopropylethylamine (1.44 mL, 5.58 mmol) was added in small portions, followed by stirring at room temperature for 5 hours. The reaction mixture was diluted with 1 N aqueous hydrochloric acid solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel flash column chromatography using hexane: ethyl acetate as mobile phase to give the desired compound (1.47 g, 91% yield) as a white solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 9.88 (s, 1H), 7.45-7.43 (d, 1H), 7.37-7.33 (m, 2H), 7.10-7.08 (d, 1H) (M, 2H), 1.40-1. 27 (m, 2H), 5.58-5.38 (m, 2H), 4.37-4.31 app br s, 9H);

^{_{13 C NMR (DMSO-d 6}} , δ = 39.52 ppm, 100 MHz): 192.42, 172.30, 157.84, 153.00, 135.18, 130.04, 121.13, 118.74, 113.90, 79.00, 66.55, 58.59, 46.21, 30.48, 29.56, 28.11, 27.94, 23.87, 23.12.

< Manufacturing example 24> (S) - tert - Butyl 2 - (5- (3- Hydroxyphenyl ) -1H- Imidazole -2 days) Pyrrolidine -One- Carboxylate Produce

(S) -1-tert-butyl 2- (2- (3-hydroxyphenyl) -2-oxoethyl) pyrrolidine-1,2-dicarboxylate (1.11 g, 3.19 mmol ) And ammonium acetate (3.68 g, 47.8 mmol) were dissolved in toluene (20 mL), and the reaction mixture was heated to 90 ° C and stirred for 20 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel flash column chromatography using hexane: ethyl acetate as mobile phase to give the desired compound (456 mg, 45% yield) as a yellow solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 11.88 (br s, 1H), 9.41 (br s, 1H), 7.34-7.11 (m, 4H), 6.60 (s, 1H), 4.85 (M, 3H), 1.39-1.16 (app br s, 9H), 1.35-1.30 (m, ;

¹³ C NMR (DMSO-d ₆ ,? = 39.52 ppm, 100 MHz): 157.66, 153.51, 129.43, 115.25, 113.14, 111.25, 78.32, 55.33, 48.72, 46.42, 33.49, 31.93, 27.96, 23.93,

< Manufacturing example 25> tert - butyl 2,2 ' - ((( Sulfonylbis ( Oxy )) Bis (3,1- Phenylene )) Bis (1H- Imidazole -5,2- Dill )) (2S, 2'S) - Bis (pyrrolidine-1-carboxylate) Produce

(479 mg, 1.45 mmol) obtained in the above Production Example 24 and the (S) -tert-butyl 2- (5- (3-hydroxyphenyl) -1H-imidazol- , Cesium carbonate (217 mg, 0.666 mmol) and 1,1'-sulfonyldiimidazole (120 mg, 0.605 mmol) were dissolved in dimethylformamide (10 mL), and the reaction mixture was refluxed at 60 ° C for 12 hours . The reaction mixture was filtered through a short silica column and then concentrated in vacuo. The residue was purified by silica gel flash column chromatography using hexane: ethyl acetate as a mobile phase to give the desired compound (388 mg, 89% yield) as a white solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 12.04-11.97 (br d, 2H), 8.21-7.76 (t, 4H), 7.64-7.61 (d, 1H), 7.52-7.44 (q 2H), 3.39-3.36 (m, 2H), 2.22-2.15 (m, 2H), 7.37-7.20 (m, 2H), 6.93-6.74 (m, 2H), 1.98-1.79 (m, 6H), 1.38-1.14 (app br s, 18H);

¹³ C NMR (DMSO-d ₆ ,? = 39.52 ppm, 100 MHz): 153.38, 150.43, 138.11, 131.32, 130.48, 123.45, 119.17, 117.87, 116.43, 116.24, 78.24, 55.23, 46.30, 33.28, 27.86,

< Manufacturing example 26> 2- Bromo -1- (4- Fluoro -3- Hydroxyphenyl ) Ethane Produce

Ethyl acetate (5 mL) / chloroform (5 mL) of 4'-fluoro-3'-hydroxyacetophenone (100 mg, 0.649 mmol) and copper (II) bromide (174 mg, 0.779 mmol) . The reaction mixture was filtered to remove copper (I) bromide. The filtrate was concentrated in vacuo to give 2-bromo-1- (4-fluoro-3-hydroxyphenyl) ethanone (123 mg, 81%) as a yellow solid.

^{_{1 H NMR (CDCl 3, δ}} = 7.26 ppm, 400 MHz): 7.67-7.64 (m, 1H), 7.56-7.51 (m, 1H), 7.19-7.13 (m, 1H), 5.63 (s, 1H), 4.38 (s, 2H);

¹³ C NMR (CDCl ₃ ,? = 77.16 ppm, 100 MHz): 190.18, 155.97, 153.50, 144.29, 131.19, 122.62, 118.44, 116.35, 30.63;

^{19 F NMR (376 MHz, CDCl} 3): -130.70

< Manufacturing example 27> (S) -1- tert -Butyl 2- (2- (4- Fluoro -3- Hydroxyphenyl )-2- Oxoethyl ) &Lt; / RTI > pyrrolidine-l, 2-dicarboxylate

Bromo-1- (4-fluoro-3-hydroxyphenyl) ethan-1-one (97.0 mg, 0.416 mmol) and N-Boc-L-proline (108 mg, 0.499 diisopropylethylamine (94 μL, 0.541 mmol) was added dropwise to acetonitrile (10 mL) at room temperature, and the mixture was stirred at room temperature for 5 hours. The mixture was poured into 1N aqueous HCl solution and extracted with methylene chloride. The organic layer was dried over magnesium sulfate and purified by column chromatography (hexane / ethyl acetate) to obtain (S) -1-tert-butyl 2- (2- (4- fluoro- Oxoethyl) pyrrolidine-1,2-dicarboxylate (110 mg, 72%) as a white solid.

^{_{1 H NMR (DMSO-d 6}} , = 2.5 ppm, 400 MHz): 10.43 (s, 1H), 7.55-7.48 (m, 2H), 7.34-7.29 (m, 1H), 5.56-5.36 (m, 2H) (M, 3H), 1.36 (m, 3H), 3.35-3.04 (m, s, 9H);

^{_{13 C NMR (DMSO-d 6}} , δ = 39.52 ppm, 100 MHz): 191.37, 172.33, 155.97, 153.00, 145.44, 130.79, 120.36, 116.90, 116.55, 79.06, 66.41, 58.56, 46.22, 30.47, 29.55, 27.96, 23.88, 23.12;

^{19 F NMR (376 MHz, DMSO} -d 6): -127.51.

< Manufacturing example 28> (S) - tert Butyl 2- (5- (4- Fluoro -3- Hydroxyphenyl ) -1H-imidazol-2-yl) pyrrolidine-1-carboxylate

(S) -1-tert-butyl 2- (2- (3-hydroxyphenyl) -2-oxoethyl) pyrrolidine-1,2-dicarboxylate (203 mg, 0.554 mmol ) And ammonium acetate (640 mg, 8.30 mmol) were suspended in toluene (10 mL). The reaction mixture was heated to 90 DEG C and stirred for 20 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated in vacuo. Was purified by column chromatography (hexane / ethyl acetate) to give (S) -tert-butyl 2- (5- (4-fluoro-3-hydroxyphenyl) -1H- imidazol-2-yl) pyrrolidine -1-carboxylate (101 mg, 52%) as a yellow solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 12.06-11.76 (m, 1H), 9.70 (s, 1H), 7.35 (s, 2H), 7.10-7.01 (m, 2H), 4.80 1H), 4.72 (s, 3H), 4.73 (d, 1H), 3.52 (s, 1H), 2.32-2. 15 (m, 1H), 1.97-1.76 (m, 4H), 1.39-1.15 (app br s,

³ C NMR (DMSO-d ₆ ,? = 39.52 ppm, 100 MHz): 153.39, 150.76, 144.58, 138.79, 131.95, 115.97, 115.18, 113.60, 111.31, 78.60, 58.75, 55.20, 46.28, 33.32, 27.88, 23.14;

^{19 F NMR (376 MHz, DMSO} -d 6): -140.30.

< Manufacturing example 29> (S) - tert Butyl 2- (5- (4- Fluoro -3- ( Fluorosulfonyloxy ) Phenyl) -1H-imidazol-2-yl) pyrrolidine-1-carboxylate

(S) -2- (5- (4-fluoro-3-hydroxyphenyl) -1H-imidazol-2-yl) pyrrolidine- 1-carboxylate obtained in Preparation 28 mg, 0.259 mmol) and N, N-diisopropylethylamine (76.8 μL, 0.441 mmol) in methylene chloride (5 mL) sulfuryl fluoride at room temperature for 5 hours. The mixture was poured into 1N aqueous HCl solution and extracted with methylene chloride. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. (S) -tert-butyl 2- (5- (4-fluoro-3- (fluorosulfonyloxy) phenyl) -1H-imidazol- -Carboxylate (33.4 mg, 30%) as a white oil.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400 MHz): 12.07-12.00 (d, 1H), 8.03-8.01 (d, 1H), 7.91-7.87 (m, 1H), 7.66-7.64 (m (M, 1H), 7.58-7.54 (t, 1H), 4.82-4.77 (d, 1H), 3.53 (s, 1H), 3.34-3.29 , &Lt; / RTI > 3H), 1.39-1.15 (app s, 9H);

^{_{13 C NMR (DMSO-d 6}} , δ = 39.52 ppm, 100 MHz): 153.36, 151.81, 151.06, 149.33, 136.79, 133.63, 125.85, 118.19, 113.46, 78.26, 55.23, 46.31, 33.29, 31.84, 27.86, 23.83, 23.10;

^{_{19 F NMR (DMSO-d 6}} , 376 MHz,): 39.85, -134.19.

< Manufacturing example 30> (S) - tert -Butyl 2- (5- (3- ( tert - Butyl dimethylsilyloxy )-4- Fluorophenyl ) -1H-imidazol-2-yl) pyrrolidine-1-carboxylate

(S) -2- (5- (4-fluoro-3-hydroxyphenyl) -1H-imidazol-2-yl) pyrrolidine- 1-carboxylate obtained in Preparation 28 methylene chloride (10 mL) of imidazole (218 mg, 3.21 mmol) was stirred at room temperature for 4 hours. The mixture was poured into water and extracted with methylene chloride. The organic layer was dried over magnesium sulfate and purified by column chromatography (hexane / ethyl acetate) to give (S) -tert-butyl 2- (5- (3- (tert- butyldimethylsilyloxy) -4- Yl) pyrrolidine-1-carboxylate (638 mg, 69%) as a viscous white oil.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 12.12-11.81 (m, 1H), 7.43 (s, 1H), 7.35-7.31 (m, 2H), 7.23-7.10 (m, 1H) , 4.83-4.76 (m, 1H), 3.53 (s, 1H), 2.21-2.10 (m, 1H), 1.98-1.84 (s, 9 H), 0.18 (s, 6 H);

^{_{13 C NMR (DMSO-d 6}} , δ = 39.52 ppm, 100MHz): 153.10, 150.70, 142.40, 138.33, 132.30, 118.02, 117.76, 116.26, 116.07, 111.83, 78.15, 55.30, 46.25, 33.25, 31.81, 27.84, 25.42 , 23.73, 23.06, 18.01, -4.82;

^{19 F NMR (376 MHz, DMSO} -d 6): -136.21.

< Manufacturing example 31> 3-Amino-2- Of fluorophenol Produce

10 wt% Pd / C (100 mg) was added while stirring 2-fluoro-3-nitro phenol (2.0 g, 12.7 mmol) in methanol (50 mL) at room temperature. After stirring for 24 hours under a hydrogen gas, Pd / C was removed with a Celite filter. The filtrate was concentrated in vacuo to give 3-amino-2-fluorophenol (1.65 mg, 99%) as a dark solid.

^{_{1 H NMR (CD 3 OD,}} δ = 3.31 ppm, 400MHz): 6.69-6.65 (t, 1H), 6.34-6.25 (m, 2H);

¹³ C NMR (CD ₃ OD,? = 49.00 ppm, 100 MHz)? 146.13, 143.90, 141.59, 124.71, 109.49, 107.95;

^{19 F NMR (376 MHz, CD} 3 OD): -161.96.

< Manufacturing example 32> (S) - tert -Butyl 2- (2- Fluoro -3- Hydroxyphenylcarbamoyl ) Pirley Di-1-carboxylate < / RTI >

To a solution of 3-amino-2-fluorophenol (1.60 g, 12.6 mmol), N-Boc-L-proline (3.25 g, 15.1 mmol) and EDCI (2.11 g, 16.4 mmol) (30 mL) were stirred at room temperature for 16 hours. The mixture was poured into 1N aqueous HCl solution and extracted with methylene chloride. The organic layer was dried over magnesium sulfate and purified by column chromatography (hexane / ethyl acetate) to obtain (S) -tert-butyl 2- (2-fluoro-3- hydroxyphenylcarbamoyl) pyrrolidin- -Carboxylate (3.79 g, 93%) as a white solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 500MHz): 9.84 (s, 1H), 9.63 (s, 1H), 7.32-7.21 (m, 1H), 6.90-6.89 (d, 1H), 6.71 (D, IH), 4.42-4.33 (m, IH), 3.40 (s, IH), 3.36-3.32 , 1.40-1.31 (app br s, 9H);

¹³ C NMR (DMSO-d ₆ ,? = 39.52 ppm, 125 MHz): 171.90, 153.34, 145.34, 142.79, 127.08, 123.46, 114.31, 113.46, 78.66, 60.03, 46.67, 31.23, 28.02, 23.43;

^{19 F NMR (376 MHz, DMSO} -d 6): -147.91, -149.01.

< Manufacturing example 33> (S) - tert -Butyl 2- (2- Fluoro -3- ( Fluorosulfonyloxy ) Phenylcarbamoyl ) Pyrrolidine-1-carboxylate

(S) -2 - ((2-fluoro-3-hydroxyphenyl) carbamoyl) pyrrolidine-1-carboxylate (350 mg, 1.08 mmol) obtained in Preparation Example 32 and N, N -Diisopropylethylamine (244 [mu] L, 1.40 mmol) in methylene chloride (10 mL) was stirred at room temperature for 5 hours under sulfuryl fluoride. The mixture was poured into 1N aqueous HCl solution and extracted with methylene chloride. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Pyrrolidine-1-carboxylate (364 mg, 83%) was obtained as a white solid in the form of white Oil.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 10.18 (s, 1H), 8.04-7.95 (d, 1H), 7.54 (s, 1H), 7.39-7.35 (t, 1H), 4.45 3H), 1.40-1.31 (app s, 9H (m, IH), 3.36 (s, );

¹³ C NMR (DMSO-d ₆ ,? = 39.52 ppm, 100 MHz): 172.20, 153.08, 146.52, 144.00, 136.75, 128.31, 124.97, 118.45, 78.61, 59.87, 46.55, 31.04, 29.94, 27.86, 23.94, 23.30;

^{_{19 F NMR (DMSO-d 6}} , 376 MHz,): 39.69, -139.30.

< Manufacturing example 34> (S) - tert -Butyl 2- (3- ( tert - Butyl dimethylsilyloxy )-2- Fluorope Ylcarbamoyl) pyrrolidine-1-carboxylate < / RTI >

(S) -2 - ((2-fluoro-3-hydroxyphenyl) carbamoyl) pyrrolidine-1-carboxylate (300 mg, 0.925 mmol) obtained in Preparation 32, tert- butyl Methylene chloride (10 mL) of dimethylsilyl chloride (209 L, 1.39 mmol) and imidazole (189 mg, 2.77 mmol) was stirred at room temperature for 4 hours. The mixture was poured into water and extracted with methylene chloride. The organic layer was dried over magnesium sulfate and purified by column chromatography (hexane / ethyl acetate) to give (S) -tert-butyl 2- (3- (tert- butyldimethylsilyloxy) -2- Yl) pyrrolidine-1-carboxylate (194 mg, 48%) as a viscous white oil.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 9.71 (s, 1H), 7.54-7.38 (m, 1H), 7.02-6.98 (t, 1H), 6.78-6.74 (t, 1H) , 4.40-4.33 (m, 1H), 3.43-3.38 (m, 1H), 2.24-2.08 (m, 1H), 1.91-1.77 (m, 3H), 1.40-1.30 s, 9H), 0.17 (s, 6H);

^{_{13 C NMR (DMSO-d 6}} , δ = 39.52 ppm, 100 MHz): 171.82, 153.14, 142.85, 127.23, 123.61, 123.56, 117.48, 116.90, 78.51, 59.85, 46.54, 31.05, 27.88, 25.38, 23.32, 18.00, -4.84;

^{19 F NMR (376 MHz, DMSO} -d 6): -143.28.

< Manufacturing example 35> 2S, 2'S ) - die - tert (2-fluoro-3,1-phenylene)) bis (azaenediyl) bis (oxomethylene) dipyrrolidine -1-carboxylate

(S) -2 - ((3 - ((tert-butyldimethylsilyl) oxy) -2-fluorophenyl) carbamoyl) pyrrolidine- 1-carboxylate 146 (S) -2 - ((2-fluoro-3 - ((fluorosulfonyl) oxy) phenylcarbamoyl) pyrrolidine- (162 mg, 0.399 mmol) and DBU (10.0 [mu] L, 0.07 mmol) in methylene chloride (10 mL) were stirred at 50 [deg.] C for 24 hours. The mixture was poured into 1N aqueous HCl solution and extracted with methylene chloride. The organic layer was dried over magnesium sulfate and purified by column chromatography (hexane / ethyl acetate) to give (2S, 2'S) -di-tert- butyl 2,2 '- (3,3'-sulfonylbis Bis (oxymethylene) dipyrrolidine-1-carboxylate (231 mg, 98%) as a white solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 10.12 (s, 2H), 8.00-7.97 (t, 1H), 7.90-7.87 (t, 1H), 7.43-7.40 (t, 2H) (M, 2H), 3.39-3.39 (m, 2H), 3.30 (m, 2H), 2.32-2.11 (m, 2H), 1.91-1.76 6H), 1.40-1.29. (app br s, 18H);

¹³ C NMR (DMSO-d ₆ ,? = 39.52 ppm, 100 MHz): 172.17, 153.07, 137.06, 128.08, 124.67, 124.04, 118.49, 78.61, 59.83, 46.55, 31.04, 29.98, 27.90, 23.95, 23.31;

^{19 F NMR (376 MHz, DMSO} -d 6): -138.71.

< Manufacturing example 36> (S) - tert -Butyl 2- (3- (5 - ((S) -1- (tert-butoxycarbonyl) pyrrolidine-2-carboxamido) -2-fluorophenoxypropionyloxy) -2- Phenylcarbamoyl) pyrrolidine-1-carboxylate < / RTI >

pyrrolidine-1-carboxylate (118 mg, 0.269 mmol) was reacted with tert-butyl (S) -2 - ((3 - ((tert- butyldimethylsilyl) oxy) -4-fluorophenyl) (S) -2 - ((2-fluoro-3- ((fluorosulfonyl) oxy) phenylcarbamoyl) pyrrolidine- 1-carboxylate (109 mg, 0.269 mmol) and DBU (8.0 μL, 0.05 mmol) in methylene chloride (20 mL) were stirred at 50 ° C. for 24 hours. The mixture was poured into 1N aqueous HCl solution and extracted with methylene chloride. The organic layer was dried over magnesium sulfate and purified by column chromatography (hexane / ethyl acetate) to obtain (S) -tert-butyl 2- (3- (5 - ((S) -1- (tert- Pyrrolidine-1-carboxylate (77.8 mg, 41%) was obtained as a white solid < RTI ID = 0.0 & &Lt; / RTI >

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400 MHz): 10.33 (s, 1H), 10.11 (s, 1H), 8.12-7.90 (m, 2H), 7.61 (s, 1H), 7.54- 2H), 3.40 (s, 2H), 2.21 (m, 2H), 3.40 (s, s, 2H), 1.88-1.79 (m, 6H), 1.39-1.23 (app br s, 18H);

¹³ C NMR (DMSO-d ₆ ,? = 39.52 ppm, 100 MHz): 171.95, 153.61, 153.04, 149.87, 147.41, 137.09, 136.21, 128.05, 124.70, 124.01, 119.90, 117.92, 113.55, 78.61, 60.45, 46.56, 30.92, 30.12, 27.88, 23.99, 23.39;

^{19 F NMR (376 MHz, DMSO} -d 6): -135.48, -138.91.

< Manufacturing example 37> 2S, 2'S ) - die - tert -Butyl 2,2 '- (5,5' - (3,3'-sulfonylbis (oxy) bis (4-fluoro-3,1-phenylene) -Diiyl)) < / RTI > dipyrrolidine-1-carboxylate

(S) -2- (5- (3 - ((tert-butyldimethylsilyl) oxy) -4-fluorophenyl) -lH- imidazol-2-yl) pyrrolidine- (295 mg, 0.639 mmol), tert- butyl (S) -2- (5- (4-fluoro-3 - ((fluorosulfonyl) oxy) Methylene chloride (10 mL) of pyrrolidine-1-carboxylate (302 mg, 0.702 mmol) and DBU (220 L, 1.47 mmol) was stirred at 50 占 폚 for 24 hours. The mixture was poured into 1N aqueous HCl solution and extracted with methylene chloride. The organic layer was dried over magnesium sulfate and purified by column chromatography (hexane / ethyl acetate) to give (2S, 2'S) -di-tert-butyl 2,2 '- (5,5' Yl) dipyrrolidine-1-carboxylate (305 mg, 63%) was obtained in the same manner as in (1) %) As a white solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400 MHz): 12.01 (s, 2H), 7.92-7.91 (d, 2H), 7.82 (s, 2H), 7.58 (s, 2H), 7.52- 2H), 2.32-2.13 (m, 2H), 1.95-1.84 (t, 2H), 3.74-3.17 (m, 2H) 1.37-1.14 (app br s, 18H);

^{_{13 C NMR (DMSO-d 6}} , δ = 39.52 ppm, 100 MHz): 153.35, 152.22, 150.24, 136.98, 136.87, 133.21, 125.00, 118.39, 117.68, 113.11, 78.24, 55.22, 46.29, 33.23, 31.78, 27.83, 23.77, 23.07;

^{19 F NMR (376 MHz, DMSO} -d 6): -133.22.

< Manufacturing example (S) - tert - butyl 2- (5- (4- ( tert - Butyl dimethylsilyloxy ) Phenyl) -1H-imidazol-2-yl) pyrrolidine-1-carboxylate

pyrrolidine-1-carboxylate (333 mg, 1.01 mmol), tert-butyldimethyl (4-hydroxyphenyl) Methylene chloride (10 mL) of silyl chloride (228 mg, 1.52 mmol) and imidazole (110 mg, 1.62 mmol) was stirred at room temperature for 4 hours. The mixture was poured into water and extracted with methylene chloride. The organic layer was dried over magnesium sulfate and purified by column chromatography (hexane / ethyl acetate) to give (S) -tert-butyl 2- (5- (4- (tert- butyldimethylsilyloxy) phenyl) Yl) pyrrolidine-1-carboxylate (269 mg, 60%) as a viscous white oil.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 500MHz): 11.77 (s, 1H), 7.60-7.59 (d, 2H), 7.30 (s, 1H), 6.81-6.80 (d, 2H), 4.83 (M, 1H), 3.53-3.50 (m, 1H), 3.37-3.34 (m, 1H), 2.23-2.12 s, 9H), 0.95 (s, 9H), 0.18 (s, 6H);

³ C NMR (DMSO-d ₆ ,? = 39.52 ppm, 125 MHz): 153.70, 153.37, 139.36, 128.82, 125.44, 119.76, 78.12, 55.20, 46.25, 33.30, 31.76, 27.88, 25.57, 23.79, 23.05, 17.94, 3.21, -4.52.

< Manufacturing example (S) - tert -Butyl 2- (5- (3- (4- (2 - ((S) -1-tert-butoxycarbonylpyrrolidin-2-yl) -1H-imidazol- ) Phenyl) -1H-imidazol-2-yl) pyrrolidine-1-carboxylate

(S) -2- (5- (4 - ((tert-butyldimethylsilyl) oxy) phenyl) -lH- imidazol-2-yl) pyrrolidine- 1 -carboxylate (851 mg, (S) -2- (5- (3 - ((fluorosulfonyl) oxy) phenyl) -1 H-imidazol-2-yl) pyrrolidine- 1-carboxylate mg, 2.30 mmol) and DBU (631 [mu] L, 4.22 mmol) in methylene chloride (20 mL) were stirred at 50 [deg.] C for 24 hours. The mixture was poured into 1N aqueous HCl solution and extracted with methylene chloride. The organic layer was dried over magnesium sulfate and purified by column chromatography (hexane / ethyl acetate) and prep. LC to give (S) -tert-butyl 2- (5- (3- (4- (2 - ((S) -1-tert-butoxycarbonylpyrrolidin- Phenyl) -1H-imidazol-2-yl) pyrrolidine-1-carboxylate (721 mg, 52%) as a white solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 8.25-8.04 (m, 6H), 7.66-7.51 (d, 4H), 5.12 (s, 2H), 3.63 (s, 2H), 3.41 (s, 2H), 2.38 (s, 2H), 2.07 - 1.91 (m, 6H), 1.38 - 1.15. (app br s, 18H);

^{_{13 C NMR (DMSO-d 6}} , δ = 39.52 ppm, 100 MHz): 153.71, 152.45, 150.67, 150.56, 150.22, 149.56, 131.39, 127.37, 124.78, 122.07, 117.89, 116.19, 115.71, 79.19, 52.97, 46.45, 32.89, 31.98, 27.70, 23.92, 23.38.

< Manufacturing example 40> 2S, 2'S ) - die - tert - butyl 2,2 '- (5,5'- (4,4'-sulfonylbis (oxy) ratio (4-fluorophenyl) bis (1H-imidazol-5,2-diyl)) dipyrrolidine-1-carboxylate

tert- butyl (S) -2- (5- (4- hydroxy-phenyl) -1H- imidazol-2-yl) pyrrolidine-l-carboxylate (311 mg, 0.472 mmol), Cs 2 CO 3 ( 154 mg, 0.472 mmol) and 1,1'-sulfonyldiimidazole (85 mg, 0.429 mmol) were suspended in DMF (10 mL). The reaction mixture was heated to 60 DEG C and stirred for 12 hours. The mixture was filtered through a short silica column and evaporated in vacuo. The crude product was purified by column chromatography (hexane / ethyl acetate) to give (2S, 2'S) -di-tert- butyl 2,2 '- (5,5' - (4,4'-sulfonylbis 1-phenylene)) bis (1H-imidazol-5,2-diyl)) dipyrrolidine-1-carboxylate (254 mg, 82%) as a yellow solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 11.99 (s, 2H), 7.88-7.85 (d, 3H), 7.53 (s, 2H), 7.39-7.38 (d, 3H), 7.30 2H), 3.29-3.25 (m, 1 H), 4.01-3.98 (d, IH) , 2.22-2.14 (m, 2H), 2.05-1.93 (m, 2H), 1.85-1.71 (m, 4H), 1.39-1.15 (app br s, 18H);

¹³ C NMR (DMSO-d ₆ ,? = 39.52 ppm, 100 MHz): 174.64, 153.35, 147.86, 125.70, 121.14, 78.34, 59.58, 55.23, 46.36, 33.31, 31.01, 29.99, 28.03, 23.89,

< Example 1> Dimethyl ((1R, 1'R) - ((2S, 2'S) - ((( Sulfonylpis (4,1- Phenylene )) Bis (Azanediyl) bis (carbonyl)) bis (pyrrolidine-2,1-diyl)) bis (2-oxo-1-phenylethane-2,1-diyl)) dicarbamate

(S) -2 - ((4 - ((R) -1- (tert-butoxycarbonyl) pyrrolidine- 2- carboxamido) phenyl) sulfonyl) phenyl) carbamoyl) Pyrrolidine-1-carboxylate (172 mg, 0.268 mmol) was dissolved in trifluoroacetic acid / dichloromethane (1/1) mixed solution (4 mL) and stirred at room temperature for 30 minutes. The solvent was concentrated in vacuo and the concentrated reaction product, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI) (133 mg, 0.696 mmol), hydroxybenzotriazole hydrate (90.1 mg, 0.667 mmol) and (R) -2- (methoxycarbonylamino) -2-phenylacetic acid (134 mg, 0.642 mmol) obtained in Preparation Example 3 were added to N, N- Was added to dichloromethane (10 mL) of isopropylethylamine (233 mL, 1.28 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with 1N aqueous hydrochloric acid solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel flash column chromatography using dichloromethane: methanol as mobile phase to obtain the desired compound (111 mg, 50% yield) as a white solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 10.37 (s, 2H), 7.87-7.85 (d, 4H), 7.82-7.80 (d, 4H), 7.73-7.57 (q, 2H) 2H), 3.80-3.70 (m, 2H), 3.52 (s, 2H), 7.40-7.29 (m, 9H), 7.20-6.99 6H), 3.20-3.14 (q, 2H), 2.02-1.94 (m, 4H), 1.91-1.78 (m, 4H);

¹³ C NMR (DMSO-d ₆ ,? = 39.52 ppm, 100 MHz): 171.04, 168.34, 156.03, 143.36, 137.19, 135.31, 128.58, 127.99, 119.23, 60.68, 56.62, 51.63, 46.94, 29.17, 24.27.

< Example 2> Bis (4 - ((S) -1 - ((R) -2 - (( Methoxycarbonyl ) Amino) -2- Phenylacetyl ) Pyrrolidine -2-carboxamido) phenyl) sulfate

(S) -2 - ((4 - ((4- ((R) -1- (tert-butoxycarbonyl) pyrrolidine- 2- carboxamido) phenoxy) (50.0 mg, 0.0741 mmol) was dissolved in a mixed solution (2 mL) of trifluoroacetic acid / dichloromethane (1/1) , And the mixture was stirred at room temperature for 30 minutes. The solvent was concentrated in vacuo and the concentrated reaction product, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI) (64.5 mg, 0.193 mmol), hydroxybenzotriazole hydrate (26.0 mg, 0.193 mmol) and (R) -2- (methoxycarbonylamino) -2-phenylacetic acid (37.2 mg, 0.178 mmol) obtained in Preparative Example 3 were collectively treated with N, N-diisobutylaluminum Was added to dichloromethane (5 mL) of propylethylamine (64.5 mL, 0.371 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with 1N aqueous hydrochloric acid solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel flash column chromatography using dichloromethane: methanol as mobile phase to obtain the desired compound (37.6 mg, 59% yield) as a white solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 10.14 (s, 1H), 7.76-7.52 (m, 7H), 7.42-7.32 (m, 12H), 7.23-7.09 (m, 1H) 2H), 2.04-1.80 (m, 8H), 5.51-5.49 (d, 2H), 4.40-4.38 (d, 2H), 3.82 );

¹³ C NMR (DMSO-d ₆ ,? = 39.52 ppm, 100 MHz): 170.58, 168.16, 156.37, 144.93, 46.90, 29.30, 29.13, 24.72.

< Example Preparation of bis (4 - ((S) -1 - ((methoxycarbonyl) -D-valyl) pyrrolidine-2-carboxamido) phenyl)

(S) -2 - ((4 - ((4- ((R) -1- (tert-butoxycarbonyl) pyrrolidine- 2- carboxamido) phenoxy) (48.9 mg, 0.0725 mmol) was dissolved in a mixed solution (2 mL) of trifluoroacetic acid / dichloromethane (1/1) , And the mixture was stirred at room temperature for 30 minutes. The solvent was concentrated in vacuo and the concentrated reaction product, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI) (36.1 mg, 0.188 mmol), hydroxybenzotriazole hydrate (25.5 mg, 0.188 mmol) and (R) -2- (methoxycarbonylamino) -3-methylbutanoic acid (30.5 mg, 0.174 mmol) obtained in Preparation Example 1 were collectively treated with N, N-di Was added to dichloromethane (5 mL) of isopropylethylamine (63.1 mL, 0.362 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with 1N aqueous hydrochloric acid solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel flash column chromatography using dichloromethane: methanol as mobile phase to give the desired compound (58.0 mg, 86% yield) as a white solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 10.00 (s, 2H), 7.74-7.72 (d, 4H), 7.42-7.34 (q, 6H), 4.42-4.40 (d, 2H) 2H), 3.79 (s, 2H), 3.63-3.60 (d, 2H), 3.54 (s, 6H), 2.13-1.91 (m, 10H), 0.89-0.78 12H);

^{_{13 C NMR (DMSO-d 6}} , δ = 39.52 ppm, 100 MHz): 170.68, 170.24, 156.92, 144.95, 138.55, 121.51, 120.49, 60.26, 58.00, 54.92, 51.57, 47.10, 29.73, 29.38, 24.33, 19.06, 18.31.

< Example 4> bis (3 - ((S) -1 - ((R) -2 - ((methoxycarbonyl) amino) -2-phenylacetyl) pyrrolidine-2-carboxamido) phenyl) Produce

(S) -2 - ((3 - ((3- ((R) -1- (tert-butoxycarbonyl) pyrrolidine- 2- carboxamido) phenoxy) (192 mg, 0.285 mmol) was dissolved in a mixed solution (2 mL) of trifluoroacetic acid / dichloromethane (1/1) , And the mixture was stirred at room temperature for 30 minutes. The solvent was concentrated in vacuo and the concentrated reaction product, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI) (142 mg, 0.741 mmol), hydroxybenzotriazole hydrate 0.741 mmol) and (R) -2- (methoxycarbonylamino) -2-phenylacetic acid (143 mg, 0.684 mmol) obtained in Preparative Example 3 were added to N, N- Was added to dichloromethane (5 mL) of isopropylethylamine (248 mL, 1.42 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with 1N aqueous hydrochloric acid solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel flash column chromatography using dichloromethane: methanol as mobile phase to give the desired compound (13.2 mg, 5.4% yield) as a white solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 10.25 (s, 1H), 7.88-7.85 (d, 3H), 7.72-7.70 (d, 2H), 7.63-7.61 (d, 2H) , 7.50-7.47 (t, 2H), 7.40-7.30 (m, 8H), 7.16-7.10 (q, 2H), 5.50-5.48 (d, 2H), 4.38-4.36 d, 2H), 3.52 (s, 6H), 3.20-3.17 (m, 2H), 2.02-1.79 (m, 8H);

¹³ C NMR (DMSO-d ₆ ,? = 39.52 ppm, 100 MHz): 170.82, 168.37, 149.87, 140.74, 137.19, 130.68, 128.60, 128.36, 128.02, 118.36, 115.47, 111.33, 60.71, 56.67, 51.63, 29.22, 24.30.

< Example 5> bis (4- (2 - ((S) -1 - ((R) -2- Methoxycarbonylamino ) -3- Methylbutanoyl ) Pyrrolidin-2-yl) -1H- Imidazole -5 days) Phenyl ) Sulphate Produce

Synthesis of di- tert -butyl 2,2 '- (((sulphonylbis (oxy)) bis (4,1-phenylene)) bis (1H- (Pyrrolidine-1-carboxylate) (89.5 mg, 0.124 mmol) was dissolved in a trifluoroacetic acid / dichloromethane (1/1) mixed solution (2 mL), and the mixture was stirred at room temperature for 30 minutes . The solvent was concentrated in vacuo and the concentrated reaction product, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI) (61.9 mg, 0.323 mmol), hydroxybenzotriazole hydrate (43.6 mg, 0.323 mmol) and (R) -2- (methoxycarbonylamino) -3-methylbutanoic acid (52.2 mg, 0.298 mmol) obtained in Preparation Example 1 were collectively treated with N, N-di Was added to dichloromethane (5 mL) of isopropyl ethylamine (108 μL, 0.142 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with 1N aqueous hydrochloric acid solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel flash column chromatography using dichloromethane: methanol as mobile phase to give the desired compound (76.9 mg, 74% yield) as a white solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 8.09 (s, 2H), 7.96-7.94 (d, 4H), 7.65-7.62 (d, 3H), 7.58-7.52 (m, 1H) 2H), 3.53 (s, 2H), 7.25-7.23 (d, 2H), 5.19-5.16 (q, 2H), 4.19-4.15 (m, 2H), 3.91-3.83 6H), 2.38-2.36 (t, 2H), 2.08-1.94 (m, 8H), 0.90-0.85 (q, 10H), 0.71-0.70 (d, 1H), 0.35-0.34 (d, 1H);

¹³ C NMR (DMSO-d ₆ ,? = 39.52 ppm, 100 MHz): 170.80, 156.87, 149.61, 149.58, 127.33, 122.04, 115.87, 57.82, 53.19, 51.59, 47.02, 30.90, 29.71, 24.35, 19.29, 17.87.

< Example 6> bis (4- (2 - ((S) -1 - ((R) -2- Methoxycarbonylamino )-2- Phenylacetyl ) blood Yl) -1H-imidazol-5-yl) phenyl) sulfate

Synthesis of di- tert -butyl 2,2 '- (((sulphonylbis (oxy)) bis (4,1-phenylene)) bis (1H- (105 mg, 0.145 mmol) was dissolved in a mixed solution (6 mL) of trifluoroacetic acid / dichloromethane (1/1), and the mixture was stirred at room temperature for 30 minutes . The solvent was concentrated in vacuo and the concentrated reaction product, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI) (72.6 mg, 0.349 mmol), hydroxybenzotriazole hydrate (51.2 mg, 0.379 mmol) and (R) -2- (methoxycarbonylamino) -2-phenylacetic acid (75.2 mg, 0.350 mmol) obtained in Preparative Example 3 were added to N, N- Was added to dichloromethane (5 mL) of isopropylethylamine (127 μL, 0.728 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with 1N aqueous hydrochloric acid solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel flash column chromatography using dichloromethane: methanol as mobile phase to give the desired compound (56.1 mg, 43% yield) as a white solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400 MHz): 8.14 (s, 1H), 8.07 (s, 1H), 7.98-7.96 (d, 2H), 7.92-7.85 (q, 2H), 1H), 7.80-7.78 (d, 1H), 7.71-7.60 (m, 5H), 7.39 (s, 4H), 7.35-7.34 2H), 2.38-2.23 (m, 2H), 3.51 (s, 6H) ), 2.09-1.86 (m, 6H);

^{_{13 C NMR (DMSO-d 6}} , δ = 39.52 ppm, 100 MHz): 168.99, 158.56, 156.34, 149.72, 149.43, 136.85, 131.43, 128.68, 128.32, 128.12, 127.45, 127.25, 122.10, 115.93, 57.00, 53.48, 51.62, 47.00, 30.81, 24.14.

< Example Preparation of bis (3 - ((S) -1 - ((methoxycarbonyl) -D-valyl) pyrrolidine-2-carboxamido) phenyl)

(S) -2 - ((3 - ((3- ((R) -1- (tert-butoxycarbonyl) pyrrolidine- 2- carboxamido) phenoxy) (66.0 mg, 0.0978 mmol) was dissolved in a mixed solution (2 mL) of trifluoroacetic acid / dichloromethane (1/1) , And the mixture was stirred at room temperature for 30 minutes. The solvent was concentrated in vacuo and the concentrated reaction product, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI) (48.8 mg, 0.254 mmol), hydroxybenzotriazole hydrate (34.4 mg, 0.254 mmol) and the (R) -2- (methoxycarbonylamino) -3-methylbutanoic acid (41.1 mg, 0.235 mmol) obtained in Preparation Example 1 were collectively treated with N, Was added to dichloromethane (5 mL) of isopropyl ethylamine (85.2 mL, 0.489 mmol) and stirred overnight at room temperature. The reaction mixture was diluted with 1N aqueous hydrochloric acid solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel flash column chromatography using dichloromethane: methanol as mobile phase to give the desired compound (42.5 mg, 55% yield) as a white solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 10.13 (s, 2H), 7.87 (s, 2H), 7.62-7.60 (d, 2H), 7.49-7.45 (t, 3H), 7.36 2H), 3.62-3.60 (d, 2H), 3.32-3.60 (d, 2H) , 3.54 (s, 6H), 2.14-1.94 (m, 10H), 0.88 (app br s, 12H);

^{_{13 C NMR (DMSO-d 6}} , δ = 39.52 ppm, 100 MHz): 170.97, 170.23, 156.92, 149.86, 140.73, 130.61, 118.27, 115.37, 111.26, 60.32, 57.98, 51.54, 47.10, 29.76, 24.37, 19.07, 18.28.

< Example Pyrrolidin-2-yl) -1H-imidazole (hereinafter referred to as " -5-yl) phenyl) sulfate

Synthesis of di- tert -butyl 2,2 '- (((sulphonylbis (oxy)) bis (4,1-phenylene)) bis (1H- Bis (pyrrolidine-1-carboxylate) (134 mg, 0.185 mmol) was dissolved in a trifluoroacetic acid / dichloromethane (1/1) mixed solution (6 mL), and the mixture was stirred at room temperature for 30 minutes . The solvent was concentrated in vacuo and the concentrated reaction product, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI) (62.3 mg, 0.482 mmol), hydroxybenzotriazole hydrate (65.2 mg, 0.482 mmol) and (R) -2- (methoxycarbonylamino) -3-methylbutanoic acid (78.0 mg, 0.445 mmol) obtained in Preparation Example 1 were collectively treated with N, N-di Was added to dichloromethane (10 mL) of isopropylethylamine (240 μL, 0.927 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with 1N aqueous hydrochloric acid solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel flash column chromatography using dichloromethane: methanol as mobile phase to obtain the desired compound (119 mg, 77% yield) as a white solid.

^{_{1 H NMR (DMSO-d 6}} , δ 2.5 ppm, 500MHz): 12.20 (app br s, 2H), 7.98-7.96 (d, 1H), 7.82-7.78 (m, 2H), 7.75 (s, 1H), 2H), 7.42-7.38 (m, 1H), 7.35-7.28 (m, 1H), 7.23-7.21 (m, 2H) ), 5.62-5.61 (d, IH), 5.06-5.04 (d, IH), 4.12-4.09 (t, IH), 3.99-3.95 (t, IH), 3.86-3.83 (m, 3H), 1.83 (m, 2H), 1.43-1.40 (m, 2H) 1H), 1.66-1.61 (q, 1H), 0.89-0.88 (d, 8H), 0.67-0.66 (d, 2H), 0.27-0.25 (d, 3H).

¹³ C NMR (DMSO-d ₆ , δ 39.52 ppm, 125 MHz): 173.34, 171.22, 170.26, 157.00, 150.40, 126.87, 124.28, 119.02, 109.76, 59.52, 58.07, 54.66, 51.40, 29.54, 19.19,

< Example 9> bis (3- (2 - ((S) -1 - ((R) -2- Methoxycarbonylamino ) -2-phenylacetyl) pyrrolidin-2-yl) -1H- Imidazole -5 days) Phenyl ) Sulphate Produce

(2,2 '- (((sulfonylbis (oxy)) bis (3,1-phenylene)) bis (1H-imidazol-5,2-diyl)) obtained in Preparation Example 25) (2S, 2'S) -bis (pyrrolidine-1-carboxylate) (185 mg, 0.256 mmol) was dissolved in a trifluoroacetic acid / dichloromethane (1/1) mixed solution (6 mL) And the mixture was stirred at room temperature for 30 minutes. The solvent was concentrated in vacuo and the concentrated reaction product, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI) (128 mg, 0.667 mmol), hydroxybenzotriazole hydrate (90.1 mg, 0.667 mmol) and (R) -2- (methoxycarbonylamino) -2-phenylacetic acid (129 mg, 0.615 mmol) obtained in Preparation Example 3 were added to N, N- Was added to dichloromethane (10 mL) of diisopropylethylamine (223 mL, 1.28 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with 1N aqueous hydrochloric acid solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel flash column chromatography using dichloromethane: methanol as mobile phase to obtain the desired compound (97.2 mg, 67% yield) as a yellow solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 12.05 (br s, 1H), 7.96 (s, 1H), 7.94-7.64 (m, 5H), 7.50 (s, 1H), 7.39- 2H), 5.15-5.05 (d, 2H), 4.18-3.67 (m, 2H), 3.55 (s, 6H), 7.25 (m, 13H), 7.00-6.93 3.43-3.41 (t, 1H), 3.11 (s, 1H), 1.98-1.72 (m, 8H);

^{_{13 C NMR (DMSO-d 6}} , δ = 39.52 ppm, 100 MHz): 173.42, 172.13, 168.36, 155.99, 150.45, 149.61, 137.22, 130.56, 128.40, 127.69, 124.24, 123.55, 119.01, 116.33, 109.82, 72.32, 60.30, 58.13, 56.98, 55.24, 51.62, 46.67, 31.12, 29.22, 24.02.

< Example 10> Bis (5 - ((S) -1 - ((R) -2 - (( Methoxycarbonyl ) Amino) -2- Phenylacetyl ) Pyrrolidine Carboxamido) -2-methylphenyl) Sulphate Produce

(S) -2 - ((3 - ((5 - ((R) -1- (tert- butoxycarbonyl) pyrrolidine- 2- carboxamido) -2-methylphenoxy (113 mg, 0.161 mmol) was dissolved in a mixed solution (4 mL) of trifluoroacetic acid / dichloromethane (1/1) , And the mixture was stirred at room temperature for 30 minutes. The solvent was concentrated in vacuo and the concentrated reaction product, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI) (78.1 mg, 0.418 mmol), hydroxybenzotriazole hydrate (90.1 mg, 0.667 mmol) and (R) -2- (methoxycarbonylamino) -2-phenylacetic acid (80.7 mg, 0.386 mmol) obtained in Preparative Example 3 were added to N, N- Was added to dichloromethane (10 mL) of isopropylethylamine (137 mL, 0.804 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with 1N aqueous hydrochloric acid solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel flash column chromatography using dichloromethane: methanol as mobile phase to obtain the desired compound (105 mg, 74% yield) as a white solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 10.36-10.19 (d, 2H), 7.94-7.89 (d, 2H), 7.75-7.67 (q, 2H), 7.58 (s, 2H) 2H), 3.53 (s, 2H), 4.63 (d, 2H) 6H), 3.18-3.09 (d, 2H), 2.22 (s, 6H), 1.99-1.78 (m, 8H);

^{_{13 C NMR (DMSO-d 6}} , δ = 39.52 ppm, 100 MHz): 170.59, 168.36, 156.07, 148.28, 138.47, 136.85, 132.01, 128.61, 128.05, 124.63, 118.45, 111.44, 60.69, 56.69, 51.64, 46.98, 29.26, 24.31, 15.26.

< Example 11> Bis (5 - ((S) -1 - (( Methoxycarbonyl ) -D-valyl) Pyrrolidine -2- Carbox ami -2-methylphenyl) sulfate

(S) -2 - ((3 - ((5 - ((R) -1- (tert- butoxycarbonyl) pyrrolidine- 2- carboxamido) -2-methylphenoxy (106 mg, 0.147 mmol) was dissolved in a mixed solution (4 mL) of trifluoroacetic acid / dichloromethane (1/1) , And the mixture was stirred at room temperature for 30 minutes. The solvent was concentrated in vacuo and the concentrated reaction product, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI) (73.0 mg, 0.381 mmol), hydroxybenzotriazole hydrate (90.1 mg, 0.667 mmol) and (R) -2- (methoxycarbonylamino) -3-methylbutanoic acid (61.6 mg, 0.352 mmol) obtained in Preparation Example 1 were collectively treated with N, N-di Was added to dichloromethane (10 mL) of isopropylethylamine (128 mL, 0.732 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with 1N aqueous hydrochloric acid solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel flash column chromatography using dichloromethane: methanol as mobile phase to give the desired compound (63.6 mg, 53% yield) as a white solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 10.03 (s, 2H), 7.88 (s, 2H), 7.54-7.52 (d, 2H), 7.36-7.32 (t, 4H), 4.38 2H), 3.51 (s, 3H), 2.39 (s, 3H), 2.36 (s, (m, 10H), 0.87-0.75 (app br s, 12H);

^{_{13 C NMR (DMSO-d 6}} , δ = 39.52 ppm, 100 MHz): 170.71, 170.17, 156.90, 148.21, 138.42, 131.96, 124.52, 118.32, 111.29, 60.25, 57.95, 51.54, 47.09, 29.77, 24.36, 19.08, 18.29, 15.22.

< Example 12> 3 - ((S) -1 - ((R) -2 - ( Methoxycarbonyl ) Amino) -2- Phenylacetyl ) Pyrrolidine Carboxamido) phenyl (4 - ((S) -1 - ((R) -2 - ( Methoxycarbonyl ) Amino) -2- Phenylacetyl ) Pyrrolidine-2-carboxamido) phenyl) sulfate

Butyl (R) -2 - ((3 - ((4 - ((S) -1- (tert-butoxycarbonyl) pyrrolidine- 2- carboxamido) (102 mg, 0.151 mmol) was added to a mixed solution (6 mL) of trifluoroacetic acid / dichloromethane (1/1) to give the title compound After dissolution, the mixture was stirred at room temperature for 30 minutes. The solvent was concentrated in vacuo and the concentrated reaction product, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI) (75.2 mg, 0.392 mmol), hydroxybenzotriazole hydrate (53.0 mg, 0.392 mmol) and (R) -2- (methoxycarbonylamino) -2-phenylacetic acid (77.9 mg, 0.362 mmol) obtained in Preparative Example 3 were added to N, N- Was added to dichloromethane (10 mL) of isopropylethylamine (131 mL, 0.754 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with 1N aqueous hydrochloric acid solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel flash column chromatography using dichloromethane: methanol as mobile phase to give the desired compound (106.7 mg, 83% yield) as a white solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 10.51-10.16 (m, 2H), 7.93-7.87 (t, 1H), 7.78-7.77 (d, 2H), 7.74-7.72 (t, 2H), 7.67-7.54 (m, 2H), 7.50-7.47 (t, 1H), 7.44-7. 41 (m, 5H), 7.38-7.35 (m, 2H), 4.59-4.37 (m, 2H), 3.85-3.81 (q, 1H), 3.72-3.62 3.53 (s, 6H), 3.22-3.10 (m, 2H), 2.05-1.77 (m, 8H);

^{_{13 C NMR (DMSO-d 6}} , δ = 39.52 ppm, 100 MHz): 170.59, 168.40, 156.09, 149.89, 145.03, 140.74, 138.70, 137.21, 130.65, 128.62, 128.06, 121.61, 120.65, 118.31, 115.50, 111.35, 60.71, 56.71, 51.65, 46.98, 29.25, 24.30.

< Example 13> 3 - ((S) -1 - (( Methoxycarbonyl ) -D-valyl) Pyrrolidine -2- Carbox amido ) Phenyl (4 - ((S) -1 - (( Methoxycarbonyl ) -D-valyl) Pyrrolidine -2- Carbox amido ) Phenyl) Sulphate Produce

Butyl (R) -2 - ((3 - ((4 - ((S) -1- (tert-butoxycarbonyl) pyrrolidine- 2- carboxamido) (56.3 mg, 0.0834 mmol) was added to a mixed solution (2 mL) of trifluoroacetic acid / dichloromethane (1/1) to give the title compound After dissolution, the mixture was stirred at room temperature for 30 minutes. The solvent was concentrated in vacuo and the concentrated reaction product, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI) (72.7 mg, 0.217 mmol), hydroxybenzotriazole hydrate (29.3 mg, 0.217 mmol) and (R) -2- (methoxycarbonylamino) -3-methylbutanoic acid (35.1 mg, 0.200 mmol) obtained in Preparation Example 1 were collectively treated with N, N-di Was added to dichloromethane (5 mL) of isopropylethylamine (72.7 mL, 0.417 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with 1N aqueous hydrochloric acid solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel flash column chromatography using dichloromethane: methanol as mobile phase to give the desired compound (46.7 mg, 71% yield) as a white solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 10.64-10.02 (q, 2H), 7.87 (s, 1H), 7.76-7.73 (d, 2H), 7.61-7.59 (d, 2H) 2H), 3.79 (s, 2H), 3.64-3.58 (q, 2H) 2H), 3.55 (s, 6H), 3.48-3.46 (m, 1H), 2.16-2.08 (m, 2H), 2.04-1.92 (m, 8H), 0.88-0.77 (app br s, 12H);

^{_{13 C NMR (DMSO-d 6}} , δ = 39.52 ppm, 100 MHz): 171.01, 170.71, 170.24, 156.92, 149.85, 144.94, 140.71, 138.67, 130.61, 121.57, 120.50, 118.19, 115.42, 111.22, 60.32, 60.27, 58.01, 51.56, 47.11, 29.76, 29.41, 29.37, 24.39, 24.35, 19.09, 18.32.

< Example 14> Bis (2- Fluoro -5 - ((S) -1 - ((R) -2 - (( Methoxycarbonyl ) Amino) -2- Pe Yl) acetyl) pyrrolidine-2-carboxamido) phenyl) sulfate

(S) -2 - ((3 - ((5 - ((R) -1- (tert- butoxycarbonyl) pyrrolidine- 2- carboxamido) -2-fluorophenoxy (97.7 mg, 0.137 mmol) was dissolved in a mixed solution of trifluoroacetic acid / dichloromethane (1/1) 4 mL), and the mixture was stirred at room temperature for 30 minutes. The solvent was concentrated in vacuo and the concentrated reaction product, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI) (68.5 mg, 0.357 mmol), hydroxybenzotriazole hydrate (90.1 mg, 0.667 mmol) and (R) -2- (methoxycarbonylamino) -2-phenylacetic acid (69.0 mg, 0.330 mmol) obtained in Preparation Example 3 were added to N, N- Was added to dichloromethane (10 mL) of isopropylethylamine (120 mL, 0.687 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with 1N aqueous hydrochloric acid solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel flash column chromatography using dichloromethane: methanol as mobile phase to give the desired compound (63.4 mg, 52% yield) as a white solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 10.28 (s, 2H), 8.08-8.06 (t, 2H), 7.74-7.72 (d, 2H), 7.65 (s, 2H), 7.55 2H), 7.42-7.30 (m, 9H), 7.06-7.04 (t, 1H), 5.52-5.50 (d, 2H), 4.37-4.35 ), 3.53 (s, 6H), 3.20-3.18 (d, 2H), 2.04-1.77 (m, 8H);

^{_{13 C NMR (DMSO-d 6}} , δ = 39.52 ppm, 100 MHz): 170.71, 168.39, 156.07, 149.70, 147.73, 137.20, 136.26, 128.59, 128.03, 119.96, 117.92, 113.47, 60.69, 56.67, 51.63, 46.96, 29.21, 24.31;

^{_{19 F NMR (DMSO-d 6}} , 470 MHz): -135.20.

(2,2 '- (((sulfonylbis (oxy)) bis (3,1-phenylene)) bis (1H-imidazol-5,2-diyl)) obtained in Preparation Example 25) (2S, 2'S) -bis (pyrrolidine-1-carboxylate) (117 mg, 0.163 mmol) was dissolved in a trifluoroacetic acid / dichloromethane (1/1) mixed solution (6 mL) And the mixture was stirred at room temperature for 30 minutes. The solvent was concentrated in vacuo and the concentrated reaction product, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI) (81.1 mg, 0.423 mmol), hydroxybenzotriazole hydrate (90.1 mg, 0.667 mmol) and (S) -2- (methoxycarbonylamino) -3-methylbutanoic acid (68.4 mg, 0.391 mmol) obtained in Preparation Example 2 were dissolved in N, N- Was added to dichloromethane (10 mL) of isopropylethylamine (142 mL, 0.814 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with 1N aqueous hydrochloric acid solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel flash column chromatography using dichloromethane: methanol as mobile phase to give the desired compound (60.8 mg, 44% yield) as a yellow solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 11.98 (br s, 1H), 7.98-7.96 (d, 1H), 7.77-7.75 (d, 3H), 7.71-7.69 (d, 1H ), 7.59 (s, IH), 7.53-7.45 (q, 3H), 7.42-7.38 (t, IH), 7.28-7.26 ), 4.05-4.01 (t, 2H), 3.86-3.76 (m, 4H), 3.53 (s, 6H), 2.12-2.07 (m, 4H), 1.94-1.87 (m, 6H), 0.91-0.80 br s, 12H);

¹³ C NMR (DMSO-d ₆ ,? = 39.52 ppm, 125 MHz): 170.39, 156.79, 150.38, 149.79, 131.10, 129.85, 127.81, 126.60, 123.92, 118.76, 116.80, 110.28, 57.71, 57.23, 54.72, 53.63, 51.27 , 29.93.

< Example 16> Bis (2- Fluoro -5 - ((S) -1 - (( Methoxycarbonyl ) -D-valyl) Pyrrolidine -2-carboxamido) phenyl) sulfate

(S) -2 - ((3 - ((5 - ((R) -1- (tert- butoxycarbonyl) pyrrolidine- 2- carboxamido) -2-fluorophenoxy Pyrrolidine-1-carboxylate (83.7 mg, 0.118 mmol) was dissolved in a mixture of trifluoroacetic acid / dichloromethane (1/1) 4 mL), and the mixture was stirred at room temperature for 30 minutes. The solvent was concentrated in vacuo and the concentrated reaction product, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI) (58.7 mg, 0.306 mmol), hydroxybenzotriazole hydrate (90.1 mg, 0.667 mmol) and (R) -2- (methoxycarbonylamino) -3-methylbutanoic acid (49.5 mg, 0.283 mmol) obtained in Preparation Example 1 were collectively treated with N, N-di Was added to dichloromethane of isopropyl ethylamine (103 mL, 0.589 mmol) and stirred overnight. The reaction mixture was diluted with 1N aqueous hydrochloric acid solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel flash column chromatography using dichloromethane: methanol as mobile phase to give the desired compound (77.7 mg, 80% yield) as a white solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 500MHz): 10.15 (s, 2H), 8.04 (s, 2H), 7.63-7.61 (d, 2H), 7.52-7.48 (t, 2H), 7.36 2H), 3.63-3.54 (m, 2H), 3.53 (s, 6H) , 2.15-2.08 (m, 2H), 2.08-1.84 (m, 8H), 0.87-0.76 (app br s, 12H);

¹³ C NMR (DMSO-d ₆ ,? = 39.52 ppm, 125 MHz): 170.87, 170.22, 156.93, 149.64, 147.66, 136.25, 120.42, 119.35, 117.33, 113.56, 113.09, 60.63, 59.92, 57.96, 51.42, 29.95, , 19.09, 18.29;

^{_{19 F NMR (DMSO-d 6}} , 376 MHz): -135.35.

< Example 17> Bis (3 - ((S) -1 - ((R) -2 - (( Methoxycarbonyl ) Amino) -2- Phenylacetyl ) Pyrrolidine -2-carboxamido) -2-methylphenyl) sulfate

Pyrrolidine) -2-carboxamido) -2-methylphenyl 3- ((R) -1 - ((R) -2 - ((methoxycarbonyl) amino) ((R) -2 - ((methoxycarbonyl) amino) -2-phenylacetyl) pyrrolidine-2-carboxamido) , 0.117 mmol) was dissolved in a trifluoroacetic acid / dichloromethane (1/1) mixed solution (4 mL), and the mixture was stirred at room temperature for 30 minutes. The solvent was concentrated in vacuo and the concentrated reaction product, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI) (39.3 mg, 0.304 mmol), hydroxybenzotriazole hydrate (41.0 mg, 0.304 mmol) and (R) -2- (methoxycarbonylamino) -2-phenylacetic acid (58.7 mg, 0.280 mmol) obtained in Preparation Example 3 were collectively treated with N, N-di Was added to dichloromethane (10 mL) of isopropylethylamine (151 L, 0.584 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with 1N aqueous hydrochloric acid solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel flash column chromatography using dichloromethane: methanol as mobile phase to give the desired compound (84.5 mg, 85% yield) as a white solid.

^{_{1 H NMR (DMSO-d 6}} , δ 2.5 ppm, 400MHz): 9.73-9.56 (d, 2H), 7.76-7.58 (m, 2H), 7.48-7.21 (m, 15H), 7.12-6.67 (m, 1H ), 5.52-5.43 (m, 2H), 4.65-4.47 (m, 2H), 3.85 (s, 1H), 3.75-3.62 , 2H), 2.16 (s, 6H), 2.00 - 1.73 (m, 8H)

¹³ C NMR (DMSO-d ₆ ,? 39.52 ppm, 100 MHz): 170.42, 168.79, 156.10, 148.60, 138.23, 137.08, 128.63, 128.08, 126.83, 126.04, 125.26, 118.25, 60.56, 56.82, 51.57, , 24.33, 11.27.

< Example 18> bis (3- (2 - ((S) -1 - ((R) -2- Methoxycarbonylamino ) -3,3-di Methylbutanoyl ) Pyrrolidine Yl) -1H- Imidazole -5 days) Phenyl ) Sulphate Produce

Synthesis of di- tert -butyl 2,2 '- (((sulphonylbis (oxy)) bis (4,1-phenylene)) bis (1H- (Pyrrolidine-1-carboxylate) (50 mg, 0.0694 mmol) was dissolved in a trifluoroacetic acid / dichloromethane (1/1) mixed solution (6 mL), and the mixture was stirred at room temperature for 30 minutes . The solvent was concentrated in vacuo and the concentrated reaction product, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI) (34.6 mg, 0.180 mmol), hydroxybenzotriazole hydrate (24.4 mg, 0.667 mmol) and (S) -2- (methoxycarbonylamino) -3,3-dimethylbutanoic acid (31.5 mg, 0.166 mmol) were collectively treated with N, N-diisopropylethyl Amine (60.4 L, 0.347 mmol) in dichloromethane (10 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with 1N aqueous hydrochloric acid solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel flash column chromatography using dichloromethane: methanol as mobile phase to give the desired compound (43.8 mg, 73% yield) as a white solid.

¹ H NMR (DMSO-d ₆ , 隆 2.5 ppm, 400MHz): 8.07-7.83 (m, 1H), 7.78-7.71 (m, 4H), 7.66-7.63 (t, 1H), 7.57-7.40 ), 7.29-7.21 (m, 2H), 7.08-7.06 (d, 1H), 5.42-5.05 (m, 2H), 4.21-4.19 (d, 2H), 3.81-3.68 , 6H), 2.18-2.08 (m, 3H), 2.02-1.66 (m, 5H), 0.94-0.88 (app br s,

¹³ C NMR (DMSO-d ₆ ,? 39.52 ppm, 125 MHz): 172.72, 169.67, 156.85, 150.38, 130.54,128.62,127.37,125.07,124.52,123.52,119.62,119.14,116.42,109.89,83.42,62.76,59.16, 53.84, 52.52, 51.49, 47.52, 34.60, 30.87, 26.25, 24.38, 16.48.

< Example 19> Bis (4- (2 - ((S) -1 - ((S) -2- ( Methoxycarbonylamino ) -3- Methylbutanoyl ) Pyrrolidin-2-yl) -1H-imidazol-5-yl) phenyl) Sulphate Produce

(2S, 2 ' S) di-tert-butyl 2,2 '- (((sulfonylbis (oxy) Trifluoroacetic acid (3 mL) / methylene chloride (3 mL) of bis (pyrrolidine-1-carboxylate) (171 mg, 0.237 mmol) was stirred at room temperature for 30 minutes. The volatiles were removed in vacuo and EDCI (118 mg, 0.615 mmol), hydroxybenzotriazole hydrate (83.1 mg, 0.615 mmol) and (S) -2- (methoxycarbonylamino Was added methylene chloride (5 mL) of N, N-diisopropylethylamine (206 [mu] L, 1.18 mmol) over a period of 4 minutes to the mixture of the above reaction (99.4 mg, 0.568 mmol) The mixture was stirred overnight at room temperature. The mixture was poured into 1N aqueous HCl solution and extracted with methylene chloride. The organic layer was dried over magnesium sulfate and purified by column chromatography (methylene chloride / methanol) to obtain the desired compound (25.0 mg, 13%) as a white solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 11.88 (s, 2H), 7.88-7.81 (m, 4H), 7.52 (s, 2H), 7.39-7.37 (d, 4H), 7.29 2H), 4.08-3.99 (m, 2H), 3.80-3.74 (m, 4H), 3.54 (s, 6H), 2.14 (s, 2H), 1.99-1.91 (m, 6H), 1.86-1.76 (m, 2H), 0.89-0.83 (q, 12H);

^{_{13 C NMR (DMSO-d 6}} , δ = 39.52 ppm, 100 MHz): 173.49, 170.41, 170.24, 156.82, 147.85, 125.65, 121.17, 59.24, 58.01, 54.18, 51.46, 46.84, 30.93, 29.85, 24.27, 18.95, 18.51.

< Example 20> 3- (2 - ((S) -1 - ((S) -2- ( Methoxycarbonylamino ) -3- Methylbutanoyl ) Pyrrolidine Yl) -1H- Imidazole -5 days) Phenyl 4- (2 - ((S) -1 - ((S) -2- ( Methoxycarbonylamino ) -3-methylbutanoyl) Pyrrolidine Yl) -1H- Imidazole -5 days) Phenyl Sulphate Produce

(S) -2- (5- (3 - ((4- (2 - ((S) -1- (tert- butoxycarbonyl) pyrrolidin- (177.0 mg, 0.246 mmol) in trifluoroacetic acid (3 mL) was added to a solution of 3-bromo-3- mL) / methylene chloride (3 mL) was stirred at room temperature for 30 minutes. The volatiles were removed in vacuo and treated with EDCI (122 mg, 0.639 mmol), hydroxybenzotriazole hydrate (86.3 mg, 0.639 mmol), (S) -2- (methoxycarbonylamino Was added methylene chloride (10 mL) of N, N-diisopropylethylamine (214 [mu] L, 1.23 mmol) over 4 minutes to a mixture of 3- The reaction mixture was stirred overnight at room temperature. The mixture was poured into 1N aqueous HCl solution and extracted with methylene chloride. The organic layer was dried over magnesium sulfate and purified by column chromatography (methylene chloride / methanol) to obtain the desired compound (110 mg, 54%) as a yellow solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 11.92-11.86 (d, 2H), 7.85-7.83 (d, 2H), 7.76-7.73 (m, 2H), 7.61 (s, 1H) , 7.54 (s, IH), 7.48-7.44 (t, IH), 7.39-7. 36 (d, 2H), 7.31-7.26 (t, 2H), 7.19-7.16 4H), 1.94-1.87 (m, 6H), 0.89 (s, 2H) -0.80 (m, 12H);

¹³ C NMR (DMSO-d ₆ ,? = 39.52 ppm, 125 MHz): 170.35,156.77,151.39,149.67,147.82,137.76,135.00,131.43,125.64,123.38,121.04,117.89,116.19,113.71,119.19,57.99, , 51.44, 48.61, 46.79, 30.96, 30.87, 29.84, 24.26, 18.51.

< Example 21> 3- (2 - ((S) -1 - ((S) -2- Methoxycarbonylamino )-2- Phenylacetyl ) Pyrrolidine Yl) -1H-imidazol-5-yl) phenyl 4- (2 - ((S) -1 - ((S) -2- Methoxycarbonylamino ) -2-phenylacetyl) pyrrolidin-2-yl) -1H-imidazol-5-yl) phenyl sulfate

(S) -2- (5- (3 - ((4- (2 - ((S) -1- (tert- butoxycarbonyl) pyrrolidin- Trifluoroacetic acid (3 (3-trifluoromethyl-phenyl) -1H-imidazol-2-yl) pyrrolidine-1-carboxylate (123.0 mg, 0.171 mmol) mL) / methylene chloride (3 mL) was stirred at room temperature for 30 minutes. The volatiles were removed in vacuo and EDCI (85.2 mg, 0.444 mmol), hydroxybenzotriazole hydrate (60.0 mg, 0.444 mmol), (R) -2- (methoxycarbonylamino Methylene chloride (10 mL) of N, N-diisopropylethylamine (85.2 [mu] L, 0.464 mmol) was added over 4 minutes to a mixture of 4- The reaction mixture was stirred overnight at room temperature. The mixture was poured into 1N aqueous HCl solution and extracted with methylene chloride. The organic layer was dried over magnesium sulfate and purified by column chromatography (methylene chloride / methanol) to obtain the title compound (43.3 mg, 28%) as a yellow solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 8.19-8.06 (m, 2H), 7.98-7.96 (d, 2H), 7.91-7.83 (m, 2H), 7.73-7.64 (m, 2H), 3.91-3.85 (d, 1H), 3.80-3.71 (m, 2H), 3.58 1H), 3.54-3.51 (app bra, 6H), 3.46-3.38 (d, 1H), 3.17-3.15 (d, 1H), 2.36-1.89 (m, 8H);

^{_{13 C NMR (DMSO-d 6}} , δ = 39.52 ppm, 125MHz): 168.99, 156.34, 155.97, 150.33, 149.40, 136.86, 131.50, 128.69, 128.62, 128.31, 128.12, 127.79, 127.44, 127.23, 124.83, 122.11, 122.06 , 117.94, 115.90, 57.00, 56.73, 53.48, 51.62, 47.01, 30.88, 24.14.

< Example 22> 3- (2 - ((S) -1 - ((R) -2- ( Methoxycarbonylamino ) -3- Methylbutanoyl ) Pyrrolidine Yl) -1H-imidazol-5-yl) phenyl 4- (2 - ((S) -1 - ((R) -2- Methoxycarbonylamino ) -3- Tilbutanoyl ) Pyrrolidine Yl) -1H- Imidazole -5 days) Phenyl Sulphate Produce

(S) -2- (5- (3 - ((4- (2 - ((S) -1- (tert- butoxycarbonyl) pyrrolidin- Yl) pyrrolidine-1-carboxylate (108 mg, 0.149 mmol) was added to a solution of trifluoroacetic acid (3 mg, mL) / methylene chloride (3 mL) was stirred at room temperature for 30 minutes. The volatiles were removed in vacuo, and EDCI (74.3 mg, 0.388 mmol), hydroxybenzotriazole hydrate (52.4 mg, 0.388 mmol) and (R) -2- (methoxycarbonylamino Was added methylene chloride (10 mL) of N, N-diisopropylethylamine (130 [mu] L, 0.746 mmol) over 4 minutes to a mixture of 3- The reaction mixture was stirred overnight at room temperature. The mixture was poured into 1N aqueous HCl solution and extracted with methylene chloride. The organic layer was dried over magnesium sulfate and purified by column chromatography (methylene chloride / methanol) to obtain the desired compound (40.5 mg, 33%) as a yellow solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400 MHz): 8.13-8.08 (d, 2H), 7.95-7.87 (m, 4H), 7.78-7.63 (m, 3H), 7.54-7.48 (m 2H), 3.68-3.68 (m, 2H), 3.68-3.66 (d, 2H), 3.53 (s, 2H) , 6H), 2.36 (s, 2H), 2.08-1.96 (m, 8H), 0.90-0.68 (m, 12H);

¹³ C NMR (DMSO-d ₆ ,? = 39.52 ppm, 101 MHz): 170.80, 158.49, 158.15, 156.87, 150.32, 149.57, 131.43, 127.33, 124.70, 122.08, 120.79, 117.78, 116.21, 115.85, 57.84, 51.59, 47.00, 30.89, 29.70, 24.34, 19.28, 17.89.

< Example 23> 2- Fluoro -3 - ((R) -1 - ((R) -2- ( Methoxycarbonylamino )-2- Phenylacetyl ) Pyrrolidine-2-carboxamido) phenyl < RTI ID = 0.0 > 2- Fluoro -3 - ((S) -1 - ((R) -2- ( Methoxycarbonylamino Phenoxy) -2-phenylacetyl) pyrrolidine-2-carboxamido) phenylsulfate

Bis (2,2 '- ((((sulfonylbis (oxy)) bis (2-fluoro-3,1-phenylene)) bis Trifluoroacetic acid (3 mL) / methylene chloride (3 mL) of (2S, 2'S) -bis (pyrrolidine-1-carboxylate) (66.0 mg, 0.0929 mmol) was stirred at room temperature for 30 minutes. The volatiles were removed in vacuo and treated with EDCI (46.3 mg, 0.241 mmol), hydroxybenzotriazole hydrate (32.6 mg, 0.241 mmol), (R) -2- (methoxycarbonylamino Methylene chloride (10 mL) of N, N-diisopropylethylamine (80.9 [mu] L, 0.464 mmol) was added over 4 minutes to a mixture of 4- The reaction mixture was stirred overnight at room temperature. The mixture was poured into 1N aqueous HCl solution and extracted with methylene chloride. The organic layer was dried over magnesium sulfate and purified by column chromatography (methylene chloride / methanol) to obtain the desired compound (41.0 mg, 49%) as a white solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 10.21 (s, 1H), 10.10 (s, 1H), 8.02-7.97 (q, 2H), 7.72-7.66 (q, 2H), 7.41 1 H), 3.71-3.65 (m, 1 H), 4.71-4.67 (m, , 3.53 (s, 6H), 3.18-3.16 (d, IH), 3.10-3.08 (d, IH), 2.18-2.16 (d, IH), 2.03-1.78 (m, 7H);

¹³ C NMR (DMSO-d ₆ ,? = 39.52 ppm, 125 MHz): 170.92, 168.45, 168.25, 156.33, 155.97, 136.74, 128.60, 128.38, 128.35, 127.99, 124.76, 123.15, 118.26, 118.03, 60.26, 56.65, 51.55 , 46.85, 29.14, 24.69, 24.27;

^{_{19 F NMR (DMSO-d 6}} , 376 MHz): -74.67, -139.84.

< Example 24> 2- Fluoro -3 - ((R) -1 - ((R) -2- ( Methoxycarbonylamino ) -3- Methylbutanoyl ) Pyrrolidine-2-carboxamido) phenyl < RTI ID = 0.0 > 2- Fluoro -3 - ((S) -1 - ((R) -2- ( Methoxycarbonylamino Yl) -3- Methylbutanoyl ) Pyrrolidine -2- Carbox amido ) Phenyl Sulphate Produce

butyl di-tert-butyl di-tert-butyl 2,2 '- (((sulfonylbis (oxy)) bis (2-fluoro-3,1- Trifluoroacetic acid (3 mL) / methylene chloride (3 mL) of (2S, 2'S) -bis (pyrrolidine-1-carboxylate) (114 mg, 0.160 mmol) Lt; / RTI > The volatiles were removed in vacuo and EDCI (79.7 mg, 0.416 mmol), hydroxybenzotriazole hydrate (56.2 mg, 0.416 mmol) and (R) -2- (methoxycarbonylamino Was added methylene chloride (10 mL) of N, N-diisopropylethylamine (139 [mu] L, 0.800 mmol) over 4 minutes to a mixture of 3- The reaction mixture was stirred overnight at room temperature. The mixture was poured into 1N aqueous HCl solution and extracted with methylene chloride. The organic layer was dried over magnesium sulfate and purified by column chromatography (methylene chloride / methanol) to obtain the desired compound (30.8 mg, 23%) as a white solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400 MHz): 10.45-9.97 (d, 2H), 7.98-7.81 (m, 2H), 7.48-7.29 (m, 6H), 4.60-4.58 (d (M, 2H), 1.98-1.85 (m, 2H), 3.40-3.40 (m, 2H) (m, 8H), 0.89-0.71 (m, 12H);

^{_{13 C NMR (DMSO-d 6}} , δ = 39.52 ppm, 101 MHz): 170.53, 156.87, 146.52, 144.01, 137.14, 128.15, 124.70, 123.42, 118.19, 59.91, 58.04, 51.45, 48.64, 47.13, 29.75, 29.16, 24.37, 19.08, 18.32;

^{_{19 F NMR (DMSO-d 6}} , 376 MHz): -78.40, -144.44.

< Example 25> Bis (2- Fluoro -5- (2 - ((S) -1 - ((R) -2- ( Methoxycarbonylamino ) -3-methylbutanoyl) pyrrolidin-2-yl) -1H-imidazol- Sulphate Produce

Bis (1H-imidazol-5,2-diyl)) - bis (2,2'- (3 mL) / methylene chloride (3 mL) of (2S, 2'S) -bis (pyrrolidine-1-carboxylate) (57.4 mg, 0.076 mmol) was stirred at room temperature for 30 minutes. The volatiles were removed in vacuo and treated with EDCI (37.8 mg, 0.197 mmol), hydroxybenzotriazole hydrate (26.6 mg, 0.197 mmol), (R) -2- (methoxycarbonylamino ) Was added methylene chloride (10 mL) of N, N-diisopropylethylamine (66.1 [mu] L, 0.379 mmol) over 4 minutes to a mixture of 3- The reaction mixture was stirred overnight at room temperature. The mixture was poured into 1N aqueous HCl solution and extracted with methylene chloride. The organic layer was dried over magnesium sulfate and purified by column chromatography (methylene chloride / methanol) to obtain the desired compound (34.5 mg, 52%) as a yellow solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 8.08-8.06 (d, 2H), 8.01 (s, 2H), 7.92-7.91 (d, 2H), 7.80 (s, 1H), 7.73 2H), 3.17-4.13 (t, 2H), 3.87-3.86 (d, 1H), 7.69-7. 2H), 3.68-3.62 (q, 2H), 3.53 (s, 6H), 2.32 (s, 2H), 2.08-1.67 (m, 8H), 0.90-0.29 (m, 12H);

^{_{13 C NMR (DMSO-d 6}} , δ = 39.52 ppm, 101MHz): 170.71, 156.88, 149.66, 137.07, 136.94, 126.54, 120.06, 118.57, 115.78, 57.87, 53.48, 51.58, 46.95, 30.88, 29.69, 24.28, 19.25 , 18.57, 18.41, 17.93;

^{_{19 F NMR (DMSO-d 6}} , 376 MHz): -74.27.

< Example 26> Bis (2- Fluoro -5- (2 - ((S) -1 - ((R) -2- ( Methoxycarbonylamino ) -2-phenylacetyl) pyrrolidin-2-yl) -1H-imidazol- Sulphate Produce

Bis (1H-imidazol-5,2-diyl)) - bis (2,2'- (3 mL) of methyl (2S, 2'S) -bis (pyrrolidine-1-carboxylate) (37.9 mg, 0.050 mmol) in methylene chloride (3 mL) was stirred at room temperature for 30 minutes. The volatiles were removed in vacuo and EDCI (25.0 mg, 0.130 mmol), hydroxybenzotriazole hydrate (17.6 mg, 0.130 mmol) and (R) -2- (methoxycarbonylamino (25 mL) was added methylene chloride (10 mL) of N, N-diisopropylethylamine (43.6 [mu] L, 0.250 mmol) over 4 minutes to a mixture of 2- The reaction mixture was stirred overnight at room temperature. The mixture was poured into 1N aqueous HCl solution and extracted with methylene chloride. The organic layer was dried over magnesium sulfate and purified by column chromatography (methylene chloride / methanol) to obtain the target compound (23.5 mg, 12%) as a yellow solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400 MHz): 8.11-8.03 (m, 4H), 7.98-7.93 (m, 2H), 7.79-7.71 (m, 2H), 7.68-7.64 (t 2H), 7.39-7.34 (m, 6H), 7.29 (s, 2H), 6.99 (s, 2H), 5.50-5.49 (d, 2H), 5.17-5.16 ), 3.51 (s, 6H), 3.18-3.12 (q, 2H), 2.22-2.15 (m, 2H), 2.02-2.00 (d, 4H), 1.87 (s, 2H);

^{_{13 C NMR (DMSO-d 6}} , δ = 39.52 ppm, 101 MHz): 168.88, 155.95, 151.56, 149.53, 137.11, 136.95, 128.67, 128.27, 128.11, 127.78, 126.70, 120.27, 118.82, 118.63, 115.87, 56.99, 53.80, 51.61, 46.94, 30.91, 24.10;

^{_{19 F NMR (DMSO-d 6}} , 376 MHz): -78.97.

< Example 27> Bis (2- Fluoro -5- (2 - ((S) -1 - ((S) -2- ( Methoxycarbonylamino ) -3-methylbutanoyl) pyrrolidin-2-yl) -1H-imidazol-5-yl) phenyl)

Bis (1H-imidazol-5,2-diyl)) - bis (2,2'- (3 mL) of methyl (2S, 2'S) -bis (pyrrolidine-1-carboxylate) (164 mg, 0.216 mmol) in methylene chloride (3 mL) was stirred at room temperature for 30 minutes. The volatiles were removed in vacuo and EDCI (108 mg, 0.563 mmol), hydroxybenzotriazole hydrate (76.0 mg, 0.563 mmol) and (S) -2- (methoxycarbonylamino Was added methylene chloride (10 mL) of N, N-diisopropylethylamine (189 [mu] L, 1.08 mmol) over 4 minutes to a mixture of 3- The reaction mixture was stirred overnight at room temperature. The mixture was poured into 1N aqueous HCl solution and extracted with methylene chloride. The organic layer was dried over magnesium sulfate and purified by column chromatography (methylene chloride / methanol) to obtain the target compound (23.5 mg, 12%) as a yellow solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400 MHz): 8.06-8.05 (d, 2H), 7.99 (s, 2H), 7.90-7.88 (d, 2H), 7.71-7.67 (t, 2H 2H), 3.86-3.76 (m, 4H), 3.53 (s, 6H), 2.32-2.28 (t, 2H), 7.30-7.28 , 2H), 2.14-2.10 (m, 2H), 2.07-1.94 (m, 6H), 0.81-0.75 (q, 12H);

^{_{13 C NMR (DMSO-d 6}} , δ = 39.52 ppm, 101 MHz): 170.95, 158.36, 158.03, 156.88, 149.87, 137.07, 136.93, 126.37, 119.84, 118.72, 118.55, 57.93, 53.34, 51.52, 47.05, 31.00, 29.30, 24.58, 19.13, 17.99;

^{_{19 F NMR (DMSO-d 6}} , 376 MHz): -78.32, -138.05.

< Example 28> Bis (3 - ((S) -1 - ((R) -2- ( Methoxycarbonylamino ) -3- Methylbutanoyl ) blood 2-carboxamido) -2-methylphenyl) sulphate < / RTI >

Bis (2,2 '- (((sulfonylbis (oxy)) bis (2-methyl-3,1-phenylene) Trifluoroacetic acid (3 mL) / methylene chloride (3 mL) of bis (2S, 2'S) -bis (pyrrolidine-1-carboxylate) (81.1 mg, 0.115 mmol) was stirred at room temperature for 30 minutes. The volatiles were removed in vacuo and EDCI (38.8 mg, 0.300 mmol), hydroxybenzotriazole hydrate (40.5 mg, 0.300 mmol), (R) -2- (methoxycarbonylamino) Methylenebutanoic acid (48.5 mg, 0.277 mmol) was added methylene chloride (10 mL) of N, N-diisopropylethylamine (149 nuL, 0.577 mmol) over 4 minutes and the reaction mixture Was stirred overnight at room temperature. The mixture was poured into 1N aqueous HCl solution and extracted with methylene chloride. The organic layer was dried over magnesium sulfate and purified by column chromatography (methylene chloride / methanol) to obtain the desired compound (52.4 mg, 56%) as a white solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 9.96-9.35 (app s, 2H), 7.47-7.38 (m, 4H), 7.35-7.31 (t, 2H), 7.28-7.23 (t 2H), 3.52-3.53 (d, 2H), 3.51-4.50 (m, 2H) (M, 9H), 0.92-0.88 (t, 10H), 0.84-0.82 (d, 3H) , &Lt; / RTI > 1H), 0.76-0.74 (d, 1H);

¹³ C NMR (DMSO-d ₆ ,? = 39.52 ppm, 125 MHz): 170.91, 170.48, 157.03, 148.52, 138.16, 126.78, 125.72, 124.99, 118.13, 60.15, 58.15, 51.39, 47.13, 29.61, 29.08, 24.38, , 18.41, 11.10.

< Example 29> Dimethyl (2R, 2'R) -1,1'- ((2S, 2'S) -2,2 '- (4,4'-sulfonylbis (4,1- phenylene) bis (azaenediyl) Preparation of bis (3-methyl-1-oxobutane-2,1-diyl) dicarbamate bis (oxomethylene) bis (pyrrolidine-

(2S, 2'S) -bis (pyrrolidine (2-hydroxyphenyl)) - bis (2,2'- -1-carboxylate) (82.0 mg, 0.128 mmol) in trifluoroacetic acid (3 mL) / methylene chloride (3 mL) was stirred at room temperature for 30 minutes. The volatiles were removed in vacuo and EDCI (63.6 mg, 0.332 mmol), hydroxybenzotriazole hydrate (44.8 mg, 0.332 mmol) and (R) -2- (methoxycarbonylamino Was added methylene chloride (10 mL) of N, N-diisopropylethylamine (111 [mu] L, 0.638 mmol) over a period of 4 minutes to the mixture of 3-methylbutanoic acid (53.6 mg, 0.536 mmol) The mixture was stirred overnight at room temperature. The mixture was poured into 1N aqueous HCl solution and extracted with methylene chloride. The organic layer was dried over magnesium sulfate and purified by column chromatography (methylene chloride / methanol) to obtain the desired compound (53.1 mg, 55%) as a white solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 500MHz): 10.72-10.24 (app s, 2H), 7.99-7.84 (m, 4H), 7.82-7.71 (m, 4H), 7.56-7.33 (m (M, 2H), 4.41-4.40 (d, 2H), 4.10-4.07 (t, 2H), 3.78-3.68 (m, 2H), 3.63-3.59 (t, 1H), 2.18-2.09 (m, 2H), 2.04-1.82 (m, 8H), 0.88-0.85 ;

¹³ C NMR (DMSO-d ₆ ,? = 39.52 ppm, 125 MHz): 171.17, 170.18, 156.85, 143.33, 135.26, 128.36, 119.11, 60.26, 57.94, 51.55, 47.06, 29.72, 29.28, 24.33, 19.05, 18.27.

< Example 30> Bis (3- (2 - ((S) -1 - ((S) -2- ( Methoxycarbonylamino )-4- Methylpentano Yl) pyrrolidin-2-yl) -1H-imidazol-5-yl) phenyl) Sulphate Produce

(2S, 2'S) - bis (2,2'-bis (2,2'-bipyridyl) Trifluoroacetic acid (3 mL) / methylene chloride (3 mL) of bis (pyrrolidine-1-carboxylate) (70 mg, 0.0971 mmol) was stirred at room temperature for 30 minutes. The volatiles were removed in vacuo and EDCI (48.4 mg, 0.252 mmol), hydroxybenzotriazole hydrate (34.1 mg, 0.252 mmol), (S) -2- (methoxycarbonylamino) Methylene chloride (10 mL) of N, N-diisopropylethylamine (84.6 nuL, 0.486 mmol) was added over 4 minutes to a mixture of novolac acid (44.1 mg, 0.233 mmol) and the reaction mixture was stirred at room temperature overnight Lt; / RTI > The mixture was poured into 1N aqueous HCl solution and extracted with methylene chloride. The organic layer was dried over magnesium sulfate and purified by column chromatography (methylene chloride / methanol) to obtain the desired compound (52.4 mg, 63%) as a yellow solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 12.14-11.89 (d, 1H), 7.96-7.94 (d, 1H), 7.80-7.76 (m, 3H), 7.69-7.67 (d, 1H), 7.60 (s, 1H), 7.51-7.45 (q, 2H), 7.43-7. 41 (d, 1H), 7.38-7.36 2H), 3.63-3.71 (m, 2H), 3.53 (s, 6H), 3.38-3. 1H), 1.64 (s, 2H), 1.56-1.37 (m, 5H), 1.64-1.30 (m, 1.23 (s, 1H), 0.88-0.83 (m, 12H);

¹³ C NMR (DMSO-d ₆ ,? = 39.52 ppm, 125 MHz): 174.45, 170.99, 156.64, 150.40, 130.43, 126.92, 124.29, 123.41, 117.83, 116.25, 109.74, 54.43, 52.11, 51.37, 50.79, 46.37, , 30.99, 24.28, 24.04, 23.17, 22.90, 21.35, 21.10.

< Example 31> Bis (3- (2 - ((S) -1 - ((S) -2- ( Methoxycarbonylamino ) Propanoyl ) Pyrrole 2-yl) -1H-imidazol-5-yl) phenyl) Sulphate Produce

(2S, 2'S) - bis (2,2'-bis (2,2'-bipyridyl) Trifluoroacetic acid (3 mL) / methylene chloride (3 mL) of bis (pyrrolidine-1-carboxylate) (108 mg, 0.149 mmol) was stirred at room temperature for 30 minutes. The volatiles were removed in vacuo and treated with EDCI (74.3 mg, 0.388 mmol), hydroxybenzotriazole hydrate (52.4 mg, 0.388 mmol), (S) -2- (methoxycarbonylamino) propanoic acid 52.7 mg, 0.358 mmol) was added methylene chloride (10 mL) of N, N-diisopropylethylamine (130 [mu] L, 0.746 mmol) over 4 minutes and the reaction mixture was stirred overnight at room temperature. The mixture was poured into 1N aqueous HCl solution and extracted with methylene chloride. The organic layer was dried over magnesium sulfate and purified by column chromatography (methylene chloride / methanol) to obtain the desired compound (53.0 mg, 46%) as a yellow solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 7.97-7.94 (d, 1H), 7.83-7.77 (m, 4H), 7.69-7.67 (d, 1H), 7.59 (s, 1H) , 7.52-7.47 (m, 2H), 7.40-7.34 (m, 2H), 7.24-7.20 (m, 2H), 5.13-5.04 (m, 2H), 4.35-4.31 (m, 3H), 1.66-1.62 (m, 3H), 1.63-1.30 (m, m, 1 H), 1.48-1.38 (m, 1 H), 1.26-1.16 (m, 6 H);

¹³ C NMR (DMSO-d ₆ ,? = 39.52 ppm, 125 MHz): 171.03, 156.25, 150.42, 130.50, 126.95, 124.31, 123.42, 119.04, 117.89, 116.16, 109.71, 54.55, 51.36, 48.04, 46.38, 31.04, , 16.83.

< Example 32> Bis (3- (2 - ((S) -1 - ((S) -2- ( Methoxycarbonylamino )-2- Phenylacetyl ) Pyrrolidin-2-yl) -1H-imidazol-5-yl) phenyl) Sulphate Produce

(2S, 2'S) - bis (2,2'-bis (2,2'-bipyridyl) Trifluoroacetic acid (3 mL) / methylene chloride (3 mL) of bis (pyrrolidine-1-carboxylate) (81.0 mg, 0.112 mmol) was stirred at room temperature for 30 minutes. The volatiles were removed in vacuo and EDCI (56.0 mg, 0.92 mmol), hydroxybenzotriazole hydrate (39.5 mg, 0.388 mmol), (S) -2- (methoxycarbonylamino) Methylene chloride (10 mL) of N, N-diisopropylethylamine (97.8 [mu] L, 0.562 mmol) was added over 4 minutes to a mixture of thioacetic acid (56.4 mg, 0.270 mmol) Lt; / RTI > The mixture was poured into 1N aqueous HCl solution and extracted with methylene chloride. The organic layer was dried over magnesium sulfate and purified by column chromatography (methylene chloride / methanol) to obtain the target compound (28.0 mg, 28%) as a yellow solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 12.30-11.99 (d, 2H), 7.86- 7.85 (d, 1H), 7.77-7.72 (m, 3H), 7.66-7.60 (m, 3H), 7.52-7.44 (m, 3H), 7.39-7.35 (t, 6H), 7.30-7.28 (m, 2H), 7.26-7. 2H), 3.70-3.64 (q, 2H), 3.54 (s, 6H), 3.39 (s, 2H), 2.17-2. 12 (m, 1H), 2.00-1.91 (m, 6H);

¹³ C NMR (DMSO-d ₆ ,? = 39.52 ppm, 125 MHz): 168.05, 156.35, 150.41, 149.45, 137.75, 137.60, 137.12, 130.40, 128.75, 128.21, 127.65, 123.49, 117.79, 116.33, 113.67, 56.48, , 51.57, 46.42, 30.93, 24.17.

< Example 33> Bis (3 - ((S) -1 - ((S) -2- ( Methoxycarbonylamino ) -3,3- Dimethylbutanoyl ) Pyrrolidine-2-carboxamido) phenyl) - < / RTI & Sulphate Produce

(2S, 2'S) bis (2,2'-bis (2,2'-bis (diphenylphosphino) Trifluoroacetic acid (3 mL) / methylene chloride (3 mL) of bis (pyrrolidine-1-carboxylate) (11.1 mg, 0.164 mmol) was stirred at room temperature for 30 minutes. The volatiles were removed in vacuo and EDCI (81.8 mg, 0.427 mmol), hydroxybenzotriazole hydrate (57.6 mg, 0.427 mmol), (S) -2- (methoxycarbonylamino) To the mixture of dimethyl butanoic acid (74.5 mg, 0.394 mmol) was added methylene chloride (10 mL) of N, N-diisopropylethylamine (143 nuL, 0.820 mmol) over 4 min, The mixture was stirred overnight at room temperature. The mixture was poured into 1N aqueous HCl solution and extracted with methylene chloride. The organic layer was dried over magnesium sulfate and purified by column chromatography (methylene chloride / methanol) to obtain the desired compound (29.7 mg, 22%) as a white solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400 MHz): 10.41-10.16 (d, 2H), 7.88-7.82 (d, 2H), 7.62-7.60 (d, 2H), 7.48-7.44 (t 2H), 3.65-3.62 (m, 2H), 3.54 (t, 2H) (s, 6H), 2.20-2.14 (m, 2H), 2.02-1.84 (m, 6H), 0.96 (s, 18H);

^{_{13 C NMR (DMSO-d 6}} , δ = 39.52 ppm, 125 MHz): 170.94, 169.64, 156.88, 149.88, 140.90, 130.69, 118.15, 115.21, 111.11, 60.32, 59.11, 51.50, 47.94, 34.65, 29.45, 26.36, 26.22, 24.84.

< Example 34> 2- Fluoro -3 - ((S) -1 - ((R) -2- ( Methoxycarbonylamino )-2- Phenylacetyl ) Pyrrolidine -2- Carbox amido ) Phenyl 2- Fluoro -5 - ((S) -1 - ((R) -2- ( Methoxycarbonylamino )-2- Phenylacetyl ) Pyrrolidine -2- Carbox amido ) Phenyl Sulphate Produce

(S) -2 - ((3 - ((5 - ((S) -1- (tert- butoxycarbonyl) pyrrolidine- 2- carboxamido) -2-fluorophenoxy Trifluoroacetic acid (3 mL) / methylene chloride (3 mL) of pyrrolidine-1-carboxylate (62.2 mg, 0.088 mmol) Were stirred at room temperature for 30 minutes. The volatiles were removed in vacuo and treated with EDCI (43.6 mg, 0.228 mmol), hydroxybenzotriazole hydrate (30.7 mg, 0.228 mmol), (R) -2- (methoxycarbonylamino Methylene chloride (10 mL) of N, N-diisopropylethylamine (76.2 [mu] L, 0.438 mmol) was added over 4 minutes to a mixture of 4- The reaction mixture was stirred overnight at room temperature. The mixture was poured into 1N aqueous HCl solution and extracted with methylene chloride. The organic layer was dried over magnesium sulfate and purified by column chromatography (methylene chloride / methanol) to obtain the target compound (24.5 mg, 31%) as a white solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 10.46-10.11 (m, 2H), 8.11-8.01 (m, 2H), 7.74-7.64 (m, 3H), 7.55-7.50 (t, 2H), 3.81-3.67 (m, 2H), 3.52 (m, 2H) s, 6H), 3.17-3.08 (m, 2H), 2.16-1.80 (m, 8H);

¹³ C NMR (DMSO-d ₆ ,? = 39.52 ppm, 101 MHz): 170.92, 168.38, 156.30, 156.05, 149.85, 147.40, 137.16, 136.77, 136.25, 136.08, 128.58, 128.35, 128.01, 124.81, 123.48, , 117.96, 117.78, 113.31, 60.67, 56.65, 51.54, 46.94, 29.18, 24.30;

^{_{19 F NMR (DMSO-d 6}} , 376 MHz): -73.82, -135.52, -139.50.

< Example 35> 2- Fluoro -3 - ((S) -1 - ((R) -2- ( Methoxycarbonylamino ) -3- Methylbutanoyl ) Pyrrolidine -2- Carbox amido ) Phenyl 2- Fluoro -5 - ((S) -1 - ((R) -2- ( Methoxycarbonyl Amino) -3-methylbutanoyl) pyrrolidine-2-carboxamido) Preparation of phenylsulfate

(S) -2 - ((3 - ((5 - ((S) -1- (tert- butoxycarbonyl) pyrrolidine- 2- carboxamido) -2-fluorophenoxy Trifluoroacetic acid (3 mL) / methylene chloride (3 mL) of pyrrolidine-1-carboxylate (90.1 mg, 0.127 mmol) Were stirred at room temperature for 30 minutes. The volatiles were removed in vacuo and EDCI (63.2 mg, 0.330 mmol), hydroxybenzotriazole hydrate (44.5 mg, 0.330 mmol) and (R) -2- (methoxycarbonylamino Methylenebutanoic acid (53.3 mg, 0.304 mmol) in methylene chloride (10 mL) was added methylene chloride (10 mL) of N, N-diisopropylethylamine The reaction mixture was stirred overnight at room temperature. The mixture was poured into 1N aqueous HCl solution and extracted with methylene chloride. The organic layer was dried over magnesium sulfate and purified by column chromatography (methylene chloride / methanol) to obtain the desired compound (22.3 mg, 21%) as a white solid.

^{_{1 H NMR (DMSO-d 6}} , δ = 2.5 ppm, 400MHz): 10.64-9.97 (m, 2H), 8.08-8.07 (d, 1H), 7.99-7.96 (t, 1H), 7.61 (s, 1H) 2H), 3.79 (s, 2H), 7.53-7.48 (d, 1H), 7.44-7.28 (m, 4H), 4.60-4.58 2H), 3.64-3.58 (m, 2H), 3.53 (s, 6H), 2.21-2.09 (m, 2H), 1.99-1.81 (m, 8H), 0.89-0.66 (m, 12H);

¹³ C NMR (DMSO-d ₆ ,? = 39.52 ppm, 101MHz): 170.90, 170.22, 156.84, 149.90, 147.44, 146.40, 143.89, 137.12, 136.06, 128.18, 124.71, 123.31, 119.81, 117.89, 113.39, 60.28, , 51.54, 47.09, 29.75, 24.38, 19.07, 18.30;

^{_{19 F NMR (DMSO-d 6}} , 376 MHz): -135.41, -139.92.

The chemical structures of the compounds prepared in Examples 1-35 are summarized in Table 1 below.

Example
constitutional formula Example
constitutional formula

One

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

- -

< Experimental Example 1> Measurement of infection inhibition activity by hepatitis C virus

In order to measure the inhibitory activity of the compounds of the present invention represented by the formula (1) according to the present invention by the hepatitis C virus, the following experiment was conducted.

Huh 7.5.1 cells, a liver cancer cell line, was dispensed into a 12-well cell culture plate at about 50,000 per well. Dissociated cells were supplemented with 10% (v / v) FBS (Fetal Bovine Serum SH30406.02, Hyclone Co.) and 1% (v / v) antibiotics (penicillin / streptomycin solution SV30010, Hyclone Co.) The cells were cultured for 24 hours in a 6.0% carbon dioxide cell incubator (CO ₂ Incubator 311, Forma Scientific Co, Lnc. USA) at 37 ° C using a DMEM culture medium (Ducos-modified Eagle culture solution 12800-017, GIBCO Co.) And attached to the floor. Subsequently, hepatitis C virus (JFH-5aFlucm4, PLoS One. 2011; 6 (8): e228808.) With the Renilla luciferase gene was inoculated into the cells for 3 hours as a reporter Respectively. After 3 hours of virus inoculation, the cell culture medium was removed and a new cell culture medium prepared by adding the compound of Example of the present invention to the culture medium at a concentration of 1 μM was added to each well. (CO ₂ Incubator 311, Forma Scientific Co, Lnc. USA) for 3 days. Cells attached to the plate were washed with phosphate buffered saline (PBS) and lysed by treatment with 100 μL of 1 × indirect lysis buffer (passive lysis buffer, promega, E1941). The lysed cell lysate (10 μL) was injected into the Renilla luciferase assay reagent (50 μL) of the Renilla Luciferase assay system (Promega, E2820) and mixed to obtain a luminometer (GLOMAX 20/20 Luminometer, Promega) using luciferase measure program for 10 seconds. At this time, the luminescence amounts of the treated and untreated groups according to the present invention were measured three times, and their average was compared and analyzed. The luminescence amount according to the concentration of each compound was measured by a sigma plot program, The half maximal effective concentration (EC ₅₀ ) was calculated using Table 2 below.

Example HCVcc (2a) One - 2 A 3 C 4 A 5 C 6 A 7 C 8 C 9 B 10 B 11 - 12 A 13 - 14 A 15 - 16 - 17 - 18 - 19 - 20 B 21 A 22 - 23 B 24 - 25 - 26 A 27 - 28 - 29 - 30 - 31 - 32 - 33 A 34 A 35 -

(In Table 2,

Class A is greater than 1 pM and less than 1 nM of EC ₅₀ ;

Class B has an EC _{50 of} greater than 1 nM and less than or equal to 100 nM;

C rating indicates EC ₅₀ greater than 100 nM).

As shown in Table 2, it was confirmed that the compounds according to the present invention inhibit infection by Hepatitis C virus present in liver cancer cell lines at low concentrations. Examples 2, 4, 6, 9, 10, 12, 14, 20, 21, 23, 26, 33 and 34 inhibited infection by the hepatitis C virus at a low EC ₅₀ of 100 nM or less, It was found that the samples 2, 4, 6, 12, 14, 21, 26, 33 and 34 excellently inhibited infection by the hepatitis C virus even at a very low EC ₅₀ value of 1 nM or less.

Therefore, the compounds according to the present invention are excellent in the effect of inhibiting infection by hepatitis C virus, and thus can be used for the treatment and prevention of acute hepatitis C, chronic hepatitis C, cirrhosis or hepatocellular carcinoma And can be usefully used as a pharmaceutical composition for preventing or treating liver disease.

< Experimental Example 2> Measurement of hepatitis C virus replication inhibitory activity

In order to measure the replication inhibitory activity against the hepatitis C virus of the compound of formula (I) according to the present invention, the following experiment was conducted.

Huh 7.5.1 cells with NK / R2AN, a replicon capable of measuring the replication and translation process of hepatitis C virus, were dispensed into 12-well cell culture plates at about 50,000 per well . Divided cells were treated with antibiotics (penicillin / streptomycin solution SV30010, Hyclone Co.) at a final concentration of 10% (v / v) FBS (Fetal Bovine Serum SH30406.02, Hyclone Co.) (CO ₂ Incubator 311, manufactured by Forma Scientific Co, Inc) at 37 ° C using a DMEM culture medium (Ducose-modified eagle culture solution 12800-017, GIBCO Co.) supplemented with G418 (600 μg / mL, Calbiochem) Lnc. USA) for 24 hours to attach the cells to the bottom of the plate. Then, inject the new cell culture medium are created by removing the cell culture medium and added to each of the example compounds according to the invention the culture medium at a concentration of 1 pM to 1μM to each well, and 6.0% of 37 ℃ carbon dioxide cell incubator (CO ₂ Incubator 311, Forma Scientific Co, Lnc. USA) for 3 days. Cells attached to the plate were washed with phosphate buffered saline (PBS) and lysed by treatment with 100 μL of 1 × indirect lysis buffer (E1941). The lysed cell lysate (10 μL) was injected into the Renilla luciferase assay reagent (50 μL) of the Renilla Luciferase assay system (Promega, E2820) and mixed to obtain a luminometer (GLOMAX 20/20 Luminometer, Promega) for 10 seconds using a Luciferase measure program. At this time, the luminescence amounts of the treated and untreated groups according to the present invention were measured three times, and their average was compared and analyzed. The luminescence amount according to the concentration of each compound was measured by a sigma plot program, The half maximal effective concentration (EC ₅₀ ) was calculated using Table 3 below.

Example replicon (1b) One B 2 A 3 C 4 A 5 C 6 A 7 C 8 C 9 B 10 A 11 B 12 A 13 B 14 A 15 A 16 C 17 C 18 B 19 A 20 C 21 A 22 B 23 C 24 C 25 B 26 A 27 B 28 C 29 A 30 B 31 A 32 C 33 B 34 A 35 C

(In Table 3,

Class A is greater than 1 pM and less than 1 nM of EC ₅₀ ;

Class B has an EC _{50 of} greater than 1 nM and less than or equal to 100 nM;

C rating indicates EC ₅₀ greater than 100 nM).

As shown in Table 3, it was confirmed that the compounds of the examples according to the present invention inhibited the replication of hepatitis C virus at low concentrations. The compounds of Examples 1, 2, 4, 6, 9-15, 18, 19, 21, 22, 25-27, 29-31, 33 and 34 inhibited replication of hepatitis C virus even at low EC ₅₀ In particular, the compounds of Examples 2, 4, 6, 10, 12, 14, 15, 19, 21, 26, 29, 31 and 34 exhibited EC ₅₀ values of 1 nM or lower, It was found that the replication of hepatitis virus was suppressed well.

Therefore, the compounds according to the present invention are excellent in the effect of inhibiting the replication of hepatitis C virus, and therefore, the hepatitis C virus, hepatitis C virus, chronic hepatitis C virus, hepatocellular carcinoma And may be useful as a pharmaceutical composition for preventing or treating diseases.

< Formulation example 1> Sanje Produce

The compound represented by the formula (1) 2g

Lactose 1g

The above components were mixed and packed in airtight bags to prepare powders.

< Formulation example 2> Preparation of tablets

The compound represented by the formula (1) 100 mg

Corn starch 100 mg

Lactose 100 mg

Magnesium stearate 2 mg

After mixing the above components, tablets were prepared by tableting according to a conventional method for producing tablets.

< Formulation example 3> Preparation of capsules

The compound represented by the formula (1) 100 mg

Corn starch 100 mg

Lactose 100 mg

Magnesium stearate 2 mg

After mixing the above components, the capsules were filled in gelatin capsules according to the conventional preparation method of capsules.

< Formulation example 4> Preparation of injection

The compound represented by the formula (1) 100 mg

Mannitol 180 mg

Na ₂ HPO ₄ .2H ₂ O 26 mg

Distilled water 2974 mg

According to the conventional method for preparing an injectable preparation, an injectable preparation was prepared by incorporating the aforementioned components in the amounts indicated.

< Formulation example 5> Manufacture of health food

The compound represented by the formula (1) 500ng

Vitamin mixture Suitable amount

Vitamin A acetate 70 mg

Vitamin E 1.0 mg

vitamin 0.13 mg

Vitamin B2 0.15 mg

Vitamin B6 0.5 mg

Vitamin B12 0.2 mg

Vitamin C 10 mg

Biotin 10 mg

Nicotinic acid amide 1.7 mg

Folic acid 50 mg

Calcium pantothenate 0.5 mg

Mineral mixture Suitable amount

Ferrous sulfate 1.75 mg

Zinc oxide 0.82 mg

Magnesium carbonate 25.3 mg

Potassium monophosphate 15 mg

Dicalcium phosphate 55 mg

Potassium citrate 90 mg

Calcium carbonate 100 mg

Magnesium chloride 24.8 mg

Although the composition ratio of the above-mentioned vitamin and mineral mixture is comparatively mixed with a composition suitable for health food as a preferred embodiment, the compounding ratio may be arbitrarily modified, and the above ingredients are mixed according to a conventional method for producing healthy foods , Granules can be prepared and used in the manufacture of health food compositions according to conventional methods.

< Formulation example 6> Health drink Produce

The compound represented by the formula (1) 500ng

Citric acid 1000 mg

oligosaccharide 100g

Plum concentrate 2g

Taurine 1g

Purified water is added to the entire 900ml

The above components were mixed according to a conventional health drink manufacturing method, and the mixture was stirred and heated at 85 DEG C for about 1 hour. The resulting solution was filtered to obtain a sterilized container, which was sealed and sterilized, And used for manufacturing.

Although the composition ratio is relatively mixed with the ingredient suitable for the favorite drink, it is also possible to arbitrarily modify the blending ratio according to the regional and national preference such as the demand class, the demanding country, and the use purpose.

Claims

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,
A is a single bond, -O-, -NH- or C _1- ₂ alkylene;
X is selected from the group consisting of 5 to 8 heteroaryl, carbonylamino (- (C = O) NH-) or aminocarbonyl (-NH (C = O) -;
R ¹ is hydrogen, halogen or a linear or branched C _1- ₅ alkyl, C _1- ₅ alkoxy; And
R ² and R ³ are each independently hydrogen; Unsubstituted straight-chain or branched C _1- ₅ alkyl, C _1- ₅ alkoxy or C _1- ₅ alkoxy-carbonyl-amino; Or unsubstituted or substituted _6- C ₈ aryl, wherein the substituted C _6-8 aryl substituent is one or more selected from the group consisting of C _1- ₅ alkyl, C _1- ₅ alkoxy halogen and straight-chain or branched . &Lt; / RTI >

The method according to claim 1,
A is a single bond, -O- or -NH-;
X is a 5- to 8-membered heteroaryl, carbonylamino (- (C = O) NH-) or aminocarbonyl (-NH (C = O )-)ego;
R ¹ is hydrogen, C _1-5 straight or branched chain alkyl, fluoro, bromo or chloro; And
R ² and R ³ are each independently linear or branched C _1- ₅ alkyl,

Or unsubstituted or substituted phenyl, wherein said R ⁴ is a linear or branched C _1- ₃ alkyl, phenyl substituted by one or more substituents selected from the group consisting of C _1- ₃ alkyl, halogen and straight-chain or branched , &Lt; / RTI > or an optical isomer thereof or a pharmaceutically acceptable salt thereof.

The method according to claim 1,
A is a single bond or -O-;
X is

,

or

ego;
R < ¹ > is hydrogen, methyl or fluoro;
R ² and R ³ are each independently methyl, isopropyl, t-butyl,

,

or

&Lt; / RTI > or an < RTI ID = 0.0 > pharmaceutically < / RTI > acceptable salt thereof.

The method according to claim 1,
The compound represented by the formula (1) is any one selected from the group consisting of the following compounds, an optical isomer thereof or a pharmaceutically acceptable salt thereof:
(1) Synthesis of dimethyl ((1R, 1'R) - ((2S, 2'S) - (((sulfonylpiperidine (4,1- phenylene)) bis (azanediyl) bis (Pyrrolidine-2,1-diyl)) bis (2-oxo-1-phenylethane-2,1-diyl)) dicarbamate
(2) Synthesis of bis (4 - ((S) -1 - ((R) -2 - ((methoxycarbonyl) amino) -2-phenylacetyl) pyrrolidine-2-carboxamido) ;
(3) bis (4 - ((S) -1 - ((methoxycarbonyl) -D-valyl) pyrrolidine-2-carboxamido) phenyl) sulfate;
(4) Synthesis of bis (3 - ((S) -1 - ((R) -2 - ((methoxycarbonyl) amino) -2-phenylacetyl) pyrrolidine-2-carboxamido) ;
(5) Synthesis of bis (4- (2 - ((S) -1 - ((R) -2- (methoxycarbonylamino) -3-methylbutanoyl) pyrrolidin- 5-yl) phenyl) sulphate;
(6) Synthesis of bis (4- (2 - ((S) -1 - ((R) -2- (methoxycarbonylamino) -2- phenylacetyl) pyrrolidin- Yl) phenyl) sulphate;
(7) bis (3 - ((S) -1 - ((methoxycarbonyl) -D-valyl) pyrrolidine-2-carboxamido) phenyl) sulfate;
(8) Synthesis of bis (3- (2 - ((S) -1 - ((R) -2- (methoxycarbonylamino) -3-methylbutanoyl) pyrrolidin- 5-yl) phenyl) sulphate;
(9) Synthesis of bis (3- (2 - ((S) -1 - ((R) -2- (methoxycarbonylamino) -2- phenylacetyl) pyrrolidin- Yl) phenyl) sulphate;
(10) Synthesis of bis (5 - ((S) -1 - ((R) -2- (methoxycarbonyl) amino) -2-phenylacetyl) pyrrolidine- Methylphenyl) sulfate;
(11) bis (5 - ((S) -1 - ((methoxycarbonyl) -D-valyl) pyrrolidine-2-carboxamido) -2-methylphenyl) sulfate;
(12) Synthesis of 3 - ((S) -1 - ((R) -2 - ((methoxycarbonyl) amino) -2-phenylacetyl) pyrrolidine- (S) -1 - ((R) -2 - ((methoxycarbonyl) amino) -2-phenylacetyl) pyrrolidine-2-carboxamido) phenyl) sulfate;
(13) Synthesis of 3 - ((S) -1 - ((methoxycarbonyl) -D-valyl) pyrrolidine-2-carboxamido) Carbonyl) -D-valyl) pyrrolidine-2-carboxamido) phenyl) sulfate;
(14) Synthesis of bis (2-fluoro-5 - ((S) -1 - ((R) -2 - ((methoxycarbonyl) amino) -2-phenylacetyl) pyrrolidine- Di) phenyl) sulphate;
(15) Synthesis of bis (3- (2 - ((S) -1 - ((S) -2- (methoxycarbonylamino) -3-methylbutanoyl) pyrrolidin- 5-yl) phenyl) sulphate;
(16) bis (2-fluoro-5 - ((S) -1 - ((methoxycarbonyl) -D-valyl) pyrrolidine-2-carboxamido) phenyl) sulfate;
(17) Synthesis of bis (3 - ((S) -1 - ((R) -2 - ((methoxycarbonyl) amino) -2-phenylacetyl) pyrrolidine- Methylphenyl) sulfate;
(18) Synthesis of bis (3- (2 - ((S) -1 - ((R) -2- (methoxycarbonylamino) -3,3-dimethylbutanoyl) pyrrolidin- -Imidazol-5-yl) phenyl) sulphate;
(19) Synthesis of bis (4- (2 - ((S) -1 - ((S) -2- (methoxycarbonylamino) -3-methylbutanoyl) pyrrolidin- 5-yl) phenyl) sulphate;
(20) 3- (2 - ((S) -1 - ((S) -2- (Methoxycarbonylamino) -3-methylbutanoyl) pyrrolidin- Yl) -1H-imidazol-2-yl) phenyl) -4- (2 - ((S) -1 - ((S) -2- (methoxycarbonylamino) -3-methylbutanoyl) pyrrolidin- 5-yl) phenyl sulfate;
(21) 3- (2 - ((S) -1 - ((S) -2- (Methoxycarbonylamino) -2-phenylacetyl) pyrrolidin- Yl) -1H-imidazol-2-yl) -pyrrolidine The title compound was prepared from 4- (2 - ((S) -1 - ((S) -2- (methoxycarbonylamino) 5-yl) phenyl sulfate;
(22) 3- (2 - ((S) -1 - ((R) -2- (Methoxycarbonylamino) -3-methylbutanoyl) pyrrolidin- Yl) -1H-imidazol-2-yl) phenyl) -4- (2 - ((S) -1 - ((R) -2- (methoxycarbonylamino) -3-methylbutanoyl) pyrrolidin- 5-yl) phenyl sulfate;
(23) 2-Fluoro-3 - ((R) -1 - ((R) -2- (methoxycarbonylamino) -2-phenylacetyl) pyrrolidine- -Fluoro-3 - ((S) -1 - ((R) -2- (methoxycarbonylamino) -2-phenylacetyl) pyrrolidine-2-carboxamido) phenyl sulfate;
(24) 2-Fluoro-3 - ((R) -1 - ((R) -2- (methoxycarbonylamino) -3-methylbutanoyl) pyrrolidine- 2-fluoro-3 - ((S) -1 - ((R) -2- (methoxycarbonylamino) -3-methylbutanoyl) pyrrolidine-2-carboxamido) phenylsulfate;
(25) Synthesis of bis (2-fluoro-5- (2 - ((S) -1 - ((R) -2- (methoxycarbonylamino) -3-methylbutanoyl) pyrrolidin- ) -1H-imidazol-5-yl) phenyl) sulphate;
(26) bis (2-fluoro-5- (2 - ((S) -1 - ((R) -2- (methoxycarbonylamino) -2- phenylacetyl) pyrrolidin- -1H-imidazol-5-yl) phenyl) sulfate;
(27) Synthesis of bis (2-fluoro-5- (2 - ((S) -1 - ((S) -2- (methoxycarbonylamino) -3- methylbutanoyl) pyrrolidin- ) -1H-imidazol-5-yl) phenyl) sulphate;
(28) Synthesis of bis (3 - ((S) -1 - ((R) -2- (methoxycarbonylamino) -3-methylbutanoyl) pyrrolidine-2-carboxamido) ) Sulphate;
(29) Synthesis of Dimethyl (2R, 2'R) -1,1 '- ((2S, 2'S) -2,2'- (4,4'-sulfonylbis Bis (pyrrolidine-2,1-diyl)) bis (3-methyl-1-oxobutane-2,1-diyl) dicarbamate;
(30) Synthesis of bis (3- (2 - ((S) -1 - ((S) -2- (methoxycarbonylamino) -4- methylpentanoyl) pyrrolidin- 5-yl) phenyl) sulphate;
(31) Synthesis of bis (3- (2 - ((S) -1 - ((S) -2- (methoxycarbonylamino) propanoyl) pyrrolidin- Yl) phenyl) sulphate;
(32) Synthesis of bis (3- (2 - ((S) -1 - ((S) -2- (methoxycarbonylamino) -2- phenylacetyl) pyrrolidin- Yl) phenyl) sulphate;
(33) Synthesis of bis (3 - ((S) -1 - ((S) -2- (methoxycarbonylamino) -3,3-dimethylbutanoyl) pyrrolidine- ) Sulphate;
(34) 2-Fluoro-3 - ((S) -1 - ((R) -2- (methoxycarbonylamino) -2- phenylacetyl) pyrrolidine- Fluoro-5 - ((S) -1 - ((R) -2- (methoxycarbonylamino) -2-phenylacetyl) pyrrolidine-2-carboxamido) phenyl sulfate; And
(35) 2-Fluoro-3 - ((S) -1 - ((R) -2- (methoxycarbonylamino) -3-methylbutanoyl) pyrrolidine- 2-fluoro-5 - ((S) -1 - ((R) -2- (methoxycarbonylamino) -3-methylbutanoyl) pyrrolidine-2-carboxamido) phenyl sulfate.

As shown in Scheme 1 below,
A process for preparing a compound represented by the formula (1), comprising the step of reacting a compound represented by the formula (2) with a compound represented by the formula (3) to prepare a compound represented by the formula (1)
[Reaction Scheme 1]

(In the above Reaction Scheme 1,
R ¹ , R ² , R ³ , X and A are the same as defined in Formula 1 of Claim 1; And
PG is an amine protection group.

6. The method of claim 5,
The derivative 2a of the compound represented by the formula (2) wherein A is -O- in the above formula (2)
Reacting a compound represented by the formula (4) with 1,1'-sulfonyldiimidazole to prepare a compound represented by the formula (2a).
[Reaction Scheme 2]

(Reaction Scheme 2)
X and R < ¹ > are as defined in claim 1;
PG is an amine protection group; And
(2a) is a derivative of the above formula (2).

6. The method of claim 5,
The derivative 2a of the compound represented by the formula (2) wherein A is -O- in the above formula (2)
Reacting a compound represented by the formula (5) with a compound represented by the formula (6) to prepare a compound represented by the formula (2a)
[Reaction Scheme 3]

(In the above scheme 3,
X and R < ¹ > are as defined in claim 1;
PG is an amine protection group; And
(2a) is a derivative of the above formula (2).

6. The method of claim 5,
The amine protecting group may be selected from t-butyloxycarbonyl (BOC), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz) Methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), 2,2,2- trichloroethoxycarbonyl Is one selected from the group consisting of 2-trimethylsilylethoxycarbonyl (Teoc) and aryloxycarbonyl (Alloc).

A pharmaceutical composition for the prevention or treatment of hepatitis C virus-related liver disease 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.

10. The method of claim 9,
The hepatitis C virus-related liver disease is one or more liver diseases selected from the group consisting of acute hepatitis C, chronic hepatitis C, cirrhosis and hepatocellular carcinoma. A pharmaceutical composition.

A health functional food composition for preventing or ameliorating a hepatitis C virus-related liver disease 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.

13. The method of claim 12,
The hepatitis C virus-related liver disease is one or more liver diseases selected from the group consisting of acute hepatitis C, chronic hepatitis C, cirrhosis and hepatocellular carcinoma. &Lt; / RTI >